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VOLUME 38 NUMBER 4 DECEMBER 2006 KMJ KMJ KUWAIT MEDICAL JOURNAL The Official Journal of The Kuwait Medical Association EDITORIAL Science Versus Scientism 263 Belle M Hegde REVIEW ARTICLE Plant-derived Health-effects of Turmeric and Curcomenoids 267 Stig Bengmark ORIGINAL ARTICLES Feasiblity and Clinical Significance of Echocardiographic Assessment of Aortic Root Compliance in Hypertensive Patients 276 Aly Mohamad Hegazy, Laila Soud M Al-Einzi, Mohamad Hussain Al-Kandari, Bader Abdelkader Prevalence and Factors Associated with Obesity and Treatment of Blood Pressure among Kuwaiti Hypertensive Patients in a Primary Health Care Clinic 284 Nadia Yousef Al-Mahmoud Factors Influencing Outcome of Congential Diaphragmatic Hernia 287 Bhaskar Gupta Anomalous Coronary Artery from the Opposite Coronary Sinus in Young Children 292 Mustafa A Al-Qbandi, Jeffrey Smallhorn Results of Combined Proximal Crescentic Metatarsal Osteotomy and Modified Distal Soft Tissue Procedure in Severe Hallux Valgus 300 Ibrahim MAAl-Kussary, Fathy Khallaf, Mahmoud El Rayes, Mustafa Al Akkad Safety of Laparoscopy in Acute Cholecystitis 308 Wael Fathi Hassaniah, Mohamed Al Haifi, Talib Jumaa INSIGHT Computerization in Primary Care: an Insight 311 Huda I Al-Shaibani, Siham YF Al-AbdulGhafour, Amal H Al-Saqabi CASE REPORTS Neuronal Ceroid Lipofuscinoses: Report of Five Cases in Kuwait 315 Maliha Askar Soud Al-Bloushi , Jehoram T Anim , Yousif Kasim Habeeb Adrenal Carcinoma with Cardiac Metastasis in a Child: Case Report 321 Abdelmohsen Ben-Nakhi, Ali Hussain, Khaledah Dashti Excision of Ventricular Cysts of Larynx using Zero Degree and 30 Degree Endoscope 324 Pradeep Shenoy, Sohail Abdul Malik, Rashid Al Duwillah Sickle Cell Intra-Hepatic Cholestasis : A Rare but Fatal Disease 326 Saad AL-Zanki, Moza AL-Saleh Carbamezepine Induced Pseudolymphoma 329 Shahid Aziz, Abdulkarim Al Aska, Ayman M Al Kharabah Walker-Warburg Syndrome, A Case Report 332 Magdy H Shafik, Mohamed Taha Mohamed, Talaat M Yousef KU ISSN 0023-5776 Continued inside Vol. 38 No. 4 THE KUWAIT MEDICAL JOURNAL December December2006 2006 KUWAIT MEDICAL JOURNAL C O N T E N T S Continued from cover SELECTED ABSTRACTS OF ARTICLES PUBLISHED ELSEWHERE BY AUTHORS IN KUWAIT 336 FORTHCOMING CONFERENCES AND MEETINGS 339 WHO-FACTS SHEET 344 1. New Global Estimates to Mark World Sight Day 2. A Clean Bill for Indoor Use of DDT to Control Malaria 3. Emergence of XDR-TB 4. Call for Intensified Action to Halt a Quarter of a Million Tb/Hiv Deaths a Year 5. Helmet Use Saves Lives ARABIC ABSTRACTS OF ARTICLES PUBLISHED IN THIS ISSUE 349 YEARLY AUTHOR INDEX - KUWAIT MEDICAL JOURNAL (KMJ) 2006; VOLUME 38 353 YEARLY TITLE INDEX - KUWAIT MEDICAL JOURNAL (KMJ) 2006; VOLUME 38 355 ❈❈❈ View these articles at http://www.kma.org.kw/KMJ THE PUBLICATION OF ADVERTISEMENTS IN THE KUWAIT MEDICALJOURNALDOES NOT CONSTITUTE ANYGUARANTEE OR ENDORSEMENT BYTHE KUWAIT MEDICAL ASSOCIATION OR THE EDITORIAL BOARD OF THIS JOURNAL, OF THE ADVERTISED PRODUCTS, OR SERVICES, OR OF CLAIMS MADE BY THE ADVERTISERS. THE PUBLICATION OF ARTICLES AND OTHER EDITORIAL MATERIAL IN THE JOURNAL DOES NOT NECESSARILY REPRESENT POLICY RECOMMENDATIONS OR ENDORSEMENT BYTHE ASSOCIATION. PUBLISHER: The Kuwait Medical Journal (KU ISSN-0023-5776) is a quarterly publication of THE KUWAIT MEDICALASSOCIATION. Address: P.O. Box 1202, 13013 Safat, State of Kuwait; Telephone: 5316023, 5317972, 5333278 Fax: 5312630, 5333276. E-mail address: kmj @kma.org.kw COPYRIGHT: The Kuwait Medical Journal. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. Printed in Kuwait. INSTRUCTIONS FOR AUTHORS: Authors may submit manuscripts prepared in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals. These Requirements are published in each issue of the Kuwait Medical Journal. CHANGE OF ADDRESS: Notice should be sent to the Publisher six weeks in advance of the effective date. Include old and new addresses with mail codes. KUWAIT MEDICAL JOURNAL is listed in the Index Medicus for the WHO Eastern Mediterranean Region (IMEMR), the IMEMR Current Contents and available at : http://emro.who.int/EMRJorList/online.aspx KUWAIT MEDICAL JOURNAL is added to the list (The Journal of the Kuwait Medical Association) of journals adhering to the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals”, American College of Physicians, Independence Mall West, Sixth Street at Race, Philadelphia, PA 19106-1572, USA, and can be located at http://www.icmje.org/jrnlist.html KMJ Kuwait Medical Journal (KMJ) Published by the Kuwait Medical Association Previously known as The Journal of the Kuwait Medical Association (Est. 1967) Honorary President: Abdulaziz Al-Babtain EDITORIAL BOARD Editor-in-Chief: Editor: International Editor: Associate Editors: Circulation Manager: Fuad Abdulla M Hasan Adel Khader Ayed Pawan K Singal Adel A Alzayed Mousa Khoursheed Mustafa M Ridha Nasser Behbehani Homoud Fahad Al-Zuabi INTERNATIONAL ADVISORY BOARD Allan Templeton, UK Ananda S Prasad, USA Anders Lindstrand, Sweden Andrew J Rees, UK Arie van Dalen, Netherlands Belle M Hegde, India Bengt Jeppsson, Sweden Charles A Dinarello, USA Christian Imielinski, Poland Elizabeth Dean, Canada Fiona J Gilbert, UK Frank D Johnston, UK Gabrielle M Hawksworth, UK George Russell, UK Graeme RD Catto, UK Jan T Christenson, Switzerland Jaroslav Slipka, Czech Rep Jasbir S Bajaj, India John V Forester, UK Julian Little, Canada Lubomir Karagiosov, Bulgaria Lewis D Ritchie, UK Neva E Haites, UK Nirmal K Ganguli, India Oleg Eremin, UK Peter JB Helms, UK Peter RF Bell, UK Raymond M Kirk, UK S Muralidharan, India Tulsi D Chugh, India William ATweed, Canada William B Greenough, USA Zoheir Bshouty, Canada REGIONAL ADVISORY BOARD Abdulla Behbehani Abdul Mohsen Jaffar Abeer K Al-Baho Alexander E Omu Ali Al-Mukaimi Ali Al-Sayegh Asmahan Al-Shubaili Chacko Mathew Eiman M Mokaddas Faisal A Al-Kandari Habib Abul Hilal Al-Sayer Jasbir Singh Juggi John F Greally Joseph C Longenecker Kamal Al-Shoumer Kefaya AM Abdulmalek Khalid Al-Jarallah Marie T Greally Mazen Al Essa Mohamed AA Moussa Mohammed Al-Jarallah Mousa Khadadah Mubarak Al-Ajmi Mustafa Al-Mousawi Nasser J Hayat Nebojsa Rajacic Sadika Al-Awadi Saleema Al-Ramadan Sami Asfar Soad Al-Bahar Sukhbir Singh Uppal Waleed Alazmi ARABIC TRANSLATION: Arabization Centre for Medical Science (ACMLS), Kuwait EDITORIAL OFFICE Editorial Manager : Babichan K Chandy Language Editor : Abhay U Patwari EDITORIALADDRESS P.O. Box: 1202, 13013-Safat, Kuwait Telephone: (00-965) 5316023, 5317972, 5333278 - Fax: (00-965) 5312630, 5333276 E-mail: [email protected] - website: www.kma.org.kw/KMJ KUWAIT MEDICAL JOURNAL KUWAIT MEDICAL JOURNAL (KMJ) Instructions for Authors AIMS AND SCOPE The Kuwait Medical Journal (KMJ) is the official publication of the Kuwait Medical Association. It is published four times annually. Clinical, scientific or laboratory investigations of relevance to medicine are considered by the journal. Original articles, case reports, brief communications, book reviews, insights and letters to the editor can also be considered. Basic medical science articles are published under the section on Experimental Medicine. publication. Galley proof will be forwarded to the corresponding author and must be returned within 48 hours. Corrections in the galley proof must be limited to typographical errors or missing contents, if any. GENERAL The Kuwait Medical Journal is a signatory journal to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, the fifth (1997) revision of a document by the international Committee of Medical Journal Editors. A description of important features of this document is available on the Lancet website at http://www.thelancet.com. Alternatively, you may consult the following: N Engl J Med 1997; 336:307315 or order the leaflet “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” [GB£ 1 per copy] by writing to the Editor of the British Medical Journal (BMJ), BMA House, Tavistock Square, London WC1H 9JR, UK. To present your original work for consideration, one complete set of the manuscript, written in English, accompanied by tables, and three sets of figures (if applicable), should be submitted to the Editor. Authors shall provide the manuscript on an IBM compatible floppy disk also (if not sent by email). Details of the type of computer used, the software employed and the disk system, if known, would be appreciated. The KMJ editorial office uses Microsoft ‘Office 2003’ word processing and ‘Excel’ programs. Submissions through e-mail shall be followed by one set of hard copy, tables, figures (3 sets of original), if any, and the signed consent (of all the authors), mailed (by post/courier) to the editorial office. To speed up processing, author(s)’ consent letter should be faxed to the journal office (009655312630 or 5333276) or a scanned copy enclosed as attachment along with the article, in the e-mail. A manuscript will be considered for processing, only if all the relevant documents are available. Following a peer review process, the corresponding author will be advised of the acceptance or rejection of the paper and, in the event of an acceptance, the approximate date of PREPARATION OF THE MANUSCRIPT The manuscript should be typed as ‘normal text’ on one side of A4 size (29.7 x 21 cm) paper in single column format, preferably in font size no. 12. Italics should be used only to write foreign/Latin expressions/terminologies. There should be a 2 cm margin at both sides of the text and a 3 cm margin at the top and bottom of each page. The order of the text should be as follows: title page, abstract (structured) of no more than 250 words (for original articles), Key Words (no more than five in small case and arranged in alphabetical order), followed by introduction, subjects (or materials) and methods, results, discussion, acknowledgments, references, tables, legends to figures, and figures. Each section should begin on a new page. For Case Studies, provide a summary insted of the structured abstract followed by Key words. All pages should be numbered consecutively, commencing with the title page. Main headings, introduction, subjects and methods, etc., should be placed on separate lines. Key Words should be MeSH terms, and must not duplicate words already in the manuscript title; MesH terms can be checked at: <http://www.nlm.nih.gov/mesh/MBrowser.html> ETHICAL CONSIDERATIONS Where human investigations or animal experiments are a part of the study, the journal assumes that the design of the work has been approved by the local ethics committee. THE TITLE PAGE Title page of the submitted manuscript should provide a clear title of the study. Include the full names of all the authors, together with the name and address of the institution/s in which the work was done. Also, the name and address of the corresponding author to whom proofs and correspondences could be sent, are also required, together with contact e-mail address (if available) and telephone/fax numbers. If more than six authors are listed, the authors may be asked to describe the contribution of each individual. For case reports, no more than three authors are acceptable. i Instructions for Authors STRUCTURED ABSTRACT The structured abstract (no more than 250 words) must provide an overview of the entire paper, and should contain succinct statements on the following, where appropriate: Objective(s), Design, Setting, Subjects, Intervention, Main Outcome Measures, Results, and Conclusions. (See: Haynes RB, Mulrow CD, Huth AJ, Altman DG, Gardner MJ. More informative abstracts revisited. Annals of Internal Medicine 1990; 113:69-76). The structured abstract is required only for studies under the section “Original Articles”. For all other categories, a short summary followed by Key words should precede the report or review. ABBREVIATIONS Abbreviations should be defined on first use and then applied consistently throughout the article. Non-standard abbreviations or those appearing fewer than three times are not accepted. NUMBERS AND UNITS Measurements of length, height, weight and volume must be reported in metric units (meter, kilogram, liter etc.) or their decimal multiples. Temperature should be given in degrees Celsius. Blood pressure should be expressed in mm Hg, and hematological and biochemical measurements in S.I. (Systeme International) units. Use a decimal point, and not a comma, e.g., 5.7. Use a comma for numbers ≥ 10,000 (i.e., 103); for numbers ≤ 9999, do not use a comma (e.g., 6542). Numbers <10 should be written in words. TABLES Tables must be typed on separate pages and should follow the reference list. All the tables must be numbered consecutively. Each of them should have a brief heading describing its contents and duly referred to in the main text. They should be simple and information therein, not duplicated in the text. TRADE NAMES Non-proprietary (generic) names of product should be employed. If a brand name for a drug is used, the British or international non-proprietary (approved) name should be given. The source of any new or experimental preparation should also be given. DESIGN OF THE WORK This should be stated clearly. The rationale behind the choice of sample size should be given. Those about to begin randomized controlled studies may wish to study the CONSORT statement (JAMA 1996; 276: 637-639). REFERENCES References should appear in sequence and must be numbered [by Arabic numerals, in square brackets, and as superscript (e.g., [1])] in the order in which they appear in the text. At the end of the article, the full list of references should give the names and initials of all authors unless there are more than six, in which case only the first three should be given, followed by et al. The authors’ names should be followed by the title of the article, the title of the journal abbreviated in the style of the Index Medicus, the year of publication, the volume number and the first and last page numbers. References to books should give the title of the book, followed by the place of publication, the publisher, the year and the relevant pages. ILLUSTRATIONS Photomicrographs, electron micrographs or radiographs must be of high quality, and supplied in three original final copies (not photocopies, laser prints or scanned images) of size 10 x 15 cm. Photographs should fit within a print area of 164 x 235 mm. All the figures must be numbered serially and the figure number should appear on the back of each together with an arrow drawn to indicate the top edge. A photomicrograph should provide details of the staining technique and a scale bar. For figures where patient’s identity is not concealed, authors should submit a written consent of the patient or of the patient’s guardian, in case of minors. Color figures will incur a printing charge (contact the Editorial office for details). Figure legends should be listed separately on the last page of the article. If any tables, illustrations or photomicrographs have been published elsewhere, a written consent for re-production is required from the copyright holder and the author(s). The same must be attached to the manuscript. Charts and drawings must be done professionally. When charts are submitted, the numerical data on which they were based should be supplied. EXAMPLES Article Burrows B, Lebowitz MD. The β agonists dilemma (editorial). N Engl J Med 1992; 326:560-561. Book Roberts NK. The cardiac conducting system and His bundle electrogram. New York, AppletonCentury-Crofts, 1981: 49-56. ii KUWAIT MEDICAL JOURNAL COPY RIGHT The publisher reserves copyright on the Journal’s contents. No part may be reproduced, translated or transmitted in any form by any means, electronic or mechanical, including scanning, photocopying, recording or any other information storage and retrieval system without prior permission from the publisher. The publisher shall not be held responsible for any inaccuracy of the information contained therein. Book chapter Philips SJ, Whisnam JP. Hypertension and stroke. In: Laragh JH, Bremner BM, editors. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. New York: Raven Press; 1995, p 465-478. References should be limited to those relating directly to the contents of the paper. AUTHORSHIP AND CONSENT FORM All authors must give signed consent for publication in a letter of submission, which should accompany the manuscript. This letter should contain the statement that “This manuscript is an unpublished work which is not under consideration elsewhere and the results contained in this paper have not been published previously in whole or part, except in abstract form”. Each author should have participated sufficiently in the work to take public responsibility for its content. Such participation must include: conception, design, analysis, interpretation, or drafting the article for critically important intellectual content. SUBMISSION OF A MANUSCRIPT Manuscripts should be submitted to: The Editor Kuwait Medical Journal P.O. Box: 1202 13013-Safat Kuwait Telephone: (965) 5316023, 5333278; 5317972 Fax: (965) 5312630; 5333276 E-mail : [email protected] Website: www.kma.org.kw/KMJ iii Instructions for Authors December 2006 KUWAIT MEDICAL JOURNAL Editorial Science Versus Scientism Belle M Hegde The Middlesex Hospital Medical School, University of London, UK Northern Colorado University, USA, Indian Institute of Advanced Studies, Shimla, India MAHE University, Manipal, India Kuwait Medical Journal 2006, 38 (4): 263-266 “The central problem of our age is how to act decisively in the absence of certainity.” Bertrand Russell Science and scientific temper simply mean curiosity. They are efforts to get to know the secrets of Nature. Many a time, Nature refuses to fully divulge her secrets when one goes very close. Children, before they start schooling are curious, but when they come out they become, by and large, just repetitive robots because of their brainwashing in schools about the accepted norms in science. Occasionally, there are exceptions, but their numbers are very small. To swim against the current is not easy, either. Research depends on grant money; most grants come either from the government or industry. Both masters would like their interests guarded. Refutative research, which tries to demolish the scientific myths, is not funded and so is nipped in the bud. Publishing the data from those studies is almost impossible in the present atmosphere[1]. Even one’s position in a University might be threatened! Scientism, on the contrary, is like a powerful religion that tries to influence people’s understanding of this Universe in the accepted norms. Any attempt to show evidence to the contrary is being hushed up with all the might at their command. Scientism was helped by the early successes of technology based on the present scientific paradigm. Society venerates science for the simple reason that we have the telephone, electricity, easy transportation, satellites, space ships, nuclear war heads and the computers et cetera, thanks to the conventional scientific paradigm. In addition, there is this big money business in scientific technology. Powerful countries are sold to scientism because they have been able to build destructive weapons, thanks to scientism. These weapons give the countries enormous powers to dominate the world. The lure of medals and prizes and the large amount of money involved in some of the prizes like the Nobel have even made people fake research findings or plagiarize them from others without acknowledging the original source[2]. That is how science got a clean chit from society. Let us examine the present strong pillars of science to see how strong and solid they are. The Big Bang, origin and evolution of the human species, the relativity theory and, quantum mechanics are those four pillars[3]. Reductionism and statistics are the pillars of medical science and biology[4]. Darwin’s theory of evolution is found wanting in many areas. Evolution inside a species is different from evolution of a new species; a bird from a fish, for example. The latter needs thousands of biochemical reactions that individually will have no survival advantage when the ultimate new species arrives by accident[5]. The efforts by Richard Dawkins to sell Darwinism to the public are not very scientific either. One example of the very complicated eye developing from a small depression in the earlier species looks rather too simplistic[6]. The relativity theory, first developed by a German physicist, Lorenz along with the French mathematician, Poincare, had a significant contribution also from the famous Irish mathematician, Fitzgerald[7]. Albert Einstein, the deified guru of physics, had very little to do with it. Einstein, however, had contributed immensely to Brownian movement, photoelectric effect and movement of ions in solutions[8]. Einstein giving away his Nobel Prize money to his first wife, whom he had divorced by then, gives credence to the view, held by some close confidents, that the original Nobel paper of Einstein did have his wife’s name as the first author, which must have disappeared later [9]. Be that as it may, the question raised by Professor Dingle of the London University about the theory remains unanswered so far [10]. The assumption in the theory that there is same velocity of light independent of the direction of measurement Address Correspondence to: Prof. B. M. Hegde, MD, FRCP, FRCPE, FRCPG, FRCPI, FACC, FAMS, “Manjunath” Pais Hills, Bejai, Mangalore-575004, India. Tel: +91 824 245 0450. E-mail: [email protected], web site: www.bmhegde.com 264 with respect to the motion of the earth has recently been found to be inconsistent[11]. The jewel in the crown of physics, the quantum theory, does not seem to have much connection to reality. We still do not have answers to questions like a) what is a wave function, b) In the Schrödinger’s equation what are the waves “of” and what are the waves “in”, and third c) what is an electron[12]. The basic problem in the theory of evolution would be, if we accept that there is no design and there is no teleology as sold by the scientific establishment, to explain the prior existence of the DNA! The accepted laws of chemistry need chance collisions between simpler constituents[13]. Darwin’s book Descent of Man makes it mandatory for us to discount any design. Dawkin’s book The Blind Watchmaker makes an effort to whitewash these questions![14] Lamarck must have had his last laugh in his grave when he came to know that rats developed diabetes following destruction of their pancreas by drugs: they then passed the disease on to their offsprings - evolution through inheritance of acquired characteristics - Lamarckism[15]. One would benefit a lot by understanding the word Entelechy - spontaneous development of order, as opposed to entropy - disorder, first coined by the German biologist, Driesch (1867-1941) [16]. NASA claims that there is no life anywhere outside the Earth, but they could not discount bacterial life deep down the surface of Mars. There are some indicators to that possibility in the recent works. Mathematics, the foundation of all sciences, including the King of sciences, physics, cannot explain many of our experiences in life. Let me quote Albert Einstein himself here: “Insofar as the propositions of mathematics give an account of reality, they are not certain; and insofar as they are certain, they do not describe reality”[17]. If there is no design, how could a high school student, Ramanujam, write down large number of new and original theorems, some of which he could prove but, some others he simply stated as true, and were later proved by other mathematicians at the Cambridge University?[18]. The remarkable picture of that gigantic explosion, the Big Bang that began the Universe: the latter expanding ever since, is understood even by a school boy/girl. What happened before the Big Bang?[19]. Maddox, the then editor of Nature, in 1989 did write that Big Bang theory would be forgotten by 2000 AD. Edwin Hubble did put forward arguments against the theory but the big one bangs on![20]. The Tired Light hypothesis shows that the Universe is not expanding. All that we can say about the universe today is that it is very, very old. December 2006 The million dollar question as to how the world began remains unanswered![21]. Big bang and the Black holes make good material for lay books that are sold like hot cakes and make their authors very rich, but most of that stuff is still in the realm of science fiction![22, 23]. Science deals with our five senses only. What the senses cannot measure and observe does not make science in the present paradigm. However, the observers’ consciousness impinges on the findings. An electron is what it is depending on who looks at it! When no one is looking at the electron, no one knows what the electron does![24, 25]. There are a lot of things in this universe that our five senses cannot realize and they exist all the same. Science does accept that what is known today could be proven wrong or replaced by a new theory tomorrow, but to say that what we don’t know today (or what does not fit into the present paradigm) is unscientific is illogical. But that is exactly what scientism is trying to do. To give a few day-to-day examples: we are not able to measure our thoughts, our emotions, and many of our actions based on those emotions and thoughts. Do they, then, fall out side the realm of science? Do thoughts exist? Do emotions have any role in human physiology?[26]. If the answer is yes, then we need a change of paradigm in science, at least in medical science, where the RCTs (randomized controlled studies) have been sold as the last word in medical research. The truth is that there is everything wrong with this approach. No two human beings could be compared based on a few of their phenotypical features. The results are there for all to see. Most, if not all, RCTs have given unreliable results in the long run. But look at the following in the encyclopedia of RCTs published by the establishment! “A major difficulty in dealing with trial results comes from commercial, political and/or academic pressure. Most trials are expensive to run, and will be the result of significant previous research, which is itself not cheap. There may be a political issue at stake (cf. MMR vaccine) or vested interests (cf. homoeopathy). In such cases there is great pressure to interpret results in a way which suits the viewer, and great care must be taken by researchers to maintain emphasis on clinical facts. Most studies start with a ‘null hypothesis’ which is being tested (usually along the lines of ‘Our new treatment x cures as many patients as existing treatment y’) and an alternative hypothesis (‘x cures more patients than y’). The analysis at the end will give a statistical likelihood, based on the facts, of whether the null hypothesis can be safely December 2006 KUWAIT MEDICAL JOURNAL rejected (saying that the new treatment does, in fact, result in more cures). Nevertheless this is only a statistical likelihood, so false negatives and false positives are possible. These are generally set at an acceptable level (e.g., 1% chance that it was a false result). However, this risk is cumulative. There is a tendency for these two to be seized on by those who need that proof for their point of view.”[27]. Before we do more damage to mankind by blindly following the reductionist paradigm, at least in medical sciences, let us think of a new paradigm. Let research be directed to find out the myths and dogmas in the present paradigm and to replace them with newer ideas and findings that might make life easier for mankind. Of course, it might destroy our “rice bowl” for the moment, but we might get a bigger bowl in future. Scientific temper should make us identify the false dogmas and enable us to destroy them. Science is change and what does not change is not science. Professor John O’M Bockris so beautifully describes the new paradigm shift that is needed in science in his classic The New Paradigm[3]. What does not change becomes religion. That is why I sometimes feel, that scientism is a kind of religion we are made to follow blindly. Present science is excited about nanobots but does not bother about our giga problems like environmental pollution, abject poverty of the majority, preventable illnesses which kill the poor and unemployment of the majority! It is preposterous that medical science does not worry about health promotion, while it goes overboard about disease interventions, many of which make the patient worse! Sir William Osler had warned us not to intervene when the patient is doing well, but that is exactly what we do today! Medicine does not believe in the wellness concept. Everyone is ill unless proved otherwise is the present paradigm, thanks to the total body scanners. Routine check up is the biggest medical industry, while we know that predicting the future is impossible in a dynamic human system using a few data of the initial state. Even changing those parameters might not hold good as time evolves[28]. Changing those parameters might even harm patients in the long run, while it is mandatory to do so, if the patient is syptomatic and is suffering, because doctors are here to “cure rarely, comfort mostly but to console always.” The effort here is not to belittle the great strides science has made in the last two centuries. The stress here is to let the reader know that there is so much noise in this area that almost drowns the signal! Unless we silence those noises and try to pick 265 the signals, science will not progress and mankind will still be in the dark[29, 30] . Even if one person is stimulated to think on those lines, the purpose of writing this will have been achieved, despite the fact that 99% of the readers would be angry or unhappy about the contents. Conventional journals would hesitate to publish this piece for obvious reasons - their peer reviewers will not permit it and the editors dare not take the responsibility themselves! “Certainty generally is illusion and repose is not the destiny of mankind.” Oliver Wendell Holmes Jr ACKNOWLEDGMENT I remain ever grateful to Professor John O’M Bockris, Distinguished Professor and Head of Chemistry at Texas A&M University, for I have drawn very liberally from his classic The New Paradigm, published by A and M Enterprises Publishers, College Street, Texas in 2005, for this article. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Hegde BM. Need for a change in medical paradigm. Proc Royal Coll Physi Edinb 1993; 23: 9-12. Campbell EG, Louis KS, Blumenthal D. Looking a gift horse in the mouth. JAMA1999; 279: 995-999. Bockris J O’M. The New Paradigm. A&M Publishers, College Street, Texas. 2005. Milloy S. Science without Sense. Cato Institute, 1997, Washington DC. Behe MJ. Darwin’s Black Box. Free Press, New York, 1996 Dawkins R. The Blind Watchmaker. WW Norton and Co. 1996. Poincare JH. Relativity theory before Einstein. Arch Netherlands Sci 1900; 2: 232. Hey T and Walters P. Einstein’s Mirror. Cambridge University Press, 1997. Bjerknes C. Einstein as a plagiarist. XTX Corp. Downess Grove, IL. 2002. Dingle H. Science at the cross roads - Doubting relativity. Martin and O’Keefe. London, 1972. (also, Dingle’s unanswered question. Nature August 31, 1973). Michelson AAand Morley EW. Velocity of light in various directions compared to the direction of movement of the earth. Am J Sci 1887; 3: 333. Lindley D. Where does the quantum weirdness go? Basic Books 1996. Steinman G and Cole MN. Synthesis of biologically pertinent peptides under possible primordial conditions. Proceedings National Academy of Sciences of USA, 1967. Milton R. Shattering the myth of Darwinism Park Street Press, 1997. Lamarque JR. Natural History. Daterville, 1815, Paris. Freyhofer HH. The vitalism of Hans Driesch: The success and decline of a scientific theory. Peter Lang Publishing. 1982. Hey T and Walters P. Einstein’s Mirror. Cambridge University Press. 1997. 266 Science Versus Scientism 18. Kanigel R. The Man who knew Infinity- A life of the genius Ramanujam. Washington Square Press, April 1991. 19. Lorenz H, Mie G. In: Paula La Violette, Beyond the Big Bang. Park Street Press: Rochester; Vermont, 1995. 20. Tully RB. Origin of the Hubble Constant Controversy. Nature 1988; 334: 209. 21. Lerner E. The Big Bang never happened! Vintage Books. 1991. 22. Hawking S. A Brief History of Time. Bantum Books, 2000. 23. Weinberg S. The First Three Minutes. Basic Books, New York, 1997. 24. Schrödinger E. Science and Humanism, Cambridge December 2006 University Press. 1954. 25. Wigner EP. Consciousness affects wave function. In: The Scientist Speculates (ed. Good IT) Heinemann, London, 1961. 26. Penrose R. Shadows of the mind. Oxford University Press. 1994 27. Randomized controlled trial -www. wikipedia.org/wiki/ randomised controlled trials. 28. Firth WJ. Chaos - predicting the unpredictable. BMJ 1991; 303:1565-1568. 29. Pratt D. Consciousness, Causality, and new Physics. Soc Sci Explorer 1979; 11: 67-78. 30. Kaul. PN. Mind over Matter. The Scientist 2003; 17: 8. December 2006 KUWAIT MEDICAL JOURNAL Review Article Plant-derived Health-Effects of Turmeric and Curcumenoids Stig Bengmark Lund University, Lund, Sweden London University, Departments of Hepatology and Surgery, Institute of Hepatology, University College, London Medical School, United Kingdom Kuwait Medical Journal 2006, 38 (4): 267-275 ABSTRACT The world suffers an epidemic of both critical (CI) and chronic illnesses (ChDs), and both increase from year to year, and have done so for several decades. It is strongly associated to modern, so called Western, life style: stress, lack of exercise, abuse of tobacco and alcohol, and to the transition from natural unprocessed foods to processed, calorie-condensed and heat-treated foods. There is a strong association between ChDs and reduced intake of plant fibres, plant antioxidants and increased consumption of industrially produced and processed products especially dairy, refined sugar and starch products. Heating up foods such as milk (pasteurization), and production of and storage of milk powder, produces AN EPIDEMIC OF CHRONIC DISEASES AND CRITICAL ILLNESS Modern medicine has to a large extent failed in its ambition to control both acute and chronic diseases. In acute diseases; those defined as medical and surgical emergencies such as myocardial infarction, stroke and severe pancreatitis, and those related to advanced medical and surgical treatments, such as stem cell transplantation or advanced surgical operations, there is an unacceptably high morbidity and co-morbidity. Furthermore, the world suffers an epidemy of chronic diseases of a dimension never seen before, and these diseases are now like a prairie fire also spreading to so-called developing countries. Chronic diseases - including diseases such as cardiovascular and neurodegenerative conditions, diabetes, stroke, cancers and respiratory diseases - constitute 46% of the global disease burden and 59% of the global deaths today; each year on earth, approximately (app) 35 million individuals will die in conditions related to chronic diseases, and the numbers are increasing and have done so for several years [1]. Similarly, the morbidity related to advanced medical and surgical treatments and emergencies, especially infectious complications, is also fast increasing. Sepsis is the most common medical and surgical complication, estimated only large amounts of advanced glycation products (AGEs) and advanced lipoxidation products (ALEs), known as potent inducers of inflammation. Numerous plantderived, but also microbe-derived, substances, often referred to as chemopreventive agents, have documented anti-inflammatory effects and are believed to reduce speed of aging, prevent degenerative malfunctions of organs and development of acute and chronic diseases. Among them are various curcumenoids found in turmeric curry foods and, thousands more of hitherto less or unexplored substances. This review focuses on documented experimental and clinical effects of supplementation of turmeric, various curcumenoids and pure curcumin. in the US to annually affect as many as 751,000[2,3], and cause the death of app 215, 000 patients (29%)[3]. This makes sepsis the tenth most common cause of death in the country. It is especially alarming that both morbidity and mortality in critical illness (CI), especially when septic, is fast increasing and has done so for several decades. With a documented 1.5% rate of increase per year it might double within the coming 50 to 60 years. LIFE-STYLE ASSOCIATED DISEASES Accumulating evidence supports the association of ChDs to modern life style, stress, lack of exercise, abuse of tobacco and alcohol, and to the transition from natural unprocessed foods to processed, calorie-condensed and heat-treated foods. There is a strong association between ChD and reduced intake of plant fibres, plant antioxidants and increased consumption of industrially produced and processed dairy products, refined sugars and starch products. The per capita consumption of refined sugar has increased from about 0.5 kg per person per year in 1850 to almost 50 kg/person/year in the year 2000 and the per cow milk production from 2 to 50 liters/day. Dairy products, especially milk (mostly from pregnant cows) are rich in proinflammatory molecules: hormones such as Address correspondence to: Stig Bengmark, MD, PhD, FRACS (hon), FRCPS (hon),185 Barrier Point Road, Royal Docks, London, E16 2SE, United Kingdom. Tel & Fax: +44 20 7511 6842. E-mail: [email protected] 268 Plant-derived Health-Effects of Turmeric and Curcomenoids estrogens and growth factors such as IGF-1. Consumption of bovine milk has also been shown to release inflammatory mediators, increase intestinal permeability and induce leakage of larger molecules such as albumin and hyaluronan into the body. Heating up milk (pasteurization), and especially production of and storage of milk powder, produces large amounts of advanced glycation products (AGEs) and advanced lipoxidation products (ALEs)[4], known as potent inducers of inflammation. This information is especially important as many foods such as icecream, enteral nutrition solutions and baby formulas are based on milk powder. Bread, especially from glutencontaining grains, is also rich in molecules with documented pro-inflammatory effects, and bread crust is often used experimentally to induce inflammation (See further Bengmark) [5-7]. PLANT-DERIVED PROTECTION Common to those suffering from ChD as well as CI is that they suffer an increased degree of inflammation, most likely due to their Western lifestyle. We are increasingly aware that plantderived substances, often referred to as chemopreventive agents, have an important role to play in the control of inflammation. These substances are not only inexpensive, they are also easy available, and have no or limited toxicity. Among these numerous chemo-preventive agents are a whole series of phenolic and other compounds believed to reduce speed of aging and prevent degenerative malfunctions of organs, among them various curcumenoids found in turmeric curry foods and, thousands more of hitherto less or unexplored substances. However, this review will mainly focus on curcumin and its effects. Polyphenols have in the recent few years received increasing attention for their strong chemo-preventive ability. Curcumin and many other plant-derived substances are increasingly regarded as shields against disease. Curcumin is the most explored of the so called curmenoids, a family of chemo-preventive substances present in the spice turmeric. Although the substance has been known for some time, it is in the most recent years that the interest has exploded, much in parallel with increasing concern for severe sideeffects of synthetic COX-2 inhibitors, marketed by pharmaceutical industry. Most of the reported curcumin studies in the literature are experimental and few clinical studies are thus far presented. CURCUMIN - AN ANTIOXIDANT AND INHIBITOR OF NF- KB, COX-2, LOX AND INOS NF-KB plays a critical role in several signal December 2006 transduction pathways involved in chronic inflammatory diseases [8] such as asthma and arthritis and various cancers[9]. Activation of NF-KB is linked with apoptotic cell death; either promoting or inhibiting apoptosis, depending on cell type and condition. The expression of several genes such as cyclo-oxygenase-2 (COX-2), matrix metaloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF), interleukin-8 (IL-8), eotaxin, cell surface adhesion molecules and anti-apoptotic proteins are regulated by NF- KB[10]. COX-2 is inducible and barely detectable under normal physiological conditions, but is rapidly, but transiently, induced as an early response to pro-inflammatory mediators and mitogenic stimuli including cytokines, endotoxins, growth factors, oncogenes and phorbol esters. COX-2 synthesizes series-2 prostaglandins (PGE2, PGF2-α), which contribute to inflammation, swelling and pain. PGE2 promotes production of IL-10, a potent immuno-suppressive cytokine produced especially by lymphocytes and macrophages, and suppression of IL-12[11]. Inducible nitric oxid synthase (iNOS), activated by NF-KB is another enzyme that plays a pivotal role in mediating inflammation, especially as it acts in synergy with COX-2. TURMERIC - APPROVED AS FOOD ADDITIVE Curcumin, (1,7-bis (4-hydroxy-3-methoxyphenol)1,6 heptadiene-3,5-dione), a polyphenol rich in the dietary spice turmeric, is received from dried rhizozomes of the perennial herb Curcuma longa Linn, a member of the ginger family. Turmeric is mainly known for its excellent ability to preserve food and is approved as food additive in most Western countries. It is produced in several Asian and South-American countries. In India alone about 500,000 metric tons are produced each year, of which about half is exported. It has, in addition to extensive use as food additive, for generations also been used in traditional medicine for treatment of various external or internal inflammatory conditions such as arthritis, colitis and hepatitis. The molecule of curcumin resembles ubiquinols and other phenols known to possess strong antioxidant activities. Its bioavailability on oral supplementation is low, but can be improved by dissolution in ambivalent solvents (glycer ol, ethanol, DMSO) [12]. It is also reported to be dramatically elevated by co-ingestion of peperine (a component of pepper), demonstrated both in experimental animals and humans [13]. Several studies have demonstrated that curcumin is atoxic, also in very high doses[14,15]. Treatment of humans for three months with 8000 mg curcumin per day showed no side effects[15]. It is estimated that adult December 2006 KUWAIT MEDICAL JOURNAL Indians consume 80-200 mg curcumin per day[16]. A common therapeutic dose is 400-600 mg curcumin three times daily corresponding to up to 60 g fresh turmeric root or about 15 g turmeric powder. The content of curcumin in turmeric is usually 4-5 %. CURCUMIN- EFFECTIVE AGAINST STRESSINDUCED OVERINFLAMMATION Curcumin is not only an inexpensive atoxic and potent COX-2 and iNOS inhibitor[17], it is also a potent inducer of heat shock proteins (HSPs) and potential cytoprotector[18,19]. Curcumin does not only inhibit COX-2, it also inhibits lipooxygenases (LOX) and leukotreines such as LBT4 and 5HETE [20], especially when bound to phosphatidylcholine micelles[21]. It is also reported to inhibit cytochrome P450 isoenzymes and thereby activation of carcinogens[22]. Curcumin has the ability to intercept and neutralize potent pro-oxidants and carcinogens, both ROS (superoxide, peroxyl, hydroxyl radicals) and NOS (nitric oxide, peroxynitrite)[23]. It is also a potent inhibitor of TGF-β and fibrogenesis[24] which is one of the reasons, why it can be expected to have positive effects in diseases such as kidney fibrosis, lung fibrosis, liver cirrhosis and Crohn’s Disease and in prevention of formation of tissue adhesions[25]. Curcumin is suggested to to be especially effective in Th1-mediated immune diseases as it effectively inhibits Th1 cytokine profile in CD4 + T cells by interleukin-12 production[26]. Many medicinal herbs and pharmaceutical drugs are therapeutic at one dose and toxic at another, and interactions between herbs and drugs, even if structurally un-related, may increase or decrease the pharmacological and toxicological effects of either component[27,28]. It is suggested that curcumin may increase the bioavailability of vitamins such as vitamin E and also decrease cholesterol, as curcumin in experimental studies significantly raises the concentration of αtocopherol in lung tissues and decreases plasma cholesterol[29]. Polyphenols, isothiocyanates such as curcumin and flavonoids such as resveratrol, are all made accessible for absorption into the intestinal epithelial cells and the rest of the body by digestion/fermentation in the intestine by microbial flora[30]. CURCUMIN IN ACUTE AND CHRONIC DISEASES Atherosclerosis: Oxidation of low density lipoproteins (LDL) is suggested to play a pivotal role in the development of arteriosclerosis, and LDL oxidation products are toxic to various types of cells including endothelial cells. Curcumin has a strong capacity to prevent lipid peroxidation, stabilize cellular membranes, inhibit proliferation 269 of vascular smooth muscle cells, and inhibit platelet aggregation; all important ingredients in the pathogenesis of arteriosclerosis. Curcumin was found to be the most effective and quercetin the least, when curcumin, quercetin and capsaisin were compared for their ability to inhibit the initiation and propagation phases of LDL oxidation of a defined antioxidant butylated hydroxy anisole (BHA)[31]. Supply of curcumin, but also capsaicin and garlic (allecin) to rats fed a cholesterol-enriched diet prevented both increase in membrane cholesterol and increased fragility of the erythrocytes[32]. Significant prevention of early atherosclerotic lesions in thoracic and abdominal aorta are observed in rabbits fed an atherogenic diet for thirty days, accompanied by significant increases in plasma concentrations of coenzyme Q, retinol and α-tocopherol and reductions in LDL conjugated dienes and in TBARS (thiobarbituric acid-reactive substances, an expression of ongoing oxidation)[33]. Cancer: Cancer is a group of more than 100 different diseases, which manifest itself in uncontrolled cellular reproduction, tissue invasion and distant metastases[34]. Behind the development of these diseases are, most often, exposure to carcinogens, which produce genetic damage and irreversible mutations, if not repaired. During the last fifty years attempts have been made to find or produce substances that could prevent these processes, so called chemopreventive agents. Cancers are generally less frequent in the developing world, which has been associated both with less exposure to environmental carcinogens and to a richer supply of natural chemopreventive agents. The incidence per 100, 000 population is in the USA considerably higher for the following diseases compared to India: prostatic cancer (23 X), melanoma skin cancer (male 14 X, female 9 X), colorectal cancer (male,11 X, female 10 X), endometrial, cancer (9 X), lung cancer (male 7 X, female 17 X), bladder cancer (male 7 X, female 8 X) breast cancer (5 X), renal cancer (male 9 X, female 12 X)[35]. These differences are even greater for some diseases such as breast cancer and prostatic cancer when compared to China. The consumption of saturated fat and sugary foods is much less in the Asian countries, but equally important, the consumption of plants with high content of chemopreventive substances is significantly higher in these countries. As an example, the consumption of curcumin has for centuries been about 100 mg/day in these Asian countries [36]. Curcumin induces in vitro apoptosis of various tumour cell lines: breast cancer cells[36,37], lung cancer cells[38], 270 Plant-derived Health-Effects of Turmeric and Curcomenoids human melanoma cells[39], human myeloma cells[40], human leukemia cell lines[41], human neuroblastoma cells[42], oral cancer cells[43], prostatic cancer cells[44-47]. Curcumin has in experimental models also demonstrated ability to inhibit intrahepatic metastases[48]. Few in vivo experimental studies and no clinical controlled trials are this far concluded. However, a recent phase I study reported histologic improvement of precancerous lesions in one out of two patients with recently resected bladder cancer, two out of seven patients of oral leucoplakia, one out of six patients of intestinal metaplasia of the stomach, and two out of six patients with Bowen’s disease[49]. However, the main purpose of the study was to document that curcumin is not toxic to humans when taken by mouth for three months in a dose of up to 8,000 mg/day. Diabetes: Turmeric (TU, 1 g/kg body weight) or curcumin (CU, 0.08 g/kg body weight) were in a recent study supplied daily for three weeks to rats with alloxan-induced diabetes (AID) and compared to controls (CO)[50]. Significant improvements were observed in blood glucose (mg/dl CO 88.3, AID 204.4, TU 142.7, CU 140.1), hemoglobin (gm/dl CO 14.7, AID 10.8, TU 13.6, CU 13.1) and glycosylated hemoglobin (gm/dl CO 2.8, AID 11.2, TU 9.0, CU 7.8). Significant differences were also observed in TBARS in liver tissue (nmoles/g tissue CO 43.0, AID 54.0, TU 34.0, CU 29.0), TBARS in plasma (nmoles/ml CO 3.8, AID 7.3, TU 5.3, CU 4.6), in glutathione in liver (µgm/mg CO 23.4, AID 11.2, TU 16.6, CU 20.9) and glutathione in plasma (mg/dl CO 22.4, AID 14.2, TU 18.4, CU 20.1). It was also observed that the activity of sorbitol dehydrogenase (SDH), which catalyzes the conversion of sorbitol to fructose, was significantly lowered by treatment both with turmeric and curcumin. Gastric diseases: When the in vitro effects against 19 different Helicobacter pylori strains, including five cag A+ strains (cag A is the strain-specific H pylori gene linked to premalignant and malignant lesions) were studied, both treatments were found to be equally effective as both treatments did significantly reduce growth of all the strains studied[51]. Subsequent studies did also demonstrate that curcumin inhibits infection and inflammation of gastric mucosal cells through the inhibition of activation of NF-KB, degradation of IKBα, NF-KB DNA binding and the activity of IKB kinases α and β. No curcumininduced effects were observed on mitogenactivated protein kinases (MAPK), extracellular signal regulating kinases 1/2 (ERK1/2) and p38. H pylori-induced mitogenic response was completely December 2006 blocked by curcumin[52]. Significant antifungal properties against various fungal, especially phytopathogenic, organisms by curcumin are also reported[53]. Hepatic diseases: Dietary supply of curcuminoids is also reported to increase hepatic acyl-CoA and prevent high-fat diet-induced accumulation in the liver and adipose tissues in rats [54]. Ethanol-induced steatosis is known to be further aggravated by supply of PUFA-rich vegetable oils, which has been thermally oxidized. Rats fed for 45 days with a diet containing 20 % ethanol and 15 % sunflower oil, heated to 180º C for 30 min (AO), showed extensive histopathological changes with focal and feathery degeneration, micronecroses and extensive steatosis in the liver and extensive inflammation, vessel congestion and fatty infiltration in the kidneys, changes, which could largely be prevented by simultaneous supply of curcumin (CU) or particularly photo-irradiated curcumin (PCU) e.g. curcumin kept in bright sunshine for five hours[55]. Both products were supplied in a dose of 80 mg/kg body weight. Both products did significantly inhibit elevations in alkaline phosphatases (ALP): controls (CO) 85.88, PCU 239.56, CU 177.41 and PCU 149.15 and _-glutamyl transferase (GGT): CO 0.60, PCU 2.51, CU 1.43, PCU 1.15. Similar beneficial effects were observed on histology in various tissues and in hepatic content of cholesterol, triglycerides free fatty acids and phospholipids. In another study, rats were fed with fishoil and ethanol (FE) for four weeks which resulted in hepatic lesions consisting of a fatty liver, necrosis and inflammation. Supply of curcumin in a daily dose of 75 mg/kg body weight to these rats prevented the histological lesions[56]. Curcumin was observed in part to suppress NF-KB-dependent genes, to block endotoxin-mediated activation of NF-KB and to suppress the expression of cytokines, chemokines, COX-2 and iNOS in Kupffer cells. Similar effects were also observed in carbon tetrachloride-induced injuries. Pretreatment for four days with curcumin (100 mg/kg body weight) before intraperitoneal injection of CCl4 prevented subsequent increases in TBARS significantly: CO 274, CCl4 556, CU 374, alanine aminotransferase (ALT): CO 46, CCL4 182, CU 97 and aspertate aminotransferase (AST): CO 97, CCl4 330, CU 211 and in hydroxyproline (µg/g liver tissue): CO 281, CCl4 777, CU 373 [57]. Intestinal diseases: Pretreatment for ten days with curcumin in a daily dose of 50 mg/kg body weight before induction of trinitrobenzene sulphonic acid (TNBS) colitis resulted in a significant reduction in December 2006 KUWAIT MEDICAL JOURNAL degree of histological tissue injury, neutrophil infiltration (measured as decrease in myeloperoxidase activity) and lipid peroxidation (measured as decrease in malondialdehyde activity) in the inflamed colon and in a decreased serine protease activity[58]. A significant reduction in NF- KB activation and reduced levels of NO and a marked suppression of Th1 functions: IFNγ and IL-12p40 mRNA, was also observed. Curcumin was in another similarly designed study added to the diet for five days before induction of TNBS colitis, which resulted in a significant reduction in myeloperoxidase, and attenuation of the TNBSinduced message for IL-1β on semiquantitative RTPCR[59]. Western blotting revealed a significant attenuation of the activation of p38 MAPK. Curcumin was also supplied in combination with caffeic acid phenethyl ester (CAPE) to animals treated with cytostatic drugs (arabinose cytosine, Ara-C, and methotrexate, MTX)[59]. The treatment did not only inhibit the NF-KB induced mucosal barrier injury but was also shown to increase the in vitro susceptibility of the non-transformed small intestinal rat epithelial cell, IEC-6, to the cytostatic agents. Neurodegenerative diseases: A growing body of evidence implicates free radical toxicity, radical induced mutations and oxidative enzyme impairment and mitochondrial dysfunction in neurodegenerative diseases (NDD). Significant oxidative damage is observed in all NDDs, which in the case of Alzheimer disease (AD) leads to extracellular deposition of β-amyloid (Aβ) as senile plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen have proved effective in preventing progress of AD in animal models[60] but gastrointestinal and occasional liver and kidney toxicity induced by inhibition of COX-1 precludes widespread chronic use of the drug[61]. Use of antioxidants such as vitamin E (α-tocopherol) has proven rather unsuccessful even when high doses were used[62]. Vitamin E, α-tocopherol, is in contrast to γ-tocopherol a poor scavenger of nitric oxide(NO) based free radicals. Curcumin is several times more potent a scavenger than vitamin E[63] and in addition also a specific scavenger of NO-based radicals[64]. When tried in a transgenic mouse model of AD, a modest dose (24 mg/kg body weight), but not a > 30 times higher dose (750 mg/kg body weight) of curcumin significantly reduce oxidative damage and amyloid pathology [65]. Similar observations, reductions in both Aβ deposits and in memory deficits are also made in Sprague Dawley rats[66]. The age-adjusted prevalence of both AD[67] and Parkinson’s disease (PD) is in India[68] with its 271 significantly higher intake of turmeric, much lower than in Western countries, especially the USA. However, the preventive effects of consumption of turmeric can also be achieved with other polyphenol-rich fruits and vegetables if consumed in enough quantities. Blueberries, strawberries and spinach in doses of 18.6, 14.8 and 9.1 gm of dried extract/kg body weight were demonstrated to be effective in reversing age-related deficits in both neuronal and behavioural parameters[69]. A study from 1999 is of special interest: Rats on chronic ethanol supply were randomized to 80 mg/kg body weight of curcumin (CU) or control (CO) and compared to non-intoxicated normal rats (NI)[70]. The degree of histopathological changes, the levels of TBARS (NI 1.29, CU 2.41, CO 2.98), cholesterol (NI 1531.9, CU 1658.2, CO 2031.1), phospholipids (NI 1845.5, CU 2011.5, CO 2795.1), and free fatty acids (NI 26.7, CU 39.9, CO 53.1) in brain tissue were significantly improved after curcumin treatment. Ocular diseases: Cataract, an opacity of the eye lens, is the leading cause of blindness worldwide, responsible for the blindness of almost 20 million people in the world[71]. Nutritional deficiencies, especially lack of consumption of enough antioxidants, diabetes, excessive sunlight, smoking and other environmental factors are known to increase the risk of cataracts[72]. The age-adjusted prevalence of cataract in India is, however, three times that of the United States [73]. Despite this, three different experimental studies have reported significant preventive effects of curcumin against cataracts induced by naphthalene[74], galactose[75] and selenium[76]. Pancreatic diseases: The effect of curcumin to reduce the damage to pancreas was studied in two different models; cerulein-induced and ethanol and CCK-induced pancr eatitis[77]. Curcumin was administered intravenously in parallel with induction of pancreatitis. A total of 200 mg/kg body weight was administered during the treatment period of six hours. Curcumin treatment significantly reduced histological injuries, the acinar cell vacuolization and neutrophil infiltration of the pancreatic tissue, the intrapancreatic activation of trypsin, the hyperamylasemia and hyperlipasemia, and the pancreatic activation of NF-KB, IKB degradation, activation of activator protein (AP)-1and various inflammatory molecules such as IL-6, TNF-α, chemokine KC, iNOS and acidic ribosomal phosphoprotein (ARP). Curcumin did also significantly stimulate pancreatic activation of caspase-3 in both models. 272 Plant-derived Health-Effects of Turmeric and Curcomenoids Respiratory diseases: As mentioned above, curcumin is a potent inhibitor of TGF-β and fibrogenesis[25] and is thought to have positive effects in fibrotic diseases in kidneys, liver, intestine (Crohn’s Disease), body cavities (prevention of fibrous adhesions)[19] and on conditions with lung fibrosis, including cystic fibrosis. The latter is of special interest as it has been especially linked to glutathione deficiency. The effect of curcumin against amiodarone-induced lung fibrosis was recently studied in rats[78]. Significant inhibition of LDH activity, infiltration of neutrophils, eosinophils and macrophages in lung tissue, LPS-stimulated TNF-α release, phorbole myristate acetate (PMA)stimulated superoxide generation, myeloperoxidase (MPO) activity, TGF- β1 activity, lung hydroxyproline content and expression of type I collagen and c-Jun protein were observed when curcumin was supplemented in doses of 200 mg/kg body weight in parallel with intratracheal instillation of 6.25 mg/kg body weight of amiodarone. Curcumin exhibits structural similarities to isoflavonoid compounds that seem to bind directly to the CFTR protein and alter its channel properties[79]. Egan et al[80], who had previously observed that curcumin inhibits a calcium pump in endoplasmic reticulum, thought that reducing the calcium levels might liberate the mutant CFTR and increase its odds of reaching the cell surface (see also)[81]. The ∆F508 mutation, the most common cause of cystic fibrosis, will induce a misprocess in the endoplasmatic reticulum of a mutant cystic fibrosis transmembrane conductance regulator (CFTR) gene. A dramatic increase in survival rate and in normal cAMPmediated chloride transport across nasal and gastrointestinal epithelia was observed in genetargeted mice homozygous for the ∆F508 when supplemented curcumin[79]. No human studies are yet reported and it is too early to know if this treatment will be able to halt or reverse the decline in lung function also in patients with cystic fibrosis. An eventual anti-asthmatic effect of curcumin was recently tested in guinea-pigs sensitized with ovalbumin and significant reductions observed both in airway constriction and in airway hyperreactivity to histamine[82]. Tobacco/cigarette smoke (CS)-induced injuries: CS is suggested to cause 20% of all deaths and ~30% of all deaths from cancer. CS contains thousands of compounds of which about hundred are known carcinogens, co-carcinogens, mutagens and/or tumor promoters. Each puff of smoke contains over 10 trillion free radicals. Antioxidant levels in blood are also significantly reduced in smokers. Activation of NF-KB has been implicated in chemical carcinogenesis and tumorigenesis December 2006 through activation of several genes such as COX-2, iNOS, matrix metalloproteinase ((MMP)-9, IL-8, cell surface adhesion molecules anti-apoptotic protein and others. A recent study reports that curcumin abrogates the activation of NF-KB, which correlates with down-regulation of COX-2, MMP-9 and cyclin D1 in human lung epithelial cells[83]. PLANT ANTIOXIDANTS - RELEASED BY GI MICROBES (Flora) All chronic diseases are in a way related. They all develop as a result of a prolonged and exaggerated inflammation [84]. Their development can most likely be prevented or at least delayed by extensive consumption of antioxidants such as curcumin. It is important to remember, that it is almost exclusively through microbial fermentation of the different plants that bioactive antioxidants are released and absorbed. Clearly flora and supplied lactic acid bacteria/probiotics play an important role. It is therefore unfortunate that both size and diversity of flora is impaired and intake of probiotic bacteria significantly reduced among Westerners. For example, reduction in total numbers and diversity of flora is also associated with certain chronic diseases such as IBD[85].A study from 1983 demonstrated that Lb plantarum, a strong fibre fermentor, is found in only 25% of omnivorous Americans and in about 2/3 of vegetarian Americans[86]. Great differences in volume and diversity of flora have also been observed between different human cultures. It is reported that Scandinavian children as compared to Pakistani children have a much reduced flora[87]. Astronauts, who return from space flights have during the flight lost most of their commensal flora including lactobacillus species such as Lb plantarum (lost to almost 100%), Lb casei (lost to almost 100%), Lb fermentum (reduced by 43%), Lb acidophilus (reduced by 27%), Lb salivarius (reduced by 22%) and Lb brevis (reduced by 12%)[88], changes most likely attributed to poor eating (dried food, no fresh fruits and vegetables) and a much reduced intake of plant fibers and natural antioxidants, to the mental and physical stress and eventually also to the lack of physical exercise. Many individuals in Western Societies exhibit a type of “astronaut-like lifestyle” with unsatisfactory consumption of fresh fruits, vegetables, too much stress and no or little outdoor/sport activities. Furthermore, flora seems not to tolerate exposure to chemicals including pharmaceuticals. This is also demonstrated in critically ill, who most often have lost their entire lactobacillus flora[89]. A recent Scandinavian study suggest that fiber-fermenting LAB such as Lb plantarum, Lb rhamnosus and Lb paracasei ssp paracasei, present in all humans with a rural December 2006 KUWAIT MEDICAL JOURNAL lifestyle, are only found 52%, 26% and 17% respectively of persons with a more urban Western type lifestyle[90]. These LAB are present in all with more rural lifestyle. The lack of these LAB is probably negative as these LAB are unique in their ability to ferment important fibers such as inulin and phlein, otherwise resistant to fermentation by most lactobacillus species[91], and superior to other lactobacillus in their ability to eliminate pathogenic microorganisms such as Clostridium difficile[92]. CONCLUSIVE REMARKS To use medicinal plants and their active components is becoming an increasingly attractive approach for the treatment of various inflammatory disorders among patients unresponsive or unwilling to take standard medicines. Food derivates have the advantage of being relatively nontoxic. This is certainly so for turmeric and curcumin. If one chooses to supply it with the fiber, e.g., as turmeric, additional supplementation with probiotic bacteria will most likely enhance the efficacy of treatment. Increasing evidence suggest that as saturated fat in the diet increases and plant fibre intake reduces the inflammatory reaction in the body increases[93]. A high fat/low fibre diet is clearly associated with chronic diseases[94] and fruit and vegetable intake with reduction in incidence of chronic diseases[95]. Focus is increasingly turning from fibre per se to active ingredients in the plant fibres, antioxidants and anti-inflammatory agents such as curcuminoids in turmeric. Not only turmeric and curcumin, but also numerous other plants contain compounds which reduces inflammation and protect against disease. Among them are several thousands of plantderived chemo-preventive agents, polyphenols and many other, most often unexplored, substances, which seem to have potential to reduce inflammation, speed of aging, and prevent degenerative malfunctions of organs and development of chronic diseases. Among them isothiocyanates in cruciferous vegetables, anthocyanins and hydroxycinnamic acids in cherries, epigallocatechin-3-gallate (EGCG) in green tea, chlorogenic acid and caffeic acid in coffee beans and also in virgin tobacco leaves, capsaicin in hot chili peppers, chalcones in apples, euginol in cloves, gallic acid in rhubarb, hisperitin in citrus fruits, naringenin in citrus fruits, kaempferol in white cabbage, myricetin in berries, rutin and quercetin in apples and onions, resveratrol and other procyanidin dimers in red wine and virgin peanuts, various curcumenoids, the main yellow pigments in turmeric curry foods, and daidzein and genistein from the soy bean. These compounds have all slightly different functions and seem to complement each other well. 273 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. World Health Organisation. Process for a global strategy on diet, physical activity and health. WHO Geneva February 2003. 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Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol 2003; 92:1335-1339. 94. Campbell TC, Junchi C. Diet and chronic degenerative diseases: perspective from China. Am J Clin Nutr 1994; 59:S1153-S1163. 95. Knekt P, Kumpulainen J, Järvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 2002; 76:560568. KUWAIT MEDICAL JOURNAL December 2006 Original Article Feasiblity and Clinical Significance of Echocardiographic Assessment of Aortic Root Compliance in Hypertensive Patients Aly Mohamad Hegazy, Laila Soud M Al-Einzi, Mohamad Hussain Al-Kandary, Bader Abdelkader Department of Medicine, Non-Invasive Cardiac Laboratory, Farwania Hospital, Kuwait Kuwait Medical Journal 2006, 38 (4): 276-283 ABSTRACT Objectives: To evaluate the hypothesis that hypertension is associated with reduced aortic compliance and the stiff aortic root is a marker for prediction of associated coronary artery disease (CAD). Design: Cohort study conducted between January 2003 and July 2005. Setting: Non-invasive cardiac laboratory, Department of Medicine, Farwania Hospital, Kuwait. Patients and Methods: One hundred and forty hypertensive patients and 30 normotensive subjects were included in the study. All patients underwent a 24-hour ambulatory blood pressure recording, hand-grip isometric exercise echocardiography and treadmill exercise ECG test. Only 100 hypertensive patients were known to have undergone coronary angiography in the course of their clinical management and were classified into two subgroups; group Ia: included 60 patients with CAD and group Ib: included 40 patients with normal coronary angiography. Results: There was a significant increase in aortic root area (p < 0.05) in the normotensives after isomeric exercise but no significant change (p = NS) in the hypertensive patients. There was a significant reduction in aortic root compliance (p < 0.05) in the hypertensive patients than the subjects with normal blood pressure and in the hypertenisve patients with CAD than the hypertensive patients with normal coronary angiography (p < 0.05). There was a significant correlation between the blood pressure load as an independent variable and the aortic root compliance as a dependent variable (r = 0.873, p < 0.05). Predictive indices revealed that reduced aortic root compliance is valid as an indicator for the prediction of CAD as compared to ischemic heart disease (sensitivity = 69% Vs 60%, specificity = 71% Vs 67%, accuracy = 70% Vs 60.7%, positive predictive value = 81.8% Vs 46.2% and negative predictive value = 55.5% Vs 73.3%, respectively). Stepwise multivariate analysis revealed a significant relationship between age, gender, smoking status and hypercholesterolemia and reduced aortic root compliance in hypertensive patients (p < 0.05). Conclusion: Aortic root compliance is compromised in the hypertensive patients when compared with normotensives subjects and its detection is of clinical significance as the stiff aortic root can be considered a marker for prediction of the associated CAD. KEY WORDS: aortic root, isometric exercise, transthoracic echocardiography INTRODUCTION Aorta functions not only as a conduit delivering blood to the tissues but as an important modulator of the entire cardiovascular system, buffering the intermittent pulsatile output from the heart to provide steady flow to capillary beds[1]. By virtue of its elastic properties aorta influences left ventricular function and coronary blood flow[2]. Systemic hypertension, a common disorder with potentially serious complications, exerts further ill effects through structural and functional modifications of the arterial wall[3]. Previous studies using different techniques have shown that aortic elastic properties are compromised in patients with arterial hypertension [4]. Roy [5] reported that athersclerotic plaques were present diffusely in coronary artery disease of all adult necropsied patients whether with or without symptomatic ischemic heart disease and similar complicated atherosclerotic plaques were present in the aorta as well. Stefanadis et al from University of Athens, Greece described a method of obtaining aortic pressure-diameter relationship in conscious humans. With this method, aortic diameters were acquired with a high-fidelity intravascular catheter developed in our institution that has an ultrasonic displacement meter at its distal end. Aortic pre s s u res were acquired simultaneously and at the same aortic level with a catheter-tip micro m a n o m e t e r [6]. Measurement of pulse wave velocity has been extensively used providing only indirect estimations of the elastic properties of the aorta[7]. Address correspondence to: Dr. Aly M. Hegazy, MB,BCh, MSc, MD, Department of Medicine, Non-Invasive Cardiac Laboratory, Farwania Hospital, Kuwait. Tel: (0) (965) 488-2379, E-Mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL The aims of the study were to: 1. Evaluate the aortic root compliance in hypertensive patients by echocardiogram. 2. Study the association of CAD and reduced aortic root compliance. 3. Investigate the validity and reliability of aortic root compliance to predict the associated CAD. PATIENTS AND METHODS Study patients: One hundred and forty hypertensive patients and 30 control subjects were included in the study. All patients were referred by their physicians to the cardiology clinic at Farwania Hospital with a blood pressure more than 140/90 mmHg. All patients were evaluated clinically by looking at history, physical examination, 12-leads ECG and routine laboratory investigations. Exclusion criteria included patients with history of myocardial infarction, unstable angina, left main CAD, three vessel disease, intraventricular conduction disturbances, strain patterns due to left ventricular hypertrophy, atrial fibrillation, frequent ventricular ectopics, retinopathy, nephropathy, diabetes mellitus, cerebrovascular disease, significant valvular disease and pregnant women. Exclusion was based on: medical history, physical examination, fundus examination, urine analysis for proteinuria and 12-lead electrocardiogram to avoid confounding factors. There were two groups: Group I: included 140 hypertensive patients (120 males and 20 females) Group II: included 30 normotensive control subjects (25 males and 5 females) Coronary angiography: Only 100 hypertensive patients were known to have undergone coronary angiography in the course of their clinical management and were classified into two subgroups: 1. Group Ia: included 60 hypertensive patients with angiographically documented coronary artery disease. 2. Group Ib: included 40 hypertensive patients with normal coronary angiography. Blood pressure measurements: Mercury sphygmomanometer was used to measure office systolic and diastolic BP (mmHg). At least two measurements were recorded between 8 and 11 am with the patients in a sitting position with the legs uncrossed and the feet on the floor. Patients were requested to refrain from heavy exercise in the morning and to avoid cola drink, 277 coffee, tea and smoking for at least one hour before the measurement. BP was measured after the patients had rested for 15 minutes. The last five minutes of rest were spent in the measurement room with the cuff around the right upper arm. Cuff inflation pressure was then determined by palpating the disappearance and appearance of the radial pulse. Ambulatory blood pressure was recorded with an auscultatory device (Accutracker II). Correct position of the microphone was identified by palpating the brachial artery. Ambulatory BP was recorded during daytime (6 am to 10 pm) at onehour intervals and during the night (10 pm to 6 am) at 2-hour intervals. Sleep time was identified by the patient’s diary. Blood pressure load is the percentage of all systolic and diastolic BP recordings exceeding the threshold of 140/90 mmHg[8]. Pulse pressure was calculated as the difference between systolic and diastolic blood pressure. Mean blood pressure was calculated as diastolic blood pressure plus one third pulse pressure[8]. Treadmill exercise ECG test protocol: All patients in the study underwent the exercise ECG test using standard or modified Bruce models. Resting blood pressure (measured manually by arm-cuff sphygmomanometer) was measured in supine and standing positions before the test. Patients with orthostatic hypotension (defined as a decrease of > 20 mmHg of systolic blood pressure after standing) were excluded. Resting ECG was done for all patients to exclude patients with significant ST- segment changes, left bundle branch block or tachyarrhythmias. Blood pressure was recorded midway through each stage and at peak exercise. The stress ECG test was terminated if there was a decrease in blood pressure (> 20 mmHg), significant arrhythmias (non-sustained or sustained ventricular tachycardia), typical chest pain (test limiting angina) or > 2 mm ST-segment depression from baseline was noted[9]. Peak heart rate (HR): achieved percentage of age - related peak heart rate = (peak HR/220 - age) x 100. Design of the study: All patients and normotensive control subjects were informed about the study protocol. They underwent identical study protocol, transthoracic echocardiography and blood pressure measurement at rest and after hand-grip isometric exercise. Assessment of aortic root compliance: In order to assess aortic root compliance (C), aortic root area (A) was calculated from each measured aortic root dimension (D), assuming the 278 Feasiblity and Clinical Significance of Echocardiographic Assessment of Aortic Root .... aorta to be a cylinder with formula: A = π D2/4. Aortic root area (A) was normalized for body surface area in order to account for individual variability related to body size. Aortic root compliance (C) can be defined by C=∆A/∆P (cm2/m2/mmHg). Where ∆A is the variation of aortic root area index between measurements at rest and during isometric exercise and ∆P is the variation of pressure between measurements at rest and after isometric exercise[10]. Echocardiographic study: Two-dimensional and M-mode echocardiography was performed for all patients in the study using Toshiba Power Vision and a 3.5 MHZ phased array transducer. Measurements were performed according to the recommendations of the American Society of Cardiology[11]. The leading edge to leading edge convention was used. Left ventricular dimensions were measured at or immediately below the tips of mitral leaflets and averaged over five heart cycles. Left Ventricular Mass (LVM) and LVM index were calculated. Aortic measure-ments were determined at end-systole and end diastole from the leading edge of anterior wall of aorta to the leading edge of the posterior wall of aorta. Hand Grip Isometric Exercise: In order to provide aortic measurements over a range of pressures, all subjects performed isometric exercise. They were asked to resist inflation of a cuff of sphygmomanometer while aortic dimensions and blood pressure were obtained after three minutes at 50% of maximal hand grip[10]. Statistical analysis: Continuous variables are summarized as a mean ± standard deviation (SD). Comparison between two groups was performed with t - test for continuous variables and chi-square test for categorical variables. A p-value < 0.05 was considered statistically significant and a p-value < 0.01 was considered statistically highly significant. A stepwise multivariate regression model was used to identify possible independent variables associated with reduced aortic root compliance in the hypertensive patients. The strength of the association with reduced aortic compliance is presented as 95% confidence intervals. Potential confounding of clinical variables was entered as independent variables. The validity of the aortic root compliance to detect coronary artery disease and ischemic heart disease was assessed by estimating the predictive indices and Kappa coefficient to determine the overall agreement with the data obtained from the coronary angiography and the treadmill exercise ECG test. December 2006 Kappa coefficient value (k) = (Observed frequency of agreement - Expected frequency of agreement) / (Total observed - Expected frequency of agreement). Predictive indices: True positive (TP), true negative (TN), false positive (FP) and false negative (FN) were calculated. Sensitivity = TP/ (TP + FN), specificity = TN/(TN + FP), positive predictive value = TP/(TP + TN), negative predictive value =TN/(TN+TP) and accuracy = (TP + TN)/(TP + TN + FP + FN). Simple linear regression (Least-square method) was used for correlation of the aortic root compliance and the systolic blood pressure load: Y = b + aX where, a = slope of the curve and b = intercept of Y dependent axis (aortic root compliance) when X independent value (systolic blood pressure load) became zero. RESULTS Clinical characteristics: As regards the age and gender, there was no significant difference between both groups in the study (54.21 ± 7.24 versus 49.9 ± 4.41 years, respectively, p = NS, 120 (85.7%) versus 25 (83%) males, p = NS and 20 (14.3%) versus 5 (17%) females, p = NS) respectively. There was no significant difference between both groups regarding a percentage of patients with history of smoking, diabetes mellitus, and hypercholesterolemia [46 (32.7%) versus 12 (40%) patients, p = NS, 29 (20.7%) versus 7 (23%) and 42 (30%) versus 8 (27%) patients, p = NS] respectively. There was no significant difference regarding the resting heart rate between both groups (89.25 ± 5.93 versus 78.5 ± 8.72 beat/minute, respectively, p = NS) but there was a significant increase in the systolic and diastolic blood pressure in the hypertensive patients than the normotensives (177.5 ± 13.41 versus 122.35 ± 8.11 mmHg, and 105.8 ± 5.32 versus 76.84 ± 6.18 mmHg, respectively, p < 0.05). There were 46 patients with a history of antihypertenisve medication with angiotensin converting enzyme inhibitors, 32 patients were on calcium channel blockers, 35 patients were taking beta-blockers and 27 patients were on angiotensin receptors blockers. Exercise ECG test: There was no significant difference between both groups in the study as regards the duration of exercise ECG test, peak heart rate, blood pressure response during and after exercise and heart rate recovery after exercise during recovery (p = NS). There was a significant increased ST - segment December 2006 KUWAIT MEDICAL JOURNAL Table 1: Aortic root dimensions before and after isometric exercise detected by M-mode echocardiography in both study groups Variables At rest before isometric exercise Aortic Root Area (cm2) Aortic root Index (cm2/m2) After 3-minutes hand-grip isometric exercise Aortic Root Area (cm2) Aortic Root Index (cm 2/m2) Group I Group II p-value 8.10 ± 1.32 4.34 ± 0.58 7.26 ± 1.28 3.82 ± 0.64 < 0.05 < 0.05 8.99 ± 1.12 4.64 ± 0.36 8.64 ± 1.07 4.59 ± 0.62 NS NS 279 Table 2: Compliance of the aortic root in both groups Variables ∆ A (cm2/m2) ∆ P (mmHg) C (cm2/m2/mmHg) Group I Group II p-value 0.89 ± 0.08 36.1 ± 4.61 0.025±0.005 1.38 ± 0.18 26.4 ± 3.27 0.052±0.009 < 0.05 < 0.05 < 0.01 C = compliance, ∆A= difference in aortic area, ∆P= difference in systolic blood pressure Table 3: Stepwise Logistic Multivariate Analysis of patients with normal aortic function versus those with impaired aortic function as regards age, gender, smoking and hyercholesterolemia Variables Age Gender Smoking Status Hypercholesterolemia Co-efficient p-value 95% CI 0.4653 0.6301 0.5873 0.1852 < 0.05 < 0.05 < 0.05 < 0.05 1.125 - 4.091 1.021 - 3.505 1.761 - 2.723 1.420 - 2.795 depression in the hypetensive patients than the normotensive subjects (1.75 ± 0.23 versus 0.42 ± 0.11 mm, respectively, p < 0.05). Echocardiography: There was a significant increase in the left ventricular mass index (LVMI) in both hypertensive patients and normotensive subjects (147.3 ± 5.32 versus 119.4 ± 4.68 gm/m2, p < 0.05) . There was non-significant difference in the left ventricular systolic function (EF%) between both groups (62.53 ± 4.26 versus 63.41 ± 2.18%, p = NS), but there was a significant impaired diastolic function of the left ventricle in the hypertensives than normotensives as there was a significant decrease in the E/A ratio (0.88 ± 0.15 versus 1.51 ± 0.16 respectively, p < 0.05). There was no patient with signs of aortic root dissection and there were 20 patients with aortic sclerosis and the mean of the left ventricle/aorta gradient was 24 mmHg. There was no patient with intramural thrombus or pericardial effusion. There was a significant increase in the aortic root area and the aortic root area index at baseline before isometric exercise in hypertensive patients than normotensive subjects ( 8.10 ± 1.32 versus 7.26 ± 1.28 cm2, p < 0.05 and 4.34 ± 0.58 versus 3.82 ± 0.64 cm2/m2, p < 0.05, respectively), but no significant change in the aortic root area and aortic root area index after isometric exercise between both groups in the study ( 8.99 ± 1.12 versus 8.64 ± 1.07 cm2, p = NS and 4.64 ± 0.36 versus 4.59 ± 0.62 cm2/m2, p = NS, Table 1). Fig. 1: Aortic root compliance in the patients with and those without coronary artery disease There was a significant increase in the aortic area after isometric exercise in the normotensive subjects than before exercise (p < 0.05) but no significant increase after exercise in the hypertensive patients (p = NS). There was a significant decrease in the aortic root compliance in hypertensive patients than normotensive subjects (0.025 ± 0.005 versus 0.052 ± 0.009 cm2/m2/mmHg, p < 0.01, Table 2). There was a significant decrease in the aortic root compliance in hypertensive patients with coronary artery disease than those with normal coronary arteries (p < 0.05, Fig. 1). Blood pressure load: Forty-five hypertensive patients had systolic blood pressure load > 50% and 55 hypertensive patients had systolic blood pressure load < 50%. Stepwise logistic multivariate analysis revealed a significant relation between age, gender, smoking status and hypercholesterolemia as independent variables and reduced aortic root compliance in the hypertensive patients ( r = 0.4653, 0.6301, 0.5873 and 0.1852 and 95% CI = 1.125 - 4.091, 1.021 - 3.505, 280 Feasiblity and Clinical Significance of Echocardiographic Assessment of Aortic Root .... Table 4: Stepwise Logistic Multivariate Analysis of patients with normal aortic function versus those with impaired aortic function as regards antihypertensive drugs Variables Beta blockers ACE inhibitors AR Blockers Calcium channel blockers Co-efficient p-value 0.1653 0.4341 0.3821 0.1659 NS < 0.05 NS <0.05 Table 5: Agreement of the treadmill exercise ECG test and aortic root compliance as regards the prediction of ischemic heart disease 95% CI 0.524 - 1.091 1.227 - 2.893 0.761 - 1.590 1.428 - 3.236 ACE = angiotensin converting enzyme, AR = angiotensin receptors December 2006 TTT +ve Stiff aortic root 30 Compliant aorta 20 Total 50 Kappa Co-efficient value (k) = 0.635 TTT -ve 35 55 90 65 75 140 TTT = treadmill tolerance test Fig. 3: Correlation between blood pressure load and aortic root compliance in the hypertensive patients Fig. 2: The aortic root compliance among the three quintiles of the hypertensive patients 1.761 - 2.723 and 1.420 -2.795, respectively, p < 0.05, Table 3). As regards antihypertensive drugs, there was a significant relation between ACE i n h i b i t o r s and calcium channel blockers as independent variables and a reduced aortic root stiffness in hypertensive patients (R= 0.4341 & 0.1659 and 95%CI = 1.227 - 2.893 & 1.428 - 3.326 respectively, p < 0.05), but there was no significant relationship between beta blockers and angiotensin receptors blockers as independent variables and a reduced aortic root siffness in the same group (r= 0.1653 & 0.3821 and 95% CI= 0.524 - 1.091 & 0.761 - 1.590 respectively, p = NS, Table 4). Among the quintiles of the age of hypertensive patients there was an insignificant difference regarding the aortic root compliance between the first and second quintiles (p = NS), but there was a significant decrease in the aortic root compliance in the third quintile as compared with the first and the second quintiles (p < 0.5, Fig. 2). There was an agreement between data of aortic root compliance and the treadmill exercise ECG test to predict the associated ischemic heart disease with Kappa coefficient value (K) = 0.635, (Table 5) and with the data of coronary angiography to predict the associated coronary artery disease with Kappa coefficient value (K) = 0.761 (Table 6). There was a significant correlation between blood pressure load (%) and aortic root compliance (cm2/m2/mmHg) in hypertensive patients (Y= 0.041X + 0.044, r = -0.873, p < 0.05), and the aortic root compliance (0.025 cm2/m2/mmHg) of dependent Y axis corresponded with the blood pressure load (50%) of independent X axis (Fig. 3). Table 7 shows the predictive indices for prediction of the patients with coronary artery disease and to predict the ischemic heart disease. DISCUSSION Stefanadis et al[12] reported that aortic stiffness and energy loss due to wall viscosity are increased in hypertensive as compared to the normotensive patients and diltiazem administration produced an acute improvement of aortic elastic properties and a reduction of viscous energy loss. Analysis of the pressure - diameter relation loop provides a December 2006 KUWAIT MEDICAL JOURNAL Table 6: Agreement of the coronary angiography and aortic root compliance as regards the prediction of coronary artery disease Angio +ve Stiff aortic root 45 Compliant aorta 20 Total 65 Kappa Coefficient value (k) = 0.761 Table 7: Indices for prediction of coronary artery disease by echocardiographic assessment of aortic root compliance in all patients group Angio -ve 10 25 35 281 TP TN FP FN Sen Spec Acc PPV NPV 55 45 100 Prediction of IHD Prediction of CAD 30 45 55 25 35 10 20 60% 67% 60% 46% 73% 20 69% 71% 70% 81% 56% Angio = coronary angiography TP= true positive, TN = true negative, FN = false negative, FP= false positive, Sen = sensitivity, Spec = specificity, Acc = accuracy, PPV = positive predictive value, NPV = negative predictive value valuable insight into aortic mechanics. First, indices such as distensibility and slope of the pressurediameter loop may be calculated. Second, a study of the pressure-diameter relationship helps distinguish between active and passive changes in aortic elastic properties. The pressure-diameter relationship for a given subject has a sigmoid configuration. Movement of the pressure-diameter loop along this hypothetical sigmoid line suggests changes in the elastic properties of the aorta due to changes in aortic pressure alone. In contrast, shifting of essential modification of the intrinsic properties of the aorta is also due to non-passive factors[13]. Third, study of the pressure-diameter loop provides insights into aortic energetics. In specific, the area within the loop represents the energy dissipated to the viscosity of the aortic wall. Several studies suggest that in hypertension, the aorta exposed to increased intraluminal pressure undergoes an increase in mural thickness [14]. Moreover, changes in the structural components of the arterial wall, including a fall in the ratio of elastin to collagen, may account for stiffening of the aorta[15]. In addition, increased smooth muscle tension is a possible contributor to aortic wall stiffening in hypertension. Hypertension-induced endothelial cell dysfunction may also contribute to alterations of the arterial wall tone, most likely through impairment of nitric oxide-mediated vascular smooth muscle relaxation. In advanced stages of the disease, a further factor that reduces arterial compliance is the deposition of calcium[16]. The amount of severity of atherosclerosis in the coronary bed shows a positive correlation with the degree of atherosclerosis in the aorta or other major arterial branches [17]. Atherosclerotic changes in arterial wall have been shown to include smooth muscle cell proliferation, deposition of lipid and accumulation of collagen, elastin and proteoglycans. Changes in the ratio of collagen to elastin have been known to structurally affect the elastic behavior of arterial walls. Our finding of an impaired aortic root compliance in hypertensive patients with coronary artery disease is in keeping with previous smaller studies[18]. Another study has shown that proximal aortic stiffness is increased progressively with the number of diseased coronary blood vessels in patients investigated after myocardial infarction[19]. Only 100 patients were known to have undergone coronary angiography in the course of their routine clinical management and out of these only 40 patients had normal coronary arteriography, 10 patients had positive exercise test which may be due to other causes (e.g., coronary spasm or mirovascular disease), and this seems unlikely to have seriously confounded our results. We found that the age, gender, smoking status and hyper cholesterolemia were independent variables to increase the risk of the aortic stiffness and this is in an agreement with other studies[19-22]. An increase in the stiffness of the aorta with elevated plasma lipids has been related to the increased endothelium vasoactivity and decreased vasa vasorum flow. Cholesterol may enhance arterial stiffening, but this process is modulated by other risk factors for CAD[20]. Smoking is a major and independent risk factor for cardiovascular morbidity and mortality [21]. Many underlying mechanisms have been proposed for the hazardous effects of smoking, including promotion of atherogenesis, unfavourably changed lipid profile, increased blood viscosity, alterations in platelet function and promotion of thrombosis and enhanced adrenergic activity. Previous studies have shown that smoking also induces coronary artery vasoconstriction and affects arterial elastic properties unfavorably, increasing stiffness of both muscular and elastic arteries. We found that the angiotensin converting enzyme inhibitors and calcium channel blockers were independent variables for decreasing the risk of the aortic stiffness and this is in agreement with other studies[23,24]. Diltiazem has an active effect on the elastic properties of the aorta due to direct relaxation of the aortic smooth muscle and increase in the vasodilatory capacity of the vasa vasorum of the aortic wall which is decreased in chronic hypertension[3]. 282 Feasiblity and Clinical Significance of Echocardiographic Assessment of Aortic Root .... Methodological consideration: The method used in the present study provides reliable, non- invasive and valid determination of the aortic root function in hypertensive patients and can be reproduced in the hypertension clinic but the invasive methods using the high fidelity diameter measuring device and the catheter-tip micromanometer measuring aortic pressure has been validated and proved to be accurate and safe[3]. The variability of echocardiography determined indices of aortic stiffness has been found previously to be < 10% for inter-observer comparisons. For measurements repeated at 4-week intervals, intraobserver variability was < 10%[3,17]. In our study only one cardiologist performed echocardiographic assessment once. Therefore it is difficult to assess inter-observer and intra-observer variability. Department, Farwania hospital, for his advice and help in the preparation of this manuscript, and Dr Walid Ahmad Mostafa and Dr Ahmad Muneer, Cardiologists of Medicine Department, Farwania hospital, for their valuable help. REFERENCES 1. 2. 3. 4. Limitations of the study: 1. Relatively small number of patients. 2. The study was not blind to the cardiologist performing the echocardiography. 3. Blood pressure was recorded indirectly by cuff sphygmomanometer. 4. Coronary vasomotor reactivity was not included in the design of the study. 5. Pregnant women were not included in the study to avoid the confounding effect of the estrogen on the elasticity of the aorta. The aorta is more dilated and more compliant during normal human pregnancy, especially in multi-parus women [25]. 6. Hypertensive patients with end-organ damage were not included in the study. CONCLUSION Aortic root compliance is compromised in hypertensive patients as compared with normotensive subjects and it can be considered as a marker for prediction of coronary artery disease. Aortic root compliance is a precise estimate for risk stratification in the management of hypertensive patients as the serial evaluation of the aortic root stiffness allows early detection of pathologic acceleration of atherosclerotic complications. ACKNOWLEDGMENT With great honor, we thank Dr Saleh Ali AlEnezi, Chairman of Medicine Department and Dr Ahmad Al-Dousary, Consultant Endocrinologist, Medicine Department, Farwania hospital for their kind cooperation and continuous support accorded to this study. We also thank Mrs Delfeyanoum Hussain and Mrs Suzan of the Non-Invasive Cardiac Laboratory, Farwania hospital, for their cooperation in preparation of patients, Dr Samuel Cherian, Consultant Physican, Medicine December 2006 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 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Stefanadis C, Karayannacos PE, Boudoulas H, Stratos C, Vlachopoulos C, Dontas I, Toutouzas P. Medial necrosis and acute alterations in aortic distensibility following removal of the vasa vasorum of canine ascending aorta. Cardiovasc Res 1993; 27:951-956. Stefanadis C, Vlachopoulos C, Karayannacos PE, Boudoulas H, Stratos C, Filippides T, Agapitos M, Toutouzas P. Effects of vasa vasorum flow on stucture and function of the aorta in experimental animals. Circulation 1995; 91:2669-2678. Pearson AC, Guo R, Orsinelly DA, Binkley PF, Pasiersky TJ. Transesophageal echocardiographic assessment of the effects of age, gender and hypertension on thoracic aortic wall size, thickness and stiffness. Am Heart J 1994; 128:344351. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a noninvasive study. J Am Coll Cardiol 1989; 13:399-405. Beltz GG. 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Am J Obstet Gynecol 1996; 174:1708 -1717. KUWAIT MEDICAL JOURNAL December 2006 Original Article Prevalence and Factors Associated with Obesity and Treatment of Blood Pressure among Kuwaiti Hypertensive Patients in a Primary Health Care Clinic Nadia Yousef Al-Mahmoud Ehqaqi Primary Health Care Clinic (Daiya Clinic), Kuwait Kuwait Medical Journal 2006, 38 (4): 284-286 ABSTRACT Objectives: To determine the prevalence of obesity among adult hypertensive patients and to investigate associated factors and the differences in drug doses at the Daiya primary care clinic in Kuwait Design: Cross-sectional study Method: Two hundred hypertensive Kuwaiti patients on antihypertensive medication and attending the Daiya clinic during a period of six months between January and June 2004 were included in the study. Results: A high prevalence of obesity (68%) was seen among hypertensive patients. The multiple logistic regression analysis showed that the significant associated factors were non- compliance with diet (p = 0 .006) and age (< 65, p = 0.002). Factors such as intake of evening snacks and family history of obesity were not found to be significantly associated. Obese patients needed more than one drug to control their blood pressure. Conclusion: There is a high prevalence of obesity among hypertensive patients. Hence, intensive programs are recommended to control their obesity. KEYWORDS: body mass index, hypertension, obesity, primary care INTRODUCTION Obesity, according to WHO, is defined as Body Mass Index (BMI = weight in kilograms divided by height in meters squared) ≥ 30 kg/m2 and overweight as BMI ≥ 25 kg/m2[1]. Obesity, characterized by storage of additional body fat, develops when energy intake exceeds energy expenditure [2]. Epidemiological studies show that about 55% of US adult population is overweight and 22% is obese. In the last two decades obesity has increased by more than 30% in USA [1]. The prevalence of obesity in Kuwait has increased by 15.4% between 1980-81 and 1993-94 among Kuwaiti men due to modernization, affluence and concomitant changes like sedentary life style [3]. Prevalence of overweight and obesity also increased among both gender in Kuwait between 1980 - 81 and 1993 - 94. The rate of temporal changes in BMI and obesity were higher by comparison in Kuwait than in selected other countries[4,5]. Obesity, especially upper body fat distribution is an independent risk factor for the development of hypertension[6-9]. Hypertension is defined as blood pressure ≥ 140/90 mmHg with or without antihypertensive medication [10]. Recent studies showed that both systolic and diastolic blood pressure increases in a linear manner over the whole range of BMI or waist circumference[11-12]. Obesity being one of the risk factors and determinant of poor BP control, it was thought necessary to study the factors associated with obesity among hypertensive patients. Weight reduction is one of the most effective non pharmacological approach to BP control[7]. Hypothesis Majority of hypertensive patients are obese. Factors associated with obesity are lack of exercise and poor diet compliance. More number of drugs are needed to control BP among obese patients. METHODOLOGY A cross - sectional study was undertaken at the Daiya (Al - Ehqaqi) primary care clinic in Kuwait during a period of six months between January and June 2004. The study included 200 consecutive Kuwaiti hypertensive patients who attended the Daiya primary health care clinic for monthly follow - up. They were among 300 patients registered in the clinic. Non Kuwaitis were excluded. A structured questionnaire was either self administered or assisted by the author in illiterate patients. The questionnaire included the characteristics of the patients (e.g., age, gender, onset of hypertension, Address correspondence to: Dr. Nadia Yousef Al-Mahmoud, Head, Ehqaqi Primary Health Care Clinic (Daiya Clinic), Shamiya, P.0. Box 12364, Kuwait 71654. Tel & Fax:433 5653 December 2006 KUWAIT MEDICAL JOURNAL Table 1: Comparison of associated factors with levels of body mass index (BMI, kg/m 2) Factors BMI < 30 (n=63)BMI ≥ 30 (n=135) p- (*) n (%) n (%) value Exercise Does exercise No exercise Snacks in the morning Eats Does not eat Snacks in the evening Eats Does not eat Diet compliance Is compliant Not compliant Family history of obesity Had family history No family history Age < 65 ≥ 65 Mean age ± 13.2 yrs Mean age at onset of hypertension ± 13.0 yrs 0.348 19 (30.2) 44 (69.8) 32 102 (23.9) (76.1) 24 (38.1) 39 (61.9) 62 72 (46.3) (53.7) 12 (19.0) 51 (81.0) 56 79 (41.5) (58.5) 41 (56.1) 22 (34.9) 52 83 (38.5) (61.5) 9 (14.3) 54 (58.7) 40 93 (30.1) (69.9) 31 (49.2) 32 (50.8) 102 33 58.2 (75.6) (24.4) 0.281 0.002 <0.001 0.017 <0.001 50.9 *p-values were generated using chi - square test, student’s and t-test to compare means. treatment, diet compliance, exercise and family history of obesity). BP was measured using a mercury sphygmomanometer and recorded in the file (taking the last three readings in file on three separate visits at least one month apart). Thereafter, patients’ weight and height were taken by the author, used physician Balance BEAM Scale and BMI was calculated. The data was entered and analyzed in SPSS (Statistical Package for Social Sciences). Chi-square test was used for the categorical variables and pvalue < 0.05 was considered as significant. Factors associated with obesity among hypertensive patients were identified using logistic regression multivariate analysis. RESULTS The mean age of patients in the study group was 58.16 ± 13.2 years, mean age at onset of hypertension 51 ± 13.0 years and mean BMI was 32.44 ± 5.50 kg/m2. It was also found that the BP was controlled in 77% patients. The patients were classified into two groups based on their BMI. Those with a BMI ≥ 30 were considered obese while those with a BMI ≤ 30 were non - obese. According to this classification, the prevalence of obesity among hypertensive patients in this sample was 68%. There was no apparent difference in gender among the low BMI patients, but among the high BMI, there seemed to be more females (75%) than 285 Table 2: Factors associated with obesity among hypertensive patients as identified by the logistic regression analysis Variable Adjusted odds ratio Evening snack No (control) Yes Diet compliance Yes (control) No Family history of obesity No (control) Yes Age (in years) < 65 ≥ 65 95% C I p-value 2.115 0.98 - 4.566 0.056 2.581 1.316 - 5.065 0.006 1.678 0.712 - 3.953 0.236 2.922 1.48 - 5.767 0.002 Dependent variable (BMI < 30 kg/m 2 = 0 ,BMI ≥ 30 kg/m 2 = 1) 95% CI = 95% confidence interval for adjusted odds ratio males (60%). Table 1 describes comparison of associated factors with level of BMI. It was observed that eating snacks in the evening was significantly associated with obesity (41% obese versus 19% non-obese). Non-compliance to a proper prescribed diet showed that 61.5% were obese compared to 34.9% non-obese. Patients in the age group < 65 years were significantly associated with obesity (75.6%). Doing exercise and eating morning snacks had no significant association with obesity in this study A multivariate analysis was done to see the combined effect of the significant factors on obesity. Table 2 describes factors associated with obesity among hypertensive patients as identified by the logistic regression analysis. This shows that non compliance to prescribed diet (p = 0.006) and age < 65 years (p = 0.002) were significant. A significant association was found between doing exercise and blood pressure control regardless of obesity. Amongst those who did exercise, 88.2% had their BP controlled whereas in those not exercising, only 74% had their BP controlled. Among the non- obese, about 73% patients could manage to control their BP with only one drug as opposed to about 52% in the obese group which was statistically significant. DISCUSSION The prevalence of obesity among hypertensive patients was 68% in our study group. This indicates that obesity is a major risk factor for the development of hypertension as indicated by previous studies [1,6,9-13]. As obesity is independently associated with hypertension, there is a strong need to address the problem among hypertensive patients. A previous study in Kuwait reported women more obese than men[14]. This was also observed in our study. 286 Prevalence and Factors Associated with Obesity and Treatment of Blood Pressure among .... December 2006 As seen in this study, compliance to prescribed diet and not eating snacks in the evening had a significant direct association with non-obesity. This should be considered as a significant non pharmacological measure to control blood pressure [7,9-10] . The current study showed that significant proportion of obese people needed two or more drugs to control their blood pressure which again calls for losing weight as an important measure. As mentioned in some other studies, weight loss can help decrease the number and dosage of drugs which can reduce side-effects and treatment costs[7,9,12,14]. In the multivariate analysis, it was found that age factor is a strong predictor of obesity and this is high among the middle age group. The mean age of onset of hypertension in the study group was 51 years. Therefore, it can be suggested that more attention should be given to this age group by the GPs as regards their health education about obesity related hypertension[9,12,15,16]. Exercise was found to play a significant role in the control of BP. Therefore, reinforcing the need to exercise is a very important part of hypertension management[9,10,17-19]. The current study thus reinforces the obvious fact that obesity is one of the prime predisposing factors for hypertension and that all necessary measures to control obesity will facilitate any treatment for this condition. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. ACKNOWLEDGEMENTS I would like to thank Dr Madhavan Ravindran, Dr Mohamed Mosa, Dr Manal Muter and Mrs. Indu Menon for their support 17. REFERENCES 18. 1. 2. Atkinson RL. A 33- year old women with morbid obesity. JAMA2000; 283:90-94. Hamann A, Sharma AM. Genetics in obesity and obesity related hypertension. Seminars in Nephrology 2002; 22:100104. 16. 19. Al-Isa AN. Temporal changes in body mass index and prevalence of obesity among Kuwaiti men. Annals of Nutritional Metabolism 1997; 41:307-749. Al-Isa AN. Body mass index and prevalence of obesity among Kuwaitis. European Journal of Clinical Nutrition 1997; 51:743-749. Al-Isa AN. Changes in body mass index and prevalence of obesity among Kuwaitis 1980-1994. International Journal of obesity 1997; 21:1093-1099. Rocchini AB. Obesity hypertension. American Journal of Hypertension 2002; 15:505-525. Zhang R, Thakur V, Morse S, Reisin E. Renal and cardiovascular considerations for the non-pharmacological and pharmacological therapies of obesity - hypertension. Journal of Human Hypertension 2002; 16:819-827. Bell AC, Adair LS, Popkin BM. Ethnic differences in the association between body mass index and hypertension. American Journal of Epidemiology 2002; 155:346-353. Al-Turki AY. The prevalence of overweight and obesity amongst hypertensive and diabetic adult patients in primary health care. Saudi Medical Journal 2000; 21:340343. MacKnight JM. Exercise consideration in hypertension, obesity and dyslipidemia. Cinical Sports Medicine 2003; 22:101-121. Engeli S, Sharma AM. Emerging concepts in the pathophysiology and treatment of obesity-associated hypertension. Current opinion in Cardiology 2002; 17:355-359. Leiter LA, Abbot D, Campbell RC, Mendelson R, Ogilive RI, Chockalingam A. Recommendations on obesity and weight loss. Can Med Assoc J 1999; 1600:S7-S11. Hall JE. The kidney, hypertension, and obesity. Hypertension 2003; 41:625-633. Saito I, Murata k, Hirose H, Tsujika M and Kawabe H. Relation between blood pressure control, body mass index and intensity of medical treatment. Hypertension Research 2003; 26:711-715. Al-Isa AN. Prevalence of obesity among adult Kuwaitis: a cross -sectional study. Internat J Obes 1995; 19:431-433. Al-Isa AN. Changes in body mass index and prevalence of obesity among adult Kuwaiti women attending health clinics. Ann Saudi Med 1997;17:307-311. Campbell RC, Burgess E, Taylor G, et al. Lifestyle changes to prevent and control hypertension: Do they work? Can Med Assoc J 1999; 160:1341-1343 Cleroux J, Feldman RD, Petrella RJ. Recommendations on physical exercise training. Can Med Assoc J 1999; 160: s21s27. Davy KP, Hall JE. Obesity and hypertension: two epidemics or one? Am J Physiol Regul Integr Comp Physiol 2004; 286: R 803- R 813. December 2006 KUWAIT MEDICAL JOURNAL Original Article Factors Influencing Outcome of Congential Diaphragmatic Hernia Bhaskar Ramgopal Gupta Department of Pediatrics and Neonatology, Special Care Baby Unit, Khoula Hospital, Muscat, Sultanate of Oman Kuwait Medical Journal 2006, 38 (4): 287-291 ABSTRACT Objective: To assess the presentation of congenital diaphragmatic hernia and to analyze the outcome of such babies according to the the prognostic indicators in a neonatal intensive care unit Design: Retrospective Material and Method: All cases of congenital diaphragmatic hernia admitted to the neonatal intensive care unit at Khoula Hospital, Muscat, Sultanate of Oman from February 1994 to February 2001 were included in the study. The antenatal factors, presentation, resuscitation and the management of these babies were reviewed and their survival according to prognostic indicators compared with similar cases in literature. Results: A total of 10 cases of congenital diaphragmatic hernia were admitted during this seven year period with an overall mortality of 80%. Gestational age ranged from 33 weeks to full term. Eight (80%) babies had severe birth asphyxia needing intubation and ventilation soon after birth and had 100% mortality. Two (20%) babies had mild birth asphyxia and presented after eight hours of life and had 100% survival. Five (50%) had polyhydramnios and three (30%) had associated anomalies. Ventilation index was < 1000 in three ( 30%) babies with a mortality of 33.3% and > 1000 in seven (70%) babies with 100% mortality. Two ( 20%) babies operated after five days had 100% survival. Severe birth asphyxia, metabolic acidosis, hypoxia, hypercarbia and early presentation of diaphragmatic hernia had high mortality. Associated persistent pulmonary hypertension (PPHN) and pneumothorax had 100% mortality. Survival was seen in those two babies who had good prognostic factors and were operated after stabilization. Conclusion: Compared to other neonatal intensive care units, mortality rate in our unit remains high in neonates presenting with congenital diaphragmatic hernia. This is due to lack of newer modes of ventilation, nitric oxide therapy and extracorporeal membrane oxygenation (ECMO). KEY WORDS: congenital diaphragmatic hernia, prognostic indicators, ventilation index INTRODUCTION Congenital diaphragmatic hernia (CDH) is a disorder characterized by failure of the pleural and peritoneal canal to close approximately at eight week of gestation. This leads to displacement of the abdominal contents into the thoracic cavity resulting in pulmonary hypoplasia due to compression of the developing lungs by the viscera. Hernias through the posterolateral aspect of the diaphragm ( Foramen of Bochdalek) account for approximately 80% of hernias, and hernias on the left side are five times more common than on the right side. With the increased use of obstetric ultrasound, prenatal diagnosis of these hernias is common. Neonates present with asphyxia, respiratory distress, cyanosis and scaphoid abdomen. Those who develop respiratory failure within the first six hours of life have the highest mortality. Despite the advances in neonatal intensive care and ventilation the mortality remains frustratingly high. Various prognostic indicators have been suggested for survival of babies with CDH. These include birth weight, APGAR scores, age of presentation, associated congenital anomaly and ventilatory parameters like ventilation index, pCO2, pO2 and oxygenation index. Other indicators are complications like pneumothorax, persistent pulmonary hypertension (PPHN) and also types of therapies used like hyperventilation, drugs and extracorporeal membrane oxygenation (ECMO). In the past, babies with CDH were rushed immediately to the operating room without stabilization, but all the recent practice is to stabilize these patients first especially with the use of ECMO which has lead to significant improvement Address correspondence to: Dr Bhaskar Ramgopal Gupta, M.B.B.S,M.D. (Pediatrics), Pediatrician & Neonatologist, Yiaco Apollo Medical Center, Post Box 24098, Safat 13101, Kuwait. Tel No: 00965-5648040, Ext 108, Fax: 00965-5646070, E-mail: [email protected] 288 Factors Influencing Outcome of Congential Diaphragmatic Hernia Table 1: Antenatal and perinatal factors affecting mortality in babies born with CDH No. of Babies n (%) 1. Type of delivery Spontaneous vaginal delivery Emergency LSCS 2. Sex Male Female 3. Gestation Preterm Term 4. Birth Weight < 2.5 kg > 2.5 kg 5. Associated anomalies 6 Antenatal Ultrasound Polyhydramnios Diaphgrmatic hernia Not done Table 2: Factors influencing mortality in diaphragmatic hernia Mortality n (%) 8 (80) 2 (20) 6 (75) 2 (100) 6 (60) 4 (40) 4 (66.6) 4 (100) 2 (20) 8 (80) 2 (100) 6 (75) 2 (20) 8 (80) 3 (30) 2 (100) 6 (75) 3 (100) 5 (50) 3 (30) 2 (20) 5 (50) 3 (100) 1 (50) in outcome. Now the emphasis is on ventilatory strategies that minimize airway pressure and reduce barotrauma to the severely hypoplastic lungs. This retrospective analysis over a period of seven years of all babies with CDH born at Khoula Hospital Muscat, Sultanate of Oman was undertaken at a neonatal intensive care unit (NICU) where no ECMO or pediatric surgical facilities were available. The aim was to determine the presentation of congenital diaphragmatic hernia and its outcome in these babies. METHODS All babies born at Khoula Hospital from February 1994 to February 2001 with the diagnosis of CDH and admitted to the NICU were included in the study. Their case notes were retrieved and analyzed for the antenatal presentation and the postnatal outcomes. All babies were ventilated with pressure controlled, timed cycled positive pressure ventilators (Bear Cub, Sechrist and Drager ventilators). The sex of the baby, gestation, type of delivery, antenatal ultrasound for congenital anomalies, initial APGAR, the need for resuscitation and their anthropometric measurements were noted. All the babies were shifted soon after birth to the NICU and the age of presentation of the diaphgrmatic hernia was noted. Oxygen needs and ventilatory requirements like maximum pressure, oxygen and ventilation index was calculated. Arterial blood was collected and analyzed by Blood gas analyzer for initial pH, pO2, pCO2 and base excess. Ventilation and electrolytes monitoring December 2006 1. Birth Asphyxia Severe Mild 2. Time of presentation Soon after birth > 8 hours after birth 3. Site of hernia Left Right 4. Associated PPHN 5. Pneumothorax No. of Babies n (%) Mortality n (%) 8 ( 80) 2 (20) 8 (100) 0 (0) 8 (80) 2 (20) 8 (100) Nil (0) 8 (80) 2 (20) 8 (80) 3 (30) 7 (87) 1 (50) 8 (100) 3 (100) of all these babies during their stay in the NICU was done according to the unit protocols. The criteria for conventional ventilation included severe persistent metabolic acidosis, pO2 < 60 mmHg and progressively rising pCO2 > 60 mmHg. All babies had a peripheral arterial line for blood sampling. Monitoring of these babies was done by continuous recording of heart rate, temperature, pulse oximetry, respiratory rate and blood pressure recordings on a Hewlett Packard cardiac monitor. Repeated blood gas analysis according to the changes in ventilation and complete blood counts, electrolyte and blood sugar monitoring was done. Additional management of some babies with PPHN consisted of applying modalities like use of drugs such as tolazoline and prostacyclin. The response to treatment and complications of ventilation like associated pneumothorax was noted and final outcome was analyzed. As the NICU at Khoula Hospital had no facilities for pediatric surgery, the neonates were stabilized and then shifted on a transport ventilator ( D r a g e r ) to a tertiary care NICU at the Royal Hospital where they were managed by a team of pediatric surgeons and neonatologists. The time of transfer, operative management and associated mortality was also assessed. All these data was analyzed for the incidence of CDH during these seven years, its presentation and outcome. RESULTS During the seven year period from February 1994 to February 2001, there were a total of 30,157 live-born babies at Khoula hospital out of which ten had CDH. Six (60%) were female and four (40%) male. Gestational ages of these babies ranged from 33 weeks to full term. Two out of them were preterm. Eight (80%) babies were born by normal vaginal delivery and two (20%) by emergency LSCS. Polyhydramnios was noted in five (50%), December 2006 KUWAIT MEDICAL JOURNAL Table 3: Initial blood gas parameter and mortality in congenital diaphragmatic hernia No. of Babies n (%) 1 pH <7 7 (70) 7 - 7.2 2 (20) > 7.2 1 (10) 2. pO2 30-60 mm of Hg 8 (80) > 60 mm of Hg 2 (20) 3. pCO 2 > 60 mm of Hg 6 (60) < 60 mm of Hg 4 (40) 4. Severe metabolic acidosis 8 (80) 5. Ventilation Index (MAPx Respiratory rate) < 1000 3 (30) > 1000 7 (70) Table 4: Interventions and mortality in diaphragmatic hernia Mortality n (%) 7 (100) 1 (50) Nil (0) 8 (100) Nil (0) 6 (100) 2 (50) 8 (80) 1 (33.3) 7 (100) diaphragmatic hernia noted antenatally in three (30%) and associated anomalies in the form of dysmorphic features and cardiovascular anomalies in three (30%) babies (Table 1). Eight (80%) babies had severe birth asphyxia needing intubation and ventilation soon after birth with 100% mortality. Two (20%) babies had mild birth asphyxia and presented late (after 8 hours) and had 100% survival. Left sided hernia was seen in eight (80%) cases out of which seven (87%) died and right sided hernia in two cases out of which one (50%) died. PPHN was present in eight (80%) cases with 100% mortality and pneumothorax in three cases with 100% mortality (Table 2). Conventional ventilation was used in all babies using Bear Cub, Sechrist or Drager ventilators and drugs like tolazoline and prostacyclin were used in four (40%) babies with 100% mortality. Blood gas analysis showed that seven (70%) babies with an initial pH < 7 had 100% mortality. Two babies (20%) had a pH between 7-7.2 with 50% mortality and one baby (10%) with a pH > 7.2 survived. Eight babies (80%) with an initial pO2 of 30-60 mmHg had 100% mortality. Those with a pO2 > 60 mmHg (2 babies, 20%) survived. Six babies (60%) with a pCO2 > 60 mmHg died whereas four babies (40%) with a pCO2 < 60 mmHg showed a 50% mortality. Severe metabolic acidosis with base excess of more than -15 was seen in eight (80%) cases with 100% mortality. Ventilation Index, a ratio of mean airway pressure x respiratory rate was < 1000 in three (30%) babies with a mortality of 33.3% and > 1000 in seven (70%) cases with a mortality of 100% (Table 3). Six (60%) babies were stabilized and transferred to a tertiary care unit with a pediatric surgical service and four (40%) were operated. Two (20%) 289 No. of Babies n (%) 1. Age at ventilation Soon after birth > 8 hrs after birth 2. Type of ventilation Conventional Conventional with tolazoline/ prostacyclin 3. Transfer to tertiary care hospital Transferred Not transferred 4. Operated 5. Age of surgery < 5 days > 5 days Overall Mortality Mortality n (%) 8 (80) 2 (20) 8 (100) Nil (0) 10 (100) 8 (80) 4 (40) 4 (100) 6 (60) 4 (40) 4 (40) 4 (66.6) 4 (100) 2 (50) 2 (20) 2 (20) 10 (100) 2 (100) Nil (100) 8 (80) were operated within five days of birth and both died while the other two operated later survived. Four (40%) babies could not be transferred as they could not be stabilized and died at Khoula Hospital. PPHN was present in eight (80%) cases with 100% mortality and pneumothorax in three (30%) cases with 100% mortality. Conventional ventilation was used in all babies and drugs like tolazoline and prostacyclin were used in four (40%) cases with 100% mortality. The overall mortality was eight (80%) and those who survived presented late and were operated upon after the 1st week of life (Table 4). DISCUSSION The infant born with CDH presents a challenge and remains one of the most complex patients to manage. Pulmonary hypoplasia and immaturity of the lung are well-recognized definitive limitations leading to high mortality rates [1]. Congenital diaphragmatic hernia is a well-known condition for almost 200 years but its treatment strategy has changed during the past few decades. Despite these improvements the mortality rates remain frustratingly high (> 50%), especially for those presenting in the first six hours of birth[2,3]. We analyzed our experience with this condition over the last seven years in our NICU where no facilities for high frequency ventilation or ECMO were available. After the initial ventilation and stabilization these babies had to be transferred to a pediatric surgical unit in other hospital. The incidence of congenital diaphragmatic hernia in our unit was 1:3000 live births which corelates well to that reported in the literatur e. National Maternity Hospital in Dublin, Ireland reported an incidence of 1:2107 after a review of 290 Factors Influencing Outcome of Congential Diaphragmatic Hernia 99,000 patients[4]. Left sided hernia was seen in 80% cases which is similar to our finding[5]. Gestational age analysis revealed that most of our babies (80%) were term babies. Polyhydramnios was seen in 50% cases. Three of our babies were diagnosed antenatally as cases of CDH and were referred for delivery to a center with pediatric surgical facilities. But they came in labor at our institute and the babies had 100% mortality. In most centers, antenatal diagnosis with sonography is accurate in 88-94% cases as reported by Bell et al who also found polyhydramnios in most of their cases[6]. Three (30%) babies had associated anomalies in the form of dysmorphic features of Trisomy 18, hydrocephalus and ventricular septal defect with 100% mortality in this group. Associated anomalies are present in 35% of cases out of which cardiac lesions predominate and infants with associated anomalies have a low APGAR, lower pO2 and poor prognosis[7]. The Iowa city birth defects registry noted that 28% of babies with CDH had associated anomalies like meningocele, encephalocele, hydrocephalus, ventricular septal defect, vascular rings, trisomy 13 and 18, omphalocele and had poor survival rates (5%) [8]. Eight (80%) babies presented soon after birth and had severe birth asphyxia needing intubation. They were ventilated soon after birth with conventional ventilation at high parameters. This group with early presentation and low APGAR had 100% mortality. Two (20%) babies presented after eight hours and survived. The CDH study group from the department of surgery, University of Texas, Houston estimated the disease severity in first five minutes of life. Survival data on 322 consecutive live-born infants with CDH were collected from 71 institutions and factors associated with the outcome like birth-weight, APGAR score, gestational age, age at presentation and associated cardiac anomaly was analyzed. In their study APGAR score was found to be the most useful predictive equation which correlated well with the poor outcome[9]. Blood gas analysis was done on all babies soon after birth and an initial pH < 7 was seen in seven (70%) babies with 100% mortality. Mishalany et al analysed 55 patients with CDH and found that those with uncorrected pH of < 7 had 100% mortality in their series whereas those with a pH between 7 - 7.2 had 50% mortality. Early surgery and correction of acidosis did not improve the survival. They concluded that initial pH was of great prognostic importance[10]. Initial pO2 of < 60 mmHg was seen in eight (80%) of our babies with 100% mortality and > 60 mmHg in two babies who survived. December 2006 Several reports documented the fact that an initial pCO 2 of > 40 mmHg is associated with high mortality rate (between 75-100%)[11,12,13]. The outcome of CDH presenting in first six hours of life correlates to the degree of pulmonary hypoplasia as indicated by preoperative index of ventilation which if >1000 indicates a very high mortality. Ventilation index, a ratio of mean airway pressure x respiratory rate was < 1000 in three (30%) cases with 33.3% mortality and > 1000 in seven (70%) cases with 100% mortality. Bohn et al observed that when ventilation index in their series of 66 infants was > 1000 the mortality was 50%. Associated PPHN was seen in eight (80%) babies from our series with 100% mortality. Three (30%) babies developed pneumothorax with 100% mortality. Chou et al in their review of 32 babies found very high mortality rates with associated pneumothorax and PPHN. Due to lack of facilities of hyperventilation and ECMO in our unit all the babies were put on conventional ventilation. Drugs like tolazoline and prostacyclin, which are thought to reduce PPHN, were tried in four (40%) cases with 100% mortality. In a study by Bos et al, in 52 high risk babies with CDH who needed ventilation within six hours with documented PPHN in 21 (46%) cases, tolazoline did not reduce the oxygen index or alveolar arterial oxygen difference[14]. Out of six babies who were transferred, four (40%) were operated upon. Two (20%) were less than five days old and had 100% mortality while the other two babies (20%) were more than five days old and survived. The primary problem in these babies is respiratory failure not due to lung compression by the herniated viscera but due to pulmonary hypoplasia and associated pulmonary hypertension. Weber et al compared the survival rates of the three eras of management of CDH on 203 neonates. In era 1 with immediate repair the survival was 42% as compared to era 3 in which there was delayed repair of CDH with ECMO where the survival rate was 96%[13]. David et al evaluated the impact of non-standard ventilatory strategy on survival in CDH and concluded that hyperventilation with alkalinisation had a detrimental effect and should be abandoned and that the survival rates of delayed surgery and ECMO were significantly higher [15]. Ventilatory strategies that minimize airway pressure reduce the barotrauma and lung injury to the severely hypoplastic lungs, thereby improving survival of babies with CDH. Gentle ventilation which allows arterial pCO2 to be slightly higher than normal (permissive hypercapnia) and marginal post-ductal oxygenation are associated with higher survival rates than conventional ventilation. ECMO is most successful when used December 2006 KUWAIT MEDICAL JOURNAL for reversible pulmonary diseases like PPHN, meconium aspiration or PFC. In diaphragmatic hernia, ECMO has been used successfully to prevent barotrauma from mechanical ventilation and allow vasculature remodeling and thereby stabilize the baby before surgical repair. Due to underlying pulmonary hypoplasia in diaphragmatic hernia, the gain by ECMO is not substantial as compared to that in meconium aspiration syndrome. Comparative data by Ann Arbor, Michigan ECMO organization study in 1997 indicated that out of 4519 babies treated with ECMO for meconium aspiration, 94% survived as compared with only 54% survival out of 2627 babies treated for diaphragmatic hernia. CONCLUSION CDH due to its fundamental complex problems of pulmonary hypoplasia and hypertension still remains a management challenge with its high mortality. As compared to other studies the mortality rates in our study was quite high due to non-availability of newer modes of ventilation and ECMO and delay in stabilization and transfer of such neonates. REFERENCES 1. 2. 3. Muratore CS, Wilson JM. Congenital diaphragmatic hernia: where are we and where do we go from here? Semin Perinatol 2000; 24: 418-428. Juretschke LJ. Congenital diaphragmatic hernia: update and review. J Obstet Gynecol Neonatal Nurs 2000; 30:259268. Ruff SJ, Campbell JR, Harrison DF, et al. Pediatric 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 291 diaphragmatic hernia, an eleven-year experience. Am J Surg 1980; 139:641-645. Puri P, Gowman WA. Natural history of congenital diaphragmatic hernia : Implications for management. J Pediatr Surg 1984; 19:394-397. Anderson KD. Congenital diaphragmatic hernia. In Raviton MM. Ped Surgery, 4th ed, Chicago Year book Publisher Inc, p 1986. Bell MJ, Temberg JL. Antenatal diagnosis of diaphragmatic hernia. Pediatr 1977; 60:738-742. Fauza DO, Wilson JM. Congenital diaphragmatic hernia and associated anomalies: their incidence, identification and impact on prognosis. J Pediatr Surg 1994; 29:1113-1117. Wenstorm KD. Weiner CP, Hanson J. A 5-year statewide experience in congenital diaphragmatic hernia. Am J Obstet Gynecol 1991; 165: 838-842. Department of Surgery, University of Texas-Houston Medical School : Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. The congenital diaphragmatic hernia study group. J Pediatr Sur 2001; 36:141-145. Mishalany HG, Nakada K, Woolley MM. Congenital diaphragmatic hernia: eleven years experience. Arch Surg 1979; 114:1118-1123. Chou HC, Tang JR, Lai HS, et al. Prognostic indicators of survival of infants with congenital diaphragmatic hernia. J Formos Med Assos 2001; 100:173-175. Bohn D, Tamura M, Perrin D, et al. Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphological assessment. J Pediatr 1987; 111:423-431. Weber TR, Kountzman B, Dillon PA, Silen ML. Improved survival in congenital diaphragmatic hernia with evolving therapeutic strategies. Arch Surg 1998; 133:498-502. Bos AP, Tibboel D, Koot VC, Hazebroek FW. PPHN in high risk congenital diaphragmatic hernia patients: incidence and vasodilator therapy. J Pediatr Surg 1993; 28:1463-1465. David W Kays, Maz R Langham, Danile J, et al. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999; 230(3). KUWAIT MEDICAL JOURNAL December 2006 Original Article Anomalous Coronary Artery from the Opposite Coronary Sinus in Young Children Mustafa A Al-Qbandi1, Jeffrey Smallhorn2 Department of Pediatrics and Congenital Heart Diseases, Chest Disease Hospital, Kuwait Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Ontario, Canada 1 2 Kuwait Medical Journal 2006, 38 (4): 292-299 ABSTRACT Objective: To report the management of anomalous coronary artery (ACA) from the wrong aortic sinus and review the literature Background: ACA is a rare congenital lesion. It is associated with sudden death, particularly in young adolescents. Design: Retrospective study (1990 - 2004) Methods: All patients with interarterial single coronary artery arising from the aortic sinus were studied. Seven patients were identified. Transthoracic and transesophageal echocardiography were performed using high frequency transducers. Other tests used were: A 12-lead echocardiogram, 24-hour Holter, coronary angiography, exercise and Dobutamine stress testing and single-photon emission computed tomographic myocardial scintigraphy (SPECT). Extracorporeal membrane oxygenation (ECMO) was used for severe left ventricular dysfunction. Results: There were five boys and two girls. All had an intramural course of the coronary arteries. Their age range was between 2 weeks to 15 years. In four out of seven cases, it was an anomalous left coronary artery from the right anterior aortic sinus (ALCA-RAS). The other three cases were of an anomalous right coronary artery from the left aortic sinus (ARCA-LAS). In one patient, Doppler evidence of the intramural coronary artery stenosis was documented at cardiac arrest and ECMO support was needed. Conclusion: As part of first echocardiography study, all patients, regardless of their age, should have their coronary arteries screened in the echocardiography laboratories. Once coronary artery abnormalities are detected (i.e., arising from opposite sinus), efforts should be made to look for any evidence of ischemia either through noninvasive or invasive techniques. Anomalous left coronary origin from the right sinus of Valsalva can result in significant myocardial ischemia and infarction. KEYWORDS: anomalous coronary artery, echocardiography, intramural coronary artery INTRODUCTION The origin of one of the coronary arteries from the wrong aortic sinus of Valsalva with a proximal course between the aorta and pulmonary artery is a rare congenital lesion[1-4] (Fig. 1). The incidence of ectopic coronary origin from the aorta in the population is unknown. Its estimates in cardiac catheterization laboratory populations approximate 0.6%[5]. It is associated with life-threatening conditions or sudden death, particularly in young adolescents[6-8] where the majority of cases are diagnosed at autopsy[4;6] [9-11]. Some authors[12] report that this anomaly is the second most common cause of sudden death among young athletes. The diagnosis is usually made either after an acute event, or more recently as an incidental finding on routine echocardiography screening for other forms of congenital heart disease. We report seven cases where routine screening by echocardiography detected this anomaly and discuss potential management implications in this group. Also, we describe the findings in a case who presented with a sudden cardiac event. METHODS From our database (n Kuwait and Canada) we identified all cases of ALCA from the wrong aortic sinus between1990-2004. All patients represented incidental cases that were being evaluated for reasons not associated with the abnormal coronary artery. The following tests were performed: l Echocardiography: A complete transthoracic two-dimensional echocardiogram was performed in each case using an Advanced Technology Laboratory (HDI 5000) or a Hewlett Packard (HP 5500) imaging system utilizing high frequency transducers. In three cases, transesophageal echocardiography was utilized to obtain further images of the abnormal coronary artery as well as Doppler velocity profiles. Address correspondence to: Dr. Mustafa A. Al-Qbandi DCH, FAAP, FRCPC, Department of Pediatric and Congenital Heart Diseases, Chest Disease Hospital, P.O.BOX: 4082, Safat, 13081, Kuwait. Tel: +965- 4829613, Fax: +965- 4829613, E-mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL 293 Table 1: Summary of the cases of ACA Case Age Sex Diagnosis Symptoms 12-Lead ECG EchoCardiography Angio- DSE graphy Myocardial Outcome Perfusion scan 1 2 2-weeks 4 years M F ALCA-RAS ALCA-RAS Murmur Cardiac arrest TTE TTE&TEE No No No No No No 3 4 10 years 14 years M M ALCA-RAS ALCA-RAS TTE&TEE TTE Yes Yes Yes No Yes Yes Alive Death post surgery Alive Alive 5 6 7 15 years 8 years 2-weeks M M F ARCA-LAS ARCA-LAS ARCA-LAS Murmur Pre-renal transplant assessment Near syncope Murmur Murmur Normal Severe ST-depression& Left anterior hemi block Normal Normal Normal Normal Normal TTE&TEE TTE TTE Yes No No Yes No No No No No Alive Alive Alive ALCA-RAS = anomalous left coronary artery from right aortic sinus, ARCA-LAS = anomalous right coronary artery from the left aortic sinus DSE = dobutamine stress echocardiography, F = female, M = male, TEE = transesophageal echocardiography, TTE = transthoracic echocardiography l 12-lead ECG: All patients had a resting electrocardiogram (ECG). l 24-hour Holter: A Holter monitor was performed in four cases. l Exercise testing: An exercise stress test was done in two cases. l Coronary angiography: In three cases, selective coronary artery angiograms were done. l Dobutamine stress test: This was done in two cases. l Single-photon emission computed tomographic myocardial scintigraphy (SPECT): Performed with intravenous administration of 99mTc-Sestamibi during exercise and at rest 24 hours later in two cases. Extracorporeal membrane oxygenation (ECMO) was used in one patient for severe left ventricular dysfunction presenting with evidence of myocardial infarction and life threatening arrhythmia leading to cardiac arrest. RESULTS Presentation and clinical features Seven patients were identified (Table 1). Their ages ranged between two weeks to 15 years (median = 10 years) and there were five males and two females. Anomalous left main coronary artery from the right aortic sinus was identified in four cases and anomalous right coronary from the left sinus in three. There was only one death (case 2) during the course of the study. In four cases, the reason for referral was a cardiac murmur, in one it was for evaluation of a patent ductus arteriosus in a neonate with subsequent surgical ligation (case 1). An episode of near syncope was the reason for referral (case 6), which was initially felt to be vasovagal. This patient had no complaints of chest pain or palpitations. In case 4 the patient had the abnormality detected as part of a pre-renal transplant assessment in a case with nephrosclerosis. The last patient (case 2) had a Fig. 1: Coronary artery sketch: Fig.1-1: Normal coronary artery anatomy where the left coronary artery arises from the left aortic sinus and the right coronary artery arises from the right coronary sinus (appropriate sinuses). Fig. 1-2: Origin of the right coronary artery from the left aortic sinus. Fig. 1-3: Anomalous left coronary artery from the right aortic sinus. Notice the abnormal course and compression of the segment of the coronary artery between the aorta and the pulmonary artery (inappropriate sinuses). Ao = Aorta, PA= Pulmonary artery, L=Left, R=Right, N=non-coronary cusp, LAD=Left anterior descending, Cx= Circumflex artery, RCA= Right coronary artery. sudden cardiac event outside our institution where the diagnosis was made by an outside pediatric cardiologist in the emergency room. The patient was subsequently transferred to our intensive care unit for further management and required ECMO support for low cardiac output. All patients were not related to one ethnic group. Incidentally, all patients who were referred for evaluation of a cardiac murmur turned out to have an innocent murmur. Parents reported no similar problem in their close families. All patients had no birth defects. Only one patient (case 1) had PDA ligation and no other associated cardiac defects were detected in others. To date, none of the patients on follow up required surgery, except for the deceased one (case 2). Electrocardiograms (ECG’s) and exercise tests: All were normal at presentation except in case 2, which demonstrated severe ST-segment depression in all the precordial and inferior leads with evidence of left anterior hemi-block. All recorded 24-hour Holter monitors and exercise tests were normal. Echocardiography: All patients were diagnosed initially by transthoracic echocardiography (Table 1 and 2). In three cases transesophageal echocardio- 294 Anomalous Coronary Artery from the Opposite Coronary Sinus in Young Children Fig. 2: (A) Parasternal long axis view through the aortic root in a boy with anomalous left main coronary artery (LMCA) with an intramural segment of the LMCA giving the double border appearance of the aortic wall (arrowhead). Seen is a single ostium with an origin from the right coronary cusp. Right coronary artery=RCA, aorta=Ao, left ventricle=LV, right ventricle=RV. Table 2: Summary of echocardiographic features Parameter ALCA-RAS ARCA-LAS Origin Ostium Orifice (3D-image) Intramural Proximity to commissure 2D image: Parasternal long axis RAS Mostly large single Rounded or slit-like Segment course long interarterial close LAS Usually two separate Mostly slit-like Short interarterial Very close Parasternal short axis Doppler color flow Spectral Doppler flow Double border appearance of aortic wall Take off at 10 o’clock at 110 degrees followed by acute angle LMCAtake off (hockey-stick appearance) Aliasing usually seen before LMCAbifurcation Usually low pandiastolic & Slightly increased systolic flow No Take off at 12 or 1 o’clock at 160 degrees December 2006 Fig. 2:(B) Parasternal short axis view showing the intramural segment of part of the long course of the left main coronary artery (arrowheads). Aorta=Ao, pulmonary artery=PA. intramural segment was clearly seen in all cases. In those patients with anomalous right coronary artery from the left aortic sinus, the parasternal long axis view did not show the double border appearance of the aortic wall. The parasternal short axis view revealed the slit like orifice of the anomalous right coronary artery, which was even more clearly demonstrated by transesophageal and three-dimensional echocardiography (Fig. 3 A & B). In both cases the orifice was very close to the commissure between the right and left sinuses which was in contrast to cases with anomalous origin of the left coronary artery from the right aortic sinus. (spear-like appearance) No Normal flow pattern ALCA-RAS= Anomalous left coronary artery from right aortic sinus ARCA-LAS= Anomalous right coronary artery from left aortic sinus LMCA= left main coronary artery graphy was performed to further delineate the anatomy including a 3-dimensional reconstruction in case 1. In those patients with anomalous left coronary artery from the right aortic sinus the parasternal long axis view demonstrated the large single ostium, which then bifurcated into right and left main coronary arteries. The left main coronary artery then ran between the aorta and pulmonary artery with an intramural segment within the aortic wall resulting in a double border appearance of the anterior aortic wall (Fig. 2A). Similarly, the parasternal short axis view demonstrated a single large ostium that arose from the right anterior aortic sinus, which then bifurcated, into right coronary artery and a long interarterial / intramural segment (Fig. 2B). In all cases the left main coronary artery formed an acute angle with its origin. The Doppler flow patterns: Two spectral Doppler flow characteristics were identified. Firstly, in those with no evidence of obstruction the appearance was that of low velocity diastolic flow with a short but slightly increased systolic flow velocity. This appearance correlated with mild color aliasing seen in the intramural segment of the left main coronary just proximal to its bifurcation (Fig. 4 A & B). In the case with a cardiac event there was clear evidence of an obstructive flow pattern in the intramural segment, with laminar flow in the proximal interarterial segment. Of interest, this was only seen on the transesophageal study, as the intramural segment of the left coronary artery was stenotic and difficult to image from the transthoracic location. As the left main coronary artery exited from its intramural course, the vessel and its proximal branches became dilated with evidence of re-laminization of the Doppler flow signal. Spectral Doppler flow showed a high velocity systolic and diastolic flow pattern in the intramural segment with the former being 40 cm/sec and the latter 180 cm/sec. Of note, the spectral pattern at the site of origin of the left coronary artery and in the dilated segments December 2006 KUWAIT MEDICAL JOURNAL 295 Fig. 3: (A) Transesophageal echocardiographic image at mid-esophagus in short axis view at the level of aortic sinuses showing the three sinuses and the origin of the right coronary artery (RCA) from the left aortic sinus. Note the proximity to the anterior commissure. Fig. 3: (B) Three-dimensional image of the coronary artery ostia in a case of ARCA-LAS. This shows the slit-like orifice of the anomalous right coronary artery and rounded orifice of the left main coronary artery, both originating from the left coronary sinus. Fig. 4: (A) A normal spectral Doppler flow pattern seen in the anomalous left main coronary artery. A pandiastolic (D) and a short systolic (S) flow are seen. This shows a non-obstructed flow pattern. demonstrated a lower velocity pattern. (Fig. 5 A& B). M-Mode: All patients (except case 2) had normal cardiac systolic and diastolic functions at first study and on follow up. All cardiac chamber dimensions were also normal. In case 2, the patient presented with severe left ventricular dysfunction and wall motion abnormalities of the anterolateral wall. Her left ventricular ejection fraction was 5-10% requiring ECMO support. Angiography: Three cases (3, 4, and 5) underwent selective coronary angiography. The angiographic pictures correlated well with echocardiographic images and did not add any additional information (Fig. 6). Dobutamine stress echocardiography (DSE): Two cases (3 & 5) underwent this type of study to look for any evidence of wall motion abnormalities or ischemic changes. In case 3, the DSE was interpreted as demonstrating mild hypokinesia involving the apical anterior wall and the mid anterior septum. With an increasing dose of Fig. 4: (B) Doppler color flow mapping in the same patient, which shows very slight color aliasing of the intramural segment of the left main coronary artery (LMCA). Dobutamine, there was progressive increase in contractility involving all segments, apart from those mentioned above which remained mildly hypokinetic, though improved compared to baseline. This was interpreted as consistent with prior myocardial damage. In case 5, the study was interpreted as being normal. Myocardial perfusions scan: In two cases (3 & 4) single-photon emission computed tomographic myocardial scintigraphy (SPECT) was performed with intravenous administration of 99mTc-Sestamibi during exercise and at rest 24 hour later. Both showed no evidence of perfusion defects. 296 Anomalous Coronary Artery from the Opposite Coronary Sinus in Young Children Fig. 5: (A) In comparison to the case in Fig. 3, severe stenosis of the interarterial, intramural segment of the left main coronary artery before its bifurcation in a patient who presented in cardiac arrest. The transesophageal Doppler color flow pattern showing color aliasing at the stenotic intramural segment. December 2006 Fig. 5: (B) Spectral Doppler flow wave showed high peak diastolic and systolic velocities, which did not change with intravenous injection of nitroglycerine. Fig. 7: Histology specimen showing the severe fibrointimal proliferation of the intramural segment resulting in severe stenosis. Fig. 6: Right anterior oblique projection of the single coronary angiograms. This shows an unusually long segment of the left main coronary artery initially coursing posteriorly. Surgery: Only one patient underwent surgery (case 2). After a brief period of stabilization on ECMO for severe left ventricular dysfunction, the patient underwent surgical reimplantation of the anomalous left coronary artery. A vertical incision was made in the distal non- intramural segment of the left coronary artery (LCA) proper, which appeared thin-walled and measured 2-3 mm in diameter. A direct tissue connection was made between the inferior apex of the vertical aortic incision and the corresponding incision in the LCA. The anterior aspect of the connection between the LCA and the ascending aorta was augmented with a triangle-shaped patch of autologous pericardium. The segment of LCAbetween the origin of the LCA and the reconstructed LCA was not interrupted surgically with the LCA reimplantation. This patient died within 48 hours of surgical repair. The autopsy revealed severe and diffuse left ventricular myocardial infarction and a single coronary artery that arose from the right anterior sinus. The left main coronary artery was intramural in its course and showed stenosis at the segment just prior to LMCA bifurcation. The new LMCA ostium was narrowed at its suture line. Histological section of the narrowed intramural segment showed evidence of severe fibrointimal proliferation (Fig. 7). DISCUSSION When the left coronary artery arises from the right sinus of Valsalva and courses between the aorta and pulmonary artery, it invariably assumes an intramural course as it enters the aortic wall at an acute angle with typical flattening of the lumen[6;13;14]. This anomaly has strong predominance in males with rare occurrences in females. Patients often have a slit-like orifice of the LMCA origin or valve-like ridges at the ostium[4,6,10]. The angiographic December 2006 KUWAIT MEDICAL JOURNAL findings demonstrate an end-on origin of the LMCA followed by a posterior, cranial, and leftward course[3,15,16]. Dynamic systolic compression of the intramural portion of the LMCA has been observed during angiography and may potentially contribute to periods of ischemia. Taylor et al[11,17], reported that younger patients (less than or equal to 30 years of age) with an isolated coronary artery anomaly are at risk of dying suddenly and with exercise. The association of this anomaly with exercise-related sudden death has been explained by three factors[14,18]: Firstly, an outward expansion of the roots of both the aorta and pulmonary trunk during exertion, which can cause further compression of the ostial lumen of the anomalous artery; Secondly, the anomalous vessel can be compressed against the root of the pulmonary trunk, where it is firmly anchored to the infundibular septum, when the pulmonary trunk and the aortic root dilate during exertion; Thirdly, myocardial oxygen requirements increase with exertion and the consequence of myocardial ischemia may trigger life threatening ventricular arrhythmia and sudden death. Jureidini and associates[9,19] reported color Doppler mapping of the anomalous course of the LMCA between the aorta and pulmonary artery in a child. In our series, it is clearly demonstrated that a careful echocardiographic search for coronary anomalies can aid in their detection. Indeed the routine in our laboratory is to evaluate the coronary arteries in all new cases. If the anomaly is suspected and transthoracic echocardiographic images are not clear, then transesophageal echocardiography should be performed after the patient is stabilized[20]. Simply, identifying a coronary artery between the two arterial roots does not necessarily imply an intramural segment [21]. Although we maintain that angiography remains the current “gold standard’’, magnetic resonance imaging (MRI) and ultrafast computed tomography may be useful adjunctive tests. MRI showed a complimentary role and appears a promising tool for identifying such anomalies [18,22]. Recently, intravascular ultrasound and pressure-wire methods have been used for sub-classifying anomalous coronary arteries from opposite sinus and other coronary anomalies[14]. The role of stress evaluation as a predictor of ischemia in these cases when detected as an incidental finding is unclear. Although we have been using dobutamine as our agent of choice in pediatric patients, adenosine, arbutamine or dipyridamole are other agents used frequently in adult patients[13,23,24]. There is, however, enough data to support Dobutamine stress test in patients with Kawasaki disease[25]. In case 2, it was recommended 297 to the family that PET (positron emission tomography) might be useful adjunct as this has the added advantage of assessing both flow and metabolic activity[26]. While the diagnosis of this lesion has been facilitated by careful echocardiographic evaluation of the coronary arteries [27], the indication for intervention is less clear. The use of extracorporeal membrane oxygenation (ECMO) is justified in certain cases with severely reduced ventricular systolic function as a bridge to heart transplantation[28]. Certainly, in those with evidence of ischemia the need for surgical intervention is fairly clear. However, in pediatric patients where the finding is incidental, with no evidence of ischemia at rest or on stress, the argument for intervention is less compelling. This relates to the lack of long term data in those young patients who have undergone surgery, versus the natural history in a case where the finding is incidental. Although there are multiple case reports of the relationship between this lesion and ischemia, there are no studies that address the frequency of ischemia in asymptomatic patients. There is medium term data in complete transposition of great arteries and an intramural left coronary artery [29]. Although an arterial switch is the current treatment of choice, postoperative ischemia is far more prevalent than cases with the more usual coronary artery patterns[30,31]. One could argue that there are younger patients than the majority of cases identified with an intramural left coronary artery, however, a comparison of the natural history versus treated population are absent. The operative repair is the one described by Mustafa and colleagues[13,32] in which the intramural segment of the LMCAis unroofed after detachment of the intercoronary commissure, with creation of a neocoronary ostium in the left sinus of Valsalva. Subsequently, the intercoronary commissure is resuspended. In adult population, the incidence of late cardiac events (late cardiac death, re-operation, myocardial infarction) was lower in patients who received internal thoracic artery graft versus saphenous vein graft and had better survival rate at eight years (91.1% versus 85.3%, respectively)[33]. In contrast, long-term patency and re-operation rates have yet to be determined in the pediatric population. On the basis of a literature review and their own experience with this lesion, Liberthson et al[5] have found that the average age of the 20 reported patients who died suddenly was 16 years (range 1 - 36 years). All of their six older patients (age 36 to 70 years) with this anomaly had angina pectoris and atherosclerotic vessels. This difference may relate to the more rigid coronary arteries in an older individual being less susceptible to torsion 298 Anomalous Coronary Artery from the Opposite Coronary Sinus in Young Children and resultant ischemia in comparison to a young adolescent male. He also found that atrial pacing may reveal ischemic changes during cardiac catheterization. This has lead some cardiologist to use calcium channel blocking agent or beta-blocker to limit the attainment of threateningly high heart rates. In general, management is guided by: mode of presentation, age at presentation, size of ectopic coronary artery, presence of related proximal coronary artery obstruction, and lifestyle of individual patient. Patients younger than 40 years with large ectopic arteries, functional and anatomic compromise, and ischemic or arrhythmic complications require intervention. For patients older than 50 years, specific therapy are rarely required. Lastly, for patients between 40 and 50 years care must be individualized[34]. Our present recommendation is the following; as part of first echocardiography study, all patients, regardless of their age, should have their coronary arteries screened in the echocardiography laboratories. Once coronary abnormalities are detected (i.e., origin from the opposite sinus), efforts should be made to look for any evidence of ischemia either through invasive or noninvasive techniques. 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KUWAIT MEDICAL JOURNAL December 2006 Original Article Results of Combined Proximal Crescentic Metatarsal Osteotomy and Modified Distal Soft Tissue Procedure in Severe Hallux Valgus Ibrahim MAAl-Kussary1,2, Fathy Khallaf 1, Mahmoud El Rayes 1, Mustafa Al Akkad1 Department of Orthopedics, 1Al-Jahra Hospital, 2Al-Razi Hospital, Kuwait Kuwait Medical Journal 2006, 38 (4): 300-307 ABSTRACT Objective: To review subjective, objective, and complication results of surgery of combined proximal crescentic metatarsal osteotomy and modified distal soft tissue procedure in adult foot severe hallux valgus deformities Design: Retrospective clinical study Setting: Al-Jahra Hospital Orthopedic Department and Al-Razi Orthopedic Hospital Methods: We retrospectively studied the results for thirty consecutive patients (38 feet), in whom a severe hallux valgus deformity with hallux valgus angle (HVA) > 40º and first / second inter-metatarsal angle (1/2 IMA) > 16º had been corrected surgically. The surgery included proximal crescentic osteotomy of the first metatarsal, lateral release of the distal soft tissues, excision of the medial eminence, plication of the medial part of the capsule of the 1st metatarso-phalageal joint (1st MTP) and a modification of Z-plasty lengthening of the extensor hallucis longus (EHL) tendon. The patients were followed up for an average of twenty-eight months (range 17-47 months). Results: The preoperative HVA averaged 48º and postoperative angle averaged 13º. The preoperative 1/2 IMA averaged 18º and postoperative angle averaged 7º. Ninety-three percent of the patients were satisfied with the results of the procedure. They stated that, given the same circumstances, they would have the operation again. A clinical and radiological excellent to good correction was achieved in 95% of the feet (excellent in 79% and good in 16%) with an average American Orthopedic Foot and Ankle Society (AOFAS) hallux score of 92 out of 100 points. Complication: included recurrence of gross hallux valgus deformity in two dissatisfied patients (2 feet, 6.6%) and mild under-correction of six feet in four patients (13%). However, the patients were satisfied with the relief of pain and the cosmetic appearance of their feet. Hypothesia along the medial aspect of the great toe occurred in two patients (2 feet, 6.6%). Pin track infection occurred in two patients (2 feet, 6.6%) and deep infection in one patient. All were cured after debridment and antibiotics. Conclusion: According to the results of this report and other studies in the literature, proximal crescentic metatarsal osteotomy combined with distal lateral release, medial repair and lengthening of the EHLtendon is a reliable and successful surgery for treating severe hallux valgus deformity. KEYWORDS: hallux valgus, metatarsal deformity, proximal crescentic osteotomy INTRODUCTION The deformity of hallux valgus is the lateral deviation of the great toe. It is associated with other pathological features which include: medial deviation of the first metatarsal (metatarsus primus varus) with increased inter-metatarsal angle (IMA) between the first and second metatarsals, prominent medial eminence, contracted soft-tissue structures on the lateral side of the great toe, lateral displacement of the sesamoids and contracture of the extensor and flexor tendons leading to lateral rotation of the metatarsal head and pronation of the hallux[1-4]. A hallux valgus angle (HVA) > 40º and inter-metatarsal angle (1/2 IMA) > 16º are the radiological features defining severe hallux valgus. Commonly, the severe hallux valgus is characterized by progressive subluxation and incongruity of the first metatarso-phalangeal joint with altered distal metatarsal articular angle (DMAA). The deformity is attributed to congenital hereditary metatarsus primus varus with 55-60% positive family history and to the acquired splayed foot secondary to weak intrinsics with contribution from the effect of shoe wearing [5, 6]. More than 130 different surgical procedures have been described to treat this deformity[5,8,9]. The main procedures to surgically treat severe hallux valgus include: proximal osteotomy to correct the first metatarsal deformity by opening a wedge, closing a wedge, crescentic and proximal chevron Address correspondence to: Dr. Ibrahim M.A Al-Kussary, MD, Orthopedic Department, Al-Jahra Hospital, P.O. Box 723, 01009 Kuwait. Tel : (+965) 7432347, (+965) 6541933, Fax: (+965) 4588408, E-mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL Sammarco osteotomies with distal soft-tissue release and medial plication. It also includes scarf, Mau and Ludloff ostotomies[2,3,5,7,8]. The first tarsometatarsal arthrodesis is also an option in the surgical management of severe hallux valgus with hypermobile first ray or as salvage after failed other bunion repair surgeries[7,9]. Post-surgical complications are always the concern of both patients and surgeons and include: recurrence of deformity, poor cosmetic appearance, under-correction, over-correction with hallux varus deformity, shortening of the first ray, and elevation of the first ray causing transfer lesion to second metatarsal head (transfer metatarsalgia)[3,5,8,9]. In this report, we present the subjective, objective, radiological and complication results of surgical treatment of severe hallux valgus by proximal dome osteotomy with distal soft tissue release and medial plication. We added a modification of Z-plasty of the extensor hallux longus (EHL) tendon through the dorso-medial incision to the distal soft tissue procedure[11]. PATIENTS AND METHODS Between May 1996 and April 2003, thirty consecutive patients with thirty-eight feet of severe hallux valgus were treated surgically in Al-Razi Orthopedic Hospital and Jahra General Hospital, Kuwait. The patients who were retrospectively interviewed, gave their informed consent before entering the trial and were examined clinically, radiologically and complicationwise as also for assessment of their satisfaction with the results of the surgery. The pre and post-operative clinical data were gathered according to guidelines recommended by the American Orthopedic Foot and Ankle Society AOFAS)[8]. The weight-bearing dorso-plantar and lateral feet radiograms were collected from the patient’s medical records and compared with final follow-up evaluation. Outcome: The primary outcome of this study was the clinical and radiological correction of the severe hallux valgus deformity. The secondary outcome was the patient’s satisfaction regarding the correction of the deformity. Clinical assessment: The series of patient in this study included thirty consecutive patients with thirty-eight feet, who had a severe degree of hallux valgus deformity. The deformity was unilateral in twenty-two patients (73%) and bilateral in eight patients (27%) with ratio 3:1. There were 25 female (83%) and five male patients (17%) with ratio 5:1. The average age was thirty-eight years and the range was 22-48 years. 301 The indication was pain and deformity in twentyseven patients (90%) including the twenty-five females and only pain in the remaining three males (10%). Twenty patients (67%) suffered from problems with shoe fitting and desired operative correction. Pre and post-operative assessment was made according to the protocol of the American Orthopedic Foot and Ankle Society (AOFAS). This system provides a score ranging from Zero to 100 points, which takes into consideration both subjective and objective elements such as pain (maximum score = 40 points), functional capacity (maximum score = 45 points), and hallux alignment (maximum score = 15 points). Other factors that were evaluated in the clinical assessment were any limitation of daily and/or sports or recreational activity, the type of shoes that the patient could wear, the stability of the 1st MTP and interphalangeal joints, and the presence of calluses. The patient’s satisfaction with the outcome (satisfied or unsatisfied) was also elicited. The active and passive range of motion of the first metatarsophalangeal joint was measured with a goniometer (with the patient not bearing weight, with measurement of angle between the proximal segment of the great toe and the plantar surface of the foot). The advantage of using the plantar surface of the foot as the point of reference is that Zero degree represents the functionally neutral position of the toe. Active and passive dorsiflexion and plantar flexion were recorded from this neutral axis of reference. Rotational mal-alignment (pronationsupination deformity) of the great toe was graded: no rotation was considered to be grade Zero; rotation of less than 25 degrees, grade 1; rotation of 25 to 45 degrees, grade 2; and rotation more than 45 degrees, grade 3. The assessment was made with the patient standing. The pronation of the hallux was documented in the patients’ medical records in 24 patients (80%), 27 feet (71%). The hypermobility of the metatarsocuniform (MTC) joint was not documented in any patient’s record in this series. Radiological assessment: The radiological assessment of patients’ preoperative radiographs included: the HVA, the 1/2 IMA, the DMAA, the subluxation of the first metatarso-phalangeal joint (1st MTP), the position of the sesamoids, the lengths of the first and second metatarsals (so that any post-operative shortening could be measured accurately), and the osteoarthritic changes of the metatarso-phalangeal joints. The hallux valgus angle (HVA) is subtended by lines along the long axis of the first metatarsal and the proximal phalanx. Normally, the HVA is < 15º. The inter-metatarsal angle 1/2 IMA is subtended by lines along the longitudinal axis of the first and 302 Results of Combined Proximal Crescentic Metatarsal Osteotomy and Modified Distal Soft ..... December 2006 Table 1: Pre-operative clinical assessment Parameter Patient’s complaints Pain only Pain and deformity Wearing shoes problems Objective findings Severe hallux valgus Pronation of the hallux Hypermobility of MTC joint Result n (%) 03 (10) 27 (90) 20 (67) 38 (100) 24 (63) None centrally in 20 feet (52.5%) and laterally in 18 feet (47.5%). Osteoarthritis of the 1st MTP was not observed in any of the preoperative radiographs. A summary of the pre-operative clinical assessment is shown in Table 1. Fig. 1: Measurement of the DMAA (it is the angle subtended by a line drawn perpendicular to the metatarsal articular surface and the longitudinal axis of the first metatarsal). second metatarsals. Normally the 1/2 IMA is < 9º. The distal metatarsal articular angle (DMAA) describes the lateral scope of the articular surface in relation to the long axis of the first MT as shown in Fig. 1. Normally, the DMAAis < 100º. The position of the tibial sesamoid on the antero-posterior (dorsi-plantar) radiographs was described as medial, lateral, or central in relation to a line drawn along the centre of the longitudinal axis of the first metatarsal. The sesamoid was considered to be medial, if 75 per cent of it was located medial to the central line and as lateral, if 75 per cent of it was located lateral to the central line. Otherwise, the sesamoid was considered to be located centrally. Normally, on the dorso-plantar view the metatarsal head overlies both the tibial and fibular sesamoids and the tibial one is medial to the longitudinal axis of the first metatarsal. The average pre-operative HVA was 48º (range = 43º- 54º) and the average of pre-operative 1/2 IMA was 18º (range = 16º-22º). The MTP joint was subluxated pre-operatively in all patients (100%), but DMAA was normal in 13 feet (33%). The average of the abnormal DMAA was 113º (range = 104º-117º). The tibial sesamoid was located Statistical Analysis : Due to the small sample size of thirty patients (thirty-eight feet) of hallux valgus in the study, Student - t test was chosen to estimate the significance of the difference in pre-operative and postoperative HVA and 1/2 IMA values. Because the outcome of the surgery was uncertain in reducing the HVA and 1/2 IMA, an independent parametric two- sided (tailed) test was used. This particular kind of statistical tests allows larger variance and have longer tails than the standard normal distribution, which fits the data and the nature of this study and being parametric makes it more powerful in detecting significance. The over-all level of alpha significance (p-value) in the study was 0.05 and there is a 26 percent chance of at least one spuriously significant difference over-all (p = 1[1-0.05]). Surgical Technique: A prophylactic antibiotic (1 gm) from the third generation of cephalosporins is routinely injected IV with induction of anesthesia and before application of the tourniquet. The distal soft tissue procedure to correct a hallux valgus deformity consists of several steps and was performed through two incisions. The first is made dorsally in the line of the first web space of the foot to release the adductor hallucis, and to release tendon from the base of the proximal phalanx and the fibular sesamoid, the transverse inter-metatarsal ligament and the lateral capsule of the first metatarso-phalangeal joint. The second incision is made midline over the medial eminence to remove the medial eminence and perform a capsulorraphy. The proximal osteotomy is done through a four-centimeter dorsal and longitudinal third incision that starts over the base of the first metatarsal and ends just proximal to the metatarso- December 2006 KUWAIT MEDICAL JOURNAL Table 2: Post-operative clinical results Parameter Result n (%) Subjective Pain relief Comfortable shoe fitting Satisfaction with surgery Objective Excellent correction Good correction Recurrence AOFAS hallux score 27 (90) 18 (60) 28 (93) 30 (80) 6 (15.7) 2 (5.3) Average score 92 points, range (81-97 points) 303 Table 3: Pre-operative versus post-operative clinical assessment Parameter Pre-operative assessment n (%) Post-operative results n (%) Pain 30 (100) 03 (10) Mild pain p ≤ 0.05 significant Shoe fitting problems 20 (67) 2 (7) p ≤ 0.05 significant Hallux valgus deformity 38 feet (100) 2 (5.3) Recurrence Highly significant p < 0.01 Table 5: Post-operative complications Complication Table 4: Pre-operative versus post-operative radiological findings Parameter Pre-op assessment M (range) HVA 1/2 IMA DMAA o o o 48 (43 -54 ) o o o 18 (16 -22 ) o <100 in 13 feet (34%) Tibial sesamoid Medial in 0 feet Shortening of 1st MTB --- NA Dorsal angulation --- NA O-A1st MTP --- NA Post-op results M (range) o o o 13 (8 - 22 ) o o o 7 (5 -12 ) o <100 in 34 feet (90%) Medial in 28 feet (74%) 6.3% (1.7%-11%) 15 feet (39%) One foot (2%) Level of significance p ≤ 0.05 significant p ≤ 0.05 significant p ≤ 0.05 significant p < 0.01 highly significant Not significant p ≤ 0.05 significant Not significant M = mean NA= not available cuneiform joint. The metatarsal osteotomy is begun one to one and half centimeter distal to the metatarso-cuneiform joint with the use of an oscillating saw that has a curvilinear blade with the concavity of the cut directed proximally (dome or crescentic shaped osteotomy). The osteotomy is displaced by retraction and pushing of the proximal fragment medially and moving the distal portion laterally with supination and rotation around the proximal fragment. This usually results in a lateral displacement of the distal portion by about 3 - 5 mm to reduce the 1/2 IMA and correct the metatarsus primus varus deformity of the 1st metatarsal. The supination of the distal portion of the metatarsal osteotomy and the great toe reduces the sesamoids beneath the metatarsal head correcting the great toe pronation, which mostly accompanies severe hallux valgus. The site of osteotomy is stabilized by either two K-wires (in thirty feet) or by 4 mm cancellous screw (in eight feet). The medial part of the joint capsule is repaired with the great toe held in neutral dorsi-flexion plantar-flexion position with slight varus over correction. Through the second medial incision, the extensor hallucis longus tendon is accessed and lengthened by Z-plasty according to its tension after the correction of hallux valgus deformity by Level of significance Medial hypothesia of the hallux Pin track infection Deep infection Mild under- correction Recurrence of gross hallux valgus Osteoarthritis 1st MTP n (%) Feet (%) 2 (6.6) 2 (6.6) 1 4 (13) 2 (6.6) 1 2 (5.3) 2 (5.3) 1 6 (15.7) 2 (5.3) 1 proximal osteotomy and the distal capsulorrphy and lateral release. Post-operatively, the hallux is protected in the corrected position by using P.O.P slipper cast, which encases the hallux and foot without immobilizing the ankle allowing its free movements. The patient is allowed to walk from the second post-operative day in the non-weight bearing mode using crutches. Follow-up: The patients were followed-up for an average of twenty-eight months (range 17- 47 months). During the follow-up the cast and the K-wires were removed 4-6 weeks post-operatively and the patient started on a physiotherapy program for active and passive dorsi-flexion and plantar flexion exercises of the hallux and other toes. The patient was allowed to bear weight partially and then fully aided by crutches eight weeks post-operatively. After 10-12 weeks post-operatively, the patients discarded crutches and returned to normal activities. RESULTS The results were categorized into subjective, objective, radiological and complications. A- Subjective results: Out of all 30 patients (100%) who complained of pain in their feet located primarily around the 1st MP joint pre-operatively, only three had persistent mild discomfort post-operatively (10%). Out of 20 patients (67%) with shoe-fitting problems preoperatively, 18 (90%) could be fitted with the same shoe more comfortably post-operatively and 14 (70%) of these patients could even be fitted with a 304 Results of Combined Proximal Crescentic Metatarsal Osteotomy and Modified Distal Soft ..... December 2006 Fig. 2a Fig. 2b Fig. 2c Fig. 2: Severe hallux valgus deformity with severe subluxation of the first metatarsophalangeal joint in the right foot of a 32 years old male patient a. Pre-operative standing antero-posterior radiograph; b. Post-operative standing antero-posterior radiograph; c. Final follow up radiograph after four years; d: Photograph of the right foot showing satisfactory correction of the deformity. narrower shoe. The status of two patients (10%) remained unchanged with regard to the fitting of shoes. Twentyeight patients (93%) were satisfied with the results of surgery and the shape of their foot or feet. Two patients (6.6%) were dissatisfied with the operative result due to Fig. 2d: recurrence of the hallux valgus deformity to its pre-operative magnitude and persistence of pain. B- Objective results: The hallux valgus deformity was corrected to a clinically neutral hallux with regard to the valgusvarus deformity in 30 feet (80%). Six feet (15.7%) had residual mild hallux valgus. Two feet (5.3%) in two patients had recurrence of gross hallux valgus post-operatively. Active dorsi-flexion of the first MP joint averaged 50º with a range of 25º- 65º. The average passive dorsi-flexion was 60 degrees with a range of 30º-70º. The post-operative active plantar flexion averaged 26 degrees with a range of 10-45 degrees and the passive average was 35 degrees with a range of 15 - 50 degrees. There was residual hallux pronation in three feet (18%) in three patients (10%). The post-operative results are shown in Table 2. The post-operative clinical assessment has been further elaborated by using the American Orthopedic Foot and Ankle Society (AOFAS) hallux score[5,7,9]. The average score among thirty patients in this study was 92 out of 100 points with a range of 81- 97 points. A comparison of the pre-operative assessment and post-operative results is shown in Table 3. C- Radiological Results: The osteotomy site was united in all feet, irrespective of the method of fixation. The HVA was corrected an average of 35 degrees after the procedure. The post-operative latest follow-up average HVA was 13 degrees (range = 8 - 22 degrees) and it was less than 10º in 19 patients (50%) with 26 feet (68.4%). 1/2 IMA was corrected to an average of 11 degrees. The angle averaged 7º (range 5º-12º) as shown in (Fig. 2: a, b, c) & (Fig. 3: a, b, c). Post-operatively, the tibial sesamoid was positioned medially in 28 feet (74%), centrally in seven feet (18.5%) and laterally in the remaining three feet (7.5%). In the latest postoperative weight bearing antero-posterior foot radiograph, the DMAA was corrected to <100º in 34 feet (90%) and > 100º in four patients and the averaged DMAA December 2006 Fig. 3a KUWAIT MEDICAL JOURNAL Fig. 3b 305 Fig. 3c Fig. 3: Severe hallux valgus deformity with severe subluxation of 1st MTPjoint in the left foot of a 25 years-old female patient. a. Preoperative standing antero-posterior radiograph; b. Postoperative standing antero-posterior radiograph; c. Final follow up radiograph after three years; d. Photograph of the left foot-showing correction of the deformity was 9º The subluxation of 1st MP joint was corrected in 35 feet (95%) while it recurred in two feet (5%). The length of 1st and 2nd metatarsals was measured with weight b e a r i n g radiographs to Fig. 3d determine metatarsal shortening after surgery. The method of measuring first metatarsal shortening is shown in Fig. 4. The percentage of shortening of the first metatarsal averaged 6.3% (range = 1.7% - 11%) after the osteotomy. Post-osteotomy, the first metatarsal dorsal angulation (elevation) malunion was noticed in 15 feet in 12 patients (40%). Dorsal angulation occurred in four feet where the osteotomy was fixed by 4.0 mm cancellous screw and in two of them the angulation was noticed in the immediate post-operative radiographs and in the other two, the angulation was noticed during the late followup (50% of the osteotomies fixed by screws). Dorsal angulation occured in 11 feet where the osteotomy was fixed by K-wire (36.6% of the feet fixed by K- wires), four of them noticed in immediate postoperative radiographs and the rest were observed late in the follow-up. The osteoarthritic changes in the 1st MTP joint noted, in latest follow-up in one foot with narrowing of the joint space and subchondral sclerosis. Acomparison of pre-operative and post-operative radiological assessment is shown in Table 4. Complications: Hypothesia on the medial aspect of the hallux due to digital nerve injury was noted in two patients (6.6%). In two patients (6.6%) where the metatarsal osteotomy was fixed by K-wires, pin track infection occurred which was cured by local debridment and antibiotics. Deep infection occurred in one patient (3.3%), which was treated by wound debridment under general anesthesia and antibiotics and this subsided with wound healing three weeks after the debridment surgery. No painful transfer metatarsalgia with or without plantar keratosis under the head of second metatarsal developed after surgery in any patient. Recurrence of gross deformity occurred in two feet (5.3%) in two patients (6.6%). Six feet (15.7%) in four patients (13%) had mild residual deformity of hallux valgus but the patients were satisfied with the cure of pain and the cosmetic appearance of their feet. Over correction with hallux varus deformity was not noticed in any of the patients in this series (Table 5). 306 Results of Combined Proximal Crescentic Metatarsal Osteotomy and Modified Distal Soft ..... December 2006 Fig. 4: Measuring first metatarsal shortening (X is the midpoint of AB. The percentage of shortening of first metatarsal is then expressed as X1/X2 pre-operative divided by X1/X2 at review x 100). DISCUSSION Selection of the operative technique for correction of the bony deformities in hallux valgus patients is mainly based on the first to second intermetatarsal angle (1/2 IMA). Severe deformity where the 1/2 IMA is > 16º can be corrected using proximal metatarsal osteotomies (proximal chevron, crescentic, opening, and closing wedge osteotomy) with distal soft tissue procedures [2,4,9]. Arthrodesis is also advocated in severe painful hallux valgus[5]. Reported series show that success rates for the proximal osteotomies are comparable, achieving satisfactory results in the zone of 80 to 90%[7,9]. The studies have shown, as well that those proximal osteotomies may lead to substantial complications, including first metatarsal elevation, metatarsal shortening and transfer metatarsalgia due to altered forefoot loading[3,11,12,13]. Regardless of adequate fixation of the first metatarsal proximal osteotomy, dorsal angulation has been reported to occur in the range of 28 - 82% patients undergoing the procedures. Although this angulation may occur as an intra-operative technical failure, post-operative dorsi-flexion can similarly occur as a result of early weight bearing on a relatively unstable osteotomy. One of the big advantages of proximal osteotomies is that it achieves an actual instead of relative correction of the intermetatarsal angle [3,5,7,11]. The crescentic basilar osteotomy, in particular, has the problems of sagittal instability and postoperative first metatarsal dorsal angulation, most likely due to poor osteotomy placement and difficulty in fixation. But the technique still provides a powerful tool to correct wide intermetatarsal angles with minimal shortening. One could also adjust the procedure in order to obtain exact correction without additional wedging and facilitate triplanar correction by angling the osteotomy in various directions. The rate of first metatarsal dorsal angulation was 39% in this study distributed among the cases fixed by K-wires (36.6%) and osteotomies fixed by screws (50%) with a difference which does not reflect any statistical significance. However, none of the patients developed transfer metatarsalgia, most likely due to low incidence of first metatarsal minimal shortening (average of 6.3%). One of these complications aggravates the other in that if there is both shortening and dorsi-flexion, the problem of a transfer lesion is compounded. There are times when dorsi-flexion occurs with minimal shortening and no problem results[15,17]. In 1982, Cedell and Astrom reported the results of a basal dome osteotomy and distal soft tissue procedure in forty-six feet. The results were excellent in 78% of the feet and good in 11%[12,13]. In 1992, Mann reported the results of proximal Crescentic osteotomy with distal soft-tissue repair in seventy-five patients (109 feet). A majority (93%) of the patients were satisfied with the surgery[18,19]. In our series, 93% patients were satisfied with the outcome of surgery. Excellent correction of the severe hallux valgus was achieved in 79% patients and good correction in 16% patients with average AOFAS hallux score of 92 points (range = 81-97 points). This conforms to the results of Dome osteotomy and distal soft tissue procedures in the literature. However, most of the literature reports had a heterogeneous group of mild, moderate and severe hallux valgus. To the best of our knowledge, this is the first series of only severe hallux valgus treated by proximal dome osteotomy, distal soft tissue lateral release and medial repair[3,4,13,20]. The modification of adding Z-plasty of the extensor hallux longus tendon to the distal soft tissue procedure (to reduce the possibility of recurrence by decreasing the bowstring effect of the EHL after deformity correction by osteotomy) may play a role in having only two cases of recurrence in this series of severe hallux valgus after surgery. December 2006 KUWAIT MEDICAL JOURNAL The rate of permanent complications in this series was in four patients (13%) but none of our patients complained of transfer metatarsalgia with or without plantar callosity beneath the second metatarsal head and only one patient had osteoarthritis in the 1st MTP joint. The rate of complications in this study is very similar to what is mentioned in other reports in the literature[7,9,21,22]. Proximal crescentic metatarsal osteotomy with distal soft tissue procedure modified by extensor hallucis longus Z-plasty has proved effective in relieving symptoms and in restoring feet appearance in severe hallux valgus deformity to nearly normal shape and function with a low rate of recurrence and other complications. The significance of the impact of our distal soft tissue modification in hallux valgus correction surgery will need further evidence by planning a randomized prospective study. CONCLUSION We believe according to the results of this study and other reports in the literature that the proximal crescentic metatarsal osteotomy combined with distal lateral release, medial repair and lengthening of the EHL is a reliable and successful surgical technique in treating severe hallux valgus deformity in adult feet. The technique is simple, has a low rate of complications and is associated with durable correction relieving the patients’ symptoms enough to justify its recommendation. ACKNOWLEDGEMENT We would like to express our thanks to Dr Samir AbdAlRazek, Head, Department of Orthopedics, Al Razi Hospital for his great support. We also appreciate the help rendered to us by Dr Gehan Baker, Dr Mohamed Baker, Dr Montasser Bashir, Dr Osama Sobhy and Dr Hazem Hantera for their great support. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. REFERENCES 1. 2. 3. 4. Carr CR, Boyd BM. Correctional Osteotomy for metatarsus primus valgus. J Bone Joint Surg 1968; 50-A:1353-1367. Bargman J, Corless J, Gross AE, Lange F. A review of surgical procedures for hallux valgus. Foot Ankle 1980; 1:39-43. Donick II, Berlin SJ, Block LD, Costa AJ, Fox JS, Martorana VJ. An approach for hallux valgus surgery-fifteen years review, part II. J Foot Surg 1980; 19:171-184. McBride ED. The McBride bunion hallux valgus operation. Refinements in the successive surgical steps of the operation. J Bone Joint Surg 1967; 49-A:1675-1683. 20. 21. 22. 307 Kernozek TW, Elfessi A, Sterriker SA. Clinical and biomechanical risk factors of patients diagnosed with hallux valgus. J Am Podiat Med Assoc 2003; 93:97-103. Breslauer C, Cohen M. Effect of proximal articular set angle-correction osteotomies on the hallucal sesamoid apparatus: a cadaveric and radiographic investigation. J Foot Ankle Surg 2001; 40:366-373. Mc Cluskey LC, Johnson JE, Wynarsky GT, Harris GF. Comparison of stability of proximal Crescentic metatarsal osteotomy and proximal horizontal “V” osteotomy. Foot Ankle Int 1994; 15:263-270. Smith RW, Reynolds JC, Stewart MJ. Hallux valgus assessment. Report of research committee of American Orthopedic Foot and Ankle Society. Foot Ankle 1984; 5:92103. Trnka HJ, Muhlbawer M, Zembsch A, Hungerford M, Ritschl P. Basal closing wedge osteotomy for correction of metatarsus varus: 10 to 22 years follow-up. Foot Ankle Int 1999; 20:171-177. Groulier P, Currale G, Prudent HP, Vedel F. Result of treatment of hallux valgus with modified McBride operation with or without supplementary phalangeal or metatarsal osteotomy. French J Orthop Surg 1988; 2:412421. Easley ME, Kiebzak GM, Davis WH, Anderson RB. Prospective randomized comparison of proximal crescentic and proximal chevron osteotomies for correction of hallux valgus deformity. Foot Ankle Int 1996; 17:307-316. Shaw AH, Pack LG. Osteotomies of the first ray for hallux abudcto- valgus deformity. J Am Podiatr Med Assoc 1974; 64: 567-580. Mann RA, Coughlin MJ. Hallux valgus - etiology, anatomy, treatment and surgical considerations. Clin Orthop 1981; 157:31-41. Michael J, Coughlin B, Idaho. Hallux valgus: An instructional course lecture, The Am Academy of orthopedic surgeons. J Bone Joint Surg 1996; 78:932-966. Cohen M, Roman A, Ayres M, Freedline A. The crescentic shelf osteotomy. J Foot Ankle Surg 1993; 32:209-226. Carpenter B, Motley A. Adding stability to the crescentic basilar metatarsal osteotomy. J Am Podiatr Med Assoc 2004; 94:5. Cedell CA, Astrom M. Proximal metatarsal osteotomy in hallux valgus. Acta Orthop. Scandinavia 1982; 53:1013-1018. Resch Sylvia, Stenstrom Anders, Eguard Nils. Proximal closing wedge osteotomy and abductor tenotomy for treatment of hallux valgus. Foot Ankle 1989; 9:272-280. Johnson JE, Clinton TO, Boxter DE, Gottlieb MS. Comparison of chevron osteotomy and modified McBride bunionectomy for correction of mild to moderate hallux valgus deformity. Foot Ankle 1991; 12:61-68. Jones KJ, Feiwell LA, Freedman EL, Cachiolo A. The effect of chevron osteotomy with lateral capsular release on the blood supply to the first metatarsal head. J Bone Joint Surg 1995; 77- A:197- 204. Mann RA, Sally Rudicel, Graves SC. Repair of hallux valgus with a distal soft tissue procedure and proximal metatarsal osteotomy. J Bone Joint Surg 1992; 74-A:124-129. Mann RA. Distal soft tissue procedures and proximal metatarsal osteotomy for correction of hallux valgus deformity. Orthopedics 1990; 13:1013-1018. KUWAIT MEDICAL JOURNAL December 2006 Original Article Safety of Laparoscopy in Acute Cholecystitis Wael Fathi Hassaniah, Mohamed Al Haifi, Talib Jumaa Department of Surgery, Al Amiri Hospital, Kuwait Kuwait Medical Journal 2006, 38 (4): 308-310 ABSTRACT Objective: Laparoscopic Cholecystectomy (LC) is the gold-standard procedure for chronic cholecystitis. However, its safety in acute cholecystitis has been questioned because of the abnormal anatomy associated with the acute inflammation. Our aim was to evaluate the safety of LC in acute cholecystitis. Design: Retrospective Setting: Department of Surgery, Al-Amiri Hospital, Kuwait Material and Methods: During the period 1992 -1999, 300 patients with acute cholecystitis were evaluated. We assessed the efficacy of LC by studying the postoperative hospital stay; and its safety by studying the rate of conversion, especially by adopting the policy of early conversion whenever the anatomy was obscure. The morbidity associated with LC in acute cholecystitis was evaluated. Results: Postoperative hospital stay was one day in 45% and two days in 23% patients. Our conversion rate was 15%. Major postoperative complications were seen in 4% cases. There was no incidence of CBD injury. Conclusion: LC is a safe and effective procedure for acute cholecystitis if the policy of early conversion when anatomy is obscured is adopted. KEYWORDS: acute cholecytitis, common bile duct injury, laparoscopic cholecystectomy INTRODUCTION Laparoscopic Cholecystectomy (LC) is now considered as the procedure of choice for patients with gall bladder disease, especially those with chronic cholecystitis[1,2] due to reduced postoperative hospital stay and early return to work. However, in acute cholecystitis (AC), the presence of edema and inflammation that results in obscuring the anatomy, make the operative dissection much more difficult and this could result in higher morbidity and reduced benefit from the laparoscopic approach[3,4]. In our experience, LC for AC is a safe and effective method for management of AC with an acceptable rate of conversion and morbidity[5,6]. This has been accomplished by a low threshold for conversion when anatomy is distorted. MATERIALS AND METHODS Two thousand seven hundred and fifty patients, who underwent LC from February 1992 until October 1999, were retrospectively evaluated. Three hundred patients presented with acute cholecystitis. The diagnosis was based on history, clinical examination, the presence of fever, leucocytosis and diagnostic evidence of AC by ultrasound examination. Operative time, conversion rate, the reasons for conversion and postoperative complications were evaluated in both urgent and emergency cases. Technique: LC was done by using the four port technique. A needle aspiration of the gall bladder was done at the beginning of the procedure to facilitate grasping the gall bladder wall which is usually thickened due to the inflammation. Omental adhesions were released by blunt dissection to identify the Callot’s triangle. If traction of the Hartman’s pouch was not feasible by the usual graspers, we used the Wolf grasper which has a good grip on the wall by the sharp stems. Traction on the fundus was facilitated by a stitch which was then caught by a grasper. If the dissection at the Callot’s triangle was difficult, then an attempt was made at identifying the structures first by fundus dissection. Electrocautery dissection was used to expose the cystic duct and the cystic artery. This was facilitated by the use of hydro-dissection with the suction tube. For thick and wide cystic ducts, a Roeder loop knot was used to secure them. We did not do routine intra-operative cholangiogram. Patients with raised liver enzymes or suspected of having common bile duct stones had a preoperative endoscopic retrograde cholangiopancreatogram (ERCP)[7,8,9]. The gall bladder and any spilled stones were collected in a retrieval bag which was extracted through an extended umbilical port. Draining the liver bed was not done Address correspondence to: Dr Wael Fathi Hassaniah, PO Box 1002 - Hawalli, Kuwait. E-mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL Table 1: Reasons for prolonged hospital stay (more than one day) Reason Conversion Gall bladder pathology Patient’s request Complications No. of cases 45 50 15 27 309 Table 2: Reasons for conversion Reason for conversion Gall bladder pathology Abnormal anatomy Bile leak and stone spillage Abdominal adhesions Cystic artery bleeding Common bile duct injury Bowel injury No. of cases 35 20 15 4 2 0 0 Table 3: Operative complications Complication Bleeding Common bile duct injury Cystic duct injury G B puncture Liver trauma No. of cases 12 Nil 4 45 6 routinely and it’s use was left to the judgement of the operating surgeon. RESULTS LC was attempted in 300 patients with a clinical and radiological diagnosis of AC. Out of these patients, 120 (40%) were male and 180 (60%) female. The mean age was 45 years (range 17 - 73 years). The mean operating time was 80 minutes (range 45 - 310 minutes). The mean postoperative hospital stay was 1.56 days (range 1 - 20 days). One day postoperative hospital stay was seen in 137 (45%) and two days hospital stay in 69 (23%) patients. The remaining patients stayed for more than two days. The reasons of prolonged hospital stay (more than one day) are shown in Table 1. In some cases, there was more than one reason to account for the increased hospital stay. The conversion rate was 15% (45). The reasons for conversion are shown in Table 2. There was again more than one reason for conversion to open cholecystectomy. Pre-operative ERCP was done in 42 cases. The indications were raised liver function tests or evidence of dilated common bile duct by ultrasound. ERCP was abnormal in only 20 (47%) cases where stones were found and extracted. Postoperative ERCPwas done in eight cases and was abnormal in seven (87%) cases. Postoperative ERCPwas done to deal with retained stones (2 cases), postoperative complications such as bile leak (3 cases) and pancreatitis (2 cases). Our operative complications are shown in Table 3, and postoperative complications in Table 4. Re-admission to hospital was considered as a minor complication and was seen in 11 cases; out of which two cases were due to retained stones, three cases were found to have small non-drainable Table 4: Post-operative complications Complication Major complications Common bile duct Injury Bleeding Bile leak Abdominal collection Melena Pancreatitis Minor complications Re-admission Wound Complications Others: Medical or anesthesia related No. of Cases Nil 1 3 5 1 2 11 20 15 abdominal collection, two cases due to non-specific abdominal pain and four cases due to upper abdominal pain that was due to peptic ulcer. Other minor complications included those due to anesthesia or associated medical disease like ischemic heart disease, heart failure and hypertension. DISCUSSION Laparoscopic cholecystectomy done electively has significant benefits for the patients, including short hospitalization and reduced wound complications. In our experience, these benefits have also been achieved for patients with acute cholecystitis, where the majority of our patients stayed postoperatively for short periods (45% stayed for one day and 23% stayed for two days). Twenty (6.6%) patients suffered from minor wound complications like wound seromas or superficial wound infection. The presence of edema, inflammation, fibrosis and sometimes necrosis with gangrene make dissection of the Callot’s triangle and the gall bladder more difficult, especially if associated with omental adhesions. This can lead to more procedure-related complications. An aspiration needle can be used to decompress the edematous and thick-walled gall bladder which would facilitate grasping the wall. Also, the use of stronger tooth graspers for the cephalad fundus retraction helped. For thickened cystic ducts, the use of extra 310 Safety of Laparoscopy in Acute Cholecystitis large clips or roeder loop and the use of a bag for retrieval of the gall bladder through an extended umbilical port is useful. Closed suction drainage of the liver bed was performed in cases with bile leakage, spilled stones, presence of extensive necrosis in the liver bed and in cases with thickened cystic duct where there is a potential for bile leak. In spite of this modified technique the anatomy remains unclear; therefore a low threshold for conversion should be maintained to avoid serious complications, especially common bile duct injury[10]. Our conversion rate was 15% and is similar to the conversion rates in published literature[11,12]. Our postoperative complications rate was 19.3%. However, major complications were only 4% as shown in Table 4. We had no common bile injury and only one case of intra- abdominal bleeding that was from the liver bed. This patient required a laparotomy. We had three cases of bile leak, two cases from cystic duct and one case from gall bladder bed. All cases were managed conservatively by ERCP and percutaneous aspiration of the collection under ultrasound guidance [13,14]. One patient had malena after ERCP. Abdominal collection was seen in five cases. Three were managed conservatively and in two patients, aspiration under ultrasound guidance was done[15]. CONCLUSION Laparoscopic cholecystectomy for acute cholecystitis is an effective procedure due to reduced postoperative hospital stays and wound complications. It is also safe due to reduced postoperative morbidity and with an acceptable rate of conversion. This is achieved by a policy of early conversion in cases where the anatomy is not clear. REFERENCES 1. Schirmer BD, Edge SB, Dix J, Hyser MJ, Hanks JB, Jones RS. Laparoscopic cholecystectomy: Treatment of choice for symptomatic cholelithiasis. Ann Surg 1991; 213:665-676. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. December 2006 Anderson RE, Hunter JG. Laparoscopic cholecystectomy is less expensive than open cholecystectomy. Surg Laparosc Endosc 1991; 1:82-84. Cuschieri A, Dubois F, Mouiret P, Becker H, Buess G, et al. The European Experience with laparoscopic cholecystectomy. Am J Surg 1991; 161:385-387. Kum CK, Goh PM, Isaac JR, Tekant Y, Ngoi SS. Laparoscopic cholecystectomy for acute cholecystitis. Br J Surg 1994; 81:1651-1654. Lujan JA, Parrilla P, Robles R, Marin P, Torralba JA, GarciaAyllon J. Laparoscopic cholecystectomy vs open cholecystectomy in the treatment of acute cholecystitis: a prospective study. Arch Surg 1998; 133:173-175. Eldar S, Sabo E, Nash E, Abrahamson J, Matter I. Laparoscopic cholecystectomy for acute cholecystitis: prospective trial. World J Surg 1997; 21:540-545. Phillips EH: Controversies in the management of common duct calculi. Surg Clin North Am 1994; 74:931-948. Fernandez M, Csendes A, Yarmuch J, Diaz H, Silva J. Management of common bile duct stones: the state of the art in 2000. Int Surg 2003; 88:159-163. Liu CL, Fan ST, Lai EC, Lo CM, Chu KM. Factors affecting conversion of laparoscopic cholecystectomy to open surgery. Arch Surg 1996; 131:98-101. Lo CM, Fan ST, Liu CL, Lai EC, Wong G; Early decision for conversion of laparoscopic to open cholecystectomy for treatment of acute cholecystitis. Am J Surg 1997; 173:513517. Johansson M, Thune A, Blomqvist A, Nelvin L, Lundell L. Management of acute cholecystitis in the laparoscopic era: results of a prospective, randomized clinical trial. J Gastrointest Surg 2003; 7:642-645. Cox MR, Wilson TG, Luck AJ, Jeans PL, Padbury RTA, Toouli J. Laparoscopic cholecystemy for acute inflammation of the gall bladder.Ann Surg 1993; 218:630-634. Mehta SN, Pavone E, Barkun JS, Cortas GA, Barkun AN. A review of the management of post cholecystectomy bile leak during the laparoscopic era. Am J Gastroenterol 1997; 92:1262-1267. Bose SM, Mazumdar A, Singh V. The role of endoscopic procedures in the management of post-cholecystectomy and post-traumatic biliary leak. Surg Today 2001; 31:45-50. Lee VS, Chari RS, Cucchiarro G, Meyers WC. Complications of laparoscopic cholecystectomy. Am J Surg 1993; 165:527-532. December 2006 KUWAIT MEDICAL JOURNAL Insight Computerization in Primary Care: an Insight Huda I Al-Shaibani1, Siham YF Al-AbdulGhafour2, Amal H Al-Saqabi3 Al-Shiab Primary Health Care Centre, Hawalli, Kuwait 2 Primary Health Care, Hawalli, Health Area, Kuwait 3 Sabah Al Salim North Primary Care Centre, Kuwait 1 Kuwait Medical Journal 2006, 38 (4): 311-314 ABSTRACT We present our experience with the first year of computerization in the Primary Health Care (PHC) Centers in Hawalli Health Area. Diagnoses were entered according to the ICD-10 Classification by PHC Physicians. Data could be retrieved from eight centers. The percentage of recording was calculated and diseases were tabulated under different body systems. Out of 1.5 million visits received, only 0.7 million were entered (47%), with considerable variations among different centers (15-84%). The great majority of visits entered (88%) were for acute conditions. Eighty-six thousand visits (12%) were for chronic conditions, of which diabetes (28%) and hypertension (13%) were the commonest. Difficulties leading to the low percentage of recordings were: insufficient users’ training, system closure during holidays, slow response to users or maintenance needs and shortage of supportive personnel. Despite these difficulties, we consider the experience as promising. The PHC Physicians have the impetus to improve. We could develop an idea on the pattern of illnesses dealt with in PHC centres. The potential for improving patient care, research and planning, based on the critical appraisal of retrieved data is discussed. The need to have emphasis laid on organizational issues and users’ needs, rather than merely on administrative and financial issues, is highlighted. KEY WORDS: automated database, database information retrieval, research in general practice. INTRODUCTION During the 1980s and 1990s, general practices including primary care, have increasingly become computerized[1], might reach over eighty percent before the turn of the century[2].A great potential for this development in boosting epidemiologic research and patient care was lately realized [2]. Databases provide an efficient means of storing and retrieving large amounts of well-structured data[3]. Health professionals need to become skilled in the critical appraisal and interpretation of reports based on the collection of these data and their use in policy making [4]. Computers were introduced in the primary health care (PHC) centers in Hawalli Health Area in 2003. Physicians started entering patients’ information in 2004, following one session of demonstration. Implementing electronic medical records (EMR) requires a substantial start up effort and ongoing training at the practice site [5], with emphasis laid on organizational issues and users’ problems rather than merely on devices[6]. We herein report our experience with the first year of computerization in our PHC centers. The basic epidemiologic features of diseases dealt with in those centers are highlighted. Limitations and areas where there is a place for improvement are discussed and the potential for research in PHC setup, based on the retrieval and use of computer based data is emphasized. METHODS We analyzed the computer-based records from eight of the 13 PHC centers in Hawalli Health Area. Five centers were not included in the study for the following reasons: incomplete information in one, no computerization in two and renovation of other two centers. A permission to conduct such analysis was officially obtained from the Area Director. The unanimity and confidentiality of patients were protected as the analysis was restricted to the diagnoses made without reference to patients’ specifications. A computer print was forwarded to the Head of Primary Care (a co-author) from each of the eight PHC centers. It contains the number of patients with specific diagnoses entered according to the ICD-10 diagnostic code and tabulated under various body systems and other headings. Address correspondence to: Dr. Huda I Al-Shaibani, P.O. Box 24169 Safat 13103 Kuwait. Tel: 5524364 312 Computerization in Primary Care: an Insight December 2006 Table 1: Percentage of computer entry in eight primary health care centres in Hawalli Health Area during 2004 Table 2: The leading ten diagnoses in primary health care centers in Hawalli Health Area during 2004 PHC Centre Order Total no. of No. of visits Percentage visits entered in EMR* of computerization Salwa 317,500 Salmiyah West 291,426 Sabah Al-Salim South 209,606 Jabriyah 196,210 Rumithiyah 196,183 Bayan 154,689 Meshrif 115,543 Al-Shiab 37,933 Total 1519,090 139,729 146,535 118,754 37,957 29,801 113,710 93,813 31,944 712,243 44 50 57 19 15 74 81 84 47 * EMR: Electronic medical records The percentage of computer entry in individual PHC centers was calculated as the ratio of the number of visits entered to the actual number of visits received by the centers. The actual numbers of visits were obtained from the annual report of Hawalli Health Area[7]. The quality of recording has not been examined. The obstacles leading to incomplete entry of patients’ data have been periodically reported to one of the authors. The total number of cases entered under various body systems was calculated, and only the leading five systems were presented for the sake of simplicity. For the same reason we presented the leading ten diagnoses, out of about 500 listed. An attempt was made to identify chronic conditions generally known to be associated with morbidity and/or mortality, from acute and trivial conditions, as well as conditions listed under communicable disease. Only univariate analysis was performed using numbers and percentages to show the frequency of various entities, as we do not have a comparative set of data on which we can apply multivariate analysis. RESULTS The total number of visits seen in the area was approximately 2.3 million, of which 1.52 million were seen in the eight PHC centes where the study took place[7]. Of these, 712,243 visits were actually entered in the computer by 103 PHC physicians (47%). This low rate of entry can be attributed to several factors: frequent breakdowns and delay of maintenance, the lack of follow-up demonstrations, the shutting down of the system during weekends and public holidays, and the very short consultation time during rush hours. Individual PHC centers varied considerably in the percentage of computer entry (Table 1), between 15 and 84 percent. Centers with the lowest rate of 1 2 3 4 5 6 7 8 9 10 Diagnosis Number entered Percent from total Upper respiratory infections Bronchial asthma Bronchitis Hypertension Gastroenteritis Allergic rhinitis Muscle spasms and cramps Conjunctivitis Diabetes Backache Subtotal 241,269 34,499 26,618 23,894 21,934 18,488 14,477 12,884 11,662 11,091 416,816 33.9 4.8 3.5 3.4 3.1 2.6 2.0 1.8 1.6 1.6 58.3 entry are those open on weekends and public holidays, each serving 3-4 residential areas. Computers could not be used as the PHC centers were not interconnected during 2004. This problem was solved in 2005. The leading ten diagnoses are depicted in Table 2, and they constituted 58 percent of the entered workload. Four of these, first to third and sixth were respiratory illnesses. Eight of these illnesses are trivial and only two (diabetes and hypertension) are associated with mortality or morbidity. The total number of cases entered in the computer under the leading five body systems is shown in Table 3. Respiratory system disorders were responsible for 46 percent of the total workload, followed by the digestive system (8%). Non-morbid conditions (examinations for school entry, for joining sports, vaccination, etc) accounted for 15 percent of cases, leaving 15 percent for all other systems. Thirty diagnoses, chosen because they are associated with mortality and/or morbidity and need chronic care, were responsible for a total of 86, 494 entered visits (12%). The leading diagnoses are depicted in Table 4. The remaining 88% of cases entered were acute, mostly trivial conditions, and consumed over 80 percent of time available for primary care practitioners to practice acute, preventive and chronic care. Only 3,715 incidents of communicable diseases were recorded (Table 5), and 90 percent of these were due to chickenpox. There were only three cases of whooping cough and 17 cases of tuberculosis. Of particular interest is the finding of 194 records of gonococcal infections. The incomplete patient information and the low percentage of computer entry (47%), both precluded the estimation of prevalence and incidence rates as well as the reporting on mortality or morbidity statistics. December 2006 KUWAIT MEDICAL JOURNAL Table 3: The leading five body systems under which diagnoses were entered in the computer records of eight primary health care centres in Hawalli Health Area in 2004 No. of Cases Percent Respiratory system Digestive system Skin Musculo-skeletal system Cardiovascular system 325,593 56,199 44,741 44,522 28,180 46 8 6 6 4 Subtotal 499,235 70 Table 5: Visits due to communicable diseases in eight primary health care centres during 2004 Disease Chickenpox Gonococcal infections Mumps Rubella Measles Tuberculosis Whooping cough Total Number 3,352 194 75 50 24 17 3 3,715 DISCUSSION The low recording rate of 47 percent (Table 1) was not unexpected in view of difficulties encountered during the initial implementation. Users’ training was limited to a single session of demonstration, the system used to be shut down during holidays, and the responses to maintenance and user requests were not prompt. In three centers however, the rate of recording exceeded 70 percent (Table 1), an evidence that PHC physicians have the impetus to improve on this issue. These difficulties have long been recognized[5], as initial implementation had laid emphasis on devices rather than organizational issues[6]. Financial and administrative restraints compromised optimal utilization of the system[6], which must be primarily targeted at the user, as the time needed to adequately train him is substantial[8]. He should be supported by the introduction of clinical decision support systems, which provide him with useful information regarding diagnosis, therapy and prognosis [8, 9]. Computers have great potential for epidemiologic research[2] and promote more effective patient care by reliably and effectively storing and retrieving patient data[3,4,8,9]. We were able to develop an idea on the pattern of health problems in our PHC centers (Tables 2-5), and the opportunities for research in PHC centers should be enhanced. The physician is an information manager, who processes, 313 Table 4: Morbid conditions that need chronic care and carry mortality and morbidity risks Morbid condition(s) Hypertension Diabetes Chronic arthritis Hypercholesterolemia and obesity Migraine Heart disease Other 24 diagnoses Total Number 23,839 11,662 4,893 2,570 2,421 1,041 40,068 86,494 retrieves and applies information related to all aspects of patient management[10]. Hence, his information needs must be met[8,11]. This may entail finding the relevant resources, mastering new and multiple applications and ensuring ongoing education[8]. Family practice has been slowly but steadily dominating primary care in Kuwait [13]. Acute problems were responsible for 88 percent of visits to our PHC centers (Tables 2, 3), compared to 58 percent reported elsewhere[14]. It is well known that acute care cannot be deferred[12], hence, time available for chronic care is compromised[8,12]. It is less than 10 minutes in our PHC centers[7] and compares poorly with an average of 20 minutes recommended to complete a chronic care visit[12], of which 86 thousand cases were entered. This may reflect negatively on the quality of care as well as on the efficiency of data recording. We have so far, not encountered issues related to the inherent threat to patients’ privacy and confidentiality, usually due to unauthorized access to patient information [15]. This is particularly relevant to sexually-transmitted diseases like gonococcal infections (Table 5), and epilepsy, to mention examples. This important issue needs to be considered, as lack of confidentiality could lead to a breakdown of doctor-patient relationship[1,15]. We believe the introduction of computerization is a leap forward and the first year of implementation was a success despite limitations. Physicians in PHC centers are encouraged to retrieve, collect and use stored data for improvement of care as well as for research. Policy makers need to develop a critical appraisal of retrieved data and reports based on this retrieval and use this in planning. We recommend that health authorities lay more emphasis on users’ needs. This includes ongoing training at the practice site, provision of expert advice and meeting his information needs, particularly, clinical decision support systems. 314 Computerization in Primary Care: an Insight ACKNOWLEDGMENT The authors wish to thank Dr Muhammed AlAyyad, Director, Hawalli Health Area for his encouragement and support and the 103 primary health care physicians who painstakingly managed to enter patient data. Our thanks to Dr Faisal AF ElKhuffash, consultant paediatrician, Mubarak AlKabeer Hospital for his continued help and support during the preparation of the manuscript. 10. REFERENCES 11. 1. 2. 3. 4. 5. Ridsdale L, Hudd S. Computers in the consultation: the patient’s view. Br J Gen Practice 1994; 44:367-369. Walton R, Randall T. Communication in the year 2000. Br J Gen Practice 1994; 44:434-435. Wyatt J. Computer-based Knowledge Systems. Lancet 1991; 338:1431-1436. Heller RF, Page I. A population perspective to evidencebased medicine: evidence for population health. J Epidemiol Community Health 2002; 56:45-47. Ariza AJ, Binns HJ, Christoffer KK. Evaluating computer capabilities in a primary health care practice-based research 6. 7. 8. 9. 12. 13. 14. 15. December 2006 networks. Ann Fam Med 2004; 2:418-420. Wyatt JC. Hospital information management: The need for critical leadership. Br Med J 1995; 311:175-180. Al-Abdulghafour SYF. Annual Report, 2004. Hawalli Health Area. Westberg EE, Miller RA. The basis for using the internet to support the information needs of primary care. J Am Med Inform Assoc 1999; 6:6-25. Weisman F, Hasman A, van den Herik HJ. Information retrieval: State of the art. Int J Med Inform 1997; 47:5-26. Levinson DJ. Information, computers and clinical practice (commentary). Am J Med Assoc 1983; 5: 607-609. Covell DG, Uman GC, Manning PR. Information needs in office practice: are they being met? Ann Int Med 1985; 103:596-599. Ostbye T, Yarnall KSH, Krayse KM, Pollak Kl, Gradison M, Michener JL. Is there time for management of patients with chronic disease in primary care? Ann Fam Med 2005; 3: 209214. Fraser RG. Developing family practice in Kuwait. Br J Gen Practice 1995; 45: 102-105. Stange KC, Zyzanski SJ, Jean CR, et al. Illuminating the ‘black box’. A description of 4454 visits to 138 family physicians. J Fam Practice 1998; 46:377-389. Carman D, Britten N. Confidentiality of medical records: the patients perspective. Br J Med Practice 1995; 45:485-488. December 2006 KUWAIT MEDICAL JOURNAL Case Report Neuronal Ceroid Lipofuscinoses: Report of Five Cases in Kuwait Maliha Askar Soud Al-Bloushi 1, Jehoram T Anim 2, Yousif Kasim Habeeb 1 Department of Pediatrics, Neurology Unit, Mubarak Al-Kabeer Hospital, Kuwait 2 Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait 1 Kuwait Medical Journal 2006, 38 (4): 315-320 ABSTRACT We report upon five children with neuronal ceroid lipofuscinoses diagnosed over an eight year period (19962004) in the pediatric neurology unit of a tertiary service hospital in Kuwait. Three cases were diagnosed by lysosomal enzymes while the two other cases were confirmed by skin biopsy. Although molecular genetic studies, when available, allow for definitive diagnosis, ultrastructural studies of skin biopsy material are simple available alternative. We feel that this disorder is under diagnosed and skin biopsies should be utilized when this disorder is considered. KEYWORDS: neuronal ceroid lipofuscinoses, neurodegenerative disease, skin biopsy INTRODUCTION Neuronal ceroid lipofuscinoses (NCLs) constitute the most common group of progressive neurodegenerative diseases in children with an autosomal recessive inheritance[1,2]. Clinicopathologic and genetic studies have proved that NCLs constitute a group of highly heterogeneous disorders[3,4]. The precise cause remains undetermined but all available evidence suggest an inborn error of metabolism[5]. The NCLs include eight forms that result from genetic deficiency on genes CLN (1) to CLN (8) [6]. Four classic forms which include infantile (INCL), late infantile (LINCL), juvenile (JNCL) in addition to adult (ANCL) form and four variants of LINCL[6]. The disease is characterized by visual impairment, progressive myoclonic epilepsy, decline in cognitive and motor skills resulting in premature death[1,7,8]. The course reflects progressive neurodegeneration. The diagnosis is usually made based on demonstration of autoflourescent lysosomal lipopigment in rectal biopsies and skin biopsies[9,10]. With recent advances in molecular genetics, diagnosis of certain subtypes is possible, without the need for invasive procedures like rectal biopsies. Thus, prenatal diagnosis became an option. CASE REPORTS Case 1 BA was the first born male child of a young Kuwaiti couple who are distant relatives. He had uneventful pre and perinatal periods. He was born at term weighing 3 kg. He was seen at nine months and was considered entirely normal although his parents thought he had poor eye contact and appeared socially indifferent. There was some concern regarding his development; although he sat independently at eight months and walked unassisted at 16 months, he did not respond appropriately to verbal stimuli. He was first seen by a neurologist at the age of 22 months. By this time he was showing signs of regression as he had lost some of his acquired milestones: stopped walking independently, lost speech (he used to say up to three words), stopped laughing when tickled and lost some manual skills such as waving good bye. Examination revealed no dysmorphic features. He was socially indifferent with no eye contact and an expressionless child. His weight was on the 20th centile, length on the 40th centile but he had microcephaly (below the 3rd centile). Few myoclonic jerks were noted during examination. Ophthalmologic examination was normal including both fundi. Cranial nerve examination was normal. He could sit unsupported with good head control. He had normal power in all muscle groups but hypotonia with brisk tendon reflexes and negative Babinski sign. The rest of his examination was negative. All his laboratory investigations were normal, including blood and cerebrospinal fluid lactate, liver function, calcium, magnesium, peroxisomal address correspondence to: Dr Maliha A. AL-Bloushi, Department of Pediatrics, Mubarak Al-Kabeer Hospital, Kuwait. Tel: 5318502, Pager: 9174029, E-mail: [email protected] 316 Neuronal Ceroid Lipofuscinoses: Report of Five Cases in Kuwait December 2006 Fig. 1: H&E stained section shows brownish pigment granules in dermal fibroblasts (arrows). Fig. 2: The granules stained positively with sudan black, suggesting a ceroid-lipofuscin nature (arrows). function tests, lysosomal enzymes, urine organic acid and aminoacid chromatography and karyotype. EEG was moderately abnormal with abnormal background activity. Electroretinogram (ERG) suggested a marked disturbance with almost loss of function in the visual pathways to the cerebral cortex. Visual evoked potential (VEP) was normal. Brain MRI showed severe cerebral atrophy with hypointense thalami and incomplete myelination of the white matter. His hearing threshold was equivocal in both ears. The diagnosis of INCL and LINCL were considered which are caused by deficiency of palmitoyl protein thioesterase (PPT) and tripeptidyl amino peptidase I (TPP) respectively. PPT assay showed low levels of 0.6 nmol/hr/mg ptn (normal range of 17-139) consistent with the diagnosis of INCL with normal TPP assay. He was treated with sodium valproate for his myoclonic seizures with relatively good control. The clinical course was of progressive deterioration and regression. When last seen he was eleven years old with severe spastic quadriplegia and contractures at all joints, decorticate posturing and pendular nystagmus. Case 4 The fourth case is RS, the product of a full term delivery. She had uneventful pre, peri and neonatal periods. Her parents were related and she had one healthy brother. She was developmentally normal with no problems till the age of three years when she, according to the parents, started to lose milestones: lost speech at three years had deterioration in motor skills with frequent falls and was unable to climb stairs at four years. From the age of 4.4 years, she had frequent myoclonic seizures. We saw her for the first time at the age of five years. Examination revealed a friendly girl, interested in her surroundings. There was no dysmorphism although she had microcephaly, with weight and height on the 50th centile. Her gait was spastic. Cranial nerve examination was normal including both fundi. She had generalized hypertonia with clonus at the ankles, brisk deep tendon reflexes and positive Babinski sign. There was no weakness in any muscle groups, no neurocutaneous stigmata, normal liver size and no palpable spleen. All her laboratory investigations were normal including blood lactate, blood ammonia, liver function tests, calcium, magnesium, bicarbonate, peroxisomal function, lysosomal enzymes, urine organic acid and aminoacid chromatography karyotype. EEG was markedly abnormal. Brain MRI showed cerebral atrophy with hypointense thalami with incomplete myelination of the white matter in the occipital region. Full thickness skin biopsy confirmed the diagnosis of neuronal ceroid lipofuscinoses. Skin biopsy specimen was divided into three portions. One portion was fixed in 3% glutaraldehyde and processed for electron microscopy. A second portion was fixed in 10% buffered formalin and processed routinely for light microscopy. The third portion was sectioned fresh on a cryostat, mounted in saline and examined under fluor escence microscope. H&E stained sections showed Case 2 and 3 The second and third cases are siblings of case one, a girl (ten year old now) and a boy (eight year old) both of whom had similar presentation and course. The PPT assay was also low in both: 1.9 nmol/hr/mg ptn and 1.1 nmol/hr/mg ptn respectively. Both mother and father had the enzyme assay. It was 10.3 nmol/hr/mg ptn in the former and 20 nmol/hr/mg ptn in the latter suggestive of carrier state in both parents. All had normal TPP levels. The mother became pregnant for the fourth time in 2002 and chorionic villous sampling (CVS) of her fetus revealed PPT level of 44 nmol/hr/mg ptn. She gave birth to a healthy boy who is now two year old. December 2006 KUWAIT MEDICAL JOURNAL 317 Fig. 3: The granules demonstrate whitish autofluorescence under the fluorescence microscope (asterisk). brownish pigment granules in dermal fibroblasts (Fig. 1) as well as within sweat gland epithelium. The granules were negative with stains for melanin and haemosiderin but stained positively with sudan black, suggesting a ceroid-lipofuscin nature (Fig. 2). Electron microscopy showed amorphous densities and residual bodies (Fig. 3). The granules also demonstrated whitish autofluorescence under the fluorescence microscope (Fig. 4). She was treated with sodium valproate for her epilepsy with good control of her seizures but there was progressive deterioration in her motor skills leading to loss of ability to walk independently. Case 5 MF is a girl who was born after normal pregnancy at term to distantly related parents. She had three healthy siblings. She had acquired normal skills till the age of seven years when she had few attacks of generalized tonic clonic seizures for which she was treated with carbamazepine, with good control for two years. She presented to us at nine years of age with progressive speech loss, change in behavior and interactions and loss of sphincter control. She became withdrawn and stopped going to school because of her condition and worsening seizures. Examination revealed a wasted child, not interactive and not interested in her surroundings. Her head circumference was on the 25th centile, weight on the 10th centile and height below the third centile. There was no opthalmoplegia but she was not fixing or following. Her fundi were normal. She was unable to sit still. She had rigidity in the lower limbs more than the upper limbs. There was ankle contracture and she demonstrated intention tremor with myoclonia. She had no neurocutaneous stigmata or organomegaly. She followed a relentlessly progressive course involving loss of motor, visual and cognitive functions. She had difficulty with swallowing and Fig. 4: Electron microscopy showing amorphous densities and residual bodies. was kept on nasogastric feeding. She also developed recurrent cough probably secondary to aspiration. She was treated with sodium valproate for her epilepsy. All her investigations were normal including blood and cerebrospinal fluid (CSF) lactate, CSF routine and titers for chronic infections including measles, liver function, calcium, magnesium, blood biotinidase activity, peroxisomal function, lysosomal enzymes, karyotype, urine organic acid and aminoacid chromatography and nerve conduction study. EEG was markedly abnormal but not suggestive of subacute sclerosing panencephalitis (SSPE). Brain MRI showed hypointense thalami with increased signal intensity in the occipital white matter affecting right more than left. The diagnosis was confirmed by skin biopsy demonstrating autoflourescent intracellular material. DISCUSSION NCLs are relatively frequent group of inherited disorders. They occur world-wide with varying incidence[11]. In Europe the incidence is 1.2-1.6 / 100,000 live births[12]. Cumulative incidence was 1.61 / 100,000 live births but 0.87 / 100,000 for JNCL and 0.73 for the infantile NCL[12]. The highest reported incidence is in Finland (1:20,000 live birth)[11]. Common to all NCLs is lysosomal accumulation of autoflourescent ceroid lipopigment material in neural and extraneural cells [1,9]. The autoflourescent 318 Neuronal Ceroid Lipofuscinoses: Report of Five Cases in Kuwait December 2006 Table 1: Characterestics of the major neuronal ceroid lipofuscinoses [5] Range Onset (Yr) Mean Onset (Yr) Juvenile 4-9 5.93 ± 1.35 Late infantile/ early childhood Infantile 1-3 2.54 ± 0.71 0 - 1.5 Adult 27 - 28 Atypical Variable First Symptom Visual, behavioral Seizures 0.96 ± 0.50 Deterioration myoclonus 29.67 ± 4.80 Seizures/ motor Variable Variable Course Incidence EM (% Neuronal PredoOnset to Ceroidminant Death Lipofucinoses) Findings Genetics Chromosome Chronic 16 49 FP AR D16 Acute 6 21 CL AR Not D16 Acute 4 9 GR AR DI Chronic > 20 9 GR AR/AD UNK Variable > 20 12 Variable Unknown Unknown FP = Fingerprint cytosomes; CL = curvilinear cytosomes; GR = granular cytosomes; AR = autosomal recessive; AD = autosomal dominant; UNK = unknown genetics; D = chromosome intracellular lipopigment tend to distend the cytoplasm of affected cells. Despite the multisystem distribution, only brain tissue shows severe dysfunction and cell death[4,5]. It is now known that ceroid and lipofuscin are composed of many different substances, including lipids, waxy pigments and a variety of proteins[5]. The cytosomes consists of mixtures of four distinct and characteristic membrane-bound osmiophilic profiles; classic lipofuscin, fingerprint profiles which predominate in chronic juvenile form, curvilinear inclusion bodies in infantile forms and pure granular profiles which predominate in some infantile and in late adult type[5]. The disorder is characterized by visual impairment, progressive myoclonic epilepsy, cognitive decline and premature death[1,7, 8]. The course reflects progressive neurodegeneration. Eventually every patient shows psychomotor deterioration. The outcome is always lethal within a few years[13]. Retinal degeneration is an early consequence[14,15]. The electroretinogram (ERG) is abnormal early in all three types of childhood NCL and eventually is totally ablated[14,16]. The NCLs are subdivided into several subtypes (Table 1) according to age of onset, clinical course and ultrastructural features of the storage material. The three main childhood varieties include infantile NCL (INCL) or (CLN1), late-infantile NCL ( LINCL) or (CLN2) and juvenile NCL (JNCL) or (CLN3)[8,17]. Molecular genetics of these three subtypes was recently clarified. In the first subtype, INCL, or Santavuori - Haltia - Hagberg disease, there are mutations in genes encoding a lysosomal enzyme, palmitoyl protein thioesterase 1(PPT1) with locus CLN1 on chromosome 1p32[18]. This type is associated with predominance of granular inclusions in biopsied material. Cases 1-3 in this study represent this subtype based on demonstration of low PPT levels in the subjects and borderline levels in both parents making them obligate carriers. Mutations in CLN1 gene also result in different childhood phenotypes (LINCL and JNCL) with granular osmiophilic deposits[18,19]. In addition to childhood forms, mutations in this gene also result in NCL in adults with onset in the fourth decade [20]. All CLN1 patients are deficient in PPT1. Similar to childhood forms with granular osmiophilic deposits, few cases were reported in a ANCL with autosomal dominant inheritance (Parry type) but interestingly with normal PPT1 enzyme level probably indicating gene distinct from CLN1-CLN8 genes [21]. The second subtype, LINCL, or JanskyBielschowsky disease, is caused by mutations in CLN2 gene which encodes a lysosomal enzyme tripeptidyl peptidase 1 (TPP1) with locus on chromosome 11p15[2,18]. The fourth case is an example of this subtype based on the age of presentation and characteristic inclusions seen in the skin biopsy. The third subtype, JNCL or Batten disease, is caused by mutations in gene encoding a 438aminoacid membrane protein (CLN3 on chromosome 16p12.1) commonly related to 1.02kb deletion[5,18]. There is predominance of curvilinear inclusion bodies in biopsied material. This is represented by our fifth case. As in this case, it is characterized clinically by visual and behavioral problems with slow progression over a few years [5]. The mean age of onset is 5.93 ± 1.35 years with onset between four and nine years. In contrast to our case, seizures occur later in life. Usually, the initial symptom is visual deterioration but in our case speech loss was the initial concern. It is possible that visual problems were not noted initially or were overshadowed by more obvious symptoms of speech loss and impaired interaction. Other childhood forms include Finnish variant LINCL (CLN5) with locus on chromosome 15q21- December 2006 KUWAIT MEDICAL JOURNAL 23[18] and Northern epilepsy or progressive epilepsy with mental retardation (CLN8)[22]. A total of 114 mutations have been described in the five human genes which cause NCL [23]. Early diagnosis is mandatory for avoiding further cases in families with hereditary metabolic brain disorders[24]. Diagnosis is made on the basis of clinical, electrophysiological, radiological and pathologic examination including electron microscopy[6]. Although only biochemical and molecular gentetic studies allow for definitive diagnosis, ultrastructural studies of biopsy material are still very useful [2]. Numerous tissues and organs are available for biopsy, among them brain (historical), rectum, skeletal muscle and peripheral nerve (largely by coincidence), skin and conjunctiva (the latter inferior to former in diagnostic yield) [10]. Unfortunately, the most convenient diagnostic method of examining circulating lymphocytes was not done. Treatment includes supportive measures and anticonvulsant medication. Neuropathologic and neuroradiologic explanation of clinical symptomatology correlates best with neuronal loss and not neuronal storage[25]. This neuronal loss especially of dopaminergic neurons makes patients with JNCL and ANCL more susceptible to develop a life-threatening condition, neuroleptic malignant syndrome, after exposure to antipsychotic therapy. It should be considered when these patients develop hyperthermia, autonomic instability, extrapyramidal symptoms with or without altered level of consciousness. A high index of suspicion with early intervention is vital to avoid lethal outcome of neuroleptic malignant syndrome[26-28]. Early diagnosis is important for genetic counseling. Delay in diagnosis could be avoided by high index of suspicion in patients with unexplained visual loss, careful examination of lymphocytes for vacuolation and inclusion bodies together with molecular genetics studies. If our first case was diagnosed early in the course, genetic counseling and perinatal diagnosis would have helped the family to avoid having further cases. Whether this is a true statement or not, is to be debated as abortion is generally prohibited in Islamic culture with only few exceptions. However, the first family in this study did resort to this option. REFERENCES 1. 2. Weimer JM, Kriscenski-Perry E, Elshatory Y, Pearce DA. The Neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease. Neuromolecular Med 2002; 1:111-124. Wisniewski KE , Kida E, Golabek AA, Kaczmarski W , 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 319 Connel F, Zhong N. Neuronal ceroid lipofuscinoses: classification and diagnosis. Adv Genet 2001; 45:1-34. Mitchison HM, Mole SE. Neurodegenerative disease: The neuronal ceroid lipofuscinoses (Batten disease). Curr Opin Neurol 2001; 14:795-803. Kida E, Golabek AA, Wisniewski KE. Cellular pathology and pathogenic aspects of Neuronal ceroid lipofuscinoses . Adv Genet 2001; 45:35-68. Dyken PR. Neuronal ceroid-lipofuscinoses. Pediatrics Neurology, Principles and Practice, 1999:839-846. Zong N. Neuronal ceroid lipofuscinoses and possible pathogenic mechanism. Mol Genet Metab 2000; 71:195-206. Peltonen L, Savukoski M, Vesa J. Genetics of the neuronal ceroid lipofuscinoses. Curr Opin Genet Dev 2000; 10:299305. Goebel HH. The neuronal ceroid-lipofuscinoses. Semin Pediatr Neurol 1996; 3:270-278. Sondhi D, Hackett NR, Apblett RL, Kaminsky SM, Pergolizzi RG, Crystal RG. Feasiblilty of gene therapy for late neuronal ceroid lipofuscinosis. Arch Neurol 2001; 58:1793-1798. Goebel HH. Morphologic diagnosis in Neuronal ceroid lipofuscinosis. Neuropediatrics 1997; 28:67-69. Santavuori P, Lauronen L, Kirveskari E , Aberg L, Sainio K, Autti T. Neuronal ceroid lipofuscinoses in childhood. Neurol Sci 2000; 21:35-41. Crow YJ, Tolmie JL, Howatson AG , Patrick WJ, Stepenson JB. Batten disease in the west of Scotland 1974-1995 including five cases of the juvenile form with granular osmiophilic deposits. Neuropediatrics 1997; 28:140-144. Jongen PJ, Gabreels FJ, Stekhoven JH, Renier WO, Le Coultere R, Begeer JH. Early infantile form of neuronal ceroid lipofuscinosis. Four Dutch cases and review of the literature. Clin Neurol Neurosurg 1987; 89:161-167. Wilkinson ME. Ceroid lipofuscinosis, neuronal 3, JuvenileBatten disease: case report and literature review. Optometry 2001; 72:724-728. Birch DG. Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: An overview. Mol Genet Metab 1999; 66:356-366. Weleber RG. The dystrophic retina in multisystem disorders:the electroretinogram in neuronal ceroid lipofuscinoses. Eye 1998; 12:580-590. Gardiner RM. Genetic analysis of Batten disease. J Inherit Metab Dis 1993; 16:787-790. Mole S, Gardiner M. Molecular genetics of the Neuronal ceroid lipofuscinoses. Epilepsia 1999; 40:29-32. Wisniewski KE, Kida E, Connel F, Zhong N. Neuronal ceroid lipofuscinoses research update. Neurol Sci 2000; 21:S49-56. Van Digglen OP, Thobois S, Tilikete C, et al. Adult Neuronal Ceroid Lipofuscinosis with Palmitoyl-Protein Thioesterase Deficiency: First adult-onset patients of a childhood disesase. Ann Neurol 2001; 50:269-272. Nijssen PC, Ceuterick C, van Diggelen OP, et al. Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency. Brain Pathol 2003; 13:574-581. Ranta S, Lehesjoki AE. Northern epilepsy, a new member of the NCLfamily. Neurol Sci 2000; 21:S43-47. Mole SE, Zhong NA, Sarpong A, et al. New mutations in the neuronal ceroid lipofuscinosis genes. Eur J Paediatr Neurol 2001; 5:7-10. Santavuori P, Vanhanen SL, Autti T. Clinical and neuroradiological diagnostic aspects of neuronal ceroid lipofuscinoses disorders. Eur J Paediatr Neurol 2001; 5:157161. 320 Neuronal Ceroid Lipofuscinoses: Report of Five Cases in Kuwait 25. Boustany RM. Neurology of neuronal ceroid- lipofuscinoses: late infantile and juvenile types. Am J Med Genet 1992; 42:533-535. 26. Vercammen L, Buyse GM, Proost JE, et al. Neuroleptic malignant syndrome in juvenile neuronal ceroid lipofuscinosis associated with low-dose risperidone December 2006 therapy. J Inherit Metab Dis 2003; 26:611-612. 27. Refi A, Schneider MF, Hoyer A, et al. Neuroleptic malignant syndrome in Kufs’ disease. J Neurol Neurosurg Psychiatry 2003; 74:385-387. 28. Gupta S, Nihalani ND. Neuroleptic Malignant Syndrome. Prima Care Companion J Clin Psychiatry 2004; 6:191-104. December 2006 KUWAIT MEDICAL JOURNAL Case Report Adrenal Carcinoma with Cardiac Metastasis in a Child: Case Report Abdelmohsen Ben-Nakhi, Ali Hussain, Khaledah Dashti Department of Radiology, Mubarak Al-Kabeer Hospital, Ministry of Public Health, Kuwait Kuwait Medical Journal 2006, 38 (4): 321-323 ABSTRACT Adrenal carcinoma is very rare in children, and cardiac metastasis from this tumor is even rarer. We present such a case and discuss its management. A ten year old boy presenting with hirsutism was referred to the radiology department of Mubarak Al-Kabeer Hospital for investigation. The investigations performed included US of the abdomen and CT examination of the chest and abdomen. In addition, the patient also had hormonal and routine biochemical investigations. The Ultrasound and CT examinations revealed a solid mass arising from the right adrenal gland, infiltrating into the inferior vena cava and extending into the right atrium. Ultrasound guided fine needle aspiration of the mass, confirmed the diagnosis of adrenal carcinoma. The case is reported because of its rare nature. KEYWORDS: adrenal carcinoma, cardiac metastasis, imaging INTRODUCTION Adrenocortical carcinoma is a rare malignancy in childhood[1, 2] . Extension of this tumor through the IVC into the right atrium is even rarer. The estimated incidence of this tumor is about 1 in 1, 700,000[1]. There are limited reports of cases with extension into the IVC and the right atrium. To our knowledge only ten such cases have been previously reported including one case with a tumor in the left adrenal gland[3]. We report the case of a ten year old boy with a right adrenocortical carcinoma, extending into the IVC and the right atrium. To our knowledge this is the first case report from the middle east region. CASE REPORT A ten-year-old Omani boy presented in January 2001 with a three month history of weight gain and edema of both lower limbs in addition to features of precocious puberty (facial, axillary and pubic hair) for two years. Physical examination revealed a short-statured and grossly overweight child with signs of precocious puberty. The genitalia appeared small and an adequate examination was not possible because of gross obesity. Examination of the cardio-vascular system at the time of admission revealed raised BP (165/95) and pansystolic murmur over the tricuspid area. On abdominal examination an ill defined mass was palpable in the right hypochondrium extending to the right lumbar region. Hormonal study revealed that testosterone (47 nmol/l), 17 OH progesterone (21 nmol/l), DHEAS (45 nmol/l) and androstendione (14 nmol/l) were all raised. The serum biochemistry, liver and renal functions were unremarkable. Ultrasound examination of the abdomen showed a large solid mass arising from the right adrenal gland measuring 12 cm in diameter, infiltrating into the IVC (Fig 1a) and extending into the right atrium (Fig 1b). CT scan of the chest and abdomen was done for further workup. It confirmed the right adrenal mass (Fig 2a) extending into the IVC (Fig 2b) and the right atrium (Fig 2c). The lungs were clear and there was no evidence of bone metastasis of the scanned bones. The intracardiac extension of the mass was also confirmed on echocardiogram. Ultrasound guided fine needle aspiration biopsy confirmed adrenocortical carcinoma. The child’s parents refused any treatment and got discharged against medical advice. The child was readmitted two weeks later with acute cardiac failure and died on the third day of admission. DISCUSSION Adrenal cortical carcinoma is a rare tumor in children comprising only 0.2 % of all childhood malignant tumors. It often presents with a large Address correspondence to: Dr. Abdelmohsen Ben-Nakhi, Department of Radiology, Mubarak Al-Kabeer Hospital, P.O. Box 43787, Code-32052 Hawally, Kuwait. Tel: +965 5336856, Mobile: +965 6322229, Fax: + 965 5618866, E-mail: [email protected] 322 Adrenal Carcinoma With Cardiac Metastasis in a Child: Case Report Fig 1a December 2006 Fig 1b Fig 1: Ultrasound examination showing large tumor thrombus in the IVC (a) [arrows] extending into the right atrium (b) Fig 2a Fig 2c Fig. 2: CT scan of upper abdomen showing the large adrenal mass infiltrating into the IVC (a & b [arrow heads]) and extending into the right atrium (c) [arrows] Fig 2b abdominal mass and signs of precocious puberty[1]. Despite its often dramatic presentation, there typically is long delay between the onset of symptoms and the time of diagnosis. The clinical features of the tumor include those caused by the local mass effect, such as flank pain and abdominal fullness and of those caused by unregulated hormone production by the tumor[4]. With cortical over production signs and symptoms of Cushing’s syndrome are noted. Androgen secretion, which is less common, results in virilization, hirsutism and amenorrhea. The clinical features of right atrial involvement are due to central pulmonary embolization and cardiac and / or valve obstruction, often with associated congestive heart failure. Ultrasound, CT and MRI studies are the main and effective imaging investigations in assessing the local as well as the IVC and intracardiac extension of the tumor[5]. MRI is shown to be the December 2006 KUWAIT MEDICAL JOURNAL most sensitive method of diagnosing virilising adrenocortical tumors in children[6]. The use of Ga67 scintigraphy in detecting tumor recurrence and in assessing response to therapy has been reported[1]. Due to the delay in diagnosis, adrenocortical carcinoma is a fatal disease with poor prognosis. Complete surgical resection is the only treatment that offers potentially long term disease free survival[4]. Chemotherapy with Ortho Para DDD is recommended for treatment of residual or recurrent tumor after surgery or for patients with metastatic disease. The mean survival without treatment is approximately three months and with treatment the five years survival is about 30%. The poor prognosis is mainly due to the long delay between the symptoms and the time of diagnosis. In conclusion, it is imperative that the physician performs cardiovascular examination in suspected 323 or proven cases of adrenal carcinoma and recognize the endocrine manifestations of the tumor for prompt treatment. REFERENCES 1. 2. 3. 4. 5. 6. Giles RH, Pozza LD, Uren R. Ga-67 scintigraphy in a child with adrenocortical carcinoma. Clinical Nuclear Medicine 1993; 18:642-645. Zderic SA. Renal and adrenal tumors in children. Urol Clin North Am 2004; 31:607-617. Lee JJ, Kupfer J, Raissi S, Geller SA and Siegel RJ. Rapid Extension of left adrenocortical carcinoma into the right atrium. Journal of American Society of Echocardiography 1998; 11:86-88. Dunnick NR. Adrenal Carcinoma. Radiology Clinic North Am 1995; 32:99-108. Ribeiro J, Ribeiro RC, Fletcher BD. Imaging findings in pediatric adrenocortical carcinoma. Pediatr Radiol 2000; 30:45-51. Bonfig W, Bittmann I, Bechtold S, Kammer B, Noelle V, Arleth S, Raile K, Schwarz HP. Virilising adrenocortical tumours in children. Eur J Pediatr 2003; 162:623-628. KUWAIT MEDICAL JOURNAL December 2006 Case Report Excision of Ventricular Cysts of Larynx using Zero Degree and 30 Degree Endoscope Pradeep Shenoy, Sohail Abdul Malik, Rashid Al Duwillah, Department of Otorhinolaryngology, Armed Forces Hospital, Kuwait Kuwait Medical Journal 2006, 38 (4): 324-325 ABSTRACT A case of ventricular cyst of larynx has been described, where 0º and 30º nasoendoscope was used to get good access and complete excision. Clinical presentation and treatment of ventricular cyst of larynx in literature has been discussed. Though these are rare they could present as an emergency at any age. KEY WORDS: deroofing, marsupialization, unroofed, ventricular cyst of larynx, 0º and 30º rigid nasoendoscope CASE REPORT A 23-year-old male patient attended the ENT clinic with dysphonea, muffled voice and painful swelling in the left side of the neck for the past three days. Indirect laryngoscopy revealed pooling of saliva and a globular cystic swelling in the left ventricle. Neck examination unveiled a diffuse swelling in the left anterior triangle. After 48 hours of intravenous antibiotics and steroids, the ventricular and neck swelling was more localized. It was confirmed by X - ray (Fig. 1) and CT scan of neck (Fig. 2). CT scan of the neck showed a well-defined peripherally enhancing cystic lesion in the supraglottic compartment of the larynx measuring 3.6 x 3 x 1.7 cm in size and it was arising from the left ventricle, extending into the lumen medially and paraglottic space laterally through the thyrohyoid membrane. Fiberoptically guided nasoendotracheal intubation was done. Boyle-Davis gag with a long tongue blade was used to get good exposure and the cyst was decapped using 0º and 30º Hopkins nasoendoscope (Fig. 3). The raw area after unroofing was cauterized (Fig. 4). Postoperative period was uneventful. The patient was discharged after 48 hours with no further recurrence. DISCUSSION Laryngeal ventricle cysts are rare and less common in the pediatric population than in adults[1]. Congenital laryngeal cyst has an incidence of 1.82 per 100,000 live births[2]. Congenital cysts are asymptomatic unless they are large enough to cause stridor and respiratory obstruction in infants and children[3]. The most common symptoms of a laryngeal cyst are hoarseness, local foreign body sensation and dysphonea[4]. Small cysts are not obvious at endoscopy and are indeed buried below the mucosa in soft tissues[5]. Flexible fiberoptic laryngoscopy could help to detect medium and large cysts[2]. CT scan proved useful for intralaryngeal location and planning of the surgical excision[6]. Small and medium sized cysts are excised using carbondioxide laser[7] or cup forceps[5]. Endoscope deroofing is as effective as endoscopic excision but is technically simpler and thus is recommended as the treatment of choice[2]. Recurrence rate is higher after endoscopic marsupialization procedures[8]. Repeated needle aspiration of the cyst failed to provide sustained clinical improvement[6]. Laryngeal cysts, when they are large and becomes extra laryngeal by piercing the thyrohyoid membrane are excised by paramedian or laryngofissure approach[3]. CONCLUSION We have reported and discussed the clinical presentation of a ventricular cyst in an adult. Rigid Hopkins fiberoptic nasoendoscope (0º and 30º) was used to access the cyst and complete its excision. ACKNOWLEDGEMENT Our special thanks to Colonel Ali Ahmed Essa, Director of Armed Forces Hospital, Kuwait for his kind permission to present this case study and to Mr C M Khan, Medical Secretary for his secretarial assistance. Address correspondence to: Dr. Pradeep Shenoy, DLO, FRCS, Post Box No. 8728, 22058 - Salmiya, Kuwait. Tel: 5623257 (Res), 9756935 (Mobile), Fax: +965 - 5623257, Email: [email protected] December 2006 KUWAIT MEDICAL JOURNAL Fig. 1: Plain X-ray of the ventricular cyst Fig. 2: CT Scan of ventricular cyst Fig. 3: Endoscopic view of ventricular cyst Fig. 4: Endoscopic view after unroofing and cautry REFERENCES 5. 1. 2. 3. 4. Civantos FJ, Holinger LD. Laryngoceles and saccular cysts in infants and children. Arch Otolaryngol Head Neck Surg 1992; 118:296-300. Pak MW, Woo JK, Van Hasselt CA, et al. Congenital laryngeal cysts: Current approach to management. J Laryngol Otol 1996; 110:856-858. Forte V, Warshawski J, Thorner P, et al. Unusual laryngeal cysts in the newborn. Int J Pediatr Otorhinolaryngol 1996; 37:261-267. Newman BH, Taxy TB, Laker HI, et al . Laryngeal cysts in adults: A clinicopathologic study of 20 cases. Am J Clin Pathol 1984; 81:715-720. 6. 7. 8. 325 Torium DM, Miller DR, Holinger LD. Acquired subglottic cysts in premature infants. International Journal of Paediatric Otolaryngology 1987; 14:151-160. Ostfield E, Hazan I, Rabinson S, et al. Surgical management of congenital supraglottic lateral saccular cysts. International Journal of Paediatric Otorhinolaryngology 1990; 19:289-294. Martinez Devesa P, Gherfoor K, Lioyd S, et al. Endoscopic CO2 Laser management of laryngocele. Laryngoscope 2002; 112:1426-1430. Hogikyan ND, Bastian RW. Endoscopic CO2 Laser excision of large or recurrent laryngeal saccular cysts in adults. Laryngoscope 1997; 107:260-265. 326 KUWAIT MEDICAL JOURNAL December 2006 Case Report Sickle Cell Intra-Hepatic Cholestasis : A Rare but Fatal Disease Saad Al-Zanki, Moza Al-Saleh Department of Medicine, Al-Amiri Hospital, Kuwait Kuwait Medical Journal 2006, 38 (4): 326-328 ABSTRACT Sickle cell intra-hepatic cholestasis is a rare but potentially fatal complication of sickle cell disease. It is characterized by fever, jaundice, tender hepatomegaly, coagulopathy and acute liver failure. Early identification is essential and the only effective treatment reported is exchange transfusions. We describe one Hemoglobin SS patient and review the literature. KEYWORDS: exchange transfusions, jaundice, sickle cell intra-hepatic cholestasis, INTRODUCTION In clinical studies, it was noted that there is an association between sickle cell disease and hepatic dysfunction[1-5].These dysfunctions occur mainly in patients with homozygous sickle cell anemia but to a lesser extent in patients with sickle cell trait, sickle C disease and hemoglobin S B-thalassemia. One of the rare but potentially fatal complications of sickle cell anemia is known as sickle cell intra-hepatic cholestasis, a clinical syndrome thought to represent a severe form of hepatic crisis[3]. Sickle cell intrahepatic cholestasis is characterized by the acute onset of hepatomegaly, extreme hyperbilirubinemia with a level of 273 mg/dl (around 4600 µmol/l) documented in one patient[6], coagulopathy and acute liver failure[4,7]. Recent reports have described reversal of this process within 48 hours in seven patients with vigorous exchange transfusions and correction of coagulopathy with fresh frozen plasma [6,8-12]. We describe one patient with sickle cell anemia with recurrent admissions due to fever, jaundice, leukocytosis, coagulopathy and extreme hyperbilirubinemia. We also describe the types of hepatic injuries and clinical syndromes found in sickle cell anemia patients with particular attention to sickle cell intra-hepatic cholestasis. CASE REPORT Mr HN is a 22-year-old Kuwaiti male studying Dentistry in Egypt and who is known to have sickle cell disease. He presented to the medical department complaining of fever and generalized body aches for two days accompanied by jaundice. He informed that jaundice was on and off for the last Address correspondence to: Dr.Saad AL-Zanki, Mishref [email protected] two years and was associated with intermittent episodes of itching and dark urine. This was on a background history of intermittent right upper quadrant pain, anorexia and weight loss of six kilograms over the last two months. There was no history of nausea, vomiting, bleeding or change in bowel habits. He stated that he was admitted once at the age of six years for an exchange transfusion, but he denie any previous admissions with vaso-occlusive crises. He was on ibuprofen and mefenamic acid for pain and on phenobarbitone for itching. On physical examination, he was febrile and deeply jaundiced with a pulse rate of 90 per minute (regular) and a blood pressure of 110/70 mmHg. He had no stigmata of chronic liver disease and no hepatic flab. Abdominal examination revealed a tender upper abdomen with a hepatomegaly of 3 cm below the costal margin. Other systems examination was unremarkable. His initial investigations showed the following; FBC: Hb 114 g/l; MCV 104.2 fl (80-96 fl); WBC 15.7 x 109 /l; Platelets 223 x 10 9 /l and Reticulocyte count of 5.7 %. LFT showed total bilirubin 417 µmol/l; direct bilirubin 236.3 µmol/l; ALT 329 IU/l; AST 826 IU/l; LDH 1248 IU/l; ALP 625 IU/l; Amylase 324 IU/l. Urine routine and microscopy revealed trace proteins; +urobilinogen; +bilirubin; +erythrocytes. Serum urea and electrolytes were normal. An abdominal ultrasound was normal apart from one single large stone in the gallbladder with no CBD dilatation. P.O.Box 1813, Zip code 40169, Kuwait. Tel: +965- 53882376, Mob: +965- 9852353, E-mail: December 2006 KUWAIT MEDICAL JOURNAL Fig 1: Liver biopsy showing early fine fibrosis (top arrow) and bile duct proliferation (bottom arrow) [H&E x 300] HN was admitted to the medical ward where i.v. fluids, cefotaxime and metronidazole were initiated. The next morning, an urgent ERCP was done which was found to be normal apart from the single large gallbladder stone. Later, the hematologist and hepatologist were consulted. Our hematologist advised for exchange transfusion and the hepatologist asked for the following investigations: Ceruloplasmin: normal. Ferritin 1185.9 µg/l (20260 µg/l); IgA6.22 g/l (0.8-4 g/l); IgG 17.2 g/l (7-18 g/l); IgM 0.82 g/l (0.4-2.5 g/l). ANA, AMA, LKM, ASM and reticulin were negative. Virology screening: Hep BsAg (negative); Anti HCV (negative); HIV test (negative) Hemoglobin electrophoresis post first exchange transfusion showed: HbF 3%, HbS 35%, HbA2 2.2%. Four days later, the condition of the patient improved and all cultures were found to be negative. On the seventh day, the patient was discharged home and his liver function tests on discharge were as follows: Total bilirubin 415 µmol/l; direct bilirubin 271.4 µmol/l; ALT 55 IU/l; AST 187 IU/l; ALP 103 IU/l. Ten days post discharge, the patient was readmitted with fever, deep jaundice and right upper quadrant pain. Serum biochemical findings included AST/ALT 157/56 IU/l; total bilirubin 593 µmol/l; direct bilirubin 374 µmol/l; ALP 99 IU/l; Reticulocyte count was 7.22%; LDH was not done. Next day, a liver biopsy was done and showed: bile plugs in some bile ducts; moderately expanded portal tracts with edema; bile duct proliferation (Fig.1); early fine fibrosis (Fig.1); sickled cells in sinusoids (Fig. 2); areas of peliosis hepatic; mild siderosis in kupffer cells. These histologic findings are consistent with a major bile duct obstruction; therefore, a second ultrasound abdomen was done which showed mild common bile duct dilatation of six mm with mild intra-hepatic dilatation. It was followed by a second ERCP which was the same as the first one and papillotomy was done. Post- 327 Fig 2: Liver biopsy showing sickled cells in sinusoids (arrows) [H&E x 300] procedure, the patient had worsening of his liver function biochemistry and was discharged against medical advice. Three weeks later, the patient was admitted again with abdominal pain, nausea and vomiting. His liver function test showed; total bilirubin 433 µmol/l; direct bilirubin 213 µmol/l; ALT 33 IU/l; AST 127 IU/l; ALP 158 IU/l. The patient agreed for a second exchange transfusion (40 days after the first one) and liver function biochemistry showed ; total bilirubin 342 µmol/l; direct bilirubin 164 µmol/L; ALT 22 IU/l; AST 99 IU/l; ALP 102 IU/l. Ten days later, a third exchange transfusion was done with a liver biochemistry post transfusion showing; total bilirubin 192 µmol/l; direct bilirubin 95 µmol/l; ALT 34 IU/l; AST 137 IU/l; ALP 127 IU/l. Later, the patient decided to travel to the UK for continuation of his treatment. On discharge, his HbS was 18%. Patient expired two months later. DISCUSSION Hepatic injuries in sickle cell disease most commonly occur due to multiple transfusions secondary to iron overload, or acute/chronic hepatitis C. It can also occur as a complication of chronic hemolysis, like the development of pigment stones with consequent cholecystitis or choledocholithiasis. Furthermore but less common, hepatic injury can be directly related to the sickling process and hence the term most often used to describe these syndromes is sickle cell hepatopathy e.g., acute hepatic crisis and hepatic sequestration crisis. Sickle cell intra-hepatic cholestasis is a rare form of sickle cell hepatopathy. It is potentially fatal with a poor prognosis[3,13-16]. Therefore, early identification is essential. It is thought to represent a severe form of hepatic crisis [3]. The presentation is similar to acute sickle hepatic crisis with fever, right upper quadrant pain, nausea, vomiting, tender hepatomegaly and a 328 Sickle Cell Intra-Hepatic Cholestasis : A Rare but Fatal Disease striking jaundice. Sheehy[3] described this syndrome as a very severe form of hepatic crisis marked by sudden onset of severe right upper quadrant pain, progressive hepatomegaly, coagulopathy with hemorrhage and extreme hyperbilirubinemia. In one case report, bilirubin level reached 273 mg/dl[6] (around 4600 µmol/l). This is caused by a combination of ongoing hemolysis, intra-hepatic cholestasis and renal impairment. Despite its fatality, we were able to find reports describing seven patients who did survive with vigorous exchange transfusions and correction of coagulopathy with fresh frozen plasma [6,8-12]. Shao and Orringer[9] have described two cases of sickle cell intra-hepatic cholestasis with similar presentations, but in which very different therapeutic approaches led to very different clinical outcomes. The first patient presented with jaundice, right upper quadrant pain, nausea, fever and leukocytosis. Ultrasound abdomen showed multiple gallbladder stones with no ductal dilatation. The decision was made to perform a cholecystectomy for him. The procedure went well with no complications but eleven days later the patient expired. The second patient had similar clinical features and even worse blood chemistry. His surgery was cancelled and the decision was made to perform exchange transfusions using packed red blood cells and fresh frozen plasma. Post exchange transfusion, all his hematological parameters improved and he underwent an uneventful cholecystectomy six weeks later. They concluded that early identification of this clinical syndrome is essential, as exchange transfusions with both packed red blood cells and fresh frozen plasma can often correct the coagulopathy. They also suggested that any type of surgical intervention is best deferred until the patient has had sufficient time to recover from the acute illness. In our patient, sickle cell intra-hepatic cholestasis was not the first in our list of differential diagnosis, first due to its rarity, and secondly due to the fact that this patient had a fairly uncomplicated sickle cell anemia over twenty two years of his life, with no history of vaso-occlusive crisis or regular exchange transfusions. Once the diagnosis had been made and exchange transfusions started, the patient’s condition along with his liver function biochemistry improved dramatically. In summary, we have reported a case of sickle cell intra-hepatic cholestasis. Whereas the presenting manifestations include fever, right upper quadrant pain, tender hepatomegaly and leukocytosis, the most striking clinical feature is extreme hyperbilirubinemia. December 2006 Awareness and early recognition of this potentially fatal condition is important, as exchange transfusions can often reverse the process of intra-hepatic cholestasis and can be life saving. ACKNOWLEDGMENT We thank all our friends and colleagues in Dr S Narayanan’s unit in Amiri Hospital, Kuwait for their support. We would also offer special thanks to Dr S Narayanan, consultant physician, Dr John Patrick Madda, consultant pathologist and Dr Amal Khamis, consultant hematologist for their time, effort and advise in the preparation of this report. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Bauer TW, Moore GW, Hutchins GM. The liver in sickle cell disease. A clinicopathologic study of 70 patients. Am J Med 1980; 69:833-837. Jonson CS, Omata M, Tong MJ, Simmons JF Jr., Weiner J, Tatter D. Liver involvement in sickle cell disease. Medicine 1985; 64:349-356. Sheehy TW. Sickle cell hepatopathy. South Med J 1977; 70:533-538. Schbert TT. Hepatobiliary system in sickle cell disease. Gastroenterology 1986; 90:2013-2021. Rosenblate HJ, Eisenstein R, Holmes AW. The liver in sickle cell anemia.A clinical-pathologic study. Arch Pathol 1970; 90:235-245. Stephan JL, Merpit-Gonon E, Richard O, Raynaud-Ravni C, Freycon F. Fulminant liver failure in a 12-year-old girl with sickle cell anemia: favourable outcome after exchange transfusions. Eur J Pediatr 1995; 154:469-471. Serjeant GR. The liver. In: Sickle cell disease. Oxford, England: Oxford University Press; 1985, p 101-108. Sheehy TW, Law DE, Wade BH. Exchange transfusion for sickle cell intrahepatic cholestasis. Arch Intern Med 1980; 140:1364-1366. Shao SH, Orringer EP. Sickle cell intrahepatic cholestasis: approach to a difficult problem. Am J Gastroenterol 1995; 90:2048-2050. Svarch E, Gonzalez A, Villaescusa R, Basanta P. Plasma exchange for acute cholestasis in homozygous sickle cell disease. Haematologia 1986; 9:49-51. Morrow JD, McKenzie SW. Survival after intrahepatic cholestasis associated with sickle cell disease. J Tenn Med Assoc 1986; 79:199-200. Betrosian A, Balla M, Kafiri G, Palamarou C, Sevastos N. Reversal of liver failure in sickle cell vaso-occlusive crisis. Am J Med Sci 1996; 311:292-295. Green TW, Conley CL, Berthrong M. The liver in sickle cell anemia. Bull J Hopkins Hosp 1953; 92:99-122. Song YS. Hepatic lesions in sickle cell anemia. Am J Pathol 1957; 33:331-344. Klion FM, Weiner MJ, Schaffner F. Cholestasis in sickle cell anemia. Am J Med 1964; 37:829-832. Owen DM, Aldridge JE, Thompson RB. An unusual hepatic sequela of sickle cell anemia: A report of five cases. Am J Med Sci 1965; 249:175-185. December 2006 KUWAIT MEDICAL JOURNAL Case Report Carbamezepine Induced Pseudolymphoma Shahid Aziz, Abdulkarim Al Aska, Ayman M Al Kharabah Department of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia Kuwait Medical Journal 2006, 38 (4): 329-331 ABSTRACT Aromatic anticonvulsants like phenytoin, carbamezepine, and phenobarbitone are rarely associated with a syndrome that mimics malignant lymphoma and is known as pseudolymphoma syndrome (PLS). A 20-yearold female after being started on carbamezepine for epilepsy for four weeks presented with two-week history of high grade fever with chills and rigors, a generalized itchy erythematous rash, lymphadenopathy, jaundice and hepato-splenomegaly. Her complete blood count (CBC) showed eosinophilia (17%) and liver function tests (LFTs) showed marked elevation of transaminases and direct hyperbilirubinemia. Lymph node biopsy showed reactive hyperplasia. She improved dramatically after stopping her carbamezepine therapy and is doing fine on topiramate 400 mg orally twice daily. With a two year follow up, there was no recurrence of the reported symptoms. The differentiation of PLS from true lymphoma is very important as making a wrong diagnosis of malignant lymphoma in a patient with PLS can be catastrophic. KEYWORDS: anticonvulsant therapy, lymphoma INTRODUCTION Pseudo lymphoma syndrome is a rare side effect of anticonvulsant therapy characterized by fever, skin rash and lymphadenopathy that mimics malignant lymphoma and mycosis fungoides. The condition is potentially life threatening and clinician awareness of this rare side effect of anticonvulsant therapy is important because early recognition and withdrawal of the offending agent most of the times results in dramatic and complete recovery, although death can occur with extensive skin involvement, liver failure or agranulocytosis. CASE REPORT A 20-year-old female patient presented with a two-week history of high grade fever with sweating, chills and rigors. Fever was associated with a generalized erythematous itchy rash all over her body. For the last one week she also noticed yellow discoloration of her eyes and skin with dark colored urine. She had been on carbamezepine therapy for tonic-clonic seizures for the past four weeks. There was history of joint pains in all the joints without redness or swelling and limitation of movement on examination. She had a temperature of 39 ºC, a pulse rate of 110/min and was jaundiced, with bilateral submandibular, cervical and axillary lymph nodes 2-3 cm in size, firm, non-tender and mobile. There was an erythematous, maculopapular rash involving her face, trunk, back and limbs with scratch marks over it. She had hepato-splenomegaly as well. Rest of her systemic examination was u n remarkable. Her CBC and LFT results are summarized in Table 1 and 2 respectively. Her chest X-ray was normal. Serum carbamezepine level was 3.1 mg/ml and a throat swab showed no growth. Her IgM antibodies to cytomegalovirus (CMV), Epstein bar virus (EBV) and hepatitis A virus (HAV) were negative, hepatitis B surface antigen (HbsAg) and hepatitis C virus antibodies (HCVAb) were also negative. Monospot test and antinuclear antibodies (ANA) were negative. A b d o m i n a l ultrasound confirmed hepato-splenomegaly and no other intra-abdominal masses were detectable. Echocardiography was normal. Her lymph node biopsy showed reactive hyperplasia with no malignant cells. Bone marrow aspiration and biopsy was normal. Her carbamezepine was stopped and she was started on topiramate for her epilepsy. No systemic steroids were given. After two days, her fever subsided and by the 5th day the rashes started to fade out along with reduction in the size of lymph nodes. She was discharged home 10 days after admission in good health and was seen three months later in our outpatient clinic. There were no palpable lymph nodes, liver or spleen, her haematological indices and LFTs were also found to be normal. With a two-year follow up, there was no recurrence of the reported symptoms. Address Correspondence to: Dr. Shahid Aziz MRCP (UK), Department of Medicine (38), King Khalid University Hospital, P. O. Box 7805, Riyadh 11472, Kingdom of Saudi Arabia. Fax; 0096614670999, E-mail: [email protected] 330 Carbamezepine Induced Pseudolymphoma Table 1: Complete blood count Table 2: Serum biochemistry and LFTs On admission After 10 days After 3 months WBC (X109/l) HB (gm/dl) MCV (fl) MCH (pg) Platelets (X109/l) N L EOS MONO ESR (mm/hr) 5.30 11 84.3 28.4 286 41% 36% 17% 5% 15 December 2006 5.40 11.1 85 29.3 425 40% 44% 5% 11% 20 4.80 12 82.4 30 350 50% 39% 4% 6% 19 N: Neutrophils, L: Lymphocytes, EOS: Eosinophils, M: Monocytes DISCUSSION Carbamezepine is an aromatic anticonvulsant with tricyclic structure related to phenytoin, phenobarbital and primidone[1]. Pseudolymphoma syndrome (PLS) is a rare side effect of carbamezepine therapy but is well known with phenytoin therapy as dilantin hypersensitivity syndrome[2] or phenytoin syndrome[3]. Patricia Tennis et al [4], reported the risk of developing hypersensitivity syndrome with carbamezepine as 1 - 4.1 per 10,000 new users and 2.3 to 4.5 per 10,000 new users of phenytoin. Some authorities suggested that we differentiate between anticonvulsant hypersensitivity syndrome and PLS on clinical ground but the differentiation seems to be arbitrary as there is considerable overlap in clinical presentation and histopathological findings for the two entities[1,3]. Patients may present with fever (75-100%) which is usually high grade and swinging, skin rash (90%), facial edema (2588%), lymphadenopathy (63-70%) which may be tender, hepatomegaly and hepatitis (25-60%), myalgia and arthralgia (21%), pharyngitis (10%)[2,3]. Haematological abnormalities are protean and range from lecuocytosis and leucopenia, agranulocytosis, lymphocytosis, atypical lymphocytes, blast cells, eosinophilia, monocytosis, pancytopenia, coagulation disorders to hypo and hypergamma-globulinemia. Our patient also showed eosinophilia of 17% in her initial CBC, which returned to normal within two weeks after withdrawal of the offending drug. Hepatic injury is usually mild and most of the times patients recover within a few weeks after the cessation of causative agent. Failure to stop the causative drug early may lead to more severe hepatic injury[2,3] and severe hepatitis is a poor prognostic sign. Death can occur due to liver failure. Our patient showed marked impairment of her liver function tests in the initial report in the form of predominantly direct hyperbilirubinemia, high alkaline phosphatase and transaminases, which started to improve after the cessation of the offending drug and returned to normal within three months. On admission Urea (mmol/l) Creatinine (µmol/l) Total bilirubin(µmol/l) Direct bilirubin(µmol/l) Total proteins (gm/l) Albumin (gm/l) Alk Phos (U/l) ALT (U/l) AST (U/l) GGT (U/l) 2.5 41 150 125 56 25 980 262 194 539 After 10 days 3.6 46 54 39 65 29 756 129 99 453 After 3 months 3.5 43 16 3 71 32 150 47 29 47 Alk Phos: Alkaline Phosphatase, ALT: Alanine amino transferase, AST: Aspartate aminotransferase, GGT: Gamma glutamyl transferase Lung involvement may occur in the form of pneumonitis[1], bronchiolitis obliterans organizing pneumonia (BOOP)[5], bronchial mucosal ulceration and desquamation[6] which can be fatal. Serious disturbances in pulmonary diffusion capacity may be present even in the absence of changes on chest X-ray[7]. Lymph node biopsy most of the times shows reactive hyperplasia (as in our patient) but features resembling malignant lymphoma may be seen such as destruction of nodal architecture[8], atypical lymphocytes with CD3, CD20, CD30 positivity[3,9,10] and large cells indistinguishable from Reed Sternberg cells[11]. Cutaneous biopsies may show features resembling mycosis fungoides (MF) such as epidermotrophism of atypical lymphocytes and Partier’s microabscesses. However, features favouring PLS over MF are the presence of marked spongiosis, necrotic keratinocytes and eosinophilic infiltrate in the epidermis, and in the dermis papillary dermal edema, extravasated erythrocytes, lymphocytes within the dermis larger than those in epidermis and infiltration of various inflammatory cells including neutrophils[3]. T cell receptor-γ gene rearrangement studies may show monoclonal rearrangement in PLS caused by valproate but not in PLS caused by carbamezepine[3,9]. The exact pathophysiology of PLS is not known. However, toxic metabolic theory proposed by Shear and Spielberg[12] and Spielberg et al [13,14] seems to be most appropriate. According to this theory aromatic anticonvulsants (carbamezepine, phenytoin and phenobarbital) are metabolized by cytochr ome P450 to a toxic metabolite arene oxide, which is detoxified by the enzyme epoxide hydrolase. Deficiency of this enzyme leads to accumulation of arene oxide in the body that acts as haptens[2,3,4]. This also explains the cross reactivity seen between aromatic anticonvulsants. Also the first degree relatives of the patients with PLS are at increased risk of developing the syndrome if exposed to aromatic anticonvulsant due to the deficiency of the December 2006 KUWAIT MEDICAL JOURNAL enzyme epoxide hydrolase. An autosomal pattern of inheritance has been suggested for this deficiency[2]. But as PLS can be caused by valproate, which has a different structure and is not metabolized to arene oxide, it seems that other mechanisms may operate, of which T-cell dysregulation or dysfunction is one possibility. Immediate management other than supportive measures includes cessation of the causative agent and this usually results in rapid recovery. Systemic corticosteroids are of no benefit, but patients with progressive disease despite cessation of causative agent may benefit from them. However, data supporting this, is lacking. For future control of epilepsy in these patient anticonvulsants with a different structure such as Lamotrigine, gabapentin and topiramate can be used. CONCLUSIONS PLS is a rare side effect of carbamezepine therapy for which early recognition and cessation of the causative agent is important as it results in dramatic and complete recovery. Death can occur in PLS due to extensive skin involvement, liver failure and agranulocytosis. Once PLS occurs during the course of any anticonvulsant therapy, this will affect the future management of the underlying disorder for which the anticonvulsant was used, as there is cross reactivity between aromatic anticonvulsants and valproate. Lamotrigine, gabapentin and topiramate can be used in these patients. Aromatic anticonvulsants should be used with caution in first degree relatives of the patients with PLS as they are at higher risk of developing the syndrome. REFERENCES 1. David LNathan, Donald V Belsito. Carbamezepine induced pseudo lymphoma with CD-30 Positive cells. J Am Acad Dermatol 1998; 38:806-809. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 331 Carmela C Vittorio, Jennie J Muglia. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995; 155:2285-2290. T S Choi, K S Doh, S H Kim, M S Jang, K S Suh, S T Kim. Clinicopathological and genotypic aspects of anticonvulsantinduced pseudo lymphoma syndrome. Br J Dermatol 2003; 148:730-736. Patricia Tennis, Robert S Stern. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamezepine, or sodium valproate. Neurology 1997; 49:542-46. R Banka, M J Ward. Bronchiolitis obliterans and organizing pneumonia caused by carbamezepine and mimicking community acquired pneumonia. Postgrad Med J 2002; 78:621-622. S E Handfield-Jones, R E Jenkins, S J Whittaker, C P Besse and D HcGibbon. The anticonvulsant hypersensitivity syndrome. Br J Dermatol 1993; 129:175-177. Tijhvis GJ, Strijbos JH, Van Ermen A, Offerman JJ, Dubois AE. Generalized side effects with the use of carbamezepine. Ned Tijdshr Geneeskd 1995; 139:2265-2268. Rispal P Lassuer C, Labouyrie E, Doutre MS, et al. Pseudo lymphoma induced by carbamezepine. Rev Med Intern 1995; 16:214-218. O Cogrel, M Beylot-Barry, B Vergier, et al. Sodium valproate induced cutaneous pseudo lymphoma followed by recurrence with carbamezepine. Br J Dermatol 2001; 144:1235-1238. Yeo W, Chow J, Wong N, Chan AT, Johnson PJ. Carbamezepine induced lymphadenopathy mimicking Ki-l (CD30+) T-cell lymphoma. Pathology 1997; 29:64-66. P Yates, G Stockdill, M McIntyre. Hypersensitivity to carbamezepine presenting as pseudo lymphoma. J Clin Pathol 1986; 39:1224-1228. Shear NH, Spielberg SP. Anticonvulasnt hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest 1988; 82:1826-1832. Spielberg SP, Gordon GB, Blake DA, Mellits DE, Bross DS. Anticonvulsant toxicity in vitro: possible role of arene oxides. J Pharmacol Exp Ther 1981; 217:386-389. Spielberg SP, Gordon GB, Blake DA, Goldstein DA, Herlong HF. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981; 305: 722-727. 332 KUWAIT MEDICAL JOURNAL December 2006 Case Report Walker-Warburg Syndrome: A Case Report Magdy H Shafik1, Mohamed Taha Mohamed1, Talaat M Yousef2 Department of Pediatrics, Farwaniya Hospital, Kuwait Department of Radiology, Farwaniya hospital, Kuwait 1 2 Kuwait Medical Journal 2006, 38 (4): 332-335 ABSTRACT Congenital muscle dystrophy (CMD) is a group of disorders characterized by significant muscle weakness early in life. Two broad groups of CMD are recognized; those with major brain anomalies and those without. Walker-Warburg syndrome (WWS) belongs to the first group. It is a rare autosomal recessive, genetically heterogeneous disorder characterize by a triad of CMD, brain and eye anomalies. Clinical features and brain magnetic resonance imaging (MRI) findings previously used to diagnose the syndrome remain valid. In the presence of an affected sibling, prenatal diagnosis is possible by fetal brain MRI and/or vaginal sonography. Mapping of the WWS gene is still not possible. We report a Kuwaiti girl with WWS. The diagnosis was based on clinical, neurophysiological and MRI findings. To the best of our knowledge, this is the first case of WWS to be reported, with some details, in the Arab population. KEYWORDS: cobblestone cortex, congenital muscle dystrophy, type II lissencephaly INTRODUCTION The muscular dysfunction in children with congenital muscle dystrophy (CMD) results from deficiency or dysplasia of a group of proteins that are vital for skeletal muscle action. Many of these proteins play an important role during brain development. That is why brain anomalies occur in some groups of congenital muscle dystrophy. Merosin (laminin α 2) is an example of the skeletal muscle proteins. This, with other proteins, is likely to have a regulatory role in neuronal migration and organization of the cortex during brain development. Deficiency or dysfunction of some of these proteins may explain the neuronal migration defects (overmigration) in the group of CMD that is associated with brain malformation [1]. Walker-Warburg Syndrome (WWS) is the most severe form of CMD that is associated with brain and eye anomalies. The diagnostic criteria for WWS have been established by Dobyns et al[2] in 1989. They suggested CMD, type II lissencephaly, cerebellar malformation and ocular anomalies (mainly retinal and anterior chamber malformation) to be the principal diagnostic features of WWS. Other brain anomalies, such as occipital encephalocele, absent corpus callosum and fusion of the hemispheres were reported in some patients with WWS. Though not constant in all patients, these anomalies were considered in favor of the diagnosis of this syndrome and, in association with the severity of the brain malformation, are helpful in distinguishing WWS from another clinically similar disorder, that is muscle - eye - brain disease (MEB)[3]. CASE HISTORY The patient was a fifteen- month-old girl, who was born at term by an elective cesarean section. She was the second child to a first cousin parents with one healthy male sibling. Aroutine antenatal ultrasonographic examination at 24 weeks of gestation revealed cerebral ventriculomegaly. At birth, her weight (2.2 kg) and height (44 cm) were just below the 5th percentile for age, while the head circumference (36cm) was on the 95th percentile. Examination revealed some dysmorphic features in the form of brachycephalic skull, depressed nasal bridge, widely spaced eyes with bilateral corneal opacities, epicanthic folds and rocker bottom feet deformity. System review revealed a hypotonic baby with absent deep tendons reflexes, poor muscle power and weak sucking reflex. No other abnormal findings could be detected. Bilateral glaucoma with irido-corneal adhesions (Peter’s anomaly) was diagnosed upon ophthalmological evaluation. Address correspondence to: Dr. Magdy H. Shafik, Department of Pediatrics, Farwaniya hospital, P.O.box 43375, Hawally 32048, Kuwait. Tel: 00965-2626769, Mob: 009659535979, E- mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL 333 Ü ð Fig. 2a Fig. 1: Sagittal SE 440/22 image shows agyria, ventriculomegaly, thin corpus callosum, collicular fusion, pontine and cerebeller hypoplasia, and a distinctive dorsal kinking at the mesencephalic-pontine junction (a forme fruste occipital encephalocele). ð Ü î Mesencephalic - pontine kinking Thin corpus callosum Collicular fusion Routine biochemical investigations, screening for congenital infections, inborn error of metabolism and chromosomal anomalies were normal. Cerebral computerized tomography (CT) at age of one week confirmed the antenatal ultrasonographic findings of ventriculomegaly. Serum creatinine phosphokinase (CK) enzyme level was high (1400 U/l) at age of 10 days. Nasogastric tube feeding was commenced in the second week of life due to poor sucking and frequent choking episodes. This is continued till date. Brain MRI at age of three weeks showed gross ventriculomegaly, thin corpus callosum, pontine and cerebellar hypolplasia, collicular fusion, dorsal kinking of the brain stem, nearly complete agyria and irregular gray-white matter junction, a pattern characteristic of cobblestone lissencephaly. A ventriculo-peritoneal shunt was inserted at age of one month due to progressive head enlargement. A repeated serum CK enzyme level at five and twelve months of age revealed high levels (540 and 490 U/l respectively). Electromyography (EMG) at age of 13 months showed a myopathic pattern Follow up examination of the child at age of 15 months showed that she is markedly hypotonic with absent deep tendons reflexes and severely failing to thrive {Weight (5kg), Height (63 cm) and head circumference (40 cm) were all far below the 5th percentile for age}. Developmentally, she was globally delayed with very poor visual and hearing abilities. Fig. 2b Fig. 2 a & b: Axial (a) and coronal (b) SE 440/22 images shows vermian hypoplasia, marked ventriculomegaly and smooth brain with periventricular irregular low signal intensities representing irregular cortical projections into the underlying white matter giving an irregular gray - white matter junction ➮ irregular gray - white matter junction DISCUSSION WWS is a rare form of congenital muscle dystrophy (CMD) which is associated with brain malformation and eye anomalies. The first case was reported by Walker [4] in 1942 who described a case of lissencephaly (Greek, smooth brain) and eye anomalies. Familial occurrence was first reported by Chemke et al[5] as he noted three out of seven siblings of 3rd cousin parents were affected. Warburg[6] reported several patients with hydrocephalus and retinal detachment. She suggested an autosomal recessive inheritance noting the occurrence of the syndrome in a sibling of related parents[7]. Myopathy was first reported by Williams et al [8] as part of the syndrome. In the past WWS was known as HARD ± E syndrome (Hydrocephalus, Agyria, Retinal Dysplasia ± Encephalocele). The condition is usually lethal 334 Walker-Warburg Syndrome: A Case Report within the first few months of life. Survival beyond three years is unusual [3]. WWS shows some similarities with two other syndromes, namely Muscle-Eye-Brain disease (MEB) and Fukuyama muscle dystrophy (FMD). In all these three syndromes there are muscle dystrophies, eye anomalies and brain malformation. WWS is the most severe form of the three syndromes in terms of brain malformation[9]. Brain anomalies in WWS were given the term “cobblestone complex” by Cormand et al[3]. These anomalies include the neuropathological findings of “cobblestone cortex” with multiple coarse gyri and agyric regions[10]. Radiologicaly, MRI brain shows markedly dilated lateral ventricles, irregular grey - white matter junction, absent or hypoplastic corpus callosum, flat brain stem and cerebellar hypoplasia with minimal brain convolutions resembling lissencephaly[3]. These features are typically reported in the MRI study of our patient (Fig. 1& Fig. 2 a & b). The term “type II lissencephaly” (with disorganized cortical layers) describes the minimal brain convolutions in WWS, and is used to characterize it from the classic 4 -layer ed lissencephaly[2]. Occiptal encephalocele is in favour of the diagnosis of WWS[3]. This is seen in our case as a forme fruste (aborted form) with dorsal kinking of the brain stem (Fig. 1). Ocular anomalies in WWS include microphthalmia, congenital cataract, retinal dysplasia, buphthalamus, chamber dysgenesis, corneal clouding, Peter ’s anomaly and congenital glaucoma (the last three findings were reported in our case). Congenital muscle dystrophy (CMD) as part of the syndrome, has been shown in our case both clinically (hypotonia with absent deep tendon reflex) and by elevated CK on many occasions after the age of six months, with myopathic pattern of EMG. CK level normally can be as high as 700 U/l immediately after delivery, but falls to normal range (5-130U/l) by 6-10 weeks[11]. In patients with CMD, CK may reach thousands, early in life, reflecting wide spread muscle necrosis in the perinatal period. Later on, these patients have low or normal CK because of lack of muscle mass and limited mobility [9]. While the molecular genetic basis of FMD and MEB disease are clearly identified, the molecular and genetic basis of WWS is still unclear [3]. Mutation in O-mannosyltransferase gene (POMT1) was found in 20% of patients with WWS phenotype studied by Beltran et al[12]. They explained the severe neuronal migration defect in WWS by mutation in this gene. This gene encodes synthesis of an December 2006 enzyme that catalyze the first step in synthesis of a specific glycosylated protein called α-dystroglycan, which is found in brain, muscles and peripheral nerves of mammals [13]. However, POMT1 gene mutation was not found in cases studied by Jiemenz et al[14] though they found almost complete absence of α-dystroglycan with mild reduction in laminin-alpha 2 (merosin) in muscles of patients with WWS. They assumed that muscle degeneration in WWS is due to defective αdystroglycan / laminin α 2 axis in the muscle fiber’s basal lamina. Moreover, mutation in fukutin gene (responsible for Fukuyama muscle dystrophy) has been reported by others[15,16] in patients with phenotypic features of WWS. Their results confirm that WWS is a genetically heterogenous condition. Although the phenotypic features of the three syndromes (WWS, FCMD, and MEB) might overlap, lack of consistent ocular abnormalities in FCMD allowed a clear clinical demarcation of this syndrome. Moreover, identification of the gene responsible for FCMD on chromosome 9 (q31q33)[17] allows this syndrome to be defined at molecular and genetic level. The presence of severe neurological changes both clinically and in the cerebral MRI studies, as reported in our patient, plus evidence of CMD are considered enough for WWS to be clearly differentiated from MEB[3]. Moreover, the MEB gene was recently localized to chromosome 1(p32-p34)[18], and this allows MEB and WWS to be classified as distinct disorders on both clinical and genetic grounds. Although molecular genetic study was not possible in our case, the diagnosis was confirmed by the typical clinical picture and the MRI findings in association with evidence of CMD. This is in keeping with the diagnostic criteria of WWS in other literature[3,19]. Lack of consistent chromosomal abnormalities in WWS makes prenatal diagnosis a difficult task. However, prenatal diagnosis can be suspected by fetal brain MRI [20] and/or transvaginal fetal neurosonography[21]. Both methods allow lissencephaly to be detected prenatally. This in association with ventriculomegaly allows easy identification of an affected fetus especially with positive family history of a similar case. Proper counseling can thus be provided for parents, taking in consideration the poor prognosis of such condition. ACKNOWLEDGEMENT We are thankful to Dr Essam A Ismail, Consultant in Pediatrics, Farwaniya Hospital whose bright ideas helped the diagnosis of such a case and also for his revision of the manuscript. December 2006 KUWAIT MEDICAL JOURNAL REFERENCES Villanova M, Malandrini A, Toti P, et al. Localization of merosin in the normal human brain : implications for congenital muscular dystrophy with merosin deficiency. J Submicrosc Cytol Pathol 1996; 41:173-180. 2. Dobyns WB, Pagan RA, Armstrong D, et al. Diagnostic criteria for Walker- Warburg syndrome. Am J Med Genet 1989; 32:195-210. 3. Cormand B, Pihko H, Bayes M, Valanne L, et al. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 2001; 56:1059-1069. 4. Walker AE. Lissencephally. Arch Neurol Psychiatry 1942; 48:13-29. 5. Chemke J, Czernabilsky B, Mundel G, Barishaky YR. A familial syndrome of central nervous system and ocular malformation. Clin Genet 1975; 7:1-7. 6. Warburg M. Heterogeneity of congenital retinal nonattachment, falciforum folds, and retinal dysplasia . A guide to genetic counseling. Hum Hered 1976; 26:137-148. 7. Warburg M. Hydrocephaly, congenital retinal non- attachment, congenital falciform fold. Am J Ophthal 1978; 85:88-94. 8. Williams RS, Swisher CN, Jennings M, Ambler M, Caviness VS Jr. Cerebro-ocular dysgenesis (Walker-Warburg syndrome): neuropathologic and etiologic analysis. Neurology 1984; 34:1531-1541. 9. Mathews KD. Muscular dystrophy overview: genetic and diagnosis. Neurol Clin 2003; 21:795-816. 10. Haltia M, Levio I, Somer H, et al. Muscle- eye- brain disease: a neuropathological study. Ann Neurol 1997; 41:173-180. 11. Gilboa N, Swanson JR. Serum creatinine kinase in normal newborn. Arch Dis Child 1976; 51:283-285. 12. Beltran D, Currier S, Steinberecher A, et al. Mutation in the O-mannosyltransferase gene POMTI give rise to the severe 1. 13. 14. 15. 16. 17. 18. 19. 20. 21. 335 neuronal migration disorder Walker- Warburg syndrome. Am J Hum Genet 2002; 71:1033-1043. Sasaki T, Yamada H, Malsumura K, Shimizu T, Kobata A, Endo T. Detection of O-mannosylglycans in rabbit skeletal muscle alpha-dystroglycan. Biochem Biophys Acta 1998; 1425:599-606. Jiemenez MC, Torelli S, Brown SC, et al. Profound skeletal muscle depletion of alpha dystroglycan in WWS. Eur J Pediatr Neurol 2003; 7:129-137. Beltran D, Van Bokhoven H, Van Beusekom E, Van den Akker W, et al. A homozygous nonsense mutation in the fukutin gene causes a Walker-Warburg syndrome phenotype. J Med Genet 2003; 40:845-848. Silan F, Yoshioka M, Kobayashi K, et al. A new mutation of Fukutin gene in a non- Japanese patient. Ann Neurol 2003; 53:392-396. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, et al. An ancient retrotransposal insertion causes Fukuyamatype congenital muscle dystrophy. Nature 1998; 394:388392. Cormand B, Avela K, Pikko H, et al. Assignment of muscleeye-brain disease gene to 1 p32-p34 by linkage analysis and homozygosity mapping. Am J Hum Genet 1999; 64:126-135. Dobyns WB, Kirkpalru JP, Hittner HM, Roberts R, Kretzer FL, et al. Syndrome with lissencephaly II: Walker-Warburg and cerebro-oculo-musclar syndrome and a new syndrome with type II lisencephaly . Am J Med Genet 1985; 22:157195. Okamura K, Murotsuki J, Sakai T, Matsumoto K, Shirane R, Yajima A. Prenatal diagnosis of lissencephaly by magnetic resonance image. Fetal diag Ther 1993; 8:56-59. Ana M, Abdon A, Patricia M. Walker-Warburg syndrome, case report and review of the literature. J Ultrasound Med 2001; 20:419-426. KUWAIT MEDICAL JOURNAL December 2006 Selected Abstracts of Articles Published Elsewhere by Authors in Kuwait Kuwait Medical Journal 2006, 38 (4): 336-338 Subjective Quality of Life of Outpatients with Diabetes: Comparison with Family Caregivers’ Impressions and Control Group Awadalla AW, Ohaeri JU, Tawfiq AM, Al-Awadi SA Department of Psychiatry, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, Kuwait 13110. E-mail: [email protected] J Natl Med Assoc. 2006; 98:737-745 Background: There is a paucity of studies on comparison of quality of life (QOL) of type-1 and type2 diabetes patients, and the impact of family caregivers’ impressions on the QOL of patients. Objectives: To assess the subjective QOL of Sudanese diabetics using the WHOQOL-Bref, compared with a general population sample; examine caregiver-patient concordance; and assess the variables that impact on QOL. Method: The responses of 105 outpatients with type-1 diabetes and 136 with type-2 diabetes were compared with their family caregivers’ impressions and 139 general population subjects. Results: Patients were predominantly dissatisfied with their life circumstances. Type-1 diabetics had significantly lowest QOL scores, while the control group had highest scores. Having additional medical problems; having diminished sexual desire; and being young, unemployed and single were associated with poor QOL, but illness duration was not. Type-2 diabetics had lesser concordance with caregivers. The only predictor of patients’ QOL was the caregivers’ impression of patients’ QOL. Conclusions: Caregivers’ impression of patients’ QOL impacted on outcome. Caregiver education is, therefore, important. The factors associated with QOL indicate a group that needs focused attention. The good QOL for type-2 and nonsignificance of illness duration encourage therapeutic optimism. The Effect of Seventy-Two-Hour Continuous Infusion of Long-acting Natriuretic Peptide on Acute Ischemic Renal Failure in the Rat Alhumoud HM Department of Medicine, Division of Nephrology, Faculty of Medicine, College of Medicine, Kuwait University, Safat, Kuwait. E-mail: [email protected] Ren Fail 2006; 28:577-581 Objectives: Atrial natriuretic peptide (ANP(1-28)) protects the kidneys against acute renal failure in animals; however, its use in humans has been disappointing. Long-acting natriuretic peptide (LANP(1-30)) has natriuretic and diuretic actions similar to ANP(1-28), but it has a longer half-life and a different receptor site. Therefore, this study’s aim was to determine if LANP(1-30) has better renal protection than ANP(1-28), which may make it useful in the treatment of acute renal failure. Subjects/Methods: Three groups of male Sprague-Dawley rats were used, each with a body weight between 250-300 gm. Group 1 (ischemia only, n = 6) had a right nephrectomy followed by 30 minutes of left renal pedicle clamping. Group 2 (LANP Peptide treated, n = 7) had renal ischemia similar to Group 1, followed by an intraperitoneal bolus of 10 microg of LANP(1-30) and the placement of miniosmotic pumps delivering LANP(1-30) at a rate of 1 microg/hr for 72 hours. Group 3 (controls, n = 6) was used to measure the baseline creatinine level and had no renal ischemia or surgery. Results: Seventy-two hours post-renal ischemia, the weight loss in the ischemia group was similar to the peptide treated group (7.65 +/- 1.14% and 10.03 +/- 0.9% body weight loss, respectively, p = 0.126). The ischemia group had significantly higher creatinine levels compared to the controls (66.3 +/- 5.3 versus 30.1 +/- 0.9 micromol/L, p = 0.002). The peptide-treated group had higher creatinine (174.1 +/- 77.8 versus 66.3 +/- 5.3 micromol/L, p = 0.035) and LANP(1-30) levels (673.14 +/- 69.64 versus 45.83 +/- 8.45 pg/mL, p = 0.001) than the ischemia group. Conclusion: Prolonged use of LANP(1-30) has no renal protective effect. December 2006 KUWAIT MEDICAL JOURNAL 337 High Prevalence and Level of Resistance to Metronidazole, but Lack of Resistance to Other Antimicrobials in Helicobacter Pylori, Isolated from A Multiracial Population in Kuwait John Albert M, Al-Mekhaizeem K, Neil L, Dhar R, Dhar PM, Al-Ali M, Al-Abkal HM, Haridas S. Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait Aliment Pharmacol Ther 2006; 24:1359-1366 Background: The primary treatment regimen for Helicobacter pylori infection for Kuwaitis does not contain metronidazole, but that for expatriates does. There is also increasing failure of antimicrobial therapy. Aim: To determine the susceptibility of H. pylori from upper gastrointestinal biopsies of Kuwaitis and non-Kuwaitis to find out if differences existed in the susceptibilities of the isolates from the two different populations. Methods: The susceptibilities of 96 H. pylori isolates were tested against metronidazole, amoxicillin, clarithromycin and tetracycline by the E test. The rdxA gene was analysed from selected metronidazole-susceptible and metronidazole-resistant strains to find out polymorphism and the basis of metronidazole resistance. Results: Approximately, 70% of isolates from both populations were metronidazole resistant with 65% isolates showing high minimum inhibitory concentration values of >256 mug/mL. No resistance to the other three antimicrobials was found. There were novel nonsense and missense mutations with no deletion in the rdxAgene by insertion of mini-IS605. Conclusions: The prevalence and level of metronidazole resistance in H. pylori in the two populations was high with no difference, in spite of different treatment regimens. Metronidazole resistance in this transitional country appeared to be independent of prior metronidazole use for treatment of H. pylori infection. Determinants of Plasma Homocysteine in Relation to Hematological and Biochemical Variables in Patients with Acute Myocardial Infarction Marouf R, Zubaid M, Mojiminiyi OA, Qurtom M, Abdella NA, Al Wazzan H, Al Humood S Department of Pathology, Kuwait University, Faculty of Medicine, Kuwait. E-mail:[email protected] South Med J 2006; 99:811-816 Background: Elevated plasma total homocysteine (tHcy) is a risk factor for coronary artery disease (CAD), but the mechanism is not known. This study evaluates the determinants and associations of tHcy in patients presenting with acute myocardial infarction (AMI). Methods: Plasma concentration of tHcy, protein C, protein S, and antithrombin were measured in 210 (177 males and 33 females) patients with first AMI and 167 (87 males and 80 females) controls. Serum vitamin B12, folate, creatinine, lipid profile, fasting glucose, full blood count and red cell folate were determined. Creatinine clearance was calculated using the modification of diet in renal disease formula. Univariate and multivariate analyses were used to determine the associations of tHcy. Results: Mean tHcy was higher in male than female patients. On logistic regression analysis, the most important determinants oftHcy in the patients were age, creatinine, creatinine clearance, vitamin B12 and red cell folate. When study patients were compared with the controls, tHcy, fasting glucose and serum creatinine were significantly higher, while creatinine clearance and HDL cholesterol were significantly lower in the study patients. Logistic regression analysis showed significant association of tHcy with AMI, odds ratio = 1.39, in the presence of other confounding factors. Conclusion: Our results show that tHcy is a significant risk factor for CAD in our patient population. The determinants in the patients are age, glomerular filtration rate and the status of vitamins B12 and folate. The above determinants should be kept in mind when using tHcy as a risk factor for CAD. 338 December 2006 Prevalence and Associations of Low Plasma Erythropoietin in Patients with Type 2 Diabetes Mellitus Mojiminiyi OA, Abdella NA, Zaki MY, El Gebely SA, Mohamedi HM, Aldhahi WA. Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait. E-mail: [email protected] Diabet Med. 2006; 23: 839-844 Aims: Low plasma erythropoietin (EPO) is a key causal factor in the anaemia of diabetic patients. The aim of this study was to investigate the prevalence of anaemia in relation to EPO in patients with Type 2 diabetes. Methods: In a clinic-based cross-sectional study of 161 Type 2 diabetes patients, we measured EPO, ferritin and full blood count. The patients were classified on the basis of the urine albumin:creatinine excretion ratio as normo-, micro- or macroalbuminuric. Serum creatinine, cystatin C and glomerular filtration rate (GFR) calculated from cystatin C were used as markers of renal function. All the patients were assessed for symptoms and signs of diabetic complications, including diabetic peripheral sensory neuropathy (PSN). Results: Twenty-one (13.0%) patients were anaemic; 80 patients (49.7%) had low EPO (< 5 mU/ml), of whom 28.8% had a GFR < 60 ml/min per 1.73 m2; 57.5% were normoalbuminuric, 33.7% were microalbuminuric and 8.8% macroalbuminuric. Although EPO was significantly higher in anaemic patients compared with non-anaemic patients, the EPO response was inappropriate for the degree of anaemia. Of patients with PSN, 66.7% had low EPO but there was no significant difference in EPO between patients with and without PSN. Log EPO correlated significantly with urine microalbumin:creatinine ratio and logistic regression analysis showed that haemoglobin, age and urine microalbumin: creatinine ratio were the main determinants of EPO. Conclusion: The degree of microalbuminuria is the most significant determinant of plasma EPO, which is often low or inappropriately normal in diabetic patients with and without anaemia. Treatment of Calculi in Kidneys with Congenital Anomalies: An Assessment of the Efficacy of Lithotripsy Al-Tawheed AR, Al-Awadi KA, Kehinde EO, Abdul-Halim H, Hanafi AM, Ali Y Department of Surgery (Division of Urology), Mubarak Al-Kabeer Hospital, Safat, Kuwait. Urol Res 2006; 34:291-298 We studied the effectiveness of extracorporeal shock wave lithotripsy (ESWL) in the treatment of stones in kidneys with congenital anomalies to determine factors that may affect the results. Patients found to have renal calculi in kidneys with different types of congenital anomalies were treated using ESWL. All patients were investigated by intravenous urography (IVU) to confirm the diagnosis. J stents were inserted prior to therapy in renal units with calculi exceeding 1.5 cm in diameter. Complications encountered and factors affecting success using this treatment modality were analysed. Twenty-five patients (18 males, 7 females) were studied between August 1988 and July 2005. There were nine patients with horseshoe kidneys, eight with ectopic kidneys, three with malrotated kidneys, two with duplex renal system, and one patient each with polycystic kidneys and hypoplastic kidney. The IVU showed 31 isolated calyceal or renal pelvic stones with mean stone burden of 1.44cc. All 25 patients were treated by lithotripsy. Twenty-four (77.4%) renal units (in 19 patients) were completely cleared of stones, 2 (6.5%) renal units (2 patients) were partially cleared of calculi and the procedures failed in 5 (16.1%) renal units (4 patients). Out of five renal units in which the procedures failed, open surgery was performed in three renal units and percutaneous nephrolithotomy (PCNL) was performed in two. None of the 25 patients developed any major complications. No significant adverse changes in renal function tests were observed at 3-month follow-up. The stone-free rate was influenced and reduced by stone size and location in the pelvicalyceal system. Calculi in kidneys with congenital anomalies may be treated successfully by ESWL as a first-line therapy in the majority of patients. With position modifications, localization of stones may be facilitated and disintegrated. The outcome in patients so treated does not differ significantly from that in those with normal kidneys. December 2006 KUWAIT MEDICAL JOURNAL Forthcoming Conferences and Meetings Compiled and edited by Babichan K Chandy Kuwait Medical Journal 2006, 38 (4): 339-342 Internal Medicine: Diabetes/Endocrinology Dec 02-09, 2006 Tampa, FL, United States Contact: Continuing Education Inc, 5700 4th St. N, St. Petersburg FL 33703 Tel: 1-800-422-0711 / 727-526-1571; Fax: 727-527-3228 E-Mail: [email protected] IDF 2006 19th World Diabetes Congress Dec 05-07, 2006 Cape Town, South Africa Contact: Congress Unit, International Diabetes Federation, Avenue Emile De Mot 19, B-1000 Brussels Tel: 32-25-431-631; Fax: 32-25-385-114 E-Mail: [email protected] The Medical Management of AIDS: A Comprehensive Review of HIV Management Dec 07-09, 2006 San Francisco, CA, United States Contact: UCSF Office of Continuing Medical Education, 3333 California Street, Room 450, San Francisco, CA94118 Tel: 415-476-4251 / 415-476-5808; Fax: 415-476-0318 / 415-502-1795 E-Mail: [email protected] Immunological Intervention in Human Disease (A2) Jan 06-11, 2007 Big Sky, MT, United States Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230 ; Fax: 970-2621525 E-Mail: [email protected] Obesity: Peripheral and Central Pathways Regulating Energy Homeostasis (J2) Jan 14 -17, 2007 Keystone, CO, United States Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230; Fax: 970-262-1525 E-Mail: [email protected] Mast Cells, Basophils, and IgE: Host Defense and Disease (A6) Jan 20 - 24, 2007 Copper Mountain, CO, United States Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230 ; Fax: 970-2621525 E-Mail: [email protected] Exacerbations of Airway Disease Dec 08-10, 2006 San Juan, Puerto Rico Contact: Roni LaVine Tel: 732-438-0622; Fax: 732-438-6672 E-Mail: [email protected] Modern Achievements of Cardiology in Development of New Cardiological Products by Results of Last Clinical Trials Jan 30-31, 2007 Kiev, Ukraine Contact: Dr Markov Tel:38-0-632-776-465; Fax:38-0-445-331-270 E-Mail:[email protected] Clinical Genetics Dec 14-15, 2006 Coventry, England, United Kingdom Contact: Dr Charlotte Moonan Tel: 02-476-523-540; Fax: 02-476-523-701 E-Mail: [email protected] Regional Asthma Congress Jan 31 - Feb 02, 2007 Hurgada, Egypt Contact: Prof.Kamal Maurice Hanna Tel:20-105-310-087; Fax:20-24-186-586 E-Mail:[email protected] Medical Devices, Ultrasound - 2006 Dec 16-17, 2006 Kiev, Ukraine Contact: Dr Markov Tel: 00-380-445-331-270 ; Fax: 00-380-445-331-270 E-Mail: [email protected] Women’s Malignancies Feb 02-04, 2007 Tehran, Iran Contact: Dr Akbari or mrs Shadi Tel: 00-982-122-724-090; Fax: 00-982-122-724-090 E-Mail: [email protected] 340 Forthcoming Conferences and Meetings New Horizons in Anesthesiology Feb 04-09, 2007 Steamboat Springs, CO, United States Contact: Office of Continuing Medical Education Tel:404-727-5695; Fax:404-727-5667 E-Mail:[email protected] Practical Updates in Anesthesiology Feb 05-09, 2007 Puerto Vallarta, Puerto Rico Contact: Jenny J. Mace Tel:734-936-4235; Fax:734-936-9091 E-Mail:[email protected] Clinical Audit 2007 Feb 06-07, 2007 London, England, United Kingdom Contact: Clare Gallagher Tel:02-0-85-411-399 E-Mail:[email protected] 45th Clinical Conference in Pediatric Anesthesiology Feb 09-11, 2007 Anaheim, CA, United States Contact: Tivi Ortiz Tel:323-669-2262; Fax:323-660-8983 E-Mail:[email protected] 17th Symposium Intensive Medicine and Intensive Care Feb 14-16, 2007 Bremen, Germany Contact: Mrs. Kordula Grimm Tel:00-49-0-421-3505-206; Fax:00-49-0-421-3505-340 E-Mail:[email protected] Advances in Clinical Anesthetic Practice Feb 17-21, 2007 Rancho Mirage, CA, United States Contact: Shirley Jones Tel:909-558-8173; Fax:909-558-0360 E-Mail:[email protected] 2nd Scientific Conference of the Saudi Cancer Foundation: CANCER FORUM 2007 Feb 21-22, 2007 Al-Khobar, Saudi Arabia Contact: Dr/ Ibrahim F. Al-Sheneber Tel: 96-68-647-557; Fax: 96-638-649-884 E-Mail: [email protected] Mayo Clinic Symposium on Anesthesia and Perioperative Medicine Feb 21-24, 2007 Scottsdale, AZ, United States Contact: Mayo Clinic Continuing Medical Education Tel:480-301-4580; Fax:480-301-8323 E-Mail:[email protected] December 2006 10th Annual Conference of Indian Association of Cardiovascular and Thoracic Anaesthesiologists Feb 23-25, 2007 Chandigarh, India Contact: Prof. GD Puri Tel:91-1-722-756-509 E-Mail:[email protected] Difficult Airway Course: Anesthesia Feb 23-25, 2007 Miami, FL, United States Contact: Julie Vissers Tel:503-635-4761; Fax:404-795-0711 E-Mail:[email protected] Breast Cancer Managment and Psychosocioeconomical Effect Feb 23-25, 2007 Tehran, Iran Contact: Dr Akbari or Mrs Shadi Tel: 00-982-122-724-090 ; Fax: 00-982-122-724-090 E-Mail: [email protected] Pain Management Feb 23-27, 2007 Saskatchewan, Canada Contact: CME Office Tel:306-966-7787 / 306-766-4016; Fax:306-966-7673 / 306-766-4019 E-Mail:[email protected] / [email protected] Imaging Immune Responses (J7) Feb 25 - Mar 01, 2007 Keystone, CO, United States Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230 ; Fax: 970-2621525 E-Mail: [email protected] Third Oman International Anaesthesia and Critical Care Conference Feb 27, 2007 - Mar 01, 2007 Muscat, Oman Contact: Mr. Abdulfattah Qandeel Tel:96-824-599-689 / 24-599-837; Fax:96-824-599967 E-Mail:[email protected] 6th World Congress of the International Society for Apheresis Mar 02-04, 2007 Yokohama, Japan Contact: Tadao Akizawa Tel: 440-358-1102; Fax: 440-358-1104 E-Mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL “IX International Symposium on Respiratory Viral Infections” Mar 03-07, 2007 Causeway Bay, Hong Kong Contact: Roni LaVine Tel:1-212-988-7732; Fax:1-212-717-1222 E-Mail:[email protected] Immunologic Memory (C4) Mar 03 - 08, 2007 Santa Fe, NM, United States Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230; Fax: 970-262-1525 E-Mail: [email protected] Advances in Internal Medicine Mar 04-09, 2007 Park City, UT, United States Contact: Jessica Kuo Tel: 801-581-7606; Fax: 801-581-5393 E-Mail: [email protected] The 2nd World Congress on Gender-Specific Medicine Mar 08-11, 2007 Rome, Italy Contact: Ms. Michal Pink Tel: 9723-56-66-166; Fax: 972-3-56-66-177 E-Mail: [email protected] Pediatric Anesthesiology 2007 Mar 08-11, 2007 Phoenix, AZ, United States Contact: Society for Pediatric Anesthesia Tel:804-282-9780; Fax:804-282-0090 E-Mail:[email protected] Perioperative Management Mar 11-14, 2007 Marco Island, FL, United States Contact: Office of Continuing Medical Education Tel:410-955-2959; Fax:410-955-0807 E-Mail:[email protected] The 5th International Conference on Pain Control and Regional Anaesthesia Mar 14-18, 2007 Hong Kong, China Contact: Jo Watling Tel:00-448-700-132-930; Fax:00-448-900-132-940 E-Mail:[email protected] CREF 27: The San Diego Cardiothoracic Surgery Symposium: Science and Techniques of Perfusion Mar 15-18, 2007 San Diego, CA, United States Contact: Karen S. Morgan Tel:1-805-534-0300; Fax:1-805-534-9030 E-Mail:[email protected] 341 9th Gastrointestinal Endoscopy Course & Workshop Mar 18-20, 2007 Riyadh, Saudi Arabia Contact: Department of Gastroenterology Tel: 966-1-479-1000 Ext.5265 or 966-1-477-7714 Ext.6385; Fax: 966-1-476-0853 E-Mail: [email protected] 10th Mayo Clinic Endocrine Course Mar 18-23, 2007 Kohala Coast, HI, United States Contact: Dr. WF Young Tel: 507-284-2509; Fax: 507-284-0532 E-Mail: [email protected] Society of Cardiovascular Anesthesiologists 12th Annual Update on Cardiopulmonary Bypass Mar 18-24, 2007 Whistler, BC, Canada Tel:804-282-0084; Fax:804-282-0090 E-Mail:[email protected] Difficult Airway Course: Anesthesia Mar 19-22, 2007 Kahuku, HI, United States Contact: Julie Vissers Tel:503-645-4761; Fax:404-795-0711 E-Mail:[email protected] STD Intensive Mar 19-23, 2007 Cincinnati, OH, United States Contact: Office of Continuing Education Tel:1-800-207-9399 / 513-558-7277; Fax:513-5581708 / 513-558-1756 E-Mail:[email protected] The 5th Annual Scientific Conference of The Saudi Thoracic Society and The 24th Regional Meeting of IUAT & LD Mar 20-22, 2007 Riyadh, Saudi Arabia Contact: Professor Mohamed Al-Hajjaj Tel: 00-96-612-488-966; Fax: 00-96-612-487-431 E-Mail: [email protected] Australasian Society for Infectious Diseases Scientific Meeting 2007 Mar 22-24, 2007 Hobart, Australia Contact: ASHM Conference Team Tel:61-282-040-770; Fax:61-292-124-670 E-Mail:[email protected] 342 Forthcoming Conferences and Meetings 3rd World Congress Abdominal Compartment Syndrome Mar 22-24, 2007 Antwerp, Belgium Contact: Werner Van Cleemputte, Managing Director Medicongress Waalpoel 28/34, B-9960 Assenede, Belgium Tel:32-0-93-443-959; Fax:32-0-93-444-010 E-Mail:[email protected] Obstetrical Anesthesia 2007 Mar 22-25, 2007 San Francisco CA United States Contact: Office of Continuing Medical Educaton Tel:415-476-5808; Fax:415-502-1795 2nd International Congress of Molecular Medicine Mar 24-28, 2007 Istanbul, Turkey Contact: Prof. Dr.Turgay Isbir Tel: 90-2-126-351-959; Fax: 90-2-126-351-959 E-Mail: [email protected] HIV Vaccines: From Basic Research to Clinical Trials (X7) Mar 25-30, 2007 Whistler, BC, Canada Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230; Fax: 970-262-1525 E-Mail: [email protected] Molecular and Cellular Determinants of HIV Pathogenesis (X8) Mar 25-30, 2007 Whistler, BC, Canada Contact: Kellie McConnell Tel: 800-253-0685 / 970-262-1230; Fax: 970-262-1525 E-Mail: [email protected] December 2006 27th International Symposium on Intensive Care and Emergency Medicine Mar 27-30, 2007 Brussels, Belgium Contact: Marcos Garcia Tel:32-25-553-631; Fax:32-25-554-555 E-Mail:[email protected] 4th International Symposium on Diabetes and Pregnancy Mar 29-31, 2007 Istanbul, Turkey Contact: Amy Altwerger Tel: 41-229-080-488; Fax: 41-22-732-285 E-Mail: [email protected] New Horizons in Anesthesiology Apr 01-06, 2007 Cozumel, Mexico Contact: Office of Continuing Medical Education Tel:404-727-5695; Fax:404-727-5667 E-Mail:[email protected] International Scientific Congress for Young Doctors Apr 04-08, 2007 Donetsk, Ukraine Contact: Anatoliy Tel:8-10-380-050-211-54-33; Fax:8-10-380-062-33455-39 E-Mail:[email protected] The International Conference on Transfusion Medicine May 07-09, 2007 Tehran, Iran Contact: Meeting Organiser Tel:982-188-601-573; Fax:982-188-601-573 E-Mail:[email protected] 11th Pan Arab Conference on Diabetes PACD11 Mar 27-30, 2007 Cairo, Egypt Contact: Mahmoud Ibrahim MD Tel: 20-122-131-868 / 20-101-560-794; Fax: 20-22723-693 / 20-22-564-365 E-Mail: [email protected] International Workshop on Tuberculosis Vaccines 2007 - TBVaccines2007 May 13-17, 2007 Varadero Beach, Matanzas, Cuba Contact: Dr. Armando Acosta / Dr. Mar’a Elena Sarmiento Tel:537-216-911; Fax:537-208-6075 E-Mail:[email protected] First International Conference on E-Medicine Mar 27-30, 2007 Cairo, Egypt Contact: Amr Ibrahim Tel: 20-122-131-868 / 20-101-560-794; Fax: 2022723-693 E-Mail: [email protected] 10th Jubilee International Multidisciplinary Neuroscience Conference Stress and Behavior May 16-19, 2007 St. Petersburg, Russia Contact: Dr. Allan V. Kalueff, Conference Chair Tel: 358-0-442-865-613 E-Mail: [email protected] December 2006 KUWAIT MEDICAL JOURNAL Interventional Ultrasound - Clinical applications May 21-23, 2007 City: Ravello - Amalfi Coast, Italy Contact:Dr. L.Tarantino Tel: 39-0-818-817-059; Fax: 39-0-818-891-302 E-Mail: [email protected] Neurologic Emergencies and Neurocritical Care May 22-25, 2007 City: New York ,NY Country, United States Contact:Center for Continuing Education, Columbia University, College of Physicians & Surgeons, 630 West 168th Street, Unit 39, New York, NY 10032 Tel: 212-305-3334; Fax: 212-781-6047 E-Mail: [email protected] ICN Conference, CNR and Regulation Conference May 27- Jun 03, 2007 City:Yokohama, Japan Contact:Marije Wiegerinck Tel : 31-205-040-203; Fax:31-205-040-225 E-Mail:[email protected] 11th Congress of the Movement Disorder Society June 03-07, 2007 City:Istanbul, Turkey Contact: The Movement Disorder Society, 611 East Wells Street, Milwaukee, WI 53202 USA Tel: 1-414276-2145; Fax: 1-414-276-3349 E-Mail: [email protected] HIV/AIDS 2007 Jun 06-11, 2007 Kololi, Gambia Contact: Anthony F. England, Ph.D. Tel: 31-302-145-715; Fax: 31-302-145-715 E-Mail: [email protected] 2nd International Congress on Neuropathic Congress June 07-10, 2007 City:Berlin, Germany Contact :Ilana Eliav Tel : 41-229-080-488; Fax: 41-227-322-850 E-Mail: [email protected] 3rd International Workshop on HIV and Hepatitis Co-infection June 07-09, 2007 City: Paris, France Contact: Jo-Els van der Woude Tel: 31-302-307-147; Fax:31-302-307-148 E-Mail: [email protected] 343 4th World Congress of the International Society of Physical and Rehabilitation Medicine June 10-14, 2007 City:Seou, Korea, Republic of Contact: 4th ISPRM Secretariat Tel: 82-2-566-6339 Fax:82-2-565-2434 E-Mail: [email protected] 3rd International Congress on Gastrointestinal Oncology June 14-16, 2007 City: Hersonissos, Crete island, Greece Contact: Mrs Tina Fragkaki Tel: 302-109-730-697; Fax: 302-109-767-208 E-Mail: [email protected] Well Aging, Andropause, Menopause June 15-16, 2007 City: Luxembourg, Luxembourg Contact: Monardo Claudine Tel: 35-226-264-134; Fax:35-226-264-175 E-Mail:[email protected] 3rd International Conference on Birth Diseases and Disabilities Jun 17-22, 2007 Rio de Janeiro, Brazil Contact: Monica Cevidanes, PMP Tel: 55-212-266-9150; Fax: 55-212-266-9175 E-Mail: [email protected] Clinical Trials Results of Gastroenterological Products, Practical Value from the Point of View of Evidence Medicine Jun 19-20, 2007 City: Kiev, Ukraine Contact: Dr Markov Tel: 38-0-632-776-465; Fax: 38-0-445-331-270 E-Mail: [email protected] Diabetes Camp June 23-30, 2007 City: Seattle, WA, United States Contact: Sandra Barnhart Tel: 1-800-422-0711; Fax:727-527-3228 E-Mail: [email protected] 17th International Epilepsy Symposium: Epilepsy Surgery June 27-29, 2007 City: Cleveland, OH, United States Contact: The Cleveland Clinic Center for Continuing Education, 9500 Euclid Ave. KK31, Cleveland, Ohio 44195 Tel: 954-659-5490 / 800-762-8173 / 216-444-5696; Fax:954-659-5491 E-Mail:[email protected] KUWAIT MEDICAL JOURNAL December 2006 WHO-Facts Sheet 1. New Global Estimates to Mark World Sight Day 2. A Clean Bill for Indoor Use of DDT to Control Malaria 3. Emergence of XDR-TB 4. Call for Intensified Action to Halt a Quarter of a Million TB/HIV Deaths a Year 5. Helmet Use Saves Lives Compiled and edited by Babichan K Chandy Kuwait Medical Journal 2006, 38 (4): 344-348 1. NEW GLOBAL ESTIMATES TO MARK WORLD SIGHT DAY Sight test and glasses could dramatically improve the lives of 150 million people with poor vision A simple sight test and eyeglasses or contact lenses could make a dramatic difference to the lives of more than 150 million people who are suffering from poor vision. Children fail at school, adults are unable to work and families are pushed into poverty as a result of uncorrected visual impairment. To mark World Sight Day, 12 October 2006, the World Health Organization (WHO) has released new global estimates which, for the first time, reveal that 153 million people around the world have uncorrected refractive errors (more commonly known as near-sightedness, far-sightedness and astigmatism). Refractive errors can be easily diagnosed, measured and corrected with eyeglasses or contact lenses, yet millions of people in low and middle income countries do not have access to these basic services. Without appropriate optical correction, millions of children are losing educational opportunities and adults are excluded from productive working lives, with severe economic and social consequences. Individuals and families are frequently pushed into a cycle of deepening poverty because of their inability to see well. At least 13 million children (age 5 to 15) and 45 million working-age adults (age 16 to 49) are affected globally. Fully 90% of all people with uncorrected refractive errors live in low and middle income countries. “These results reveal the enormity of the problem,” said Dr Catherine Le Galès-Camus, WHO Assistant Director-General, Noncommunicable Diseases and Mental Health. “This common form of visual impairment can no longer be ignored as a target for urgent action.” WHO previously estimated that 161 million people were visually impaired from eye diseases such as cataract, glaucoma and macular degeneration. Uncorrected refractive errors were not included in these earlier estimates. These latest WHO estimates add to the previous number and effectively double the estimated total number of visually-impaired people worldwide, bringing it to some 314 million people globally. The estimates also confirm that uncorrected refractive errors are a leading cause of visual impairment worldwide. As part of the VISION 2020 Global Initiative to eliminate avoidable visual impairment and blindness worldwide, WHO has been working with its partners to improve access to affordable eye exams and eyeglasses for people in low and middle income countries. This new information concerning the prevalence of refractive errors will strengthen the efforts of the VISION 2020 partnership to raise awareness of the magnitude of the problem and spur increased commitment for action. “Correction of refractive errors is a simple and cost-effective intervention in eye care,” said Dr Serge Resnikoff, Coordinator of WHO’s Chronic Disease Prevention and Management unit. “Now that we know the extent of the problem of uncorrected refractive errors, especially in low and middle income countries, we must re-double our efforts to ensure that every person who needs help is able to receive it.” Note: Refractive errors occur when the eye is not able to correctly focus images on the retina. The result is blurred vision, which is sometimes so severe that it creates functional blindness for affected individuals. The three most common refractive errors are: l Myopia (nearsightedness) - this is difficulty in seeing distant objects clearly. l Hyperopia also known as Hypermetropia Address correspondence to: Office of the Spokesperson, WHO, Geneva. Tel.: (+41 22) 791 2599; Fax (+41 22) 791 4858; Email: [email protected]; Web site: http://www.who.int/ December 2006 KUWAIT MEDICAL JOURNAL (farsightedness) - this is difficulty is seeing close objects clearly. l Astigmatism - This is distorted vision resulting from an irregularly curved cornea. For more information contact:Alexandra Touchaud, Communication officer, WHO Geneva, Tel: +41 22 791 5053, Mobile: +41 79 754 7763, Email: [email protected]. Dr JoAnne Epping-Jordan, Senior Programme Adviser, WHO Geneva, Tel. direct: +41 22 791 4646, Email: [email protected]. 2. A CLEAN BILL FOR INDOOR USE OF DDT TO CONTROL MALARIA WHO promotes indoor spraying with insecticides as one of three main interventions to fight Malaria Nearly thirty years after phasing out the widespread use of indoor spraying with DDT and other insecticides to control malaria, the World Health Organization (WHO) today announced that this intervention will once again play a major role in its efforts to fight the disease. WHO is now recommending the use of indoor residual spraying (IRS) not only in epidemic areas but also in areas with constant and high malaria transmission, including throughout Africa. “The scientific and programmatic evidence clearly supports this reassessment,” said Dr Anarfi Asamoa-Baah, WHO Assistant Director-General for HIV/AIDS, TB and Malaria. “Indoor residual spraying is useful to quickly reduce the number of infections caused by malaria-carrying mosquitoes. IRS has proven to be just as cost effective as other malaria prevention measures, and DDT presents no health risk when used properly.” WHO actively promoted indoor residual spraying for malaria control until the early 1980s when increased health and environmental concerns surrounding DDT caused the organization to stop promoting its use and to focus instead on other means of prevention. Extensive research and testing has since demonstrated that well-managed indoor residual spraying programmes using DDT pose no harm to wildlife or to humans. “We must take a position based on the science and the data,” said Dr Arata Kochi, Director of WHO’s Global Malaria Programme. “One of the best tools we have against malaria is indoor residual house spraying. Of the dozen insecticides WHO has approved as safe for house spraying, the most effective is DDT.” Indoor residual spraying is the application of long-acting insecticides on the walls and roofs of houses and domestic animal shelters in order to kill 345 malaria-carrying mosquitoes that land on these surfaces. “Indoor spraying is like providing a huge mosquito net over an entire household for aroundthe-clock protection,” said U.S. Senator Tom Coburn, a leading advocate for global malaria control efforts. “Finally, with WHO’s unambiguous leadership on the issue, we can put to rest the junk science and myths that have provided aid and comfort to the real enemy - mosquitoes - which threaten the lives of more than 300 million children each year.” Views about the use of insecticides for indoor protection from malaria have been changing in recent years. Environmental Defense, which launched the anti-DDT campaign in the 1960s, now endorses the indoor use of DDT for malaria control, as does the Sierra Club and the Endangered Wildlife Trust. The recently-launched President’s Malaria Initiative (PMI) announced last year that it would also fund DDT spraying on the inside walls of households to prevent the disease. Programmatic evidence shows that correct and timely use of indoor residual spraying can reduce malaria transmission by up to 90 percent. In the past, India was able to use DDT effectively in indoor residual spraying to cut dramatically the number of malaria cases and fatalities. South Africa has again re-introduced DDT for indoor residual spraying to keep malaria case and fatality numbers at all-time low levels and move towards malaria elimination. Today, 14 countries in Sub-Saharan Africa are using IRS and 10 of those are using DDT. The World Health Organization also called on all malaria control programmes around the world to develop and issue a clear statement outlining their position on indoor spraying with long-lasting insecticides such as DDT, specifying where and how spraying will be implemented in accordance with WHO guidelines, and how they will provide all possible support to accelerate and manage this intervention effectively. “All development agencies and endemic countries need to act in accordance with WHO’s position on the use of DDT for indoor residual spraying,” said Richard Tren, Director of Africa Fighting Malaria. “Donors in particular need to help WHO provide technical and programmatic support to ensure these interventions are used properly.” Indoor residual spraying is one of the main interventions WHO is now promoting to control and eliminate malaria globally. A second is the widespread use of insecticide-treated mosquito nets. While the use of bed nets has long been encouraged by WHO, the recent development of “long-lasting insecticidal nets” (LLINs) has 346 WHO-Facts Sheet dramatically improved their usefulness. Unlike their predecessors, the long-lasting nets need not be re-dipped in buckets of insecticide every six months as they remain effective for up to five years without retreatment. Finally, for those who do ultimately become sick with malaria, more effective medicines are increasingly becoming available. Unlike previous antimalarials that have been rendered useless in many regions due to drug resistance, Artemisinin Combination Therapies (ACTs) are now recommended. These lifesaving medications are becoming more widely available throughout the world. In January of this year, WHO took stringent measures to help prevent future resistance to antimalarial medicines by banning the use of malaria monotherapy. An example of the negative consequences of drug resistance is apparent in the threat it poses to intermittent preventive treatment in pregnancy (IPTp), a crucial strategic intervention to protect pregnant women from the consequences of malaria. Each year, more than 500 million people suffer from acute malaria, resulting in more than one million deaths. At least 86 percent of these deaths are in sub-Saharan Africa. Globally an estimated 3,000 children and infants die from malaria every day and 10,000 pregnant women die from malaria in Africa every year. Malaria disproportionately affects poor people, with almost 60 percent of malaria cases occurring among the poorest 20 percent of the world’s population. For more information contact: In Washington, DC: Jim Palmer at 1 (202) 262-9823, or Michael Riggs at 1 (202) 669-2163. In Geneva: Ed Vela at +41 22 7914550 or Shiva Murugasampillay at +41 22 791-1019. 3. EMERGENCE OF XDR-TB WHO concern over extensive drug resistant TB strains that are virtually untreatable The World Health Organization (WHO) has expressed concern over the emergence of virulent drug-resistant strains of tuberculosis (TB) and is calling for measures to be strengthened and implemented to prevent the global spread of the deadly TB strains. This follows research showing the extent of XDR-TB, a newly identified TB threat which leaves patients (including many people living with HIV) virtually untreatable using currently available anti-TB drugs. What is XDR-TB? MDR-TB (Multidrug Resistant TB) describes strains of tuberculosis that are resistant to at least the two main first-line TB drugs - isoniazid and December 2006 rifampicin. XDR-TB, or Extensive Drug Resistant TB (also referred to as Extreme Drug Resistance) is MDR-TB that is also resistant to three or more of the six classes of second-line drugs. The description of XDR-TB was first used earlier in 2006, following a joint survey by WHO and the US Centers for Disease Control and Prevention (CDC). Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care. Problems include incorrect drug prescribing practices by providers, poor quality drugs or erratic supply of drugs, and also patient non-adherence. What is the current evidence of XDR-TB? Recent findings from a survey conducted by WHO and CDC on data from 2000-2004 found that XDR-TB has been identified in all regions of the world but is most frequent in the countries of the former Soviet Union and in Asia. Scarce drug resistance data available from Africa indicate that while population prevalence of drug resistant TB appears to be low compared to Eastern Europe and Asia, drug resistance in the region is on the rise. Given the underlying HIV epidemic, drugresistant TB could have a severe impact on mortality in Africa and requires urgent preventative action. What action is required to prevent XDR-TB? XDR-TB poses a grave public health threat, especially in populations with high rates of HIV and where there are few health care resources. Recommendations outlined in the WHO Guidelines for the Programmatic Management of Drug Resistant Tuberculosis include: l strengthen basic TB care to prevent the emergence of drug-resistance l ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission l increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients l increase investment in laboratory infrastructures to enable better detection and management of resistant cases. For more information contact: Glenn Thomas, Stop TB Department, WHO, Mobile: +41 79 509 0677, email: [email protected]. Dr Karin Weyer, Director, South African Medical Research Council, Unit for TB Operational and Policy Research, Tel: +27.12.339-8550, Mobile: +27 82 4608836, email: [email protected]. December 2006 KUWAIT MEDICAL JOURNAL 4. CALL FOR INTENSIFIED ACTION TO HALT A QUARTER OF A MILLION TB/HIV DEATHS A YEAR “Joint TB and HIV interventions can save lives and must be accelerated” says international Aids society president Leading HIV experts called on the global HIV community to intensify collaboration on tuberculosis control, to prevent the deaths of a quarter of a million people living with HIV (PLHIV) a year. At the XVI International AIDS Conference in Toronto this year, HIV Director Dr Kevin De Cock and TB/HIV Coordinator Dr Paul Nunn, both from WHO, were joined by Dr Helene Gayle, the International AIDS Society President. Together, they urged HIV health workers to target and scaleup joint activities for tuberculosis and HIV. “TB prevention, diagnostic and treatment services must become core functions of all HIV services,” said Dr De Cock. “People living with HIV are more vulnerable to TB, even if they’re on antiretroviral therapy. TB can be treated and cured so most of these deaths are absolutely preventable. HIV policy-makers, health ministers and health workers all have a vital role in making sure that deaths from TB are reduced.” “Joint TB and HIV interventions can save lives and must be accelerated,” said Dr Gayle. “More than a third of all people infected with HIV are also infected with the tuberculosis bacillus, which causes the deaths of a quarter of a million people living with HIV, every year.” “This is important research which shows that TB preventive treatment is successful in reducing TB cases in PLHIV, even for those who are already taking life-saving antiretroviral drugs.” said Dr Richard Chaisson, Principal Investigator a Brazilbased study. He also emphasized that research into new TB drugs, diagnostics and vaccines appropriate for PLHIV, and operational studies and effective models to deliver the services to those who need them, are urgently needed. “We have the essential know-how and policy guidance to address TB among PLHIV and progress has been documented. However, the progress has been slow, compared to the scale of the problem,” said Dr Paul Nunn of WHO’s Stop TB Department. “In countries dually affected by TB and HIV these interventions should be rapidly scaled up and implemented through effective collaboration between HIV and TB control programmes, and general health services. Two years ago, Nelson Mandela warned the world that ‘We can’t fight AIDS unless we do much more to fight TB.’ “Mr Mandela’s warning on HIV and TB still needs to be 347 translated into large scale action. Commitments made at the G8, UN and African Union summits must be experienced by the actual communities most affected by the dual epidemics, particularly in Africa where HIV-related TB deaths are the highest in the world”. Globally, TB is second only to HIV as an infectious killer of adults, causing nearly nine million cases of active TB disease and two million deaths every year. In countries with a high prevalence of TB, HIV programmes must scale up TB prevention, diagnosis and treatment. For more information contact: In Toronto: Carole Francis, Tel: +41 79 54 079 56, email: [email protected]. Glenn Thomas, Tel: +41 79 50 906 77, [email protected] 5. HELMET USE SAVES LIVES Increasing helmet use promoted as an effective method of reducing road injuries and deaths Each year, about 1.2 million people die as a result of road traffic crashes, and millions more are injured or disabled. Most of the deaths are preventable. In many low-income and middleincome countries, users of two-wheelers particularly motorcyclists - make up more than 50% of those injured or killed on the roads. Head injuries are the main cause of death and disability among motorcycle users, and the costs of head injuries are high because they frequently require specialized medical care or long-term rehabilitation. Wearing a helmet is the single most effective way of reducing head injuries and fatalities resulting from motorcycle and bicycle crashes. Wearing a helmet has been shown to decrease the risk and severity of injuries among motorcyclists by about 70%, the likelihood of death by almost 40%, and to substantially reduce the costs of health care associated with such crashes. The World Health Organization (WHO) is intensifying efforts to support governments, particularly those in low-income and middleincome countries, to increase helmet use through a new publication, Helmets: a road safety manual for decision-makers and practitioners. The manual is a follow-up to the World report on road traffic injury prevention, published in 2004 by WHO and the World Bank, which provided evidence that establishing and enforcing mandatory helmet use is an effective intervention for reducing injuries and fatalities among twowheeler users. The manual has been produced under the auspices of the UN road safety collaboration, in collaboration with the Global Road Safety Partnership, the FIA Foundation for 348 WHO-Facts Sheet the Automobile and Society, and the World Bank, as one of a series of documents that aim to provide practical advice on implementing the recommendations of the World Report. The importance of increasing helmet use follows dramatic growth in motorization around the world, largely from increasing use of motorized twowheelers, particularly in Asian countries. In China, for example, motorcycle ownership over the last ten years has increased rapidly. In 2004, it was estimated that more than 67 million motorcycles were registered in the country, and approximately 25% of all road traffic deaths were among motorcyclists and their passengers. “We want to make helmet use a high priority for national public health systems,” says Dr. Anders Nordström, Acting Director-General of WHO. “We need to stress not only the effectiveness of helmets in saving lives, but the fact that helmet programmes are good value for money. Countries will recoup their investment in these programmes many times over through savings to their health care systems, as well as savings to other sectors.” Many countries have succeeded in raising rates of helmet use through adopting laws that make helmet use compulsory, enforcing these laws, and raising public awareness about the laws, as well as the benefits of helmet use. This new helmet manual draws on such examples. In Thailand, for instance, 80% of the 20 million registered motorized vehicles are motorcycles. In 1992, when helmet use was not mandatory, 90% of deaths resulting from traffic injuries were among motorcycle users, almost all due to head injuries. Legislation passed in the north-eastern province of Khon Kaen to make helmet use mandatory, supported by enforcement and publicity programmes, led to a 40% reduction in head injuries among motorcyclists and a 24% drop in motorcyclist December 2006 deaths within the two years This new manual provides technical advice to governments on the steps needed to assess current helmet use, and then design, implement and evaluate a helmet use programme. The manual addresses specific issues pertinent to many lowincome and middle-income countries, such as: l What can be done to protect the large number of children who ride as passengers on their parents’ motorcycles? l Are there financial disincentives in place that make helmets unaffordable and thus reduce their use, for example, sales tax, or import duties that could be removed by governments in efforts to increase helmet use? l How can enforcement be consistent and effective when resources are constrained? Should countries aim to implement a comprehensive helmet law, or is it more appropriate to phase in a law, in order to allow the traffic police to manage the new responsibility? The manual will be implemented in a number of countries over the next two years, starting in the ASEAN region through the Global Road Safety Partnership’s GRSI initiative, but extending to cover countries from Africa, Latin America and the Middle East. In addition to the publication of this manual, WHO has also established a network of experts working to increase helmet use, and supports helmet programmes directly in its country work on road safety. For more information contact: Laura Sminkey, Communications Officer, Department of Injuries and Violence Prevention, WHO/Geneva, tel: +41 22 791 4547 e-mail: [email protected] December 2006 THE KUWAIT MEDICAL JOURNAL Yearly Author Index Kuwait Medical Journal (KMJ) 2006; Volume 38 The Kuwait Medical Journal 2006, 38 (4): 353-354 Abdelhadi MSA . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Abdelkader B . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 Aboobacker KC . . . . . . . . . . . . . . . . . . . . . . . . . 147 Abu Tiban FMA . . . . . . . . . . . . . . . . . . . . . . . . . 144 Abubacker S . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Akbar MAJ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Akhtar S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Akhtar SS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Al Akkad M . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Al Aska A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Al Duwillah R . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 Al Fahmy M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Al Haifi M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Al Kharabah AM . . . . . . . . . . . . . . . . . . . . . . . . 329 Al Khulaifi Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Al Sayegh A . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Al Terkait N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Al-AbdulGhafour SYF . . . . . . . . . . . . . . . . . . . . 311 Al-Ali NS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Al-Anazi KA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Al-Anizi F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Al-Bloushi MAS . . . . . . . . . . . . . . . . . . . . . . . . 315 Al-Einzi LSM . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 Al-Eisa IS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Al-Fadli HAS . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Al-Faraj JM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Al-Ghareeb H . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Al-Hashash W . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Al-Humaidhi A . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Ali JI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Al-Jady AHA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Al-Jarki FA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Al-Jasem L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Al-Jassar T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Al-Jasser AM . . . . . . . . . . . . . . . . . . . . . . . . 171, 214 Al-Kandari MH . . . . . . . . . . . . . . . . . . . . . . . . . 276 Al-Khaldy JA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 AlKharji F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Al-Kussary IMA . . . . . . . . . . . . . . . . . . . . . . . . . 300 Al-Leithy M . . . . . . . . . . . . . . . . . . . . . . . . . . . . .191 Al-Mahmoud NY . . . . . . . . . . . . . . . . . . . . . . . . 284 Al-Maskari M . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Al-Mehza AM . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Al-Mutairi N . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Al-Mutar MS . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Al-Nakib W . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Alnaqdy A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Alotaibi S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Al-Qabandi W . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Al-Qatan HAY . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Al-Qbandi MA . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Al-Rayes M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 AL-Saleh M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Al-Sanae A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Al-Saqabi AH . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Al-Sawan RMZ . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Al-Shaibani HI . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Al-Sharkawy IAM . . . . . . . . . . . . . . . . . . . . . . . 147 Alshemmeri N . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Al-Terkit AM . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Al-Yahya AA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 AL-Zanki S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Anim JT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Asadi-Pooya AA . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Aziz S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Babay HAH . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Bader HES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Baidas G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Basheer H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Behbehani JH . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Bengmark S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 Ben-Nakhi A . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Botta GA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Bourhama MH . . . . . . . . . . . . . . . . . . . . . . . . . . .147 354 Yearly Author Index - Kuwait Medicl Journal (KMJ) 2006; Volume 38 December 2006 Budhdev JA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Malik SA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 Burud S . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94, 232 Chacko N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Dashti K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Davies W . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Devasia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Dowod TM . . . . . . . . . . . . . . . . . . . . . . . 43, 94, 232 El Rayes M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Mapkar OAW . . . . . . . . . . . . . . . . . . . . . . . . 53, 211 El-Din HMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 El-Kishawi A . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 El-Morshidy AF . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Fahmy ML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Fakher O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 George A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Ghaddar RK . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Ghoneim I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Giacometti L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Gnanaraj L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Gopalakrishnan G . . . . . . . . . . . . . . . . . . . . 56, 114 Gupta A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Gupta B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Gupta RK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Habeeb YK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Hadi I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1, 169 Hafez M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Hammouda A . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Hashem A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Hassaniah WF . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Hayat A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Hegazy AM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 Hegde BM . . . . . . . . . . . . . . . . . . . . . . . . . . . 83, 263 Hussain A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Ibrahim MK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Jawad NH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Johny KV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Jumaa T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Kashef S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Kekre N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Khallaf F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Khan AM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Khan FA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Lasheen I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Loutfy SA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Mahseen SA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Masoud GM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Mehrabi L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Moghnai O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Mohamed MT . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Mohammed HRA . . . . . . . . . . . . . . . . . . . . . . . . 107 Mukherjee A . . . . . . . . . . . . . . . . . . . . . . . . . . 56, 114 Nadi HM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Nampoory N . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Newman IM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Oommen MJ . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Oudjhane K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Pacsa A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Paramasivam RB . . . . . . . . . . . . . . . . . . . . . . . . . 141 Parappil H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Rabia F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Radhakrishan SB . . . . . . . . . . . . . . . . . . . . . . . . . 211 Radwan MM . . . . . . . . . . . . . . . . . . . . . . . . . . . .100 Rajaian S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Rani GR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Sadak SA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Senok AC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Shafik MH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Shalan YAF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Sharma PN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Sharma AK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Sheikh MK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Shenoy JN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Shenoy P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 Smallhorn J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Soni AL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46, 138 Suresh CG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Surrun SK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Szucs G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Tamimi DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Tayeh R . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107 Thrikovil SV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Uboweja AK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Vurgese TA . . . . . . . . . . . . . . . . . . . . . . . . . . . 53, 211 Xeroulis GJ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Yousef TM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Zubaid M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 December 2006 THE KUWAIT MEDICAL JOURNAL Yearly Title Index Kuwait Medical Journal (KMJ) 2006; Volume 38 The Kuwait Medical Journal 2006, 38 (4): 355-356 3C Syndrome (Cranio-Cerebello-Cardiac Dysplasia) Or Ritscher- Schinzel Syndrome: A Rare Case Report with Review of Literature. 38(2): 138-140. Comparison of Compliance Versus Non-Compliance to Anti-hypertensive Agents in Primary Health Care - An Area Based Study. 38(1): 28-32. A Novel use of Ureteroscope for a Non-Urological Cause - A Point of Technique. 38(1): 56-58. Comparison of Susceptibility Testing Methods for the Detection of Methicillin/Oxacillin Resistance in Staphylococcus Aureus. 38(3): 198-202. A Travel Abroad - Associated Case of Legionella Pneumonia. 38(1): 59-60. Accuracy of Axillary Temperature Compared with Rectal Temperature in Sick Children. 38(1): 25-27. Adrenal Carcinoma with Cardiac Metastasis in a Child: Case Report. 38(4): 321-323 Anomalous Coronary Artery from the Opposite Coronary Sinus in Young Children. 38(4): 292-299. Antibody Prevalence and Genotype-Specific Protective Immunity against Mumps Vi ru s Infection in Children from Kuwait. 38(1): 21-24. Bacteremia due to Stenotrophomonas Maltophilia in Patients with Haematological Malignancies. 38(3): 214-219. Bone Involvement in Hodgkin’s Disease at Presentation: A Series of Three Case Reports with a Brief Review. 38(2): 133-135. Breast Lymphoma: Case Report and Review of Literature. 38(1): 37-39. Burned-out Testicular Germ Cell Mimicking Lymphoma. 38(3): 235-237. Tumour Burns and Congenital Indifference to Pain in Two Sisters: A Case Report. 38(1): 40-42. Caffey Silverman Disease: Case Report and Literature Review. 38(1): 49-52. Carbamezepine Induced Pseudolymphoma. 38(4): 329-331. Changing Trends in Acute Myocardial Infarction Management: A Five -Year Study. 38(3): 207-210. Chronic Pain Clinic in Kuwait: Are We Prepared? 38(3): 169-170. Computerization in Primary Care: an Insight. 38(4): 311-314. Congenital Bronchial Atresia: CT- 3D Image Reconstruction and Virtual Navigation. 38(3): 238240. Coronary Angiogram is not the Diagnostic Gold Standard: Plea for Parsimony. 38(2): 83-84. Dislocation of the Extensor Tendons Over the Metacarpophalangeal Joints. 38(1): 7-9. Early Neonatal Hypernatremia with Intraventricular Hemorrhage - An Unusual Presentation in Two Cases. 38(1): 46-48. Early Radiological Results of Femoral Va ru s Derotation Osteotomy in Spastic Cerebral Palsy. 38(3): 191-197. Evidence-Based Medicine: Why and How? 38(1): 1-2. Excision of Ventricular Cysts of Larynx using Zero Degree and 30 Degree Endoscope. 38(4): 324-325. Extended-Spectrum Beta-Lactamases (ESBLs): A Global Problem. 38(3): 171-185. Factor XIII Deficiency in a Kuwaiti Child. Typical Presentation with Delayed Diagnosis. 38(2): 147-148. Factors Influencing Outcome of Congential Diaphragmatic Hernia. 38(4): 287-291. Factors Underlying Bottle-feeding Practice in Kuwait (2001). 38(2): 118-121. Fatal Case of Systemic Salmonella Infection with Acute Renal Failure, Haemolytic-Uraemic Syndrome and Rhabdomyolisis. 38(3): 229-231. 356 Yearly Title Index – Kuwait Medical Journal (KMJ) 2006 - Volume 38 Feasiblity and Clinical Significance of Echocardiographic Assessment of Aortic Root Compliance in Hypertensive Patients. 38(4): 276-283. Frequency and Etiology of Hyponatremia in Adult Hospitalized Patients in Medical Wards in a General Hospital in Kuwait. 38(3): 211-213. Frequency of Thyroid Microsomal and Thyroid Peroxidase Antibody Levels in a Selected Group of Omani Patients with Graves Disease. 38(1): 10-13. Gitelman’s Syndrome: A Separate Disorder or a Variant of Bartter’s Syndrome. 38(2): 144-146. Guillain-Barr syndrome in a Patient with RomanoWard Syndrome: A Case Report. 38(1): 53-55. Hepatitis C Virus Infection in Non-Hodgkin’s Lymphoma Patients: Virological Evaluation. 38(2): 122-127. Human Cytomegalovirus Infections in Pregnancy and the Newborn: Epidemiology, Laboratory Diagnosis and Medico-Legal Aspects. 38(2): 85-93. Mirizzi Syndrome: A Review of the Literature. 38(1): 3-6. Neuronal Ceroid Lipofuscinoses: Report of Five Cases in Kuwait. 38(4): 315-320. Osler-Weber-Rendu and Liver Transplant. 38(3): 186-190. Persistent Narrow Complex Tachycardia; What is the Diagnosis? 38(3): 226-228. Plant-derived Health-effects of Turmeric and Curcomenoids. 38(4): 267-275. Pretransplant Antitubercular Therapy - How Long? 38(2): 114-117. Prevalence and Factors Associated with Obesity and Treatment of Blood Pressure among Kuwaiti Hypertensive Patients in a Primary Health Care Clinic. 38(4): 284-286. Prevalence and Risk Factors for Diabetic Retinopathy among Kuwaiti Diabetics. 38(3): 203-206. Prevalence of Osteoporosis and Determinants of Bone Mineral Density in Healthy CommunityDwelling Kuwaiti Men Aged 50 Years or Older. 38(1): 14-20. December 2006 Profile of Vitiligo in Farwaniya Region in Kuwait. 38(2): 128-132. Profound Hyperkalemia and the Electrocardiogram. Lack of Correlation: A Case Report. 38(3): 232-234. Results of Combined Proximal Crescentic Metatarsal Osteotomy and Modified Distal Soft Tissue Procedure In Severe Hallux Valgus. 38(4): 300-307. Reversible Posterior Leukoencephalopathy Syndrome: A Review with Two Illustrative Cases. 38(2): 94-99. Risk Factors in Acute Poisoning in Children - A Retrospective Study. 38(1): 33-36. Safety of Laparoscopy for Acute Cholecystitis. 38(4): 308-310. Science Versus Scientism. 38(4): 263-266. Sheesha Smoking among a Sample of Future Teachers in Kuwait. 38(2): 107-113. Sickle Cell Intra-Hepatic Cholestasis : A Rare but Fatal Disease. 38(4): 326-328. Smoking among Health Care Workers of the Capital Governorate Health Region, Kuwait: Prevalence and Attitudes. 38(2): 100-106. Successful Treatment of Pyogenic Granuloma Complicating Motility Peg Hydroxyapatite Orbital Implant Using Topical Steroids Alone - A Case Report. 38(2): 141-143. Superior Mesenteric Artery Syndrome: An Uncommon cause of Intestinal Obstruction; Report of Two Cases and Review of Literature. 38(3): 241-244. Transient Central Diabetes Insipidus in a Female Patient with Thrombotic Thrombocytopenic Purpura and Ectopic Pregnancy: A Possible Link Case Report. 38(1): 43-45. Unusual Presentation of a Common Disease: Disseminated Tuberculosis Presenting as Osteomyelitis. 38(2): 136-137. Urinary Tract Infection in Boys Less Than Five Years of Age: A General Pediatric Perspective. 38(3): 220-225. Walker-Warburg Syndrome, A Case Report. 38(4): 332-335.
