Letters and Corrections

Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Life Expectancies: Population or Person? To the Editor: We applaud Sox and colleagues' analysis (1) of the role of exercise testing in coronary artery disease. We are concerned, however, with the interpretation of the results, specifically, how one assesses the average change in the life expectancy for an entire cohort as opposed to a change for a single individual. The authors state, for example, that for 60-year-old men with at least one risk factor, the average increase in life expectancy for the cohort is 17 days. However, given that the prevalence of disease is presumed to be 0.15, the average change in life expectancy for someone who actually has the disease is 17/0.15 or 113 days (and would be even higher for those with left main disease). This figure compares favorably with the 110 days of life gained by reducing diastolic blood pressure from 110 to 90 mm Hg in 60-year-old men with hypertension. We believe that many people do not appreciate the meaning of marginal differences in life expectancy and that there is great variation among judgments of what constitutes trivial extensions of life expectancy (2). The population-based number of 17 days may have a different meaning to some than the 113-day Framing effects are well known (3), and the authors (1) include a section on other ways to express results using a variant of the number-needing-treatment method of Laupacis and colleagues (4). We believe, however, that the average life expectancy gain of the cohort is an outcome measure that obscures information needed by patients to make decisions. We suggest that life expectancy gains for those with the disease should also be represented. In that way doctors and patients can best use population-based life expectancy figures for decision-making. In response: Screening and other diagnostic strategies are invariably applied to heterogeneous populations. There are always at least two subgroups: those with and those without the disease. In our report (1), the summary estimate of 17 days of life is a weighted average of the therapeutic outcomes for members of each group, where the weights are the probabilities of being in each of the groups. It would be misleading to present the larger figure for life gained (113 days for the 15% who prove to have disease) without reference to the fact that this estimate is conditional upon being in the small subgroup of participants who have disease. These groups could be divided further-for example, into subgroups of diseased patients based on their coronary anatomy. Then the benefit in the highest-risk subgroup would be even greater. However, all who are screened, including the majority who do not benefit, bear the costs and risks of the strategy. As an extreme example, a strategy of monthly computed tomographic scans to detect lung cancer might yield large benefits for the few subjects who are spared death, but to assess the value of such a strategy we must include the impact upon the many people who do not have disease and would not be saved (and, indeed, could be harmed) by the strategy. We agree that the way results are presented can influence the way they are interpreted. Readers who prefer more detailed analysis or alternative presentations of results can find in our article (1) the probabilities and life expectancies associated with each branch of the decision tree. Because the results and assumptions of our analysis are described explicitly, our findings are subject to sensitivity analysis, review, revision, and debate. We feel that the cost-effectiveness ratio is the most informative, succinct summary of the results of the analysis. However, a summary estimate is just that: a summary. We hope that decision-makers will take advantage of the data presented in our analysis to inform their decision-making to the level of detail that best suits their own purposes. Alan Cardiac Rehabilitation Services and Risk Reduction To the Editor: The review by Drs. Greenland and Chu (1) on cardiac rehabilitation services and the accompanying position paper (2) developed by the Health and Policy Committee, American College of Physicians base their discussions of program components on a definition of cardiac rehabilitation that focuses on the restorative function of this intervention. Although programs for cardiac rehabilitation were originally based on a restorative model of care Also of concern are the conclusions regarding exclusion criteria reached by the Health and Public Policy Committee in the accompanying position paper (2), which was also authored by Drs. Greenland and Chu. With recent angiographic evidence of atherosclerotic regression in the coronary, carotid, and peripheral circulations of human subjects who have lowered their serum cholesterol levels dramatically (5), it seems limiting to suggest that only those persons with a demonstrated "cardiac-related disability in physical capacity" are appropriate candidates for cardiac rehabilitative effort (2). In its concluding remarks, the Committee proposes a judicious selection of candidates for the estimated $108 million spent annually on cardiac rehabilitation efforts. This sum is minimal, however, when compared with the billions of dollars spent on palliation of the vascular complications of atherosclerosis, which have been shown to be modified, if not avoided, by the risk-factor modification efforts of cardiac rehabilitation programs. All would agree that controlling the growth of the national health-care budget is long overdue, yet limiting the growth of cardiac rehabilitation programs rather than increasing programs to reduce risks for the population at large and for those already affected by coronary heart disease can only increase the burden of atherosclerotic diseases and the costs of their "high tech" treatments. population of patients. I concur with Dr. Downing that a rationale exists upon which physicians and other health-care professionals might offer services for risk-factor reduction to many groups of patients not covered specifically by our critique of cardiac rehabilitation services. However, in the review (1) we stated clearly that our analysis was based on a "critical review of the published articles on the benefits and risks of cardiac rehabilitation services. . . with primary emphasis on the role of cardiac rehabilitation after myocardial infarction." We also stated that "many survivors of myocardial infarction could theoretically benefit from organized attempts to help them stop smoking, lower their blood lipids, and control hypertension or other standard risk factors." The question we intended to address in our review was whether the published medical literature supports the application of specialized cardiac rehabilitation services as an especially effective means of reducing cardiac risk factors in patients with coronary artery disease-not whether such treatments could be of theoretical benefit to this group of patients. As we noted, there is no body of published evidence to support the routine addition of treatments for riskfactor reduction to organized cardiac rehabilitation services for survivors of myocardial infarction. For that matter, I could find no evidence that routine efforts at risk-factor reduction in the form of organized programs are preferable to other forms of medical care for primary or secondary prevention of coronary artery disease. Consequently, our conclusions could not advocate or support the use of such treatments, even though, as Dr. Downing points out, such efforts have theoretical appeal. Jill Downing, MD I applaud the efforts of those interested in primary, secondary, or tertiary prevention of coronary artery disease and challenge clinical scientists to promote research that will support the addition of such clinical services on a more routine basis in the future. Philip Greenland, MD SI and Presently Conventional Units To the Editor: Having grown up in the era of metric units, I am pleased to see that medical literature is finally adopting SI units (le Systeme internationale d'Unites). It is especially fitting now that research has clearly become more international, with workers from many countries often laboring on the same projects simultaneously. Problems always emerge with any attempt at modernization, however, including the chance that those unfamiliar with the new systems will be left behind. This particular problem surfaced for me after reading the article (1) on methylprednisolone therapy in alcoholic hepatitis by Carithers and colleagues. The study design, methods, eligibility criteria, and results were clearly stated, and the article was well worth clipping and saving. As I was putting it in my file, however, I tried mentally to compare the patients featured with my own. Just how severe was the hepatitis described? Was the bilirubin concentration 5 times normal? 20 times normal? No normal values were given in the new SI units. It is a simple matter to convert miles to kilometers, and pounds to kilograms, but to convert SGOT levels from international units per litre to microkatals per litre, bilirubin concentrations from micromoles to milligrams per decilitre, and so on, requires the memorization of molecular weights and catalytic constants. It simply discourages the comparison of pre-SI with post-SI patients. To make matters worse, the patients featured in this article (1) were accrued from 1979 to 1984, a period in which no one in American medicine used SI units. Thus, the data must have been converted to SI format for publication, and the conversion factors then removed from the manuscript. There is no reason to close off the literature from those readers whose laboratory slips may still express values in milligrams per decilitre. Simply print the normal ranges for the new units when they are first mentioned in the article, and even the most Neanderthal of medical readers will have some point of reference from which to begin counting on his (opposable) thumbs. We do offer authors the option of including present metric units with SI units, and only a fraction of authors ask for it. Dr. Giacoppe's view is reasonable, and we shall suggest to authors that they include non-SI units, at least for measurements that are central evidence for a paper's main conclusion. -The Editor The Metaraminol Test and Adverse Cardiac Effects To the Editor: Familial Mediterranean fever (FMF) is a hereditary disorder of unknown cause. The diagnosis is not difficult when a family history is relevant and diagnostic criteria are met (1, 2). Barakat and colleagues A 38-year-old woman had a family history of familial Mediterranean fever and occasionally had diffuse abdominal tenderness. She reported no history of fever, chest pain, arthralgia, or skin manifestations, and she did not have hypertension or cardiac disease. In view of a possible diagnosis of familial Mediterranean fever, and with informed consent of the patient, a metaraminol test was done. A baseline, standard electrocardiogram (ECG) was obtained, and supine blood pressure, pulse rate, and temperature were recorded. Throughout the test period the patient was monitored. An intravenous infusion of normal saline, 500 mL, to which was added a 10-mg dose of metaraminol bitartrate, was given for 4 hours. Thirty minutes after beginning the test, the patient had chest pain with coronary characteristics and palpitations. An ECG showed a bigeminal rhythm. The metaraminol infusion was discontinued, and 5 minutes later the patient was asymptomatic, and the ECG was normal. A week later, an exercise ECG was negative. Although Barakat and colleagues (4) did not report any serious side effects in their experience with metaraminol tests (80 cases), we agree with Cattan and colleagues (5) that this test is not harmless and that it should not be used unless absolutely necessary, possibly in patients with paucisymptomatic forms of lateonset familial Mediterranean fever who do not have a relevant family history. We think the criteria established by Sohar and colleagues (1) and Eliakim and colleagues (2) and a family history are sufficient for the diagnosis of most cases. Collagenous Colitis and Histiocytic Lymphoma To the Editor: Collagenous colitis is a relatively rare cause of watery diarrhea and abdominal pain and is characterized histologically by a thickened band of collagen beneath the colonic mucosa epithelium. I report a case of collagenous colitis associated with diffuse histiocytic lymphoma, which responded to sulfasalazine and steroid enemas, even as lymphoma progressed. A 78-year-old woman with a 1-year history of diarrhea was admitted in February 1988 for a presumed stroke with mild aphasia. In the past year she had had four to five loose stools per day. At admission, cultures of the stool and examination for ova and parasites were negative. Colonoscopy was done and was remarkable only for decreased haustral markings. A random biopsy sample showed thickened subepithelial collagen deposition consistent with collagenous colitis. Staining of the biopsy sample was negative for iron and amyloid. She was treated with sulfasalazine and steroid enemas with resolution of her diarrhea. Magnetic resonance imaging of her head showed a parietal lesion, a biopsy specimen of which showed diffuse histiocytic lymphoma. She was not considered a candidate for chemotherapy and had skin-flap closure with palliative cranial radiation therapy. Progression of her lymphoma was manifested by increased cervical lymphadenopathy. She died, and an autopsy was not done. A patient with Hodgkin lymphoma and collagenous colitis has been described (1). In this case, collagenous colitis was thought to reflect a paraneoplastic phenomenon. The patient's diarrhea showed significant improvement after both treatment with prednisone-based chemotherapy and clinical improvement of her lymphoma. Collagenous colitis can have a variable course (2), and spontaneous resolution without therapy has been reported (3). Therefore, it is difficult to assess treatment success in patients with collagenous colitis. The patient with Hodgkin lymphoma had been treated with a corticosteroid, which has been used successfully in the past for treating collagenous colitis (2, 4, 5). It is unclear whether the collagenous colitis improved because of the prednisone or because of the improvement of the lymphoma after chemotherapy. A paraneoplastic phenomenon, however, would not be a consideration in my patient because her diarrhea resolved after treatment with sulfasalazine and local steroid enemas. Sulfasalazine has not been shown to have any effect on lymphomas. Although there may be systemic absorption of the steroid from the enemas, the patient's diarrhea improved even as lymphoma progressed. Collagenous colitis is a rare disease and its exact incidence has yet to be determined. The finding of lymphoma in two patients with collagenous colitis may suggest that an association exists. DavidB. Edwards, MD Pancytopenia and Methotrexate with TrimethoprimSulfamethoxazole To the Editor: Kozarek and colleagues (1) found a dramatic clinical improvement in patients treated with methotrexate who had refractory Crohn colitis and an incomplete remission of chronic ulcerative colitis. Of 21 patients, 14 were also receiving either sulfasalazine or metronidazole (exact number of patients not mentioned). The risk of bone marrow suppression is increased when other antifolate drugs (derivatives of sulfonamides, trimethoprim) are used simultaneously with methotrexate. Besides additive folate antagonism, other pharmacologic mechanisms, such as competition with tubular secretion and displacement from albumin binding sites, play an important role in interactions of sulfonamides and methotrexate. Moreover, it was shown that sulfasalazine inhibits the hydrolysis of polyglutamyl folate and the intestinal transport of folate in patients with ulcerative colitis (2). Pancytopenia due to the combined use of methotrexate and trimethoprim-sulfamethoxazole has been reported in two patients with rheumatoid arthritis (3, 4). We report two additional cases of this severe side effect. In case 1, an 81-year-old woman had refractory rheumatoid arthritis and impaired renal function (creatinine, 166 jixmol/L) and was treated with methotrexate, 5 mg weekly for 6 weeks. Cystitis {Escherichia coli) was treated with trimethoprim, 300 mg daily. One week after starting trimethoprim, bone marrow suppression developed (leukocytes, 1.9 X 10VL; platelets, 15 X 10VL; hemoglobin, 6.3 mmol/L). Both methotrexate and trimethoprim were discontinued. Blood cell counts returned to normal in 2 weeks. One month after discharge she died of severe bronchopneumonia (determined at autopsy). In case 2, a 7 5-year-old woman with refractory rheumatoid arthritis and impaired renal function (estimated creatinine clearance, 40 mL/min) was receiving methotrexate, 5 mg weekly. A recurrent cystitis was treated with trimethoprim-sulfamethoxazole. Shortly after beginning trimethoprim-sulfamethoxazole, bone marrow suppression developed (hemoglobin, 5.6 mmol/L; leukocytes, 1.6 X 10 9 /L; platelets, 23 X 10VL). A bone marrow biopsy specimen showed hypocellularity. Both drugs were discontinued, and therapy with leucovorin was begun; she recovered in several weeks. These two patients were not treated with the combination of sulfasalazine and methotrexate; however, other antifolate drugs were used in conjunction with methotrexate. Additive folate antagonism, independent of which antifolate drug was used simultaneously with methotrexate, seemed to play a central role in inducing bone marrow suppression in these patients. We do not recommend prescribing other drugs with antifolate action simultaneously with methotrexate. The toxicity of and the possibility of adverse drug interactions with methotrexate are increased in the presence of other risk factors such as old age, hypalbuminemia, impaired renal function, and decreased bone marrow reserve (5). Acknowledgment: We thank Drs. J. Rasker, W. Hissink Muller, and J. Haverman for allowing us access to their patients

Symptoms associated with victimization in patients with schizophrenia and related disorders

Background: Patients with psychoses have an increased risk of becoming victims of violence. Previous studies have suggested that higher symptom levels are associated with a raised risk of becoming a victim of physical violence. There has been, however, no evidence on the type of symptoms that are linked with an increased risk of recent victimization. Methods: Data was taken from two studies on involuntarily admitted patients, one national study in England and an international one in six other European countries. In the week following admission, trained interviewers asked patients whether they had been victims of physical violence in the year prior to admission, and assessed symptoms on the Brief Psychiatric Rating Scale (BPRS). Only patients with a diagnosis of schizophrenia or related disorders (ICD-10 F20–29) were included in the analysis which was conducted separately for the two samples. Symptom levels assessed on the BPRS subscales were tested as predictors of victimization. Univariable and multivariable logistic regression models were fitted to estimate adjusted odds ratios. Results: Data from 383 patients in the English sample and 543 patients in the European sample was analysed. Rates of victimization were 37.8% and 28.0% respectively. In multivariable models, the BPRS manic subscale was significantly associated with victimization in both samples. Conclusions: Higher levels of manic symptoms indicate a raised risk of being a victim of violence in involuntary patients with schizophrenia and related disorders. This might be explained by higher activity levels, impaired judgement or poorer self-control in patients with manic symptoms. Such symptoms should be specifically considered in risk assessments

Cardiac murmurs: echocardiography in the assessment of patients requiring antibiotic prophylaxis for dental treatment

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Traditionally patients who indicate that they have a heart murmur or who indicate that they have had rheumatic fever are given antibiotic prophylaxis for dental treatment. This is commonly done without further assessment of the patient’s actual endocarditis risk. Echocardiography is a noninvasive method of assessing cardiac valve function and haemodynamics. Methods: Consecutive patients who were referred to a private practice oral and maxillofacial surgeon for dentoalveolar surgery and indicated that they had a cardiac problem and usually had antibiotic prophylaxis, were evaluated. Those with a clear indication for prophylaxis, for example had prosthetic heart valves or previous infective endocarditis, received antibiotic prophylaxis. Where there was uncertainty, they were referred for an echocardiogram, and if abnormal, a formal cardiology review. Results: Three hundred and seventy patients out of approximately 20 000 (1.85 per cent) indicated that they had a cardiac murmur and usually received antibiotic prophylaxis for dental treatment between 1 February 1997 and 1 February 2005. Two hundred and sixty-two (71 per cent) were female and 108 (29 per cent) were male; age range 0.7 to 98 years, average 37.6 years. Two hundred and seventy (72 per cent) had normal hearts with no indication for antibiotic prophylaxis. Of the 100 (28 per cent) patients with abnormal findings, they were on average older; 49.5 years, range 0.7 to 87 years. Of these, 50 (14 per cent) met current indications for antibiotic prophylaxis. Conclusion: Patients who present for dental treatment indicating that they require antibiotic prophylaxis for cardiac condition need to be fully evaluated. In this study only 50 of 370 patients (14 per cent) required antibiotic prophylaxis. The remaining 320 (86 per cent) would have no benefit but a risk of adverse reaction to the antibiotic.M. Ching, I. Straznicky and AN Gos

Non-invasive Predictors of Human Cortical Bone Mechanical Properties: T2-Discriminated 1H NMR Compared with High Resolution X-ray

Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, 1H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that 1H NMR signals were better predictors of yield stress, peak stress, and pre-yield toughness than were the X-ray derived signals. These 1H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP

The architecture of parallel fiber axons contacting cerebellar Purkinje neurons retains spatial information over long distances. Parallel fiber synapses can trigger local dendritic calcium spikes, but whether and how this calcium signal leads to plastic changes that decode the parallel fiber input organization is unknown. By combining voltage and calcium imaging, we show that calcium signals, elicited by parallel fiber stimulation and mediated by voltage-gated calcium channels, increase non-linearly during high-frequency bursts of electrically constant calcium spikes, because they locally and transiently saturate the endogenous buffer. We demonstrate that these non-linear calcium signals, independently of NMDA or metabotropic glutamate receptor activation, can induce parallel fiber long-term potentiation. Two-photon imaging in coronal slices revealed that calcium signals inducing long-term potentiation can be observed by stimulating either the parallel fiber or the ascending fiber pathway. We propose that local dendritic calcium spikes, evoked by synaptic potentials, provide a unique mechanism to spatially decode parallel fiber signals into cerebellar circuitry changes