Benfluorex and Unexplained Valvular Heart Disease: A Case-Control Study

Background

Recent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation.

Methods

We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1^st 2003 and June 30^th 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an “explained” mitral regurgitation. Other patients were considered as having an “unexplained” mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an “explained” mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians.

Results

Out of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of benfluorex was reported in 22 patients: 19 of the 27 cases, versus 3 of the 54 controls, odds-ratio 17.1 (3.5 to 83), adjusted for body mass index, diabetes and dexfenfluramine use.

Conclusion

The use of benfluorex is associated with unexplained mitral regurgitation.     

Is Early Tuberculosis Death Associated with Increased Tuberculosis Transmission?

Introduction

Tuberculosis (TB) is now a relatively uncommon disease in high income countries. As such, its diagnosis may be missed or delayed resulting in death before or shortly after the introduction of treatment. Whether early TB death is associated with increased TB transmission is unknown. To determine the transmission risk attributable to early TB death we undertook a case-control study.

Methods

All adults who were: (1) diagnosed with culture-positive pulmonary TB in the Province of Alberta, Canada between 1996 and 2012, and (2) died a TB-related death before or within the first 60 days of treatment, were identified. For each of these “cases” two sets of “controls” were randomly selected from among culture-positive pulmonary TB cases that survived beyond 60 days of treatment. “Controls” were matched by age, sex, population group, +/- smear status. Secondary cases of “cases” and “controls” were identified using conventional and molecular epidemiologic tools and compared. In addition, new infections were identified and compared in contacts of “cases” that died before treatment and contacts of their smear-matched “controls”. Conditional logistic regression was used to find associations in both univariate and multivariate analysis.

Results

“Cases” were as, but not more, likely than “controls” to transmit. This was so whether transmission was measured in terms of the number of “cases” and smear-unmatched or -matched “controls” that had a secondary case, the number of secondary cases that they had or the number of new infections found in contacts of “cases” that died before treatment and their smear-matched “controls”.

Conclusion

In a low TB incidence/low HIV prevalence country, pulmonary TB patients that die a TB-related death before or in the initial phase of treatment and pulmonary TB patients that survive beyond the initial phase of treatment are equally likely to transmit.     

Bubble Stability Test Compared with Lecithin Assay in Prediction of Respiratory Distress Syndrome

A simple test for surfactant, utilizing bubble stability in ethanol, was performed in 106 samples of amniotic fluid obtained from 94 patients. Of these patients 80 delivered within 48 hours of the collection of the sample. The results were compared with the lecithin concentration in the same amniotic fluid samples and with the quality of respiration in the neonate. The test was “positive,” indicating fetal pulmonary maturity, in 37 cases and none of these infants developed respiratory distress syndrome (R.D.S.). In only one of these cases, however, was gestation less than 37 weeks. The test was “intermediate” or “negative” in 43 cases but in 35 of these infants respiration at birth was perfectly normal.Performed by the method described by its originators, this simple test gives too many false negative results to be of value in routine clinical practice, although a positive result is helpful. The concept of the test is ingenious, however, and further developments may be expected.     

Bedside determination of left atrial pressure

An investigation was conducted to assess the accuracy of left heart filling pressures determined by a right heart catheter introduced at the bedside. Twelve patients were studied after open cardiac surgery by simultaneously recording pressures from both sides of the pulmonary capillary bed with a direct left atrial catheter and a flow-directed pulmonary arterial catheter. The mean pulmonary artery “occluded” pressure was shown to be a highly reliable index of mean left atrial pressure in all cases. It was much more accurate than pulmonary end-diastolic pressure, especially in six patients with pre-existing pulmonary hypertension.     

A Theoretical Study of Pulmonary Capillary Gas Exchange and Venous Admixture

A model of pulmonary capillary gas exchange and venous admixture is presented and the inclusion of this model into a model of the entire respiratory system is discussed. Partial pressure and concentration gradients for nitrogen, helium, oxygen, and carbon dioxide are predicted. The cases of breathing room air and 10% oxygen are studied. In both of these studies the Bohr and Haldane effects are included, and the “physiological” dissociation curves of oxygen and carbon dioxide are predicted for the normal case as blood flows from the venous blood end of the capillary to the arterial blood end. Venous admixture effects are also calculated for both of these cases. The effects of emphysema, pulmonary congestion, and altered cardiac function on the gradients are studied.     

Chest Radiographic Patterns and the Transmission of Tuberculosis: Implications for Automated Systems

BackgroundComputer-aided detection to identify and diagnose pulmonary tuberculosis is being explored. While both cavitation on chest radiograph and smear-positivity on microscopy are independent risk factors for the infectiousness of pulmonary tuberculosis it is unknown which radiographic pattern, were it detectable, would provide the greatest public health benefit; i.e. reduced transmission. Herein we provide that evidence.Objectives1) to determine whether pulmonary tuberculosis in a high income, low incidence country is more likely to present with “typical” adult-type pulmonary tuberculosis radiographic features and 2) to determine whether those with “typical” radiographic features are more likely than those without such features to transmit the organism and/or cause secondary cases.MethodsOver a three-year period beginning January 1, 2006 consecutive adults with smear-positive pulmonary tuberculosis in the Province of Alberta, Canada, were identified and their pre-treatment radiographs scored by three independent readers as “typical” (having an upper lung zone predominant infiltrate, with or without cavitation but no discernable adenopathy) or “atypical” (all others). Each patient’s pre-treatment bacillary burden was carefully documented and, during a 30-month transmission window, each patient’s transmission events were recorded. Mycobacteriology, radiology and transmission were compared in those with “typical” versus “atypical” radiographs.FindingsA total of 97 smear-positive pulmonary tuberculosis cases were identified, 69 (71.1%) with and 28 (28.9%) without “typical” chest radiographs. “Typical” cases were more likely to have high bacillary burdens and cavitation (Odds Ratios and 95% Confidence Intervals: 2.75 [1.04–7.31] and 9.10 [2.51–32.94], respectively). Typical cases were also responsible for most transmission events—78% of tuberculin skin test conversions (p<0.002) and 95% of secondary cases in reported close contacts (p<0.01); 94% of secondary cases in “unreported” contacts (p<0.02).ConclusionAs a group, smear-positive pulmonary tuberculosis patients with typical radiographic features constitute the greatest public health risk. This may have implications for automated detection systems.     

Neonatal Respiratory Distress: Experience at The Hospital for Sick Children,Toronto, 1960-1961

Four hundred and thirty infants selectively referred to the Newborn Unit of The Hospital for Sick Children, Toronto, with the symptom of respiratory distress, were reviewed. There were 142 cases of the “idiopathic respiratory distress syndrome” (IRDS), of which 67 were fatal. The remainder included 100 cardiac (76 deaths), 63 extra-pulmonary (28 deaths) and 109 other specific pulmonary conditions (54 deaths). Of the 109, half were due to massive aspiration. Serial observations and radiographs led to correct clinical diagnosis in 85% of necropsy-proved cases of IRDS and in a comparable proportion of all other conditions. The incidence and mortality rate of IRDS were twice as high in males as in females. A significant number of premature infants have transient respiratory distress after birth, and diagnostic criteria for inclusion in any study should be defined in detail. This study emphasized the large contribution of disorders of the respiratory and cardiac systems to neonatal mortality and led to the formation of a special department for intensive care and research in these conditions.     

Partial Endocardial Cushion Defects

Seven partial endocardial cushion defects have been diagnosed and treated surgically without mortality—six of the ostium primum type and one with a defect from left ventricle to right atrium. The last patient likely has an associated cardiomyopathy. The most serious complication of repair is damage to the bundle of His.The electrocardiogram is helpful in diagnosis, showing left axis deviation in standard leads and right ventricular hypertrophy in chest leads (92%). The vector-cardiogram in the frontal plane shows counterclockwise rotation with the loop usually above the isoelectric line (97%). This is due to congenital aberration of the left bundle branch rather than to left ventricular hypertrophy from mitral incompetence. Radiography demonstrates moderate cardiac enlargement with right-sided hypertrophy, a prominent pulmonary artery, and pleonemic lung fields. Cardiac catheterization reveals a moderate rise in oxygen saturation at atrial level and a further minimal increase at ventricular level. The left atrial trace may show a minimal “c-v” configuration, with the “v” wave equal to the “a”.     

Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub-Phenotypes and Predictive Criteria by Long-Term Follow-Up

Background

To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major obstacle to the interpretation of therapeutic trials

Methodology/Principal Findings

A retrospective single institution long-term follow-up study was carried out in DMD patients with both complete lack of muscle dystrophin and genotyping. An exploratory series (series 1) was used to assess phenotypic heterogeneity and to identify early criteria predicting future outcome; it included 75 consecutive steroid-free patients, longitudinally evaluated for motor, respiratory, cardiac and cognitive functions (median follow-up: 10.5 yrs). A validation series (series 2) was used to test robustness of the selected predictive criteria; it included 34 more routinely evaluated patients (age>12 yrs). Multivariate analysis of series 1 classified 70/75 patients into 4 clusters with distinctive intellectual and motor outcomes: A (early infantile DMD, 20%): severe intellectual and motor outcomes; B (classical DMD, 28%): intermediate intellectual and poor motor outcome; C (moderate pure motor DMD, 22%): normal intelligence and delayed motor impairment; and D (severe pure motor DMD, 30%): normal intelligence and poor motor outcome. Group A patients had the most severe respiratory and cardiac involvement. Frequency of mutations upstream to exon 30 increased from group A to D, but genotype/phenotype correlations were restricted to cognition (IQ>71: OR 7.7, 95%CI 1.6–20.4, p<0.003). Diagnostic accuracy tests showed that combination of “clinical onset <2 yrs” with “mental retardation” reliably assigned patients to group A (sensitivity 0.93, specificity 0.98). Combination of “lower limb MMT score>6 at 8 yrs” with “normal or borderline mental status” reliably assigned patients to group C (sensitivity: 1, specificity: 0.94). These criteria were also predictive of “early infantile DMD” and “moderate pure motor DMD” in series 2.

Conclusions/Significance

DMD can be divided into 4 sub-phenotypes differing by severity of muscle and brain dysfunction. Simple early criteria can be used to include patients with similar outcomes in future therapeutic trials.     

Tuberculosis: A Challenge to the General Practitioner

Of 157 patients dying of tuberculosis in Ontario (1960) 132 (87.4%) suffered from the pulmonary form of the disease (incidence 2.6 per 100,000). In the same year, 1632 of 1847, or 88.3%, active new cases reported had the pulmonary type and 183 additional cases were reported without details as to type of disease. Thus, in 1960, a total of 2030 new cases of tuberculosis were reported in Ontario.Of 1367 patients with pulmonary tuberculosis (reinfection type), 357 (26.1%) had “far advanced” disease and 613 (44.8%) had “moderately advanced” disease.This high percentage of patients with “moderately advanced” to “far advanced” disease at the time of diagnosis constitutes the real challenge to physicians in private practice, who made the diagnosis in 45% of cases.Emergence of resistant strains of bacteria increases the urgency of prompt diagnosis and treatment. The most vulnerable population segment is the 15-30 year age-group, many of whom are negative intracutaneous reactors. A high index of suspicion is necessary, particularly in certain segments of the population with a high incidence of infection, combined with a careful history, meticulous physical examination, intracutaneous tests, chest and other radiographs, and appropriate bacteriological studies.     

Analysis of Minimal Functions of Simian Virus 40 II. Enhancement of Oncogenic Transformation in Vitro by UV Irradiation

After light UV irradiation (5,000 to 10,000 ergs/mm²) “complete” and “defective” simian virus 40 (SV40) showed an enhancement of oncogenic transformation capacity in Syrian hamster kidney cells in vitro up to 180 and 270% of the controls, respectively. Simultaneously with the enhancement of transformation, an increase in T-antigen induction was observed in CV-1 cells infected with light UV-irradiated SV40; infectivity, however, was correspondingly reduced by 1 log₁₀. After strong UV irradiation (10,000 to 80,000 ergs/mm²) of “complete” and “defective” SV40, transformation capacity in vitro proved to be the most resistant viral function. It was only slightly reduced in comparison with a 4 to 5 log₁₀ reduction of infectivity. T-antigen induction of SV40 was also equally resistant to strong UV irradiation. We found no evidence of “multiplicity reactivation” involved in the high resistance of transformation capacity of SV40 after UV irradiation. Syrian hamster kidney cells transformed in vitro by UV-irradiated SV40 contained the SV40-specific T-antigen and showed the same morphology and growth characteristics as cells transformed by non-irradiated “complete” or “defective” SV40. They induced malignant tumors after subcutaneous inoculation into Syrian hamsters.     

Restless Legs Syndrome in Chronic Pulmonary Disease

Eight consecutive patients referred for neurological opinion because of very severe “restless legs” all suffered from chronic pulmonary disease. It was considered that the restless legs syndrome was not a metabolic consequence of respiratory failure but a nervous manifestation of their invalidism.     

Factitious Aortic Valve Insufficiency

One hundred consecutive aortograms, performed with careful attention to recommended technical details, were reviewed to identify cases of “factitious” aortic valve insufficiency, viz. aortic regurgitation seen during aortography for which there is no clinical evidence. Five patients with this condition were identified. Two of these subsequently underwent mitral valve replacement under cardiopulmonary by-pass. Aortic insufficiency was not detected during this procedure and the aortic valve appeared to be anatomically normal at postmortem examination. That factitious aortic insufficiency may exist should be remembered when aortography is used to differentiate aortic from pulmonary valve insufficiency.     

Les sténoses pulmonaires périphériques congénitales: Présentation de 16 observations et revue de la littérature

Sixteen cases of peripheral pulmonary stenosis have been studied clinically and by cardiac catheterization. Diagnosis has been proved in all cases by manometric measurements and/or cineangiocardiography. All patients except two were below 2 years of age. Ten cases were of type I, i.e. the stenosis was localized to the pulmonary trunk or its main branches. Six patients were of type III, i.e. they had diffuse stenosis of the pulmonary arterial tree. The physical findings, which in many cases are typical and include the presence of a systolic murmur over both lung fields, should alert the physician to the diagnosis at the bedside. At cardiac catheterization the configuration of the pressure tracing in the main pulmonary artery is typical, showing an abrupt rise and fall of the systolic wave followed by a low situated dicrotic notch. There is no doubt that in the past many cases of peripheral pulmonary stenosis have been wrongly diagnosed as “essential pulmonary hypertension”.     

Ventilatory Tests and Pulmonary Conductance in Hospitalized Patients

In a series of 49 patients, including individuals with varying lung pathology and some older patients with no lung disease, the usual excellent correlation between first-second forced expiratory volume and maximum breathing capacity was found (coefficient of correlation=0.88). The first-second forced expiratory volume and maximum mid-expiratory flow rate were also seen to be closely related (coefficient of correlation=0.87). The relationship between these ventilatory tests and direct mechanical measurements of pulmonary resistance, however, was not as striking. Reduction in pulmonary compliance not due to loss or removal of pulmonary tissue did not affect the interrelationships between these tests. First-second forced expiratory volume, expressed as a percentage of the predicted vital capacity, was more closely related to the expression “% of predicted maximum breathing capacity” than the first-second forced expiratory volume, expressed as a percentage of the actual vital capacity (p<.05).     

Impact of specific training and competition on myocardial structure and function in different age ranges of male handball players

Handball activity involves cardiac changes and demands a mixture of both eccentric and concentric remodeling within the heart. This study seeks to explore heart performance and cardiac remodeling likely to define cardiac parameters which influence specific performance in male handball players across different age ranges. Forty three players, with a regular training and competitive background in handball separated into three groups aged on average 11.78±0.41 for youth players aka “schools”, “elite juniors” 15.99±0.81 and “elite adults” 24.46±2.63 years, underwent echocardiography and ECG examinations. Incremental ergocycle and specific field (SFT) tests have also been conducted. With age and regular training and competition, myocardial remodeling in different age ranges exhibit significant differences in dilatation’s parameters between “schools” and “juniors” players, such as the end-diastolic diameter (LVEDD) and the end-systolic diameter of the left ventricle (LVESD), the root of aorta (Ao) and left atrial (LA), while significant increase is observed between “juniors” and “adults” players in the interventricular septum (IVS), the posterior wall thicknesses (PWT) and LV mass index. ECG changes are also noted but NS differences were observed in studied parameters. For incremental maximal test, players demonstrate a significant increase in duration and total work between “schools” and “juniors” and, in total work only, between “juniors” and “seniors”. The SFT shows improvement in performance which ranged between 26.17±1.83 sec to 31.23±2.34 sec respectively from “seniors” to “schools”. The cross-sectional approach used to compare groups with prior hypothesis that there would be differences in exercise performance and cardiac parameters depending on duration of prior handball practice, leads to point out the early cardiac remodeling within the heart as adaptive change. Prevalence of cardiac chamber dilation with less hypertrophy remodeling was found from “schools” to “juniors” while a prevalence of cardiac hypertrophy with less pronounced chamber dilation remodeling was noted later.     

Comparison by Controlled Clinical Trial of Streptokinase and Heparin in Treatment of Life-threatening Pulmonary Embolism

Treatment with heparin or streptokinase was allocated randomly to 30 patients with life-threatening pulmonary embolism verified by angiography. Treatment was given for 72 hours and pulmonary angiography was repeated. There was significantly greater (P < 0·001) evidence of thrombolysis in those patients treated with streptokinase compared with those treated with heparin. The reduction of systolic and mean pulmonary arterial pressures was also significantly greater (P < 0·05 and P < 0·02 respectively) in the streptokinase group.Seven patients failed to complete 72 hours of the trial treatment: five successfully underwent pulmonary embolectomy. Six of these “failures” had initial pulmonary angiographic scores of 24 or more and systemic systolic blood pressure recordings of 100 mm Hg or less. Patients with these features should probably be considered for pulmonary embolectomy as the initial treatment.A febrile reaction commonly occurred in the streptokinase group; otherwise side effects were no more common than in the heparin group.     

Accelerated Wound Closure In Vitro by Fibroblasts from a Subgroup of Cleft Lip/Palate Patients: Role of Transforming Growth Factor-α

In a fraction of patients surgically treated for cleft lip/palate, excessive scarring disturbs maxillary growth and dento-alveolar development. Since certain genes are involved in craniofacial morphogenesis as well as tissue repair, a primary defect causing cleft lip/palate could lead to altered wound healing. We performed in vitro wound healing assays with primary lip fibroblasts from 16 cleft lip/palate patients. Nine foreskin fibroblast strains were included for comparison. Cells were grown to confluency and scratch wounds were applied; wound closure was monitored morphometrically over time. Wound closure rate showed highly significant differences between fibroblast strains. Statistically, fibroblast strains from the 25 individuals could be divided into three migratory groups, namely “fast”, “intermediate”, and “slow”. Most cleft lip/palate fibroblasts were distributed between the “fast” (5 strains) and the “intermediate” group (10 strains). These phenotypes were stable over different cell passages from the same individual. Expression of genes involved in cleft lip/palate and wound repair was determined by quantitative PCR. Transforming growth factor-α mRNA was significantly up-regulated in the “fast” group. 5 ng/ml transforming growth factor-α added to the culture medium increased the wound closure rate of cleft lip/palate strains from the “intermediate” migratory group to the level of the “fast”, but had no effect on the latter group. Conversely, antibody to transforming growth factor-α or a specific inhibitor of its receptor most effectively reduced the wound closure rate of “fast” cleft lip/palate strains. Thus, fibroblasts from a distinct subgroup of cleft lip/palate patients exhibit an increased migration rate into wounds in vitro, which is linked to higher transforming growth factor-α expression and attenuated by interfering with its signaling.     

The Effectiveness of a ‘Train the Trainer’ Model of Resuscitation Education for Rural Peripheral Hospital Doctors in Sri Lanka

Background

Sri Lankan rural doctors based in isolated peripheral hospitals routinely resuscitate critically ill patients but have difficulty accessing training. We tested a train-the-trainer model that could be utilised in isolated rural hospitals.

Methods

Eight selected rural hospital non-specialist doctors attended a 2-day instructor course. These “trained trainers” educated their colleagues in advanced cardiac life support at peripheral hospital workshops and we tested their students in resuscitation knowledge and skills pre and post training, and at 6- and 12-weeks. Knowledge was assessed through 30 multiple choice questions (MCQ), and resuscitation skills were assessed by performance in a video recorded simulated scenario of a cardiac arrest using a Resuci Anne Skill Trainer mannequin.

Results/Discussion/Conclusion

Fifty seven doctors were trained. Pre and post training assessment was possible in 51 participants, and 6-week and 12-week follow up was possible for 43, and 38 participants respectively. Mean MCQ scores significantly improved over time (p<0.001), and a significant improvement was noted in “average ventilation volume”, “compression count”, and “compressions with no error”, “adequate depth”, “average depth”, and “compression rate” (p<0.01). The proportion of participants with compression depth ≥40mm increased post intervention (p<0.05) and at 12-week follow up (p<0.05), and proportion of ventilation volumes between 400-1000mls increased post intervention (p<0.001). A significant increase in the proportion of participants who “checked for responsiveness”, “opened the airway”, “performed a breathing check”, who used the “correct compression ratio”, and who used an “appropriate facemask technique” was also noted (p<0.001). A train-the-trainer model of resuscitation education was effective in improving resuscitation knowledge and skills in Sri Lankan rural peripheral hospital doctors. Improvement was sustained to 12 weeks for most components of resuscitation knowledge and skills. Further research is needed to identify which components of training are most effective in leading to sustained improvement in resuscitation.