The heart and cardiac conduction system in polymyositis-dermatomyositis: A clinicopathologic study of 16 autopsied patients

We reviewed the clinical records of 16 patients with polymyositis-dermatomyositis syndromes autopsied at The Johns Hopkins Hospital to determine the nature and extent of cardiac involvement and its correlation with the severity of disease as a whole. The adult patients ranged in age from 32 to 84 years (average 56); the 2 children were aged 2 and 10 years. The duration of disease ranged from 1 to 72 months (average 21). Seven patients had dermatomyositis, 5 had dermatomyositls with malignancy, 2 had childhood dermatomyositis and 2 had an overlap syndrome. Seven patients had clinical evidence of congestive heart failure, 4 of whom had microscopic evidence of myocarditis. Two patients had bundle branch block; in 1 there was direct involvement of the conduction system by myositis and contraction band necrosis. Evidence of active myocarditis was present in 4 patients (25 %); all had congestive failure. Focal myocardial flbrosis was present in 4 patients. Vascular alterations were present in the coronary arteries in 5 patients (31 %). Three had active vasculitis, 1 had Intimai proliferation and 1 had medial sclerosis with calcification. All patients with active myocarditis had skeletal muscle involvement. Nine patients had myositis without myocarditis. There was no correlation of overall severity of the disease with the presence or absence of active myocarditis. The present study shows that cardiac involvement may be common in polymyositis; congestive failure or conduction abnormalities arising in this setting may be indicative of myocarditis.     

Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances.

Cushing's syndrome (CS), which is caused by excessive circulating glucocorticoid concentrations, is rare in the paediatric age range but presents a diagnostic and therapeutic challenge. Most paediatric endocrinologists have limited experience of managing children or adolescents with CS and thus benefit from close consultation with colleagues who treat adult patients. A protocol for investigation is required that broadly follows the model for adult patients. Here, the epidemiology and diagnosis of different causes of CS are discussed according to typical age of presentation. Treatment strategies for adrenocorticotrophic hormone (ACTH)-independent and ACTH-dependent CS are described and critically appraised. The management of paediatric CS patients after cure also presents challenges for optimizing growth, bone health, reproduction and body composition from childhood into and during adult life.     

Screening for colorectal cancer on the front line

OBJECTIVE: The aim of this study was to assess knowledge, beliefs, and practices of primary care clinicians regarding colorectal cancer screening. METHODS: We surveyed 77 primary care providers in six clinics in central Massachusetts to evaluate several factors related to colorectal cancer screening. RESULTS: Most agreed with guidelines for fecal occult blood test (97%) and sigmoidoscopy (87%), which were reported commonly as usual practice. Although the majority (86%) recommended colonoscopy as a colorectal cancer screening test, it was infrequently reported as usual practice. Also, 36% considered barium enema a colorectal cancer screening option, and it was rarely reported as usual practice. Despite lack of evidence supporting effectiveness, digital rectal examinations and in-office fecal occult blood test were commonly reported as usual practice. However, these were usually reported in combination with a guideline-endorsed testing option. Although only 10% reported that fecal occult blood test/home was frequently refused, 60% reported sigmoidoscopy was. Frequently cited patient barriers to sigmoidoscopy compliance included fear the procedure would hurt and that patients assume symptoms occur if there is a problem. Perceptions of health systems barriers to sigmoidoscopy were less strong. CONCLUSIONS: Most providers recommended guideline-endorsed colorectal cancer screening. However, patient refusal for sigmoidoscopy was common. Results indicate that multiple levels of intervention, including patient and provider education and systems strategies, may help increase prevalence.     

Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance

OBJECTIVE: Tamoxifen induced hepatotoxicity has not been investigated in breast cancer patients with pre-existing liver steatosis. The aim of our study was to investigate the most common predisposing factors for non-alcoholic fatty liver disease in breast cancer patients with liver steatosis, treated with adjuvant tamoxifen therapy, in order to evaluate their role in the appearance of tamoxifen induced hepatotoxicity. METHODS: Clinical and laboratory evaluation, including an oral glucose tolerance test, was done in 60 women with breast cancer and liver steatosis before the beginning of adjuvant tamoxifen treatment and every 6 months during treatment. Tamoxifen induced hepatotoxicity was defined as abnormal liver function tests during tamoxifen treatment whereas these test results were below the normal range at baseline control. Statistical evaluation of data was performed using parametric methodology (the chi-squared test, and Student's t-test, P < 0.05). RESULTS: Twenty-six patients (43.3%) exhibited tamoxifen induced hepatotoxicity (group A) whereas 34 (56.7%) did not (group B). The mean overall follow-up period for the whole group was 37.5 months (SD 27.8, range 6-120 months) and did not differ between the two groups (P = 0.055). There was significant statistical difference in body mass index (BMI) and baseline fasting glucose, cholesterol and triglyceride levels between the two groups. Eighteen of 26 patients (69.2%) from group A had impaired glucose tolerance compared with only 8/34 patients (23.5%) from group B (P < 0.001), a finding observed even in BMI matched patients from the two groups (62.5% vs 12.5%, P = 0.002). CONCLUSIONS: Tamoxifen induced hepatotoxicity is observed in a great proportion of breast cancer patients with pre-existing liver steatosis, especially those with higher BMI and higher glucose and lipid levels at baseline control. Glucose intolerance before the beginning of tamoxifen treatment seems to be a predictor of the hepatotoxicity, unrelated to baseline BMI.     

The mortality consequences of the continued use of chloroquine in Africa: experience in Siaya,western Kenya

In spite of increasing resistance, chloroquine remains the primary drug for treatment of malaria in most sub-Saharan African countries. We evaluated the effect of drug treatment policy on the case-fatality rates of children, adjusting for differing distributions of malaria and severe anemia. In 1991, 63% of children were treated with chloroquine while the remaining 37% were treated with a regimen that would eliminate and clear parasitemia. Case-fatality rates were 13% and 4.1%, respectively; the proportion of deaths attributable to chloroquine treatment was 69%. The trend in case-fatality rates for malaria decreased as an increasing proportion of children received an effective treatment regimen; adjusted malaria case-fatality rates were 5.1%, 3.6%, and 3.3% in 1992, 1993, and 1994, respectively, when 85% of children in 1992 and 97% of children in 1993-1994 received effective therapy. These 4 years of data provide strong evidence that continued use of chloroquine in areas with resistance is contributing to excess Plasmodium falciparum-related deaths.     

Cardiopulmonary exercise variables in diastolic versus systolic heart failure

The response to cardiopulmonary exercise (CPX) in patients with heart failure (HF) with normal left ventricular (LV) ejection fractions (EFs) is not well characterized. To determine if CPX testing could distinguish between patients with HF with normal EFs (>50%; i.e., diastolic HF) and those with decreased EFs (> or =50%; i.e., systolic HF), CPX responses were compared between 185 patients with systolic HF (79% men, mean age 62.6 +/- 10.9 years) and 43 with diastolic HF (54% men, mean age 67.4 +/- 9.8 years) enrolled in a phase II multicenter clinical trial. All patients were evaluated with echocardiography and a standardized CPX test as part of the trial. CPX variables, including oxygen uptake at peak exercise (peak VO(2)) and the slope of the ventilation/carbon dioxide production ratio (VE/VCO(2)), were determined and analyzed by core laboratory personnel. Echocardiographic measurements included the LV EF, the E/A ratio, filling time, cavity volumes, right ventricular function, and mitral regurgitation. Patients in the diastolic HF group tended to be older (p <0.08), with more women (p <0.006) and with greater body mass indexes (p <0.02), than those in the systolic HF group. There was no significant difference in the use of beta blockers or the incidence of coronary artery disease. Patients with diastolic HF had decreased E/A ratios (0.9 +/- 0.4 vs 1.4 +/- 1.1, p <0.02, diastolic HF vs systolic HF) and increased filling times (30.4 +/- 3.2 vs 26.5 +/- 4.7 ms, p <0.01, diastolic HF vs systolic HF). No significant differences in peak VO(2) (14.4 +/- 1.9 vs 15.6 +/- 3.2 ml/kg/min, p = 0.06, diastolic HF vs systolic HF) were observed. The VE/VCO(2) ratios for the 2 groups were abnormal and comparable (32 2 +/- 7.5 vs 34.0 +/- 8.3, p = 0.3, diastolic HF vs systolic HF). In conclusion, the CPX response in patients with diastolic HF and systolic HF is markedly abnormal and indistinguishable with regard to peak VO(2) and ventilation despite marked differences in the LV EF.     

Stress and relapse to drug seeking: studies in laboratory animals shed light on mechanisms and sources of long-term vulnerability

Relapse is a major characteristic of drug addiction disorders and remains the primary problem for treatment. Recently, there has been hope that these disorders may be amenable to pharmacological treatments that have successfully treated other psychopathological disorders. Pharmacological approaches to drug abuse have tended to be guided by the primary drug used by the individual, though substitution has been the guiding principle in some instances, as in the case of methadone maintenance in opioid addiction. Alternatively, blockade or antagonism of the effects of the primary drug being abused has been tried, as in the case of using naltrexone to treat opioid or alcohol addiction. Though reportedly successful in some populations, it is not clear that these approaches effectively control craving for 'highs' or euphoric experiences or a return to drug use as a response to stressful life experiences. Recent experimental studies of the factors that induce craving and relapse to drug use in both humans and laboratory animals, such as drug-related cues, re-exposure to the drug itself, or exposure to stressful events, have shown that the effects of these different events are mediated by dissociable neurochemical circuitry. Another finding that emerges from these studies is that the motivation underlying drug seeking induced by events that precipitate relapse is intensified by the duration and amount of pre-exposure to a drug and the passage of time since withdrawal of the drug. One implication of such findings for the treatment of addiction is that whatever approach is taken, treatment will have to be multifaceted and maintained over an extended period of time after the initial termination of drug use.     

Radiographic hand joint space width assessed by computer is a sensitive measure of change in early rheumatoid arthritis

OBJECTIVE: To compare changes in the computerized measurement of radiographic hand joint space width (JSW) to changes in modified Sharp scores in a retrospective 2-year study of early rheumatoid arthritis (RA). METHODS: First and last standard clinical hand radiographs of 245 patients with RA were analyzed blind using purpose-written computer software to measure changes in JSW for proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints in the 3 middle fingers of each hand. Before measurement, the radiographs were scored independently by 2 radiologists using a modification of Sharp scoring. RESULTS: The paired changes in JSW (-0.051 +/- 0.005 mm) and Sharp score (+3.81 +/- 0.50) were both significant over the study duration. In measured joints showing an increase in joint space narrowing (JSN) score, 92% had a corresponding reduction in JSW. In patients with an increase in total score, including JSN and erosion scores in fingers and wrists, 84% had a corresponding reduction in mean (PIP + MCP) JSW. Patients with no change in Sharp score (47%) still experienced a significant reduction in measured JSW (-0.027 +/- 0.006 mm). HLA-DR genetic markers of severe disease progression were associated with significantly greater reductions in JSW but not increases in Sharp score. (Values: mean +/- standard error of mean). CONCLUSION: Measured JSW averaged over 6 PIP and 6 MCP joints was a valid and more sensitive measure of change than total Sharp score in this study of early RA.     

Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes

Reactive oxygen species (ROS)-mediated cell injury contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction. Protection against ROS requires maintenance of endogenous thiol pools, most importantly, reduced glutathione (GSH), by NADPH. In cardiomyocytes, GSH resides in two separate cellular compartments: the mitochondria and cytosol. Although mitochondrial GSH is maintained largely by transhydrogenase and isocitrate dehydrogenase, the mechanisms responsible for sustaining cytosolic GSH remain unclear. Glucose-6-phosphate dehydrogenase (G6PD) functions as the first and rate-limiting enzyme in the pentose phosphate pathway, responsible for the generation of NADPH in a reaction coupled to the de novo production of cellular ribose. We hypothesized that G6PD is required to maintain cytosolic GSH levels and protect against ROS injury in cardiomyocytes. We found that in adult cardiomyocytes, G6PD activity is rapidly increased in response to cellular oxidative stress, with translocation of G6PD to the cell membrane. Furthermore, inhibition of G6PD depletes cytosolic GSH levels and subsequently results in cardiomyocyte contractile dysfunction through dysregulation of calcium homeostasis. Cardiomyocyte dysfunction was reversed through treatment with either a thiol-repleting agent (L-2-oxothiazolidine-4-carboxylic acid) or antioxidant treatment (Eukarion-134), but not with exogenous ribose. Finally, in a murine model of G6PD deficiency, we demonstrate the development of in vivo adverse structural remodeling and impaired contractile function over time. We, therefore, conclude that G6PD is a critical cytosolic antioxidant enzyme, essential for maintenance of cytosolic redox status in adult cardiomyocytes. Deficiency of G6PD may contribute to cardiac dysfunction through increased susceptibility to free radical injury and impairment of intracellular calcium transport. The full text of this article is available online at http://www.circresaha.org.     

Pouchogram: Predictor of clinical outcome following ileal pouch-anal anastomosis

Among 914 patients undergoing ileal pouch-anal anastomosis (IPAA) between January 1981 and June 1989, 463 (51 percent) had a pouchogram (meglumine diatrizoate [Gastrografin; E.R. Squibb & Sons, Inc., Princeton, NJ] enema) to assess anastomosis and ileal pouch integrity before closure of the ileostomy. The aim was to determine whether a pouchogram was useful in predicting clinical outcome. Results: Abnormal findings were present in 74 patients (16 percent). These included anastomotic and pouch leaks and anstomotic strictures. Pouchograms were normal in the remaining 389 patients (84 percent). The incidence of significant anastomotic stricturing requiring dilatation under anesthesia was much higher in the abnormal than in the normal pouchogram group (33 percent vs. 4 percent, respectively; P less than 0.001). More significantly, an abnormal pouchogram was associated with an overall long-term failure rate of 23 percent, compared with 6 percent for a normal pouchogram (P less than 0.001). Conclusion: Abnormal findings in a pouchogram prior to ileostomy closure indicated those patients at high risk of long-term complications following IPAA.