Susceptibility of mice genetically deficient in SP-A or SP-D gene to Invasive Pulmonary Aspergillosis

Pulmonary surfactant proteins, SP-A and SP-D, are carbohydrate pattern recognition molecules of innate immunity, which significantly enhance phagocytosis and killing of Aspergillus fumigatus, a pathogenic fungus, by neutrophils and macrophages. The present study examined the susceptibility of immunosuppressed SP-A gene deficient (SP-A^?/?) or SP-D gene deficient (SP-D^?/?) mice to A. fumigatus conidia challenge compared to wild-type (WT) mice. A. fumigatus-challenged SP-A^?/? (SP-A^?/? IPA) mice showed less mortality (40%) than the WT-IPA mice (100%) and increased mortality (60%) following administration of SP-A with decreased TNF-α and IFN-γ to IL-4 ratio than SP-A^?/? IPA mice. The SP-D^?/? IPA mice (57.14%) showed similar mortality as WT-IPA mice (60%). However, the SP-D ^?/? IPA mice (42.86% mortality on day 2) died earlier than the WT-IPA mice (20% mortality on day 2), showed a higher hyphal density and tissue injury in lungs. Treatment with SP-D or a recombinant fragment of human SP-D rhSP-D reduced the mortality to 50% and 33%, respectively, concomitant with higher IFN-γ to IL-4 ratios in treated SP-D^?/? mice, compared to untreated control group. The results showed that SP-D gene deficient mice are more susceptible to IPA while SP-A gene deficient mice acquire resistance to IPA.     

Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer

Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of ∼14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8–7.4], P < 10⁻¹⁰), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10⁻⁵). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.Targets of polycomb group proteins (PCGTs) are repressed in human embryonic and adult stem cells (Lee et al. 2006). The repression mechanism involves chromatin modifications and is reversible, allowing stem cells and multipotent progenitors to differentiate into committed cell lineages through expression of specific PCGTs. Recently, we and others have demonstrated that stem cell PCGTs in human embryonic stem cells (hESC) are far more likely to undergo cancer-specific promoter DNA hypermethylation than non-targets, suggesting a stem-cell origin model of cancer. In this model, PCGTs in stem cells would gradually undergo de novo methylation, irreversibly locking cells in an undifferentiated state of self-renewal and thereby predisposing them to subsequent malignant transformation (Ohm et al. 2007; Schlesinger et al. 2007; Widschwendter et al. 2007). However, the mechanisms and factors contributing to this de novo methylation are not yet known.Age is by far the strongest demographic risk factor for cancer. Besides time-dependent DNA damage (Hoeijmakers 2009), there is now also substantial evidence that aging affects DNA methylation (DNAm) of specific loci, including cancer-related genes (Issa et al. 1994, 1996; Ahuja et al. 1998; Nakagawa et al. 2001; So et al. 2006; Fraga and Esteller 2007; Fraga et al. 2007; Bjornsson et al. 2008; Christensen et al. 2009). Based on these observations, we hypothesized that age may induce DNAm of PCGTs, and thereby predispose to cancer. Although blood and epithelial cells originate from different germ layers, we speculated that genes that are mandatory for the differentiation of epithelial cells are more likely to become methylated with increasing age in non-epithelial tissue such as blood. Hence, in order to identify age-dependent CpGs that may be important in the biology of epithelial cancers, we first retrieved an age-dependent signature from peripheral blood cells, then validated the age signature in independent blood samples and normal epithelial tissues, and finally tested the biological relevance of this signature in epithelial neoplasias.     

Right ventricular dysfunction and adverse outcome in patients with advanced heart failure

BackgroundIn patients with heart failure (HF) from left ventricular systolic dysfunction, the presence of coexistent right ventricular (RV) dysfunction is associated with poor exercise capacity and reduced survival. We sought to determine whether a simple measure of RV function, the RV myocardial performance index (RV MPI), is associated with adverse outcome in a population of advanced heart failure patients selected to receive cardiac resynchronization therapy (CRT).Methods and ResultsThe RV MPI was measured on 77 consecutive preimplantation echocardiograms. The relationship between RV MPI and the end point of all-cause mortality, transplantation, or ventricular assist device placement was evaluated. The end point occurred in 28 patients (36%) during a median follow-up of 21 months. The median RV MPI was 0.73 (interquartile range 0.51–0.89). Worse RV function, as demonstrated by a higher RV MPI, was seen in those patients who reached the end point compared with those who did not (0.83 vs. 0.69, P = .004). The highest tercile of RV MPI was associated with a 3.3-fold increased risk of poor outcome (95% CI 1.3–8.5). Each 0.1 unit increase in RV MPI was associated with a 16% increased risk (95% CI 8–26). After adjusting for other echocardiographic variables, RV MPI remained significantly associated with the outcome.ConclusionIn a population of advanced HF patients selected to receive CRT, RV dysfunction, as assessed by the RV MPI, is associated with adverse outcome. Wider use of this simple nongeometric parameter may help to identify patients for whom options for further intervention should be carefully evaluated.     

Roles of syndecan-1, bcl6 and p53 in diagnosis and prognostication of immunoproliferative small intestinal disease

AIM: To evaluate roles of syndecan-1, bcl6 and p53 in diagnosis and prognostication of immunoproliferative small intestinal disease (IPSID) and to study profiles of kappa (κ) and lambda (λ) light chains and IgA heavy chain. METHODS: The study consisted of 11 cases of IPSID and similar number of controls which included 11 of normal intestinal mucosa and 11 of high grade B cell lymphoma of ileum. The parameters analyzed included clinical profiles, biochemical and other laboratory investigations, radiologic and histological findings including immunohistochemistry. RESULTS: All IPSID cases had demonstrable serum IgA heavy chain and heavy mucosal plasma cell infiltration. According to Galian's histological staging, there were 4 patients with stage A and 7 with stage B.κandλlight chains were over-expressed in 7 patients; 1 stage A patient had H pylori-positive active gastritis and eradication of H pylori led to disease remission. Stage A biopsies had higher expression for syndecan-1, while stage B had higher expression for bcl6 and p53. Syndecan-1,κandλ, light chains and IgA heavy chain showed inverse relationship with bcl6 and p53. All patients were treated with doxycycline. CHOP regime was added in 5 patients who developed frank lymphoma. Three died of the disease due to extensive organ infiltration. CONCLUSION: Certain immunomarkers like syndecan-1,κandλ, light chains and IgA heavy chain could be of much help in identifying early stage IPSID. Stage B IPSID showed higher expression for bcl6 and p53 than stage A IPSID. bcl6 and p53 expressions correlated with a more advanced disease stage and aggressive tumour behavior.     

Are there gender differences in diabetes care among elderly medicare enrolled veterans?

OBJECTIVE: To examine gender differences in diabetes care process measures and intermediate outcomes among veteran clinic users. DESIGN: A retrospective cohort study using Veterans Health Administration (VHA) and Medicare files of VHA clinic users with diabetes. Diabetes care process measures were tests for hemoglobin A1c (HbA1c), low-density lipoprotein (LDL-C) values, and eye exams. Intermediate outcomes were HbA1c and LDL-C values below recommended thresholds. Chi-square tests and logistic regressions were used to assess gender differences. PARTICIPANTS: Study population included 3,225 women and 231,922 men veterans with diabetes, enrolled in Medicare fee-for-service and alive at the end of fiscal year 2000. RESULTS: Overall, there were no significant gender differences in HbA1c or LDL-C testing. However, women had higher rates in these process measures than men among the non-African American minorities. Women were more likely to have completed eye exams (odds ratio [OR]=1.11; 99% confidence interval [CI]=1.10, 1.23) but were less likely to have LDL-C under 130 mg/dL (OR=0.77; 99% CI=0.69, 0.87). CONCLUSIONS: Among VHA patients with diabetes, clinically significant gender inequality was not apparent in most of diabetes care measures. However, there was evidence of better care among nonwhite and non-African American women than their male counterparts. Further research on interaction of race and gender on diabetes care is needed. This includes evaluation of integrated VHA women’s health programs as well as cultural issues. Lower LDL-C control among women suggests areas of unmet needs for women and opportunities for future targeted quality improvement interventions at system and provider levels.     

Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials

To evaluate the evidence for the use of probiotics in the prevention of acute diarrhoea, we did a meta-analysis of the available data from 34 masked, randomised, placebo-controlled trials. Only one trial was community based and carried out in a developing country. Most of the remaining 33 studies were carried out in a developed country in a health-care setting. Evaluating the evidence by types of acute diarrhoea suggests that probiotics significantly reduced antibiotic-associated diarrhoea by 52% (95% CI 35-65%), reduced the risk of travellers' diarrhoea by 8% (-6 to 21%), and that of acute diarrhoea of diverse causes by 34% (8-53%). Probiotics reduced the associated risk of acute diarrhoea among children by 57% (35-71%), and by 26% (7-49%) among adults. The protective effect did not vary significantly among the probiotic strains Saccharomyces boulardii, Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus bulgaricus, and other strains used alone or in combinations of two or more strains. Although there is some suggestion that probiotics may be efficacious in preventing acute diarrhoea, there is a lack of data from community-based trials and from developing countries evaluating the effect on acute diarrhoea unrelated to antibiotic usage. The effect on acute diarrhoea is dependent on the age of the host and genera of strain used.     

Cellular localization and trafficking of tissue factor

Tissue factor (TF) is the cellular receptor for clotting factor VIIa (FVIIa). The formation of TF-FVIIa complexes on cell surfaces triggers the activation of coagulation cascade and cell signaling. In the present study, we characterized the subcellular distribution of TF and its transport in fibroblasts by dual immunofluorescence confocal microscopy and biochemical methods. Our data show that a majority of TF resides in various intracellular compartments, predominantly in the Golgi. Tissue factor at the cell surface is localized in cholesterol-rich lipid rafts and extensively colocalized with caveolin-1. FVIIa binding to TF induces the internalization of TF. Of interest, we found that TF-FVIIa complex formation at the cell surface leads to TF mobilization from the Golgi with a resultant increase in TF expression at the cell surface. This process is dependent on FVIIa protease activity. Overall, the present data suggest a novel mechanism for TF expression at the cell surface by FVIIa. This mechanism could play an important role in hemostasis in response to vascular injury by increasing TF activity where and when it is needed.