Added value of the measles-rubella supplementary immunization activity in reaching unvaccinated and under-vaccinated children, a cross-sectional study in five Indian districts, 2018-20.

INTRODUCTION: Supplementary immunization activities (SIAs) aim to interrupt measles transmission by reaching susceptible children, including children who have not received the recommended two routine doses of MCV before the SIA. However, both strategies may miss the same children if vaccine doses are highly correlated. How well SIAs reach children missed by routine immunization is a key metric in assessing the added value of SIAs. METHODS: Children aged 9 months to younger than 5 years were enrolled in cross-sectional household serosurveys conducted in five districts in India following the 2017-2019 measles-rubella (MR) SIA. History of measles containing vaccine (MCV) through routine services or SIA was obtained from documents and verbal recall. Receipt of a first or second MCV dose during the SIA was categorized as "added value" of the SIA in reaching un- and under-vaccinated children. RESULTS: A total of 1,675 children were enrolled in these post-SIA surveys. The percentage of children receiving a 1st or 2nd dose through the SIA ranged from 12.8% in Thiruvananthapuram District to 48.6% in Dibrugarh District. Although the number of zero-dose children prior to the SIA was small in most sites, the proportion reached by the SIA ranged from 45.8% in Thiruvananthapuram District to 94.9% in Dibrugarh District. Fewer than 7% of children remained measles zero-dose after the MR SIA (range: 1.1-6.4%) compared to up to 28% before the SIA (range: 7.3-28.1%). DISCUSSION: We demonstrated the MR SIA provided considerable added value in terms of measles vaccination coverage, although there was variability across districts due to differences in routine and SIA coverage, and which children were reached by the SIA. Metrics evaluating the added value of an SIA can help to inform the design of vaccination strategies to better reach zero-dose or undervaccinated children.

Exploring inter-organ crosstalk to uncover mechanisms that regulate ß-cell function and mass.

Impaired ß-cell function and insufficient ß-cell mass compensation are twin pathogenic features that underlie type 2 diabetes (T2D). Current therapeutic strategies continue to evolve to improve treatment outcomes in different ethnic populations and include approaches to counter insulin resistance and improve ß-cell function. Although the effects of insulin secretion on metabolic organs such as liver, skeletal muscle and adipose is directly relevant for improving glucose uptake and reduce hyperglycemia, the ability of pancreatic ß-cells to crosstalk with multiple non-metabolic tissues is providing novel insights into potential opportunities for improving ß-cell function and/or mass that could have beneficial effects in patients with diabetes. For example, the role of the gastrointestinal system in the regulation of ß-cell biology is well recognized and has been exploited clinically to develop incretin-related antidiabetic agents. The microbiome and the immune system are emerging as important players in regulating ß-cell function and mass. The rich innervation of islet cells indicates it is a prime organ for regulation by the nervous system. In this review, we discuss the potential implications of signals from these organ systems as well as those from bone, placenta, kidney, thyroid, endothelial cells, reproductive organs and adrenal and pituitary glands that can directly impact ß-cell biology. An added layer of complexity is the limited data regarding the relative relevance of one or more of these systems in different ethnic populations. It is evident that better understanding of this paradigm would provide clues to enhance ß-cell function and/or mass in vivo in the long-term goal of treating or curing patients with diabetes.

Novel factors modulating human ß-cell proliferation.

ß-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of ß-cells, and an understanding of the cellular mechanism(s) that regulate ß-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human ß-cell proliferation is one potential approach to restore ß-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance ß-cell replication in animal models or cell lines, promoting effective human ß-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human ß-cell proliferation including WS6, an IkB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3ß and DYRK1A inhibitors; osteoprotegrin and Denosmab, receptor activator of NF-kB (RANK) inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of human diabetes.

IL-6 alters osteocyte signaling toward osteoblasts but not osteoclasts.

Mechanosensitive osteocytes regulate bone mass in adults. Interleukin 6 (IL-6), such as present during orthodontic tooth movement, also strongly affects bone mass, but little is known about the effect of IL-6 on osteocyte function. Therefore we aimed to determine in vitro whether IL-6 affects osteocyte mechanosensitivity, and osteocyte regulation of osteoclastogenesis and osteoblast differentiation. MLO-Y4 osteocytes were incubated with/without IL-6 (1 or 10 pg/mL) for 24 hr. Subsequently, osteocytes were subjected to mechanical loading by pulsating fluid flow (PFF) for 1 hr. Mouse osteoclast precursors were cultured for 7 days on top of IL-6-treated osteocytes. Conditioned medium from osteocytes treated with/without IL-6 was added to MC3T3-E1 pre-osteoblasts for 14 days. Exogenous IL-6 (10 pg/mL) did not alter the osteocyte response to PFF. PFF significantly enhanced IL-6 production by osteocytes. IL-6 enhanced Rankl expression but reduced caspase 3/7 activity by osteocytes, and therefore did not affect osteocyte-stimulated osteoclastogenesis. Conditioned medium from IL-6-treated osteocytes reduced alkaline phosphatase (ALP) activity and Runx2 expression in osteoblasts, but increased expression of the proliferation marker Ki67 and osteocalcin. Our results suggest that IL-6 is produced by shear-loaded osteocytes and that IL-6 may affect bone mass by modulating osteocyte communication toward osteoblasts.

Modulation of ß-cell function: a translational journey from the bench to the bedside.

Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human ß-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in ß-cells are critical for compensatory islet growth in response to insulin resistance. Rodents with tissue-specific knockout of the insulin receptor in the ß-cell (ßIRKO) show reduced first-phase glucose-stimulated insulin secretion (GSIS) and with aging develop glucose intolerance and diabetes, phenotypically similar to the process seen in human T2D. Expression of multiple insulin signalling proteins is reduced in islets of patients with T2D. Insulin potentiates GSIS in isolated human ß-cells. Recent studies in humans in vivo show that pre-exposure to insulin increases GSIS, and this effect is diminished in persons with insulin resistance or T2D. ß-Cell function correlates to whole-body insulin sensitivity. Together, these findings suggest that pancreatic ß-cell dysfunction could be caused by a defect in insulin signalling within ß-cell, and ß-cell insulin resistance may lead to a loss of ß-cell function and/or mass, contributing to the pathophysiology of T2D.

Growth factor signalling in the regulation of α-cell fate.

Glucagon plays critical roles in regulating glucose homeostasis, mainly by counteracting the effects of insulin. Consequently, the dysregulated glucagon secretion that is evident in type 2 diabetes has significant implications in the pathophysiology of the disease. Glucagon secretion from pancreatic α-cells has been suggested to be modulated by blood glucose, signals from the nervous system and endocrine components. In addition to these regulators, intraislet factors acting in a paracrine manner from neighbouring ß-cells are emerging as central modulator(s) of α-cell biology. One of the most important of these paracrine factors, insulin, modulates glucagon secretion. Indeed, the α-cell-specific insulin receptor knockout (αIRKO) mouse manifests hypersecretion of glucagon in the postprandial stage and exhibits defective secretion in fasting-induced hypoglycaemia, together mimicking the α-cell defects observed in type 2 diabetes. Interestingly, αIRKO mice display a progressive increase in ß-cell mass and a concomitant decrease in α-cells. Lineage trace analyses reveal that the new ß-cells originate, in part, from the insulin receptor-deficient α-cells indicating a critical role for α-cell insulin signalling in determining ß-cell origin. Our studies also reveal that glucagon-like peptide-1 (GLP-1) treatment of αIRKO mice suppresses glucagon secretion despite absence of functional insulin receptors precluding a role for insulin in GLP-1 action on α-cells in this model. These findings highlight the significance of insulin signalling in the regulation of α-cell biology.

The roles of telomeres and telomerase in beta-cell regeneration.

Telomerase is a specialized reverse transcriptase that is responsible for extending and preserving the end of the chromosomes (telomeres). Telomerase plays a key role in regulating the lifespan of mammalian cells and is involved in critical aspects of cellular ageing processes. In this review, we will briefly summarize our current understanding of the functions of telomeres, telomerase and their regulation. Considering that compensatory islet hyperplasia and beta-cell regeneration play important roles in the prevention and/or delay of the onset of overt diabetes, we will also examine current literature regarding the effects of diabetes on telomere shortening and provide insights from our own studies on the role of telomerase in beta-cell regeneration.

Differential expression of cell cycle proteins during ageing of pancreatic islet cells.

One of the major challenges for developmental biologists and investigators in the field of diabetes over the last few decades has been to dissect the origin of pancreatic endocrine cells and to accurately understand the mechanisms that regulate islet cell regeneration. While significant advances have been made recently, there continues to be a paucity of knowledge regarding the growth factor signalling pathways that directly regulate the proteins involved in islet cell cycle control. We will discuss recent work in these areas and provide insights from our studies into age-dependent alterations in the expression of growth factor signalling proteins and cell cycle proteins in islet cells.

Inheritance of pollen-less anthers and "thrum" and "pin" flowers in periwinkle.

Two mutants, 1 with small, pollen-less anthers (OR-EA) and another with "pin" flowers (EMS 13-2), in contrast to "thrum" flowers found in normal periwinkle (Catharanthus roseus) plants, were isolated after induced mutagenesis in strain OR and cultivar, "Dhawal," respectively. Inheritance of these 2 traits, pollen-less anthers, and pin flowers was studied by crossing the mutants with their respective parental strains. Segregation ratios observed in F(2) and testcross generations of the cross OR-EA x OR suggested that the pollen-less anthers trait was determined by duplicate recessive genes. Data obtained from F(2) and F(3) generations of the cross involving mutant EMS 13-2 with pin flowers and its parental variety Dhawal, suggested that production of pin (mutant) and thrum (normal) flowers was under the control of inhibitory epistatic interaction between 2 independently inherited genes.

Microsurgical anatomy of the middle cerebral artery.

BACKGROUND: The microsurgical anatomy of the middle cerebral artery (MCA) is of particular interest to the cerebrovascular surgeon. The purpose of this study was to define the microsurgical anatomy of the MCA and its various branches in the Indian population. METHODS: Ten MCAs were studied from five cadaveric brain specimens. The authors studied the outer diameter, length, branches, perforators and site of these on the main trunk (M1), the division of the main trunk, the secondary trunks and their various cortical branches using the operating microscope under 5-20x magnification. RESULTS: The outer diameter of the MCA main trunk ranges from 2.5 to 4 mm with a mean of 3.35 mm. The superolateral branches consisted of polar temporal artery and anterior temporal artery that had a common origin and sometimes the uncal artery or the accessory uncal artery. Perforators or lenticulostriate arteries were seen in the inferomedial surface all along the length of M1. Eight bifurcations and two trifurcations were noted. Cortical branches and their origin are discussed. CONCLUSION: Although the microsurgical anatomy of the MCA in Indian population correlated with the findings in the western literature, some structural and statistical variations were noted.

A study of leucorrhoea in reproductive age group women of Nagpur City.

A community based cross-sectional study was conducted in reproductive age group women in an urban community of Nagpur, to assess the prevalence of leucorrhoea and the factors influencing the same in these women. The study participants included 506 females, out of which 149 were unmarried and 357 were married. Detailed history and clinical examination was done in all the females including gynecological examination in all the married females. Leucorrhoea was present in 139 (27.47%) females. Leucorrhoea was found significantly more in married females as compared to unmarried (p < 0.001), pregnant as compared to non-pregnant (OR = 2.10, 95% C.I. = 1.02-4.32), and women of lower socioeconomic status (p < 0.001), women with high parity (p < 0.001). Use of Cu-T was not associated with Leucorrhoea (p > 0.05).

Allelic differences at two loci govern different mechanisms of intraflower self-pollination in self-pollinating strains of periwinkle.

Periwinkle [Catharanthus roseus (L.) G. Don], an ornamental and medicinal plant, is a self-compatible, insect-pollinated plant species in which intraflower self-pollination does not occur because of spatial separation of the stigma and anthers. Recently three self-pollinating strains-MJ, VI, and OR-were identified. Self-pollination in these strains was found to be brought about by continuous increase in gynoecium length from anthesis to self-pollination, in contrast to non-self-pollinating strains, in which the stigma remained below the base of the anthers from anthesis to flower drop. Self-pollination in these strains was found to be controlled by duplicate, recessive genes. Self-pollination in strains MJ and VI was brought about by an increase in gynoecium length resulting from an increase in the length of the ovary, while in the strain OR, the increase in gynoecium length was because of an increase in the length of the style from anthesis to self-pollination. The three strains were intercrossed to determine the relationship between genes governing self-pollination in these strains. The F(1) plants and all plants of the F(2) generation of the cross MJ x VI exhibited self-pollination that was brought about by an increase in the length of the ovary, indicating that the same genes were involved in these two strains. The F(1) plants of crosses OR x MJ and OR x VI, exhibited self-pollination that was brought about by an increase in the length of the ovary, indicating that self-pollination brought about by an increase in the length of the ovary was dominant over self-pollination brought about by an increase in the length of the style. In the F(2) and backcross [(OR x MJ) x OR and (OR x VI) x OR] generations, both self-pollinating and non-self-pollinating plants were observed. The ratio of plants with self-pollination brought about by an increase in the length of the ovary, non-self-pollinating plants, and plants with self-pollination brought about by an increase in the length of the style in the F(2) and backcross generations fit 9:6:1 and 1:2:1 ratios, respectively. All plants of the backcrosses [(OR x MJ) x MJ and (OR x VI) x VI] exhibited self-pollination brought about by an increase in the length of the ovary. The results thus supported the earlier finding that self-pollination in the studied strains was controlled by duplicate, recessive genes and suggested that three alleles at two loci determine the occurrence or nonoccurrence of intraflower self-pollination in periwinkle.

Inheritance of flower color in periwinkle: orange-red corolla and white eye.

The commonly found flower colors in periwinkle (Catharanthus roseus)--pink, white, red-eyed, and pale pink center--are reported to be governed by the epistatic interaction between four genes--A, R, W, and I. The mode of inheritance of an uncommon flower color, orange-red corolla and white eye, was studied by crossing an accession possessing this corolla color with a white flowered variety (Nirmal). The phenotype of the F(1) plants and segregation data of F(2) and backcross generations suggested the involvement of two more interacting and independently inherited genes, one (proposed symbol E) determining the presence or absence of red eye and another (proposed symbol O) determining orange-red corolla.

beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.

Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function.

Role of socio-economic factors and cytology in cervical erosion in reproductive age group women.

A cross-sectional study involving 357 females in the reproductive age group (15-44) was conducted in an urban community of Nagpur with the objective of studying the role of socio-economic factors & cytology in cervical erosion. Cervical erosion was detected in 82 (22.96%) females. Out of these mild dysplasia was seen in 9.75% females & moderate dysplasia in 2.43% females. High percentages of inflammatory smears i.e. (75.68%) were obtained in women with cervical erosion. Cervical erosion was more common in illiterate & women with low literacy status as compared to women with higher education. Majority of cases of cervical erosion (75.6%) were detected in women with high parity. A statistically significant association was found between lower socio-economic status, early age at marriage & ocurrence of cervical erosion (p<0.001 & p<0.01 respectively). The study concludes that socio-economic factors such as illiteracy and low literacy status, lower socio-economic status, early age at marriage and high parity are contributory for the occurrence of cervical erosion and regular cytological screening by Pap smear will help in early detection of carcinoma cervix and thereby reduce the morbidity and mortality caused by the same.

Symmetry C18 column: a better choice for the analysis of indole alkaloids of Catharanthus roseus.

By virtue of the different elution patterns of vindoline, catharanthine, vincristine and vinblastine present in the leaves of Catharanthus roseus plants, a Symmetry C18 column provided a better resolution for all of these compounds as compared with other C18 columns. The binary gradient system with a linear gradient profile, employed in a method developed using a Symmetry C18 column, gave excellent peak symmetry, resolution and reproducibility. Detection was performed at 220 nm which presented better absorptivity for these indole alkaloids giving a minimum detection limit of 0.5 microgram. Photodiode array detection was used to determine the homogeneity and purity of each compound. The described analysis is rapid and economical to perform as small amounts of solvent are consumed per analysis, and the method will find application where a large number of samples are to be analysed as, for example, in crop improvement studies where plants need to be selected regularly on the basis of alkaloid production.

Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells.

Insulin signaling is mediated by a complex network of diverging and converging pathways, with alternative proteins and isoforms at almost every step in the process. We show here that insulin activates the transcription of its own gene and that of the beta cell glucokinase gene (betaGK) by different mechanisms. Whereas insulin gene transcription is promoted by signaling through insulin receptor A type (Ex11-), PI3K class Ia, and p70s6k, insulin stimulates the betaGK gene by signaling via insulin receptor B type (Ex11+), PI3K class II-like activity, and PKB (c-Akt). Our data provide evidence for selectivity in insulin action via the two isoforms of the insulin receptor, the molecular basis being preferential signaling through different PI3K and protein kinases.

Evidence for a circulating islet cell growth factor in insulin-resistant states.

Insulin resistance is a feature of many common disorders including obesity and type 2 diabetes mellitus. In these disorders, the beta-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in beta-cell mass, or both. To determine whether the beta-cell response might relate to a circulating growth factor, we have transplanted normal islets under the kidney capsule of normoglycemic insulin-resistant mice with two different models of insulin resistance: lean mice that have a double heterozygous deletion of the insulin receptor and insulin receptor substrate-1 (DH) or the obese, hyperglycemic ob/ob mice. In the grafts transplanted into both hosts, there was a marked increase in beta-cell mitotic activity and islet mass that was comparable with that observed in the endogenous pancreas. By contrast, islets of the DH mouse transplanted into normal mice showed reduced mitotic index. These data suggest the insulin resistance is associated with a circulating islet cell growth factor that is independent of glucose and obesity.

A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.