Genetic diversity of foot-and-mouth disease virus serotype O in Pakistan and Afghanistan, 1997–2009

Foot-and-mouth disease (FMD) is endemic in Pakistan and Afghanistan; serotypes O, A and Asia-1 of the virus are responsible for the outbreaks in these countries with FMDV type O usually being the most common. In the present study, the nucleotide sequences encoding the FMDV capsid protein VP1 from virus samples were determined. Phylogenetic analysis of the serotype O FMD viruses circulating in Pakistan and Afghanistan between 1997 and 2009 revealed the presence of at least three different lineages within the ME-SA (Middle East South Asia) topotype. The three lineages detected in this study are Pak98, Iran2001 and PanAsia. The PanAsia lineage is currently dominant in the area and is evolving with time as revealed by the appearance of distinct variants e.g. PanAsia-II and a new variant designated here as PanAsia-III. The rates of evolution of the O-PanAsia-II and III sublineages prevalent in the region were found to be 6.65 × 10⁻³ (95% CI = 5.49–7.80 × 10⁻³) and 7.80 × 10⁻³ (95% CI = 6.72–8.89 × 10⁻³) substitutions per nucleotide per year, respectively. The present study reveals the presence of multiple (sub-)lineages of FMDV serotype O co-circulating in the region and that significant new variants are frequently emerging.     

Crimean-Congo hemorrhagic fever virus infection triggers the upregulation of the Wnt signaling pathway inhibitor genes

Virus Genes - Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic agent. Thus far, vaccines and specific antiviral therapies are not available against the threat of infection. Our...     

Value and risk of laparoscopic surgery in hemophiliacs—experiences from a tertiary referral center for hemorrhagic diatheses

Purpose

Laparoscopic surgery (LS) is gaining popularity worldwide because of benefits like faster recovery, earlier hospital discharge, and better cosmetic results. In hemophiliacs, surgery in general harbors an increased risk for severe complications. Whether LS or conventional surgery (CS) should be recommended in these patients is controversial and therefore the issue of our present study.

Methods

We performed a retrospective matched-pair analysis including laparoscopically operated non-hemophiliacs (LONH), laparoscopically operated hemophiliacs (LOH), and conventionally operated hemophiliacs (COH) concerning duration of surgery, drainages, hospital stay, complications, factor use (VIII, IX, and X), and blood values. Mann-Whitney U test was used (significance level P?=?0.05).

Results

No significant differences were found in duration of surgery and drains in laparoscopically or conventionally operated hemophiliacs versus matched pairs. Complication rate did not differ among the different groups. Concerning the total duration of hospital stay (t-DHOS) and the postoperative duration of hospital stay (p-DHOS), there was no statistical difference between LOH versus matched LONH. However, in COH versus matched LOH, a longer time was required for preparation and recovery (t-DHOS, P?=?0.04; p-DHOS, P?<?0.001). Also, the median factor supply perioperatively including the day of surgery did not differ between laparoscopically versus conventionally operated hemophiliacs.

Conclusions

Our study underscores the safety and benefits of laparoscopic procedures in hemophiliacs by showing a significantly shorter hospital stay for these patients resulting in reduced therapeutic costs and a faster mobilization. Still, the surgical and perioperative management of hemophiliacs continues to be a challenge requiring an experienced interdisciplinary team.     

Hydrogen sulphide and tempol treatments improve the blood pressure and renal excretory responses in spontaneously hypertensive rats

Oxidative stress and suppressed H₂S production lead to increased renal vascular resistance, disturbed glomerular hemodynamics, and abnormal renal sodium and water handling, contribute to the pathogenesis and maintenance of essential hypertension in man and the spontaneously hypertensive rat. This study investigated the impact of H₂S and tempol alone and in combination on blood pressure and renal hemodynamics and excretory functions in the SHR. Groups of WKY rats or SHR (n?=?6) were treated for 4?weeks either as controls or received NaHS (SHR?+?NaHS), tempol (SHR?+?Tempol), or NaHS plus tempol (SHR?+?NaHS?+?Tempol). Metabolic studies were performed on days 0, 14, and 28, thereafter animals were anaesthetized to measure renal hemodynamics and plasma oxidative and antioxidant markers. SHR control rats had higher mean arterial blood pressure (140.0?±?2 vs. 100.0?±?3?mmHg), lower plasma and urinary H₂S, creatinine clearance, urine flow rate and urinary sodium excretion, and oxidative stress compared to WKY (all p?p?2S and tempol together resulted in greater reductions in blood pressure and normalization of kidney function compared with either compound alone.     

Physical violence by husbands: magnitude, disclosure and help-seeking behavior of women in Bangladesh

This paper explores the magnitude of physical violence by husbands, the disclosure of it and the help-seeking behavior of abused women in urban and rural Bangladesh. The data come from a larger study on domestic violence against women conducted in Bangladesh during 2000-2004. All ever-married women covered by the population-based survey component (n=2702) conducted in 2001 were included in the current analysis. We also draw on in-depth interviews with 28 women who were physically abused by their husbands. Results show a high prevalence of lifetime physical spousal violence against women: 40% in urban and 42% in rural areas. Most of the abused women (66%) were silent about their experience. The main reasons behind this silence were high acceptance of violence, stigma and fear of greater harm. Sixty percent of urban and 51% of rural abused women never received any help from others. Only 2% ever sought help from institutional sources, from where support was not forthcoming. Women approached these sources only when they could not endure anymore or the violence became life threatening or children were at risk. The findings show that although providing appropriate services is absolutely necessary, it is also important to foster the use of such services and to help women overcome the barriers for accessing these services.     

Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and In Silico Studies

ERAP1 is a key aminopeptidase involved in peptide trimming before major histocompatibility complex (MHC) presentation. A single nucleotide polymorphism (SNP) in the ERAP1 gene can lead to impaired trimming activity and affect ERAP1 function. ERAP1 genetic variations have been linked to an increased susceptibility to cancer and autoimmune disease. Here, we report the discovery of novel ERAP1 inhibitors using a high throughput screening approach. Due to ERAP1 broad substrate specificity, the hit finding strategy included testing inhibitors with a range of biochemical assays. Based on the hit potency, selectivity, and in vitro absorption, distribution, metabolism, excretion, and toxicity, the benzofuran series was selected. Fifteen derivatives were designed and synthesized, the compound potency was improved to the nanomolar range, and the structure–activity relationship supported by modeling studies.     

Prognostic value of troponins in sepsis: a meta-analysis

Rationale

The role of biomarkers such as troponin in risk stratification of sepsis is still debated. The aim of this meta-analysis is to assess the relation between troponin elevation in sepsis and mortality.

Methods

All observational studies from Embase, Medline and those manually searched up to September 2010 were included. Studies identified were those which reported on patients with a diagnosis of sepsis and if a 2 × 2 table could be constructed based on troponins and death. We pooled the relative risk (RR) and odds-ratio (OR) using the inverse variance method in studies that conducted univariate and multivariable (adjusted) analysis.

Main results

Thirteen studies encompassing 1,227 patients were included. The prevalence of elevated troponin was 61 % ([95 %] CI 58–64 %). Elevated troponin was significantly associated with all-cause mortality (RR 1.91; CI 1.63–2.24), with homogeneity across studies. In adjusted analysis (four studies comprising 791 patients) according to prognostic scores, elevated troponin was associated with an increased risk of death (OR 1.92; CI 1.35–2.74). The area under the ROC curve was 0.68 (CI 0.63–0.71). Pooled sensitivity and specificity were 77 % (CI 61–88) and 47 % (CI 30–64) with heterogeneity across studies. It corresponded to positive and negative likelihood ratios of 1.50 (95 % CI: 1.20–1.90) and 0.49 (CI 0.38–0.64), respectively.

Conclusions

Elevated troponin identifies a subset of patients with sepsis at higher risk of death. Further studies are needed to define the precise role of troponins and their optimal cut-offs.     

Case-Case-Control Study of Patients with Carbapenem-Resistant and Third-Generation-Cephalosporin-Resistant Klebsiella pneumoniae Bloodstream Infections

Strains of third-generation-cephalosporin-resistant Klebsiella pneumoniae (3GCRKP) and carbapenem-resistant K. pneumoniae (CRKP) are rapidly spreading. Evidence is needed to establish whether differences exist between patients at risk for 3GCRKP and those at risk for CRKP bloodstream infections (BSIs); thus, this retrospective case-case-control study was conducted to determine if the risk factors for these two infections differ. The inclusion criteria for cases were positive blood cultures for K. pneumoniae, first episode of BSI, age of ≥18 years, and susceptibility results indicating resistance to either third-generation cephalosporins (3GCRKP group) or carbapenems and cephalosporins (CRKP group). Controls were patients admitted for ≥72 h and were matched to cases by month/year and medical unit. Variables of interest were analyzed by univariate analysis, and those of significance were analyzed by logistic regression. In total, 111 patients with 3GCRKP BSIs and 43 patients with CRKP BSIs were matched to 154 controls. Multivariate analyses of 3GCRKP case and control groups demonstrated that a length of stay (LOS) of >40 days (odds ratio [OR], 17.7; 95% confidence interval [CI], 3.7 to 84.3), the use of antibiotics in the past 90 days (OR, 4.3; 95% CI, 1.5 to 11.9), and the presence of a central venous catheter (OR, 4.1; 95% CI, 1.3 to 13.4) were independent risk factors. Multivariate analyses of the CRKP case and control groups demonstrated that a LOS of >40 days (OR, 13.5; 95% CI, 2.9 to 62.8) and the use of antibiotics in the past 90 days (OR, 5.9; 95% CI, 1.3 to 26.5) were independent risk factors. Similar factors put patients at risk for these two types of K. pneumoniae BSIs.     

β-Cell Failure in Type 2 Diabetes: A Case of Asking Too Much of Too Few?

The islet in type 2 diabetes (T2DM) is characterized by a deficit in β-cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low β-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased β-cell workload results in T2DM in some but not all individuals. We propose that the extent of the β-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate β-cell mass in the face of subsequent insulin resistance may expose β-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising β-cell function and inducing β-cell apoptosis.