Nemaline myopathy in a newborn infant: a rare muscle disorder.

Nemaline myopathy (NM) is a genetically and clinically heterogeneous muscle disorder, defined by the presence of characteristic nemaline bodies on muscle biopsy. The disease has a wide spectrum of phenotypes, ranging from forms with neonatal onset and fatal outcome to asymptomatic forms. The neonatal form is severe and usually fatal. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis difficult during infancy. There is no curative treatment. L-tyrosine may prevent aspiration by reducing pharyngeal secretions and drooling. Most of the patients die from respiratory and cardiac failure. This article discusses a newborn infant who presented with generalized weakness and respiratory failure. Partial response to L-tyrosine treatment was noted. The case is worth presenting to remind clinicians of congenital myopathies in the differential diagnosis of floppy infant during neonatal period and to emphasize the importance of muscle biopsy in diagnosis.

Symptoms and quality of life in obese children and adolescents with non-alcoholic fatty liver disease.

BACKGROUND: Data on the quality of life (QOL) of children with non-alcoholic fatty liver disease (NAFLD) are needed to estimate the true burden of illness in children with NAFLD. AIM: To characterize QOL and symptoms of children with NAFLD and to compare QOL in children with NAFLD with that in a sample of healthy children. METHODS: Quality of life and symptoms were assessed in children with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network. PedsQL scores were compared with scores from healthy children. For children with NAFLD, between-group comparisons were made to test associations of demography, histological severity, symptoms and QOL. RESULTS: A total of 239 children (mean age 12.6 years) were studied. Children with NAFLD had worse total (72.8 vs. 83.8, P < 0.01), physical (77.2 vs. 87.5, P < 0.01) and psychosocial health (70.4 vs. 81.9, P < 0.01) scores compared with healthy children. QOL scores did not significantly differ by histological severity of NAFLD. Fatigue, trouble sleeping and sadness accounted for almost half of the variance in QOL scores. Impaired QOL was present in 39% of children with NAFLD. CONCLUSIONS: Children with NAFLD have a decrement in QOL. Symptoms were a major determinant of this impairment. Interventions are needed to restore and optimize QOL in children with NAFLD.

Chemoprevention for Barrett's esophagus trial. Design and outcome measures.

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.

Gender representation in trials.

The perception is that women have been understudied relative to men. It has been sufficient to cause Congress to enact legislation to require that a clinical trial must be "designed and carried out in a manner sufficient to provide for a valid analysis of whether the variables being studied in the trial affect women ellipsis differently than other subjects in the trial." We looked for evidence as to whether the perception has a basis in fact by looking at measures of gender-based research effort. Clinical trials, published between 1966 and 1998 in U.S. journals and indexed in MEDLINE, were classified by gender. Reports of trials appearing in five widely circulated medical journals (Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, and New England Journal of Medicine) in 1985, 1990, and 1995 were retrieved and read to obtain counts of the numbers of males and females represented in trials published in those journals. For reports of trials published in U.S. journals, the percent involving males and females, males only, females only, and those where gender was not specified were 55.2%, 12.2%, 11.2%, and 21.4%, respectively. Counts of males and females represented in the reports of trials appearing in the five aforementioned journals were 355,624 and 550,743, respectively. We did not find evidence of systematic effort bias against females.

FDA censoring of manufacturers' postmarketing commitments in HIV/AIDS drug approval letters.

CONTEXT: Changing evidentiary standards and partial shift of the investigational phase of drug approval process to the postmarketing phase. OBJECTIVE: To determine the availability of information for independent researchers needed to examine accelerated drug approvals to determine how they differ from traditional drug approvals in the HIV/AIDS domain. DESIGN: Identification of all approved HIV/AIDS and AIDS-related conditions drugs between 1987 and 1999. Follow-up of postmarketing study requirements in the approval letters addressed to the manufacturers. SETTING: Accelerated approval has been expanded to other disease conditions in the past decade. INTERVENTION: Request of approval letters from the U.S. Food and Drug Administration for 76 regulatory actions including expanded access and accelerated and traditional approvals for 42 drugs under the Freedom of Information Act (FOIA) between September 1998 and October 1999. MAIN OUTCOME MEASURE(S): Obtainability of approval letters and uncensored postmarketing study requirements. RESULTS: Fifty-five approval letters were received. Postmarketing study commitments of manufacturers were censored in 25 letters received. We were unable to obtain uncensored copies of those approval letters as of May 2000. Censoring was associated with whether (1) the Prescription Drug User Fee Act of 1992 was applicable to the drug (odds ratio (OR) = 5.7, 95% confidence interval (CI) = 1.4- 23.7) and (2) the new drug application was for a new molecular entity or new drug formulation (OR = 4.2, 95% CI = 1.3 -13.6). CONCLUSIONS: Continued secrecy may stifle independent research and hinder health care providers and patients in making informed decisions.

Exercise electrocardiography test in patients with aortic stenosis. Differential features from that of coronary artery disease.

BACKGROUND AND AIM OF THE STUDY: Studies that have been conducted with an exercise test in patients with aortic stenosis (AS) have demonstrated that results of an exercise test can mimic that of coronary artery disease (CAD). The objective of our study was to investigate if there was any differential feature(s) of an exercise test in patients with AS compared to those with CAD. METHODS: We prospectively studied 42 patients with AS (AS group, age 37 +/- 23, range 8-75) with an averaged maximal gradient of 42 +/- 19 mmHg (range 26-95). All patients had undergone a coronary angiography within 1 week of the exercise test and none had CAD. Another 100 patients with CAD, diagnosis proven with coronary angiography, comprised our second group for the comparison (CAD group). Cornell protocol was used in all patients. RESULTS: ST-segment depression was observed in all patients (160 +/- 25 microV in AS group and 170 +/- 20 microV in CAD group, P>0.05). Thirty-four (81%) patients in AS group and 88 (88%) patients in CAD group exceeded the classical threshold for the test positivity (P>0.05). ST/HR slopes derived from heart rate adjustment to ST-segment level did not differ between the study groups (3.2 +/- 2.3 and 3.7 +/- 2.2 microV/beat/min, in AS and CAD groups, respectively, P>0.05). Recovery-phase patterns of ST-segment in heart rate domain were quite different between AS and CAD (clockwise loop: 86% vs. 0%; counterclockwise loop: 9% vs. 88% in AS group and CAD group, respectively, both P<0.0001). Percentage of intermediate loop was 5% in AS group and 12% in CAD group (P>0.05). CONCLUSIONS: Our study demonstrated that patients with AS could be distinguished from those with CAD with the method of rate-recovery loop analysis.

High prevalence of hypercoagulable states in patients with recurrent thrombosis of mechanical heart valves.

BACKGROUND AND AIMS OF THE STUDY: Thrombosis is one of the most feared and life-threatening complications of mechanical heart valves (MHV), with an incidence of 1-3 per 100 patient-years. Hypercoagulable states are highly prevalent in the general population and can predispose MHV to thrombus formation. Thus, we conducted a study to investigate the frequency of hypercoagulable states in patients with MHV who had recurrent thrombosis at least twice after valve implantation. METHODS: Fifteen patients (mean age 42 +/- 11 years; range: 18 to 55 years) with recurrent thrombosis of MHV (2.4 +/- 0.8 recurrences/patient) (group 1) and 15 matched patients (mean age 40 +/- 12 years; range: 18 to 55 years) with MHV without thrombosis (group 2) were followed up with transthoracic and transesophageal echocardiography. Patients' sera were monitored for antibodies to cardiolipin (ACLA-IgG and ACLA-IgM), phosphatidylserine (APSA), lupus-type anticoagulant (LA) and lipoprotein(a) (LP(a)). RESULTS: Average values for group 1 versus group 2 were: ACLA-IgG (normal range < 15 GPLU/ml) 24.7 +/- 14.6 versus 6.2 +/- 2.7 (p < 0.001); ACLA-IgM (< 12.5 MPLU/ml) 7.9 +/- 5.0 versus 3.3 +/- 1.7 (u = 185; p < 0.001); APSA (< 12 RLU/ml) 4.8 +/- 5.7 and 2.9 +/- 1.2 (p = 0.56); and LP(a) (< 30 mg/dl) 36.5 +/- 26.5 and 13.4 +/- 7.1 (p < 0.001). The frequency of LA-positive cases was 4/15 in group 1 and 0/15 in group 2 (p > 0.05). The frequency of abnormally high levels of ACLA-IgG was 9/15 in group 1 and 0/15 in group 2 (p < 0.001); of ACLA-IgM, 2/15 in group 1 and 0/15 in group 2 (p > 0.05); of APSA, 1/15 in group 1 and 0/15 in group 2 (p > 0.05); and of LP(a), 5/15 in group 1 and 0/15 in group 2 (p < 0.05). At least one of the factors included in this study was abnormal in 14 of 15 (93%) patients (p < 0.0001). CONCLUSIONS: Hypercoagulable states are highly prevalent in patients with recurrent thrombosis of MHV. All patients evaluated for therapy of obstructive thrombosis of MHV should be investigated for hypercoagulable state. Moreover, in high-risk patients, surgical replacement of the MHV with a bioprosthesis should be considered.