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Changing epidemiology, rapid urbanization, and rising expectations of populations are creating new challenges and opportunities for India's primary healthcare system. A group of primary care experts, practitioners, and researchers got together to design key elements of primary healthcare models for the future that would address these challenges and make use of emergent opportunities in rural and urban India. Based on experiences and evidence from India and across the globe shared in the consultation, the article lays out a vision and components of India's primary healthcare for future. It provides answers to questions such as how will healthcare be financed and organized, what mechanisms will assure quality of services, who will provide primary healthcare, and what role will technology have. Finally, it provides an agenda for primary healthcare practitioners and researchers to translate this vision into action.

Abstract Background Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS. Results Here we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters. Conclusions In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.

OBJECTIVE:In this secondary analysis of data from an intervention trial, we assessed the performance of Mid Upper Arm Circumference (MUAC) as a predictor of mortality in children aged 6-59 months from Delhi, India, one year after their initial MUAC measurements were taken. Additionally, we assessed MUAC as an absolute value and MUAC z-scores as predictors of risk of mortality. METHODS:In the trial, children were screened using MUAC prior to referral to the study clinic. These children were revisited a year later to ascertain their vital status. Baseline MUAC and MUAC z-scores were used to categorize children as severely (MUAC

Background & Aims: Microbial dysbiosis and aberrant hostâmicrobe interactions in the gut are believed to contribute to the development and progression of Crohnâs disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine. Methods: Paraffin blocks were obtained from 12 CD patients undergoing ileocecal resection, and healthy ileum samples (inflammatory bowel diseaseâfree controls) were obtained from 12 patients undergoing surgery for right-sided colon cancer. Diseased and healthy-appearing ileum was identified using microscopy, and paraffin blocks were macrodissected using a core needle to specifically isolate DNA. Illumina Whole Genome Sequencing was used for microbial sequence identification and subsequent taxonomic classification using the PathSeq tool. Results: We observed significant differences between the microbiome of CD samples vs inflammatory bowel diseaseâfree controls, including depletion of Bacteroidetes and Clostridia. Notably, microbial composition at the phyla level did not differ markedly between healthy and diseased areas of CD patients. However, we observed enrichment of potentially pathogenic organisms at the species level. Conclusions: Our study showed dysbiosis within deeper layers of the ileum of CD patients, specifically enrichment of enterotoxigenic Staphylococcus aureus and an environmental Mycobacterium species not described previously. Future studies with larger cohort sizes are warranted to confirm these findings. Studies would benefit from effective microbial DNA extraction methods from paraffin sections and host nucleic acid depletion approaches to increase microbial read coverage. Keywords: Crohn's Disease, Deeper Mucosal Layers, Microbial Dysbiosis

Background: Hepatitis C (HCV) is the most common indication for liver transplantation in the US. Objective: Since steroids are the major stimulus of viral replication, we postulated that steroid-free immu-nosuppression might be a safer approach. Methods: From January 1995 to October 2002, we used steroid plus calcineurin inhibitor (CNI) immuno-suppression after liver transplantation for HCV (steroid group, n=81). From October 2002 to June 2007, rabbit antithymocyte globulin (RATG) induction, followed by CNI and azathioprine (RATG group, n=73) was utilized. Results: There were no differences in 1- and 3-year patient/allograft survival rates. The incidence of acute rejection rate (19% vs. 28%), of biopsy-proven HCV recurrence (70% vs. 75%), and chronic rejection (6% vs. 9%) were comparable. The mean time to develop recurrent HCV was significantly longer in the RATG group (16.2 vs. 9.2 months, p=0.008). The incidence of severe portal fibrosis appears to be lower in RATG group compared to the steroid group; 14% vs. 4% (p=0.07). Conclusions: RATG induction is safe and effective after liver transplantation for HCV, but has no impact on the incidence of HCV recurrence and patient/allograft survival. However, a significant delay in time to HCV recurrence and a trend toward less rejection and portal fibrosis was observed.

The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.

The ammonium source of nitrogen is often considered less desirable than other nitrogen sources for some plants. Nitrate is believed–by many people– to be superior to ammonium nitrogen for citrus, especially under acid soil conditions.

Glucocorticoid-induced TNF receptor family-related protein (GITR) regulates the function of both T cells and antigen-presenting cells (APCs), while the function of GITR ligand (GITR-L) is largely unknown. Here we evaluate the role of GITR-L, whose expression is restricted to APCs, in the development of enterocolitis. On injecting naive CD4+ T cells, GITR-L-/- Rag-/- mice develop a markedly milder colitis than Rag-/- mice, which correlates with a 50% reduction of Ly6C+CD11b+MHCII+ macrophages in the lamina propria and mesenteric lymph nodes. The same result was observed in αCD40-induced acute colitis and during peritonitis, suggesting an altered monocyte migration. In line with these observations, the number of nondifferentiated monocytes was approximately 3-fold higher in the spleen of GITR-L-/-Rag-/- mice than in Rag-/- mice after αLCD40 induction. Consistent with the dynamic change in the formation of an active angiotensin 1I type 1 receptor (AT1) dimer in GITR-L-/- splenic monocytes during intestinal inflammation, the migratory capability of splenic monocytes from GITR-L-deficient mice was impaired in an in vitro transwell migration assay. Conversely, αGITR-L reduces the number of splenic Ly6Chi monocytes, concomitantly with an increase in AT1 dimers. We conclude that GITR-L regulates the number of proinflammatory macrophages in sites of inflammation by controlling the egress of monocytes from the splenic reservoir. [ABSTRACT FROM AUTHOR]

Objectives: In a community randomized trial, we aimed to promote exclusive breastfeeding and appropriate complementary feeding practices in under-twos to ascertain the feasibility of using available channels for nutrition counselling, their relative performance and the relationship between intensity of counselling and behaviour change. We also assessed whether using multiple opportunities to impart nutrition education adversely affected routine activities.Methods: We conducted a community randomized, controlled effectiveness trial in rural Haryana, India, with four intervention and four control communities. We trained health and nutrition workers in the intervention communities to counsel mothers at multiple contacts on breastfeeding exclusively for 6 months and on appropriate complementary feeding practices thereafter. The intervention was not just training health and nutrition workers in counselling but included community and health worker mobilization.Findings: In the intervention group, about 32% of caregivers were counselled by traditional birth attendants at birth. The most frequent sources of counselling from birth to 3 months were immunization sessions (45.1%) and home visits (32.1%), followed closely by weighing sessions (25.5%); from 7 to 12 months, home visits (42.6%) became more important than the other two. An increase in the number of channels through which caregivers were counselled was positively associated with exclusive breastfeeding prevalence at 3 months (p = 0.002), consumption of milk/cereal gruel or mix use at 9 months (p = 0.004) and 18 months (p = 0.003), undiluted milk at 9 months (p<0.0001) and 24 hour non-breast-milk energy intakes at 18 months (p = 0.023), after controlling for potential confounding factors. Intervention areas, compared with the control, had higher coverage for vitamin A (45% vs. 11.5%) and iron folic acid (45% vs. 0.4%) supplementation.Conclusions: Using multiple available opportunities and workers for counselling caregivers was feasible, resulted in high coverage and impact, and instead of disrupting ongoing services, resulted in their improvement. [ABSTRACT FROM AUTHOR]

According to the ‘hygiene hypothesis’, enhanced microbial exposure due to early childhood infections leads to a reduction of Th2-mediated allergic diseases and inflammatory bowel disease. To begin to elucidate the mechanisms underlying this hypothesis, we studied development of Th2-mediated colitis of the TCRα knockout (KO) mouse in both a specific pathogen-free (SPF) facility and a conventional (CV) facility. After more than five generations in each facility, TCRα KO mice kept in the CV facility developed dramatically less colitis than mice that were kept in the SPF facility. Surprisingly, the suppression of colitis in the CV facility correlated with a significant increase in natural IgM production by B-1 B cells. In contrast, B cell-deficient TCRα double-knockout (αμ DKO) mice maintained in the CV facility continued to develop severe colitis, strongly suggesting that B-1 B cells contributed to the suppression of colitis. Indeed, the adoptive transfer of B-1 B cells isolated from the peritoneal cavity of TCRα KO mice (SPF) into αμ DKO mice (CV) suppressed the development of colitis in the recipient mice. We conclude that B-1 cells play a regulatory role in Th2-mediated colitis under non-hygienic conditions, possibly by generating natural antibodies in response to microbial flora. [ABSTRACT FROM AUTHOR]