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Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age group. PCOS has been frequently associated with insulin resistance and obesity. Although most of the cases with PCOS are obese or overweight, a significant proportion of patients have normal body mass index (BMI≤25 kg/m2) that makes diagnostic work up and therapeutic approach more difficult. These cases are referred to as “lean PCOS.” Methods: This hospital based prospective, comparative cross-sectional study was conducted to estimate the insulin levels and insulin resistance in lean versus over-weight or obese PCOS patients and to evaluate the correlation of BMI with clinical parameters, serum insulin levels, and hormone profile in these patients. Patients were grouped according to their BMI: Lean group-(n=46) BMI

Background: Pregnancy induced hypertension is the most common complication of pregnancy. It affects 5-7% of pregnant women. Pregnancy induced hypertension is characterized by vasospasm which is associated with platelet aggregation and reduced uteroplacental flow. In addition to these, altered renal function tests can also worsens the condition. This influences the maternal as well as fetal outcome. Aims: To prevent the complications of pregnancy induced hypertension and for proper management of these cases present study was conducted. Materials and Methods: The present study was conducted in 300 subjects grouped into 120 cases of normal pregnancy, 150 cases of pregnancy induced hypertensives, 30 cases of eclamptics and serum uric acid level was measured in these. Results and Discussion: elevated level of serum uric acid was seen with increase in gestation period and rise in diastolic blood pressure. The p- value was estimated by student t-test in different groups and was found to be Conclusion: Hence Serum Uric acid is the significant and reliable indicator for pregnancy induced hypertension to prevent the fetal and maternal mortality and morbidity. Keywords: Eclampsia, Gestational hypertension, Hyperuricemia, Pre-eclampsia, Pregnancy induced hypertension(PIH).

Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional β cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and β cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature β-like cells to form islet-sized enriched β-clusters (eBCs). eBCs display physiological properties analogous to primary human β cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus–secretion coupling in mature β cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived β cells that resemble their endogenous counterparts. Nair et al. report the generation of human ESC-derived mature and functional β cells in vitro with a culture system including a step to induce clustering of immature β-like cells.

Background: Stress incontinence is one of the most common but debilitating health issue among women. It has a detrimental effect on overall health and quality of life of women. Trans obturator tape (TOT) has emerged as a promising treatment modality. The aim of present study was to assess the usefulness of TOT in terms of change in quality of life of stress incontinence patients.Methods: The study was performed at Department of Obstetrics and Gynecology, Acharya Shri Chandler of Medical Sciences (ASCOMS), Jammu. A total of 50 symptomatic women were enrolled in the study and underwent TOT procedure using outside-in technique. The quality of life of women was assessed at enrolment and 12 months after the procedure using King’s Health Questionnaire (KHQ). Change in QOL was assessed using paired ‘t’-test.Results: After 12 months follow-up, a total of 27 (54%) patients were entirely symptom free. As compared to pre-treatment QOL assessment on KHQ for general health/incontinence impact, quality of life and symptom scores a % decline of 73.2%, 79.8% and 78.4% was observed. For all the three parts, the change in scores was significant statistically. No other complications and side effects were reported.Conclusions: TOT is a useful procedure which provided symptomatic relief as well as QOL enhancement.

Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional β cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and β cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature β-like cells to form islet-sized enriched β-clusters (eBCs). eBCs display physiological properties analogous to primary human β cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus-secretion coupling in mature β cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived β cells that resemble their endogenous counterparts.

Methods are provided for the simple, fast, effective and safe directed differentiation of embryonic stem cells into pancreatic beta-like cells secreting insulin in response to glucose levels. The cells are useful transplant therapeutics for diabetic individuals.

Cellular identity is established by genetic, epigenetic, and environmental factors that regulate organogenesis and tissue homeostasis. Although some flexibility in fate potential is beneficial to overall organ health, dramatic changes in cellular identity can have disastrous consequences. Emerging data within the field of pancreas biology are revising current beliefs about how cellular identity is shaped by developmental and environmental cues under homeostasis and stress conditions. Here, we discuss the changes occurring in cellular states upon fate modulation and address how our understanding of the nature of this fluidity is shaping therapeutic approaches to pancreatic disorders such as diabetes and cancer.

Pancreatic β cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in β-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal β cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that β-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult β cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal β that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the β cell reverts to a less functional one in response to proliferative cues., Adult beta cells, which are highly specialised insulin-secreting cells, rarely replicate. Puri et al. demonstrate that beta cell proliferative capacity is inversely correlated with their functionality and differentiation state, by inducing proliferation of adult cells with ectopic overexpression of the cell cycle regulator c-Myc.

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

Background: Pelvic organ prolapse is common in women and 7-9% undergo surgical repair. Abdominal sacrocolpopexy and sacrohysteropexy is the most durable operation for vault prolapse and Nulliparous prolapse respectively. The objectives of this study were to describe Anatomic and symptomatic outcomes up to 5 years after abdominal sacrocolpopexy or sacrohysteropexy.Methods: This study was conducted in ASCOMS hospital for a cohort of patients who underwent abdominal sacrocolpopexy (ASC) or sacrohysteropexy (ASH) in 2 years (2013-2015) and follow up done for a period of 5 years from 2015-2019. These patients were evaluated for subjective and objective outcomes following ASC and ASH. women completed questionnaires and were examined in gynaecology clinic. Prospective follow up study using standarised examination with pelvic organ prolapse quantification system (POP-Q) and questionnairesResults: In the present study, there was low incidence of intraoperative and postoperative complications as well as long term complications were significantly low. The anatomical cure rate and patient satisfaction rate was both 100%.Conclusions: Abdominal sacrocolpopexy for vault prolapse and sacrohysteropexy for Nulliparous prolapse is safe and effective method and is considered gold standard for treatment of Apical compartment prolapse.

Organ formation is achieved through the complex interplay between signaling pathways and transcriptional cascades. The canonical Wnt signaling pathway plays multiple roles during embryonic development including patterning, proliferation and differentiation in distinct tissues. Previous studies have established the importance of this pathway at multiple stages of pancreas formation as well as in postnatal organ function and homeostasis. In mice, gain-of-function experiments have demonstrated that activation of the canonical Wnt pathway results in pancreatic hypoplasia, a phenomenon whose underlying mechanisms remains to be elucidated. Here, we show that ectopic activation of epithelial canonical Wnt signaling causes aberrant induction of gastric and intestinal markers both in the pancreatic epithelium and mesenchyme, leading to the development of gut-like features. Furthermore, we provide evidence that β -catenin-induced impairment of pancreas formation depends on Hedgehog signaling. Together, our data emphasize the developmental plasticity of pancreatic progenitors and further underscore the key role of precise regulation of signaling pathways to maintain appropriate organ boundaries., This work was supported by Nicolás Monardes program of Andalusian Ministry of Health (www.juntadeandalucia.es/fundacionprogresoysalud/es), Grant number: C-0015-2014 (DAC); Andalusian Ministry of Science and Innovation (www.juntadeandalucia.es/innovacioncienciayempresa), Grant number: CTS-7478 (DAC); Ministry of Economy and Competitiveness, Spain (www.mineco.gob.es), Grant number: SAF2011-26805 (DAC); Ministry of Economy and Competitiveness, Spain (www.mineco.gob.es), predoctoral fellowship number: BES-2009-012084 (JLMB); Ministry of Economy and Competitiveness, Spain (www.mineco.gob.es), Ramon y Cajal Program number: RYC-2013-14533 (AR); Instituto de Salud Carlos III, Spain (www.isciii.es) cofunded by Fondos FEDER, Grant Number: PI14/00804 (AR); and National Institute of Health, US (www.nih.gov) Grant Number: DK105831 (MH).

The pancreas has been the subject of intense research due to the debilitating diseases that result from its dysfunction. In this review, we summarize current understanding of the critical tissue interactions and intracellular regulatory events that take place during formation of the pancreas from a small cluster of cells in the foregut domain of the mouse embryo. Importantly, an understanding of principles that govern the development of this organ has equipped us with the means to manipulate both embryonic and differentiated adult cells in the context of regenerative medicine. The emerging area of lineage modulation within the adult pancreas is of particular interest, and this review summarizes recent findings that exemplify how lessons learned from development are being applied to reveal the potential of fully differentiated cells to change fate.

OBJECTIVE—The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant tumors of the kidney, central nervous system, and pancreas. RESEARCH DESIGN AND METHODS—We use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic β-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh−/− islets, insulin secretion is measured in vivo and in vitro, and quantitative PCR is used to identify changes in gene expression. RESULTS—Loss of VHL in β-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for β-cell specification and development, it is critical for β-cell function. Insulin production is normal in β-cells lacking VHL; however, insulin secretion in the presence of high concentrations of glucose is impaired. Furthermore, the loss of VHL leads to dysregulation of glycolytic enzymes, pointing to a perturbation of the intracellular energy homeostasis. CONCLUSIONS—We show that loss of VHL in β-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in β-cell function. We believe that the β-cell–specific Vhlh-deficient mice might be a useful tool as a “genetic hypoxia” model, to unravel the possible link between hypoxia signaling and impairment of β-cell function.

Current knowledge about developmental processes in complex organisms has relied almost exclusively on analyses of fixed specimens. However, organ growth is highly dynamic, and visualization of such dynamic processes, e.g., real-time tracking of cell movement and tissue morphogenesis, is becoming increasingly important. Here, we use live imaging to investigate expansion of the embryonic pancreatic epithelium in mouse. Using time-lapse imaging of tissue explants in culture, fluorescently labeled pancreatic epithelium was found to undergo significant expansion accompanied by branching. Quantification of the real-time imaging data revealed lateral branching as the predominant mode of morphogenesis during epithelial expansion. Live imaging also allowed documentation of dynamic beta-cell formation and migration. During in vitro growth, appearance of newly formed beta-cells was visualized using pancreatic explants from MIP-GFP transgenic animals. Migration and clustering of beta-cells were recorded for the first time using live imaging. Total beta-cell mass and concordant aggregation increased during the time of imaging, demonstrating that cells were clustering to form "pre-islets". Finally, inhibition of Hedgehog signaling in explant cultures led to a dramatic increase in total beta-cell mass, demonstrating application of the system in investigating roles of critical embryonic signaling pathways in pancreas development including beta-cell expansion. Thus, pancreas growth in vitro can be documented by live imaging, allowing visualization of the developing pancreas in real-time.

The mammalian Golgi apparatus exists as stacks of cisternae that are laterally linked to form a continuous membrane ribbon, but neither the molecular requirements for, nor the purpose of, Golgi ribbon formation are known. Here, we demonstrate that ribbon formation is mediated by specific membrane-fusion events that occur during Golgi assembly, and require the Golgi proteins GM130 and GRASP65. Furthermore, these GM130 and GRASP65-dependent lateral cisternal-fusion reactions are necessary to achieve uniform distribution of enzymes in the Golgi ribbon. The membrane continuity created by ribbon formation facilitates optimal processing conditions in the biosynthetic pathway.

The cis-Golgi protein GPP130 reversibly redistributes to endosomes upon pH disruption, but the identity of the endosomes and the involved cycling route are unknown. It is also unknown whether any other early Golgi proteins participate in this pathway. Here, we analyze GPP130 and the structurally related Golgi protein GP73. Unlike the TGN marker TGN38/46, GPP130 and GP73 colocalized in the early Golgi and redistributed to the ER after brefeldin A treatment. Nevertheless, after pH disruption by monensin, GPP130 and GP73 redistributed to endosomes containing redistributed TGN38/46, but not other endosomal markers. In common with TGN38/46, the redistribution involved transient appearance on the plasma membrane, and upon monensin washout, the proteins moved back to the Golgi along a microtubule- and PI3 kinase-independent route. Although GP73 did not associate with GPP130, its steady-state Golgi targeting was also mediated by a lumenal predicted coiled-coil stem domain. These findings indicate that at least two early Golgi proteins, each containing stem domain Golgi targeting determinants, cycle to the cell surface and back along the late endosome independent TGN38/46 pathway.

Precise functioning of the pancreatic β cell is paramount to whole-body glucose homeostasis, and β-cell dysfunction contributes significantly to diabetes mellitus. Using transgenic mouse models, we demonstrate that deletion of the von Hippel-Lindau (Vhlh) gene (encoding an E3 ubiquitin ligase implicated in, among other functions, oxygen sensing in pancreatic β cells) is deleterious to canonical β-cell gene expression. This triggers erroneous expression of factors normally active in progenitor cells, including effectors of the Notch, Wnt, and Hedgehog signaling cascades. Significantly, an up-regulation of the transcription factor Sox9, normally excluded from functional β cells, occurs upon deletion of Vhlh. Sox9 plays important roles during pancreas development but does not have a described role in the adult β cell. β-Cell-specific ectopic expression of Sox9 results in diabetes mellitus from similar perturbations in β-cell identity. These findings reveal that assaults on the β cell that impact the differentiation state of the cell have clear implications toward our understanding of diabetes mellitus.

Mutations in the human homolog of the Vhlh gene [encoding the von-Hippel Lindau (VHL) protein] lead to tumor development. In mice, depletion of Vhlh in pancreatic s-cells causes perturbed glucose homeostasis, but the role of this gene in other pancreatic cells is poorly understood. To investigate the function of VHL/HIF pathway in pancreatic cells, we inactivated Vhlh in the pancreatic epithelium as well as in the endocrine and exocrine lineages. Our results show that embryonic depletion of Vhlh within the pancreatic epithelium causes postnatal lethality due to severe hypoglycemia. The hypoglycemia is recapitulated in mice with endocrine-specific removal of Vhlh, while animals with loss of Vhlh predominantly in the exocrine compartment survive to adulthood with no overt defects in glucose metabolism. Mice with hypoglycemia display diminished insulin release in response to elevated glucose. Significantly, the glucagon response is impaired both in vivo (circulating glucagon levels) as well as in an in vitro secretion assay in isolated islets. Hypoxia also impairs glucagon secretion in a glucagon-expressing cell line in culture. Our results reveal a novel role for the hypoxia/HIF pathway in islet hormone secretion and maintenance of the fine balance that allows for the establishment of normoglycemia.

Peri-centrosomal positioning of the mammalian Golgi apparatus is known to involve microtubule-based motility, but its importance for cellular physiology is a major unanswered question. Here, we identify golgin-160 and GMAP210 as proteins required for centripetal motility of Golgi membranes. In the absence of either golgin, peri-centrosomal positioning of the Golgi apparatus was disrupted while the cytoskeleton remained intact. Although secretion persisted with normal kinetics, it was evenly distributed in response to wounding rather than directed to the wound edge. Strikingly, these cells also completely failed to polarize. Further, directionally persistent cell migration was inhibited such that wound closure was impaired. These findings not only reveal novel roles for golgin-160 and GMAP210 in conferring membrane motility but also indicate that Golgi positioning has an active role in directed secretion, cell polarity, and wound healing.

It is unclear whether the mammalian Golgi apparatus can form de novo from the ER or whether it requires a preassembled Golgi matrix. As a test, we assayed Golgi reassembly after forced redistribution of Golgi matrix proteins into the ER. Two conditions were used. In one, ER redistribution was achieved using a combination of brefeldin A (BFA) to cause Golgi collapse and H89 to block ER export. Unlike brefeldin A alone, which leaves matrix proteins in relatively large remnant structures outside the ER, the addition of H89 to BFA-treated cells caused ER accumulation of all Golgi markers tested. In the other, clofibrate treatment induced ER redistribution of matrix and nonmatrix proteins. Significantly, Golgi reassembly after either treatment was robust, implying that the Golgi has the capacity to form de novo from the ER. Furthermore, matrix proteins reemerged from the ER with faster ER exit rates. This, together with the sensitivity of BFA remnants to ER export blockade, suggests that presence of matrix proteins in BFA remnants is due to cycling via the ER and preferential ER export rather than their stable assembly in a matrix outside the ER. In summary, the Golgi apparatus appears capable of efficient self-assembly.

β cell dysfunction with subsequent apoptosis is considered a significant contributor to the development of type 2 diabetes. Emerging data from Talchai etal. suggest β cell dedifferentiation as an alternative mechanism of insulin insufficiency that might be more amenable to intervention in at least a subset of patients.

The cis-Golgi protein GPP130 reversibly redistributes to endosomes upon pH disruption, but the identity of the endosomes and the involved cycling route are unknown. It is also unknown whether any other early Golgi proteins participate in this pathway. Here, we analyze GPP130 and the structurally related Golgi protein GP73. Unlike the TGN marker TGN38/46, GPP130 and GP73 colocalized in the early Golgi and redistributed to the ER after brefeldin A treatment. Nevertheless, after pH disruption by monensin, GPP130 and GP73 redistributed to endosomes containing redistributed TGN38/46, but not other endosomal markers. In common with TGN38/46, the redistribution involved transient appearance on the plasma membrane, and upon monensin washout, the proteins moved back to the Golgi along a microtubule- and PI3 kinase-independent route. Although GP73 did not associate with GPP130, its steady-state Golgi targeting was also mediated by a lumenal predicted coiled-coil stem domain. These findings indicate that at least two early Golgi proteins, each containing stem domain Golgi targeting determinants, cycle to the cell surface and back along the late endosome independent TGN38/46 pathway.