Improvements to water purification and sanitation infrastructure may reduce the diarrheal burden in a marginalized and flood prone population in remote Nicaragua

<p>Abstract</p> <p>Background</p> <p>The isolated northern region of Nicaragua has one of the highest rates of diarrheal disease in Central America. Political and environmental hardships faced by inhabitants of this region are contributing factors to this health inequity. The aim of this study was to assess the relationship between water and latrine infrastructure and the prevalence of diarrhea in this region.</p> <p>Methods</p> <p>A population-based, cross-sectional survey of women of reproductive age was conducted in the Sahsa region of northern Nicaragua in July, 2009. Households were selected by two stage cluster sampling methodology. A questionnaire was administered in Spanish and Miskito with assessment of household and socioeconomic conditions, sanitation practices, and health care access. Diarrhea prevalence differences at the household level over a two week reporting period were estimated with a standardized instrument which included assessment of water treatment and latrine use and maintenance.</p> <p>Results</p> <p>There were 189 women enrolled in the current study. The use of water purification methods, such as chlorine and filters, and latrine ownership were not associated with reduced prevalence of household diarrhea in the two week reporting period. Latrine overflow, however, was associated with an increased prevalence of diarrhea during the same two week period [adjusted prevalence difference and 95% CI: 0.19 (0.03, 0.36)].</p> <p>Conclusions</p> <p>Simple, low cost interventions that improve water and latrine infrastructure may reduce the prevalence of diarrheal disease in the isolated regions of Nicaragua and Central America.</p

Evolution of cooperation in stochastic games

Social dilemmas occur when incentives for individuals are misaligned with group interests 1-7 . According to the 'tragedy of the commons', these misalignments can lead to overexploitation and collapse of public resources. The resulting behaviours can be analysed with the tools of game theory 8 . The theory of direct reciprocity 9-15 suggests that repeated interactions can alleviate such dilemmas, but previous work has assumed that the public resource remains constant over time. Here we introduce the idea that the public resource is instead changeable and depends on the strategic choices of individuals. An intuitive scenario is that cooperation increases the public resource, whereas defection decreases it. Thus, cooperation allows the possibility of playing a more valuable game with higher payoffs, whereas defection leads to a less valuable game. We analyse this idea using the theory of stochastic games 16-19 and evolutionary game theory. We find that the dependence of the public resource on previous interactions can greatly enhance the propensity for cooperation. For these results, the interaction between reciprocity and payoff feedback is crucial: neither repeated interactions in a constant environment nor single interactions in a changing environment yield similar cooperation rates. Our framework shows which feedbacks between exploitation and environment - either naturally occurring or designed - help to overcome social dilemmas

Reduction of Cross-Reactive Carbohydrate Determinants in Plant Foodstuff: Elucidation of Clinical Relevance and Implications for Allergy Diagnosis

Background: A longstanding debate in allergy is whether or not specific immunoglobulin-E antibodies (sIgE), recognizing cross-reactive carbohydrate determinants (CCD), are able to elicit clinical symptoms. In pollen and food allergy, $20% of patients display in-vitro CCD reactivity based on presence of a1,3-fucose and/or b1,2-xylose residues on N-glycans of plant (xylose/fucose) and insect (fucose) glycoproteins. Because the allergenicity of tomato glycoallergen Lyc e 2 was ascribed to N-glycan chains alone, this study aimed at evaluating clinical relevance of CCD-reduced foodstuff in patients with carbohydrate-specific IgE (CCD-sIgE). Methodology/Principal Findings: Tomato and/or potato plants with stable reduction of Lyc e 2 (tomato) or CCD formation in general were obtained via RNA interference, and gene-silencing was confirmed by immunoblot analyses. Two different CCD-positive patient groups were compared: one with tomato and/or potato food allergy and another with hymenopteravenom allergy (the latter to distinguish between CCD- and peptide-specific reactions in the food-allergic group). Nonallergic and CCD-negative food-allergic patients served as controls for immunoblot, basophil activation, and ImmunoCAP analyses. Basophil activation tests (BAT) revealed that Lyc e 2 is no key player among other tomato (glyco)allergens. CCDpositive patients showed decreased (re)activity with CCD-reduced foodstuff, most obvious in the hymenoptera venomallergic but less in the food-allergic group, suggesting that in-vivo reactivity is primarily based on peptide- and not CCDsIgE. Peptide epitopes remained unaffected in CCD-reduced plants, because CCD-negative patient sera showed reactivity similar to wild-type. In-house-made ImmunoCAPs, applied to investigate feasibility in routine diagnosis, confirmed BAT results at the sIgE level. Conclusions/Significance: CCD-positive hymenoptera venom-allergic patients (control group) showed basophil activation despite no allergic symptoms towards tomato and potato. Therefore, this proof-of-principle study demonstrates feasibility of CCD-reduced foodstuff to minimize ‘false-positive results’ in routine serum tests. Despite confirming low clinical relevance of CCD antibodies, we identified one patient with ambiguous in-vitro results, indicating need for further component-resolved diagnosis

Integrated syphilis/HIV screening in China: a qualitative analysis

<p>Abstract</p> <p>Background</p> <p>The last decade has seen enormous advances in HIV treatment and care, but how to implement scaled up HIV testing, prevention, and treatment in low-income areas still presents a formidable public health challenge. South China faces expanding syphilis and sexually transmitted HIV epidemics, but health systems characteristics important for scaling up syphilis and HIV testing have not been defined.</p> <p>Methods</p> <p>A purposive sample to ensure public, private, and public-private hybrid STI clinic inclusion was selected in a South China city. Eight key informant interviews were conducted with the STI clinic manager, followed by eight focus group discussions with physicians. Data collection relied on a semi-structured format that included questions in each of the following domains: 1) clinical facilities; 2) laboratory capacity with a focus on syphilis/HIV diagnosis; 3) clinic personnel; 4) physical space with a focus on locations to disclose confidential results; 5) financial support.</p> <p>Results</p> <p>Public STI clinics had free syphilis testing/treatment and laboratory facilities to perform essential syphilis and HIV tests. However, despite serving a large number of STI patients, private STI clinics lacked nontreponemal syphilis testing, HIV testing, and had fewer connections to the public health infrastructure. Formally trained assistant physicians were 2.5 times as common as physicians at STI clinics. Only one of the 8 sites had onsite voluntary counseling and testing (VCT) services available.</p> <p>Conclusion</p> <p>These STI case studies reveal the potential for expanding integrated syphilis/HIV services at public STI clinics in China. More health services research is needed to guide scale-up of syphilis/HIV testing in China.</p

Ex vivo modelling of drug efficacy in a rare metastatic urachal carcinoma

Background Ex vivo drug screening refers to the out-of-body assessment of drug efficacy in patient derived vital tumor cells. The purpose of these methods is to enable functional testing of patient specific efficacy of anti-cancer therapeutics and personalized treatment strategies. Such approaches could prove powerful especially in context of rare cancers for which demonstration of novel therapies is difficult due to the low numbers of patients. Here, we report comparison of different ex vivo drug screening methods in a metastatic urachal adenocarcinoma, a rare and aggressive non-urothelial bladder malignancy that arises from the remnant embryologic urachus in adults. Methods To compare the feasibility and results obtained with alternative ex vivo drug screening techniques, we used three different approaches; enzymatic cell viability assay of 2D cell cultures and image-based cytometry of 2D and 3D cell cultures in parallel. Vital tumor cells isolated from a biopsy obtained in context of a surgical debulking procedure were used for screening of 1160 drugs with the aim to evaluate patterns of efficacy in the urachal cancer cells. Results Dose response data from the enzymatic cell viability assay and the image-based assay of 2D cell cultures showed the best consistency. With 3D cell culture conditions, the proliferation rate of the tumor cells was slower and potency of several drugs was reduced even following growth rate normalization of the responses. MEK, mTOR, and MET inhibitors were identified as the most cytotoxic targeted drugs. Secondary validation analyses confirmed the efficacy of these drugs also with the new human urachal adenocarcinoma cell line (MISB18) established from the patient’s tumor. Conclusions All the tested ex vivo drug screening methods captured the patient’s tumor cells’ sensitivity to drugs that could be associated with the oncogenic KRASG12V mutation found in the patient’s tumor cells. Specific drug classes however resulted in differential dose response profiles dependent on the used cell culture method indicating that the choice of assay could bias results from ex vivo drug screening assays for selected drug classes

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria

<p>Abstract</p> <p>Background</p> <p>The sun-dried rind of the immature fruit of pomegranate (<it>Punica granatum</it>) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by <it>Plasmodium falciparum</it>, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The <it>in vitro </it>anti-plasmodial activity of <it>Punica granatum (Pg) </it>was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response.</p> <p>Methods</p> <p>From the methanolic extract of the fruit rind, a fraction enriched in tannins (<it>Pg</it>-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the <it>Pg</it>-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated.</p> <p>Results</p> <p><it>Pg</it>-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. <it>Pg</it>-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription.</p> <p>Conclusions</p> <p>The beneficial effect of the fruit rind of <it>Punica granatum </it>for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria.</p

Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines

Phenotypic variation results from variation in gene expression, which is modulated by genetic and/or epigenetic factors. To understand the molecular basis of human disease, interaction between genetic and epigenetic factors needs to be taken into account. The asthma-associated region 17q12-q21 harbors three genes, the zona pellucida binding protein 2 (ZPBP2), gasdermin B (GSDMB) and ORM1-like 3 (ORMDL3), that show allele-specific differences in expression levels in lymphoblastoid cell lines (LCLs) and CD4+ T cells. Here, we report a molecular dissection of allele-specific transcriptional regulation of the genes within the chromosomal region 17q12-q21 combining in vitro transfection, formaldehyde-assisted isolation of regulatory elements, chromatin immunoprecipitation and DNA methylation assays in LCLs. We found that a single nucleotide polymorphism rs4795397 influences the activity of ZPBP2 promoter in vitro in an allele-dependent fashion, and also leads to nucleosome repositioning on the asthma-associated allele. However, variable methylation of exon 1 of ZPBP2 masks the strong genetic effect on ZPBP2 promoter activity in LCLs. In contrast, the ORMDL3 promoter is fully unmethylated, which allows detection of genetic effects on its transcription. We conclude that the cis-regulatory effects on 17q12-q21 gene expression result from interaction between several regulatory polymorphisms and epigenetic factors within the cis-regulatory haplotype region

Identification and Characterization of a New Orthoreovirus from Patients with Acute Respiratory Infections

First discovered in the early 1950s, reoviruses (respiratory enteric orphan viruses) were not associated with any known disease, and hence named orphan viruses. Recently, our group reported the isolation of the Melaka virus from a patient with acute respiratory disease and provided data suggesting that this new orthoreovirus is capable of human-to-human transmission and is probably of bat origin. Here we report yet another Melaka-like reovirus (named Kampar virus) isolated from the throat swab of a 54 year old male patient in Kampar, Perak, Malaysia who was suffering from high fever, acute respiratory disease and vomiting at the time of virus isolation. Serological studies indicated that Kampar virus was transmitted from the index case to at least one other individual and caused respiratory disease in the contact case. Sequence analysis of the four small class genome segments indicated that Kampar and Melaka viruses are closely related. This was confirmed by virus neutralization assay, showing an effective two-way cross neutralization, i.e., the serum against one virus was able to neutralize the other. Although the exact origin of Kampar virus is unknown, epidemiological tracing revealed that the house of the index case is surrounded by fruit trees frequently visited by fruit bats. There is a high probability that Kampar virus originated from bats and was transmitted to humans via bat droppings or contaminated fruits. The discovery of Kampar virus highlights the increasing trend of emergence of bat zoonotic viruses and the need to expand our understanding of bats as a source of many unknown viruses