The Wellcome Trust Research Laboratory

Vellore, India

The Wellcome Trust Research Laboratory

Vellore, India
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Grassly N.C.,Imperial College London | Kang G.,The Wellcome Trust Research Laboratory | Kampmann B.,Imperial College London
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2015

The reason for holding a meeting to discuss biological challenges to vaccines is simple: not all vaccines work equally well in all settings. This special issue reviews the performance of vaccines in challenging environments, summarizes current thinking on the reasons why vaccines underperform and considers what approaches are necessary to understand the heterogeneity in responses and to improve vaccine immunogenicity and efficacy. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


Farrar J.,University of Oxford | Farrar J.,Hospital for Tropical Diseases | Hotez P.J.,The Texas Institute | Junghanss T.,University of Heidelberg | And 3 more authors.
Manson's Tropical Diseases: Twenty-Third Edition | Year: 2013

2014 BMA Medical Book Awards Highly Commended in Public Health category! From the difficult to diagnose to the difficult to treat, Manson's Tropical Diseases prepares you to effectively handle whatever your patients may have contracted. Featuring an internationally recognized editorial team, global contributors, and expert authors, this revised and updated medical reference book provides you with the latest coverage on parasitic and infectious diseases from around the world. © 2015 Elsevier Ltd. All rights reserved.


PubMed | The Wellcome Trust Research Laboratory and Center for Stem Cell Research
Type: | Journal: Cardiovascular toxicology | Year: 2016

Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.


Paul A.,The Wellcome Trust Research Laboratory | Babji S.,The Wellcome Trust Research Laboratory | Sarkar R.,The Wellcome Trust Research Laboratory | Lazarus R.P.,The Wellcome Trust Research Laboratory | Kang G.,The Wellcome Trust Research Laboratory
Indian Pediatrics | Year: 2016

Objective: To compare serum, salivary and fecal IgA responses in infants and adults following rotavirus vaccination. Study design: Laboratory testing of samples from clinical trials. Setting: Medical College Hospital. Participants: 13 healthy adult volunteers not given vaccine, 20 healthy adult volunteers given one dose of bovine rotavirus tetravalent vaccine (Shantha Biotechnics), and 88 infants given 3 or 5 doses of Rotarix. Outcome measures: Serum, salivary and fecal IgA at one or more time points. Methods: IgA antibodies were estimated in serum, saliva and fecal samples by enzyme-linked immunosorbent assay, and normalized to total IgA in saliva. Results: In naturally infected adult volunteers, comparing serum and salivary IgA showed significant positive correlation (r=0.759; P=0.003). Of 20 vaccinated adults, complete samples showing change were available for 10; among them there was a significant positive correlation (P<0.05) between pre-vaccination serum and pre-vaccination salivary IgA but not between post-vaccination serum and post-vaccination salivary IgA. Of 88 infants given 3 or 5 doses of vaccine, 13 had more than 4-fold IgA response in serum, saliva and fecal samples, 6 had a 2-4 fold increases in all specimens. There was weak correlation between seroconversion rates measured by serum and salivary antibody responses. Salivary and stool assays were able to detect seroconversion in a few children in whom there was no detectable response in serum. Conclusions: Evaluation of multiple samples is useful for intensive experimental study designs and may help improve our understanding of the induction and dynamics of immune responses to rotavirus vaccination. © 2016, Indian Academy of Pediatrics.


Ramachandran A.,University of Kansas Medical Center | Ramachandran A.,The Wellcome Trust Research Laboratory | Lebofsky M.,University of Kansas Medical Center | Yan H.-M.,University of Kansas Medical Center | And 2 more authors.
Archives of Toxicology | Year: 2015

Chronic hepatitis C virus (HCV) infection predisposes patients to develop liver failure after acetaminophen (APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected. HCV transgenic mice with higher liver injury had lower liver glutathione levels, elevated mitochondrial oxidative stress and enhanced release of apoptosis-inducing factor (AIF) from the mitochondria. This was accompanied by induction of a higher ER stress response and induction of autophagy. Transgenic animals showing protection against liver injury had a robust recovery of liver glutathione content at 6 h when compared to wild-type animals, accompanied by reduction in mitochondrial oxidative stress and AIF release. This was accompanied by an elevation in glutathione S-transferase mRNA levels and activity, which suggests that an efficient clearance of the reactive intermediate may contribute to the protection against APAP hepatotoxicity in these mice. These results demonstrate that while HCV infection could exacerbate APAP-induced liver injury due to induction and amplification of mitochondrial oxidant stress, it could also protect against injury by activation of APAP scavenging mechanisms. © 2015, Springer-Verlag Berlin Heidelberg.


Balamurugan R.,The Wellcome Trust Research Laboratory | Chandragunasekaran A.S.,The Wellcome Trust Research Laboratory | Chellappan G.,The Wellcome Trust Research Laboratory | Rajaram K.,The Wellcome Trust Research Laboratory | And 2 more authors.
Indian Journal of Medical Research | Year: 2014

Background & objectives: The human gut microbiota play a significant role in nutritional processes. The concept of probiotics has led to widespread consumption of food preparations containing probiotic microbes such as curd and yogurt. Curd prepared at home is consumed every day in most homes in southern India. In this study the home-made curd was evaluated for lactic acid bacteria (LAB) with probiotic potential.Methods: Fifteen LAB (12 lactobacilli, 1 Lactococcus, 2 Leuconostoc) and one yeast isolated from home-made curd were evaluated for resistance to acid, pepsin, pancreatin and bile salts; antimicrobial resistance; intrinsic antimicrobial activity; adherence to Caco-2 epithelial cells; ability to block pathogen adherence to Caco-2 cells; ability to inhibit interleukin (IL)-8 secretion from HT-29 epithelial cells in response to Vibrio cholerae; and ability to induce anti-inflammatory cytokine expression in THP-1 monocyte cells.Results: lactobacillus abundance in fermenting curd peaked sharply at 12 h. Nine of the strains survived exposure to acid (pH 3.0) for at least one hour, and all strains survived in the presence of pancreatin or bile salts for 3 h. None showed haemolytic activity. All were resistant to most antimicrobials tested, but were sensitive to imipenem. Most strains inhibited the growth of Salmonella Typhimurium while five inhibited growth of V. cholerae O139. Seven strains showed adherence to Caco-2 cells ranging from 20-104 per cent of adherence of an adherent strain of Escherichia coli, but all inhibited V cholerae adherence to Caco-2 cells by 20-100 per cent. They inhibited interleukin-8 secretion from HT-29 cells, in response to V cholerae, by 50-80 per cent. Two strains induced IL-10 and IL-12 messenger ribonucleic acid (mRNA) expression in THP-1 cells.Interpretation & conclusions: LAB in curd had properties consistent with probiotic potential, but these were not consistent across species. LAB abundance in curd increased rapidly at 12 h of fermentation at room temperature and declined thereafter. © 2014, Indian Council of Medical Research. All rights reserved.


Grassly N.C.,Imperial College London | Grassly N.C.,The Wellcome Trust Research Laboratory | Kang G.,The Wellcome Trust Research Laboratory | Kampmann B.,Imperial College London | Kampmann B.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

The reason for holding a meeting to discuss biological challenges to vaccines is simple: not all vaccines work equally well in all settings. This special issue reviews the performance of vaccines in challenging environments, summarizes current thinking on the reasons why vaccines underperform and considers what approaches are necessary to understand the heterogeneity in responses and to improve vaccine immunogenicity and efficacy. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


PubMed | The Wellcome Trust Research Laboratory
Type: Journal Article | Journal: Obstetric medicine | Year: 2016

Acute fatty liver of pregnancy (AFLP), characterized by hepatic microvesicular steatosis, is a sudden catastrophic illness occurring almost exclusively in the third trimester of pregnancy. Defective fatty acid oxidation in the fetus has been shown to be associated with this disease. Since the placenta has the same genetic makeup as the fetus and as AFLP patients generally recover following delivery, we hypothesized that the placenta might be involved in pathogenesis of this disease. In an animal model of hepatic microvesicular steatosis (using sodium valproate), we found that microvesicular steatosis results in mitochondrial structural alterations and oxidative stress in subcellular organelles of the liver. In placentas from patients with AFLP, we observed placental mitochondrial dysfunction and oxidative stress in subcellular organelles. In addition, defective placental fatty acid oxidation results in accumulation of toxic mediators such as arachidonic acid. Escape of these mediators into the maternal circulation might affect the maternal liver resulting in microvesicular steatosis.


Ramachandran A.,University of Kansas Medical Center | Ramachandran A.,The Wellcome Trust Research Laboratory | Mcgill M.R.,University of Kansas Medical Center | Xie Y.,University of Kansas Medical Center | And 3 more authors.
Hepatology | Year: 2013

Acetaminophen (APAP) overdose is a major cause of hepatotoxicity and acute liver failure in the U.S., but the pathophysiology is incompletely understood. Despite evidence for apoptotic signaling, hepatic cell death after APAP is generally considered necrotic in mice and in humans. Recent findings suggest that the receptor interacting protein kinase 3 (RIP3) acts as a switch from apoptosis to necrosis (programmed necrosis). Thus, the aim of the current investigation was to determine if RIP3 is involved in APAP-induced liver cell death. APAP (200-300 mg/kg) caused glutathione depletion and protein adduct formation, oxidant stress, mitochondrial release of apoptosis inducing factor, and nuclear DNA fragmentation resulting in centrilobular necrosis in C57Bl/6J mice. Inhibiting RIP3 protein induction with antisense morpholinos in wild-type animals or using RIP3-deficient mice had no effect on protein adduct formation but attenuated all other parameters, including necrotic cell death, at 6 hours after APAP. In addition, cultured hepatocytes from RIP3-deficient mice showed reduced injury compared to wild-type cells after 24 hours. Interestingly, APAP-induced mitochondrial translocation of dynamin-related protein 1 (Drp1), the initiator of mitochondrial fission, was inhibited by reduced RIP3 protein expression and the Drp1 inhibitor MDIVI reduced APAP-induced cell death at 24 hours. All of these protective effects were lost after 24 hours in vivo or 48 hours in vitro. Conclusion: RIP3 is an early mediator of APAP hepatotoxicity, involving modulation of mitochondrial dysfunction and oxidant stress. Controlling RIP3 expression could be a promising new approach to reduce APAP-induced liver injury, but requires complementary strategies to control mitochondrial dysfunction for long-term protection. © 2013 by the American Association for the Study of Liver Diseases.


PubMed | The Wellcome Trust Research Laboratory
Type: Journal Article | Journal: The Indian journal of medical research | Year: 2014

The human gut microbiota play a significant role in nutritional processes. The concept of probiotics has led to widespread consumption of food preparations containing probiotic microbes such as curd and yogurt. Curd prepared at home is consumed every day in most homes in southern India. In this study the home-made curd was evaluated for lactic acid bacteria (LAB) with probiotic potential.Fifteen LAB (12 lactobacilli, 1 l0 actococcus , 2 Leuconostoc) and one yeast isolated from home-made curd were evaluated for resistance to acid, pepsin, pancreatin and bile salts; antimicrobial resistance; intrinsic antimicrobial activity; adherence to Caco-2 epithelial cells; ability to block pathogen adherence to Caco-2 cells; ability to inhibit interleukin (IL)-8 secretion from HT-29 epithelial cells in response to Vibrio cholerae; and ability to induce anti-inflammatory cytokine expression in THP-1 monocyte cells.Lactobacillus abundance in fermenting curd peaked sharply at 12 h. Nine of the strains survived exposure to acid (pH 3.0) for at least one hour, and all strains survived in the presence of pancreatin or bile salts for 3 h. None showed haemolytic activity. All were resistant to most antimicrobials tested, but were sensitive to imipenem. Most strains inhibited the growth of Salmonella Typhimurium while five inhibited growth of V. cholerae O139. Seven strains showed adherence to Caco-2 cells ranging from 20-104 per cent of adherence of an adherent strain of Escherichia coli, but all inhibited V. cholerae adherence to Caco-2 cells by 20-100 per cent. They inhibited interleukin-8 secretion from HT-29 cells, in response to V. cholerae, by 50-80 per cent. Two strains induced IL-10 and IL-12 messenger ribonucleic acid (mRNA) expression in THP-1 cells.LAB in curd had properties consistent with probiotic potential, but these were not consistent across species. LAB abundance in curd increased rapidly at 12 h of fermentation at room temperature and declined thereafter.

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