Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3β Pathway in Mice

Background

Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR), an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA)-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs) and mouse lung fibroblasts (mLFs).

Methods

Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR) in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT) in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s) of airway remodeling.

Results

In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.

Conclusion

Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.     

Detailed Analysis of Gene Polymorphisms Associated with Ischemic Stroke in South Asians

The burden of stroke is disproportionately high in the South Asian subcontinent with South Asian ethnicity conferring a greater risk of ischemic stroke than European ancestry regardless of country inhabited. While genes associated with stroke in European populations have been investigated, they remain largely unknown in South Asians. We conducted a comprehensive meta-analysis of known genetic polymorphisms associated with South Asian ischemic stroke, and compared effect size of the MTHFR C677T-stroke association with effect sizes predicted from homocysteine-stroke association. Electronic databases were searched up to August 2012 for published case control studies investigating genetic polymorphisms associated with ischemic stroke in South Asians. Pooled odds ratios (OR) for each gene-disease association were calculated using a random-effects model. We identified 26 studies (approximately 2529 stroke cases and 2881 controls) interrogating 33 independent genetic polymorphisms in 22 genes. Ten studies described MTHFR C677T (108 with TT genotype and 2018 with CC genotype) -homocysteine relationship and six studies (735 stroke cases and 713 controls) described homocysteine-ischemic stroke relationship. Risk association ORs were calculated for ACE I/D (OR 5.00; 95% CI, 1.17–21.37; p = 0.03), PDE4D SNP 83 (OR 2.20; 95% CI 1.21–3.99; p = 0.01), PDE4D SNP 32 (OR 1.57; 95% CI 1.01–2.45, p = 0.045) and IL10 G1082A (OR 1.44; 95% CI, 1.09–1.91, p = 0.01). Significant association was observed between elevated plasma homocysteine levels and MTHFR/677 TT genotypes in healthy South Asians (Mean difference (ΔX) 5.18 µmol/L; 95% CI 2.03–8.34: p = 0.001). Our results demonstrate that the genetic etiology of ischemic stroke in South Asians is broadly similar to the risk conferred in Europeans, although the dataset is considerably smaller and warrants the same clinical considerations for risk profiling.     

Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde,Ecuador

Background

We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era.

Methods

Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (household-contact characteristics).

Results

Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was <18 months and had vomiting, with household contact <10 years and those sharing a room with the index case being more susceptible. We found no evidence of asymptomatic infections leading to disease transmission.

Conclusion

Transmission rates of rotavirus are high in households with an infected child, while background infections are rare. We have identified factors associated with transmission (vomiting/young age of index case) and susceptibility (young age/sharing a room/being a sibling of the index case). Vaccination may lead to indirect benefits by averting episodes or reducing symptoms in vaccinees.     

cDNA Cloning and Molecular Modeling of Procerain B,a Novel Cysteine Endopeptidase Isolated from Calotropis procera

Procerain B, a novel cysteine protease (endopeptidase) isolated from Calotropis procera belongs to Asclepiadaceae family. Purification of the enzyme, biochemical characterization and potential applications are already published by our group. Here, we report cDNA cloning, complete amino acid sequencing and molecular modeling of procerain B. The derived amino acid sequence showed high sequence homology with other papain like plant cysteine proteases of peptidase C1A superfamily. The three dimensional structure of active procerain B was modeled by homology modeling using X-ray crystal structure of actinidin (PDB ID: 3P5U), a cysteine protease from the fruits of Actinidia arguta. The structural aspect of the enzyme is also discussed.     

Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence

Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60–21.78) and 8.60 years (range = 3.08–13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01×10⁻⁵) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10⁻⁵) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.     

Childhood Intussusception: A Literature Review

Background

Postlicensure data has identified a causal link between rotavirus vaccines and intussusception in some settings. As rotavirus vaccines are introduced globally, monitoring intussusception will be crucial for ensuring safety of the vaccine programs.

Methods

To obtain updated information on background rates and clinical management of intussusception, we reviewed studies of intussusception in children <18 years of age published since 2002. We assessed the incidence of intussusception by month of life among children <1 year of age, seasonality, method of diagnosis, treatment, and case-fatality.

Findings

We identified 82 studies from North America, Asia, Europe, Oceania, Africa, Eastern Mediterranean, and Central & South America that reported a total of 44,454 intussusception events. The mean incidence of intussusception was 74 per 100,000 (range: 9–328) among children <1 year of age, with peak incidence among infants 5–7 months of age. No seasonal patterns were observed. A radiographic modality was used to diagnose intussusception in over 95% of the cases in all regions except Africa where clinical findings or surgery were used in 65% of the cases. Surgical rates were substantially higher in Africa (77%) and Central and South America (86%) compared to other regions (13–29%). Case-fatality also was higher in Africa (9%) compared to other regions (<1%). The primary limitation of this review relates to the heterogeneity in intussusception surveillance across different regions.

Conclusion

This review of the intussusception literature from the past decade provides pertinent information that should facilitate implementation of intussusception surveillance for monitoring the postlicensure safety of rotavirus vaccines.     

The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control

Globally, norovirus is associated with approximately one-fifth of all diarrhea cases, with similar prevalence in both children and adults, and is estimated to cause over 200,000 deaths annually in developing countries. Norovirus is an important pathogen in a number of high-priority domains: it is the most common cause of diarrheal episodes globally, the principal cause of foodborne disease outbreaks in the United States, a key health care–acquired infection, a common cause of travel-associated diarrhea, and a bane for deployed military troops. Partly as a result of this ubiquity and burden across a range of different populations, identifying target groups and strategies for intervention has been challenging. And, on top of the breadth of this public health problem, there remain important gaps in scientific knowledge regarding norovirus, especially with respect to disease in low-income settings.Many pathogens can cause acute gastroenteritis. Historically, rotavirus was the most common cause of severe disease in young children globally. Now, vaccines are available for rotavirus and are universally recommended by the World Health Organization. In countries with effective rotavirus vaccination programs, disease due to that pathogen has decreased markedly, but norovirus persists and is now the most common cause of pediatric gastroenteritis requiring medical attention. However, the data supporting the precise role of norovirus in low- and middle-income settings are sparse. With vaccines in the pipeline, addressing these and other important knowledge gaps is increasingly pressing.We assembled an expert group to assess the evidence for the global burden of norovirus and to consider the prospects for norovirus vaccine development. The group assessed the evidence in the areas of burden of disease, epidemiology, diagnostics, disease attribution, acquired immunity, and innate susceptibility, and the group considered how to bring norovirus vaccines from their current state of development to a viable product that will benefit global health.

Summary Points

• Diagnostic improvements have fundamentally changed our understanding of norovirus. The current evidence suggests that disease burden of norovirus is high, second only to rotavirus as a cause of severe acute gastroenteritis in children in developed countries, and that it is a key cause of diarrhea-associated morbidity and mortality worldwide.
• Young children experience the highest incidence of disease; severe outcomes are most common among young children and the elderly.
• Immunity is of limited duration and is strain- or genotype-specific, with little or no protection conferred across genogroups.
• Innate susceptibility to noroviruses is determined by the host’s genetics of glycan expression; individuals with a functional FUT2 gene (known as secretors) have greater susceptibility to certain common viruses.
• Recent progress has been made in the development of in vitro cell culture for norovirus as well as in the identification of candidate immune correlates of protection.
• Norovirus vaccines are steadily moving through the development pipeline. All of these products are based on the production of virus like particles (VLPs) or P particle subunit in expression systems. Initial human challenge studies have demonstrated safety, immunogenicity, and efficacy.
• One of the challenges for developing targeted interventions, including a norovirus vaccine, is that many distinct population groups, based on demographics (e.g., children, elderly) or risk (e.g., food handlers, military, travelers, health care workers), are affected.