The role of transforming growth factor beta signaling in cardiac hypertrophy and fibrosis in heart failure

Objective. To determine whether transforming growth factor beta (TGF-β) receptor blockade using an oral antagonist has an effect on cardiac myocyte size in the hearts of transgenic mice with a heart failure phenotype. ^ Methods. In this pilot experimental study, cardiac tissue sections from the hearts of transgenic mice overexpressing tumor necrosis factor (MHCsTNF mice) having a phenotype of heart failure and wild-type mice, treated with an orally available TGF-β receptor antagonist were stained with wheat germ agglutinin to delineate the myocyte cell membrane and imaged using fluorescence microscopy. Using MetaVue software, the cardiac myocyte circumference was traced and the cross sectional area (CSA) of individual myocytes were measured. Measurements were repeated at the epicardial, mid-myocardial and endocardial levels to ensure adequate sampling and to minimize the effect of regional variations in myocyte size. ANOVA testing with post-hoc pairwise comparisons was done to assess any difference between the drug-treated and diluent-treated groups. ^ Results. There were no statistically significant differences in the average myocyte CSA measured at the epicardial, mid-myocardial or endocardial levels between diluent treated littermate control mice, drug treated normal mice, diluent-treated transgenic mice and drug-treated transgenic mice. There was no difference between the average pan-myocardial cross sectional area between any of the four groups mentioned above. ^ Conclusions. TGF-β receptor blockade using oral TGF-β receptor antagonist does not alter myocyte size in MHCsTNF mice that have a phenotype of heart failure. ^

Selection of body fat distribution indices in adults and associations with plasma lipid metabolism variables

Body fat distribution is a cardiovascular health risk factor in adults. Body fat distribution can be measured through various methods including anthropometry. It is not clear which anthropometric index is suitable for epidemiologic studies of fat distribution and cardiovascular disease. The purpose of the present study was to select a measure of body fat distribution from among a series of indices (those traditionally used in the literature and others constructed from the analysis) that is most highly correlated with lipid-related variables and is independent of overall fatness. Subjects were Mexican-American men and women (N = 1004) from a study of gallbladder disease in Starr County, Texas. Multivariate associations were sought between lipid profile measures (lipids, lipoproteins, and apolipoproteins) and two sets of anthropometric variables (4 circumferences and 6 skinfolds). This was done to assess the association between lipid-related measures and the two sets of anthropometric variables and guide the construction of indices.^ Two indices emerged from the analysis that seemed to be highly correlated with lipid profile measures independent of obesity. These indices are: 2*arm circumference-thigh skinfold in pre- and post-menopausal women and arm/thigh circumference ratio in men. Next, using the sum of all skinfolds to represent obesity and the selected body fat distribution indices, the following hypotheses were tested: (1) state of obesity and centrally/upper distributed body fat are equally predictive of lipids, lipoproteins and apolipoproteins, and (2) the correlation among the lipid-related measures is not altered by obesity and body fat distribution.^ With respect to the first hypothesis, the present study found that most lipids, lipoproteins and apolipoproteins were significantly associated with both overall fatness and anatomical location of body fat in both sex and menopausal groups. However, within men and post-menopausal women, certain lipid profile measures (triglyceride and HDLT among post-menopausal women and apos C-II, CIII, and E among men) had substantially higher correlation with body fat distribution as compared with overall fatness.^ With respect to the second hypothesis, both obesity and body fat distribution were found to alter the association among plasma lipid variables in men and women. There was a suggestion from the data that the pattern of correlations among men and post-menopausal women are more comparable. Among men correlations involving apo A-I, HDLT, and HDL$\sb2$ seemed greatly influenced by obesity, and A-II by fat distribution; among post-menopausal women correlations involving apos A-I and A-II were highly affected by the location of body fat.^ Thus, these data point out that not only can obesity and fat distribution affect levels of single measures, they also can markedly influence the pattern of relationship among measures. The fact that such changes are seen for both obesity and fat distribution is significant, since the indices employed were chosen because they were independent of one another. ^

Natural history of placebo treatment in adults acquiring travelers' diarrhea in Mexico

The natural history of placebo treated travelers' diarrhea and the prognostic factors of recovery from diarrhea were evaluated using 9 groups of placebo treated subjects from 9 clinical trial studies conducted since 1975, for use as a historical control in the future clinical trial of antidiarrheal agents. All of these studies were done by the same group of investigators in one site (Guadalajara, Mexico). The studies are similar in terms of population, measured parameters, microbiologic identification of enteropathogens and definitions of parameters. The studies had two different durations of followup. In some studies, subjects were followed for two days, and in some they were followed for five days.^ Using definitions established by the Infectious Diseases society of America and the Food and Drug Administration, the following efficacy parameters were evaluated: Time to last unformed stool (TLUS), number of unformed stools post-initiation of placebo treatment for five consecutive days of followup, microbiologic cure, and improvement of diarrhea. Among the groups that were followed for five days, the mean TLUS ranged from 59.1 to 83.5 hours. Fifty percent to 78% had diarrhea lasting more than 48 hours and 25% had diarrhea more than five days. The mean number of unformed stools passed on the first day post-initiation of therapy ranged from 3.6 to 5.8 and, for the fifth day ranged from 0.5 to 1.5. By the end of followup, diarrhea improved in 82.6% to 90% of the subjects. Subjects with enterotoxigenic E. coli had 21.6% to 90.0% microbiologic cure; and subjects with shigella species experienced 14.3% to 60.0% microbiologic cure.^ In evaluating the prognostic factors of recovery from diarrhea (primary efficacy parameter in evaluating the efficacy of antidiarrheal agents against travelers' diarrhea). The subjects from five studies were pooled and the Cox proportional hazard model was used to evaluate the predictors of prolonged diarrhea. After adjusting for design characteristics of each trial, fever with a rate ratio (RR) of 0.40, presence of invasive pathogens with a RR of 0.41, presence of severe abdominal pain and cramps with a RR of 0.50, number of watery stools more than five with a RR of 0.60, and presence of non-invasive pathogens with a RR of 0.84 predicted a longer duration of diarrhea. Severe vomiting with a RR of 2.53 predicted a shorter duration of diarrhea. The number of soft stools, presence of fecal leukocytes, presence of nausea, and duration of diarrhea before enrollment were not associated with duration of diarrhea. ^

The incidence of necrotizing changes in adults with pneumococcal pneumonia

Background. Necrotizing pneumonia is generally considered a rare complication of pneumococcal pneumonia in adults. We systematically studied the incidence of necrotizing changes in adult patients with pneumococcal pneumonia, and examined the severity of infection, the role of causative serotype and the association with bacteremia. ^ Methods. We used a data base of all pneumococcal infections identified at our medical center between 2000 and 2010. Original readings of chest X-rays (CXR) and computerized tomography (CT) were noted. All images were then reread independently by 2 radiologists. The severity of disease was assessed using the SMART-COP scoring system. ^ Results. There were 351 cases of pneumococcal pneumonia. Necrosis was reported in no original CXR readings and 6 of 136 (4.4%) CTs. With re-reading, 8 of 351 (2.3%) CXR and 15 of 136 (11.0%) CT had necrotizing changes. Overall, these changes were found in 23 of 351 (6.6%, 95% CI 4.0 - 9.1) patients. The incidence of bacteremia and the admitting SMART-COP scores were similar in patients with and without necrosis (P=1.00 and P=0.32, respectively). Type 3 pneumococcus was more commonly isolated from patients with than from patients without necrotizing pneumonia (P=0.05), but a total of 10 serotypes were identified among 16 cases in which the organism was available for typing. ^ Conclusions. Necrotizing changes in the lungs were seen in 6.6% (95% CI 4.0 - 9.1) of a large series of adults with pneumococcal pneumonia. Patients with necrosis were not more likely to have bacteremia or more severe disease. Type 3 pneumococcus was commonly implicated, but 9 other serotypes were also identified.^

Importance of antibiotic class to the development of Clostridium difficile infection (CDI) in adults: A systematic review

C. difficile causes gastrointestinal infections in humans, including severe diarrhea. It is implicated in 20%-30% of cases of antibiotic-associated diarrhea, in 50%-70% of cases of antibiotic-associated colitis, and in >90% of cases of antibiotic-associated pseudomembranous colitis. Exposure to antimicrobial agent, hospitalization and age are some of the risk factors that predispose to CDI. Virtually all hospitalized patients with nosocomially-acquired CDI have a history of treatment with antimicrobials or neoplastic agent within the previous 2 months. The development of CDI usually occurs during treatment with antibiotics or some weeks after completing the course of the antibiotics. ^ After exposure to the organism (often in a hospital), the median incubation period is less than 1 week, with a median time of onset of 2days. The difference in the time between the use of antibiotic and the development of the disease relate to the timing of exogenous acquisition of C. difficile. ^ This paper reviewed the literature for studies on different classes of antibiotics in association with the rates of primary CDI and RCDI from the year 1984 to 2012. The databases searched in this systematic review were: PubMed (National Library of Medicine) and Medline (R) (Ovid). RefWorks was used to store bibliographic data. ^ The search strategy yielded 733 studies, 692 articles from Ovid Medline (R) and 41 articles from PubMed after removing all duplicates. Only 11 studies were included as high quality studies. Out of the 11 studies reviewed, 6 studies described the development of CDI in non-CDI patients taking antibiotics for other purposes and 5 studies identified the risk factors associated with the development of recurrent CDI after exposure to antibiotics. ^ The risk of developing CDI in non-CDI patients receiving beta lactam antibiotics was 2.35%, while fluoroquinolones, clindamycin/macrolides and other antibiotics were associated with 2.64%, 2.54% and 2.35% respectively. Of those who received beta lactam antibiotic, 26.7% developed RCDI, while 36.8% of those who received any fluoroquinolone developed RCDI, 26.5% of those who received either clindamycin or macrolides developed RCDI and 29.1% of those who received other antibiotics developed RCDI. Continued use of non-C. difficile antibiotics especially fluoroquinolones was identified as an important risk factor for primary CDI and recurrent CDI. ^

Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults

Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C → T polymorphism in the MTHFR gene results in thermolability and reduced MTHFR activity that decreases the pool of methylTHF and increases the pool of methyleneTHF. Recently, another polymorphism in MTHFR (1298 A → C) has been identified that also results in diminished enzyme activity. We tested whether carriers of these variant alleles are protected from adult acute leukemia. We analyzed DNA from a case–control study in the United Kingdom of 308 adult acute leukemia patients and 491 age- and sex-matched controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. The MTHFR 677TT genotype was lower among 71 acute lymphocytic leukemia (ALL) cases compared with 114 controls, conferring a 4.3-fold decrease in risk of ALL [odds ratio (OR = 0.23; 95% CI = 0.06–0.81]. We observed a 3-fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymorphism (OR = 0.33; 95% CI = 0.15–0.73) and a 14-fold decreased risk of ALL in those with the MTHFR 1298CC variant allele (OR = 0.07; 95% CI = 0.00–1.77). In acute myeloid leukemia, no significant difference in MTHFR 677 and 1298 genotype frequencies was observed between 237 cases and 377 controls. Individuals with the MTHFR 677TT, 1298AC, and 1298CC genotypes have a decreased risk of adult ALL, but not acute myeloid leukemia, which suggests that folate inadequacy may play a key role in the development of ALL.

Effectiveness and Content Analysis of Interventions to Enhance Oral Antidiabetic Drug Adherence in Adults with Type 2 Diabetes : Systematic Review and Meta-Analysis

Peer reviewed

Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults

Objectives: To assess whether antibiotic treatment for acute cough is effective and to measure the side effects of such treatment.

Routine protein energy supplementation in adults: systematic review

Objectives: To determine whether routine oral and enteral nutritional supplementation can improve the weight, anthropometry, and survival of adult patients.

Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials

Objective: To determine whether preventive treatment for tuberculosis in adults infected with HIV reduces the frequency of tuberculosis and overall mortality.