Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1.

OBJECTIVE: To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1). BACKGROUND: Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1. METHODS: We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials. RESULTS: There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment. CONCLUSIONS: Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.

Leukocyte CTG repeat length correlates with severity of myotonia in myotonic dystrophy type 1.

OBJECTIVE: To quantitate hand muscle myotonia and to assess the relationship between CTG repeat length and myotonia in myotonic dystrophy type 1 (DM1). METHODS: First dorsal interosseous twitch and tetanic contractions evoked by single and 10-Hz ulnar nerve stimulation were recorded with a force transducer in 15 patients with genetically confirmed DM1 and 15 control subjects. An automated computer program analyzed three single and three tetanic recordings per subject on 2 successive days by placing cursors along the declining (relaxation) phase of the force recordings at 90, 50, and 5% of peak force (PF) and calculating relaxation times (RT) between these points. RESULTS: Tetanic and twitch RT was longer and PF lower in patients than subjects. RT (90 to 5%) was above the normal mean + 2.5 SD in 13 tetanic (87%) and 11 (73%) twitch patient recordings. In DM1, prolongation of RT was due mainly to delay in the terminal (50 to 5%), rather than the initial (90 to 50%) phase of relaxation, and was much greater in tetanic than single-twitch recordings. Mean test-retest variability was 19% for tetanic RT and 16% for tetanic PF. In DM1, both tetanic and twitch RT were positively correlated with leukocyte CTG repeat length. CONCLUSIONS: In DM1, myotonia of intrinsic hand muscles can be quantitated reliably by automated analysis of tetanic and twitch RT, targeting, in particular, the terminal phase of muscle relaxation after tetanic stimulation. Severity of hand muscle myotonia depends on CTG repeat length consistent with a "triplet repeat dosage" effect on chloride channel mRNA splicing and function.

Diagnostic value of tests that discriminate between exudative and transudative pleural effusions. Primary Study Investigators.

STUDY OBJECTIVE: To (1) determine appropriate decision thresholds and diagnostic accuracies for pleural fluid (PF) tests that discriminate between exudative and transudative pleural effusions, and (2) evaluate the quality of the primary investigations. DESIGN: Formal meta-analysis of studies that report the diagnostic value of pleural fluid tests. SETTING: Data collected from international academic medical centers. PATIENTS: Hospitalized patients undergoing thoracentesis for pleural effusions. INTERVENTIONS: Primary investigators were requested to transmit original data from patients described in their studies. MEASUREMENTS AND RESULTS: Eight primary studies described 1,448 patients with one or more of the following tests: protein (P)-PF, P-PF/serum ratio (R), bilirubin (BILI)-R, lactate dehydrogenase (LDH)-PF, LDH-R, cholesterol (C)-PF, C-R, and albumin gradient. We found that all eight tests had similar diagnostic accuracies when evaluated by receiver operating characteristic (ROC) analysis except for BILI-R, which was less diagnostically accurate. Decision thresholds determined by ROC analysis differed from previously reported values for LDH-PF (>0.45 upper limits of normal) and C-PF (>45 mg/dL). Paired and triplet test combinations tended to have higher diagnostic accuracies compared with individual tests, but examination of the odds ratios with 95% confidence intervals did not identify a clearly superior test combination. Limitations of the primary studies presented a high likelihood of bias affecting their results. CONCLUSIONS: Several strategies exist for clinicians in utilizing PF tests to classify effusions as exudates or transudates but accurate interpretations of these test results will require better designed studies.

Publications in subspecialty journals on end-of-life ethics.

BACKGROUND: Factors that impede patient adoption of advance directives and inhibit physician-patient discussions about end-of-life issues remain incompletely defined. Determination of publication rates of articles on end-of-life ethics in different subspecialty journals may provide insight into physicians' reluctance to promote advance directives for their patients, which appears to vary between subspecialty fields. OBJECTIVE: To determine publication rates of items on end-of-life issues and other ethics topics. METHODS: We surveyed core journals from 1976 to 1995 in cardiology (n = 5), critical care medicine (n = 1), nephrology (n = 4), oncology (n = 7), and pulmonary medicine (n = 2). RESULTS: Critical care medicine (50.4%; 95% confidence interval [CI], 45.0%-55.8%) and pulmonary medicine (27.6%; 95% CI, 22.7%-32.5%) journals published considerably more articles on end-of-life issues than journals in cardiology (4.1%; 95% CI, 0.8%-7.4%), nephrology (11.0%; 95% CI, 7.9%-14.1%), or oncology (6.9%; 95% CI, 1.5%-12.3%). Oncology (30.7%; 95% CI, 25.3%-36.1%), critical care medicine (29.6%; 95% CI, 24.2%-35.0%), and pulmonary medicine (21.5%; 95% CI, 16.6%-26.4%) journals published more items pertaining to all ethics-related topics compared with cardiology (11.0%; 95% CI, 7.3%-14.7%) or nephrology (7.3%; 95% CI, 4.2%-10.4%) journals. Oncology journal ethics articles most often pertained to informed consent or research issues. CONCLUSIONS: Different internal medicine subspecialty fields demonstrate markedly different patterns of publishing items on topics pertaining to end-of-life issues.

Prospective validation of an acute respiratory distress syndrome predictive score.

We derived an Acute Respiratory Distress Syndrome Score (ARDS Score) from previously described training set data. To validate its diagnostic accuracy for identifying a complicated course (early death or prolonged intubation) in acute lung injury, 50 patients were prospectively scored using an ARDS Score decision threshold of > or = 2.5 to discriminate between an uncomplicated (successful extubation after < or = 14 d) and complicated course. Predictor factors incorporated in the ARDS Score were collected on Day 4 and Day 7 of ARDS and included PaO2/PAO2 ratio, required positive end-expiratory pressure (PEEP), and chest radiograph progression. The diagnostic accuracy of the ARDS Score for determining a complicated course as well as overall survival was compared with three other available indices. Using receiver operating characteristic (ROC) analysis, the ARDS Score and Lung Injury Score (LIS) had the greatest diagnostic accuracy for determining a complicated course, but the Simplified Acute Physiology Score (SAPS Score) (score > or = 14) more accurately identified survival. The LIS components of static respiratory system compliance (Crs) and chest radiograph description did not differ between patient groups. The interobserver concordance of the dynamic chest radiograph interpretation included in the ARDS Score was significant (p < 0.05). We conclude that the previously derived ARDS Score has valid diagnostic accuracy for identifying patients with ARDS who will follow a complicated course.

Gelatin sponge model of effector recruitment: tumoricidal activity of adherent and non-adherent lymphokine-activated killer cells after culture in interleukin-2.

This study examined the specific tumoricidal activity of lymphokine-activated killer (LAK) cells derived from tumor-infiltrating lymphocytes that prevent the growth of secondary tumors in animals harboring progressing primary tumors. A pre-implanted gelatin sponge was employed to capture infiltrating host effectors during the expression of concomitant tumor immunity. Additionally, this study compared the cytolytic activity of these sponge-derived cells with those of counterpart splenic lymphocytes. The cells from both sources were cultured for 4 days in IL-2 to generate LAK cells which were further expanded in IL-2-containing medium for up to 11 days. The cytotoxic activities of these cells were measured in a Chromium-51 release assay. The data revealed that the culture of splenic, or sponge-derived lymphocytes results in the emergence of non-adherent and adherent cell populations with LAK activity. The 4-day sponge-derived LAK cells (adherent and non-adherent) exhibited significant cytolysis of EMT6 cells while the spleen-derived counterparts showed minimal cytotoxicity toward these targets. Some NK activity in LAK cells derived from both sources was evident by their lysis of YAC-1 cells. LAK cells from both sources were incapable of lysing histo-compatible EL-4 (H-2b) tumor cells. The lysis of the EMT6 cells by the sponge-derived LAK cells was maintained over an 11-day period of culture in IL-2. Conversely, the spleen-derived LAK cells were unable to significantly lyse EMT6 cells during this period of in vitro culture. These results show the superior specific tumoricidal activity of LAK cells derived from lymphocytes mediating tumor rejection in vivo (sponge-derived) over that of counterpart splenic lymphocytes.