Jagriti Upadhyay

Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps

OBJECTIVE To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Feltys syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. RESULTS Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. CONCLUSION Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.

The role of leptin in regulating bone metabolism

Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature the indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk-benefit of leptins use in metabolic bone disease particularly in leptin deficient individuals.

The syndrome of hypoparathyroidism, deafness, and renal anomalies.

OBJECTIVE We review the syndrome of hypoparathyroidism, deafness, and renal anomalies (HDR syndrome). METHODS The current understanding and relevant literature pertaining to the background, genetic considerations, clinical features, prognosis, and treatment of HDR syndrome are reviewed. RESULTS The combination of hypoparathyroidism, deafness, and renal anomalies constitutes an unusual syndrome associated most commonly with haploinsufficiency in GATA3, which encodes a transcription factor that binds to the (A/T) GATA (A/G) consensus DNA sequence. Sensorineural hearing loss is the most consistently expressed clinical feature, being present in almost all affected individuals, and the combination of hypoparathyroidism and hearing impairment occurs in well over 90% of those affected, with various renal anomalies being the most heterogeneous feature of the classic triad. We characterize, in tabular form, the individual cases described in the literature and propose a classification scheme based on the presence or absence of renal anomalies. We also include the specific genetic abnormality and renal anomaly associated with each individual case. CONCLUSION HDR syndrome is a heterogeneous syndrome most commonly associated with GATA3 haploinsufficiency.

Pharmacotherapy of type 2 diabetes: An update

Type 2 diabetes (T2DM) is a leading cause of morbidity and mortality worldwide and a major economic burden. The prevalence of T2DM is rising, suggesting more effective prevention and treatment strategies are necessary. The aim of this narrative review is to summarize the pharmacologic treatment options available for patients with T2DM. Each therapeutic class is presented in detail, outlining medication effects, side effects, glycemic control, effect on weight, indications and contraindications, and use in selected populations (heart failure, renal insufficiency, obesity and the elderly). We also present representative cost for each antidiabetic category. Then, we provide an individualized guide for initiation and intensification of treatment and discuss the considerations and rationale for an individualized glycemic goal.

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

Lorcaserin is a serotonin 5-hydroxytryptamine 2c receptor agonist effective in treating obesity. Studies in rodents have shown that lorcaserin acts in the brain to exert its weight-reducing effects, but this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants and used functional MRI to study the effects of lorcaserin on the brain. Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. Decreases in emotion- and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. Decreases in caloric intake, weight, and BMI correlated with activations in the amygdala, parietal, and visual cortices at baseline. These data suggest that lorcaserin exerts its weight-reducing effects by decreasing attention-related brain activations to food cues (parietal and visual cortices) and emotional and limbic activity (insula, amygdala). Results indicating that baseline activation of the amygdala relates to increased efficacy suggest that lorcaserin would be of particular benefit to emotional eaters.

Obesity as a Disease

Obesity is a complex disease with many causal factors, associated with multiple comorbidities that contribute to significant morbidity and mortality. It is a highly prevalent disease that poses an enormous health and economic burden to society. This article reviews the mechanisms of obesity and its related comorbidities.

Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy

BACKGROUND Several myokines are produced by cardiac muscle. We investigated changes in myokine levels at the time of acute myocardial infarction (MI) and following reperfusion in relation to controls. METHODS Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable coronary artery disease (CAD) subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and degree of stenosis were recorded. Irisin, follistatin, follistatin-like 3, activin A and B, ALT, AST, CK and CK-MB were measured at baseline and 6 or 24h after the intervention. RESULTS MI and CAD patients had lower irisin than controls (p<0.001). MI patients had higher follistatin, activin A, CK, CK-MB and AST than CAD patients and controls (all p≤0.001). None of the myokines changed following reperfusion. Circulating irisin was associated with the degree of stenosis in all patients (p=0.05). Irisin was not inferior to CK-MB in predicting MI while folistatin and activin A could discriminate MI from CAD patients with similar to CK-MB accuracy. None of these myokines was altered following PCI in contrast to CK-MB. CONCLUSIONS Irisin levels are lower in MI and CAD implying that their production may depend on myocadial blood supply. Follistatin and activin A are higher in MI than in CAD suggesting increased release due to myocardial necrosis. They can predict MI with accuracy similar to CK-MB and their role in the diagnosis of MI remains to be confirmed by prospective large clinical studies.

Tuberculosis of the Adrenal Gland: A Case Report and Review of the Literature of Infections of the Adrenal Gland

Infections of the adrenal glands remain an important cause of adrenal insufficiency, especially in the developing world. Indeed, when Thomas Addison first described the condition that now bears his name over 150 years ago, the vast majority of cases were attributable to tuberculosis. Here we describe a classic, but relatively uncommon, presentation in the United States of adrenal insufficiency followed by a review of the current literature pertaining to adrenal infections.

White matter microstructure and cognitive decline in metabolic syndrome: a review of diffusion tensor imaging

Metabolic syndrome is a cluster of cardiovascular risk factors defined by the presence of abdominal obesity, glucose intolerance, hypertension and/or dyslipidemia. It is a major public health epidemic worldwide, and a known risk factor for the development of cognitive dysfunction and dementia. Several studies have demonstrated a positive association between the presence of metabolic syndrome and worse cognitive outcomes, however, evidence of brain structure pathology is limited. Diffusion tensor imaging has offered new opportunities to detect microstructural white matter changes in metabolic syndrome, and a possibility to detect associations between functional and structural abnormalities. This review analyzes the impact of metabolic syndrome on white matter microstructural integrity, brain structure abnormalities and their relationship to cognitive function. Each of the metabolic syndrome components exerts a specific signature of white matter microstructural abnormalities. Metabolic syndrome and its components exert both additive/synergistic, as well as, independent effects on brain microstructure thus accelerating brain aging and cognitive decline.

Irisin and leptin concentrations in relation to obesity, and developing type 2 diabetes: A cross sectional and a prospective case-control study nested in the Normative Aging Study

OBJECTIVE To investigate the associations between irisin and leptin levels in obesity and insulin resistance in a cross sectional study. To assess the potential role of irisin and leptin as a predictive marker of T2DM using a nested case-control study. METHODS Both studies were designed within the longitudinal VA NAS cohort. The cross sectional study involved 111 non obese and 105 obese subjects who were subdivided into two groups based on their fasting glucose tolerance. In the nested 1:3 case-control study, 47 subjects with T2DM and 140 non-diabetic controls were selected. Serum samples collected 3-5 years before the diagnosis of T2DM were analyzed. Irisin and leptin concentrations were measured using a validated ELISA and radioimmunoassay respectively. RESULTS In the cross-sectional study, irisin did not differ between groups based on their fasting glucose tolerance. When subjects were grouped based on obesity status, both irisin and leptin concentrations were significantly higher in obese compared to the non-obese group (p=0.03 and <0.001, respectively). Irisin concentrations positively correlated with leptin concentrations (r= 0.392, P < 0.001). In the nested case control study, leptin concentrations were a significant predictor of developing diabetes (p=0.005) in unadjusted models, but not after correcting for BMI, whereas irisin concentrations did not play a role of comparable significance. CONCLUSIONS Leptin concentrations are higher in the obese group irrespective of their glucose tolerance. Obese individuals with impaired fasting glucose have higher concentrations of circulating irisin compared to non-obese subjects with normal glucose tolerance. Irisin concentrations do not predict risk of developing diabetes prospectively.