TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes

<p>Abstract</p> <p>Background</p> <p>Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to developing countries in tropical regions and one of its important features is invariable progression to diabetes, a condition called fibro-calculous pancreatic diabetes (FCPD), but the nature of diabetes in TCP is controversial. We analysed the recently reported type 2 diabetes (T2D) associated polymorphisms in the <it>TCF7L2 </it>gene using a case-control approach, under the hypothesis that <it>TCF7L2 </it>variants should show similar association if diabetes in FCPD is similar to T2D. We also investigated the interaction between the <it>TCF7L2 </it>variants and N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations, since they are strong predictors of risk for TCP.</p> <p>Methods</p> <p>Two polymorphisms rs7903146 and rs12255372 in the <it>TCF7L2 </it>gene were analyzed by direct sequencing in 478 well-characterized TCP patients and 661 healthy controls of Dravidian and Indo-European ethnicities. Their association with TCP with diabetes (FCPD) and without diabetes was tested in both populations independently using chi-square test. Finally, a meta analysis was performed on all the cases and controls for assessing the overall significance irrespective of ethnicity. We dichotomized the whole cohort based on the presence or absence of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations and further subdivided them into TCP and FCPD patients and compared the distribution of <it>TCF7L2 </it>variants between them.</p> <p>Results</p> <p>The allelic and genotypic frequencies for both <it>TCF7L2 </it>polymorphisms, did not differ significantly between TCP patients and controls belonging to either of the ethnic groups or taken together. No statistically significant association of the SNPs was observed with TCP or FCPD or between carriers and non-carriers of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations. The minor allele frequency for rs7903146 was different between TCP and FCPD patients carrying the N34S <it>SPINK1 </it>variant but did not reach statistical significance (OR = 1.59, 95% CI = 0.93–2.70, P = 0.09), while, <it>TCF7L2</it><it/>variant showed a statistically significant association between TCP and FCPD patients carrying the 26V allele (OR = 1.69, 95% CI = 1.11–2.56, P = 0.013).</p> <p>Conclusion</p> <p>Type 2 diabetes associated <it>TCF7L2 </it>variants are not associated with diabetes in TCP. Since, <it>TCF7L2 </it>is a major susceptibility gene for T2D, it may be hypothesized that the diabetes in TCP patients may not be similar to T2D. Our data also suggests that co-existence of <it>TCF7L2 </it>variants and the <it>SPINK1 </it>and <it>CTSB </it>mutations, that predict susceptibility to exocrine damage, may interact to determine the onset of diabetes in TCP patients.</p

Cancer risk in persons with HIV/AIDS in India: a review and future directions for research

Background India has a large and evolving HIV epidemic. Little is known about cancer risk in Indian persons with HIV/AIDS (PHA) but risk is thought to be low. Methods To describe the state of knowledge about cancer patterns in Indian PHA, we reviewed reports from the international and Indian literature. Results As elsewhere, non-Hodgkin lymphomas dominate the profile of recognized cancers, with immunoblastic/large cell diffuse lymphoma being the most common type. Hodgkin lymphoma is proportionally increased, perhaps because survival with AIDS is truncated by fatal infections. In contrast, Kaposi sarcoma is rare, in association with an apparently low prevalence of Kaposi sarcoma-associated herpesvirus. If confirmed, the reasons for the low prevalence need to be understood. Cervical, anal, vulva/vaginal and penile cancers all appear to be increased in PHA, based on limited data. The association may be confounded by sexual behaviors that transmit both HIV and human papillomavirus. Head and neck tumor incidence may also be increased, an important concern since these tumors are among the most common in India. Based on limited evidence, the increase is at buccal/palatal sites, which are associated with tobacco and betel nut chewing rather than human papillomavirus. Conclusion With improving care of HIV and better management of infections, especially tuberculosis, the longer survival of PHA in India will likely increase the importance of cancer as a clinical problem in India. With the population's geographic and social diversity, India presents unique research opportunities that can be embedded in programs targeting HIV/AIDS and other public health priorities

A Pro-Cathepsin L Mutant Is a Luminal Substrate for Endoplasmic-Reticulum-Associated Degradation in C. elegans

Endoplasmic-reticulum associated degradation (ERAD) is a major cellular misfolded protein disposal pathway that is well conserved from yeast to mammals. In yeast, a mutant of carboxypeptidase Y (CPY*) was found to be a luminal ER substrate and has served as a useful marker to help identify modifiers of the ERAD pathway. Due to its ease of genetic manipulation and the ability to conduct a genome wide screen for modifiers of molecular pathways, C. elegans has become one of the preferred metazoans for studying cell biological processes, such as ERAD. However, a marker of ERAD activity comparable to CPY* has not been developed for this model system. We describe a mutant of pro-cathepsin L fused to YFP that no longer targets to the lysosome, but is efficiently eliminated by the ERAD pathway. Using this mutant pro-cathepsin L, we found that components of the mammalian ERAD system that participate in the degradation of ER luminal substrates were conserved in C. elegans. This transgenic line will facilitate high-throughput genetic or pharmacological screens for ERAD modifiers using widefield epifluorescence microscopy

Identifying the Rules of Engagement Enabling Leukocyte Rolling, Activation, and Adhesion

The LFA-1 integrin plays a pivotal role in sustained leukocyte adhesion to the endothelial surface, which is a precondition for leukocyte recruitment into inflammation sites. Strong correlative evidence implicates LFA-1 clustering as being essential for sustained adhesion, and it may also facilitate rebinding events with its ligand ICAM-1. We cannot challenge those hypotheses directly because it is infeasible to measure either process during leukocyte adhesion following rolling. The alternative approach undertaken was to challenge the hypothesized mechanisms by experimenting on validated, working counterparts: simulations in which diffusible, LFA1 objects on the surfaces of quasi-autonomous leukocytes interact with simulated, diffusible, ICAM1 objects on endothelial surfaces during simulated adhesion following rolling. We used object-oriented, agent-based methods to build and execute multi-level, multi-attribute analogues of leukocytes and endothelial surfaces. Validation was achieved across different experimental conditions, in vitro, ex vivo, and in vivo, at both the individual cell and population levels. Because those mechanisms exhibit all of the characteristics of biological mechanisms, they can stand as a concrete, working theory about detailed events occurring at the leukocyte–surface interface during leukocyte rolling and adhesion experiments. We challenged mechanistic hypotheses by conducting experiments in which the consequences of multiple mechanistic events were tracked. We quantified rebinding events between individual components under different conditions, and the role of LFA1 clustering in sustaining leukocyte–surface adhesion and in improving adhesion efficiency. Early during simulations ICAM1 rebinding (to LFA1) but not LFA1 rebinding (to ICAM1) was enhanced by clustering. Later, clustering caused both types of rebinding events to increase. We discovered that clustering was not necessary to achieve adhesion as long as LFA1 and ICAM1 object densities were above a critical level. Importantly, at low densities LFA1 clustering enabled improved efficiency: adhesion exhibited measurable, cell level positive cooperativity

Genetic Patterns of Domestication in Pigeonpea (Cajanus cajan (L.) Millsp.) and Wild Cajanus Relatives

Pigeonpea (Cajanus cajan) is an annual or short-lived perennial food legume of acute regional importance, providing significant protein to the human diet in less developed regions of Asia and Africa. Due to its narrow genetic base, pigeonpea improvement is increasingly reliant on introgression of valuable traits from wild forms, a practice that would benefit from knowledge of its domestication history and relationships to wild species. Here we use 752 single nucleotide polymorphisms (SNPs) derived from 670 low copy orthologous genes to clarify the evolutionary history of pigeonpea (79 accessions) and its wild relatives (31 accessions). We identified three well-supported lineages that are geographically clustered and congruent with previous nuclear and plastid sequence-based phylogenies. Among all species analyzed Cajanus cajanifolius is the most probable progenitor of cultivated pigeonpea. Multiple lines of evidence suggest recent gene flow between cultivated and non-cultivated forms, as well as historical gene flow between diverged but sympatric species. Evidence supports that primary domestication occurred in India, with a second and more recent nested population bottleneck focused in tropical regions that is the likely consequence of pigeonpea breeding. We find abundant allelic variation and genetic diversity among the wild relatives, with the exception of wild species from Australia for which we report a third bottleneck unrelated to domestication within India. Domesticated C. cajan possess 75% less allelic diversity than the progenitor clade of wild Indian species, indicating a severe “domestication bottleneck” during pigeonpea domestication

Demographic, socio-economic, and cultural factors affecting fertility differentials in Nepal

<p>Abstract</p> <p>Background</p> <p>Traditionally Nepalese society favors high fertility. Children are a symbol of well-being both socially and economically. Although fertility has been decreasing in Nepal since 1981, it is still high compared to many other developing countries. This paper is an attempt to examine the demographic, socio-economic, and cultural factors for fertility differentials in Nepal.</p> <p>Methods</p> <p>This paper has used data from the Nepal Demographic and Health Survey (NDHS 2006). The analysis is confined to ever married women of reproductive age (8,644). Both bivariate and multivariate analyses have been performed to describe the fertility differentials. The bivariate analysis (one-way ANOVA) was applied to examine the association between children ever born and women's demographic, socio-economic, and cultural characteristics. Besides bivariate analysis, the net effect of each independent variable on the dependent variable after controlling for the effect of other predictors has also been measured through multivariate analysis (multiple linear regressions).</p> <p>Results</p> <p>The mean numbers of children ever born (CEB) among married Nepali women of reproductive age and among women aged 40-49 were three and five children, respectively. There are considerable differentials in the average number of children ever born according to women's demographic, socio-economic, and cultural settings. Regression analysis revealed that age at first marriage, perceived ideal number of children, place of residence, literacy status, religion, mass media exposure, use of family planning methods, household headship, and experience of child death were the most important variables that explained the variance in fertility. Women who considered a higher number of children as ideal (β = 0.03; p < 0.001), those who resided in rural areas (β = 0.02; p < 0.05), Muslim women (β = 0.07; p < 0.001), those who had ever used family planning methods (β = 0.08; p < 0.001), and those who had a child-death experience (β = 0.31; p < 0.001) were more likely to have a higher number of CEB compared to their counterparts. On the other hand, those who married at a later age (β = -0.15; p < 0.001), were literate (β = -0.05; p < 0.001), were exposed to both (radio/TV) mass media (β = -0.05; p < 0.001), were richest (β = -0.12; p < 0.001), and were from female-headed households (β = -0.02; p < 0.05) had a lower number of children ever born than their counterparts.</p> <p>Conclusion</p> <p>The average number of children ever born is high among women in Nepal. There are many contributing factors for the high fertility, among which are age at first marriage, perceived ideal number of children, literacy status, mass media exposure, wealth status, and child-death experience by mothers. All of these were strong predictors for CEB. It can be concluded that programs should aim to reduce fertility rates by focusing on these identified factors so that fertility as well as infant and maternal mortality and morbidity will be decreased and the overall well-being of the family maintained and enhanced.</p

Understanding Communication of Sustainability Reporting: Application of Symbolic Convergence Theory (SCT)

The purpose of this paper is to investigate the nature of rhetoric and rhetorical strategies that are implicit in the standalone sustainability reporting of the top 24 companies of the Fortune 500 Global. We adopt Bormann’s (Q J Speech 58(4):396–407, 1972) SCT framework to study the rhetorical situation and how corporate sustainability reporting (CSR) messages can be communicated to the audience (public). The SCT concepts in the sustainability reporting’s communication are subject to different types of legitimacy strategies that are used by corporations as a validity and legitimacy claim in the reports. A content analysis has been conducted and structural coding schemes have been developed based on the literature. The schemes are applied to the SCT model which recognizes the symbolic convergent processes of fantasy among communicators in a Society. The study reveals that most of the sample companies communicate fantasy type and rhetorical vision in their corporate sustainability reporting. However, the disclosure or messages are different across locations and other taxonomies of the SCT framework. This study contributes to the current CSR literature about how symbolic or fantasy understandings can be interpreted by the users. It also discusses the persuasion styles that are adopted by the companies for communication purposes. This study is the theoretical extension of the SCT. Researchers may be interested in further investigating other online communication paths, such as human rights reports and director’s reports

Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis

10.1371/journal.pone.0053830PLoS ONE81

The global distribution of fatal pesticide self-poisoning: Systematic review

<p>Abstract</p> <p>Background</p> <p>Evidence is accumulating that pesticide self-poisoning is one of the most commonly used methods of suicide worldwide, but the magnitude of the problem and the global distribution of these deaths is unknown.</p> <p>Methods</p> <p>We have systematically reviewed the worldwide literature to estimate the number of pesticide suicides in each of the World Health Organisation's six regions and the global burden of fatal self-poisoning with pesticides. We used the following data sources: Medline, EMBASE and psycINFO (1990–2007), papers cited in publications retrieved, the worldwide web (using Google) and our personal collections of papers and books. Our aim was to identify papers enabling us to estimate the proportion of a country's suicides due to pesticide self-poisoning.</p> <p>Results</p> <p>We conservatively estimate that there are 258,234 (plausible range 233,997 to 325,907) deaths from pesticide self-poisoning worldwide each year, accounting for 30% (range 27% to 37%) of suicides globally. Official data from India probably underestimate the incidence of suicides; applying evidence-based corrections to India's official data, our estimate for world suicides using pesticides increases to 371,594 (range 347,357 to 439,267). The proportion of all suicides using pesticides varies from 4% in the European Region to over 50% in the Western Pacific Region but this proportion is not concordant with the volume of pesticides sold in each region; it is the pattern of pesticide use and the toxicity of the products, not the quantity used, that influences the likelihood they will be used in acts of fatal self-harm.</p> <p>Conclusion</p> <p>Pesticide self-poisoning accounts for about one-third of the world's suicides. Epidemiological and toxicological data suggest that many of these deaths might be prevented if (a) the use of pesticides most toxic to humans was restricted, (b) pesticides could be safely stored in rural communities, and (c) the accessibility and quality of care for poisoning could be improved.</p