Iron status of children aged 9-36 months in an urban slum Integrated Child Development Services project in Delhi

OBJECTIVE: To assess the magnitude/severity and possible etiology of anemia and iron deficiency among children 9-36 months of age. METHODS: A population-based study on the prevalence, etiology of anemia and iron status in 545 children, 9-36 months of age, was conducted in an urban slum ICDS (Integrated Child Development Services) project in North-East Delhi. Hemoglobin and serum ferritin was estimated and information on socio-economic, demographic, parasitic infection/infestation and dietary intake was collected. RESULTS: Prevalence of anemia (using WHO cut-off values of Hb >11.0 g/dl) among children, 9-36 months of age, was 64%, of these 7.8% had severe anemia (Hb >7.0 g/dl). Using 10.0 g/dl as the Hb cut-off point 44% children less than 18 months of age in the present study population were anemic. On a sub-sample study, 88% children were estimated to be iron deficient, with serum ferritin concentration less than 12 microg/L. The peripheral smear red cell morphology showed 33.9% as microcytic-hypochromic and 37.1% as dimorphic. Dimorphic anemia was 55% in moderate anemia group. The energy and iron intakes were 56% and 45%, respectively of the Recommended Dietary Allowances (RDA). The parasitic infestation/infection was not related to the prevalence or severity of anemia. CONCLUSION: In Delhi, high prevalence of moderate to severe anemia and iron deficiency with vitamins folate and/or B12 among children under 3 years of age in an ICDS block in operation for 20 years is of concern. Dietary origin was the main cause of anemia in this age group.     

Robot-assisted laparoscopic prostatectomy for a giant prostate with retrieval of vesical stones

Aim  

To report and describe the technique of robot assisted prostatectomy (RAP) and retrieval of vesical stones.     

The Skeletal Subsystem as an Integrative Physiology Paradigm

Homeostatic bone remodeling depends on precise regulation of osteoblast-osteoclast coupling through intricate endocrine, immune, neuronal, and mechanical factors. The osteoblast-osteoclast model of bone physiology with layers of regulatory complexity can be investigated as a component of a local skeletal subsystem or as a part of a complete whole-body system. In this review, we flip the traditional investigative paradigm of scientific experimentation (“bottom–top research”) to a “top–bottom” approach using systems biology. We first establish the intricacies of the two-cell model at the molecular signaling level. We then provide, on a systems level, an integrative physiologic approach involving many recognized organ-level subsystems having direct and/or indirect effects on bone remodeling. Lastly, a hypothetical model of bone remodeling based on frequency and amplitude regulatory mechanisms is presented. It is hoped that by providing a thorough model of skeletal homeostasis, future progress can be made in researching and treating skeletal morbidities.     

Denosumab for the Treatment of Osteoporosis

Being a connective tissue, bone can increase or decrease its mass through the process of remodeling. Using a discovery in the mid-1980s—that tumor necrosis factor (TNF) could dramatically increase formation of osteoclasts (the cells that break down bone)—researchers at Amgen (Thousand Oaks, CA) discovered a TNF-like molecule that regulated bone resorption. Elevations in the expression of this molecule, receptor activator of nuclear factor-κB ligand (RANKL), can cause excessive bone destruction. A blocking antibody to RANKL named denosumab inhibits osteoclast formation and bone degradation. In a large multicenter clinical trial, known as the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), the effects of denosumab were tested in 60- to 90-year-old women over 3 years. Statistically significant reductions in fracture risk at the vertebral column, hip, and nonvertebral sites were associated with increases in bone mineral density (BMD) and reciprocal decreases in markers of bone resorption. However, the FREEDOM trial did not test the most beneficial use of a resorption blocking drug—to target the rapid bone loss that occurs in late perimenopause and early postmenopause. One adverse effect from denosumab is cellulitis, and research in animals suggests that RANKL/RANK interaction is needed for Langerhans cell (LC) survival in the skin. Further mechanistic and clinical studies on the role of RANKL in the skin are needed.     

Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5

Microtubule-associated protein tau is abnormally hyperphosphorylated, glycosylated, and aggregated in affected neurons in Alzheimer's disease (AD). We recently found that the aberrant tau glycosylation precedes tau hyperphosphorylation in AD brain. In the present study, we developed assays to determine phosphorylation and dephosphorylation of tau at specific phosphorylation sites by using glycosylated tau purified from AD brain as a substrate. We then studied the effects of the aberrant glycosylation on phosphorylation and dephosphorylation of tau at each specific phosphorylation site. We found that deglycosylation of the aberrantly glycosylated tau decreased the subsequent phosphorylation of tau at Ser214, Ser262, and Ser356 in vitro by protein kinase A. On the other hand, deglycosylation of tau positively modulated the subsequent dephosphorylation by protein phosphatase 2A and protein phosphatase 5 in vitro at the phosphorylation sites Ser198, Ser199, and Ser202.Our results suggest that the aberrant glycosylation may modulate tau protein at a substrate level so that it is easier to be phosphorylated and more difficult to be dephosphorylated at some phosphorylation sites in AD brain. The combined impact of this modulation may be to make tau more susceptible to becoming abnormally hyperphosphorylated.     

Immunological mechanisms underpinning faecal microbiota transplantation for the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease that results from a dysregulated immune response against specific environmental triggers in a genetically predisposed individual. Increasing evidence has indicated a causal role for changes in gut microbiota (dysbiosis) contributing to this immune-mediated intestinal inflammation. These mechanisms involve dysregulation of multiple facets of the host immune pathways that are potentially reversible. Faecal microbiota transplantation (FMT) is the transfer of processed stool from a healthy donor into an individual with an illness. FMT has shown promising results in both animal model experiments and clinical studies in IBD in the resolution of intestinal inflammation. The underlying mechanisms, however, are unclear. Insights from these studies have shown interactions between modulation of dysbiosis via changes in abundances of specific members of the gut microbial community and changes in host immunological pathways. Unravelling these causal relationships has promising potential for a translational therapy role to develop targeted microbial therapies and understand the mechanisms that underpin IBD aetiopathogenesis. In this review, we discuss current evidence for the contribution of gut microbiota in the disruption of intestinal immune homeostasis and immunoregulatory mechanisms that are associated with the resolution of inflammation through FMT in IBD.     

Dysregulation of Insulin Signaling,Glucose Transporters,O-GlcNAcylation,and Phosphorylation of Tau and Neurofilaments in the Brain : Implication for Alzheimer’s Disease

Recent studies have suggested a possible role of insulin dysfunction in the pathogenesis of sporadic Alzheimer’s disease (AD). In AD, brain glucose metabolism is impaired, and this impairment appears to precede the pathology and clinical symptoms of the disease. However, the exact contribution of impaired insulin signaling to AD is not known. In this study, by using a nontransgenic rat model of sporadic AD generated by intracerebroventricular administration of streptozotocin, we investigated insulin signaling, glucose transporters, protein O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain. We found impaired insulin signaling, overactivation of glycogen synthase kinase-3β, decreased levels of major brain glucose transporters, down- regulated protein O-GlcNAcylation, increased phosphorylation of tau and neurofilaments, and decreased microtubule-binding activity of tau in the brains of streptozotocin-treated rats. These results suggest that impaired brain insulin signaling may lead to overactivation of glycogen synthase kinase-3β and down-regulation of O-GlcNAcylation, which, in turn, facilitate abnormal hyperphosphorylation of tau and neurofilaments and, consequently, neurofibrillary degeneration.Alzheimer’s disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia in, and eventually, death of the affected individuals. In less than 1% of cases, AD is caused by autosomal dominant mutations of presenilin-1, presenilin-2, or β-amyloid precursor protein. Most AD cases are sporadic and are believed to result from multiple etiologic factors including genetic susceptibility (such as the ApoE4 allele) and environmental and metabolic factors.¹ One of these factors, impaired brain glucose metabolism, can be detected many years before the appearance of clinical symptoms of AD.² We recently found that altered O-GlcNAcylation, an O-linked post-translational modification of nucleocytoplasmic proteins by a monosaccharide β-N-acetylglucosamine (O-GlcNAc), of the microtubule-associated protein tau, links the impairment of brain glucose metabolism to hyperphosphorylation of tau.^3,4 On the basis of these findings, we hypothesized that the impairment of brain glucose metabolism contributes to neurodegeneration via down-regulation of O-GlcNAcylation, which is regulated by glucose metabolism, and the resultant abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration in AD.⁵Peripheral glucose metabolism is mainly regulated by insulin. Recent studies have indicated that insulin signaling also regulates glucose metabolism in the brain and plays important roles in neural development and neuronal activities and affects learning and memory.⁶ The role of possible insulin dysfunction in AD has been suggested recently.^7,8,9,10 However, how the impaired insulin signaling contributes to the pathogenesis of AD is not known.To investigate the possible pathogenic mechanism related to the impaired brain insulin signaling and glucose metabolism in sporadic AD, we investigated insulin signaling pathways, glucose transporters (GLUT), protein O-GlcNAcylation and phosphorylation of tau and neurofilaments (NFs) in a rat model of sporadic AD, which was generated by intracerebroventricular (i.c.v.) injection of streptozotocin (STZ).^11,12,13 STZ is a glucosamine-nitrosourea compound and is commonly administrated peripherally to generate animal models of diabetes because of its ability to damage insulin-producing cells and to increase insulin resistance. We found the impaired insulin signaling pathway, overactivation of glycogen synthase kinase-3β (GSK-3β), decreased major glucose transporters, down-regulation of protein O-GlcNAcylation, increased phosphorylation of tau and NFs, and decreased microtubule-binding activity of tau in the brain of the rat model of AD. Our results provide in vivo evidence showing that impaired brain insulin signaling and O-GlcNAcylation contribute to hyperphosphorylation of tau and NFs.     

Role of L-selectin in the development of autoimmune diabetes in non-obese diabetic mice

Autoimmune diabetes is characterized by an early mononuclear infiltration of pancreatic islets and later selective autoimmune destruction of insulin-producing beta cells. Lymphocyte homing receptors have been considered candidate targets to prevent autoimmune diabetes. L-selectin (CD62L) is an adhesion molecule highly expressed in naive T and B cells. It has been reported that blocking L-selectin in vivo with a specific antibody (Mel-14) partially impairs insulitis and diabetes in autoimmune diabetes-prone non-obese diabetic (NOD) mice. In the present study we aimed to elucidate whether genetic blockade of leukocyte homing into peripheral lymph nodes would prevent the development of diabetes. We backcrossed L-selectin-deficient mice onto the NOD genetic background. Surprisingly NOD/L-selectin-deficient mice exhibited unaltered islet mononuclear infiltration, timing of diabetes onset and cumulative incidence of spontaneous diabetes when compared to L-selectin-sufficient animals. CD4, CD8 T cells and B cells were present in islet infiltrates from 9-week-old L-selectin-sufficient and -deficient littermates. Moreover, total splenocytes from wild-type, heterozygous or NOD/L-selectin-deficient donor mice showed similar capability to adoptively transfer diabetes into NOD/SCID recipients. On the other hand, homing of activated, cloned insulin-specific autoaggressive CD8 T cells (TGNFC8 clone) is not affected in NOD/L-selectin-deficient recipients. We conclude that L-selectin plays a small role in the homing of autoreactive lymphocytes to regional (pancreatic) lymph nodes in NOD mice.