Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

<p>Abstract</p> <p>Background</p> <p>Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM) host defense and production of lipid mediators during the neonatal period compared to adult AMs.</p> <p>Methods</p> <p>AMs were harvested from young (day 7 and day 14) and adult (~10 week) rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR.</p> <p>Results</p> <p>AMs from young animals (day 7 and 14) were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF)- α. In addition, young AMs produce more prostaglandin (PG) E₂, a suppressor of host defense, and less leukotriene (LT) B₄, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE₂and LTB₄; however, there was no change in the expression of E prostanoid (EP) receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE₂as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE₂by aspirin nor the addition of exogenous LTB₄rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7) AMs compared to adult AMs.</p> <p>Conclusion</p> <p>These results suggest that elevated production of PGE₂and decreased production of LTB₄do not contribute to impaired opsonized macrophage phagocytosis and highlight an important difference between young and adult AMs.</p

Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice

Background Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-α-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury.Methodology/Principal Findings Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-α receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-α receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway.Conclusions/Significance Inhibition of MMP and TACE activity with Marimastat during chronic CCl4administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases

Runs of homozygosity and testicular cancer risk

Background: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. / Objective: To examine whether RoH are associated with TGCT risk. / Methods: We performed a genome‐wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. / Results: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13‐11p14.3, 5q14.1‐5q22.3 and 13q14.11‐13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13‐11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. / Discussion and conclusion: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls

Diosgenin, a Steroidal Saponin, Inhibits Migration and Invasion of Human Prostate Cancer PC-3 Cells by Reducing Matrix Metalloproteinases Expression

BACKGROUND: Diosgenin, a steroidal saponin obtained from fenugreek (Trigonella foenum graecum), was found to exert anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis in a variety of tumor cells. However, the effect of diosgenin on cancer metastasis remains unclear. The aim of the study is to examine the effect of diosgenin on migration and invasion in human prostate cancer PC-3 cells. METHODS AND PRINCIPAL FINDINGS: Diosgenin inhibited proliferation of PC-3 cells in a dose-dependent manner. When treated with non-toxic doses of diosgenin, cell migration and invasion were markedly suppressed by in vitro wound healing assay and Boyden chamber invasion assay, respectively. Furthermore, diosgenin reduced the activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatin zymography assay. The mRNA level of MMP-2, -9, -7 and extracellular inducer of matrix metalloproteinase (EMMPRIN) were also suppressed while tissue inhibitor of metalloproteinase-2 (TIMP-2) was increased by diosgenin. In addition, diosgenin abolished the expression of vascular endothelial growth factor (VEGF) in PC-3 cells and tube formation of endothelial cells. Our immunoblotting assays indicated that diosgenin potently suppressed the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, extracellular signal regulating kinase (ERK) and c-Jun N-terminal kinase (JNK). In addition, diosgenin significantly decreased the nuclear level of nuclear factor kappa B (NF-κB), suggesting that diosgenin inhibited NF-κB activity. CONCLUSION/SIGNIFICANCE: The results suggested that diosgenin inhibited migration and invasion of PC-3 cells by reducing MMPs expression. It also inhibited ERK, JNK and PI3K/Akt signaling pathways as well as NF-κB activity. These findings reveal new therapeutic potential for diosgenin in anti-metastatic therapy

Arsenic migration to deep groundwater in Bangladesh influenced by adsorption and water demand

Drinking shallow groundwater with naturally elevated concentrations of arsenic is causing widespread disease in many parts of South and Southeast Asia. In the Bengal Basin, growing reliance on deep (\u3e150 m) groundwater has lowered exposure. In the most affected districts of Bangladesh, shallow groundwater concentrations average 100 to 370 μg L−1, while deep groundwater is typically \u3c 10 μg L−1. Groundwater flow simulations have suggested that, even when deep pumping is restricted to domestic use, deep groundwater in some areas of the Bengal Basin is at risk of contamination. However, these simulations have neglected the impedance of As migration by adsorption to aquifer sediments. Here we quantify for the first time As sorption on deeper sediments in situ by replicating the intrusion of shallow groundwater through injection of 1,000 L of deep groundwater modified with 200 μg L−1 of As into a deeper aquifer. Arsenic concentrations in the injected water were reduced by 70% due to adsorption within a single day. Basin-scale modelling indicates that while As adsorption extends the sustainable use of deep groundwater, some areas remain vulnerable; these areas can be prioritized for management and monitoring

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Not AvailableOpen field rice strawburning causes air pollution, GHGs emission (7300 kg CO2-equivalent per hectare), soil nutrient and biodiversity losses and human health hazards. Huge amount (731 million tons (MT)) of rice straw is produced globally in which India contributed around 126.6 MT, and 60% of them are burnt on the field. Once a wealth, the straw now became a waste subjected to burning due to technical, structural, institutional, and socioeconomic challenges. However, straw could be sustainably used to produce bioethanol, biochar, compost, mushroom, fuel-briquette, fuel-pellets, pulp, animal-feed, eco-panel, erosion-control material, and in-situ addition in conservation agriculture. In this review, we elaborated the technical and economic potential of the alternative straw management practices along with their tangible and intangible benefits, primarily on Indian context. The economic and environmental gains and losses of alternate straw management options were estimated. We found that the net gain (both economic and environmental gain) of US$664 per hectare due to production of bioethanol from straw followed by biochar conversion (US$ 183 ha−1), and conservation agriculture (CA) practices (US$131 ha−1). While in Indian context there was a net loss of US$ 107/ha due to burning which includes both environmental (intangible) US$81 ha−1 and economic (tangible) losses US$ 112/ha−1. The estimates indicated the potential gains/losses based on the measured, analyzed, and published data assuming that proper and efficient infrastructure and policy support would be assured during the sustainable management of the straw.Not Availabl

Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04)

PURPOSE: In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). PATIENTS AND METHODS: Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. RESULTS: With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. CONCLUSION: Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL