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KUOPION YLIOPISTON JULKAISUJA D. LÄÄKETIEDE 424 KUOPIO UNIVERSITY PUBLICATIONS D. MEDICAL SCIENCES 424 PÄIVI SUTINEN Pathophysiological Effects of Vibration with Inner Ear as a Model Organ Doctoral dissertation To be presented by permission of the Faculty of Medicine of the University of Kuopio for public examination in Auditorium ML2, Medistudia building, University of Kuopio, on Friday 25 th January 2008, at 12 noon Department of Physical Medicine and Rehabilitation Kuopio University Hospital Department of Otolaryngology University of Tampere Department of Physical Medicine and Rehabilitation North Karelia Central Hospital, Joensuu JOKA KUOPIO 2008 Distributor : Kuopio University Library P.O. Box 1627 FI-70211 KUOPIO FINLAND Tel. +358 17 163 430 Fax +358 17 163 410 www.uku.fi/kirjasto/julkaisutoiminta/julkmyyn.html Series Editors: Professor Esko Alhava, M.D., Ph.D. Institute of Clinical Medicine, Department of Surgery Author´s address: North Karelia Central Hospital Department of Physical Medicine and Rehabilitation Tikkamäentie 16 FI-80210 JOENSUU FINLAND Tel. +358 13 171 2890 Fax +358 13 171 2880 Supervisors: Professor Ilmari Pyykkö, M.D., Ph.D. Department of Otolaryngology Tampere University Hospital Docent Olavi Airaksinen, M.D., Ph.D. Department of Physical Medicine and Rehabilitation Kuopio University Hospital Researcher Jing Zou, M.D., Ph.D. Department of Otolaryngology Tampere University Hospital Reviewers: Docent Marja Mikkelsson, M.D., Ph.D. Päijät-Häme Intermunicipal Federation for Social Services and Health Care Lahti Docent Erna Kentala, M.D., Ph.D. Department of Otolaryngology Helsinki University Hospital Opponent: Docent Karl-August Lindgren ORTON Invalidisäätiö Hospital Helsinki Professor Raimo Sulkava, M.D., Ph.D. School of Public Health and Clinical Nutrition Professor Markku Tammi, M.D., Ph.D. Institute of Biomedicine, Department of Anatomy ISBN 978-951-27-0944-1 ISBN 978-951-27-1041-6 (PDF) ISSN 1235-0303 Kopijyvä Kuopio 2008 Finland Sutinen, Päivi. Pathophysiological effects of vibration with inner ear as a model organ. Kuopio University Publications D. Medical Sciences 424. 2008. 94 p. ISBN 978-951-27-0944-1 ISBN 978-951-27-1041-6 (PDF) ISSN 1235-0303 ABSTRACT Hand-arm vibration syndrome (HAVS) is a symptom entity that consists of disturbances in the circulation of the fingers (Vibration White Finger or VWF), peripheral nerves of the hands and arms, and possibly muscle, joint and autonomic nervous system disorders. Changes in HAVS were assessed in a cross-sectional and in a longitudinal study of forestry workers. Sensorineural and musculoskeletal symptoms were studied. Changes in vibrotactile perception threshold were evaluated and the tonic vibration reflex was measured in posturography. An animal model was created to assess inner ear damage after vibration exposure. The prevalence of vibration-induced white finger (VWF) decreased from 17 to 8 percent in the cohort of 52 forestry workers. Numbness increased. Rotator cuff syndrome was diagnosed in 19% of men on the right side. Hand-arm vibration associated with the right rotator cuff syndrome. Numbness was associated with pain in upper extremities. Subjects with tension neck had excessive deviation of position in the lateral and anteroposterior direction in posturography during and after vibration-induced stimulation of neck and lumbar area. In vibrotactile perception threshold measurement, tactile acuity worsened in the cohort study. The threshold metric was the summed normalized threshold shift constructed for each subject. The positive predictive value of the metric was 71%. In an animal model, temporal bone vibration was used to assess the hearing loss caused by vibration. After bone vibration 60 % of the guinea pigs developed a threshold shift exceeding 10 decibel (dB) at least at two frequencies. Exposure to vibration at higher frequencies (500-1000 Hertz, Hz) produced stronger TS than exposure to frequencies 32-250 Hz. Temporal bone vibration caused expression of tumor necrosis factor alpha (TNF-α) and its‟ receptors (TNF R1, TNF R2) in the cochlea. The expression of TNF R2 was stronger than that of TNF R1. Vibration also induced vascular endothelial growth factor VEGF and its‟ receptor (VEGF R2) expression in the cochlea. The results indicate that VWF and numbness have possibly different pathophysiological mechanism. In the forestry workers, the strenuous work was associated with musculoskeletal disorders and partly explains the numbness. The animal model provides a new understanding of mechanisms leading to vibration-induced cochlear changes and cellular damage. The frequency of vibration influences the threshold shift of hearing in the vibrated cochlea. In the animal model, the expression of TNF-α and VEGF in the vibrated cochlea seems to cause tissue remodeling. The inner ear changes may also model vibration-induced damages in the hand-arm vibration syndrome. Shift to lower frequencies of vibration is advisable. National Library of Medicine Classification: WA 400, WE 805, WV 270 Medical Subjects Headings: Biomechanics; Cochlea; Cohort Studies; Cross-Sectional Studies; Forestry; Guinea Pigs; Hand-Arm Vibration Syndrome/etiology; Hand-Arm Vibration Syndrome/physiopathology; Hearing Loss, Sensorineural; Mechanoreceptors/physiology; Musculoskeletal Diseases; Neck Muscles: Innervation, Neck Pain/physiopathology; Occupational diseases; Occupational Exposure; Posture/physiology; Receptors, Tumor Necrosis Factor type I, Receptors, Tumor Necrosis Factor type II, Stress; Mechanical; Tumor Necrosis Factor- alpha; Vascular Endothelial Factor- alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth factor Receptor-2; Vibration/adverse effects To Erkki, Laura, Tuuli, Martti and Anton ACKNOWLEDGEMENTS This study was carried out in conjunction with the Institute of Occupational Health, Helsinki, Department of Otolaryngology of Karolinska Institute, Stockholm, Department of Otolaryngology, Tampere University, Tampere, and Department of Physical Medicine and Rehabilitation, North Karelia Central Hospital, Joensuu and Department of Physical Medicine and Rehabilitation, Kuopio University Hospital. I want to thank Medical Directors of North Karelia Central Hospital Pertti Palomäki and Antti Turunen and former Head of Department of Physical Medicine and Rehabilitation Eero Oura for kind support for my research. This work was financially supported by the Forestry Workers Fund, Finnish National Board of Forestry, and the Government special funds allocated to the North Karelia Central Hospital and Kuopio University Hospital. I am grateful for the forestry workers in Suomussalmi, who participated in this study, and I appreciate the co-operation of occupational health services and Martti Seppänen in Ämmänsaari. I express my sincere thanks to late colleague, my friend, Kaija Koskimies, Ph.D., who asked me to join the research team in Suomussalmi study. She eagerly helped me in the first steps of scientific studies and showed the way to go. I am deeply indebted to my supervisor Professor Ilmari Pyykkö, Head of the Department of Otolaryngology in Tampere University Hospital. He introduced the world of scientific research to me. He constantly supported me throughout the years. His inspiring personality and constructive criticism have carried me forward. Without him this thesis would never have been finished. I express my gratitude to my supervisor, Docent Olavi Airaksinen, Head of the Department of Physical Medicine and Rehabilitation in Kuopio, for his valuable and constructive comments on my work. I am also very grateful to my third supervisor, researcher Jing Zou Ph.D., Department of Otolaryngology, Tampere University, for his co-operation, enthusiasm and support. He created the first animal model to study the vibration-induced hearing loss (2001), and he made the laboratory studies of the immunohistochemistry in the animal model. He taught me to understand the nature of hearing loss in the animal studies. Special thanks to Esko Toppila, Ph.D., Institute of Occupational Health, Helsinki, who gave me valuable advice in Physics. His kind friendship and help have been important to me. He, together with Professor Jukka Starck, Head of Physics Department, Institute of Occupational Health, has made the technical measurements of balance and animal studies possible, for which I am very grateful. I wish to thank Heikki Aalto, Ph.D., who made the recordings of postural stability and who often encouraged me. I am also very thankful for Professor Anthony Brammer, who made the recordings of the vibrotactile perception thresholds, and discussed the topic of sensorineural changes thoroughly. I greatly appreciate his expertise and friendliness. I thank Professor Lisa Hunter for her contribution in the hearing loss study. I acknowledge the collaboration of Ulysses Diva, Ph.D. and Doctors Timo Hirvonen, Risto Kaksonen, Hisayoshi Ischizaki and Professor Hannu Alaranta. I sincerely appreciate the work of the reviewers Docent Marja Mikkelsson, PäijätHäme Intermunicipal Federation for Social Services and Health Care, and Docent Erna Kentala, Department of Otolaryngology, Helsinki University Hospital, for their valuable comments on my thesis. I thank Doctor Jukka Alm for teaching the basics of statistics and statistician Pirjo Halonen, University of Kuopio, and Professor Juha Alho, University of Joensuu, for analyzing the study results with me. I express my gratitude to librarian Pirkko Pussinen in North Karelia Central Hospital. I am indebted to my colleague, Katri Laimi, M.D., Ph.D., for her continuous support as a researcher and as a friend. I give my warmest thanks to my twin-sister Paula Rajaniemi for helping me with secretarial work, my daughter Tuuli Gröhn for checking the references and my friends Ilkka Jormanainen, Adele Botha, Antony Harfield, Ph.D., and Clint Rogers, Ph.D., for technical support. I am thankful to Marilyn Thompson, M.Tchg., for her editing. I am indebted to colleagues and other staff in my Department of Physical Medicine and Rehabilitation for allowing me to leave the daily work because of the thesis. I express my deep gratitude to Liisa Mustala, M.D., for her comments on the thesis and for hosting me in Tampere. During all these years, my parents, sisters and children have supported and inspired me, for which I am truly thankful. Finally I owe my deepest gratitude to my husband Erkki, for his enduring encouragement, sense of humor and love. And I thank all of my friends for prayers, because without miracles this thesis would not have been possible. ABBREVIATIONS ABR CGRP CSF CTS dB ENMG FA-I FA-II FSBP% HAVS Hz IHC ISO OHC PBS SA-I SA-II SD SNHL SPL SSRE TN TNF-α TNF R1 TNF R2 TS VAS VEGF VEGF R1 VEGF R2 VPT VWF Auditory Brainstem Response Calcitonin-gene related peptide Cerebrospinal fluid Carpal tunnel syndrome Decibel Electroneuromyography Fast-adapting receptor I Fast-adapting receptor II Percentage of finger systolic blood pressure Hand-Arm Vibration Syndrome Hertz Inner hair cell International Organization for Standardization Outer hair cell Phosphate buffer saline Slowly adapting receptor I Slowly adapting receptor II Standard deviation Sensorineural hearing loss Sound pressure level Shear stress response element Tension neck Tumor Necrosis Factor alpha Tumor Necrosis Factor alpha receptor 1 Tumor Necrosis Factor alpha receptor 2 Threshold shift Visual analogue scale Vascular Endothelial Growth Factor Vascular Endothelial Growth Factor receptor 1 Vascular Endothelial Growth Factor receptor 2 Vibrotactile perception threshold Vibration-induced White Finger LIST OF ORIGINAL PUBLICATIONS I. Sutinen P, Toppila E, Starck J, Brammer A, Zou J, Pyykkö I. Hand-arm vibration syndrome with use of anti-vibration chain saws: 19-year follow-up study of forestry workers. Int Arch Occup Environ Health 2006; 79(8): 665-71. II. Brammer AJ, Sutinen P, Diva UA, Pyykkö I, Toppila E, Starck J. Application of metrics constructed from vibrotactile threshold to the assessment of tactile sensory changes in the hands. Submitted for publication (Journal of the Acoustic Society) III. Koskimies K, Sutinen P, Aalto H, Starck J, Toppila E, Hirvonen T, Kaksonen R, Ishizaki H, Alaranta H, Pyykkö I. Postural stability, neck proprioception and tension neck. Acta Oto-Laryngol Suppl 1997;529:95-7 IV. Sutinen P, Zou J, Hunter LL, Toppila E, Pyykkö I. Vibration-induced hearingloss: mechanical and physiological aspects. Otol Neurotol 2007; 28(2): 171-7. V. Zou J, Pyykkö I, Sutinen P, Toppila E. Vibration induced hearing loss in guinea pig cochlea: expression of TNF-alpha and VEGF. Hear Res 2005; 202(1-2):1320. The Roman numbers in the text refer to the above publications TABLE OF CONTENTS 1 2 INTRODUCTION ..................................................................................................................... 15 LITERATURE REVIEW ......................................................................................................... 17 2.1 ENERGY PRINCIPLE OF VIBRATION DAMAGE ............................................................................. 17 2.2 ACUTE BIOLOGICAL RESPONSE TO VIBRATION EXPOSURE ........................................................ 18 2.3 HAND-ARM VIBRATION SYNDROME.......................................................................................... 18 2.3.1 Vascular changes: vibration-induced white finger ........................................................ 18 2.3.2 Sensorineural changes of HAVS .................................................................................... 22 2.3.3 Musculoskeletal changes ............................................................................................... 25 2.4 PREVALENCE OF HAND-ARM VIBRATION SYNDROME ............................................................... 27 2.5 PREVENTION OF VIBRATION DISORDERS ................................................................................... 28 2.6 PHYSIOLOGICAL RESPONSES OF VIBRATION AND NOISE............................................................ 29 2.6.1 Inner ear: cochlea .......................................................................................................... 29 2.6.2 Vestibulospinal system and postural stability ................................................................ 30 2.6.3 Vision and proprioception in postural stability ............................................................. 30 2.6.4 Cochlear injury: mechanisms of noise-induced hearing loss ........................................ 31 2.6.5 Animal model for vibration-induced functional changes ............................................... 33 3 4 PURPOSE OF THE STUDY .................................................................................................... 35 MATERIALS AND METHODS .............................................................................................. 36 4.1 SUBJECTS AND EXPERIMENTAL ANIMALS ................................................................................. 36 4.2 MEDICAL HISTORY ................................................................................................................... 36 4.3 MEDICAL EXAMINATION .......................................................................................................... 37 4.4 TESTS USED FOR ASSESSING MUSCULOSKELETAL FUNCTION IN 1995 ....................................... 38 4.5 MEASUREMENT OF VIBROTACTILE PERCEPTION THRESHOLDS .................................................. 38 4.5.1 Apparatus....................................................................................................................... 38 4.5.2 Method ........................................................................................................................... 39 4.5.3 Metric for threshold shift ............................................................................................... 39 4.6 FORCE PLATFORM POSTUROGRAPHY ........................................................................................ 41 4.7 CALCULATION OF LIFETIME DOSE ............................................................................................ 41 4.8 ANIMAL EXPERIMENTS ............................................................................................................. 42 4.8.1 Vibration delivery .......................................................................................................... 42 4.8.2 Measurement of hearing ................................................................................................ 43 4.8.3 Analysis of cytokines with immunohistochemistry ......................................................... 44 4.9 STATISTICS ............................................................................................................................... 45 5 RESULTS ................................................................................................................................... 46 5.1 HAND-ARM VIBRATION SYNDROME WITH USE OF ANTI-VIBRATION CHAIN SAWS: 19-YEAR FOLLOW-UP STUDY OF FORESTRY WORKERS (I) ...................................................................................... 46 5.1.1 Cross-sectional study ..................................................................................................... 46 5.1.2 19-year-cohort ............................................................................................................... 46 5.2 APPLICATION OF METRICS CONSTRUCTED FROM VIBROTACTILE THRESHOLD TO THE ASSESSMENT OF TACTILE SENSORY CHANGES IN THE HANDS (II) ............................................................ 51 5.2.1 Summed normalized threshold shifts.............................................................................. 51 5.2.2 Summed normalized threshold changes ......................................................................... 53 5.2.3 The correlations between the threshold metrics, age and grip force ............................. 54 5.2.4 Prediction of numbness from summed normalized threshold shift................................. 55 5.3 POSTURAL STABILITY, NECK PROPRIOCEPTION AND TENSION NECK. (III) ................................. 55 5.4 VIBRATION-INDUCED HEARING LOSS: MECHANICAL AND PHYSIOLOGICAL ASPECTS (IV)......... 56 5.4.1 Transfer factor ............................................................................................................... 56 5.4.2 Threshold shift immediately following vibration ........................................................... 57 5.4.3 Recovery after vibration ................................................................................................ 58 5.5 VIBRATION INDUCED HEARING LOSS IN GUINEA PIG COCHLEA: EXPRESSION OF TNF-ALPHA AND VEGF (V) ....................................................................................................................................... 59 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 6 Expression pattern of TNF-α in the vibration stimulated cochlea ................................. 59 Expression pattern of TNF receptors in the vibration stimulated cochlea .................... 59 Expression pattern of VEGF in the vibration stimulated cochlea.................................. 60 Expression pattern of VEGF receptors in the vibration stimulated cochlea.................. 60 Hearing loss after vibration ........................................................................................... 61 DISCUSSION ............................................................................................................................. 62 6.1 6.2 6.3 6.4 6.5 6.6 METHODOLOGICAL ASPECTS .................................................................................................... 62 CLINICAL ASPECTS OF VIBRATION- INDUCED HEALTH HAZARDS .............................................. 63 CLINICAL ASPECTS OF SENSORY THRESHOLD CHANGES ........................................................... 66 POSTURAL STABILITY AND NECK PAIN ..................................................................................... 67 INNER EAR AS A MODEL ORGAN FOR SENSORINEURAL DAMAGE ............................................... 68 UPREGULATION OF THE CYTOKINES DURING VIBRATION EXPOSURE ........................................ 70 7 CONCLUSION .......................................................................................................................... 71 8 REFERENCES........................................................................................................................... 72 15 1 INTRODUCTION Local vibration to hands occurs when the hands grasp vibrating tools and vibration enters the body through the hands. Occupationally important sources of hand-arm vibration are mainly prevalent in industry, construction or agriculture (Loriga 1911, Pelmear 2003). Vibration is principally contacted with palm and fingers, but vibration may be transmitted from hand to whole upper extremity and even further (Békésy 1939). Long-lasting or excessive vibration has been associated with various disorders in epidemiological studies. In 1911 Loriga reported that miners using pneumatic drills suffered from attacks of vascular disturbances of finger circulation, the so called white fingers (Loriga 1911). Since then Hamilton reported vasomotor disturbances in stone cutters (Hamilton 1918, Hamilton 1930) and later other researchers reported the same kind of disturbances in other users of vibrating tools; such as in airplane industry workers, grinders, forestry workers and rock drillers (Dart 1946, Agate and Druett 1947, Kylin and Lindström 1968, Seppäläinen 1972, Pyykkö 1974, Taylor et al. 1984, Starck et al. 1984) Hand-arm vibration syndrome (HAVS) consists of disturbances in the circulation of the fingers (vibration white finger, VWF) and in the peripheral nerves of the hands and arms (Seppäläinen 1972, Pelmear 2003). It may include muscle, bone and joint disorders (Färkkilä 1978, Iwata 1968, Laitinen et al. 1974, Pyykkö 1986). Autonomic nervous system involvement is not yet delineated. The symptoms of HAVS may either coexist or occur separately. In Nordic countries the symptoms of HAVS became alarmingly high in the middle of the 1960‟s in forestry work. The prevalence of HAVS peaked in the early 70‟s, when the prevalence of HAVS was 40-47 % (Hellström and Andersen 1972, Pyykkö 1974) in forestry workers and it dropped to 5% in the 1980‟s (Koskimies 1992). VWF was also common in foundry chipping/ grinding workers (with prevalence of 21%) in Italy (Bovenzi et al. 1987), in pedestal grinders with a prevalence of 74-100% (Starck et al. 1983, Hayward and Griffin 1986, Seppäläinen et al. 1986), in rock drillers with prevalence of 36- 50% (Chatterjee et al. 1978, Pelmear et al. 1987, Bovenzi et al. 1988). Recently, in a large survey of metal workers, the prevalence of HAVS was 8.4% (Sauni et al. 2006). Different frequencies, durations and intensities of vibration exposure can cause variable VWF and sensorineural changes (Griffin 2004). VWF and sensorineural changes occur and progress independently (Pelmear 2003). Different tools have different times of onset of symptoms, e.g. chain sawing with older type of chain saws elicited HAVS in a few years (Koskimies 1992) in comparison with a longer latency of new chain saws. There is a classification of HAVS concerning VWF and neurological disorders, according the Stockholm workshop scale. The purpose of the Stockholm workshop scale is to standardize the classification of symptom intensity in order to compare the different tools and frequencies causing HAVS. Vibrotactile perception threshold measurement is one of the methods to analyze sensorineural symptoms. 16 Pathophysiology is not yet fully delineated (Chetter et al. 1998, Herrick 2005). Vibration may induce structural changes in nerves and muscles. Vibration increases perineural edema of epineural and endoneural connective tissue (Lundborg et al. 1987). In rat tails, excessive vibration resulted in detachment of myelin sheath, deranged paranodal regions and reduced nerve conduction (Chang et al. 1994). In neuromuscular effects of vibration, studied by Necking et al (1996a), there is an increase of the crosssectional area of type I and IIC muscle fibers in comparison with controls. The muscle nuclei are more centrally positioned (Necking et al. 1996b) Takeuchi (1986) and Strömberg et al (1997) found demyelination of nerves and perineural and perivascular fibrosis in vibration-exposed workers. In another study, fractionated nerve conduction velocity across the carpal tunnel showed bimodal distribution: one group had a carpal tunnel- like syndrome and the other group had a more distal dysfunction (Rosen et al.1993). In addition to vascular and neurological symptoms, musculoskeletal disorders also occur after vibration exposure. In one study, a combination of muscle force, repetition, elevated upper extremity posture and vibration exposure was associated with increased prevalence of the rotator cuff tendonitis (Viikari-Juntura 1998). Musculoskeletal disorders connected to vibration exposure need more research. Whole body vibration occurs when the human body is supported on a vibrating surface, e.g. in vehicles. Whole body vibration does not cause any generally accepted diseases - except low back pain- and it is not included in this book. The purpose of this study was to evaluate HAVS in a cohort of forestry workers, to study changes of the postural stability during the vibration perturbation and to understand the mechanisms leading to vibration-induced hearing loss and cellular damage in the animal model. The inner ear damage model was used to provide insight into vibration-induced disorder in the HAVS. 17 2 LITERATURE REVIEW 2.1 Energy principle of vibration damage The references were searched from Medline and Pubmed in the beginning; during the years, many searches were made with different search strategies, including the years 1911-2007. The magnitude of vibration is usually measured by its acceleration (root mean square value) and frequency (Griffin 2004). According to the standard, the risk is proportional to the total vibration energy, i.e. magnitude and duration of exposure. The international standard ISO 5349 uses frequency weighted values over the range of about 5 to 1500 Hz (ISO 5349-1, 2001). The value given is that by which the vibration magnitude at each frequency is multiplied in order to weight it according to its influence on the body. It provides a model that can be used to predict the prevalence of VWF. Tominaga (2005) reported that current weighting should be changed by way of weighting less to low frequency and more to high frequencies. The EU-legislation defines in directive (Directive 2002/44/EC) that the action limit value is 2.5 ms-2 for 8 hr exposure. If this value is not exceeded, no protective actions are required. The limit value for hand-arm vibration of 8-hour exposure is 5 ms-2, which cannot be exceeded at work. In addition, the directive requires that the effect of vibration impulsiveness is taken into account. The harmfulness of impulsiveness has been shown (Starck 1984, Starck and Pyykkö 1986) but so far no limit value has been established. Exposure measurements should recognize that exposures are not continuous, and that there may be some recovery between exposures. A handle incorporating force and acceleration transducers was developed to measure the energy transfer (Johnson 1975). It was shown that absorbed power (energy per time) was 21 Nms-1 for rock drilling, and 2.7 Nms-1 for chiseling. The energy absorption depends on time, gripping force, vibration magnitude and the type of tool (Burström and Lundström 1994). According to Dong et al. (2005), the hand-arm system had the greatest resonance in the frequency rate of 20 to 50 Hz when testing biodynamic response. An increase of applied force increased the magnitude of biodynamic response and vibration transmission (Dong et al. 2005). No gender differences were reported (Bylund and Burström 2003). The amount of vibration energy, which is conveyed to the upper extremity, increases linearly with increasing hand grip force (Starck 1984, Starck et al. 1990, Burström and Lundström 1994). Low frequency (less than 50 Hz) impact vibration is absorbed up to the elbow (Kihlberg and Hagberg 1997) and high frequency vibration (400 Hz) is absorbed in the hand (Sörenssen and Burström 1997). Lidström (1973) suggested that energy transfer to the hand is a better indication of vibration-induced damage than the measurement of acceleration. She showed the correlation between energy absorption and HAVS (Lidström 1973). 18 2.2 Acute biological response to vibration exposure Vibration causes physiological changes in sensibility, motor control and blood circulation (Griffin 2004). Exposure to the static load does not cause any changes in finger blood flow (Bovenzi et al. 1995b, 1997b). Vibration at 125 Hz leads to temporary vibration- induced vasodilatation in the vibrated finger in healthy males, and later on, in recovery period, to cold-induced vasoconstriction, i.e. reduced finger blood flow in the ipsilateral and contralateral fingers. The mechanisms involve both local vasodilatation and central sympathetic reflex vasoconstriction activity (Bovenzi et al. 1995b). Also a reduction in toe blood flow is associated with vibration of the hand (Egan et al. 1996). The extent of decrease in digital blood flow is dependent on frequency of vibration (Bovenzi and Griffin 1997). The longer the duration of vibration exposure and the higher the magnitude of vibration, the longer was the vasoconstriction response (Bovenzi et al. 1998a, Bovenzi et al. 1999, Bovenzi et al. 2000a). After short-term exposure to vibration, temporary threshold shift (TS) for vibrotactile perception threshold (Maeda and Griffin 1993, Maeda 1994, Maeda and Griffin 1995, Malchaire et al. 1998a, Malchaire et al. 1998b), two-point discrimination (Bovenzi et al. 1997a) and nerve conduction impairment was reported (Nohara et al. 1986, Malchaire et al. 1998b). After half an hour‟s vibration exposure, temporary TS‟s occur in vibration perception threshold (VPT), and paresthesia and numbness develop; TS‟s increase concomitantly with vibration acceleration (Malchaire et al. 1998a, Malchaire et al. 1998b). Also sensorimotor reflexes such as tonic vibration reflex have been reported to be altered (Martin and Park 1997). In a study of muscular function in arm and shoulder muscles during vibration exposure, Rohmert et al (1989) found that the EMG (electromyography) index shows increase of 39% in trapezius muscle and to a lesser extent in infrapinatus, biceps and lower arm extensor muscles. The prime movers are most affected by vibration (Rohmert et al. 1989). 2.3 Hand-arm vibration syndrome 2.3.1 Vascular changes: vibration-induced white finger HAVS consists of: 1. vascular changes (VWF), 2. sensorineural changes, 3. possible bone and joint changes and 4. other possible changes, e.g. autonomic nervous system changes. The first two, vascular and sensorineural, changes can be classified according to the scales (see below).VWF consists of blanching of fingers starting from distal phalanges at the onset of symptoms (Hamilton 1918, 1930, Agate and Druett 1947, Pelmear 2003). 19 When exposure to vibration continues, the blanching can extend to proximal phalanges of fingers. Among forest workers it may occur for example after years of professional chain sawing, and is provoked by cold or damp weather (Pyykkö 1974). The attacks occur mostly in winter and may last from a few minutes to over one hour (Pyykkö 1974, Pelmear 2003). Attacks are shortened by warming. The duration varies with the condition of the environment and the intensity of the vasospasm, and the VWF attack then ends when the whole body is warmed (Pyykkö 1986). When warming occurs, blanching is followed by vasodilatation with hyperemia and pain (“hot aches”). In extremely rare cases, blanching may lead to trophic changes as ulceration or gangrene of the fingertips. During the attacks of VWF the workers can lose the touch sensation and manipulative dexterity (Sakakibara et al. 2005, Cederlund et al. 1999). Proper clothing and lunches in heated lodges reduced number and severity of VWF in Finnish forestry workers‟ population (Koskimies 1994). Smoking may influence hand-arm vibration syndrome (Cherniack et al. 2000). A scale for grading VWF has been proposed by Taylor and Pelmear (1975, refer table 1), and it was revised in a workshop in Stockholm (Gemne et al. 1987) to separate vascular and neurological scaling and to eliminate seasonal criteria. It also tried to eliminate subjective scaling in the workplace and in the home. Table 1. The Taylor-Pelmear scale for the classification of vibration-induced white finger Stage Condition of digits Work and social interference 0 No blanching No complaints 0T Intermittent tingling No interference with activities 0N Intermittent numbness No interference 1 Blanching of one or more fingertips, with or without tingling or numbness No interference 2 Blanching of one or more fingers, with numbness, usually in winter Slight interference with home and social activities 3 Extensive blanching: frequent episodes in summer as well as in winter Definite interference at work, home and with social activities, restriction of hobbies 4 Extensive blanching : frequent episodes in summer and winter Occupation changed to avoid further vibration due to symptoms 20 Table 2. Stockholm workshop scale for the classification of vibration white finger Stage Severity Condition of digits 1 Mild Occasional attacks affecting only the tips of one or more fingers 2 Moderate Occasional attacks affecting distal and middle phalanges of fingers 3 Severe Frequent attacks affecting all phalanges of most fingers 4 Very Severe As in stage 3, with trophic skin changes in finger tips The Stockholm Workshop Scale was published in 1987 (Gemne et al. 1987, refer table 2). The Stockholm Scale has been criticized for encompassing the highly subjective interpretation of frequent attacks and low sensitivity of early asymptomatic vascular injuries (Ishitake et al. 1995, Noel 2000). 2.3.1.1 Laboratory investigations of vascular changes Several laboratory tests have been used in assessment of VWF. Most of them are based on cold provocation and measurement of skin temperature or digital blood flow. Plethysmography can be used to evaluate the pulse wave forms in digital arteries preand post-cold stress. Cold provocation involves immersion of the hands in cold water (10-15 degrees). In measurement of cold provocation, the blood pressure is measured from finger (Juul and Nielsen 1981, Olsen et al. 1985). If the blood pressure is reduced more than 50% in comparison to blood pressure measured in 30°C, the result is diagnostic (Sauni et al 2006). There is a correspondence of test results and clinically staged symptoms in over 70% of cases (Juul and Nielsen 1981, Gemne and Pyykkö 1986). Finger systolic blood pressure measurement can also compare the affected finger pre-and post-cold blood pressure with the thumb, which is usually not affected (Olsen and Nielsen 1979). Finger systolic blood pressure is compared with the pressure of the arm (Ekenvall and Lindblad 1986b) after cooling the hand. Decreased systolic blood pressure of the affected finger indicates reduced circulation. Pyykkö et al. (1986a) compared the method of measurement of finger systolic blood pressure to a test in which arms and body are cooled and whitening of the digits is observed. The measurement of finger systolic blood pressure seemed to be more acceptable to patients and easier to standardize (Pyykkö et al. 1986a). Laser Doppler perfusion imaging has been studied in response to a cold provocation test. VWF patients had significantly lower values than controls during the last minutes of cold provocation (10 degrees) and the following recovery time (Miyai et al. 2005). Pyykkö et al. (1986b) used laser Doppler to identify vasomotor control abnormalities in VWF patients. The diagnostic value of the laser Doppler system has not been established. Finger skin temperature measurement is a quick and less costly method and it correlates with digital blood flow in various water temperatures, but measurement in air is unreliable because it is dependent on environmental factors, e.g. the room temperature. Despite this fact, finger skin temperature measurement has been used after 21 cooling the finger (Juul and Nielsen 1981, Bovenzi 1987, Yamada et al. 1995, Lawson and Nevell 1997). Cherniack et al. (2003) reported that finger skin temperature recovery after cold provocation in VWF subjects remained reduced even if the subject had stopped vibration exposure years ago. Infrared thermometry measurements of skin temperature rewarming time after cold provocation has also been used (Vonbierbrauer et al. 1998, Coughlin et al. 2001). The finger tip temperatures of HAVS patients remain significantly lower than pre-cooling values during a 10 minute-rewarming period (Coughlin et al. 2001). This method is relatively insensitive to provide discrimination between controls and HAVS patients. 2.3.1.2 Pathophysiological aspects of vascular changes Pathophysiology of vascular changes in HAVS is not yet fully delineated (Chetter et al. 1998, Herrick 2005). Takeuchi has reported arterial smooth muscle hypertrophy and fibrosis between endothelium and internal elastic lamina of blood vessels (Takeuchi et al. 1986, 1988). Functional vascular abnormalities have been reported: an imbalance between a potent vasoconstrictor, endothelin 1, and calcitonin-gene related peptide (CGRP), which is a powerful vasodilatator (Palmer and Mason 1996, Goldsmith et al. 1994). In VWF there is a loss of CGRP neural fibers leading to predominance of endothelin 1 (Goldsmith et al. 1994). In VWF patients, a cold challenge is connected with an increase in endothelin 1-concentrations compared to healthy subjects (Palmer and Mason 1996). There may also be impaired production of other vasodilatators such as NO (Nitric (II) oxide) and prostacyclin (Teh et al. 1995, Palmer et Mason 1996, Rajagopalan et al. 2003). Increase in peripheral resistance has been reported (Futatsuka et al. 1983, Gemne et al. 1986, Pyykkö and Gemne 1987) in the fingers of subjects with VWF during heatinduced vasodilatation. The circulation of fingers involves cholinergic, adrenergic and serotoninergic receptors in vasoregulatory systems (Lindblad and Ekenvall 1990). Several researchers have reported changes in the adrenergic function. Vasoconstriction to norepinephrine is mediated through α1- and α2- adrenoreceptors (Ekenvall et al. 1988), and during coldinduced vasoconstriction the normally silent α2C -adrenoreceptors redistribute from Golgi compartments to the cell surface (Jeyaraj et al. 2001). It may occur that, in patients with VWF, there is a lower set up-point for α2C-adrenoreceptors. Acute vibration increases alpha2C-adrenergic smooth muscle constriction (Krajnak et al 2006). Also, α1- adrenoreceptor damage may lead to α2- adrenoreceptor predominance and strengthen vasoconstrictor response (Ekenvall and Lindblad 1986, Issley et al. 1995, Stoyneva et al 2003). The autonomic nervous system may contribute to vascular changes of occupational origin (Harada 1994). Olsen et al. (1985, 1987) and Pyykkö (1986) proposed that the central sympathetic drive closes the main digital arteries. Single hand vibration induces contralateral vasoconstriction (Bovenzi et al. 1995a) and even vasoconstriction of feet (Sakakibara et Yamada 1995, Egan et al. 1996). Intravascular abnormalities have also been reported (Herrick 2005). Both central and peripheral mechanisms seem to exist. Vasoconstriction is aggravated by cold weather (Govindaraju et al. 2006); a warm climate leads to smaller prevalence of VWF (Yamamoto et al. 2002). 22 2.3.2 Sensorineural changes of HAVS Numbness of the hands and arms or a tingling in fingers and deterioration of finger tactile perception has been found in workers exposed to vibration (Seppäläinen1972, Araki et al. 1976, Brammer and Pyykkö 1987, Dahlin and Lundborg 2001). Numbness is generally reported during and after exposure. Numbness is common especially during night time (Färkkilä et al. 1985, Burke et al. 2005). Prevalence of peripheral neurological changes varies from a few percent to more than 80 percent of vibration-exposed workers (ISO5349-1). In population sample of 12,907 vibration-exposed workers, 2,607 (20.2%) reported sensory symptoms, numbness or tingling. Sensory symptoms were associated with hand-arm vibration (Palmer et al. 2000). In a group of dental hygienists using high frequency ultrasound hand pieces, 44.7% of them had paresthesia (Cherniack et al. 2006). The sensorineural changes are more common than vascular changes (Letz 1992, Virokannas 1995, Strömberg et al. 1996) and they have shorter latencies than vascular symptoms (Behrens et al. 1982). Sensorineural symptoms are usually reversible. However, they may also be irreversible (Bovenzi et al. 1994). Vibration may lead to a reduction of normal perception of touch and temperature, and manual dexterity (Sakakibara et al. 2005). Clinical tests as pinprick, light touch, 2- point discrimination and tuning fork testing are relatively insensitive and associated with developed lesions (Dellon 1980, Szabo et al. 1984). Cederlund et al. (1999) reported that the majority of HAVS patients found activities of daily living difficult, especially handling manual tools, handwriting, lifting objects, buttoning clothes and handling book. The Purdue Pegboard Test measures dexterity and gross movements of hands, fingers and arms. The Purdue pegboard test showed reduced hand function in 17 out of 20 workers (Cederlund et al. 1999). Low performance in a bean transfer test (picking up beans) was associated with increasing vibrotactile perception threshold and decreasing grip strength in Sakakibara et al‟s (2005) study; buttoning clothes and picking up small objects were difficult in HAVS patients. This might be attributed to impaired sensory feedback from SAI (Slowly adapting receptor I) and FAI (Fast adapting receptor I) afferents in glabrous skin. A classification system for severity of sensory changes has been proposed (Gemne and Saraste 1987), according to Stockholm Workshop Scale. Pelmear and Kusiak (1994) and Pelmear (2003) proposed that stage 4 should be included in the Stockholm sensorineural classification for patients with abnormal Tinel‟s and nerve conduction tests. Table 3. Stockholm workshop scale of sensorineural stages Stage Symptoms 0 SN Exposed to vibration but no symptoms 1 SN Intermittent numbness with or without tingling 2 SN Intermittent or persistent numbness, reduced sensory perception 3 SN Intermittent or persistent numbness, reduced tactile discrimination and/or manipulative dexterity Table 3 key: SN= sensorineural stage 23 In a study from a heavy engineering company, with the average tool use being 23.3 years, the individual cold provocation test did not associate with the Stockholm workshop scale, but neurological tests did associate with sensorineural staging. Vascular changes associated with age and total hours of vibration (McGeoch and Gilmour 2000). Also, perception of touch and dexterity showed a moderate association with sensorineural staging, as well as cold intolerance and pain in the upper limbs (Cederlund et al. 2003). 2.3.2.1 Laboratory investigation of sensorineural changes Neurological function can be tested with ENMG (Chatterjee et al. 1982, Brammer and Pyykkö 1987, Rosen et al. 1993, Sakakibara et al. 1998, Strömberg et al. 1999) and VPT‟s (Werner et al. 1995, Strömberg et al. 1998, Lundström et al. 1999, Strömberg et al. 1999). Thermal perception threshold testing seems to be useful in examining small nerve fiber injuries in HAVS. Warm thresholds tend to elevate and cold thresholds tend to lower (Toibana et al. 2002). The vibrotactile and thermal threshold impairments require specific testing (Strömberg et al. 1999): severe small fiber injuries of neurons can occur in the absence of nerve conduction abnormalities (Flodmark and Lundborg 1997, Ekenvall et al. 1989, Cherniack et al. 1990). Electroneuromyography (ENMG) Fractionated nerve conduction studies are important in assessing compressing neuropathies and large fiber neuropathies (Strömberg et al. 1999). Seppäläinen (1972) reported neuropathy in HAVS patients. Distal latency was lengthened and conduction velocities shorter in motor neurons (Seppäläinen 1972). Both sensory and motor conduction velocities were reduced in other studies (Juntunen et al. 1983, Brammer and Pyykkö 1987). Digital sensory nerve conduction is slowed in more than 40% of patients with VWF (Sakakibara et al. 1998). Carpal tunnel syndrome (CTS) may coexist with vibration-related neuropathy. In 47 vibration-exposed men the distal latency of median nerve was moderately increased, but it was less than in CTS patients. One group showed significant reduction in carpal tunnel and the other group more distal dysfunction (Rosen et al. 1993). It has been confirmed by others (Sakakibara et al. 1998). CTS was found in 26% of forestry workers by ENMG in 1988 (Färkkilä et al. 1988). This has been confirmed by others (Miller et al. 1994, Pelmear and Taylor 1994). Burke et al. (2005) reported that 15 per cent of 26 846 HAVS patients, miners, had also CTS. Recently it has been reported, that HAVS subjects having CTS had a great impact on their perceived ability to do everyday tasks and on their reduced quality of life, both physical and mental components (Poole and Mason 2005). Vibration-related neuropathy in the arms seems to constitute a separate entity: multiple- site- segments of the median and ulnar nerves, mainly distally to the wrist, are impaired (Sakakibara et al. 1998, Giannini et al. 1999, Bovenzi et al. 2000b, Cherniack et al. 2004). Reduced sensory nerve conduction velocity of radial nerve was reported in Japan in HAVS patients (Hirata et al. 2002) 24 Vibrotactile perception threshold (VPT) The sense of touch in the glabrous skin of the hands is mediated by neural activity in up to four populations of mechanoreceptors, which may be differentiated physiologically on the basis of their morphology, and functionally on the basis of their responses to static and dynamic skin indentation (Vallbo and Johansson 1984, Johnson 2001, Brammer et al. 2007). Table 4. Mechanoreceptors Anatomical population Function Frequency (Hertz) FAI Meissner corpuscles Gripping and holding objects 20-35 FAII Pacinian corpuscles Sensitive to vibration 100-400 SAI Merkel discs Detection of surface features 0.5-6 SAII Ruffini endings Respond to skin stretch - Table 4 key: FAI = Fast-adapting receptor I FAII=Fast-adapting receptor II SAI =Slowly adapting receptor I SAII=Slowly adapting receptor II Aatola et al. used an accelerometer to measure VPT from the middle finger of the left hand (Aatola et al. 1990). The vibration of a small plastic tip was pushing the fingertip by a constant force, and the vibration increased continuously. When feeling the vibration, the person pressed a switch in his right hand. When doing this, the switch immediately returned the vibration to null, and the vibration began again increasing. The vibration was measured from frequencies of 63, 125 and 250 Hz. The vibration was measured three times for each frequency, and the mean of these values was seen as a VPT. The temperature of the fingertip was also checked. Lundström (1985) showed that VPTs were elevated on the hands of therapists, who used ultrasound vibrators operating at 1 MHz, which is an exceptionally high vibration frequency. Vibration sensitivity of fingertips, as measured with VPT, is reduced in patients with HAVS (Coutu-Wakulczyk et al. 1997, Strömberg et al. 1998, Lindsell et al. 1999, Sakakibara et al. 2005, Brammer et al. 2007). Cederlund et al. (1999) reported that in the Semmes-Weinstein monofilament test, the small object shape identification and moving 2-point discrimination tests were indicating an abnormal outcome in activities of daily living, such as handling tools or books, handwriting and buttoning clothes. The tested males had worked with vibrating tools for a mean duration of 24 years 25 (Cederlund et al. 1999). The best predictors of the change in tactile acuity were difficulty in manipulating small objects and buttoning clothing (Coutu-Wakulczyk et al. 1997). Normative data of VPT and thermal thresholds have been published (Lindsell and Griffin 2002). A number of other sensorineural tests have also been applied (Kent et al 1998). Thermal thresholds as well as pain thresholds can be used to detect small nerve fiber injury testing in vibration-induced neuropathy (Ekenvall et al. 1986a, Toibana et al. 2000, Nilsson and Lundström 2001, Sakakibara et al 2002) Nevertheless, quantitative sensory testing lacks standardization in the population of hand-arm vibration neuropathy: it is susceptible to the effects of test methodologies (Lundström 2002). Age, outdoor or indoor temperature are confounding factors (Lindsell and Griffin 2002). Vibrotactile and thermal impairments should be measured, because ENMG does not show even severe small fiber injuries in HAVS (Ekenvall et al. 1989, Flodmark and Lundborg 1997, McGeoch et al. 2004) Thermal and vibrotactile perception measurements are correlated in vibration-exposed workers (Lindsell and Griffin 1999, Strömberg et al. 1999, Toibana et al 2000). Vibrotactile perception measurements are not in daily use yet, but mainly used in scientific studies. Quantitative sensory testing is used by neurologists, e.g. in North America. 2.3.2.2 Pathophysiological aspects of peripheral nerve changes Pathophysiological mechanism in sensorineural symptoms is not evident (Dahlin and Lundborg 2001). Biopsies have been taken from nerves (Hashimoto and Craig 1980, Takeuchi et al. 1986, 1988, Lundborg et al. 1987, 1990, Strömberg et al. 1997). Vibration increases perineural edema of epineural and endoneural connective tissue (Lundborg et al. 1987). Chang et al. (1994) found detachment of myelin sheath, constriction of the axon, and accumulation of vacuoles in peripheral nerves of rat tails exposed to vibration. These findings were confirmed by Ho and Yu (1989) and Lopata et al. (1994). Ultrastructural changes as deranged axoplasmic structure of plantar nerves could be seen to normalize in 4 weeks after vibration in the hind leg of rats (Lundborg et al. 1990). The vibration-damaged local nerve endings lead to neuronal loss, especially in the perivascular nerves in fingers containing CGRP (Goldsmith et al. 1994, Bunker et al. 1996), which is a potent vasodilatator. Takeuchi et al. (1986) found demyelination of nerves and perineural and perivascular fibrosis greater in vibration-exposed workers than in controls. Because of vibration exposure, structural nerve changes were reported in humans at wrist level: breakdown of myelin and interstitial and perineural fibrosis (Strömberg et al. 1997). Diffuse neuronal loss with neuropathy can extend from fingers to wrist, explaining poor recovery after carpal tunnel release (Strömberg et al. 1997). 2.3.3 Musculoskeletal changes Muscle-related disorders been reported after vibration exposure by subjects (Griffin 2004). Bovenzi et al. (1991) reported dose-effect relationship of vibration exposure with 26 the bicipital tendonitis and epicondylitis in forestry workers. In another epidemiological study, a combination of muscle force, repetition, elevated upper extremity posture and vibration exposure was associated with an increased prevalence of the rotator cuff tendonitis (Viikari-Juntura 1998). There is difficulty in establishing the rotator cuff syndrome associated with vibration only. There are many confounding factors for neck and upper extremity musculoskeletal disorders as awkward postures, ageing, heavy manual work and traumas (Hagberg 2002). Åström et al compared the prevalence of HAVS and musculoskeletal symptoms in 769 professional drivers of snow mobiles, and reindeer herders with randomly selected 296 male referents. Increased odds of musculoskeletal symptoms were reported in the areas of wrists, shoulders and neck with cumulative vibration exposure (Åström et al. 2006). Workers using low-frequency impact tools (less than 50Hz) in comparison with workers using non-impact tools (e.g. forest workers) reported more elbow and shoulder disorders (Bovenzi 1987, Kihlberg and Hagberg 1997). The workers with highfrequency impact tools (over 50 Hz) reported more wrist symptoms, which may be caused by the fact that high frequency impact vibration is attenuated in the hand and wrist (Kihlberg and Hagberg 1997). Bone and joint changes have been reported (Laitinen et al. 1974, Stenlund et al. 1992, Bovenzi et al. 1987) but conclusive evidence is still lacking (Gemne and Saraste 1987). Use of percussive pneumatic tools, with the repetitive frequency around 30 Hz, may be connected with bone and joint disorders (Lie 1980, Bovenzi 1987). For example, stone quarry workers with chipping hammer use were reported to have radiographic changes in the right elbow (Sakakibara et al. 1993). Forestry workers with VWF may lose more grip force in comparison to other forestry workers (Matsumoto et al. 1977, Färkkilä 1986, Sakakibara et al. 2005). Muscular fatigue assessed by maximal voluntary contraction has been found to be dependent on age and exposure to vibration and to be partly secondary to vibration-induced neuropathy (Inaba et al. 1993). Necking et al. (2002) reported that vibration-exposed workers presented weaker extrinsic and intrinsic muscle forces than the controls. 2.3.3.1 Pathophysiological aspects of muscle changes In the hind paws of rats exposed to vibration of 80 Hz, different degrees of degeneration were reported in plantar muscles as well as signs of regeneration. No changes were reported in contralateral limbs (Necking et al. 1992). In vibrated rat hind limbs, a strong increase of Insulin-like Growth Factor-1 was found in the anterior tibialis muscle and a less striking increase in the Achilles tendon (Hansson et al. 1988). It was concluded that vibration can induce reactive changes in tendon fibroblasts, which are located locally in the vibrated limb (Hansson et al. 1988). Pathological changes in hand muscles in man have been reported (Necking et al. 2004). The main morphological changes included centrally located myonuclei, fiber type grouping, angulated muscle fibers, fibrosis and regenerating fibers. The changes were associated with cumulative vibration exposure (Necking et al. 2004). 27 2.4 Prevalence of hand-arm vibration syndrome In Sweden, 11% of working men reported using hand-held vibrating tools at least half of their working day (Ekenvall et al. 1991). The main causes of hand vibration are the tools used in metal industry, forestry, construction and mining. The use of these equipments may lead to HAVS variably (Table 5). There are also differences between occupations, work places and individuals e.g. in working material, grip forces, body position, and susceptibility to attain HAVS when using vibrating tools (Bovenzi 1998b, Färkkilä et al 1985, Gemne and Lundström 1996). Table 5. Tools potentially leading to HAVS and their vibration level (latency in years) in 1968-1986. The name of the author, tool, year of publication, number of study population, and prevalence of vibration induced white fingers (VWF) are shown. In latency evaluation above the symbol ‘–‘ indicates data not available. Study Tool Year Number VWF (per cent) Latency (years) Iwata Mining 1968 225 72 - Partanen Pneumatic drills 1970 41 70 - Chatterjee et al. Pneumatic rock drills 1978 42 50 1-19 Taylor et al. Quarry hammer 1984 30 80 - Brubaker et al. Rock drill 1986 58 45 1-14 Among 344 shipyard workers, 22.7% of them had vascular symptoms and 78.2% of them had sensorineural symptoms according to the Stockholm workshop scale in Korea (Jang et al. 2002). Hill found that 50% of miners had HAVS in Canada (Hill et al. 2001). On the contrary, in Hungary 78.9% of 95 foundry workers had vascular and 65.3% had sensorineural symptoms (Kakosy et al. 2003). VWF was reported in 24% of car mechanics and 25% of them had numbness (Barregard et al. 2003). 28 Table 6. Prevalence and mean latency of vibration-induced white finger in chain saw users in 1972-1992 Study Year Number VWF (per cent) Latency (years) Hellström et al. 1972 296 47 1-18 Pyykkö 1974 118 40 4 Pyykkö et al. 1981 203 27 - Härkönen et al. 1984 279 18 - Färkkilä et al. 1988 186 5-22 - Koskimies et al. 1992 124 5 2.5-6.6 There is a trend of reduction in the prevalence and severity of VWF in forestry workers as demonstrated in table 6. HAVS has decreased because of several factors as change in vibration level (see chapter 4.7), environmental factors (as meals in warm environment, proper clothing, and transportation) and hygienic measures. 2.5 Prevention of vibration disorders In Finland about 6% of workers were exposed to hand-arm vibration in 2002. Vibration can be reduced by the use of preventive managerial, technical and individual measures (Griffin 2004). Use of vibration reduced working procedures can be planned ahead, e.g. instead of vibrating impact wrenches, drillscrewers are recommended. Tools should be designed not to require tight grip or strong push forces. Vibration reduced machinery can be designed, e.g. the use of an auto-balancing system in grinders (Cockburn 2006). Vibration reduction can be achieved by using anti-vibration grips, e.g. in chain saws (Koskimies et al. 1992) and pneumatic chisels. Grip coatings can be made of rubber or of other elastic material. Technical staff should be able to assess the amount of vibration, and equipment should be used and maintained properly (Griffin 2004). It may be beneficial to allow breaks between vibration exposures, and all workers exposed to hand-arm vibration should be warned about adverse effects of HAVS. In the risk assessment of HAVS, the effect of impulsive vibration and individual susceptibility must be taken into account. All the staff should be screened before and during the exposure of vibration at regular intervals to ensure early identification. Occupational health care should be alert in identifying HAVS. The worker himself can wear adequate clothing to avoid symptoms in a cold environment. Workers with vibration exposure should avoid smoking. In Finland enactment of the work safety, on the ground of the EU-legislation directive (Directive 2002/44/EC), regulates the measurement of vibration, the preservation of 29 exposure level assessment and risk analysis, prevention of vibration exposure and guiding of the exposed workers. Hand-Arm Vibration Syndrome Exposure of vibration: duration and intensity, impulsiveness Environmental factors Hand-grip force Ergonomic factors Susceptibility and genetic factors Preventive measures Figure 1. Factors involved in Hand-Arm Vibration Syndrome 2.6 Physiological responses of vibration and noise 2.6.1 Inner ear: cochlea Sound is a fluctuation of air pressure which induces pressure waves and the sensation of hearing (Bekesy 1932). Loudness is related to the sound pressure of the vibration. Amplitude is measured on a logarithmic scale in decibels (dB). The middle ear, i.e. the tympanic membrane and ossicular chain, convert vibrations from the air to pressure changes inside the inner ear fluids (Luxon 2003, Evans 2003). The stapes footplate in the oval window transforms the air pressure changes to fluid oscillation into the vestibular scala. The change is transmitted across the cochlear partition to the round window in the scala tympani. The pressure changes in cochlea produce traveling waves in the basilar membrane. The basilar membrane in its‟ basal portion has minimum width and maximum stiffness. For high frequencies of noise, the traveling wave is limited to 30 the basal portion. The apex has maximum width and lowest stiffness. For low frequencies of noise, the traveling wave is maximal in apex (Evans 2003). Both the inner hair cells (IHC) and the outer hair cells (OHC) respond to the fluid oscillation but have different sensitivity. (Fridberger et al 2002). The outer hair cells in the organ of Corti act like electro-mechano transducers (Brownell 2006). As a result, the movement of the OHC changes the rigidity of basilar membrane and related structures. The compliance of vibrating Organ of Corti in the area corresponding to the specific frequency is increased. The organ of Corti is tuned to enhance the sensitivity of the inner hair cells to the specific sound sequence. This tuning is further improved at a different exchange station in the brain stem and finally in the cortex. As the end result, the fine tuned signal generated by the inner hair cells is conveyed to the brain from the cochlear nerve fibres to perceive the sound (Evans 2003). 2.6.2 Vestibulospinal system and postural stability The vestibular system consists of otoliths and semicircular canals. Vestibular hair cells are also mechanoreceptors, that is, they sense head position change. The otoliths seem to operate at low frequency range, usually below 0.2 Hz. They detect linear acceleration such as gravity. The semicircular canals are capable of detecting angular acceleration of head, at frequencies of 0.5-6 Hz (Nashner 1971). The contribution of vestibular information is to maintain visual image by controlling the eyes and to stabilize the head in space (Wilson and Peterson 1978). Vestibulospinal reflexes control skeletal muscular responses for the maintenance of adequate posture. The unilateral loss of vestibular function causes a strong but usually transient postural asymmetry. Visual, vestibular and proprioceptive systems contribute to postural control and interact with one another. Afferent proprioceptive information and vestibular input converge in brainstem. It has been shown that one of the key areas in animal studies is the central cervical nucleus in the brainstem (Ragnarsson 1998). The role of central cervical nucleus in man is not delineated yet (Massazza 1923). 2.6.3 Vision and proprioception in postural stability Vision is important but not essential in postural control (Brandt et al. 1986). Postural sway is greater when eyes are closed than when eyes are open and this difference is used in postural stability assessment by determining the Romberg's quotient (Hytönen et al. 1993). Visual stabilization depends on eye-target distance (Paulus et al. 1984). To maintain postural balance during stance, postural corrections must be made continuously. Spindle afferent provide proprioceptive information that is used to trigger spinal reflexes automatically in fast corrections to transient, postural disturbance. Continuous upright stance regulation needs sensory feedback at low frequencies 0.3-1.0 Hz. Proprioception is used to detect changes in position or movement of one part relative to another part of the body. Proprioceptive receptors are situated in muscles, tendons and joints (Enbom 1990). Muscle spindles are located in the muscle, and arranged parallel to the fiber. Each muscle fiber may have several muscle spindles. The number 31 of muscle spindles is dependent on the task of the muscle. The stretching of the muscle and active muscle contraction activates the primary endings, which are branches of primary group Ia afferent nerve. The activation of primary endings releases a stretch reflex, which is monosynaptic. The reflex facilitates activity of the agonistic muscles and inhibits the activity of antagonistic muscles. Muscle stretching also activates the secondary endings. They are disynaptically connected to spinal α-motoneurons and also give information about the muscle tension to higher motor control centers of the central nervous system (Eklund and Hagbarth 1966, Prochazka and Hullinger 1983). Golgi tendon organs are proprioceptors between muscle tendon fibers. They are activated both by active muscle contraction and by passive tendon stretch. Activation of Golgi tendon organs reverses the response of muscle spindles: it facilitates the antagonistic muscles and inhibits the action of agonistic muscles. This may be a defense mechanism protecting the muscles from excessive loading and a fine tuning mechanism (Enbom 1990). Joint receptors are situated in or near the joint capsule. Activation occurs by joint movement and by the stretching of muscles attached to the joint capsule. Most afferents seem to be activated only in extreme angular displacements (Enbom 1990). Exteroceptive receptors, as presso- and mechanoreceptors, are situated in the subcutaneous tissue. They can be divided into slowly adapting (SA) or fast adapting type (FA) receptors. The pressor receptors can sense stretching of the skin (Johansson et al. 1980). The receptors in the sole of the foot have capacity to sense pressure changes to detect the change in postural sway (Johansson et al. 1982). Several studies have shown that cervical proprioception has a significant effect on orientation and posture (Pyykkö et al 1989, Revel et al.1994, Karlberg et al 1995). Neck pain patients with or without cervical root compression showed poorer postural performance in vibration-induced body sway (Karlberg et al. 1995). Revel et al. (1991, 1994) showed that tension neck patients with pain have reduced sensitivity of neck proprioception. If the initial position of head was to be re-assumed after maximal rotation to the side, the neck patients performed significantly poorer than healthy controls (Revel et al. 1991). 2.6.4 Cochlear injury: mechanisms of noise-induced hearing loss Noise is excessive auditory stimulation and it elicits shear forces in cochlea. Noise may damage the Organ of Corti, Reissner‟s membrane, basilar membrane and lateral wall of cochlear duct (Ulehlova 1983). There are two different ways that lead to cochlear injury: mechanical and metabolic (Ulehlova 1983). Intense noise (exceeding 120 dB SPL) in animals may also mechanically disrupt cochlear structures. At a lower sound pressure level, the sound can result in disturbed cochlear homeostasis and functional impairment (Scheibe 1992) by releasing free radicals (Salvi et al. 2001). When the metabolic or mechanical stress is too strong, apoptosis or necrosis occurs and cell death ensues (Ylikoski et al. 2001). Apoptosis can be seen as a counterbalance to cell division. Apoptosis does not affect the surrounding tissues. 32 Necrosis leads to disorganized breakdown of the cell, with a subsequent inflammatory process in the surrounding tissue (Leon et al. 2004). Pye and Ulehlova (1989) noted that intense noise caused drastic changes initially in the first row of OHC, followed by IHC and then the change spreads to all rows in affected area. When mechanical or metabolic stress is too high, permanent hearing loss is a result (Pyykkö et al. 2007). Changes in blood flow have been considered to contribute to that sensorineural hearing loss, SNHL (Nakashima et al. 2003). Lamm and Arnold have reported noiseinduced hearing-loss has been found parallel to a change in cochlear blood flow causing local ischemia (Lamm and Arnold 1996). The reduced pressure of oxygen is connected with accumulation of metabolites and functional alterations. The exact role of diminished cochlear blood flow is unclear and cochlear hypoxia may precede it (Lamm and Arnold 1996). During intensive noise trauma, there is an excessive release of the transmitter substance of hair cells, most likely the release of glutamate. It is toxic on nerve endings and elicits an inflow of calcium ions and subsequent swelling of the nerves. This mechanism may be involved in noise-induced hearing loss of the IHC (Puel et al 1998). NECROSIS APOPTOSIS SHEAR STRESS METABOLIC STRESS CELLULAR OXYGENATION BLOOD FLOW CHANGE TEAR DAMAGE GLUTAMATE CELL DEATH Figure 2. Mechanisms of necrosis and apoptosis Modified from Pyykkö et al. (2007). Prevention of damage to the inner ear function after noxious agents has been an area of intensive research. SNHL is known to occur after acoustic traumas. Drilling of the temporal bone during surgery exposes the cochlea to both noise and vibration (Hamernik 1989). The incidence of SNHL following surgeries involving drilling of the temporal bone has been reported to be between 3 to 5% in large series (English et al. 1973, Palva et al. 1973, 1976, Smyth et al. 1975). Others have reported even higher rates of slight post-operative SNHL, up to 55% in standard audiometric frequencies (Man and Winerman 1985, Domenech et al. 1989, Vasama 2003). 33 Variables such as drill speed, burr size and type, and site of drilling have been systematically investigated on isolated temporal bones, cadavers and an animal model (Paparella 1962, Kylen et al. 1977, Gjuric 1997). The characteristics of the drill variables and time domain of skull vibration determine the amount of vibration exposure. Noise exposure up to 125 dB in drilling (Holmquist et al. 1979, Kylen and Arlinger 1976, Urquhart et al. 1992) alone seems insufficient to cause permanent SNHL in patients, and other factors such as vibration and actual trauma to the ossicular chain may be as, or more, important than noise (Pyykkö et al. 1986c, Pyykkö et al.2003). 2.6.5 Animal model for vibration-induced functional changes 2.6.5.1 Up-regulation of growth factors in noise trauma Cells exposed to vibration or mechanically active environment respond with morphological changes caused by tangential shear forces. This cell response is called shear stress. For example endothelial cells alter their morphology, growth rate, and metabolism in response to fluid shear stress (Stamatas and McIntire 2001). There are two general ways in which the mechanical signals may be transmitted from the cellular membrane to the nucleus to induce gene regulation. One way is through cytoskeletal structures from the cellular membrane to the nucleus, intracellular junctions, and focal adhesion points (Stamatas and McIntire 2001). The other way is through diffusible secondary messengers released locally close to the membrane. These include, for example, calcium ions, adenosine triphosphate (ATP), mitogen-activated protein kinase (MAPK), and a variety of other protein kinases. Resnick et al. (1993) first reported that endothelial cells exposed to uniform laminar shear stress up-regulate a shear stress response element (SSRE). Nuclear factor-κB (NFκB) could functionally interact with the SSRE (Khachigian et al. 1995). According to the consequent research, several additional SSREs were reported later. Among these is early growth response-1 (Egr-1), which interacts with Platelet-Derived Growth FactorA, and activator protein-1 (AP-1), (Khachigian et al. 1997, Shyy et al. 1995). Recent research has shown that vascular endothelial growth factor (VEGF) and the receptors are also involved in fluid induced shear stress response (Gan et al. 2000, Milkiewicz et al. 2001, Abumiya et al. 2001, Conklin et al. 2002). In vitro study Abumiya evaluated shear stress of vascular endothelial cells and demonstrated increased VEGF R2 expression (2001). The authors interpreted this as showing that an increase in the shear stress in the vasculature by post-ischemic reperfusion stimulates a VEGF R2 expression, resulting in an increase in vascular permeability and leading to neo-vascularisation. The newly formed myofibroblasts express VEGF and VEGF R2 that seem to play a significant role in tissue repair/remodeling after myocardial infarction (Chintalgattu 2003) VEGF expression in connection to shear stress seems to be dependent on time. After longer shear stress, its expression is increased up to 14 days (Gan 2000, Milkiewicz et al. 2001). 34 In the cochlea, the hair cells are activated by shear movement in the organ of Corti during sound stimulation (Fridberger et al. 2002). In noise or vibration trauma, shear stress related response might be active in the cochlea and so lead to abnormal signal transduction. Tumor necrosis factor (TNF)-α is involved in cell damage mechanism especially through TNF receptor 1 (p55), while TNF receptor 2 (p75) can induce activation of c-Jun NH2-terminal kinases (JNK) and NF-κB (Goeddel 1999). The activation of JNK and NF-κB has the function of an anti-apoptotic agent. (Heldin and Purton 1998). When both receptors are expressed, the activation of TNF receptor 2 enhances the effects of receptor 1 activation. Also VEGF may be involved in the survival of the inner ear cells by enhancing the transport over the inner ear barrier (Zou et al. 2005, Fraenzer et al 2006). VEGF may also mediate its neural protection by upregulating Glial cell line-derived neurotrophic factor expression (Gao et al 2005). Glial cell line-derived neurotrophic factor has been found 8 hours after noise exposure, and it is involved in stress response in the cochlea (Nam et al. 2000). Glial cell line-derived neurotrophic factor is protective of noise induced cellular damage (Keithley 1998, Ylikoski et al. 1998). 35 3 PURPOSE OF THE STUDY In the present study, the purpose was to evaluate pathophysiological effects of vibration, especially: I. to evaluate the changes in the HAVS findings of forestry workers. Special interest was focused on neck, upper arm and forearm musculoskeletal disorders and their association to HAVS II. to detect threshold changes in tactile acuity over the five-year period. Changes were compared with measurements of hand grip, and with neurological symptoms among forestry workers III. to examine the changes of the postural stability during perturbation of neck and lumbar proprioceptors with vibration exposure IV. to determine the hazardousness of different frequencies of vibration: using the inner ear as a model organ V. to evaluate mechanisms leading to functional and structural vibration-induced damages: using the inner ear as a model organ 36 4 MATERIALS AND METHODS 4.1 Subjects and experimental animals I. A cross-sectional medical examination was carried out with 109 men in 1995. A cohort of forestry workers (n=52) was elected who were examined in each of examinations between 1976 and 1995 (subgroup 1). II. 18 forestry workers were examined as a cohort in 1990 and 1995 (subgroup 2) III. A cross-sectional examination was carried out in 1995 with 106 forestry workers, in connection with a compulsory medical examination (subgroup 3; 3 out of 109 subjects did not participate in postural stability measurements ) IV. Thirty pigmented guinea pigs of both sexes, weighing 400 – 760 g with normal Preyer‟s reflexes were used. V. Twelve male and female guinea pigs, weighing from 250 g to 500 g, were used in the study. Seven animals were exposed to transcranial vibration and five animals were used for control. Six animals of the vibration group and four animals of the control group were used for sectioning with immunohistochemistry. One animal in the vibration group and one in the control group were used for surface preparation with immunohistochemistry. 4.2 Medical history (I-III) Total vibration exposure was recorded during each survey totaling 11 visits in Suomussalmi County. The work of the forestry workers involved operation of lightweight chain saws for up to ten months per year. The forest workers felled and debranched trees (typically 25 - 35 cm diameter at the base), and were paid by piecework. All forestry workers were employed by the same employer. The study was combined with a compulsory medical examination. Detailed enquiries of medical history were taken with the aid of a structured questionnaire designed at the beginning of the cohort and the questionnaire was used in all study occasions. The questions were related to personal medical history and smoking. Special attention was given to an occupational history of vibration exposure and to the symptoms and signs of HAVS. The diagnosis of VWF was made according to the typical history of well-demarcated blanching of fingers after exclusion of primary Raynaud‟s phenomenon. Other possible causes of secondary Raynaud‟s phenomenon were excluded. If the forestry worker had not had an attack of VWF for at least two years, he was considered to have inactive VWF. Peripheral sensorineural disturbances such as numbness with tingling or paresthesias of hands and arms were explored as well as any subjective loss of handgrip force. Numbness was classified as present if persistent and troublesome. Each subject underwent a medical interview concerning neck and upper extremity pain. Pain in neck, upper arm, forearm, and wrist-hand regions during preceding 12 months were enquired. Intensity of cervical and lower back pain during the past 2 weeks prior to the 37 questionnaire was rated by a horizontal visual analogue scale (VAS) ranging from 0 to 100 mm (Huskisson 1982). Routine laboratory tests were made (erythrocyte sedimentation rate, hemoglobin). The routine tests did not lead to further investigations. In this follow-up study the basic questionnaire stayed the same. Prevalence of HAVS was earlier evaluated with cold provocation test in this group. It also included random sampling to exclude false negative results (Pyykkö et al 1986a). 4.3 Medical examination (I-III) The clinical examination of musculoskeletal disorders was performed by two physicians specialized in physical medicine and rehabilitation. Special attention was given to musculoskeletal neck and upper extremity disorders. A neurological examination of the upper extremities was conducted on all subjects, including sensorimotor function of the upper extremities. Cervical motion was measured with a Myrin goniometer. Clinical musculoskeletal diagnoses were modified from the criteria provided by Waris et al. (1979). No subject had a fracture of the cervical spine or upper extremity, or any malignant diseases of the neck-upper extremity. Table 7. Criteria for clinical diagnoses of musculoskeletal disorders Modified from Waris et al 1979 Tension neck Feeling of fatigue or stiffness in the neck, neck pain or headache radiating from the neck, at least two tender spots or palpable hardenings and muscle pain or tightness upon neck movement Rotator cuff syndrome In symptom cases, typical history of painful arch and intermittent pain and pronounced tenderness locally in the shoulder region were diagnostic or In addition, at least one of the following signs: painful arch test during elevation, pain in resisted abduction or resisted external rotation. Epicondylitis syndrome In symptom cases, a typical history of activity-dependent pain in the epicondyle region and local pronounced tenderness at the lateral or medial epicondyle were diagnostic, or A local pain during rest and/or movement, local tenderness at the lateral or medial epicondyle and local pain on resisted wrist extension (lateral) or wrist flexion (medial). Duration of the symptoms in this study Symptoms (pain, ache, or numbness) were present at the time of the medical examination or in the preceding last 30 days 38 4.4 Tests used for assessing musculoskeletal function in 1995 Handgrip forces were evaluated with a Jamar dynamometer (Jamar Ltd, Canada). Upper extremity functional tests developed by Soukka et al. (1989) were performed. In this assessment the validated scores ranged from 1-5 and reflected age-related muscular performance of upper limbs. The static test consists of timing how long a standing person can hold a single 10 kg load in both hands in arm‟s length and at shoulder height (up to a maximum 90 sec). The dynamic test consists of counting how many times a person can repeatedly elevate two 10 kg loads, one held in each hand, from shoulder height to full arm extension above the head when standing erect. The performance is evaluated separately in the dynamic test (Soukka et al. 1989). These tests were performed by local occupational health care nurses. 4.5 Measurement of vibrotactile perception thresholds Figure 3. Tactometer 4.5.1 Apparatus Non-invasive measurements of mechanoreceptor-specific vibrotactile thresholds were performed at the fingertips using a tactometer. The device has been described elsewhere 39 (Brammer et al. 2007), and consists of: 1) a vibration stimulator suspended from a beam balance, the fulcrum of which is mounted on a vertically adjustable track; 2) an arm rest; 3) a small diameter (3 mm) cylindrical probe through which the stimulus is applied to the skin; 4) an accelerometer and electronics to record the stimulus at the surface of the skin, and; 5) a computer to administer the stimulus consisting of pulsed sinusoidal tone bursts, and calculate perception thresholds. The tone bursts were 800 ms in duration at frequencies of 20 Hz, and above, and 1.6 s in duration at frequencies of 6.3 Hz, and below. The quiescent interval was 0.6 s. Successive bursts initially increase in intensity until stimulus has been detected (“upper” threshold). Successive bursts then decrease in intensity until the stimulus can no longer be felt, so defining the first descending or “lower” threshold. The threshold limit was detected using the Bekesy technique, which was repeated four times. The mean threshold acceleration was calculated from the arithmetic sum of ascending and descending thresholds. 4.5.2 Method The subject was seated with his forearm and hand supported horizontally below shoulder level, and positioned on the armrest for maximum comfort. This was achieved by adjusting the elbow angle and rotating the wrist. The stimulator was positioned so that a 3 mm diameter, cylindrical, flat-ended probe could be lowered onto a fingertip and maintained in contact with the skin with a static compressive force of 0.05 N. Pulsed vibrotactile stimuli were then applied to the skin at amplitudes close to the threshold of perception, according to the algorithm. The skin-stimulator contact conditions and stimulation frequencies were chosen to elicit responses from the SAI (4 and 6.3 Hz) or FAI (20 and 32 Hz) mechanoreceptor populations (Brammer and Piercy 2000). The measurement procedure was first explained to the subject, together with the sensations he was likely to feel. Several practice runs were performed to familiarize the subject with the stimuli and measurement procedure. Thresholds were determined at the fingertips of digits 3 and 5 of both hands. After extending the metrics for individual fingers to hands, and to subjects (i.e., combining data for both hands), the threshold changes are compared with hand grip force and age. The VPT measurements were made by one person (Professor Anthony Brammer). The validity of the test was tested earlier (Brammer et al. 1992). 4.5.3 Metric for threshold shift (II) When all thresholds are expressed in dB, the summed normalized threshold shift at a fingertip, TSSum(SD) , can be written (Brammer et al. 2007): Equation 1 TSSum( SD) TSSAI ( SD) TSFAI ( SD) Here the metric has been expressed in terms of the mean normalized threshold shifts recorded in each receptor population, TSSAI(SD) and TSFAI(SD), where SD stands for standard deviation: 40 Equation 2 TSSAI ( SD) TSSAI SDSAI and TSFAI(SD) has been equivalently defined. The mean receptor-specific threshold shifts from the values observed in healthy hands, TSSAI and TSFAI, are first calculated for each finger from: Equation 3 TSSAI TS4 TS6.3 2 and Equation 4 TSFAI TS20 TS32 2 where the threshold shift at a given frequency, TS4, at 4 Hz, etc., is the difference, in dB, between the observed threshold and the mean threshold recorded from the hands of healthy persons at that frequency (Brammer et al. 1993). When expressed in dB, the thresholds for a population of healthy persons may be approximated by a Gaussian distribution for each frequency. As the range of thresholds for frequencies mediated by the same receptor population are similar, or identical, the distributions may conveniently be expressed in terms of the standard deviation (SD) of their means, which are written SDSAI and SDFAI, for the SAI and FAI distributions, respectively. The threshold at a fingertip is then considered „normal‟ (N) if its value of TSSum(SD) falls within 1.96 standard deviations of the mean value recorded in the hands of healthy persons (i.e., p > 0.05). The sensitivity is considered „marginal‟ (A) if the value of TSSum(SD) falls within the parts of the distribution defined by (two-sided) probability values in the range 0.005 < p < 0.05, and „abnormal‟ (AA) if it falls within the parts of the distribution defined by (two-sided) probability values in the range 0.0005 < p < 0.005. Values of TSSum(SD) that fall within the tails of the threshold distribution for which p < 0.0005 are considered to be „very abnormal‟ (AAA). The threshold changes during the five year interval between studies have been estimated, for each finger, from the summed mean threshold change, TCSum, which becomes, when all thresholds are expressed in dB (Brammer et al. 2007): Equation 5 TCSum TCSAI TCFAI In this expression, TCSAI and TCFAI are the mean threshold changes for thresholds believed mediated by the SAI and FAI receptor populations, respectively, and are constructed from the threshold changes observed at each measurement frequency using expressions equivalent to equations 3 and 4 (e.g., with TC replacing TS, and TCSAI replacing TSSAI , etc.). The threshold change for each finger at each frequency is the difference between the thresholds recorded from the same finger in the two studies. 41 4.6 Force platform posturography (III) The movement of the centre point of force was measured with a force platform (Starck et al. 1993). Relative displacement of the body position while standing and during vibration perturbation of muscles in the neck, lumbar region or calf was studied. The test condition was randomized according to Latin square design. In the neck stimulation, two vibrators were placed paravertebrally beside the seventh vertebra and attached with elastic bands over the stimulated muscles. For lumbar stimulation, two vibrators were positioned paravertebrally on the erector spinae muscle. For stimulation of calf muscles, a vibrator was placed firmly with elastic bands on the calf muscles. Following stimulation frequencies were used (their duration plus length of subsequent stimulation-free period): 32 Hz (12 s + 15 s) and 50 Hz (12 s + 15 s). The test was performed by a physicist. Validity of the test was tested earlier (Starck et al.1993). 4.7 Calculation of lifetime dose (I) On the basis of the estimated periods of time of chain saw use, a lifetime vibration dose for each forestry worker was calculated, where aw is the frequency weighted acceleration (ms –2), th is the individual estimated daily exposure (hours/day), and td the number of working days in a year and ty is the number of years of saw use. The lifetime dose was calculated using the equation 6 (modified from Bovenzi, 1995c): Equation 6 ( (a w2 th 8 1 2 ) 2 t d t y ) 2 ( ms 4 hd ) Vibration was measured on the front and rear handles of the chain saw used in the forest districts. In order to assess the total exposure, data used from the previous surveys in the area since 1976, were reanalyzed. For vibration measurements, the accelerometers were fastened into the front and rear handles of the chain saw. The signals were amplified with a charge amplifier (Bruel and Kjaer 2635, Denmark). From the one-third octave band vibration spectra (6.3-1250 Hz), the root mean square (rms) of the frequency-weighted acceleration was calculated. A commonly used chain saw was used to model vibration for each generation of chain saws. The first generation chainsaws, used before 1972, had daily usage time of 2.5 hours with vibration level 9.1ms-2. The second-generation anti-vibration chain saws were used until the early 1980‟s 3.5 hours/day and the vibration level measured from the handle was 2.2 ms-2. After the early 1980‟s, the third generation chainsaw with a vibration level of 1.8-2.2 ms-2 were used for 4.5-5 hours/day according to measurement (Koskimies 1992). 42 4.8 Animal experiments Vibrator Power amplifier Accelerometer Vibrating probe Charge amplifier LD-vibrometer Temporal bone Spectrum analyzer Figure 4. Schematic drawing of vibration exposure Thanks to Professor Ilmari Pyykkö for allowing to use this schematic drawing. 4.8.1 Vibration delivery (IV, V) The animals were initially anaesthetized with xylazine (Rompun® 16mg/kg i.m.) and ketamine (Ketalar® 60mg/kg i.m.). The anaesthetized guinea pig was placed in a specially designed holder. A vibrating system consisting of an electromagnetic shaker with a probe (Ling TPO 1, Ling Industries, England), signal generator and power amplifier (Ling TPO 1, Ling Industries, England) was used. The frequency and intensity of the vibration could be adjusted. The vibration was delivered to the external ear canal of the guinea pig from the shaker through a custom made probe (Zou et al. 2001). To obtain equal pressure between the vibration probe and the animal‟s head, we used a balance beam with extra weight of 100g at the shaker‟s side (IV). The weight against the skull was selected to be of the same order of magnitude as the head of the guinea pig to ensure a maximum impedance match between the head and the rod. At the selected frequency range this should have only a minor effect on transmission. 43 (IV) Vibration frequencies were 32 Hz (n=5), 63 Hz (n=5), 125Hz (n=5), 250Hz (n=5), 500Hz (n=5), and 1000Hz (n=5), and vibration time was 15 min for each animal. Shaft vibration levels of the shaker ranged from 11 to 215 ms-2 at different frequencies. The skull velocities were measured and converted to acceleration (a) by the equation 7. Thus the respective stimulus acceleration of temporal bone was 4.2-18.8 ms-2. The vibration measurements were calibrated using a standard calibration (Zou et al.2001). Equation 7. Acceleration a=2·π·f·v Equation 7 Key: a= acceleration, f= frequency, v=velocity (V) Seven animals were subjected to 15 minutes of vibration at 250 Hz with a linear acceleration of 6 ms-2 measured from the temporal bone with laser vibrometer (Bruel and Kjaer 2815, Denmark). 4.8.2 Measurement of hearing (IV) Auditory brain stem response (ABR) recordings were performed with an electrophysiological recording system (SigGen system 2, Tucker-Davis Technologies, Gainesville, USA) in an electrically shielded, soundproof chamber. The ABR was recorded in the same ear that received the vibration exposure. A subdermal (active) needle electrode was inserted at the vertex, and the reference electrode was placed at the ipsilateral mastoid. The ground electrode was placed at the contralateral mastoid. Preamplifier filters were set at 30 Hz (high pass) and 3000 Hz (low pass). Tone bursts (1ms-1 rise/fall; 0.5, 1, 2, 4, 8, 16 kHz) were used to measure the animals‟ ABR thresholds. Stimuli were fed to a TDH-39 transducer connected to a tube fitted to the external ear canal. ABR thresholds were obtained at 20 dB steps and finally at 5 dB steps to identify the lowest level at which an ABR response could be visually recognized (Pratt 2003). The hearing threshold was measured before vibration, immediately after vibration, 7 days after vibration, and 14 days after vibration. (V) The bulla was opened and a silver-ball electrode was placed on the round window niche. Electrocochleography was recorded using a SigGen system (Tucker-Davis Technologies, USA). Clicks (50 µs duration) were presented at a rate of 20/s. Responses for 500 sweeps were averaged at each intensity level. Threshold was defined as the minimum intensity that elicited an accurate visible consistent waveform with an appropriate latency. Compound action potential was measured before vibration exposure, immediately thereafter, and one, two and three days after vibration exposure. After the last compound action potential measurement, the animals were perfused intracardially with physical saline and 4% formalin. Then the bulla was removed, a hole was drilled on the apex, stapes was removed and the round window membrane was penetrated to fill the inner ear with fixative. The cochlea was fixed with 4% formalin for 44 12 hours. Vibration and hearing measurements were made by two researchers (the author and the ear-nose-throat- specialist Jing Zou), in Karolinska Institute. 4.8.3 Analysis of cytokines with immunohistochemistry (V) For sectioning with immunohistochemistry, the formalin fixed bulla was rinsed in 0.1 mol/L, pH 7.4 phosphate buffer saline (PBS) and decalcified with 0.1 mol/L ethylenediaminetetraacetic acid-Na2 (EDTA-Na2) for about 6 weeks at 4˚C. After a rinse in the same PBS, the cochlea was embedded in paraffin and sectioned for 4 µm thick slices. The sections were deparaffined in xylene for 5 minutes; then placed in water through a gradationally decreased concentration of alcohol; rinsed in PBS for 2 min; treated with 0.1% trypsin at 37˚C for 10 min; treated with 0.3% Triton X-100 for 3-6 min; rinsed in PBS for 2 min; quenched in methanol peroxide mixture (5 ml 30% peroxide in 45 ml methanol) for 5 min; rinsed in PBS twice for 2 min each time; incubated with mouse monoclonal antibody against VEGF receptor 1 and receptor 2 (Sigma, USA), and TNF receptor 1 (Santa Cruz Biotechnology, Inc, USA), or goat polyclonal antibody against VEGF (Sigma, USA), TNF-α and TNF-α receptor 2 (Santa Cruz Biotechnology, Inc, USA) (1:2000 diluted in 1% bovine serum albumin, BSA) for 60 min (room temperature, likewise for all the following incubations); rinsed in PBS 3 times for 2 min each time; incubated with normal goat/mouse serum (1:20 dilution) for 15 min; incubated with biotinated goat anti-mouse IgG/mouse anti-goat IgG (1:20 diluted in 1% BSA) for 30 min; rinsed in PBS 3 times for 2 min each time; incubated with ExtrAvidin-peroxidase (1:20 diluted in 1% BSA) for 30 min; rinsed in PBS 3 times for 2 min each time; incubated with aminoethyl carbazole for 5-10 min; rinsed in pure water for 2 min; mounted in glycerine/gelatine. For the negative control, the primary antibody was replaced by PBS. For surface preparation with immunohistochemistry, the formalin fixed bulla was dissected in PBS under the stereomicroscope to remove the bony cochlear shell and rinsed in PBS 4 more times for 2 min each time. The dissected cochlea was treated with 0.3% Triton X-100 for 3-6 min; then rinsed in PBS 4 times for 2 min each time; quenched as above; rinsed in PBS twice for 2 min each time; incubated with mouse monoclonal antibody against VEGF receptor 1 and receptor 2 or goat polyclonal antibody against VEGF (1:2000 diluted in 1% bovine serum albumin) for 60 min; rinsed in PBS 5 times for 2 min each time; incubated with normal goat/mouse serum (1:20 dilution) for 15 min; incubated with biotinated mouse anti-goat IgG (1:20 diluted in 1% BSA) for 30 min; rinsed in PBS 5 times for 2 min; incubated with ExtrAvidinperoxidase (1:20 diluted in 1% bovine serum albumin) for 30 min; rinsed in PBS 5 times for 2 min; incubated with aminoethyl carbazole for 5-10 min; rinsed in pure water for 2 min and the basilar membrane was removed and cut into 6-8 pieces; then mounted in glycerine/PBS and sealed with nail polish. For the negative control, the primary antibody was replaced by PBS. 45 4.9 Statistics The results were measured in following ways: (I) The results were expressed as means and standard deviations or confidence intervals. For comparing groups, Pearson crosstabs, Fischer‟s exact test, T-test, or variance analysis was used. In comparing data, logistic linear or logistic binary regression was used. Independent variables were included either as continuous or categorical variables. When probability was less than 0.05 the statement was statistically significant. (II) Descriptive statistics and Pearson product moment correlations were calculated for the continuous variables. Contingency tables were constructed for selected symptom reports (categorical variables). The symptoms reported by the forest workers, as confirmed by the examining physician, were taken to be the “gold standard” (i.e., assumed correct), and the ability of the observed threshold shifts, expressed per subject (i.e, four fingers combined), to predict the presence or absence of a symptom has been estimated by calculating the sensitivity, specificity, positive predictive value, and false positive rate. (III) Non-parametric test (Mann-Whitney U-test) and logistic regression were used. (IV) Descriptive statistics and Pearson product moment correlations were calculated for the continuous variables. (V) Nonparametric statistics were used (Friedman‟s test). (Altman 1991). 46 5 RESULTS 5.1 Hand-arm vibration syndrome with use of anti-vibration chain saws: 19-year follow-up study of forestry workers (I) 5.1.1 Cross-sectional study Cross-sectional studies of Finnish forestry workers were made in 1976-1995, i.e. in a 19-year period, in connection of a compulsory occupational health examination. The number of workers varied from 109 to 205, and 52 workers took part in all examinations. The HAVS and musculoskeletal symptoms of the forestry workers are shown in table 8. Table 8. Outcome of cross-sectional studies in different years Year 1976 1981 1986 1990 1995 Number 205 187 183 124 109 VWF (%) 13 4 3 5 4 Numbness (%) 39 55 9 22 28 Pain (%) 26 31 12 22 26 Muscle weakness (%) 11 16 4 6 7 Table 8 key: VWF numbness pain muscle weakness = active vibration-induced white finger syndrome = numbness in the upper extremities = pain in the upper extremities = subjective hand muscle weakness 5.1.2 19-year-cohort 5.1.2.1 VWF and other symptoms In the cohort 9 out of 52 forestry workers had active, and 7 forestry workers inactive, VWF in 1976. In 1995 only 4 forestry workers had active, and 13 had inactive, VWF. There was one new case after the year 1990. In the cohort, 55% of the forestry workers were non-smokers, 15% had stopped smoking and 30% were smokers. 47 Table 9. Chain sawing and vibration energy in the cohort in 1995. VWF Chain sawing Vibration energy N 0 1 0 1 Mean 35 17 35 17 SD 201.4 246.0 181026.5 219814.9 SE mean 42.4 38.5 67975.5 57922.0 7.2 9.3 11490.0 14048.1 Table 10. Variances Levene's Test for Equality of Variances F Sig. Sig.(2tailed) Mean Differenc e SE difference 95% CI of the Difference Lower Chain sawing Vibration Energy Equal variances assumed Equal variances not assumed Equal variances assumed Equal variances not assumed 0.508 1.536 0.479 0.221 Upper 0.001 -44.6 12,2 -69.1 -20.2 0.001 -44.6 11,8 -68.6 -20.7 0.049 -38788.4 19194,4 -77341.6 -235.3 0.039 -38788,4 18148.5 -75567.1 -2009.7 In the cohort, the mean sawing time in 1995 was 246 hours times 100 versus 201 hours times 100. The right grip force was 42 (SD 7) versus 47 (SD 7) kg in VWF versus non-VWF groups. The mean sawing time (p=0.001) and right grip force (p=0.038), as measured by Jamar, differed significantly between VWF and non-VWF groups. VWF was associated with pain in the upper extremities (Pearson χ2, p= 0.000) and subjective hand muscle weakness (χ2, p=0.002). VWF and numbness were not significantly associated, but there was a trend (χ2, p= 0.059). The lifelong vibration energy exposure differed significantly between the VWF and non-VWF groups ( p=0.001). 48 Table 11. Numbness* VWF 0-1 Crosstabulation Numbness VWF 0-1 0 1 24 7 11 10 35 17 0 1 Total Total 31 21 52 Table 11 key. VWF= vibration white finger 5.1.2.2 Numbness The prevalence of numbness in the cohort ranged from 23% in 1976 to 40% in 1995. Numbness significantly differed between the years 1976-1995 (n= 0.049): 4/52 (8%) of men had less numbness and 13/52 (25%) of men had more numbness in 1995 when compared with the year 1976. Table 12. Pain * Numbness Crosstabulation Pain 0 1 Total Numbness 0 1 26 8 4 13 30 21 Total 34 17 51 Table 12 key. Pain= upper extremity pain Numbness= numbness in upper exremities Pearson χ2 Value 13.1 df 1 Asymp. Sig. (2sided) 0.000 Waking because of numbness was more usual in 1995 than 19 years before (p=0.045). Numbness was associated with right rotator cuff syndrome and epicondylitis: 7/10 of rotator cuff patients had numbness (p=0.034) and, also accordingly, 8/9 of right-sided epicondylitis patients had numbness (p=0.004). Numbness was also associated with the left-sided epicondylitis (p=0.010). 49 Table 13. Outcome of the cohort study in different years Cohort (n=52) 1976 1980 1986 1995 VWF (%) 17 6 6 8 Numbness (%) 23 44 40 40 Pain (%) 14 21 27 33 Muscle weakness (%) 2 10 6 10 Table 13 key: n VWF numbness pain muscle weakness = number of forestry workers = active vibration-induced white finger syndrome = numbness in the upper extremities = pain in the upper extremities = subjective hand muscle weakness 5.1.2.3 Pain in the upper extremities and muscle force Rotator cuff syndrome was diagnosed in 19% of 52 men in the right extremity and in 14 % in the left extremity. 17% of forestry workers had epicondylitis on the right. The diagnoses of rotator cuff syndrome and epicondylitis were found to be associated with the subjective upper extremity pain during the previous 12 months. Five forestry workers reported hand muscle weakness in 1995. When measured by Jamar, right hand grip force was 45.1 (SD 7.3) and left grip force 44.5 (SD 7.9) kg in 1995. The rightsided upper extremity static functional test (mean 3.75 SD 1.5) did not associate with rotator cuff syndrome (p=0.643) nor the right-sided dynamic (mean 3.00 SD 1.5) test (p= 0.577) with rotator cuff syndrome. In the static test, the mean score of the 52 men was 3.98 (SD 1.5) and in the dynamic test, 3.28 (SD1.4) and 3.19 (1.3), in the right and left, respectively, in the cohort. These results equated to the average population values. 5.1.2.4 Regional neck pain In the physical examination regional neck pain (i.e. TN pain) was diagnosed with 38% of patients. Regional neck pain was associated with numbness (p=0.004), subjective hand muscle weakness (p=0.003) and pain in the upper extremities (p=0.043). In groups without or with regional neck pain there was a significant difference in VAS of low back pain, 20.1 (SD 15.6) mm and 33.9 (SD 22.1) mm, respectively. There also was a difference in the Oswestry index 8.9 (SD 7.8) versus 16.5 (SD 9.0) indicating disability, respectively in groups without or with regional neck pain. 50 5.1.2.5 Modelling The odds ratio of having VWF increased by 3% per each unit of lifelong vibration energy dose (106 m 2 s-4 hd). The smokers had a 7-fold odds ratio of having VWF compared to the non-smokers. Table 14. Multivariate analysis of VWF in the cohort. B Vibrationenergy Smoking 012 Smoking 012 (1) Smoking 012 (2) Age Constant S.E. Sig. OR 0.029 0.009 1,03 -1.582 1.997 0.025 -5.179 1.361 0.985 0.076 3.763 0.001 0.025 0.245 0.043 0.741 0.169 0.21 7.36 1.02 0.01 95% C.I.for OR Lower Upper 1.01 1.05 0.01 1.07 0.88 2.96 50.76 1.19 Table 14 key. Variable of smoking: 0=no smoking, 1=stopped, 2=smoking The modeling of numbness in 1995 is shown in table 15. Lifelong vibration energy did not explain the numbness. Multivariate analysis model including age-adjusted pain in upper extremities and TN pain could explain 42% of variation in numbness. Table 15. Multivariate analysis of numbness in the cohort. B Vibrationenergy Pain Tension neck Age Constant 0.006 2.520 1.787 0.032 0.073 S.E. Sig. OR 0.007 0.364 0.99 0.834 0.003 0.796 0.025 0.071 0.654 12.43 5.97 0.97 3.400 0.983 1.08 95% C.I.for OR Lower Upper 0.98 1.01 2.42 1.26 0.84 63.80 28.39 1.11 Table 15 key. Pain= pain in the upper extremities In a multivariate analysis, both age and lifelong vibration energy modeled right rotator cuff syndrome. Modeling could explain 69% of variability of right rotator cuff syndrome. Body-mass index and smoking did not explain rotator cuff syndrome. 51 Table 16. Multivariate analysis of diagnosed right rotator cuff syndrome in the cohort. Lifelong vibration energy Body-mass index Smoking p-value Age-adjusted OR 0.032 0.440 0.167 1.04 1.13 9.54 95% C.I.for OR Lower Upper 1.00 1.07 0.82 1.56 0.39 233.37 5.2 Application of metrics constructed from vibrotactile threshold to the assessment of tactile sensory changes in the hands (II) 5.2.1 Summed normalized threshold shifts Almost 20% of the Suomussalmi forest workers employed by the National Board of Forestry were recruited into the study (23 out of 124 persons). Eighteen of the twentythree members of this subgroup (78%) attended the compulsory medical examination almost five years later and agreed to continue to participate. Data for these eighteen male subjects are presented here. Table 17. Summed normalized shifts in threshold from expected values, at followup (expressed in units of standard deviations, see equation 1 in chapter 4.5.3.) Subject Left hand Right hand Digit 3 Digit 5 Digit 3 Digit 5 1 7.1 8.0 7.0 7.1 2 3.5 0.0 1.9 -1.8 3 2.9 2.2 4.8 5.2 4 3.8 3.4 2.2 3.2 5 2.9 1.9 1.9 4.3 6 1.3 1.0 1.0 2.4 7 2.3 -0.3 -0.8 -1.8 8 3.4 3.3 0.1 2.7 9 -0.3 -1.1 -0.1 -0.2 52 Subject Left hand Right hand Digit 3 Digit 5 Digit 3 Digit 5 10 2.5 1.1 -0.3 -0.4 11 2.6 3.3 2.4 2.0 12 -0.5 -2.3 2.3 3.5 13 6.1 9.6 7.9 7.7 14 4.4 4.8 4.2 4.0 15 3.0 3.9 4.2 4.8 16 1.8 2.1 2.9 3.1 17 5.2 6.5 4.6 4.6 18 4.5 4.6 4.8 5.2 An inspection of table 17 shows that the majority of summed normalized threshold shifts are positive rather than negative, implying that the thresholds are, on average, less sensitive in this group of workers than those to be expected from persons of similar age engaged in either professional or manual work. See table 18: the individual values were compared with the boundaries for summed normalized threshold shifts Table 18. Boundaries for summed normalized threshold shifts and summed threshold changes Digit Summed threshold change between studies Summed normalized threshold shift Boundary (dB) Boundary N–A A - AA AA – AAA (dB) LH3 3.78 5.42 6.76 7.22 LH5 3.88 5.56 6.93 7.92 RH3 3.86 5.54 6.90 7.75 RH5 3.78 5.42 6.76 7.67 Table 18 key: LH= left hand, RH= right hand, 3= finger 3, 5= finger 5 N-A: marginal threshold shift boundary, A-AA: abnormal threshold shift boundary, AA-AAA very abnormal threshold shift boundary Statistically significant shifts in threshold were observed in the hands of four of the eighteen subjects at inception (5/36 hands, or 14%), and of nine of the eighteen subjects (14/36 hands, or 39%) at follow-up. Significantly, only one hand was considered to have possessed abnormal sensitivity at the inception of the study, that is, with thresholds 53 rated as AA or AAA (RH of subject #5), while a total of 5/36 hands (14%) possessed abnormal sensitivity approximately five years later at follow-up. Note that thresholds judged abnormal are reduced in sensitivity by, on average, more than three SDs from the mean thresholds recorded in the hands of healthy persons. The probability of such threshold shifts being found in 'healthy' hands is p < 0.0025. Summed threshold changes (see equation 5 in chapter 4.5.3.) in sensitivity during the time interval between studies were recorded in sixteen of the eighteen subjects (25/36 hands, or 70%) (p < 0.005), see table 19. Of these, twenty hands were assessed to be deteriorating, and four improving (one hand gave conflicting results). 5.2.2 Summed normalized threshold changes Table 19. Summed changes in threshold TCSUM between studies, in dB (see equation 5 in chapter 4.5.3.) Subject Left hand: TCSUM Right hand: TCSUM Digit 3 Digit 5 Digit 3 Digit 5 1 23.0 22.2 21.4 21.8 2 9.9 -11.5 2.9 -10.2 3 5.5 -4.6 7.1 12.2 4 13.7 M 7.6 M 5 -9.6 -8.6 -19.3 -9.3 6 4.1 25.6 12.0 9.1 7 6.2 1.0 -10.1 -10.6 8 16.3 13.4 -3.9 6.3 9 10.5 2.8 4.8 6.6 10 6.3 R 6.1 -3.7 11 3.0 8.6 7.4 3.6 12 14.5 M 13.0 M 13 20.9 34.0 35.4 19.1 14 4.9 1.9 6.6 3.8 15 16.5 19.3 18.6 22.8 16 4.2 4.4 4.4 15.7 17 13.0 22.3 18.3 14.3 18 20.8 21.9 10.8 7.0 Table 19 key: R - data rejected; M - data missing. Positive values mean deterioration and negative values mean improvement of VPT. 54 5.2.3 The correlations between the threshold metrics, age and grip force The correlations between the threshold metrics, age and grip force are shown in table 20. The thresholds shifts and maximum grip forces are those recorded at follow-up. Inspection of the correlations in table 16 reveals that the summed normalized threshold shifts and threshold changes for the SAI and FAI receptors within the fingers on the right, or left, hand are closely related. The Pearson correlation coefficients of the threshold shifts were 0.87 and 0.90 for the right and left hands, respectively (p < 0.0005), and 0.79 and 0.67 for the right and left hand, respectively, for the threshold change. Threshold shifts occurring in right and left hands are not correlated with the maximum grip force. The summed normalized TS (i.e. finger with larger TS, worse hand) and the summed threshold change are not related to age. The maximum grip force and age are negatively correlated with both hands, as might be expected. Table 20. Correlations between threshold metrics, age and grip force Correlation between: By Hand TSSum(SD) of digits 3 and 5 (RH) 0.87*** TSSum(SD) of digits 3 and 5 (LH) 0.90*** TCSum of digits 3 and 5 (RH) 0.79*** TCSum of digits 3 and 5 (LH) 0.67* TSSum(SD) and Grip Force (RH) -0.10 TSSum(SD) and Grip Force (LH) 0.00 By Subject TSSum(SD) and age 0.20 TCSum and age -0.12 Age and Grip Force (RH) -0.51* Age and Grip Force (LH) -0.41 *p < 0.05; ** p < 0.005; *** p < 0.0005 Table 20 key: TSSUM(SD)= summed normalized threshold shift TCSUM= summed threshold change RH= right hand LH= left hand 55 5.2.4 Prediction of numbness from summed normalized threshold shift The ability of the measured threshold shifts to predict the presence or absence of numbness in the hands was examined by forming contingency tables. The threshold metric was again the summed normalized threshold shift constructed for each subject (i.e., finger with larger threshold shift, worse hand). The positive predictive value of the metric was 71% and the false positive rate 18%, when the presence or absence of the symptom was defined by the boundary between „normal‟ and „marginal‟ acuity. These values were associated with a sensitivity of 83% and specificity of 82%. 5.3 Postural stability, neck proprioception and tension neck. (III) TN- patients were compared with subjects without TN (non-TN group). When the neck muscles were vibrated, the TN- group manifested greater maximum lateral deviation of position after the first and second stimulation and also a greater average deviation of position in anteroposterior direction during the second stimulation. When the lumbar muscles were stimulated, the TN-group showed greater maximum deviation of position in lateral direction after both the first and second stimulation. The TN-group had also greater anteroposterior deviation of position after the second stimulation. Figure 5. Postural stability of subjects with/without TN Figure 5 key (neck stimulation): YM1AFT = lateral deviation of position after first stimulation of neck muscles XA2 = average anteroposterior deviation of position during second stimulation of neck muscles and YM2 = lateral deviation of position during second stimulation of neck muscles. 56 Figure 6. Postural stability of subjects with /without TN Fig. 6 key (lumbar stimulation): XMBASE = baseline deviation of position (without stimulation) YM1 AFTA= lateral deviation of position after first stimulation of lumbar muscles XM2AFT = anteroposterior deviation of position after the second stimulation of lumbar muscles YM2AFT = lateral deviation of position after second stimulation of lumbar muscles During the calf muscle vibration, the sway in TN was only slightly increased during or after the vibration stimulation. The sway velocity did not differ after neck, lumbar or calf vibration stimulation in TN and non-TN groups. 5.4 Vibration-induced hearing physiological aspects (IV) loss: mechanical and 5.4.1 Transfer factor When comparing the excitation acceleration at different frequencies, the transmission was significantly better at lower frequencies (32-125 Hz) when compared with higher 57 frequencies (250-1,000 Hz). This relationship is demonstrated in Figure 7 by repeating vibration at different excitation frequencies. We found no significant resonance frequencies in the skull. The coupling factor demonstrating transmission of vibration at different frequencies were: at 32 Hz 0.45 at 63 Hz 0.32, at 125 Hz 0.45, at 250 Hz 0.08, at 500 Hz 0.05, at 1 kHz 0.01. Figure 7. Transmission of vibration as a function of vibration frequency 5.4.2 Threshold shift immediately following vibration 5.4.2.1 Threshold shift of hearing as a function of vibration frequency Different vibration frequencies had somewhat different effects on TS. Average TS (mean of all ABR frequencies) immediately after vibration, as a function of vibration frequency, were 2 dB (32Hz), 6 dB (63Hz), 8 dB (125Hz), 6 dB (250Hz), 14 dB (500Hz) and 18 dB (1000Hz). Generally, the higher vibration frequencies (500 through 1000Hz) produced more severe TS than did the lower- mid frequency vibration (32 Hz through 250 Hz) (p<0.05). The figure 8 shows the average TS immediately following vibration (at individual ABR tone burst frequencies) as a function of vibration frequency at 500 Hz. 58 50 40 30 20 10 0 -10 N= 5 5 5 5 5 5 0.5 1 2 4 8 16 Tone burst frequency (kHz) Figure 8. Threshold shift of hearing as a function of vibration frequency at 500 Hz 5.4.2.2 Threshold shift as a function of ABR frequency All the vibration experiments were pooled. From these experiments, TS as a function of ABR frequencies 0.5 kHz- 16 kHz were studied. The TSs were greater for ABR frequencies 4-16 kHz than for the lower ABR frequencies (0.5 to 2 kHz). Highfrequency hearing loss was a typical feature irrespective of vibration frequency immediately after vibration. Vulnerability of hearing caused by vibration was modeled. In statistical analysis there was an interaction between vibration frequency and TS frequency. In modeling the TS, the vibration frequency was a significant variable (p< 0.001, OR 3.0, 95% CI 2.3-3.7) and the frequency of ABR was also significant (p< 0.002, OR 1.1, 95% CI 0.4-1.2). This model could explain 31.5 % of TS variation immediately after vibration (-6.0+ 3.0∙ vibration exposure + 1.1∙ tone burst frequency). 5.4.3 Recovery after vibration Seven days after vibration, the average TS was nearly recovered to baseline thresholds. Fourteen days after vibration, recovery was even closer to the baseline measurements. 59 Immediately after vibration TS was at least 10 dB (ranging from 0 to 40) at two ABR frequencies in 60 % (18 / 30) of the animals. At day 7 the TS was at least 10 dB at 2 frequencies in 3 animals, and at day 14 in 4 animals, respectively. Average TS over all frequencies was 8.8 dB immediately after vibration exposure, 2.4 dB at day 7 and 1.3 dB at day 14. Vibration frequency was still a significant determinant for recovery (p< 0.01, OR 0.6, 95% CI 0.1-1.0) in modeling the TS at day 7. 5.5 Vibration induced hearing loss in guinea pig cochlea: Expression of TNF-alpha and VEGF (V) 5.5.1 Expression pattern of TNF-α in the vibration stimulated cochlea No TNF-α expression was detected in the normal cochlea. Vibration induced TNF-α expression appeared mainly in the reticular lamina, the bottom of the outer hair cells, Deiters‟ cells, Hensen‟s cells, Claudius cells, the internal sulcus cells, the spiral ligament, the spiral vascular prominence and the cochlear vasculature. Figure 9 Strong expression exists in the organ of Corti (), Border cell (), Claudius cell (), interdental cell, the spiral ligament () and the cochlear vasculature () Figure 9. TNF-α in the vibrated cochlea 5.5.2 Expression pattern of TNF receptors in the vibration stimulated cochlea After vibration, a weak TNF receptor 1 staining was found mainly in Hensen‟s cells, Claudius cells, the internal sulcus cells and the capillaries of the spiral ganglion. Much stronger expression of TNF receptor 2 was found mainly in the spiral ganglion cells, Hensen‟s cells, Claudius cells, the internal sulcus cells, Deiters‟ cells, the basal membrane of the organ of Corti, the spiral ligament, the spiral vascular prominence. A 60 weaker staining was found in the bottom of the outer hair cell. No TNF receptor expression was detected in the normal cochlea. 5.5.3 Expression pattern of VEGF in the vibration stimulated cochlea No VEGF expression was detected in the normal cochlea. In the vibrated cochlea, VEGF was detected in the stereocilia of the inner hair cells and the outer hair cells and supporting cells (figure 10). Especially the spiral ganglion cells, Deiters‟ cells, Hensen‟s cells, Claudius cells and the internal sulcus cells were stained. No expression of VEGF was detected in stria vascularis. Figure 10. VEGF expression in vibrated cochlea Figure 10. VEGF expression in the vibrated cochlea shown by surface preparation and immunohistochemistry. Strong expression was detected in the stereocilia () of the IHC and OHC, and the supporting cells () (400×); 5.5.4 Expression pattern of VEGF receptors in the vibration stimulated cochlea No VEGF receptor 1 or 2 expression was found in the normal cochlea. VEGF receptor 1 was not detected in the vibrated cochlea, whereas VEGF receptor 2 expression was present in the bottom of the outer hair cells, Deiters‟ cells, Hensen‟s cells, Claudius cells, the basal membrane of the organ of Corti, the internal sulcus cells, nucleus of the spiral ganglion cells, the lateral wall of scala tympani and the spiral ligament (figure 11). No expression of VEGF receptor 2 was observed in stria vascularis. 61 c. d. Figure 11a and b. VEGF R2 expression in vibrated cochlea Figure 11a. (left) VEGF R2 expression in the vibrated cochlea. a strong expression is in Hensen's cell (), Claudius cell () Border cell (), weak expression in the spiral ligament () (200×). Figure 11b. (right) Weak expression was detected in the spiral ganglion cell (). 5.5.5 Hearing loss after vibration The average hearing loss after vibration was 62 dB (SD 35 dB). One animal became deaf. We observed a tendency for recovery so that in day 4 the mean hearing threshold was 48 dB but the difference was not statistically significant (Friedman‟s test, p=0.175). 62 6 DISCUSSION In this clinical and experimental study the biological responses to vibration were evaluated. The aim was to evaluate the clinical responses among forest workers and then, in experimental study, to evaluate the vibration responses using inner ear as a model organ. In this model organ all the important elements as vascular structures, sensory cells, and nerves can be studied. Furthermore the methods to evaluate physiological responses and anatomical changes are relatively well developed for the inner ear. 6.1 Methodological aspects A part of this study was was longitudinal and the data of the forestry workers in Suomussalmi was collected over a 19 year period. The attrition rate during the years was high as it is common in longitudinal studies running for decades. In a previous study, Koskimies (1992) found that the decrease of VWF occurred mainly through the technical development of the anti-vibration chain saws, the warm transport, the protective clothing and the improved occupational health care among these forestry workers. This study confirmed the trend toward the diminution of the prevalence of VWF (Koskimies et al. 1992). However, the sample size of VWF in current study was small. For epidemiological studies, the amount of the symptomatic population should be larger. Further studies should evaluate the connection of the ergonomics with the vibration exposure. The measurements of VPT showed a good repeatability. VPT discriminated subjects with severe symptoms of HAVS. The statistical associations between threshold shifts and threshold changes in digits 3 and 5 of the same hand (table 16) suggest that in modeling the vibration damages in VPT it is advisable to consider the vibrotactile effects rather by hand than by finger. The ability of the threshold shifts to predict the numbness reported by the forest workers shows that this metric is closely associated with the tactile sensory changes occurring in the hands of these subjects. VPT can be used as a screening method, but it still needs validation of measurements. There are different types of VPT measurements in use, which makes comparison between studies difficult. With the force platform, the accuracy was mainly limited by the initial calibration that was made before every measurement. The testing with eyes closed may affect more the oldest of the group than the younger ones in general, but it may not bias the result. The most pronounced deviation of position was found during the neck and lumbar area stimulation, not during the stimulation of calf muscles. The muscles in neck area are important in proprioceptive control of balance. When comparing the vibration level of burr to the vibration of the experimental set-up in the animal model it must be noted that the measured values in burrs used in temporal bone surgery are not evaluated in a comparable way. The dominant frequencies of the 63 vibration level are not indicated in the literature. The nominal speed of the drill will be reduced during work as the drill is compressed to the bone to allow better cutting of the bone. In these circumstances the speed of drill will range around 125 to 250 Hz as in the present experiments. The size of the skull in guinea pig is much smaller than in man and thus the vibration is transmitted more easily into the animal cochlea than in a human. When evaluating the level of noise generated by the drill in the middle ear, the noise level in the guinea pig was 108 dB which is similar to that reported in clinical papers. In the instrumentation set-up described in this paper there was some non-linearity in coupling of vibration to the skull. The non-linearity indicates a variation of contact between the shaft and the skull. This may lead to reduced vibration or to impulsive excitation. If the characteristics of the skull vibration would become non-linear, the amplitude response could not be calculated from the excitation magnitude. In these cases the measurement repeatability would be poor. The linearity measurement showed that the used amplitudes were at the expected linearity range. Nevertheless, we observed at the low frequencies (32-125 Hz) decoupling in the transmission of vibration from vibrating shaft to the skull. This variation, although minor, seems to be linked to the inherent characteristics of the vibrator system rather than the skull resonances. In the guinea pig skull no definite resonances were found when using sinusoidal sweep. The behaviour of guinea pig skull is much the same as reported in human (Bekesy 1932, Tonndorf 1968). We analyzed the up-regulation of TNF-α and VEGF in cochlea after 32-1000 Hz vibration exposure. Both of these factors were found in several cell types in the cochlea after vibration. Shear stress induced VEGF expression seems to be dependent upon time. After acute shear stress as within 6 hours from the exposure Gan et al. (2000) did not found an increased expression; whereas after longer shear stress, its expression is increased up to 14 days (Milkiewicz et al. 2001). In the cochlea we observed expression of VEGF and VEGF R2 1-3 days after vibration. This is in accordance with the time limit of previous reports that protein production in the cellular machinery has a definite latency. In the guinea pig study described here, we analyzed vibration-induced health effects. There is a need for further animal studies which utilize a shear stress model applicable to HAVS. 6.2 Clinical aspects of vibration- induced health hazards In a 19-year cohort study of Finnish forestry workers we evaluated the occurrence of symptoms of hand-arm vibration syndrome and musculoskeletal disorders as rotator cuff syndrome and epicondylitis. Also a dose-response relationship with vibration and VWF, but not in numbness was demonstrated. There was a significant increase in numbness in the cohort. The sample sizes of subjects in this study were small, however, resulting in wide confidence intervals. The study concentrated on the results of the last year of the cohort. Additional studies are needed in different occupations using vibrating tools, as the work methods and tools are constantly changing. In Italian studies, Bovenzi et al. (1995c) found a dose-response relation for vibrationinduced vascular disorders; there was a 51.7% prevalence of VWF in forestry workers 64 who had used both non-AV (antivibration) and AV chain saws and a 13.4% prevalence of VWF in workers having used only AV chain saws, respectively. In Italy, the use of AV chainsaws was more recent than in Finland. The difference with Bovenzi‟s results reflects the difference in lifelong vibration energy exposure, and also differences in smoking habits. In Bovenzi et al‟s study (1995c), 70.3% of forestry workers were smokers in comparison to 30% in our study. In our study (I), the weighted acceleration of the chain saws has stayed in the range of 1.8-2.2 ms-2 since the early 1980‟s. In Japan, Mirbod et al found VWF symptoms in 9.6% of forestry workers with AV chain saws which is supportive of our study (Mirbod et al. 1995). The repeated surveys we used reduced the recall bias of VWF. In our study (I), the diagnosis of VWF was evaluated by medical history of symptom development and temporal pattern of symptoms. Earlier the symptoms of these forestry workers were evaluated with cold provocation tests. Cigarette smoking is one of the risk factors related to vascular diseases. In this study (I), we could confirm that smoking is a 7-fold risk factor of VWF. In the cohort 15% of the men had stopped smoking in 1995, which may bias the result to some extent. Cherniack et al. (2000) showed that smoking may aggravate digital arterial spasm in plethysmography. In the follow-up, we could not find a dose-response with vibration energy and numbness. There seems to be different pathophysiological mechanisms leading to sensorineural and vascular changes in vibration-exposed forestry workers (Pelmear 2003, Bovenzi et al. 2000b). Numbness is connected with vibration-induced neuropathy (Koskimies et al. 1990, Dasgupta and Harrison 1996, Cederlund et al. 1999, Bovenzi et al. 2000b). In this cohort (I), numbness varied during the 19 years. In 1983 cross-sectional study, electroneuromyography was taken from the cohort subgroup, which was randomly selected. Carpal tunnel syndrome was diagnosed in 20% of forestry workers on the basis of measurement and clinical data (Koskimies et al. 1990). Numbness was associated with upper extremity pain in our study (I). On the basis of this cohort, we cannot make a differentiation between specific neuropathies and unspecific symptom of numbness. The high prevalence of numbness in our study was exposure-independent. It confirms the result of Cherniack et al. (2000). The prevalence of numbness and upper extremity pain varied in the beginning of the1980‟s mainly because the chain saw operation time increased from 3-4 hours to 4-5 hours. In the same time, the productivity of forestry work increased. In this study, one third of forestry workers reported upper extremity pain in the cohort, which also supports other studies (Färkkilä 1978, Mirbod et al. 1995). Subjective pain in the upper extremities was associated with the shoulder and elbow musculoskeletal disorders. Right rotator cuff syndrome could be modeled by age and by lifelong vibration energy. Palmer et al. (2001) also reported increased risk of shoulder pain in the workers with daily vibration exposure. Tendons transmit mechanical tension during muscular contraction. Forces that exceed the capacity of tendon to adapt, for example because of high force or awkward posture, can result in inflammation and fibrotic changes (MacKinnon and Novak 1997). Rotator cuff syndrome has a multifactor etiology. The predisposing factor for rotator cuff syndrome is degeneration, with impairment of circulation and mechanical stress. In 65 addition to vibration exposure, the static loads and extreme postures are the risk factors in forestry work (Miranda et al. 2001). In our study, rotator cuff disorder was associated with the vibration exposure in forestry work, although the sample size was small. The diagnosis “tension neck” was adopted from Waris (1979). It closely resembles the present diagnosis of non-specific neck pain, cervicalgia (M54.2) in International Classification of Diseases (ICD-10). In this study, the degree of degeneration by x-ray was not reported, but degeneration may be a significant factor behind neck pain. It is a limitation of this study. However, the prevalence of degenerative changes of intervertebral discs and vertebrae of cervical column is high also in asymptomatic people (Gore 2001). Lateral epicondylitis is a condition of pain in the region of lateral epicondylitis, especially at the origin of extensor carpi radialis levis (Bennett 1994). Epicondylitis was less common than shoulder disorders, which may be in connection with the unemployment prior to examination. 18% of forestry workers had epicondylitis on the right. In previous studies, 29.3% of Italian forestry workers had epicondylitis (Bovenzi et al. 1991). It is in line with present results. The pathogenesis of epicondylitis is not fully understood. The main theory is that microruptures occur at the site of between the insertion of extensor muscles and bone, causing inflammation and resultant granulation tissue (Coonrad and Hooper 1973, Leach and Miller 1987) In our study, musculoskeletal investigation was carried out by two specialists in physical medicine and rehabilitation. There may be interexaminor differences in diagnosing musculoskeletal disorders, but it should not bias the result, because the main principles of the clinical examination were agreed together. Our forestry workers (I-III) were on 6-week unemployment leave prior to investigation in 1995. Their shoulder and elbow musculoskeletal disorders had time to recover. The history of shoulder and elbow disorders was carefully taken. In diagnosing rotator cuff tendinitis, the group of symptom cases of rotator cuff syndrome and the group with positive provocation test of rotator cuff syndrome (positive painful arch test during elevation, pain in resisted abduction or resisted external rotation) had to be combined (i.e. to be the “rotator cuff syndrome” group, refer to chapter 4.3.), for statistical analysis. Accordingly, also epicondylitis group of symptom cases was combined with the group of positive provocation test of epicondylitis, for statistical analysis (to be the “epicondylitis” group). This may have biased the result to some extent. However, assumingly, many of symptom cases may have had a positive provocation test earlier, during working months. This unemployment period was independent of the research. The functional upper extremity tests were earlier widely used in Finland by occupational health care. It was assumed that there is a significant difference between the groups with or without musculoskeletal symptoms. In these studies dynamic and static muscle force of upper extremities were measured. They did not differentiate between groups of having or not having rotator cuff syndrome or epicondylitis. Pain in the upper extremity may interfere with upper extremity test results to some extent and bias the result. Measurements are not recommended for use as a screening method in occupational health care. Subjective deterioration of muscle force occurred in the cohort. In a two-year followup of forestry workers in Finland, Färkkilä et al. (1986) reported a 21% loss of muscle 66 force among subjects with VWF when compared to 5% loss in asymptomatic controls. Hand muscle weakness was also reported by Bovenzi et al. (1991). . 6.3 Clinical aspects of sensory threshold changes In essence, the threshold shifts provide a measure of the status of each finger/nerve system at inception, and follow-up, for an individual relative to the mean thresholds of healthy persons, while the threshold changes provide a measure of what has happened to each finger/nerve system over the five-year period, with each subject serving as his own control. The summed normalized threshold shifts tend to follow one of several patterns. Overall, there is a general elevation in threshold (i.e., positive threshold shift) corresponding, implicitly, to a reduction in acuity in the hands of this group of forest workers. In one pattern, the elevations in threshold of digits 3 and 5 of the same hand tend to be similar in magnitude. The pattern is often common to both hands. This was more evident in the data obtained at follow-up (shown in table 13). The results strongly suggest that there are neurological changes occurring similarly in the nerve fibers and/or end organs mediating tactile perception at the fingertips of digits 3 and 5 in both hands of this subject. It may therefore be inferred that both median and ulnar sensory nerve fibers and/or end organs are affected similarly. A second pattern, which is uncommon in this group of subjects, is a variation: the magnitude of the shift differs between the left and right hands of a subject. An example is provided by the results for subject #3 (table 13). A third pattern, which is also uncommon in this group of subjects, involves larger threshold shifts in digit 3 than in digit 5 of the same hand. In this case the inference would be that the median sensory nerve fibers and/or end organs of digit 3 are more affected than the ulnar sensory nerve fibers and/or end organs of digit 5 of these hands. A corresponding fourth pattern involves larger threshold shifts in digit 5 than in digit 3 of the same hand. The interpretation would be the opposite of the third pattern. Overall, the strongest trend from study inception to follow-up is one of increasing summed normalized threshold shift. There was one exception. The thresholds of subject #5 show a marked reduction (i.e., improvement in sensitivity) from 1990 to 1995, which was coincident with a reduction in alcohol consumption during this period. A small fiber neuropathy had been detected by electroneuromyography in this subject. The progression in individual hands is obtained from the summed threshold changes over the five-year period (table 15). The common trend was one of deteriorating sensitivity, with summed mean threshold changes of up to 35.4 dB recorded. Reductions in sensitivity of threshold changes in excess of 20 dB were observed in the fingers of, in total, eight hands (table 15). Studies of the rate of threshold change with age in healthy persons (including professional and manual workers) would yield a mean summed threshold change of TCSUM 0.7 dB due to ageing during the five year period (Brammer et al. 1993), much less than the magnitude of TCSUM observed in these subjects. 67 If the thresholds recorded from the three foremen (subjects # 4, 12 and 16) included in this study (who did not work with power tools) are considered to provide a more appropriate measure of threshold change over the five year period for the lifestyle and environment of the Suomussalmi region, then the summed threshold change for persons not using power tools at work would be TCSUM = 9.7 5.0 (SD) dB, leading to a 95% confidence interval of 0 < TCSUM < 19.5. While the large confidence interval and small number of workers from which it was derived may be questioned, the changes in six subjects still remain statistically significant. Thus, arguably 40% of the remaining subjects are experiencing work-related threshold changes in their hands, assumingly caused mainly by vibration. 6.4 Postural stability and neck pain The diagnosis of TN pain was established with 27 out of 106 the forestry workers. The cervical spine of one forestry worker had been previously operated, and he had cervical syndrome with radiating pain. In the cohort (I) the TN pain was associated with Oswestry index, which reflects the disability from low back pain. Patients with neck pain had also low back pain. The other Oswestry involving neck symptoms was not used in this study, which is a restriction. Palmer et al. reported that patients with handarm vibration exposure had an increased risk of neck pain (Palmer et al. 2001) which we could not confirm. The patients with TN and without TN had similar postural responses during a stimulation-free period. Anteroposterior forward shift occurs in neck muscle vibration in healthy subjects (Pyykkö et al. 1989). In TN patients the average deviation of position in the anteroposterior direction was greater than in the control group, and also the lateral maximum deviation of position during the second stimulation. During the lumbar stimulation, the position shift forward normally occurs. It can be explained by a general alerting reaction, to achieve a safer position (Pyykkö et al. 1989). The TN group had greater maximum anteroposterior deviation of position after the second stimulation. The TN patients also manifested greater lateral maximum deviation of position after the first and second stimulation. Pain and stiffness in the neck are common in a working population. Also Karlberg found that patients with chronic cervico-brachial pain had poorer postural control (Karlberg et al. 1995) Physical work requires muscle energy. Local metabolic changes in muscle are conveyed into the brain by sensory afferent nerves and cause sensation of discomfort and fatigue (Armstrong et al. 1993) Reduced local blood flow in the trapezius correlated with myalgia and was found in connection of static load at work (Larsson et al. 1990). In TN the activation or control of afferent nerve endings may be faulty and may lead to inadequate postural responses. Low back pain was not taken into account in the TN study. In the cross sectional study TN pain was associated with low back pain. It is possible, that in this study low back pain could be involved in postural stability differences, especially during lumbar vibration stimulation. However, Luoto et al. (1998) found that with vibration stimulation of back muscles, lateral deviation of position was greater among patients 68 with low back pain, but only when eyes were open, not when they were closed. In our study, the eyes were closed during measurements 6.5 Inner ear as a model organ for sensorineural damage Sensorineural hearing loss (SHL) is well known to occur after different acoustic (vibration and noise induced) traumas, such as middle ear surgery, with an incidence of up to 5% (Kylen and Arlinger 1976). Postoperative SHL analysed in 2,303 cases of chronic otitis media showed that 0.5% became totally deaf and 0.7% acquired a high tone loss (Tos et al. 1984). Using high frequency audiometry of up to 20 kHz, the incidence of SHL has been recorded in 37.5% of patients (Domenech 1989). The mechanisms producing sensorineural hearing loss in burr vibration may be similar to those producing a sensory threshold reduction in the hands of exposed workers Transcranial vibration represents a complex interaction of transmission and damping effects of the skull, cranial contents, and surrounding soft tissues. The complex patterns of vibration transfer across the skull have been investigated with increasing resolution since Herzog and Krainz (1926), Bekesy (1932) and Barany (1938) who generated early systematic data on bone conduction (Brandt 1989). Tonndorf (1968) expanded the treatment of these data to convincingly demonstrate that modes of bone conduction are frequency dependent. The large amplitude vibration at frequencies less than 200 Hz results in the skull vibrating as a rigid body, producing a transitory type of motion as first proposed by Barany (1938). In the transitory mode the cochlear fluids are set in motion while the ossicular chain is stabilized. The result is differential vibration of mobile structures and displacement, with activation of cochlear transducers. As the frequency of stimulation is raised, “flexural-compressive” modes of stimulation begin to appear (Bekesy 1932, Tonndorf 1968). At higher frequencies the oscillatory movement is transmitted to the auditory ossicles, and into the cochlea including ossicles, labyrinths, fluids inside the cochlea, tegmentum and partially the cochlear nerve. Vibratory energy reaching the cochlea generates segmental compressions and expansions of the cochlear shell. Compressed cochlear fluids seek relief by pushing and pulling the oval and round windows. The relatively greater compliance of the round window facilitates fluid shifts from the scala vestibuli into the scala tympani, displacing the basilar membrane and cochlear transducers. The mode of cochlear shearing forces during vibration at higher frequencies might result in greater vulnerability. The phenomenon is undoubtedly complex and occurs at higher vibration frequencies and it remains to be documented what role burr vibration exposure may have in the aetiology of inner ear damage. The mechanics of hand-arm system with bones and joints represents different system. So far no studies are performed in that the different tissue compartments of the hand would be modeled in detail. Thus oscillation of vascular components, connective tissue, and sensory organs may follow the principles observed in the temporal bone. Freeman et al. (2000) and Sohmer et al. (2000) presented an interesting theory for bone conduction in humans and rodents, in that fluid pathways to the inner ear would cause the major effect of bone conduction (Freeman et al., 2000; Sohmer et al., 2000). 69 Thus, the placement of bone vibrator to the fontanel of an infant or eye or brain tissue produced equal or better hearing than placement of the bone vibrator on the frontal or mastoid bone. These experiments are difficult to interpret as a fixing method of the accelerometer to the bone was not demonstrated and the couplings of skull vibration with the soft tissue vibration were not demonstrated. These works indicate, however, that the CSF pathways may significantly modify the bone conduction. It is well accepted that shear movement exists in the organ of Corti, but no document has mentioned shear within the spiral ganglion cell. Vibration induced shear forces within the bone matrix stimulate bone cells and mechanically transform them causing upregulation of genes in the cells (Turner et al. 1994, Nomura and Takano-Yamamoto 2000). The spiral ganglion cells are surrounded by perilymph and bone matrix. The shear force produced by the transcranial vibration is conducted to the spiral ganglion cells and is able to cause shear stress. In our study (V), the strong TNF receptor 2, VEGF and VEGF receptor 2 gene expressions in the spiral ganglion cells support this hypothesis. At the vibration exposure level studied here, most of the TS of hearing was temporary and recovered within the first week. The clinical findings of temporal bone surgery in human also demonstrate that patients have a significant high tone hearing loss immediately after surgery. Vasama demonstrated TS in 55% of patients in exostosis surgery of the external auditory canal. In 10% of the patients the TS was prominent (Vasama 2003). Our results (IV) support his findings. In ear surgery it is stated that mostly the TS recovers within one week, if the level of vibration is not overwhelming and the frequency of vibration is low (Da Cruz et al. 1997, Tos et al. 1989). We observed permanent TS (at least 10 dB) in 3 out of 30 animals 7 days after the vibration exposure, and the average TS was only 2.4 dB. Transmission electron microscopy may verify any mechanical damage of the organ of Corti. This work is ongoing. Forestry workers with vibration–induced white finger have aggravated hearing loss (Pyykkö et al. 1981, 1986c, 1988, 2003). These authors showed that forestry workers with vibration-induced white fingers (VWF) had about a 10 dB greater TS in hearing than forestry workers without VWF (Pyykkö 1986c). The relationship between handarm vibration and hearing loss was confirmed only on epidemiological basis (Pyykkö et al. 1986c, 1988, Starck et al. 1988, Iki et al. 1986), and the mechanism behind the hearing loss is unknown (as is the mechanism leading to vibration damage in the tissues). Long-term vibration of hands is known to result in disturbances, especially in the circulation of hands (Koskimies et al. 1992, Griffin and Bovenzi 2002, Griffin et al. 2003). On the other hand, Palmer et al. (2002) showed that there is an association between finger blanching and hearing loss, even prior exposure to hand-arm vibration, possibly through sympathetic vasoconstriction in the cochlea. In addition to patients exposed to vibration in middle ear surgery, inner ear damage may occur in persons exposed to whole body vibration such as in tractor driving, stone work, forestry, helicopters, mining (Zou et al. 2001). These occupations may be at risk for vulnerability of noise. 70 6.6 Upregulation of the cytokines during vibration exposure We examined the possibility whether up-regulation of TNF-α and VEGF would be involved in the hearing loss (V). Although TNF-α, TNF receptor 1 and receptor 2 were observed in the vibrated cochlea, the expression of TNF receptor 2 was more prominent in the cochlea. The combination of TNF-α with TNF receptor 2 is capable of activating Jun N-terminal kinases (JNK) and nuclear factor (NF)-κB (Goeddel 1999). The activation of JNK and NF-κB has the function of an anti-apoptotic agent (Goeddel 1999, Watanabe et al. 2002, Biswas et al. 2003). On contrary, the activation of TNF receptor 1 induces apoptosis (Ashkenazi et al. 1998, Goeddel 1999). When both receptors are expressed, the activation of TNF receptor 2 enhances the effects of receptor 1 activation. The final fate of the cells should be related to the expression ratio of both receptors. Shear stress inhibits TNF-α induced apoptosis by activating phosphatidylinositol 3 (PI3)-kinase and inhibiting Caspase-3 (Pavalko et al. 2002). Vibration induced VEGF and VEGF R2 expression in the cochlea, but not VEGF R1. Our results confirm the biological significance of a previous in vitro study, which indicated that in vascular endothelial cells high shear stress induced an increase in VEGF R2 expression. This up-regulation reached its maximum and was in a linear gradient to the stress strength within a range of 2 to 40 dyne/cm2 (Abumiya et al. 2001). The authors interpreted that an increase in the shear stress in the vasculature by postischemic reperfusion stimulates VEGF R2 expression, resulting in an increase in vascular permeability and leading to neo-vascularisation. After myocardial infarction the newly formed myofibroblasts express VEGF and VEGF R2 that seem to play a significant role in tissue repair/remodelling (Chintalgattu et al. 2003). When the cochlea is exposed to mechanical vibration, a shear stress is increased in the various cell types of the cochlea with concomitant increase of expression of VEGF and VEGF R2. Thus, VEGF may contribute to tissue remodelling and angiogenesis at the site of damage in an autocrine manner and may be important in preventing further damage to the cochlea. The mostly enhanced expression was located in the spiral ganglion cells, stereocilia, supporting cells, the internal sulcus cells and epithelial cells of the lateral wall of the scala tympani. The spiral ganglion may be repaired under assistance of VEGF because both VEGF and VEGF R2 were expressed there. Seki et al. (2001) suggested that the pathophysiology underlying vibration-induced hearing loss is an increase in porosity of the blood vessels in stria vascularis and degenerative changes in the intermediate cells of stria vascularis. The exact mechanism is being investigated. Vibration damage seem to cause upregulation of TNF and TNFα-receptors in spiral ganglion cells, and may cause necrosis and apoptosis, which leads to nerve degeneration. 71 7 CONCLUSION The pathophysiological effects of vibration were studied. (I) In the cross-sectional study, the prevalence of VWF was reduced and incidence was very low. The results in the cohort study indicated that in spite of a low prevalence of VWF (8%), sensorineural symptoms as numbness increased. Numbness was exposure-independent. Musculoskeletal disorders in the cohort study were more prominent on the right upper extremity, which carries the weight of the chain saw. Vibration contributed to the development of musculoskeletal disorders in the upper extremity of forestry workers. (II) Two tools have been constructed from mechanoreceptor- specific threshold shifts and threshold changes to assess tactile sensory function in the hands of forestry workers. Four patterns of threshold shift could be identified. The most common pattern in this group of subjects involved both hands and both median and/or ulnar sensory nerve pathways. Statistically significant positive threshold changes (i.e., reductions in sensitivity) were recorded in a majority of the hands over a five-year period. The threshold shift metric is closely associated with the tactile sensory changes. (III) 27 out of 106 of forestry workers suffered from TN. TN-patients had poorer postural stability. In TN patients the activation or control of proprioceptive afferent endings may be faulty and may lead to inadequate postural reflexes. Vestibulospinal reflexes converge with proprioceptive input. There may be a mismatch of the impulses in the central control mechanisms. (IV) In the animal model of the inner ear high frequency vibration causes more injury than low frequency vibration. The vibration can be exactly dosed and the responses evaluated with ABR. (V) In vibration induced hearing loss it seems that shear stress may be the key factor for up-regulation of TNF-α, VEGF, TNF R1, TNF R2 and VEGF R2. The function of TNF-α is two-way, it can induce both cell damage and protection against apoptosis. The function of VEGF is to repair some of the damages to the cochlear cells. In the future, an approach should be taken to evaluate the role of biomechanical risk factors in connection with hand-arm vibration exposure. Neurological examination may require ENMG, VPT and quantitative sensory testing in the future. The validity of the specific VPT in forestry worker population must be verified. The inner ear damage model may provide insight into vibration-induced damages in the hand-arm vibration syndrome. It may provide a new understanding of mechanisms leading to vibration-induced hearing loss and vibration-induced cellular damage. In the future, detailed mechanism of vibration induced SNHL and pathophysiological mechanisms leading to HAVS should be researched. More studies are needed for estimating the dose response relationship of vibration and SNHL in this model. Additional studies on upregulation of cytokines involved in the apoptotic pathway, in addition to TNF-α, are suggested. Also, the studies with the electron microscopy, magnetic resonance imaging and atomic force microscopy are needed to evaluate structural changes in cellular and molecular level in the inner ear. 72 8 REFERENCES Aatola S, Färkkilä M, Pyykkö I, Korhonen O, Starck J. Measuring method for vibration perception threshold of fingers and its application to vibration exposed workers. 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Submitted for publication (Journal of the Acoustic Society) III. Koskimies K, Sutinen P, Aalto H, Starck J, Toppila E, Hirvonen T, Kaksonen R, Ishizaki H, Alaranta H, Pyykkö I. Postural stability, neck proprioception and tension neck. Acta Oto-Laryngol Suppl 1997;529:95-7 IV. Sutinen P, Zou J, Hunter LL, Toppila E, Pyykkö I. Vibration-induced hearingloss: mechanical and physiological aspects. Otol Neurotol 2007; 28(2): 171-7. V. Zou J, Pyykkö I, Sutinen P, Toppila E. Vibration induced hearing loss in guinea pig cochlea: expression of TNF-alpha and VEGF. Hear Res 2005; 202(1-2):1320. Appendix I HAASTATTELUKAAVAKE Suomussalmella (metsuritutkimus) Päivä Anamneesi: Herediteetti Lapsuus Kouluikä Sotaväki Ensi käynti lääkärillä: Minkä vuoksi: Nimi: Syntymäaika: TVD (eli VWF): on/ei tai loppunut Dg: 1. 2. 3. 1. TVD (eli VWF) alkanut: oik/vas viim.kohtaus: kohtauksen kesto (metsässä): muutos: lieventynyt/ennallaan/vaikeutunut esiintyminen: työmatkoilla/tauoilla/sahatessa/aamulla/iltapäivällä/muu,mikä paikallistuminen käteen Paikallistuminen käteen (Vasen) Paikallistuminen käteen (Oikea) Muutos:lieventynyt/ ennallaan/ vaikeutunut Sää:kuiva pakkanen/ kostea 0-sää/ myös kesällä/ muu,mikä: Kohtausten lukumäärä viikossa: <1/ 1-4/ >4 ja muutos: lieventynyt/ennallaan/ vaikeutunut 2. Puutuminen tai kipu yläraajoissa: kyllä/ei päivällä herää/ yöllä/ muulloin ei herää/ kerran viikossa/ 2-6 kertaa viikossa/ joka yö/ useammin 3. Puristusvoiman heikkeneminen kyllä/ei oikea/vasen muutos: lieventynyt/ ennellaan/ vaikeutunut 4.Nivelsärky kyllä/ei oikea: sormet, ranteet, kyynärpää ja olkapää/ kokovyläraaja muutos: lieventynyt/ ennellaan/ vaikeutunut 5. Muuta RR oik/vas La Cor Hb Pulm 6. Moottorisahahaastattelu oireet: totaalisahausmäärä (tunneissa) Muut tärisevät työkalut: Virtsa EKG: Appendix II INTERVIEW (TRANSLATED by the author of the thesis) Date Medical history Heredity Childhood Schoolyears: Army First visit to a doctor: The reason: 1.TVD (or VWF) alkanut: Name Date of birth: TVD (or VWF): yes/ no/ ended Diagnosis: 1. 2. 3. right/left Last attack the duration of the attack: change: improved/ the same as before/ deteriorated occurence: during the transfer/ brakes/ chainsawing/ in the morning/ in the afternoon/ other, what: localization in the hands: change: improved/ the same as before/ deteriorated The left hand The right hand Change: improved/ the same as before/ deteriorated Weather: dry subzero weather/ damp zero weather/ also in summer/ other, what: The amount of attacks in a week: <1/ 1-4/ >4 and change: improved/ the same as before/ deteriorated 2. Numbness or pain in the upper extremities yes/no during the daytime/ at night/ otherwise no awakening/ once a week/ 2-6 times a week/ every night/ more often change: improved/ the same as before/ deteriorated 3. Subjective hand muscle weakness yes/no right/ left change: improved/ the same as before/ deteriorated 4. Pain in upper extremities yes/no right: fingers/ wrist/ elbow/ shoulder/ the whole upper extremity left: fingers/ wrist/ elbow/ shoulder/ the whole upper extremity change: improved/ the same as before/ deteriorated 5. Else Blood pressure: right/ left extremity: ESR Hg Urine Cor Pulm EKG 6 The chain sawing time (in hours) totally Other vibrating tools: Appendix III LÄÄKÄRINTUTKIMUS (Suomussalmi) Nimi Tutkimusnumero Anamneesi: metsurivuodet, aiemmat leikkaukset ja sairaudet, sukusairaudet, liikunta, tupakointi, alkoholinkäyttö, ammatti, lomautukset Nykyoireet Pääasiallinen ongelma (potilaan ilmoittama) Tuki-liikuntaelimet: hoidot lääkitykset, myös depressiolääkitys, fysikaaliset/ fysioterapeuttiset hoidot, kuntoutusjaksot (ASLAK, tykytoiminta), muu, mikä? Hyöty hoidoista? STATUS yleisstatus, vaikutelma, sydän- ja verenkiertoelimet, keuhkot, liikehdintä Niska ja yläselkä: inspektio, ryhti, atrofia palpaatio (kaula- ja rintaranka, lihakset nh seudussa) kaularangan liikkuvuus, kompressiotesti Yläraajat: nivelten aktiivit ja passiiviset liikeradat, AC nivel, humeroskapulaarirytmi, kipukaari kiertäjäkalvosin testaus TOS testaus epikondyliittitestaus (palpaatio, provokaatiotestit) Tinel, Phalen Ihotunnot Lihasvoimat Puristusvoima/ asymmetria Jänneheijasteet VWF Alaselkä: Inspektio, ryhti Selän liikelaajuudet, Modifioitu Schober, ekstensio, lateraaliflektiot varvas-kantapääkävely kyykkyyn-ylös tasahyppely yhdellä ja kahdella jalalla jänneheijasteet Lasegue lihasvoimat ihotunnot (kosketus, kipu, vibraatio) kaudaoire? vatsalihasvoima (sit-up) lonkkien rotaatiot ja trokanterbursan palpaatio lannerangan aristus SI niveltestit Femoralisvenytys ADP ja ATP palpaatio Waddellin testit Appendix IV MEDICAL EXAMINATION (Suomussalmi) Name Number MEDICAL HISTORY: years as a forestry worker, prior operations and diseases, heredity, sports, smoking, use of alcohol, occupation, layoffs Present symptoms The main problem (by a patient) Musculoskeletal system: therapies/ treatments medication, also depression medication, physical/physiotherapy treatments, rehabilitation (also in institutions), other? Benefit from therapies/ treatments? STATUS: general status, general impression, heart and circulatory system, pulmonary status, movements Neck and upper part of trunk inspection, posture, atrophy of muscles palpation (cervical and thoracic spine, muscles in the neck-shoulder region) cervical mobility, spurling Upper extremities: active and passive movements of joints, humeroscapular rhytm, painful arch rotator cuff testing TOS testing testing of epicondylitis (palpation, provocation tests) Tinel, Phalen Sensory testing Muscle strength testing Grip force/ asymmetry Reflexes VWF Lower back: Inspection, posture Mobility, Modified Schober, exension, lateral flexion on tip-toe and on heels walking Squatting Jumping with both or one leg Reflexes Lasegue Muscle testing Sensory testing (touch, pain, vibration) cauda equina? stomach muscle testing (sit-up) rotation of hip joints, palpation of trochanter bursa tenderness of lumbar spine SI joint palpation Femoralis stretching ADP ja ATP palpation Waddell testing Kuopio University Publications D. 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