Using in vitro protein tyrosine phosphatase (PTPase) assays, we found that sodium stibogluconate, a drug used in treatment of leishmaniasis, is a potent inhibitor of PTPases Src homology PTPase1 (SHP-1), SHP-2, and PTP1B but not the dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1. Sodium stibogluconate inhibited 99% of SHP-1 activity at 10 μg/ml, a therapeutic concentration of the drug for leishmaniasis. Similar degrees of inhibition of SHP-2 and PTP1B required 100 μg/ml sodium stibogluconate, demonstrating differential sensitivities of PTPases to the inhibitor. The drug appeared to target the SHP-1 domain because it showed similar in vitro inhibition of SHP-1 and a mutant protein containing the SHP-1 PTPase domain alone. Moreover, it forms a stable complex with the PTPase: in vitro inhibition of SHP-1 by the drug was not removed by a washing process effective in relieving the inhibition of SHP-1 by the reversible inhibitor suramin. The inhibition of cellular PTPases by the drug was suggested by its rapid induction of tyrosine phosphorylation of cellular proteins in Baf3 cells and its augmentation of IL-3-induced Janus family kinase 2/Stat5 tyrosine phosphorylation and proliferation of Baf3 cells. The augmentation of the opposite effects of GM-CSF and IFN-α on TF-1 cell growth by the drug indicated its broad activities in the signaling of various cytokines. These data represent the first evidence that sodium stibogluconate inhibits PTPases and augments cytokine responses. Our results provide novel insights into the pharmacological effects of the drug and suggest potential new therapeutic applications.

BackgroundNon-protective work practices followed by farm workers during spraying of pesticides lead to occupational exposure among them.ObjectiveThis study is designed to explore the respiratory health and hematological profile of agricultural workers occupationally exposed to OP pesticides.Materials and MethodsA cross sectional study was undertaken among 166 pesticide sprayers working in mango orchards of Lucknow district in North India compared with 77 controls to assess the respiratory illness, lung functions, cholinesterase levels and hematological profile. A questionnaire based survey and clinical examination for respiratory health were conducted among study subjects. Lung function test was conducted among study subjects by using spirometer. Cholinesterase level as biomarker of OP pesticides and hematological profile of study subjects were investigated in the laboratory by following the standard protocols.ResultsOverall respiratory morbidity observed among exposed subjects was 36.75%. Symptoms for respiratory illness like dry cough, productive cough, wheezing, irritation of throat and blood stained sputum were found to be significantly more (p<0.05) among pesticide sprayers than controls. Lung function parameters viz. PEFR, FEV1, %PEFR predicted, %FEV1 predicted and FEV1/FVC were found to be significantly decreased (p<0.05) among pesticide sprayers as compared to controls. Exposure wise distribution of respiratory illness and lung functions among pesticide sprayers show that the exposure duration significantly elevates (p<0.05) the respiratory problems and significantly decreases (p<0.001) lung functions among pesticide sprayers. Activities of acetylcholinesterase and butyrylcholinesterase were found to be significantly depleted (p<0.001) among pesticide sprayers as compared to controls which show the exposure of OP pesticides among them. The hematological profile viz. RBC, WBC, monocytes, neutrophils, MCV, MCH, MCHC and platelet count were significantly altered (p<0.001) in pesticide sprayers than controls.ConclusionThis study shows that the unsafe occupational exposure of OP pesticides causes respiratory illness, decreased lung functions and hematological alterations among pesticide sprayers.

Cancer cell resistance limits the efficacy of IFNs. In this study, we show that sodium stibogluconate (SSG) and IFN-α synergized to overcome IFN-α resistance in various human cancer cell lines in culture and eradicated IFN-α-refractory WM9 human melanoma tumors in nude mice with no obvious toxicity. SSG enhanced IFN-α-induced Stat1 tyrosine phosphorylation, inactivated intracellular SHP-1 and SHP-2 that negatively regulate IFN signaling, and induced cellular protein tyrosine phosphorylation in cancer cell lines. These effects are consistent with inactivation of phosphatases as the basis of SSG anticancer activity. Characterization of SSG by chromatography revealed that only selective compounds in SSG were effective protein tyrosine phosphatase inhibitors. These observations suggest the potential of SSG as a clinically usable protein tyrosine phosphatase inhibitor in cancer treatment and provide insights for developing phosphatase-targeted therapeutics.

Developing countries use only 20% of the world's agrochemicals, yet they suffer 99% of deaths from pesticide poisoning. Pesticide poisoning is a significant problem in developing countries primarily because of unsafe pesticide application and handling practices. Safety is further exacerbated by the illiteracy and poverty that prevails in most farming communities of developing countries. Pesticides classified as being extremely or highly hazardous by FAO and WHO, including those banned by other countries, continue to be used in developing countries. Many farmers in developing countries continue to be exposed to pesticides from either storing them in or near their residences, or from inadequate or unsafe application or handling practices. Farming populations exposed to pesticides suffer from several health problems, primarily neurological abnormalities, respiratory ailments, and reproductive, endocrinological, and dermal problems. In developing countries, the scientific literature (including the Indian Institute of Toxicology Research, India) have taken the initiative to monitor health problems resulting from pesticide exposure in agrarian communities. The welfare fund for agricultural laborers could institute a special program for pesticide applicators in developing countries. The primary need, currently, in such countries is creation and implementation of sound national policies to effectively articulate appropriate guidelines for managing farm pest control activities. Such policies should be aimed at both limiting pesticide exposure and usage, but doing so without damaging the yields of food production. If such steps are taken, it is fully expected that the incidence of adverse health consequences for agrarian populations from pesticide toxicity will decrease, and the health of farmers improve.

Multilevel mixed-effects models provide better fits to the test data than OLSLR by accounting for group effects and/or within-group correlation. However, the fitted LME model poorly tracks visual field (VF) change over time. An exponential model provides a significant improvement over linear models and more accurately tracks VF change over time in this cohort.

Excessive collagen deposition may cause abnormal stiffness of the heart during hypertrophy and heart failure. The potent vasoconstrictor angiotensin II seems, via an unknown mechanism, to stimulate collagen production. This study describes the in vitro and ex vivo effects of [Sar 1 ]Ang II on collagen production by fibroblasts in culture and in beating, nonworking heart preparations. The effects of [Sar 1 ]Ang II on isolated rat hearts or rat heart fibroblasts were determined by quantifying transcript levels of collagen phenotypes I and III through videodensitometry after Northern blot analysis with specific cDNA probes (collagen [P

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Aim: The current study investigated the positive and negative psychological adaptations that are a result of secondary traumatic stress, and the role of resilience among paramedics and emergency medical technicians (EMTs). Methods: Emergency medical service (EMS) providers anonymously completed four validated questionnaires on: secondary traumatic stress, posttraumatic growth, resilience, and changes in outlook. Relationships between these constructs and demographics were explored. Findings: Overall, EMS participants reported a higher-than-average positive change in outlook. Resilience (p<0.001) was significantly inversely related to secondary traumatic stress and negative change in outlook. EMS working part-time demonstrated a significantly higher level of resilience (p=0.005) compared with full-time. Post-traumatic growth was significantly higher (p=0.03) in EMTs compared with paramedics. No significant differences (p>0.05) were detected between years of experience for any attributes analysed. Conclusion: Findings demonstrated significant correlations between secondary traumatic stress, resilience, post-traumatic growth, and changes in outlook in EMTs and paramedics.