Download -AN- 931839 -TI- General Surgery. -AU

-AN- 931839 -TI- General Surgery. -AU- Patrick Twomey, MD
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Innovations in the broad field of general surgery are dominated today by
advances in "minimally invasive surgery," ie, laparoscopic, thoracoscopic,
and similar procedures. Using modifications of earlier gynecologic and
endoscopic techniques, these developments are revolutionizing major
aspects of general surgery (and many subspecialties) at a rate that defies upto-date cataloging. Examples beyond cholecystectomy and appendectomy
include colectomy, gastrectomy, nephrectomy, splenectomy, pulmonary
resections, and even total esophagectomy and pancreaticoduodenectomy
(Whipple procedure). A nagging question remains: Granting that these
techniques are feasible, how does one know they are better than those
previously used?
The touchstone of prospective, randomized trials has not yet been applied. In
some cases such rigor is moot. For example, laparoscopic cholecystectomy
has been found to be equally effective, generally safe, and much better
tolerated than the open procedure. Outpatient or 1-day-stay procedures are
common, and with a suitably experienced team, complications are similar to
or less than those of traditional techniques. It is unlikely that a prospective,
randomized trial can be mounted in this area.
However, the most devastating complication of gallbladder surgery,
common bile duct injury, has been more common in the early application of
the laparoscopic approach. Experience has revealed the pitfalls to be
avoided and following these guidelines, this risk can be made acceptable for
the majority of patients. For the remainder, a policy of comfortable
conversion to the traditional open procedure is required.
The general surgical procedures that have been performed safely
laparoscopically or thoracoscopically can be placed into two categories. First
are those in which the same anatomic result is produced but with lessened
trauma from avoidance of a large incision. Examples include
esophagomyotomy for achalasia (Heller procedure); resection of pulmonary
blebs for pneumothorax; and pelvic lymph node dissection for staging of
prostate cancer. For these, safety, speed, and--closely related--cost are the
major issues to be resolved, since it shouldn't matter whether a cut made
here or a staple line placed there is done in an open procedure or through a
trocar. Most would welcome prospective randomized trials, but it may be
that for many of these procedures the superiority of the less-invasive
approach can be established by demonstrating safety, anatomic equivalence,
and (hopefully) no increase in overall cost.
The second category of procedures comprises variations not presently in
widespread use but that have been specially devised or adapted for
laparoscopic application. Examples include anterior seromyotomy and
posterior truncal vagotomy (Taylor procedure) for peptic ulcer disease, and
laparoscopic repair using prosthetic mesh in an intraperitoneal or
preperitoneal location for groin hernias. Experience with these variants is
insufficient to produce consensus concerning their equivalence with or
superiority to conventional approaches. There is much need in this area for
controlled trials, though none has yet been reported.
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Another unsolved problem concerns training and credentialing. With the
increasing availability of nonsurgical therapies for conditions previously
treated by surgery (peptic ulcer disease and reflux esophagitis come to
mind), the pool of patients who may benefit from some of the new
approaches is shrinking. At the same time, new trainees need to become
adept at both the new technology and, as a fall back, the traditional
procedures. Meanwhile, their mentors seek sufficient experience to ensure
their own expertise, and there is a large backlog of practicing surgeons in the
community who are also eager to master the new techniques.
There appears to be a steep learning curve for many of these techniques. In
the case of laparoscopic cholecystectomy, complications such as common
duct injury become much less common after the first dozen or so
procedures. Whether there is sufficient clinical material in most
communities to allow supervised performance of each of the new techniques
by all who wish to become credentialed remains to be seen.
In peripheral vascular surgery new technology promises to similarly expand
the applications and safety of traditional operations. A recent,
comprehensive review of endovascular surgery concludes that, using
catheter-based systems, it may be possible to replace long incisions with a
puncture, general anesthesia with local, and at the same time save money by
reducing intensive care unit and hospital stays. Best established among these
techniques is balloon angioplasty for isolated symptomatic stenoses in large
vessels such as the iliac arteries. In contrast to the situation in coronary
vessels, this approach is much less successful in smaller vessels such as at
the popliteal trifurcation or even in the superficial femoral artery. These
vessels continue to be better treated with bypass grafting, preferably using
autogenous conduits such as the saphenous vein. These and other
revascularization approaches may be assisted by vascular endoscopy, and
perhaps in the near future, by intravascular ultrasound, to assess adequacy of
reconstruction, assist in valvulotomy, and identify intimal flaps.
Less well established are the various laser and mechanical atherectomy
devices undergoing intensive clinical testing. The biggest problem with
these procedures is restenosis and occlusion, although embolization, vessel
perforation, and bleeding also sometimes occur. One approach to the
problem of restenosis that shows early promise is placement of intravascular
stents after balloon angioplasty or atherectomy. A variant of this stent, with
attachment devices on its ends, is being tested as a possible intraluminal
bridge across aortic aneurysms.
Treatment of burn, trauma, and similar critically ill patients continues to
improve as a result of improved understanding of the biology of sepsis and
organ failure. The correlation of maintenance of the gut barrier and portal
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absorption of nutrients with improved outcome is now well recognized. The
importance of early, enteral nutritional support has been confirmed in a large
prospective randomized study in trauma patients. As one pioneer in the
field, J. Wesley Alexander, MD, puts it, "Starting enteral nutrition should be
part of the initial resuscitation" (oral communication, February 1993). In
another randomized trial, the apparent benefits of "supernormal"
postoperative resuscitation guided by catheter measurements and frequent
cardiac output determinations were reported. The intent is to maximize
oxygen delivery in these hypermetabolic patients. A confirmatory trial will
be needed before this approach can be generalized.
Understanding the difficulties caused by the body's response to infection via
interleukins and other cytokines has led to exciting approaches to counteract
what appears to be a maladaptive overresponse to endotoxemia. The initial
use of monoclonal antibodies to endotoxins and to the cellular receptor to
interleukin 1 have been disappointing. Nevertheless, there is optimism that
the rapid advance in our knowledge of secondary mediators of endotoxemia
will lead to successful ways to modify the cytokine cascade and improve
outcome in the "sepsis syndrome." Problems of patient selection and high
cost will need to be addressed.
Results of trials of selective gut decontamination have been mixed. The
general consensus is that although some infections can be avoided, overall
mortality is not reproducibly influenced. Again, issues of patient selection,
emergence of resistant organisms, and cost limit the application of this
approach.
Numerous other innovations include total esophagectomy without
thoracotomy, restoration of rectal function after total proctocolectomy,
cross-species transplantation, and a host of advances in surgical
subspecialties. These exciting developments are summarized elsewhere.
-AN- 931832 -TI- Dermatology. -AU- Jeffrey S. Dover, MD, FRCPC
Kenneth A. Arndt, MD
Erythromycin resistance to group A streptococci is a serious clinical
problem because there are few alternative oral therapies for the treatment of
streptococcal infections in patients who are allergic to penicillins and
cephalosporins. In Finland between 1979 and 1989, as the use of
erythromycin was nearly tripling, an unusually high frequency of such
resistance was noted in one geographic region. A national study of 272
isolates of group A streptococci obtained from blood cultures, 3087
consecutive isolates from throat swabs, and 1349 isolates from skin swabs
revealed that the frequency of resistance to erythromycin had increased in
blood cultures from 4% in 1988 to 24% in 1990, in throat swabs from 7% in
1988 to 20% in 1990, and in skin swabs from 11% in 1988 to 31% in 1990.
This rapid and substantial increase in resistance to erythromycin in group A
streptococci and the failure of erythromycin treatment to cure throat
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infections caused by erythromycin-resistant isolates in nine of 19 patients
became a cause for considerable concern. Although the cause of increased
resistance is not precisely known, it is clear that overuse of erythromycin
played a major role. The only way to control the clinical problem appears to
be a reduction in the administration of erythromycin and other macrolide
antibiotics and the use of routine cultures to assess erythromycin resistance
of group A streptococci.
Treatment of the pruritus associated with uremia is an extremely difficult
therapeutic problem. Based on the empirical effectiveness of erythropoietin
in the treatment of uremic pruritus, DeMarchi et al performed a 10-week,
controlled, blinded, crossover trial in 10 hemodialysis patients with severe
pruritus. They noted a fourfold reduction in pruritus in eight of 10 patients,
although pruritus recurred within 1 week of discontinuing erythropoietin.
When the erythropoietin was restarted for a further 6 months in the eight
patients who showed an initial response, improvement was seen in all for the
duration of treatment. There was a concomitant decrease in plasma
histamine, suggesting that high plasma histamine levels may somehow be
related to the pruritus associated with renal failure.
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Necrobiosis lipoidica is an uncommon skin disorder found most often, but
not exclusively, in patients with diabetes. Lesions consist of single or
multiple, yellow-brown, indurated, atrophic plaques located most often on
the anterior tibial surfaces. Usually, the disease is slowly progressive. No
treatment has been shown to be reproducibly effective. In a controlled trial,
Petzel-bauer et al treated six patients with active necrobiosis lipoidica with
tapering doses of prednisolone for 7 weeks. All patients had complete
cessation of disease activity, no recurrence was noted at 8 months, and all
patients, including four diabetics, tolerated the therapy well. It appears that a
short course of corticosteroids is worth a trial in selected patients with
severe progressive necrobiosis lipoidica.
Clinicians often turn to histopathologists to help confirm a diagnosis of
cutaneous T-cell lymphoma (mycosis fungoides). Olerud and a national
panel of five to seven dermatologists and pathologists prospectively and
independently evaluated pretreatment biopsy specimens in 165 patients
referred with a diagnosis of cutaneous T-cell lymphoma. Patients with
cutaneous T-cell lymphoma were followed up for a mean (+-SD) of 6.3 (+3.5) years. The study found that histology scores did not correlate with the
stage of disease, and histopathology was not an accurate predictor of disease
outcome because the histological ratings did not discriminate between
patients who eventually had complete remission and those who either had
progressive lymphoma or died of disease. Repeated reading of selected cases
by the same panel members resulted in a changed diagnosis 15% of the time.
Based on the findings of this study, the interpretation of the pathologic
diagnosis of cutaneous T-cell lymphoma should be made with caution and
always in conjunction with clinical evaluation.
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Death rates for malignant melanoma have increased dramatically both in the
United States and in Scotland. * RF 5,6 * In the United States from 1973
through 1988, the age-adjusted melanoma death rate was higher for white
men than any other group and the death rate for malignant melanoma
increased faster among men than any other cancer. The greatest rise in
melanoma mortality occurred among men older than 50 years of age; the 5year survival rate for men older than 65 years of age was 64% compared
with 78% for the younger age group. In addition to the effects of increased
exposure to the sun, one reason for this increase is related to patterns of
melanoma discovery. Patterns of discovery were surveyed in 216 cases of
melanoma in Massachusetts where it was found that 53% of melanomas
were self-discovered; the remainder were detected by medical providers
(26%), family members (17%), and others (3%). Nearly one third of patients
could not see their own lesions easily. Women were much more likely to
discover their own lesions (66% vs 42%; P=.001) and those on their spouses
(23% vs 2%; P less than .0001) than men. Particular emphasis in targeting
men at highest risk for this disease in early detection programs is imperative.
In addition to counseling patients to look for new or changing moles,
patients should receive full-body skin examinations at regular intervals.
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Understanding the side effects of corticoste-roid use continues to evolve.
Inhaled corticoste-roids have been shown to produce similar side effects as
corticosteroids ingested either by mouth or delivered by the parenteral route.
Sixty-eight patients who had received 15 to 20 mg/d of oral prednisone for
longer than 6 months were compared with patients who had received highdose or low-dose inhaled steroids. Patients who had received oral
corticosteroids experienced 30% more cutaneous side effects (thinning of
skin and purpura), while patients who had received high-dose inhaled
corticosteroids experienced 17% more cutaneous side effects than those
individuals who received low-dose inhaled steroids.
Basal plasma cortisol levels were found to be inadequate to assess the
degree of suppression of the hypothalamic-pituitary axis. Of 279 patients
taking between 5 and 30 mg/d of prednisone orally, 46% of the 187 patients
with normal basal cortisol levels had abnormal cortisol responses to
corticotropin-releasing hormone. There was a poor correlation between the
daily dose, duration of treatment, cumulative dose, and degree of
hypothalamic-pituitary-adrenal suppression. Awareness of hypothalamicpituitary-adrenal suppression is critical to preventing acute adrenal
insufficiency; testing the cortisol response to corticotropin releasing
hormone must be performed to assess degree of adrenal suppression.
The relationship between UV light exposure and labial herpes simplex
outbreak is poorly understood. One study evaluated 196 patients with known
sun-induced oral herpes simplex viral infection in an attempt to better
understand the relationship of UV light exposure to outbreaks of herpes
labialis and the effectiveness of acyclovir in suppressing these outbreaks.
The lips were exposed to artificial UV light, and patients were treated either
before or after with oral or topical acyclovir or a placebo. Four percent of
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patients developed lesions on the lip within 1 cm of the site irradiated by
UV light. Twenty-six percent developed lesions within 48 hours; the other
72% had lesions develop between 2 and 7 days after the exposure. Oral
acyclovir, whether begun 7 days before or 5 minutes after UV light
exposure, prevented delayed lesions but not immediate lesions from
appearing. If oral acyclovir was started 48 hours after UV light exposure,
delayed lesions developed but were less severe. Topical acyclovir applied 5
minutes after UV exposure had no effect whatsoever. It appears that there is
a bimodal peak of sunlight-induced herpes simplex viral infection,
suggesting at least two different pathogenic processes. Oral acyclovir is
effective in preventing onset of delayed lesions, but appears to have no
effect in preventing lesions that develop immediately after exposure to UV
light.
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-AN- 931837 -TI- Gastroenterology. -AU- David F. Ransohoff, MD
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One of the strongly held notions of medical pathophysiology is that acid is
the primary cause of duodenal ulcers. Indeed, the term acid-peptic disease
reflects the prevailing concept of cause, and so therapy is aimed primarily at
acid. "Antacids," such as acid-neutralizing compounds, histamine2 *
blockers, or proton pump inhibitors, are indisputably effective in healing
ulcer disease and, if taken chronically, in preventing recurrence. It now
appears, however, that an even more important factor may be responsible for
ulcers (at least duodenal ulcers): infestation with Helicobacter pylori. Two
important lines of evidence now support a possible causal role. First, H
pylori is present in the antrums of virtually all persons with a duodenal ulcer
who do not use nonsteroidal anti-inflammatory drugs or do not have
Zollinger-Ellison syndrome as a possible cause of ulcer. Second, treatment
and eradication of H pylori dramatically reduces the frequency of ulcer
recurrence compared with treatment of acute ulcers by histamine2 *
blockers alone. Among persons with recurrent duodenal ulcers, treatment
with amoxicillin, metronidazole, and ranitidine led to ulcer healing in 48
(92%) of 52 persons compared with 75% among persons given ranitidine
but not antibiotics. Helicobacter pylori was eradicated in 89% and 2%,
respectively. After 12 months, duodenal ulcers recurred in 8% of persons
given antibiotics compared with 86% of persons not given antibiotics.
However, the causal role of H pylori is obscured by the fact that infestation
is so common. About 50% of older persons in the United States are infested
with H pylori, while the rate is as high as 90% of persons in some other
countries. Thus, the role is "necessary but not sufficient." Nevertheless, the
practical implications are dramatic: treatment reduces recurrence.
A new understanding of the pathophysiology of duodenal ulcers will have
dramatic effects on both treatment and diagnosis. Several important practical
issues will receive attention in coming years.
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Which persons should be treated? Some opinion suggests that all persons
with a duodenal ulcer should have a therapeutic trial to eradicate H pylori,
even if the ulcer is a first episode or uncomplicated (eg, not bleeding), while
other opinion has suggested that therapy be limited to persons with an ulcer
that has recurred or has caused a serious complication.
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When should diagnostic testing for H pylori be done? There is no evidence
yet that treatment is effective in relieving nonulcer dyspepsia. In a person
with an ulcer, is it necessary to establish that H pylori is present? Because
the prior probability of H pylori is so high in someone with a duodenal ulcer
and no history of nonsteroidal anti-inflammatory drug use or ZollingerEllison syndrome, a case can be made to treat empirically, similar to the case
for empiric penicillin treatment of adults with pharyngitis (ie, treatment
without throat culture) when the clinical setting is simply suggestive of
streptococcal sore throat.
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To prevent reinfestation with H pylori, should persons be retested and/or
retreated? In a recent study, the reinfection rate was only 2% per year,
suggesting that routine retesting may not be necessary. Simple noninvasive
tests for H pylori are not yet generally available.
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What is the best treatment regimen? A commonly used regimen in the
United States includes a 14-day course of "triple therapy" consisting of
bismuth subsalicylate, two tablets four times daily with meals and at
bedtime; tetracycline, 500 mg four times daily with meals and at bedtime;
and metronidazole, 250 mg three times daily with meals; shorter regimens
may be effective and are being assessed. Future treatment regimens will
focus on antimicrobial therapies that are quick and have fewer side effects,
such as diarrhea. Histamine2 * blockers or proton pump inhibitors, such as
omeprazole, are likely to continue to have a role in treatment of acute ulcers,
but their use in long-term suppressive therapy will probably be limited to
persons in whom H pylori cannot be successfully eradicated.
In the short span since its introduction in 1989, laparoscopic
cholecystectomy has practically replaced open cholecystectomy as the main
surgical approach to treatment of persons with uncomplicated gallstones.
Much of its popularity is due to the convenience of and speedy recovery
from the laparoscopic procedure. It is not yet clear that the laparoscopic
approach is as safe as the open approach, particularly if there is a learning
curve for the new technology. Especially disturbing are reports of bile duct
injuries, which can be devastating. Some opinion suggests that the
laparoscopic approach will eventually prove to be as safe as or safer than
open cholecystectomy.
With the increased use of laparoscopic cholesystectomy, patients and
physicians may believe that it is now easier to treat gallstones and that the
threshold for when to treat gallstones should be lowered. For two reasons
caution is in order. First, as noted, it is not yet clear that laparoscopic
cholecystectomy is safer than (or as safe as) open cholecystectomy; it is
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simply more convenient. Second, cholecystectomy has a beneficial effect on
only a limited number of symptoms and health outcomes of persons with
gallstones. Symptoms such as belching, flatulence, intolerance of fatty
foods, and dyspepsia really are "nonspecific" and will rarely respond to
treatment of gallstones. Similarly, biliary pain (or colic, as it is sometimes
mistakenly termed) is generally episodic and infrequent; thus, persons with
chronic or continuous pain are unlikely to benefit from cholecystectomy
even if they have gallstones. The problems that are caused by gallstones
include episodic biliary pain, acute cholecystitis or pancreatitis, and perhaps
gallbladder cancer. The rates at which persons develop these outcomes-which is an important consideration when deciding who needs treatment-depend on the person's symptoms from gallstones.
For persons with asymptomatic gallstones, there is general agreement that
the natural course is so benign that prophylactic treatment is not appropriate.
* RF 5,6 * In theory, prophylactic cholecystectomy would be appropriate for
the few asymptomatic persons who are highly likely to develop a serious
complication, such as acute cholecystitis or gallbladder cancer;
unfortunately, it is currently impossible to identify such persons.
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After a person has had an episode of biliary pain, the prognosis (ie, the
likelihood of developing more episodes of pain or some complication of
gallstone disease) is more ominous than that of persons with asymptomatic
stones. First, the likelihood of having at least one other episode of pain is
high, up to 60% to 70% within 2 years, and the likelihood of developing an
acute complication is about 1.5% per year. However, subsequent pain or a
complication is not inevitable, so that about 20% to 30% of persons will not
have additional pain even after prolonged follow-up. These features of the
natural course make it reasonable that some persons who have had biliary
pain may choose watchful waiting, or determining what the pain pattern is
over time before making a decision about treatment.
The rate of gallbladder cancer in persons with symptoms of pain appears to
be about 0.0008 per year, at least for persons over the age of 40 or 50 years.
While this rate may appear to be low, it amounts cumulatively over 20 years
to a risk of about 1.6% for death from gallbladder cancer and thus can
become a consideration in management. It is not clear whether the increased
rate of cancer is due to the presence of gallstones or to something else that is
associated with gallstones, such as a property of the bile.
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Colon cancer screening has long been recommended but is not widely
practiced by patients and physicians. Recently published data are likely to
lead to a dramatic reevaluation of current practice. A recent case-control
study reported that cancer mortality can be reduced by 70% with
sigmoidoscopic screening (for lesions within reach of the instrument). This
degree of mortality reduction would make sigmoidoscopic screening by far
the most effective screening modality available, far surpassing
mammographic screening or cholesterol screening. However, evidence from
a case-control study is not considered as strong as evidence from a clinical
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trial, and there is likely to be much discussion about whether clinical
practice should change on the basis of such a study. In the United Kingdom
it has been suggested that the protective effect of "once only" sigmoidoscopy
is sufficiently high to make it an attractive consideration.
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If screening the distal part of the colon is beneficial, then perhaps once-only
or infrequent screening with a full-colon examination (such as colonoscopy
or barium enema) might be even better. * RF 11,12 * It is certainly too early
to propose such an approach as a matter of public policy, in part because
much simpler approaches, such as sigmoidoscopy, are currently not popular.
But there is likely to be a vigorous discussion about the merits of one-time
or infrequent full-colon examination.
While there is good news about sigmoidoscopy screening, the news about
fecal occult blood testing is less encouraging. One case-control study
suggested that mortality might be reduced by about 20% to 30% by yearly
fecal occult blood test screening, but huge inefficiencies are incurred by
false-positive and false-negative results.
Molecular biology techniques are likely to lead to important contributions in
gastroenterology in two areas. First, molecular markers may be used to
identify gene products shed in the stool, perhaps as a kind of molecular fecal
occult blood test. Mutations of the ras gene have been detected in the stools
of persons with colorectal cancer, and this general method provides a
promising approach to diagnosis.
A second contribution of molecular biology may be in providing a
quantitative estimate of a person's lifetime risk of colorectal cancer. If
family history indicates an increased risk, * RF 16,17 * then there must be
molecular markers that can provide a precise estimate of that risk. A
quantification of risk will dramatically increase screening efficiency by
allowing effort to be focused on persons with high risk and sparing persons
with little or no risk. Risk might be indicated by age, family history,
previous screening history or--in the future--molecular markers.
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While the costs of screening may be impressive, the cost and effort are
severalfold greater for colonoscopy after a "positive" sigmoidoscopy and
then for colonoscopic surveillance every 3 to 5 years for an indefinite time,
which is currently recommended for anyone found to have an adenomatous
colon polyp at screening. These efforts represent an enormous hidden
downstream cost of screening.
Some have raised questions about the policy of studying every person with a
small adenoma found at screening sigmoidoscopy * RF 12,18 * and the
issue remains unresolved. While policies for surveillance have been widely
neglected by the authoritative policymaking organizations that have
recommended screening, the approach to surveillance is likely to receive
long-overdue attention in the coming years. Rational decisions about
surveillance practice can be made on the basis of polyp size and histologic
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characteristics, which are related to the expected prognosis of persons who
have had an adenomatous colon polyp.
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-AN- 931840 -TI- Geriatric Medicine. -AU- Carol Hutner Winograd,
MD Meghan B. Gerety, MD
Physicians are increasingly aware of the importance of common geriatric
conditions, such as symptomatic urinary tract outlet obstruction, falls, and
multiple drug use. Clinical experience and recent data now substantiate that
multifactorial treatment can help patients with prostatism and falls and can
reduce inappropriate drug use. Prostatic hyperplasia is often the underlying
cause of symptomatic outlet obstruction, nocturia, frequency, and occasional
urinary incontinence, but the association between digital examination,
voiding symptoms, and urodynamic measures of outlet obstruction is weak.
Moreover, symptoms and signs classically considered obstructive, eg,
increased postvoid residual and straining to void, can also result from a
weak detrusor muscle. Controversy exists about treatment, in part because
new medical therapies can improve symptoms.
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Surgical resection, until recently the mainstay of treatment, focuses on
relieving mechanical obstruction. Although 70% to 90% of patients
experience reduction in symptoms after surgery, the quality of life may
improve most for patients with severe symptoms. Transurethral surgery for
benign prostatic hyperplasia carries some risk of mortality (0.2%) and
substantial morbidity (7% intraoperative and 18% postoperative), which is
even higher (23% postoperative complication rate) in patients older than 80
years. The long-term complications of the traditional surgical approach
include urethral strictures, bladder neck contractures, continued or recurrent
bladder outlet obstruction, impotence, and incontinence. In addition, up to
20% of men develop symptoms leading to a second operation within 8 years
after surgery. Newer surgical techniques, such as transurethral incision of
the prostate and insertion of urethral stents have been used; these, like
prostatectomy in some cases, can be performed with the patient under local
anesthesia. These procedures may decrease morbidity, but their long-term
efficacy remains unknown.
Recently, medical therapies have been advocated for patients with benign
prostatic hyperplasia. The (alpha)-adrenergic blocking agents, eg, terazosin
and prazosin, relieve the dynamic component of obstruction by decreasing
the tone of the smooth muscle in the fibromuscular stroma of the prostatic
adenoma and in the prostatic capsule. At doses similar to or lower than those
used to treat hypertension, these drugs relax smooth muscle, decrease outlet
pressure, and provide symptomatic relief for most patients. However, their
long-term efficacy is uncertain because prostatic volume is not decreased
and the hyperplastic process may continue.
A second medical approach, hormonal manipulation, mitigates the
development of hyperplasia by preventing the conversion of testosterone to
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its tissue active form, dihydrotestosterone, by inhibiting the enzyme 5(alpha)-reductase. Controlled trials with finasteride, a 5-(alpha)-reductase
inhibitor, suggest that it has a modest effect on prostatic volume, urinary
flow rate, and symptoms. However, patients receiving the drug had a
significantly higher incidence of impotence, ejaculation disorders, and
decreased libido. Although most patients did not experience a clinically
significant decrease in symptoms, for those who did, the benefit required
nearly a year to observe. Finasteride has been shown to decrease levels of
prostate-specific antigen, thereby decreasing its utility in screening for
prostatic carcinoma. Because the prostate probably increases in size when
hormonal therapy is discontinued, the drug must be taken indefinitely, with
wholesale costs of $52.50 per month. No data exist on long-term use (either
efficacy or safety).
Newer therapies raise questions about the choice of optimal therapy. The
natural course of benign prostatic hyperplasia suggests that patients may
have waxing and waning symptoms with remissions over time. Only a
modest percentage of patients experience clinically significant increases in
symptoms that require prostatectomy over 5 years. The American Urological
Association guidelines for transurethral prostatic resection best fit younger
persons without substantial comorbid disease. Intractable symptoms of
prostatism, recurrent or persistent urinary tract infections, and related
abnormalities of the renal-urologic system may be indications for surgical
intervention. Patients who prefer surgery and are low-risk candidates should
be offered surgery. However, some indications for surgery, eg, nocturia,
urinary retention, and increased postvoid residual volume, may be transient
when caused by comorbid conditions common in geriatric patients, such as
peripheral edema, fecal impaction, or medication use. Patients with acute
retention can be treated with a drainage catheter to keep the bladder
decompressed until detrusor tone returns. The patient can then be examined
for the possibility of surgery after an adequate voiding trial.
For patients with mild symptoms or those with abnormalities precipitated by
medications, a trial of medical and/or behavioral therapy should be
considered, since such patients are less likely to benefit from surgery.
Patients who refuse surgery are also candidates for these interventions.
Effective behavioral methods include timed voiding and bladder retraining
for urinary frequency, double-voiding (Crede technique) for incomplete
emptying, and instruction for unhurried voiding for treatment of hesitancy
and incomplete emptying. Patients who are poor surgical candidates because
of multiple medical conditions, frailty, or extreme old age may obtain
symptomatic relief from medical therapy or urethral stents or transurethral
incision of the prostate. Patients with orthostasis or systolic hypotension
may not tolerate (alpha)-adrenergic antagonists. Very old men with prostatic
hyperplasia are also likely to have detrusor overactivity (involuntary bladder
contractions) and tenuous potency. They are at higher risk than younger men
for urinary incontinence and impotence (up to 18% and 34%, respectively)
after prostate surgery (when outlet pressure is reduced). Older patients
should undergo cystometry before surgery. If frequent uninhibited
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contractions are documented, patients should be informed that they are at
risk for incontinence after surgery.
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Clinical decisions should be based on both patient choice and clinical
characteristics, eg, severity of symptoms, interference of symptoms with
daily life, fears regarding surgery and cancer, appropriateness for medical or
behavioral therapies, and quality-of-life issues. The long-term benefits and
costs of both medical and surgical therapies must be considered.
Falls and fall-related injuries, a serious source of morbidity and excess
mortality in older persons, represent diagnostic and therapeutic dilemmas for
practicing physicians. Fortunately, recent studies have clarified risk factors
for falls that can be readily identified, and successful interventions are
emerging. Approximately 25% to 30% of community-dwelling people fall
each year. In nursing homes, the fall incidence is 1.6 per resident per year.
Injury serious enough to require medical attention occurs in 5% to 10% of
all falls. One in 20 falls produces a fracture, eg, wrist or hip. About half of
fallers experience multiple falls each year. These "multiple fallers" are at
greatest risk of fall-related injury, with a cumulative annual injury rate of
15% to 30%. Although hospital mortality after hip fracture has recently
declined to as low as 2% to 5%, functional recovery remains poor. Almost
half of all patients with hip fractures enter nursing homes after
hospitalization, one half suffer impairments in basic activities of daily
living, one third are impaired in instrumental activities of daily living, and
only 60% return to baseline ambulatory ability.
In addition to injury, falls significantly affect the quality of life. Half of
fallers suffer from fear of falling, and one third curtail activities because of
fear. Fallers are often encouraged to refrain from activities associated with
falling, such as ambulation and trips outside the home. Even when fallers
seek medical evaluation after injury occurs, physicians may not investigate
the cause, but simply treat the injury. In nursing homes, each fall precipitates
an incident report. Because repeated falls are taken as prima facie evidence
of poor-quality care, nursing home staff commonly restrict the activities of
fallers and may apply mechanical restraints. Multicenter trials are currently
under way to assess the risks and benefits of restraint minimization. Because
of the well-documented hazards of immobilization, misguided fall
management strategies may contribute to fall-associated functional decline,
morbidity, and mortality.
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Remediable risk factors for falls can be evaluated during a medical
encounter and need not pose an unacceptable burden on the practicing
physician. Drugs, among the most potent risk factors, are perhaps the easiest
to change. Falls are linked both to the number of medications taken and to
psychoactive drugs, especially sedative hypnotics. Long-acting benzodiazepines and neuroleptics increase the risk of hip fracture. * RF 6,9 *
Neuromuscular deficits contributing to falls can be discovered during a
simple, performance-oriented mobility assessment. This assessment
standardizes observations made by the physician as the patient moves from
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the waiting room to the examining room. Difficulty arising from a chair,
lower-extremity weakness, swaying while in a normal stance with eyes
closed, short steps, slow gait speed, and foot problems are all easily
observed predictors of falls. Recent studies indicate that improving lowerextremity strength, balance, and aerobic capacity should be part of a fall
prevention program. Weight training programs significantly improve lowerextremity strength, even for nonagenarians in nursing homes. Aerobic
exercise programs have been successful in institutional, community, and inhome settings. Promising studies employing balance training are now under
way. In a successful study to prevent hip fractures, Danish researchers
placed pads over the greater trochanters of nursing home residents. Hip
fracture risk was reduced by 54% for subjects with pads. Fractures in the
pad group all occurred when the pads were removed.
The results of two multiple risk factor intervention programs point out the
benefits of multifactorial, interdisciplinary fall assessment and offer hope of
reducing fall risk. In one nursing home study, all residents who fell received
a comprehensive assessment to identify fall risk factors. Results of the
assessment and a prioritized list of recommendations were provided to the
patients' primary care physicians. The most common recommendations were
rehabilitation to improve neuromuscular deficits, drug withdrawal, and
environmental modifications. More than 50% of all recommendations were
implemented, and subjects experienced substantial reductions (48%) in
hospitalization lasting over 2 years. In a study to reduce fall risk factors in
community dwellers after a comprehensive assessment, home modifications,
fall-related behavior changes, and exercises to improve neuromuscular
deficits were prescribed. Compliance with interventions was high (78% for
exercise interventions and 85% for behavioral changes). Preliminary results
show that falls were reduced in the intervention group.
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35
On a per capita basis, medication expenditures exceed all other out-ofpocket expenses for health care by Medicare recipients. Adverse drug
reactions may cause up to 10% of all hospital admissions. Gastrointestinal
tract ulcers and bleeding, falls, hip fractures, confusion, azotemia, and
depression have all been linked to drug toxic effects in older persons.
Surprisingly, age per se contributes relatively little to the risk of adverse
drug events. More important are the number of medications, the burden of
chronic disease, and prescribing without adjustment for age- or diseaseassociated changes in drug handling or drug response.
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Recently multidisciplinary, pragmatic studies have successfully improved
inappropriate prescribing and multiple drug use. Psychoactive drugs can be
safely discontinued in many elderly patients without worsening of behavior
or recurrence of anxiety. In a randomized trial to decrease the use of
psychoactive medications in nursing homes, a multidisciplinary educational
program was directed at nursing assistants, nurses, and physicians. This
team approach included face-to-face educational sessions about the benefits
and risks of psychoactive drug therapy with all disciplines, step-by-step
suggestions for medication reduction, and instructions for specific
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behavioral techniques to use in place of medication, eg, reassurance,
distraction, and stimulation. Antipsychotic drugs were discontinued and less
frequently prescribed. The decrease in antipsychotic drugs was not
accompanied by any increase in disruptive behavior or anxiety. In fact,
subjects whose drugs were discontinued were less likely than controls to
experience cognitive decline. Equally important, staff stress measures did
not increase. A recent retrospective study of adverse drug events in nursing
homes demonstrated that physician-pharmacist teams working together can
successfully discontinue apparently unnecessary drugs without posing
serious risk. Overall, 60% of medication discontinuations were successful
and did not require reinstitution. Histamine receptor blockers, such as
ranitidine and cimetidine, nonsteroidal anti-inflammatory agents, and oral
hypoglycemics, were the least likely to require reinstitution, while diuretics,
antihypertensives, and antianginals were often restarted. Most important, the
risks of drug discontinuation were rarely life threatening. Adverse events
that followed drug discontinuation often required a physician's attention, but
none required hospitalization and no deaths occurred.
Results from these nursing home settings can likely be generalized to
outpatient settings. We recommend that each patient's drug regimen be
reviewed at each physician visit. All drugs without a convincing indication
should be considered for discontinuation. Physicians should prioritize
medications and discontinue them one at a time. Outpatient or telephone
monitoring can detect adverse effects or relapse of the condition for which
the drug was prescribed. Steady progress is being made in understanding and
treating such problems as symptomatic outlet obstruction, falls, and multiple
drug use that previously seemed hopelessly complex. Practical solutions
feasible to implement in clinical practice are now being identified.
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-AN- 931841 -TI- Hematology. -AU- Kenneth B. Miller, MD David P.
Schenkein, MD
5
The application of recent advances in protein biochemistry and molecular
and cellular biology continues to dominate the field of hematology. These
advances in basic and applied research have led to new understandings of
disease processes, diagnostic studies, and a new generation of therapeutics.
The clinical application of these new technologies has introduced novel
approaches to treatment and diagnosis of many hematologic disorders.
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Acute promyelocytic leukemia accounts for approximately 10% to 15% of
all patients with acute leukemia. It is characterized by a unique and
diagnostic cytogenetic marker involving chromosomes 15 and 17 t(15;17).
The chromosome break point on chromosome 17 has been mapped to the
site of the retinoic acid (alpha)-receptor. The retinoic acid receptor is a
member of a family of steroid hormone nuclear receptors that are important
in the regulation and control of normal and malignant cellular differentiation
and proliferation. In acute promyelocytic leukemia, the cytogenetic
translocation results in a fusion of the retinoic acid (alpha)-gene on
chromosome 17 to a region from chromosome 15 referred to as PML (for
"promyelocytic leukemia"). The translocation encodes for a novel DNA
binding protein that results in the expression of an abnormal messenger
RNA transcript for the retinoic acid (alpha)-receptor and confers a unique
therapeutic sensitivity to one of its ligands, all-trans-retinoic acid (a vitamin
A derivative). This abnormal PML-retinoic acid (alpha)-receptor fusion
protein also appears to block myeloid differentiation. The abnormal receptor
is the target of all-trans-retinoic acid treatment. Treatment of patients with
acute promyelocytic leukemia with all-trans-retinoic acid results in
differentiation of the leukemic cells, with greater than 85% of patients
attaining a complete remission. Moreover, unlike standard induction
therapy, treatment with oral all-trans-retinoic acid is not associated with
bone marrow hypoplasia and the usual complications of cytotoxic
chemotherapy. All-trans-retinoic acid induces leukemic cells to replicate and
differentiate into cells capable of undergoing normal senescence and cell
death.
The retinoids and other nuclear receptors have a broad spectrum of biologic
activity and may be useful therapeutic agents in a number of malignant and
nonmalignant disorders. This approach of targeting therapy to an underlying
genetic abnormality is a model for the development of other agents that can
induce cellular differentiation in other leukemia and malignant disorders.
Clinical trials are presently under way to define further the role of all-transretinoic acid in acute promyelocytic leukemia and other malignant disorders.
Allogenic bone marrow transplantation is effective therapy for many
malignant and genetic disorders. However, the lack of available HLAmatched family donors has limited its use. The National Bone Marrow
Transplant Registry has recruited more than 800000 potential donors to
attempt to meet this need. To date, approximately 1600 transplants from
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HLA-matched unrelated donors have been performed. The National Bone
Marrow Transplant Program continues to expand its activities to coordinate
foreign registries and recruit minorities. Even so, a suitable donor can be
found for only about 20% of the potential transplant candidates. The use of
unrelated donors is also associated with serious side effects, including
severe graft-vs-host disease, graft failure, and opportunistic infections. The
introduction of new HLA typing techniques based on DNA polymorphisms
offers the potential of refining donor compatibility, which may result in a
decrease in the morbidity and mortality associated with unrelated
transplants. These molecular techniques have the potential to expand the use
of allogeneic bone marrow transplantation. In addition, alternate sources for
stem cells are being sought. Umbilical and placental blood can provide stem
cells for allogeneic transplants. Prenatal HLA typing has made it possible to
ascertain if a fetus is HLA identical to an affected family member, and some
transplants have been performed with umbilical cord blood when sufficient
cells were obtained for hematopoietic reconstitution. The use of cord blood
as a source of stem cells may dramatically increase the availability of
allogeneic transplants.
It is ironic that as we search for a better understanding of the mechanisms
behind the proliferative nature of malignant cells, the discovery of the
proteins involved in cell death have excited researchers in the past year.
Most hematopoietic cells are short-lived and die a very specific and
programmed cell death. This active cellular "suicide," known as apoptosis,
is characterized by distinct morphologic changes. These changes include
cytoplasmic blebbing, nuclear condensation, and DNA fragmentation in a
nucleosomelike pattern. This fragmentation results from the release of
nucleases within the cell and is pathognomonic for an apoptotic death. The
cellular programs that control cell death may be as important as those for
cell growth and may provide an additional mechanism of cell regulation.
Although a host of proteins are likely to participate in the control of
apoptosis, one protein that appears to play a pivotal role is coded for by the
bcl-2 gene. The bcl-2 gene was first isolated from the breakpoint of the
translocation of chromosome 14 and 18, which is found in more than 80%
of the follicular non-Hodgkin's lymphomas. In these lymphomas, the bcl-2
gene from chromosome 18 is inserted into the same reading frame as the
gene for the immunoglobulin heavy chain on chromosome 14, resulting in
an overexpression and dysregulation of the bcl-2 gene. Unlike other wellknown oncogenes, bcl-2 appears to exert its oncogenic effect by preventing
cell death rather than by the more conventional proliferative mechanisms. *
RF 12,13 * When the bcl-2 gene is overexpressed in hematopoietic cell lines
(lymphoid or myeloid), apoptosis is downregulated, resulting in prolonged
cell survival without evidence of cell proliferation. The cells appear to
survive outside the cell cycle in the Go * state. These aberrantly long-lived
lymphoid cells are likely to play a role in the pathogenesis of non-Hodgkin's
lymphoma.
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In addition to the more obvious role that bcl-2 dysregulation and the
downregulation of apoptosis plays in the pathogenesis of non-Hodgkin's
lymphoma, there are other important cellular processes in which apoptosis
and bcl-2 are involved. Exciting to the hematologist/oncologist is the
demonstration that bcl-2 is involved in tumor cell resistance to
chemotherapy and that certain chemotherapeutic agents kill cells by
inducing apoptosis. Two chemotherapeutic agents, fludarabine and 2-CDA,
which demonstrate activity against several of the low-grade
lymphoproliferative syndromes (chronic lymphocytic leukemia, hairy cell
leukemia, and non-Hodgkin's lymphoma), appear to induce apoptosis in
susceptible cells. Lymphocytes isolated from patients with chronic
lymphocytic leukemia demonstrate the characteristic features of apoptotic
death on exposure to physiologic concentrations of these drugs. In an
intriguing clinical correlation, lymphocytes from patients with early-stage
disease who still retain chemoresponsive disease in vivo exhibited greater
fludarabine- and 2-CDA-induced apoptosis in vitro than their late-stage
refractory counterparts. It is still unclear if the sole mechanism of action of
these agents is induction of apoptotic cell death.
The overexpression of the bcl-2 gene may also be one factor in the
development of drug resistance, as cells overexpressing bcl-2 are resistant to
many chemotherapeutic drugs in vitro. In keeping with models of bcl-2
dysregulation, drug-resistant cells expressing bcl-2 survive in the G0 * state
without evidence of proliferation. The overexpression of bcl-2 in certain
low-grade lymphomas may explain the frequent occurrence of drug
resistance and relapse.
Our understanding of the regulation of cell numbers in normal or malignant
processes must now take into consideration a complex equilibrium between
the control of cell proliferation and cell death. Studies of the control of
apoptosis and the dysregulation of the bcl-2 gene have provided a window
into the pathophysiology of both normal and malignant cell programs and
will likely lead to an understanding of the mechanism of action and the
clinical limitation of certain chemotherapeutic agents and the development
of new agents that are useful in the treatment of cancer.
-AN- 931829 -TI- Cardiovascular Disease. -AU- Joel M. Gore, MD
James E. Dalen, MD
40
Major advances in the treatment of cardiac diseases continue at a rapid rate.
Clinicians caring for patients with heart disease are bombarded with new
and often differing treatment options.
45
Intravenous thrombolytic therapy has led to a dramatic improvement in the
outlook for patients with acute myocardial infarction (MI). However,
reocclusion of the infarct-related artery occurs in some patients, leading to
increased morbidity and mortality. Early trials of routine angioplasty
immediately following thrombolytic therapy failed to show benefit
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compared with a more conservative approach in which angioplasty was only
performed as clinically indicated.
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Three studies published at the same time in the same journal * RF 1-3 *
have pointed the pendulum back toward immediate angioplasty. In these
prospective randomized trials, subjects with evolving acute MI either
underwent immediate percutaneous transluminal coronary angioplasty
(PTCA) or received intravenous thrombolytic therapy within 12 to 24 hours
of onset of chest pain, followed by 2 to 5 days of intravenous heparin
therapy and conservative management. Although immediate angioplasty was
no more effective than thrombolytic therapy in preserving myocardium, it
was more effective in restoring patency and preventing reocclusion of the
infarct-related artery. Furthermore, patients who underwent PTCA had a
shorter hospital stay, lower follow-up costs (but similar in-hospital costs),
and fewer readmissions than those who received thrombolytic therapy.
Patients treated with immediate PTCA had a lower incidence of recurrent
ischemia, reinfarction, and death than those receiving thrombolytic therapy.
Should PTCA now be the standard of care for patients with evolving acute
MI? For a minority of patients, the answer is definitely yes. This assumes
that PTCA can be performed promptly and skillfully. Immediate PTCA
should be considered for patients with contraindications to thrombolytic
therapy and in patients in cardiogenic shock or with sustained hypotension.
However, immediate PTCA for acute MI will not achieve widespread use
because of the limited availability of the procedure. Only 18% of hospitals
in the United States can perform PTCA, and even fewer can do it on an
emergency basis. In contrast, immediate intravenous thrombolytic therapy is
widely available and clearly beneficial acute MI patients.
Over the past several years, the number of patients undergoing PTCA has
approached the number undergoing coronary artery bypass graft surgery
(CABG). There are advantages and disadvantages to both PTCA and
CABG, and debate has continued as to which procedure provides optimal
treatment for patients with multiple vessel disease. Several trials are now
under way in the United States and in Europe. Two recent articles reported
preliminary results. In the Randomized Intervention Treatment of Angina
(RITA) trial, which compared coronary angioplasty with CABG surgery,
follow-up at 2.5 years for 1011 patients with unstable angina or severe
angina randomized to PTCA or CABG revealed no difference in the
principal end point--death or myocardial infarction. However, relief from
anginal symptoms was unequivocally better among CABG patients.
Recovery time after CABG was longer than after PTCA.
A study at Emory University prospectively compared PTCA and CABG in
patients with two-vessel coronary artery disease. Surgical patients (454)
were older and had more concomitant illnesses than PTCA patients (415) in
this nonrandomized study. Complete revascularization was achieved most
often in surgical patients. No PTCA patients died, compared with 1.1% of
surgical patients. Five-year survival was 93% in PTCA patients and 89% in
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surgical patients (P=.11). Additional revascularization procedures were
much more frequent in the PTCA group (43% at 5 years) than in the surgical
group (7% at 5 years; P less than .0001).
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Carotid endarterectomy has been proposed as a stroke-preventing measure
and used with increasing enthusiasm. Despite its widespread use, the
efficacy of this procedure in patients with asymptomatic carotid stenosis has
not been confirmed in randomized trials. A multicenter clinical trial was
conducted in 11 Veterans Affairs medical centers to determine the effect of
carotid endarterectomy on the combined incidence of transient ischemic
attack, transient monocular blindness, and stroke. In this trial, 444 men with
greater than 50% reduction in arterial luminal diameter were randomly
assigned to medical treatment or carotid endarterectomy groups. Surgery
reduced the overall incidence of ipsilateral neurological symptoms.
However, no significant influence of surgery on the combined incidence of
stroke and death was shown. Based on available evidence, endarterectomy
does not benefit patients with asymptomatic stenosis of the carotid artery.
This applies to patients with the most marked stenosis and to those for
whom other major surgical procedures are planned.
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Empirical antiarrhythmic drug therapy for the treatment of sustained
ventricular tachycardia and ventricular fibrillation has a low success rate.
The selection of drug treatment has centered on two methods to predict
efficacy:
electrophysiological
study
(EPS)
and
ambulatory
electrocardiographic monitoring (using a Holter monitor). The
Electrophysiological Study Versus Electrocardiographic Monitoring
(ESVEM) trial was a multicenter randomized clinical study designed to
compare the accuracy of prediction of antiarrhythmic drug efficacy made by
EPS vs Holter monitoring combined with exercise testing. Four hundred
eighty-six patients were randomized. Accurate prediction of drug efficacy
was found in 45% of the EPS-guided therapy group vs 77% in the Holter
monitor-guided group. In the Holter monitor group, left ventricular ejection
fraction was the lone univariate correlate of efficacy. Multivariate analysis
selected assessment by Holter monitor and higher left ventricular ejection
fraction as independent predictors of drug efficacy. The duration of drug
testing was considerably shorter for the Holter monitoring method. The
results of this trial underscore the difficulty confronting the clinician treating
patients with malignant ventricular arrhythmias. Implanted defibrillators
would appear to have the highest efficacy in preventing sudden cardiac
death and may replace antiarrhythmic drug therapy for the majority of highrisk patients.
Screening for and treatment of high blood cholesterol levels continues to be
a high priority for primary care physicians as well as cardiologists. The
principal goal of cholesterol level screening and treatment has traditionally
been the primary prevention of coronary heart disease. Given the high cost
(and high potential benefits) of this effort, there has been extensive
discussion with regard to the appropriate population to be screened and
treated. The original recommendation of the National Cholesterol Education
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Program was that all Americans 20 years of age or older should be screened
and treated when appropriate. In most cases, treatment was expected to be
dietary intervention. However, Ramsay et al, in a review of 16 published
controlled dietary intervention trials, reported some disappointing findings.
They reported that the response to the Step I diet in free-living subjects was
minimal. In patients with elevated cholesterol levels, the average decrease in
cholesterol was 2%. Ramsay et al concluded that these reductions were too
small to be of value in the clinical management of these patients. These
findings lend further evidence to the probability that many, or most, patients
found to have significant hypercholesterolemia will require lipid-lowering
drugs. Given the enormous expense of lifelong treatment with these drugs,
the appropriate target population for screening and treatment must be
reexamined.
LaRosa and Cleeman pointed out that the population group in which the
efficacy of lipid lowering is most evident comprises those individuals with
established coronary heart disease. This includes patients with a history of
MI and those who have undergone CABG or PTCA. Yet, only one third of
patients with established coronary artery disease and elevated cholesterol are
undergoing dietary or drug treatment to lower cholesterol levels. Hulley et al
concluded that cholesterol intervention in low-risk adults is not costeffective, and they are not convinced that this preventive intervention does
more good than harm. They recommend that screening and treatment in
young adults should be limited to those with known coronary heart disease,
or those with other unusual factors placing them at high short-term risk. The
debate over when to screen for and treat increased cholesterol levels will
continue.
Five randomized clinical trials have documented the efficacy and safety of
anticoagulation treatment to prevent stroke associated with atrial fibrillation
in patients without mitral valve disease. Compared with control groups, the
reduction in stroke was at least 60%, from 5% per year to 2% per year. The
annual incidence of serious hemorrhage in these studies was approximately
1.5% in the anticoagulant group, compared with approximately 0.5% in the
control group. Given these findings, the Third American College of Chest
Physicians Consensus Conference on Antithrombotic Therapy
recommended that all patients with atrial fibrillation should be considered
for long-term warfarin therapy unless they are under the age of 60 years and
have no evidence of cardiovascular disease or thyrotoxicosis.
Implementation of this recommendation should result in a major reduction
in the incidence of embolic stroke. Studies are still in progress to determine
whether a subset of patients with atrial fibrillation should be treated with
aspirin rather than warfarin.
The Third American College of Chest Physicians Consensus Conference on
Antithrombotic Therapy also made important recommendations regarding
the monitoring and intensity of warfarin treatment. Given the wide range in
the sensitivity of thromboplastin reagents used in North America, they
concluded that the prothrombin time ratio (patient's prothrombin time
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divided by the control prothrombin time) is no longer a safe or acceptable
parameter for monitoring warfarin therapy. They recommended that the
international normalized ratio (INR) be used. The INR is calculated by
raising the observed prothrombin time ratio to the power of the international
sensitivity index of the thromboplastin reagent that is used. The calculated
INR will represent the prothrombin time ratio that would be obtained if the
standard Manchester thromboplastin reagent (which has an international
sensitivity index of 1.0) were used. Use of this corrected prothrombin ratio
will ensure that prothrombin ratios will be comparable from day to day and
laboratory to laboratory throughout the world.
The recommended therapeutic range for oral anticoagulation therapy for all
indications except for patients with mechanical heart valves is an INR of 2.0
to 3.0. Given the high risk of thromboembolism in patients with mechanical
heart valves, an INR of 2.5 to 3.5 is recommended. The use of these new
guidelines will increase the efficacy and safety of long-term anticoagulation
therapy with warfarin.
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-AN- 931843 -TI- Infectious Diseases. -AU- Mark Y. Stoeckle, MD R.
Gordon Douglas, Jr, MD
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The resurgence of tuberculosis (TB) in the United States and the spread of
multidrug-resistant strains of TB (MDR-TB) are serious public health
threats. As recently as 1989 it seemed possible to plan for the elimination of
TB from the United States. Decades of successful control efforts had
resulted in a steady decline in the incidence of TB, from more than 84000
cases in 1953 to 22000 in 1984. However, this favorable trend ended in
1985: from 1985 to 1991, there were 39000 more cases than expected, and
the annual case rate is increasing. In response to the current epidemic, major
efforts in TB infection control and patient care have been initiated.
The human immunodeficiency virus (HIV) epidemic seems to be a
significant factor in the recent increase in TB cases. The risk of active TB
among persons with HIV is exceedingly high. For those with latent
tuberculous infection, 7% to 10% per year develop active TB as compared
with a 5% to 10% lifetime risk in healthy individuals. The risk for active
disease is even higher among HIV-infected persons who are newly exposed
to TB (estimated increased risk, 170-fold). Increased susceptibility of HIVpositive persons has contributed to outbreaks in institutional settings,
including prisons, hospitals, and residential facilities for drug treatment. In
two such outbreaks, 40% of exposed HIV-positive individuals developed
active TB, usually within a few months.
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One of the most alarming features of the current epidemic is an
unprecedented increase in the prevalence of MDR-TB. Some strains of
MDR-TB are resistant to all anti-TB medications. The MDR-TB strains
seriously hamper infection control strategies, which depend on interrupting
transmission by antibiotic treatment of infected persons and contacts.
Twelve institutional outbreaks of MDR-TB have been reported from
hospitals and correctional facilities in New York City, NY, Miami, Fla, and
San Francisco, Calif. * RF 1-4 * Transmission to medical and other
personnel has occurred during these outbreaks, with cases of active disease
and at least five deaths. The full extent of MDR-TB in the United States is
unknown since drug sensitivity data are not routinely obtained. In New York
City in 1991, 33% of TB strains were resistant to at least one drug, and 15%
were resistant to both isoniazid and rifampin, the two most effective agents
for treatment and prophylaxis of TB.
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Recent experience demonstrates that the current epidemic can be
successfully managed by adherence to basic principles of TB care: prompt
diagnosis of persons with active TB, isolation of infectious persons, and
institution and maintenance of appropriate antimicrobial therapy. Outbreaks
in institutional settings have been traced to correctable lapses, particularly
delays in diagnosis, failure to isolate infectious persons, and inappropriate
antimicrobial therapy. In New York City, where MDR-TB is common, new
patients are initially treated with four medications: isoniazid, rifampin,
ethambutol hydrochloride, and pyrazinamide. In patients who were treated
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previously, ie, in those with treatment failure or TB recurrence after initial
response, a regimen that includes at least two new drugs is used. These
regimens, combined with proper attention to isolation of persons with active
TB, have enabled successful control of nosocomial outbreaks. Major
challenges for the future are to ensure that patients complete the course of
treatment through directly observed therapy and to define effective regimens
for treatment and prophylaxis of persons with MDR-TB.
The case definition for the acquired immunodeficiency syndrome (AIDS)
has been expanded. New diagnostic criteria for HIV-positive persons
include a CD4+ T-cell count less than 0.20x10(sup 9)/L (200/(mu)L) or
CD4/CD8 ratio less than 0.14, pulmonary TB, recurrent pneumonia (two or
more episodes in a 1-year period), and invasive cervical cancer. The new
criteria underscore the importance of these conditions as manifestations of
advanced immunosuppression due to HIV and are expected to improve case
finding by identification of previously unsuspected HIV infection.
New antiviral agents offer the possibility of improved survival in patients
with AIDS. It is well recognized that drug-resistant strains of HIV emerge in
most patients after 6 to 12 months of treatment with zidovudine (AZT), but
the clinical significance of this has been uncertain. Recent studies with
didanosine (DDI) and zalcitabine (DDC) suggest that such drug-resistant
strains play an important role in AIDS progression. Like zidovudine,
didanosine and zalcitabine are nucleoside analogues that inhibit retroviral
reverse transcriptase; however, zidovudine-resistant strains usually do not
exhibit cross-resistance to didanosine or zalcitabine. In studies of patients
previously treated with zidovudine, there were fewer AIDS-related events in
patients who were switched to didanosine or zalcitabine than in those who
were maintained on zidovudine. * RF 7,8 * Current recommendations are
therefore to institute didanosine or zalcitabine in patients who are intolerant
of zidovudine or who exhibit disease progression while receiving therapy.
Didanosine and zalcitabine are associated with pancreatitis and peripheral
neuropathy; routine monitoring of amylase levels is recommended.
New infectious agents of human disease continue to be identified. Bacillary
angiomatosis is a disease that is characterized by multiple erythematous
cutaneous and subcutaneous nodules and primarily is found in HIV-infected
patients. Histological findings show capillary proliferation with large
numbers of interstitial bacilli, best demonstrated by Warthin-Starry stain.
Proliferative vascular lesions may also appear in liver (bacillary peliosis),
spleen, bone, and endobronchial sites. It recently has been shown that
bacillary angiomatosis is caused by fastidious, gram-negative, rickettsialike
organisms, either Rochalimaea henselae or Rochalimaea quintana. * RF 9,10
* The R quintana organism was originally identified as the agent of trench
fever, a louse-borne relapsing febrile illness that was first widely recognized
during World War I in Europe among troops engaged in trench warfare.
Bacillary angiomatosis appears to be a zoonosis since it is associated with
recent traumatic exposure to cats. The relationship of bacillary angiomatosis
to cat-scratch disease has not been determined. Bacillary angiomatosis is
23
reported in other immunocompromised states, including renal
transplantation and chemotherapy for leukemia. Rochalimaea species are
sensitive to many antibiotics; patients have been successfully treated with
erythromycin, doxycycline, and tetracycline.
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A molecular genetic approach was used to characterize the bacillus
associated with Whipple's disease. The presence of large numbers of rodshaped organisms in affected tissues was noted in Whipple's original report
in 1907, but all attempts to culture the organism have been unsuccessful.
Using broad-range primers, a unique bacterial ribosomal RNA sequence was
amplified from patient tissues. Sequence analysis indicates that the organism
is a novel gram-positive actinomycete distantly related to Nocardia and
Mycobacterium organisms. These techniques may prove useful in
identifying other infectious agents that are difficult to culture.
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Nosocomial infections caused by antibiotic-resistant bacteria pose
increasingly significant problems in hospitals in the United States and
around the world. Of particular concern is the spread of multiresistant
enterococci. Enterococci are the third most common cause of nosocomial
infection in the United States, including endocarditis and wound, urinary
tract, intra-abdominal, pelvic, and prosthetic device infections. Enterococci
are inherently resistant to many antibiotics but were successfully treated
with synergistic combinations of a (beta)-lactam, usually ampicillin, and an
aminoglycoside. Vancomycin hydrochloride has been effective as a secondline agent. Ampicillin resistance via (beta)-lactamase production and highlevel aminoglycoside resistance has become frequent. These strains seem to
be as pathogenic as naive strains. Vancomycin resistance in enterococci was
first described in France in 1988 and is now present in many US hospitals,
often in combination with (beta)-lactam and aminoglycoside resistance. No
effective treatment regimen has been devised for multiresistant enterococci.
Enterococci are readily transmitted from patient to patient in the absence of
strict attention to hygienic procedures: one outbreak was traced to a
contaminated rectal thermometer. These developments indicate a continued
need for synthesis of new agents with improved antimicrobial activity and
suggest that more attention needs to be paid to programs to reduce antibiotic
use, thereby decreasing the selective pressure for antibiotic resistance.
-AN- 931834 -TI- Emergency Medicine. -AU- Louis S. Binder, MD
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Research in basic and advanced cardiac life support (ACLS) continues to be
one of the most important areas in emergency medicine for investigation and
clinical progress. Preliminary studies suggested increased myocardial and
cerebral blood flow, an improved balance between myocardial oxygen
supply and demand, and improved rates of survival when larger doses (0.2
mg/kg) of epinephrine, compared with standard doses (0.01 to 0.02 mg/kg),
were used in studies of cardiac arrest. Several case reports of survival after
administration of high-dose epinephrine (HDE) have appeared in the
literature. In 1992, three rigorous, large-scale clinical trials comparing
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survival from cardiac arrest managed with HDE vs standard-dose
epinephrine (SDE) were reported.
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Stiell et al reported the outcomes of 650 patients who were randomized to
receive either HDE (7 mg) or SDE (1 mg) for up to five doses while
undergoing otherwise standard ACLS protocols in the resuscitation of
cardiac arrest (ventricular fibrillation, electromechanical dissociation, or
asystole). No significant differences were found between groups for survival
to 1 hour, survival to hospital discharge, neurologically intact survival, or
Mini-Mental State Examination scores (reflecting higher-level intellectual
functioning). Approximately half of these patients arrested in the prehospital
setting, with prolonged arrest times prior to institution of the study protocol.
Brown et al performed a study on 1280 prehospital patients who were
randomized to receive an initial dose of either HDE (0.2 mg/kg) vs SDE
(0.02 mg/kg) while undergoing standard ACLS protocols. Overall, no
significant differences were found in the number of patients achieving return
of spontaneous circulation, admission to the hospital, survival to hospital
discharge, or neurologically intact survival. However, in patients receiving
epinephrine within 10 minutes of collapse, HDE survival was 23%
compared with SDE survival of 11%. Callaham et al compared HDE, SDE,
and norepinephrine for the first three epinephrine doses administered to 816
prehospital patients undergoing ACLS and found a higher rate of return of
spontaneous circulation (13% vs 8%; P=.01) and a higher hospital
admission rate (18% vs 10%; P=.02) with HDE, but survival to discharge
did not differ between groups.
The initial promise shown in animal and human trials for HDE in cardiac
arrest was not validated in these initial large-scale clinical trials of HDE, but
benefits to subsets of cardiac arrest patients (perhaps those with shorter
response times) may yet be proven. Meanwhile, the updated "Guidelines for
Cardiopulmonary Resuscitation and Emergency Cardiac Care" from the
Emergency Cardiac Care Committee of the American Heart Association,
representing the latest consensus of emerging knowledge in the area of basic
and advanced cardiac life support, suggested that HDE may be used if SDE
has been administered but has not been effective.
The early and accurate diagnosis of acute myocardial infarction (AMI) in the
emergency department (ED) setting continues to be an important objective
to reduce subsequent morbidity and mortality, to preserve viable
myocardium via noninvasive and invasive means (emergent
revascularization surgery, coronary angioplasty, and thrombolytic therapy),
and to contain costs for patients who do not require intensive care support.
Since many patients with AMI may present atypically, and up to 50% may
initially have nondiagnostic electrocardiograms (ECGs), the diagnosis of
AMI is often delayed beyond an interventional time frame. A number of
directions have been undertaken to improve the early and accurate
identification of the patient with AMI, including computerized analysis of
initial ECGs, prehospital 12-lead ECGs, early serial cardiac isoenzyme
determination in the ED, echocardiography, computerized predictive
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instruments and algorithms, radionuclide imaging studies, and magnetic
resonance imaging.
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Gibler et al assessed ED serial creatine phosphokinase (CK)-MB sampling
(at time 0, 1, 2, and 3 hours) in 616 patients presenting with chest pain.
Fifty-five of 69 patients with nondiagnostic ECGs and subsequent AMI had
elevated CK-MB levels within 3 hours of presentation (sensitivity, 79.7%).
Sensitivity was 61 (88.4%) of 69 when ECGs and serial CK-MB
determinations were combined, and the negative predictive value of negative
serial emergency department CK-MB determinations was 96.2%. Hedges et
al compared serial emergency department ECGs with serial emergency
department CK-MB fractions in 261 patients with chest pain and found that
serial ED measurement of CK-MB fractions yielded 92% overall accuracy,
68% sensitivity, 95% specificity, and 96% negative predictive value, all
superior to serial emergency department ECG determinations. Henneman et
al found only a 45% accuracy in AMI detection with the ED application of
thallium 201 myocardial planer imaging and technetium 99m first-pass
radionuclide angiography to 47 ED patients presenting with acute chest pain
and nondiagnostic ECGs. Baxt evaluated the variables that drove the output
of an artificial neural network trained to diagnose AMI. In 716 patients with
acute chest pain, the network yielded a sensitivity of 97% and specificity of
97%; the presence of ECG findings, rales, syncope, jugular venous
distension, response to nitroglycerin, and nausea and vomiting were the
major predictive factors.
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It appears that acute serial emergency department CK-MB determinations,
artificial neural networks and other computerized instruments, and
potentially other diagnostic interventions will help rapidly identify ED
patients with AMI and nondiagnostic ECGs, safely select certain patients
without AMI who can be discharged, facilitate optimal in-hospital
dispositions, and guide acute therapeutic interventions in AMI patients.
Use of HDE in the prehospital setting is emblematic of both an increasing
quality and sophistication of the clinical abilities of emergency medicine
services systems nationally and the advancement of potentially lifesaving
interventions from the ED to the prehospital phase of management. MurphyMacabobby et al studied 115 prehospital patients attended by
nurse/paramedic teams who were endotracheally intubated with the aid of
neuromuscular paralyzing agents. An average of 2 minutes elapsed from
drug administration to intubation; all patients were intubated within three
attempts (86% on the first attempt), and no complications related to
intubation or neuromuscular blockade were found. McCabe et al studied 37
patients who received adenosine before arriving at the hospital. Twenty-six
of these patients were in paroxysmal supraventricular tachycardia and 23
(88%) converted to sinus rhythm; of the 11 other patients (nine with
supraventricular rhythms and two with ventricular tachycardia), none
sustained hemodynamic compromise or other adverse reactions to
adenosine. The prehospital use of adenosine appeared to be safe and
effective in this small trial. Aufderheide et al studied 151 patients with chest
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pain who received 12-lead ECGs before hospitalization to determine how
many were prehospital thrombolytic candidates and to estimate the potential
time saved if field thrombolysis had been initiated. Only eight of the patients
(5.3%) met criteria for prehospital thrombolytic therapy, but 43 to 50
minutes were potentially saved to administration of thrombolytics for these
patients.
The application and breadth of technologically advanced therapies available
on ambulances for prehospital use are relatively recent advances and are
collectively impressive when compared with the "load and go" approach of
10 to 20 years ago in most emergency medicine services systems. We can
expect increasing sophistication in prehospital care in the future, across a
broader array of clinical applications, based on ongoing clinical
investigations.
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A final significant development in emergency medicine to note is the
growing field of illness and injury prevention. Illness/injury surveillance and
prevention methods incorporate traditional public health methods and
involve the collection and assessment of epidemiologic data regarding a
common problem, the development and implementation of interventional
strategies and reassessment of the problem following directed intervention.
Braddock et al performed a retrospective epidemiologic review and cost
profile for motorcycle injuries in Connecticut. Death rates were highest
among 20- to 24-year-old men and unhelmeted motorcyclists (3.4-fold
increased mortality; P=.05). Twenty-two percent of all injuries were head,
neck, and spinal injuries, and mandatory helmet use was estimated to have
been able to prevent 9% of fatalities and save $5.1 million. Baraff et al
studied 129 households (190 children) that contacted a poison center
compared with 136 control households (209 children, matched for telephone
area code and prefix) that did not contact a poison center during the same
period. The annual rates of injuries per child in the poison group was 23.7%
compared with 14.8% in the control group (P=.03), suggesting that
prevention strategies might be targeted toward poison center callers as a
high-risk group.
-AN- 931846 -TI- Neurology. -AU- Robert J. Joynt, MD, PhD
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The changes in the practice of neurology have been dramatic in the past
decade. Physicians graduating over 20 years ago recollect a specialty with
great intellectual challenges but with few therapeutic opportunities. Now
therapy is advancing in many areas, and major trials are providing
information about treatment efficacy, failures, side effects, and
complications. Therapies are based on the fundamental knowledge of the
disease processes learned through the use of new research techniques.
There is now some promise of altering the course of multiple sclerosis by
vaccine therapy, intravenous immunoglobulin, or use of interferon. The
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vaccine is made up of immunogenic fragments of myelin basic protein.
Experimental studies indicate that this vaccination will largely prevent the
induction of allergic encephalomyelitis, a model for multiple sclerosis, in
laboratory animals. Intravenous immunoglobulin has been used for a
number of autoimmune disorders, including chronic inflammatory
demyelinating neuropathy, myasthenia gravis, and inflammatory
myopathies. Recently, in a preliminary study, intravenous immunoglobulin
diminished the number of exacerbations in patients with relapsing-remitting
multiple sclerosis. The use of this agent has been notably free of
complications. However, acute renal failure has occurred in two patients
receiving this therapy. Both of these patients had impaired renal function
prior to treatment, and there was evidence of damage from a high-solute
load in the renal biopsies following treatment. It is important to evaluate the
status of kidney function prior to using intravenous immunoglobulin,
particularly as its use may become more widespread.
Finally, a large multicenter group studied the efficacy of treatment by
interferon (beta)-1b (IFN(beta)) in relapsing-remitting multiple sclerosis.
The study was randomized, double-blind, and placebo-controlled using two
different doses of IFN(beta). They found fewer and less severe exacerbations
and less change on magnetic resonance imaging of the brain in the treated
group. There were very few side effects of the IFN(beta).
Two large multicenter studies have expanded the testing of tacrine, a choline
esterase inhibitor, on for patients with Alzheimer's disease. * RF 6,7 * Both
studies showed some slight value in preserving cognitive abilities, but
disappointingly little change in overall improvement in function. The studies
also showed the side effect of liver dysfunction in 20% to 40% of patients.
Editorial comments on the results of studies to date point out the difficulty
in interpretation of results with provision of proper control groups and
variations in the disease, and the fundamental problem of replacement
therapy as opposed to restorative therapy. Restorative therapy might include
the use of nerve growth factor as a means of maintaining nerve cells
supplying the necessary neurotransmitters for proper neural function. Nerve
growth factor infusion is effective in retaining nerve cell integrity after
transection of axons in experimental animals. Genetic testing in families
with Alzheimer's disease already show genetic heterogeneity, and this may
partially explain the variations in treatment trials.
Trials using human fetal tissue implants for the treatment of Parkinson's
disease have continued. Two patients with Parkinson's disease showed
improvement using new implantation techniques with fresh fetal tissue.
Positron-emission tomography studies in these patients showed increased
uptake of [F]-6-l-fluorodopa in the operated putamen where the implants
were placed. This suggests improved uptake of the tracer in the
dopaminergic system. It is likely that with the lifting of the ban on fetal
tissue implants, we will see increased research activity in the United States
using these techniques. It could also be used in other neurodegenerative
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disorders such as Alzheimer's disease, Huntington's disease, and others
where specific neurotransmitters or trophic factors are absent.
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The long quest to isolate the gene for Huntington's disease has been
accomplished. The gene is somewhat similar to the myotonic dystrophy
gene in being a trinucleotide repeat. The gene for Huntington's disease is on
chromosome 4. Isolation of the gene will allow an accurate identification of
those at risk and raises many complicated ethical issues regarding individual
choice, insurance, and the like. The discovery will also be essential to
developing therapy for this disorder.
Corticosteroids have been a common treatment for optic neuritis. Oral
prednisone is the usually prescribed method. A multicenter randomized,
controlled study using different groups of patients with acute optic neuritis
were treated with: (1) oral prednisone for 14 days, (2) intravenous
methylprednisolone for 3 days followed by oral prednisone for 11 days, and
(3) oral placebo for 14 days. The group receiving intravenous prednisolone
had faster recovery of visual function with better results at 6 months. Those
receiving oral prednisone had no better results than the placebo group and
had a higher rate of new episodes.
An ongoing controversy has been the role of carotid endarterectomy for
patients with asymptomatic carotid stenosis. These patients are normally
identified by the discovery of a bruit during a physical examination. There
has been no benefit from surgical treatment found in previous randomized
clinical trials. A multicenter clinical trial at 11 Veterans Affairs medical
centers studied 444 men with carotid stenosis of over 50% but without
symptoms. Two treatment groups were studied: (1) those who had received
surgical treatment and daily aspirin, and (2) those receiving aspirin only.
The authors found that endarterectomy reduced the number of neurologic
events defined as transient ischemic attacks and transient monocular
blindness, but had no significant influence on stroke and death. In an
editorial comment it was pointed out that other studies have not confirmed
this result and that there is a larger study currently under way looking at this
same issue. The authors suggested that the efficacy of endarterectomy for
the asymptomatic patient was not yet established.
The neuropsychological sequelae of resuscitation on out-of-hospital cardiac
arrest was studied in 155 patients. Nimodopine, a calcium entry blocking
drug, was used in a randomized, double-blind, placebo study. This drug has
previously been used to prevent or modify ischemic infarct after
subarachnoid hemorrhage. Three months after cardiac arrest, 60% of the
patients had moderate to severe cognitive defects, and this decreased to 48%
after 1 year. There were no benefits demonstrated with the use of
nimodopine.
Amyotrophic lateral sclerosis is a progressive degenerative disease affecting
the motor neurons in the brain and spinal cord. There is no treatment and
there is very little understanding of the basic process, although
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autoimmunity has been proposed as a possible cause. A recent study
demonstrating the presence of lymphocytic infiltrates in about two thirds of
cases lends some credence to an autoimmune relationship. Another finding
is the demonstration of defects in glutamate metabolism in patients with
amyotrophic lateral sclerosis. Glutamate, a neurotransmitter, is normally
released under close control with careful regulation of release and re-uptake.
In excess amounts it is an intense excitant of nerve cells and can have toxic
effects. The discovery of the abnormal metabolism suggests a therapeutic
approach via selective blocking by antagonists or protection of the nerve
cells by stabilizing the calcium homeostasis.
Therapy for migraine promises to ameliorate that common and painful
condition. Sumatriptan, a serotonin1 *-like receptor agonist, has shown
promise in reducing or eliminating the pain of migraine. Widespread usage
and clinical trials have helped establish dosage levels. Side effects of the
drug are minimized but chest pain and at least one myocardial infarction
have been reported.
Clearly, neurology has experienced a number of interesting therapeutic
advances based on mechanisms of disease. At long last, the characterization
of the neurological consultation as interesting but not useful is a thing of the
past.
-AN- 931850 -TI- Oncology. -AU- Judith E. Karp, MD Samuel Broder,
MD
Few individuals have had as much influence on our thinking about human
heredity and development as the Austrian monk, Gregor Mendel. When we
teach medical genetics, we are in effect updating Mendel's principles.
According to Mendel, for autosomal genes, a gene is a gene is a gene; that
is, all copies of a given gene are expressed equally. Although most of our
observations regarding patterns of inheritance follow the principles of
mendelian genetics, there is a growing list of discrete areas where
observation diverges from expectation, ie, nonmendelian genetics come into
play. With the advent of sophisticated molecular technology, we can dissect
the origins and patterns of transmission of specific genes, adding an
unprecedented dimension to our understanding of disease inheritance and
the factors that determine net genomic expression. This may have special
relevance for understanding the development of cancer, many forms which
are not inherited in a straightforward manner but rather evolve from a
complex interplay of multiple factors that lead to an imbalance in gene
expression.
Not only can nonmendelian genetics have a major impact on the
predisposition to cancer, but also on predisposition to many other diseases
as well. An individual's risk for developing certain malignant neoplasms
associated with loss of tumor suppressor genes (eg, some childhood cancers
such as Wilms' tumors, rhabdomyosarcoma, osteosarcoma, and
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retinoblastoma) or other disorders (eg, Huntington's chorea or disorders with
more complex inheritance patterns such as diabetes, atopy, and psoriasis)
can be transmitted by the nonmendelian process known as genomic
imprinting. * RF 1,2 * Genomic imprinting is the phenomenon whereby the
expression (or nonexpression) of a gene is determined by the parental origin
of that gene. This process occurs during germ cell maturation, influences
allele-specific expression of a gene (depending on whether the gene is
inherited from the father or the mother), and is presumably due to genespecific differences in DNA methylation. The transcription and thus the
expression of a particular gene is thought to relate, at least in part, to the
level of its DNA methylation. Genes in a methylated state may be inactive,
whereas the same genes in an unmethylated (or hypomethylated) state are
transcriptionally active. This differs from the mendelian concept of
inheritance, which assumes that the paternal and maternal alleles of all genes
are expressed equally.
The basic study of rare syndromes involving genetic and embryogenic
aberrations has repeatedly served as a window through which we can peek
and discover a fundamental principle with broad application to our
understanding of normal and perturbed growth and development. This is
historically true for tumor suppressor genes, which were first discovered to
be defective in patients with retinoblastoma, an exceedingly rare eye tumor
of children. This is also the case for genomic imprinting, where two rare
congenital neurodevelopmental disorders, Prader-Willi syndrome (PWS)
and Angelman syndrome, have provided insights into the contributions to
inheritance made by genomic imprinting. While both disorders are linked to
aberrant genetic material on the long arm of chromosome 15 (15q13), two
distinct clinical syndromes are created due to inheritance of genetic material
solely from either the mother or the father. In PWS, which is characterized
by hypotonia, hypogonadism, short stature, hyperphagia, and obesity, the
15q13 allele is inherited only from the mother due either to deletion of the
father's allele or to inheritance of both alleles from the mother (known as
maternal uniparental disomy). On the other hand, in Angelman syndrome,
which is characterized by severe mental retardation, seizures, ataxia, and
puppetlike limb movements, both 15q13 alleles are inherited from the father
and none from the mother (paternal uniparental disomy). Recent studies
have uncovered a candidate gene for PWS in a mouse model * RF 5-7 *;
this gene, known as Snrpn, encodes a small nuclear RNA-associated protein
N that regulates messenger RNA splicing, is maximally expressed in brain
tissue, and has as its human homologue the gene that maps to the critical
genomic region involved in PWS.
Genomic imprinting may also influence the expression of certain rare
cancer-prone syndromes, such as the Beckwith-Wiedemann syndrome
(BWS), Wilms' tumor, neurofibromatosis, glomus tumors, osteosarcoma,
and perhaps retinoblastoma (both osteosarcoma and retinoblastoma are
related either to structural or functional loss or to mutation of the
retinoblastoma gene). The BWS may occur sporadically or in a familial form
and is characterized by numerous growth abnormalities, such as congenital
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umbilical herniation (examphalos), macroglossia, visceromegaly,
hypoglycemia, and gigantism. This constellation of findings is related to
overexpression of either the insulin or insulinlike growth factor 2 (IGF-2)
gene located on chromosome 11p15.5. The sporadic form of BWS occurs
when two alleles of 11p15.5 are inherited from the father either as a trisomy
(from duplication of the paternal gene locus) with the maternal allele still
present or as a paternal uniparental disomy. * RF 9,10 * The growth
abnormalities may be variably expressed in the sporadic form, with the most
extreme example of variability being hemihypertrophy, where the paternal
uniparental disomy is detectable in some but not all tissues as a result of
somatic mosaicism. The familial form, however, appears to be transmitted
primarily from the mother in an autosomal-dominant pattern. * RF 11-13 *
Of particular interest, the gene for IGF-2 (a gene known to be imprinted in
both humans and mice) is located in the critical region of human
chromosome 11p15.5, which is affected in BWS and is thought to be the
candidate gene for BWS. * RF 8,11-13 *
The BWS may be particularly instructive when it comes to dissecting the
complex interrelationship between genomic imprinting and tumorigenesis.
Both sporadic and familial forms of BWS are associated with a high
incidence of embryonal malignancies, namely Wilms' tumors, adrenocortical
carcinoma, rhabdomyosarcoma, hepatoblastoma, and occasionally
neuroblastoma and pancreatic carcinoma, which (perhaps not surprisingly)
involve the same organs often involved in visceromegaly. Provocatively, the
propensity to develop certain tumors--mainly Wilms' tumors but also
rhabdomyosarcomas--seems greater in cases of paternal uniparental disomy.
This finding suggests that certain types of tumorigenesis in this setting
might relate more to the loss of the maternal allele than to duplication of the
paternal allele and that the maternal allele might express some type of tumor
suppressor activity (suppressing development of Wilms' tumors and perhaps
other BWS-linked tumors as well), * RF 12,14 * while the paternal allele
expresses a predominantly growth-promoting activity, likely due to
overexpression of IGF-2 (and perhaps other genes localizing to the 11p15.5
segment).
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Several malignancies, most notably lymphohematopoietic, are characterized
by specific gene rearrangements and reciprocal chromosomal translocations.
This area provides another example of genomic imprinting. Certain
translocations show specific, nonrandom maternal and paternal origins of
the involved chromosomal segments. Specifically, the Philadelphia
chromosome, which typifies chronic myelogenous leukemia (CML), is
formed from the translocation and recombination of the abl oncogene on
chromosome 9q34 and the breakpoint cluster region (bcr) gene on
chromosome 22q11. It has been known for some time that the abl oncogene
encodes a protein tyrosine kinase that, under normal conditions, regulates
signal transduction pathways, which maintain the balance between cellular
proliferation and differentiation. The bcr gene encodes a phosphoprotein
with two enzymatic functions--one portion functions as a serine/threonine
kinase and one functions to regulate ras oncogene activity (as a guanosine
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triphosphatase [GTPase]-activating protein [GAP] that maintains the p21ras
protein [also a signaling protein] in its inactive state). The CML cells have a
growth and survival advantage over their normal hematopoietic counterparts
that is driven by the dysregulated and constitutively expressed BCR-ABL
fusion protein encoded by the chimeric bcr-abl gene.
Now for the new twist. Recent studies demonstrate that the 9q34 segment
containing abl is derived from the father, while the 22q11 segment
containing bcr is derived from the mother. Thus, the effects of genomic
imprinting are found even in a rather common adult malignancy where there
is no obvious inheritance pattern. It is possible that the apparent
"imprinting" in the case of human bcr and abl genes in CML is acquired at a
somatic level (rather than inherited) as part of the leukemogenic process.
The ability of these genes to undergo specific translocation could also be
influenced by genomic imprinting. In addition, the apparent genomic
imprinting of human abl in the case of CML suggests that there are tissuerelated differences in the net expression of a particular gene, perhaps due to
cell type-specific differences in the methylation state of that gene or in other
factors that could alter its transcription.
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Whatever the mechanism, the parental origin of bcr and abl could, in theory,
influence the net activity of the BCR-ABL fusion protein. Intriguingly,
despite the transcription of sequences from both bcr and abl, the BCR-ABL
protein functions as a tyrosine kinase. Does the predominance of tyrosine
kinase activity (instead of GTPase activity) in some way relate to the
paternal origin of abl? Perhaps the paternal origin confers the dominant
expression of the abl-encoded portion of the fusion protein. If instead the
translocated abl gene was derived from the maternal allele, perhaps it would
fail to encode a tyrosine kinase of sufficient "strength" to be transcribed
constitutively or to dysregulate growth. From another vantage point, if the
bcr gene was paternally derived, perhaps the BCR-ABL protein would have
a net GTPase activity that, in turn, would have a net suppressive effect on
signal transduction and thereby would fail to permit a growth advantage.
These considerations are currently speculative, but they raise similar
questions regarding all translocations, ie, whether the genes involved in such
translocations are genomically imprinted and if the parental origin of the
specific translocated genes might confer (or alternatively quench) the full
phenotypic expression of malignancy.
Finally, can some common cancers result from a reversal of genomic
imprinting, ie, the activation of the wrong maternal or paternal allele, or
perhaps the aberrant activity of modifier genes in stem cells that, in turn,
leads to inappropriate expression of parental-specific alleles?
Hypothetically, certain environmental or physiological factors, eg, steroid
hormones (in particular estrogens and androgens), other growth factors
(inflammatory interleukins), dietary factors (folate, retinoids, oxidants, and
free radicals), or even environmental pollutants, could modulate the
methylation state and therefore the functional state of either a maternally or
paternally derived allele. Such modified genes may have a particular role
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(local or distant) during embryogenesis by enhancing or suppressing the
expression of parental-specific alleles in certain tissues or, in theory, in the
process of malignant transformation.
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Thus, the recent recognition of genomic imprinting in humans has
implications that may revolutionize the understanding of how cancers
develop. These new concepts will need to be absorbed by physicians during
the next decade. The process of inheritance, the delicate balance of paternal
and maternal gene expression in normal development, and the perturbation
of that balance in the process of tumorigenesis are enormously complex, and
we doubt that even Gregor Mendel would argue this point.
-AN- 931852 -TI- Orthopedics. -AU- Bernard F. Morrey, MD
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The greatest energy in orthopedics overall is directed at assessing the risks,
complications, and value of elective surgical procedures, particularly those
that involve artificial implants. Mechanisms of evaluating the effectiveness
of surgical procedures have appeared in increasing numbers in the
orthopedic literature, as they have in other medical specialties.
Anatomically, the spine remains a second focus of basic and clinical
research. While procedures are rapidly evolving on the one hand, increased
questioning of the merits of these procedures and emphasis on patient
selection and the value of nonoperative treatment are being investigated on
the other.
Issues relating to joint replacement arthroplasty continue to dominate the
orthopedic literature. Basic research to better understand the ideal fixation of
joint replacement devices has focused on interface enhancement, such as
coating the implant with hydroxyapatite. In an experiment using a dog
model, Soballe et al demonstrated that hydroxyapatite improved the
radiographic and biomechanical characteristics of implant fixation.
Significantly, however, these investigators also presented data showing that
an unstable implant is not rendered stable over time by the hydroxyapatite
surface treatment. The important point to the clinician is that this or other
surface treatments is not a substitute for absolute rigidity of the inserted
device for reliable painless fixation.
Additional and possibly worrisome query into the fate of hydroxyapatite as
an interface enhancement was provided by Bauer et al. These investigators
assessed the bone-implant interface in five patients who died with a wellsecured implant that was enhanced by hydroxyapatite surface coating. The
amount and nature of bone remodeling around the hydroxyapatite-enhanced
implant suggests that the process follows the dictates of Wolff's law, that is,
that bone is laid down proportional to the magnitude of stress in the region.
An important finding, however, was that bone does tend to resorb the
hydroxyapatite. This leaves a major question as to the long-term integrity of
the interface that occurs as a result of the remodeling process.
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An additional question regarding bone enhancement in revision surgery was
investigated by Kienapfel et al. Using a dog model, the value of autogenous
vs allograft reconstruction to stabilize the hip implant was evaluated. This
study clearly demonstrated evidence of enhanced bone formation in the
implant stabilized by the autograft compared with the allograft. Thus, both
safety and efficacy favor autogenous reconstruction over the allograft.
Even greater attention has been paid to the adverse effects of wear debris
particles generated by virtually all artificial implants. In a study of 174
consecutive total knee arthroplasties performed without cement, 16%
demonstrated osteolysis. Of particular importance is that osteolysis occurred
in both those with stable as well as unstable devices. Intracellular particles
of less than 1 (mu)m were the most common, and both polyethylene and
metal particulate debris were identified intracellularly and extracellularly.
Analagous findings were presented in a study of intracellular polyethylene
particles in 34 patients who underwent hip joint replacement. The
polyethylene particles were present in 90% of the samples. Of interest, 22 of
34 hips had intracellular metal debris, whereas 10 of 16 cemented implants
had intracellular polymethyl methacrylate. Most importantly, these data
revealing joint wear were present in both loose and well-fixed implants.
These studies support the emerging understanding that wear debris is seen
with stable and unstable implants and is not eliminated by avoiding cement
fixation.
Demographic and outcome types of data relating to joint replacement have
also been pursued over the last year. The important question of the reliability
of subjective questionnaire information from a self-administered study was
addressed. Even with relatively small sample sizes, the questionnaire used
by these investigators was sensitive enough to detect changes in the
functional and clinical condition of patients. The data correlated well with
that from other accepted measurement tools such as the arthritis impact
measurement scale. This study has considerable importance as increased
emphasis is being placed on defining subjective outcomes. Since many
patients are unwilling or unable to return for a personal evaluation, the
validity of such data and their interpretation becomes increasingly
important. In a particularly interesting study recently reported by Peterson,
the geographic variation in the rates of elective hip and knee joint
replacement arthroplasty among Medicare beneficiaries during 1988 was
assessed. Over 56000 hip and 68000 knee replacements were analyzed
among Medicare beneficiaries. Osteoarthritis was by far the most common
disorder leading to hip and knee replacement and these surgeries were
performed most frequently in patients aged 70 and 74 years, respectively.
The mortality rate was low, at 0.72% for total hip replacement and 0.45%
for total knee replacement. Further, 65% of patients were dismissed
immediately from the hospital to their own home and did not require
admission to an intermediate facility. The most surprising finding, however,
was that the rates of total hip arthroplasty as well as total knee arthroplasty
were not correlated with the number of orthopedic surgeons in a given area
but were inversely related to population density (P less than .001). Thus, the
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highest rate of replacement was in the western and midwestern states. The
explanation for this unexpected finding is not obvious but may relate to lifestyle rather than practice patterns.
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Instrumentation of the spine continues to generate intense interest as
indications expand. One report reviewed the use of pedicle screws in 38
instances of unstable lumbar fracture. Twenty-eight of the 33 patients had
returned to work eventually and all but one was satisfied with the surgery.
Yet, there were nine instances of bent or broken screws, and one patient had
continued pain. The use of pedicle fixation devices in the treatment of adult
lumbar scoliosis has also been reported. In 27 such patients Marchesi et al
reported no deaths or neural complications, and the rate of pseudarthrosis
was only 4%. These investigators felt that an improved correction of up to
50% was obtainable with such techniques and the overall rate of satisfactory
outcome was 86% over an average follow-up of 5 years. In spite of these
reports, uncertainty about the short-term and long-term complication rate
and the precise indications for this surgery still exists. In fact, the whole
question of the value of fusion over nonfusion has been questioned in a
recent review. Little if any advantage to the fusion was demonstrated by
these investigators, so that increasing caution is being expressed with regard
to indications as well as the use of this particular surgical technique. The
implications of the Food and Drug Administration approval status and the
use of such spinal fixation devices is a topic of particular concern and
intense investigation at the present.
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The influence of smoking on various musculoskeletal conditions is coming
under increasing scrutiny. Studies regarding the impact of smoking on the
incorporation of bone grafts are being discussed, but little has been
published to date. One recent investigation, however, did assess the
correlation of smoking and low back pain. This 4-year study by Boshuizen,
comparing the prevalence of low back pain among smokers and
nonsmokers, concluded that pain in the extremities is more frequently
observed and more clearly associated with smoking than pain in the upper or
lower spine. This somewhat surprising finding suggested that there may be a
general influence of smoking on pain, but did not implicate this as a major
cause of pain in the back. It was concluded that the diagnosis and prevention
of back pain should include consideration of causative factors other than
those traditionally considered.
Possibly of greatest impact to society are the occupational implications and
risk factors of patients with low back, neck, and shoulder pain. The Swedish
construction industry's Organization for the Working Environment Safety
and Health from Malmo, Sweden, analyzed over 1700 construction workers
using a questionnaire. In this study, more than 50% of workers had some
low back pain and 7% felt they had severe low back pain. This investigation
found that one of the most prominent psychological factors associated with
back pain was stress. The age-standardized prevalence rate for low back
pain was 1.6 with low stress and 3.1 with high stress. Thus, those
individuals who consider themselves to be in a stressful work environment
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had approximately twice the incidence of back pain compared with those
who perceived a less stressful working environment. In yet another attempt
to determine which factors predicted who returned to work with low back
pain, a study of 134 patients found 21 associated factors from a possible
100. Of interest, prior injuries and the stability of the family unit predicted
who returned to work after being off for more than 6 months, but did not
predict return to work for those who were off of work for less than 6
months. These and other studies attest to the extremely complex nature of
low back pain as it exists in the workplace.
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The relationship between implanted orthopedic devices and carcinogenesis
was mentioned in several case reports. Goodfellow, the editor of the Journal
of Bone and Joint Surgery, British Volume, has offered that journal as a
clearinghouse for case reports, and summarized five recent reports in which
there was an association of malignancy with joint replacement arthroplasty.
Considering the vast number of implants inserted and the overall scarcity of
data implicating neoplasms and joint replacement, Goodfellow felt
reassurred that at this time there is no suggestion in orthopedics of a causal
relationship between implant replacement and malignancy. He did, however,
appropriately emphasize that the period for such a development should be
measured in decades and not years, and continued surveillance is essential.
Rock reviewed the records of the Mayo Clinic (Rochester, Minn) and
critically interpreted the existing literature on the subject. At this time there
is no conclusive evidence of a relationship between implanted hip and knee
devices and the development of malignancy, but this question will continue
to be of great interest.
Finally, orthopedic occupational risk of human immunodeficiency virus
(HIV) infection was addressed in JAMA by Tokars et al. A survey was
conducted of 3420 orthopedic surgeons attending the 1991 annual meeting
of the American Academy of Orthopaedic Surgeons, who voluntarily agreed
to HIV testing. Among the participants, 87.4% reported a blood-skin contact
with an HIV-positive patient within the previous month. Among those
without contact, no orthopedic surgeon tested HIV-positive. Among the 108
participants with reported nonoccupational HIV risk factors, two were HIVpositive (1.9%). It was concluded that while these findings may not be
generalized to the entire profession, at this time there is no evidence of HIV
infection among orthopedic surgeons without nonoccupational risk factors.
However, the high rates of blood contact further emphasize the importance
of compliance with infection control precautions as well as the need to
develop techniques to minimize the risk of blood contact during surgical
procedures.
-AN- 931853 -TI- Otolaryngology-Head and Neck Surgery. -AUMichael E. Johns, MD John K. Niparko, MD
Within the field of otolaryngology-head and neck surgery, the pace of
technological advancement has quickened. We are witnessing rapid growth
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in the use of microscopic, endoscopic, and three-dimensional imaging
techniques. The 1990s also seem to be a watershed for the successful
application of information technologies to the communication sciences and
molecular biology. Driven by these developments, otolaryngology-head and
neck surgery continues to undergo sweeping change.
Heredity has long been recognized as playing an important, if not
determinative, role in hearing impairment. Collaborative work in molecular
genetics has now successfully mapped the genetic defects responsible for a
long list of clinical hearing disorders. At least 32 genetic forms of primary
human deafness have been identified. Consortia organized by the National
Institute on Deafness and Other Communication Disorders have successfully
linked genes responsible for Usher syndrome type I, Waardenburg's
syndrome type I, and other syndromic forms of hearing impairment. Our
understanding of the genetic anatomy of human hearing will be enhanced by
the application of molecular techniques to syndromes of hearing
impairment. Eventually this approach will also enable understanding of
cellular mechanisms underlying audition with a level of resolution not
previously attainable.
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Molecular techniques combined with morphological and physiological
investigations have shed light on the association between hearing
impairment and pigmentary disorders. Research has provided evidence that
melanocytes are vital for normal function of the stria vascularis--the
cochlea's internal vascular supply and generator of the electrical activity
within the cochlea. Studies of mice with mutations in the kinase domain of
the proto-oncogene c-kit suggest that deafness in these mice results from
impaired strial activity. This appears to be due to impaired melanocyte
migration to the stria vascularis, a process normally controlled by the c-kit
gene, and results in loss of the electrical activity that normally subserves
hearing. Clinically, hearing impairment associated with pigmentary
disturbances occurs in a number of well-defined hereditary disorders. The
animals that model these combined defects with identified mutations
provide great hope for further insights into the underlying pathogenesis of
hereditary deafness.
Hair cells constitute the specialized receptors of the inner ear. In the past, we
believed that when hair cells were destroyed they could not be replaced.
Proof that hair cells could be regenerated has come from recent avian studies
revealing that damaged ears heal when allowed to recover. * RF 3,4 * Hair
cell counts gradually increase as chicks recover from ototoxic exposure or
acoustic trauma, both known to deplete hair cell populations. Hair cell
damage apparently stimulates the development of nascent cells that
otherwise would not have formed. Further understanding of mechanisms of
regeneration may someday enable hair cell restoration in humans.
The early identification of hearing impairment in infants and children has
been facilitated by the recognition of evoked otoacoustic emissions, ie,
sounds generated within the normal cochlea in response to acoustic stimuli.
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These low-level sounds, though nonessential to hearing, are functional
echoes of elements that are essential to hearing. They can be recorded
noninvasively and rapidly and therefore provide a means of screening for
significant hearing loss. The reliability, ease of use, and low cost of evoked
otoacoustic emissions support the emergence of this modality as a means of
screening large populations in a cost-effective manner.
Applications of neuroprosthetic stimulation of auditory (re)habilitation for
profound deafness continue to evolve. As cochlear implantation gains
acceptance as a means of environment and speech sound processing, clinical
observations have improved our understanding of factors that will predict
benefit from an implant. This information is critical in enabling the
profoundly deaf and their families to make an informed choice regarding
rehabilitation strategies, particularly in the case of the deaf child.
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A recent study of 83 children who received the Nucleus 22 Cochlear Implant
(Englewood, Colo) showed that roughly 50% of the children are now able to
understand words and sentences without lipreading when there are no
prearranged responses (an "open" set), and another 25% can understand
words without lipreading when they can choose from a "closed" set of
responses. These children previously could not detect sound at
conversational speech levels. Multichannel implant users also demonstrate
skills and greater intelligibility of their speech by 30% or more. The factor
that uniquely contributes to improved performance on word recognition tests
is time since implantation. Eighteen months after implantation, the speech
perception performance of children with congenital deafness is similar to
that of children who had some period of normal auditory experience before
losing their hearing.
The benefits of prosthetic intervention in deafness may extend beyond
speech recognition. Computer-based tests of selective visual attention
revealed that deaf children have deficits in their selective visual attention,
suggesting that altered auditory input affects the development of attention
skills in children. Profoundly deaf children who use an implant for 12 to 24
months demonstrate improved visual attention skills that eventually match
those of age-matched peers who use hearing aids.
Profoundly deaf individuals who lack viable innervation of the cochlea are
not suitable candidates for cochlear implants. The auditory brain-stem
implant developed at the House Ear Institute provides the ability to directly
activate the auditory pathway in such cases. The electrode is positioned in
the lateral recess of the fourth ventricle, adjacent to the cochlear nucleus.
Twenty-five patients with neurofibromatosis type II have been implanted
with the auditory brain-stem implant during or after surgery to remove
bilateral acoustic neuromas. Eighteen of 25 patients are currently receiving
auditory stimulation without significant side effects, including 13 of the last
14 subjects implanted using intraoperative auditory monitoring. These
patients have shown the ability to use the auditory sensations provided by
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the implant to recognize environmental sounds and enhance their lipreading
abilities.
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Perhaps the most significant direction of head and neck surgery research in
the past year is the extension of molecular biology and genetics into the
study of upper aerodigestive tract malignancies. The epithelial linings of this
region are known to undergo transformation to malignancy through a series
of progressive histopathological changes. This progression has similarities
to those seen in colon and bladder cancer. The series of genetic events that
have been elucidated in the progression of these two tumor types has
prompted the exploration of similar hypothesis testing in the genetics of the
malignant transformation of the upper aerodigestive tract mucosa. In the last
year, the p53 gene mutations and p53 gene overexpression have been
reported by Someus et al, Ogden et al, and Maestro et al. Dolcetti et al
described amplification of specific sequences within chromosomes 1, 6, and
8 in patients with laryngeal carcinoma.
A great deal more must be done, but it is clear that the p53 gene mutation is
commonly associated with upper aerodigestive tract tumors and may serve
as a biological marker for early tumors.
Truelson et al reported the use of DNA content and nuclear area determined
by cytomorphometric analysis to predict the prognosis in patients with
laryngeal cancers. They found the disease-free survival and likelihood of
remaining recurrence-free correlated with a low adjusted DNA index.
Further, they found a low adjusted DNA index to be a better predictor of
tumor recurrence than the current clinical staging system.
From the clinical side, more data continue to flow from the Veterans Affairs
Cooperative Study (CSP 268), "A New Strategy to Preserve the Larynx in
Advanced Laryngeal Cancer." The study group reported in 1991 that overall
and disease-free survival rates were similar between the two randomized
groups comparing induction chemotherapy and radiation therapy with
surgery and radiation therapy. This has changed our approach to advanced
laryngeal cancer and has initiated other protocols directed at organ
preservation. Wolf and Fisher reported the effectiveness of salvage neck
dissection in patients with N2 and N3 subneck disease. They found that
patients who achieved a complete neck mass response after induction
chemotherapy had an excellent survival rate of 67% following definitive
radiation therapy to the primary site and to involved neck nodes. The
survival rate was comparable to that of patients in the study who had nodenegative laryngeal cancer. They further observed that failure to achieve a
complete neck node response after induction chemotherapy was associated
with failure of the sequentially administrated radiation therapy in its ability
to control the neck disease. They recommend that in the latter situation,
early salvage neck dissection should be part of the treatment strategy. They
noted that the response rates of the primary site and the regional nodes
frequently are mixed; therefore, the drug response must be assessed at each
site. Finally, if there is not a complete response of the neck nodes, they
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stated that neck dissection should be considered prior to or immediately
following definitive radiation therapy.
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A promising development with potential for future use in craniofacial
restoration comes from a study by Toriumi et al who used a canine model to
evaluate mandibular reconstruction with a recombinant bone-inducing
factor. The ability to bridge a bone-defective mandible has made significant
advances with the use of mandibular reconstruction plates and free
osteomyocutaneous flaps. However, these advances have shortcomings.
Toriumi et al used bone morphogenetic protein-2 in an inactive dog bone
matrix as the carrier to bridge a 3-cm, full-thickness mandibular defect. In
all the animals studied, the mandibular defect was filled with a
noncompressible mineralized bone, and the animals could chew a solid diet.
Clearly more work is needed. But this application of bone growth inducers
holds great promise not only for the reconstruction of bony defects of the
head and neck but for bone defects of other body sites.
A great deal of change has also occurred in our understanding of voice,
balance, olfactory, and pediatric airway disorders. The task in all areas of
otolaryngology-head and neck surgery is to continue to narrow the gap
between basic insights and clinical practice. Widespread adoption of new
technologies promises to assist us in this formidable challenge.
-AN- 931855 -TI- Pediatrics. -AU- Vincent A. Fulginiti, MD John E.
Lewy, MD
In the last two decades, remarkable progress has been made in our
understanding of the etiology, pathogenesis, and basic molecular processes
that result in disease. Cystic fibrosis is the most common lethal gene in our
population, occurring in the carrier state in one person of every 20 to 25, and
resulting in one in 2500 births of a child with the disease. The defect has
now been clearly identified as a mutation of a specific gene, the cystic
fibrosis transmembrane regulator (CFTR) gene, on chromosome 7. The most
common mutation results in a protein defective in phenylalanine at position
508, referred to as (Delta)F508; in addition, more than 120 other mutations
have been identified. Variance in the mutation does result in some
phenotypic variation, but concordance for (Delta)F508 leads to both
pancreatic deficiency and pulmonary disease.
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The CFTR defect leads to altered transport of sodium and chloride through
the cell, and results in defective mucus formation. This single defect
accounts for the glandular insufficiency and subsequent pathophysiological
changes characteristic of cystic fibrosis.
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Several animal models for cystic fibrosis have been developed using
embryonic stem cell technology, such that mice homozygous for defective
CFTR genes have been produced. Such mice suffer clinical disorders that
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are analogous to those in humans. It is conceivable that this model will
afford further insights into the pathogenesis and treatment of cystic fibrosis.
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The discoveries of the genetic basis for abnormal protein production and the
consequent physiological changes offer new pathways for both diagnosis
and treatment. The standard methods of diagnosis rely on either detection of
abnormal chloride secretion in sweat or, in newborns, on elevated
immunoreactive trypsinogen; these methods are still the screening tests most
commonly used, but more sophisticated DNA analysis will gradually replace
this method. The DNA analysis is capable of detection rates of up to 95% in
North American whites with cystic fibrosis who possess the two most
common mutations. Laboratories can measure more than 10 of the mutations
described to date, and DNA analysis can detect the carrier state in most
persons.
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Recently, preimplantation diagnostic testing was conducted on oocytes
collected from couples in whom each partner was identified as being
(Delta)F508-positive. Using in vitro fertilization, biopsy of cleavage-stage
embryos, and amplification of DNA from embryonic cells, one pregnancy
resulted in a child who was free of the defect in both chromosomes 7.
The most exciting prospects are for direct attacks on the defect, rather than
reliance on management of the end results, ie, traditional treatment for
pulmonary and gastrointestinal complications. Initially, attempts to provide
normal tissue were designed for use in pulmonary and hepatic
transplantation. These methods probably will be supplanted by a more direct
approach to the pathophysiological defect, and even to correction of the
genetic defect. Exciting experimental findings include use of a blockade of
the "sodium pump" by amiloride hydrochloride, use of DNA as an aerosol,
use of various substances intended to alter the characteristic abnormal
mucus in the airways, and replacement gene therapy. Recently, a vector
adenovirus, altered to contain the normal cystic fibrosis gene, was
administered to cotton rats by placement in the airway, using a transfection
method developed with retroviruses. The rats produced normal human
CFTR for a period of weeks after administration. Human trials are
anticipated in order to test efficacy, safety, and side effects. If effective, the
prospect of a "genetic cure" appears feasible.
Recombinant technology has propelled us into a new era of therapeutics.
Among the nearly boundless possibilities, recombinant growth hormone and
erythropoietin illustrate the influence and utility of molecular biology
research in the treatment of children.
In addition to the treatment of children with growth hormone deficiency,
recombinant growth hormone has had particular utility in the treatment of
children with growth retardation associated with chronic renal failure. In
spite of scrupulous attention to nutrition, treatment of osteodystrophy, and
adequate dialysis, end-stage renal failure is still frequently associated with
severe growth retardation in infants and children. Growth hormone levels
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are characteristically normal or somewhat elevated. Insulin-like growth
factor 1 (IGF-1) production is decreased, as is its bioactivity, while the
binding protein IGFBP-3 is increased. Treatment with recombinant human
growth hormone increases the serum concentration of IGF-1, improves
somatomedin bioactivity, and results in improved growth velocity. Growth
hormone treatment in children with chronic renal failure who have not
reached the need for dialysis has resulted in improved growth velocity
without evidence of glomerular hyperfiltration.
Hematopoietic growth factors have been characterized and produced by
recombinant techniques. The availability of recombinant erythropoietin has
contributed to the understanding of erythropoietin structure and regulation
and has had important therapeutic implications. It is being studied in a
variety of hemolytic, aplastic, and myelodysplastic anemias, anemia of
prematurity, following cardiac transplantation, and other anemic states. Its
utility with the anemia associated with end-stage renal failure has been well
demonstrated in children. These patients characteristically develop a severe
anemia associated with shortened red blood cell survival, "uremic"
inhibition of erythropoiesis, increased blood loss, and an inadequate
response of erythropoietin for the degree of anemia. The treatment of
patients with end-stage renal disease with recombinant erythropoietin
introduced in 1989 has been found to be extremely effective therapy. It has
virtually eliminated the need for transfusions in these patients. Studies of the
effect of the correction of anemia on appetite, energy levels, and school
performance are in progress, as are evaluations of the risks of the therapy
(eg, hypertension, hyperkalemia, and thrombosis of vascular access for
hemodialysis).
The hallmark of pediatric medicine is prevention. By offering advice as to
diet, exercise, life-style, drug/alcohol/substance abuse, and by use of
immunizations, many adult diseases may be altered or prevented. However
effective these measures are, they may pale in comparison with the
possibilities of genetic prevention.
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Genetic diagnosis depends on first identifying the location and function of
genes--the primary ambition of the Human Genome Project. The technology
of DNA analysis has spun off from this basic DNA research and has proven
effective at identifying many genes and their functions.
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In addition to cystic fibrosis, there is a growing list of diseases for which
specific genetic information is available: the opsonic defect in immunodeficient children, Marfan syndrome, Waardenburg's syndrome, type II
diabetes, familial Mediterranean fever, muscular dystrophy, epidermolysis
bullosa, retinitis pigmentosa, Gaucher's disease, malignant hyperthermia,
fragile X syndrome, and Kallmann's syndrome. Many of these are manifest
in children, and some are lethal. Other efforts include the mapping of the sex
chromosomes, which may contain important information concerning gender
and gender-related health or disease issues.
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The second step is to be able to diagnose these disorders either in the
heterozygote parents, in the early stages of pregnancy, or early in life. This is
becoming rapidly possible because of new techniques to analyze human
DNA.
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The most telling step in the completion of the genetic diagnosis-treatment
cycle is the ability to alter the defective gene to normalcy shortly after
fertilization or in the live human. This fantasy has become a reality in
experimental trials. Among diseases for which trials for alteration of the
defect are under way are adenosine deaminase deficiency in severe
combined immunodeficiency, certain cancers (melanoma, ovarian cancer,
neuroblastoma, and leukemia), hemophilia B, and cystic fibrosis. As of this
writing, 37 such projects have been approved throughout the world, 18 of
which promise an immediate therapeutic benefit.
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Gene transfer techniques use a carrier of the normal gene, placed there by
recombinant technology, which can incorporate that information into human
cells, enabling production of an otherwise absent product. Two girls are
proof that the method works; both had deficiency of adenosine deaminase,
essential for normal immune function, and were destined to eventually die
from their inability to control infectious agents. Both were the subjects of
gene transfer, which corrected their deficiency of this critical enzyme, and
both are healthy 2 years after treatment.
Hence, the future for preventive medicine appears to be entering a new
phase. Instead of indirect measures to deal with the end result of genetic
disorders, it is likely that some of these conditions will yield to genetic
transfer, a direct method that essentially prevents the disease entirely. Of
course, much must be accomplished before this becomes a reality, including
many trials measuring both efficacy and safety, and consideration or
resolution of the many ethical dilemmas that will occur. Vectors that are
safe for human administration must be found and tested exhaustively before
general application. They need to provide specific correction without
causing disturbing side effects or insertion of unwanted genetic material.
The ethical issues will be difficult to resolve but must be faced, as the
technology is moving at such a rapid pace that we may have biologic
answers before the ethical questions are formulated, let alone resolved.
-AN- 931830 -TI- Clinical Pharmacology. -AU- Marcus M. Reidenberg,
MD The need to understand drug metabolism in everyday therapeutics was
illustrated recently by the dramatic case of torsades de pointes arrhythmia
occurring in a patient receiving terfenadine. This patient had very high
serum levels of terfenadine while taking ordinary doses of the drug. The
patient was also taking ketoconazole, which inhibited the enzyme that
metabolizes terfenadine and led to the very high terfenadine levels and
serious toxicity. This impairment of metabolism was verified in a group of
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normal volunteers who experienced prolongation of the QT interval during
concomitant administration of the drugs.
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The basis of the interaction involves the enzyme that metabolizes
terfenadine, cytochrome P450IIIA4. This enzyme in the liver is one of many
cytochrome P-450 enzymes (P for pigment, 450 for the maximum
wavelength absorption when exposed to carbon monoxide) that metabolize
drugs. There are several different families of cytochrome P-450 enzymes
with different patterns of substrate specificity. One of these families,
cytochrome P450IIIA, metabolizes nifedipine and other dihydropteridines,
cyclosporine, erythromycin, some benzodiazepines, and quinidine. The
metabolism of erythromycin by this enzyme has been used to develop a
breath test to measure the activity of the P450IIIA4 enzyme. A methyl group
on erythromycin is removed by this enzyme, oxidized to carbon dioxide, and
exhaled. If the erythromycin is synthesized with a radioactive methyl group
carbon (C), then the exhaled carbon dioxide will be radioactive. By trapping
and measuring the radioactive carbon dioxide, the rate of metabolism of
erythromycin can be estimated. This erythromycin breath test has been
proven to measure cytochrome P450IIIA activity and predicts the rate of
metabolism of cyclosporin, one of the drugs metabolized by this enzyme.
This method will be useful to identify drugs and other compounds that
inhibit this enzyme, as well as to determine an individual's intrinsic level of
enzyme activity.
The cytochrome P-450 enzyme that has been most studied and appears to be
the most important to individualizing therapy thus far is cytochrome
P450IID6. This enzyme metabolizes the tricyclic antidepressants, some
(beta)-blockers, codeine bioactivation to morphine, some neuroleptics, and
some antiarrhythmics. About 7% of the US population is deficient in this
enzyme and fails to metabolize drugs via this pathway at a normal rate. In
addition, individuals with normal enzyme activity will slowly metabolize
drugs that are substrates for it if they take other drugs that inhibit P450IID6.
The inhibition of cytochrome P450IID6 by fluoxetine increased tricyclic
antidepressant levels when fluoxetine was added to tricyclic drug regimens.
These new studies demonstrate the continuing importance of understanding
clinical drug metabolism in the practice of medicine.
Many clinical trials have included too few subjects to produce definitive
results. How best to combine the results of different clinical trials to produce
a single valid conclusion has been an issue in clinical pharmacology and the
rest of medicine since literature reviews were first conducted. Although
formal statistical methodology for combining clinical trial results, or metaanalysis, is an improvement over earlier methods of less formal literature
review and interpretation, one must not let the rigor and formality of the
statistics give the analysis more credibility than the underlying data deserve.
A number of issues concerning the interpretation of meta-analyses have
been raised, particularly which studies to include in the analysis. There are
two steps to this process. The first step is to evaluate the quality of the study
and give appropriate weighting to the quality of the study. This was
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illustrated by a letter in The Lancet in which the authors noted that a metaanalysis of studies comparing low-molecular-weight heparin with standard
heparin included the multicenter trial report and an individual center report
from the same multicenter trial, while excluding two other individual center
reports because they were not of "high quality." Therefore, the meta-analysis
incorrectly included some cases from the same study twice. Also relevant to
the issue of weighting a report for quality is when the same case is
considered high-quality research in one article and low-quality research in
another. Since the reports of the research are judged for quality rather than
the research itself, the published report may not reveal some information
about the research. This reaffirms the importance of including full, detailed
descriptions of the methodology in all published research articles and
specifying when cases presented in an article are also part of a multicenter
study.
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The second step when deciding which studies should be included is
discerning which trials have been carried out but not published. Since
"positive" studies are more likely to be published than "negative" studies, a
search of published studies alone is more likely to yield a "positive" result in
a meta-analysis than if all study results including unpublished results are
included. Levy recommended creation of a central nongovernmental registry
of all initiated clinical trials, with mandated periodic progress reports and
final end-of-study reports to be published in a manner analogous to
dissertation abstracts, as a way to address the problem of lack of publication
of "negative" studies.
These two problems, redundant publication and lack of publication of
"negative" studies, limit the definitiveness of meta-analyses and the certainty
with which a continuing "cumulative meta-analysis" should change medical
practice as soon as results pass some predetermined statistical test of
significance.
Nitric oxide, synthesized from l-arginine, has been identified as the
endothelium-derived relaxing factor first described by Furchgott and
Zawodzki in 1980. It is now known to have many biologic effects including
regulation of vascular tone, neurotransmission, and immune system defense.
The pharmacology of nitric oxide is undergoing extensive study at this time.
Recently, an inhibitor of nitric oxide synthesis, N`N-dimethylarginine, has
been found to accumulate in patients with renal failure and may be one
mechanism leading to elevated blood pressure in some patients with renal
failure. Nitric oxide appears to be an important cause of the vasodilatation
manifested in septic shock. Two patients with septic shock reported in 1991
were treated with a different nitric oxide synthase inhibitor, Nmethylarginine, which increased blood pressure. Some patients with adult
respiratory distress syndrome have been treated with inhalation of nitric
oxide. They experienced a decrease in pulmonary artery pressure and an
increase in arterial oxygenation while receiving the drug. Since nitric oxide
has so many different effects, the development of medications that increase
or inhibit nitric oxide synthesis may lead to therapeutic advances.
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Finding an effective way to help obese people lose weight has been a
chronic struggle. Drug therapy for weight loss tends to be belittled in any
serious discussion of the subject, because patients often lose weight while
taking the drugs but rapidly regain the weight once they stop.
A 4-year, randomized, placebo-controlled clinical trial of the combination of
fenfluramine hydrochloride and phentermine in the treatment of obesity was
recently completed. This clinical trial, comprising several different studies
performed sequentially in the same cohort of patients, found that these
drugs, which act on the serotonin pathway of nerve transmission, led to
definite weight loss that was maintained in many patients for as long as they
took the medication. This study is a methodological landmark in weight loss
research in that it succeeded in keeping 48 subjects (out of 121 who started)
in the study for the full 4 years.
Another recent landmark study was the final report of the international study
of agranulocytosis and aplastic anemia, published in 1991. This was a
population-based, case-control study in seven countries covering a
population of 23 million people with the goal of 100% ascertainment of
cases of these conditions. There were 537 cases of agranulocytosis and 215
cases of aplastic anemia collected during the study. The drug etiology of
some of these cases was inferred from calculating the relative risk (RR) by
comparing cases with controls. Tables listing RRs for many drugs are given.
Drugs associated with increased RR include antithyroid drugs (RR=97),
trimethoprim-sulfamethoxazole (RR=15), carbamazapine (RR=11), and
sulfonylureas (RR=4.5). Of even greater interest was that a multitude of
drugs incriminated as causing agranulocytosis on the basis of case reports
failed to show an increased RR in this methodologically superior study. This
comprehensive study of these two conditions is an example of
epidemiologic techniques used in clinical pharmacology to assess adverse
events and gain meaningful information about the cause of these events and
the role of specific drugs in their etiologies.
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