Infectious disease burden in Gujarat (2005–2011): comparison of selected infectious disease rates with India

Background India is known to be endemic to numerous infectious diseases. The infectious disease profile of India is changing due to increased human environmental interactions, urbanisation and climate change. There are also predictions of explosive growth in infectious and zoonotic diseases. The Integrated Disease Surveillance Project (IDSP) was implemented in Gujarat in 2004. Methods We analysed IDSP data on seven laboratory confirmed infectious diseases from 2005–2011 on temporal and spatial trends and compared this to the National Health Profile (NHP) data for the same period and with other literature. We chose laboratory cases data for Enteric fever, Cholera, Hepatitis, Dengue, Chikungunya, Measles and Diphtheria in the state since well designed vertical programs do not exist for these diseases. Statistical and GIS analysis was done using appropriate software. Results Our analysis shows that the existing surveillance system in the state is predominantly reporting urban cases. There are wide variations among reported cases within the state with reports of Enteric fever and Measles being less than half of the national average, while Cholera, Viral Hepatitis and Dengue being nearly double. Conclusions We found some limitations in the IDSP system with regard to the number of reporting units and cases in the background of a mixed health system with multiplicity of treatment providers and payment mechanisms. Despite these limitations, IDSP can be strengthened into a comprehensive surveillance system capable of tackling the challenge of reversing the endemicity of these diseases and preventing the emergence of others

Can Administration of Potentized Homeopathic Remedy, Arsenicum Album, Alter Antinuclear Antibody (ANA) Titer in People Living in High-Risk Arsenic Contaminated Areas? I. A Correlation with Certain Hematological Parameters

To examine whether elevated antinuclear antibody (ANA) titers reported in random human population of arsenic contaminated villages can be reverted to the normal range by administration of a potentized homeopathic drug, Arsenicum album, randomly selected volunteers in two arsenic contaminated villages and one arsenic-free village in West Bengal (India) were periodically tested for their ANA titer as well as various blood parameters in two types of experiments: ‘placebo-controlled double blind’ experiment for shorter duration and ‘uncontrolled verum fed experiment’ for longer duration. Positive modulation of ANA titer was observed along with changes in certain relevant hematological parameters, namely total count of red blood cells and white blood cells, packed cell volume, hemoglobin content, erythrocyte sedimentation rate and blood sugar level, mostly within 2 months of drug administration. Thus, Arsenicum album appears to have great potential for ameliorating arsenic induced elevated ANA titer and other hematological toxicities

Transcriptomic and phenotypic analysis of murine embryonic stem cell derived BMP2+ lineage cells: an insight into mesodermal patterning

Transcriptome analysis of BMP2+ cells in comparison to the undifferentiated BMP2 ES cells and the control population from 7-day old embryoid bodies led to the identification of 479 specifically upregulated and 193 downregulated transcripts

Can Homeopathic Arsenic Remedy Combat Arsenic Poisoning in Humans Exposed to Groundwater Arsenic Contamination?: A Preliminary Report on First Human Trial

Groundwater arsenic (As) has affected millions of people globally distributed over 20 countries. In parts of West Bengal (India) and Bangladesh alone, over 100 million people are at risk, but supply of As-free water is grossly inadequate. Attempts to remove As by using orthodox medicines have mostly been unsuccessful. A potentized homeopathic remedy, Arsenicum Album-30, was administered to a group of As affected people and thereafter the As contents in their urine and blood were periodically determined. The activities of various toxicity marker enzymes and compounds in the blood, namely aspartate amino transferase, alanine amino transferase, acid phosphatase, alkaline phosphatase, lipid peroxidation and reduced glutathione, were also periodically monitored up to 3 months. The results are highly encouraging and suggest that the drug can alleviate As poisoning in humans

Measuring fidelity, feasibility, costs: an implementation evaluation of a cluster-controlled trial of group antenatal care in rural Nepal

Background Access to high-quality antenatal care services has been shown to be beneficial for maternal and child health. In 2016, the WHO published evidence-based recommendations for antenatal care that aim to improve utilization, quality of care, and the patient experience. Prior research in Nepal has shown that a lack of social support, birth planning, and resources are barriers to accessing services in rural communities. The success of CenteringPregnancy and participatory action women’s groups suggests that group care models may both improve access to care and the quality of care delivered through women’s empowerment and the creation of social networks. We present a group antenatal care model in rural Nepal, designed and implemented by the healthcare delivery organization Nyaya Health Nepal, as well as an assessment of implementation outcomes. Methods The study was conducted at Bayalata Hospital in Achham, Nepal, via a public private partnership between the Nepali non-profit, Nyaya Health Nepal, and the Ministry of Health and Population, with financial and technical assistance from the American non-profit, Possible. We implemented group antenatal care as a prospective non-randomized cluster-controlled, type I hybrid effectiveness-implementation study in six village clusters. The implementation approach allows for iterative improvement in design, making changes to improve the quality of the intervention. Assessments of implementation process and model fidelity were undertaken using a mobile checklist completed by nurse supervisors, and observation forms completed by program leadership. We evaluated data quarterly using descriptive statistics to identify trends. Qualitative interviews and team communications were analyzed through immersion crystallization to identify major themes that evolved during the implementation process. Results A total of 141 group antenatal sessions were run during the study period. This paper reports on implementation results, whereas we analyze and present patient-level effectiveness outcomes in a complementary paper in this journal. There was high process fidelity to the model, with 85.7% (95% CI 77.1–91.5%) of visits completing all process elements, and high content fidelity, with all village clusters meeting the minimum target frequency for 80% of topics. The annual per capita cost for group antenatal care was 0.50 USD. Qualitative analysis revealed the compromise of stable gestation-matched composition of the group members in order to make the intervention feasible. Major adaptations were made in training, documentation, feedback and logistics. Conclusion Group antenatal care provided in collaboration with local government clinics has the potential to provide accessible and high quality antenatal care to women in rural Nepal. The intervention is a feasible and affordable alternative to individual antenatal care. Our experience has shown that adaptation from prior models was important for the program to be successful in the local context within the national healthcare system. Trial registration ClinicalTrials.gov Identifier: NCT02330887, registered 01/05/2015, retroactively registered

TGFβ-Stimulated MicroRNA-21 Utilizes PTEN to Orchestrate AKT/mTORC1 Signaling for Mesangial Cell Hypertrophy and Matrix Expansion

<div><p>Transforming growth factor-β (TGFβ) promotes glomerular hypertrophy and matrix expansion, leading to glomerulosclerosis. MicroRNAs are well suited to promote fibrosis because they can repress gene expression, which negatively regulate the fibrotic process. Recent cellular and animal studies have revealed enhanced expression of microRNA, miR-21, in renal cells in response to TGFβ. Specific miR-21 targets downstream of TGFβ receptor activation that control cell hypertrophy and matrix protein expression have not been studied. Using 3′UTR-driven luciferase reporter, we identified the tumor suppressor protein PTEN as a target of TGFβ-stimulated miR-21 in glomerular mesangial cells. Expression of miR-21 Sponge, which quenches endogenous miR-21 levels, reversed TGFβ-induced suppression of PTEN. Additionally, miR-21 Sponge inhibited TGFβ-stimulated phosphorylation of Akt kinase, resulting in attenuation of phosphorylation of its substrate GSK3β. Tuberin and PRAS40, two other Akt substrates, and endogenous inhibitors of mTORC1, regulate mesangial cell hypertrophy. Neutralization of endogenous miR-21 abrogated TGFβ-stimulated phosphorylation of tuberin and PRAS40, leading to inhibition of phosphorylation of S6 kinase, mTOR and 4EBP-1. Moreover, downregulation of miR-21 significantly suppressed TGFβ-induced protein synthesis and hypertrophy, which were reversed by siRNA-targeted inhibition of PTEN expression. Similarly, expression of constitutively active Akt kinase reversed the miR-21 Sponge-mediated inhibition of TGFβ-induced protein synthesis and hypertrophy. Furthermore, expression of constitutively active mTORC1 prevented the miR-21 Sponge-induced suppression of mesangial cell protein synthesis and hypertrophy by TGFβ. Finally, we show that miR-21 Sponge inhibited TGFβ-stimulated fibronectin and collagen expression. Suppression of PTEN expression and expression of both constitutively active Akt kinase and mTORC1 independently reversed this miR-21-mediated inhibition of TGFβ-induced fibronectin and collagen expression. Our results uncover an essential role of TGFβ-induced expression of miR-21, which targets PTEN to initiate a non-canonical signaling circuit involving Akt/mTORC1 axis for mesangial cell hypertrophy and matrix protein synthesis.</p> </div

Akt2 causes TGFβ-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression.

TGFβ promotes podocyte hypertrophy and expression of matrix proteins in fibrotic kidney diseases such as diabetic nephropathy. Both mTORC1 and mTORC2 are hyperactive in response to TGFβ in various renal diseases. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. We identified that deptor downregulation by TGFβ maintains hyperactive mTOR in podocytes. To unravel the mechanism, we found that TGFβ -initiated noncanonical signaling controls deptor inhibition. Pharmacological inhibitor of PI 3 kinase, Ly 294002 and pan Akt kinase inhibitor MK 2206 prevented the TGFβ induced downregulation of deptor, resulting in suppression of both mTORC1 and mTORC2 activities. However, specific isoform of Akt involved in this process is not known. We identified Akt2 as predominant isoform expressed in kidney cortex, glomeruli and podocytes. TGFβ time-dependently increased the activating phosphorylation of Akt2. Expression of dominant negative PI 3 kinase and its signaling inhibitor PTEN blocked Akt2 phosphorylation by TGFβ. Inhibition of Akt2 using a phospho-deficient mutant that inactivates its kinase activity, as well as siRNA against the kinase markedly diminished TGFβ -mediated deptor suppression, its association with mTOR and activation of mTORC1 and mTORC2. Importantly, inhibition of Akt2 blocked TGFβ -induced podocyte hypertrophy and expression of the matrix protein fibronectin. This inhibition was reversed by the downregulation of deptor. Interestingly, we detected increased phosphorylation of Akt2 concomitant with TGFβ expression in the kidneys of diabetic rats. Thus, our data identify previously unrecognized Akt2 kinase as a driver of TGFβ induced deptor downregulation and sustained mTORC1 and mTORC2 activation. Furthermore, we provide the first evidence that deptor downstream of Akt2 contributes to podocyte hypertrophy and matrix protein expression found in glomerulosclerosis in different renal diseases

miR-21/PTEN/Akt axis regulates mesangial cell matrix protein expression in response to TGFβ.

<p>Mesangial cells were transfected with miR-21 Sponge and siPTEN or scrambled RNA as indicated in panels A and B. Similarly, mesangial cells were transfected with miR-21 Sponge and Gag-Akt as indicated in panels C and D. The transfected cells were incubated with 2 ng/ml TGFβ for 24 hours. The cell lysates were immunoblotted with fibronectin, PTEN, actin (panel A), collagen I (α2), PTEN, actin (panel B), fibronectin, Akt, actin (panel C) and collagen I (α2), Akt, actin (panel D) antibodies as indicated.</p

miR-21/PTEN/Akt axis regulates mesangial cell protein synthesis and hypertrophy in response to TGFβ.

<p>Mesangial cells were cotransfected with miR-21 Sponge and siRNAs targeting PTEN mRNA (siPTEN) or scrambled RNA (Scr) (panels A and B). Mesangial cells were cotransfected with miR-21 Sponge and constitutively active Gag-Akt as indicated (panels C and D). The transfected cells were starved for 16 hours prior to incubation with 2 ng/ml TGFβ for 24 hours. Protein synthesis (panels A and C) and hypertrophy (panels B and D) were determined as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042316#s4" target="_blank">Materials and Methods </a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042316#pone.0042316-Das1" target="_blank">[23]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042316#pone.0042316-Mahimainathan1" target="_blank">[25]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042316#pone.0042316-Dey1" target="_blank">[55]</a>. Mean ± SE of 3 measurements is shown. For panel A, *p<0.01 vs control; **p<0.01 vs TGFβ; #p<0.05 vs miR-21 Sponge plus TGFβ. For panel B, *p<0.05 vs control; **p<0.05 vs TGFβ; #p<0.05 vs miR-21 Sponge plus TGFβ. For panel C, *p<0.05 vs control; **p<0.05 vs TGFβ; #p<0.05 vs miR-21 Sponge plus TGFβ. For panel D, *p<0.01 vs control; **p<0.05 vs TGFβ; #p<0.05 vs miR-21 Sponge plus TGFβ. Bottom panels show expression of PTEN and Akt in representative samples. Actin expression was used as a control for immunoblotting.</p