Showing papers by "Sridevi Devaraj published in 2018"

Gut Microbiome in Obesity, Metabolic Syndrome, and Diabetes.

Abstract: Obesity and diabetes are worldwide epidemics. There is also a growing body of evidence relating the gut microbiome composition to insulin resistance. The purpose of this review is to delineate the studies linking gut microbiota to obesity, metabolic syndrome, and diabetes. Animal studies as well as proof of concept studies using fecal transplantation demonstrate the pivotal role of the gut microbiota in regulating insulin resistance states and inflammation. While we still need to standardize methodologies to study the microbiome, there is an abundance of evidence pointing to the link between gut microbiome, inflammation, and insulin resistance, and future studies should be aimed at identifying unifying mechanisms.

Diabetes Mellitus-Induced Long Noncoding RNA Dnm3os Regulates Macrophage Functions and Inflammation via Nuclear Mechanisms

Abstract: Objective- Macrophages play key roles in inflammation and diabetic vascular complications. Emerging evidence implicates long noncoding RNAs in inflammation, but their role in macrophage dysfunction associated with inflammatory diabetic complications is unclear and was therefore investigated in this study. Approach and Results- RNA-sequencing and real-time quantitative PCR demonstrated that a long noncoding RNA Dnm3os (dynamin 3 opposite strand) is upregulated in bone marrow-derived macrophages from type 2 diabetic db/db mice, diet-induced insulin-resistant mice, and diabetic ApoE-/- mice, as well as in monocytes from type 2 diabetic patients relative to controls. Diabetic conditions (high glucose and palmitic acid) induced Dnm3os in mouse and human macrophages. Promoter reporter analysis and chromatin immunoprecipitation assays demonstrated that diabetic conditions induce Dnm3os via NF-κB activation. RNA fluorescence in situ hybridization and real-time quantitative PCRs of subcellular fractions demonstrated nuclear localization and chromatin enrichment of Dnm3os in macrophages. Stable overexpression of Dnm3os in macrophages altered global histone modifications and upregulated inflammation and immune response genes and phagocytosis. Conversely, RNAi-mediated knockdown of Dnm3os attenuated these responses. RNA pull-down assays with macrophage nuclear lysates identified nucleolin and ILF-2 (interleukin enhancer-binding factor 2) as protein binding partners of Dnm3os, which was further confirmed by RNA fluorescence in situ hybridization immunofluorescence. Furthermore, nucleolin levels were decreased in diabetic conditions, and its knockdown enhanced Dnm3os-induced inflammatory gene expression and histone H3K9-acetylation at their promoters. Conclusions- These results demonstrate novel mechanisms involving upregulation of long noncoding RNA Dnm3os, disruption of its interaction with nucleolin, and epigenetic modifications at target genes that promote macrophage inflammatory phenotype in diabetes mellitus. The data could lead to long noncoding RNA-based therapies for inflammatory diabetes mellitus complications.

Fecal microbiome signatures are different in food-allergic children compared to siblings and healthy children.

Abstract: Background Intestinal microbes have been shown to influence predisposition to atopic disease, including food allergy. The intestinal microbiome of food-allergic children may differ in significant ways from genetically similar non-allergic children and age-matched controls. The aim was to characterize fecal microbiomes to identify taxa that may influence the expression of food allergy. Methods Stool samples were collected from children with IgE-mediated food allergies, siblings without food allergy, and non-allergic controls. Stool microbiome characterization was performed via next-generation sequencing (Illumina) of the V1V3 and V4 variable regions of the 16S rRNA gene. Bacterial diversity, evenness, richness, and relative abundance of the operational taxonomic units (OTUs) were evaluated using QIIME. ANOVA and Welch's t test were utilized to compare groups. Results Sixty-eight children were included: food-allergic (n = 22), non-food-allergic siblings (n = 25), and controls (n = 21). When comparing fecal microbial communities across groups, differences were noted in Rikenellaceae (P = .035), Actinomycetaceae (P = .043), and Pasteurellaceae (P = .018), and nine other distinct OTUs. Food-allergic subjects had enrichment for specific microbes within the Clostridia class and Firmicutes phylum (Oscillobacter valericigenes, Lachnoclostridium bolteae, Faecalibacterium sp.) compared to siblings and controls. Identification of Clostridium sp. OTUs revealed differences in specific Clostridia drive the separation of the allergic from the siblings and controls. Alistipes sp. were enriched in non-allergic siblings. Conclusions Comparisons in the fecal microbiome of food-allergic children, siblings, and healthy children point to key differences in microbiome signatures, suggesting the role of both genetic and environmental contributors in the manifestation of food-allergic disease.

Subcutaneous adipose tissue biology in metabolic syndrome.

Abstract: Metabolic syndrome (MetS) is a common global problem that comprises the cardio-metabolic cluster and predisposes to both diabetes and cardiovascular diseases Although the pathogenic mechanisms have not been elucidated, both increased inflammation and insulin resistance play a pivotal role It appears that both monocyte/macrophages and adipose tissue (AT) conspire to accentuate both the pro-inflammatory state and increased insulin resistance Whilst there are scant data on visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) biology, there are data on subcutaneous adipose tissue (SAT) dysregulation There is a significant increase in macrophages and crown-like structures in the SAT of patients with MetS With respect to adipokines, there is an increase in plasma leptin, plasminogen activator inhibitor-1, retinol-binding protein-4 (RBP-4), chemerin, serum amyloid-A, C-reactive protein (CRP), interleukin-1, -6, -8, lipopolysaccharide, fetuin A (FetA) and a decrease in adiponectin and omentin-1 All of the abnormalities in plasma were also confirmed for SAT-secreted adipokines except for adiponectin and RBP-4 which derive largely from VAT As many of these biomediators correlate with both insulin resistance and increased inflammation, we can posit that dysregulation of SAT is detrimental and contributes to both the pathogenesis of MetS and its sequalae Furthermore, as future directions, much work is needed with respect to VAT/EAT biology, autophagy, sirtuins, the gut microbiome, browning of AT, to further elucidate this common syndrome and identify potential therapeutic targets to forestall its serious complications

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Abstract: Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.

Exploratory lipidomics in patients with nascent Metabolic Syndrome

Abstract: Background Metabolic Syndrome (MetS) is a cardio-metabolic cluster that confers an increased risk of developing both diabetes and atherosclerotic cardiovascular disease (ASCVD). The mechanisms governing the increased ASCVD risk remains to be elucidated. Moreover, lipidomics poses as an exciting new tool that has potential to shed more light on the pathogenesis of MetS. Objective The aim of this study was to explore the lipidome in an unbiased fashion in patients with nascent MetS uncomplicated by diabetes and CVD. Methods Patients with nascent MetS (n = 30) without diabetes or ASCVD and controls (n = 20) who participated in the study had normal hepatic and renal function. Early morning urine samples from patients were collected and frozen at −70° until analysis. Lipidomic analyses were undertaken at the National Institute of Health Western Metabolomics Center. Results Phosphatidylcholine 34:2, PC (34:2) was significantly increased in patients with MetS compared to controls. PC (34:2) had a significant positive correlation with waist circumference, plasma glucose, free fatty acid, and triglyceride levels. It had a significant positive correlation with pro-inflammatory markers such as plasma hs CRP, IL-1b, and IL-8. Additionally, PC (34:2) significantly correlated positively with Leptin and inversely with adiponectin. Levels of various acyl carnitines and PC34:1 were not significantly altered. Conclusion We propose that PC (34:2) could emerge as a novel biomarker in MetS that promotes a pro-inflammatory state.

Community-acquired Acute Kidney Injury Among Children Seen in the Pediatric Emergency Department.

Abstract: Objectives Acute kidney injury (AKI) is a significant risk factor for morbidity and mortality in children. Little is known about community-acquired AKI (CA-AKI) in the pediatric emergency department (PED). Early recognition of AKI allows for nephroprotective measures. The goal of this investigation was to determine the incidence of CA-AKI and the frequency of clinician identified CA-AKI to better inform future nephroprotective interventions. Methods This was a retrospective cross-sectional study in the PED of a children's hospital. Children 1 month to 18 years of age seen in the PED from January 1 to December 31, 2015, and in whom at least one creatinine level was obtained were included. Patients with chronic kidney disease or end-stage renal disease or who died in the PED were excluded. Patients had CA-AKI based on modified Kidney Disease-Improving Global Outcomes criteria using the creatinine obtained in the PED compared to age-specific norms. Patients were considered identified if the PED clinician diagnosed AKI. The primary outcome was the incidence of CA-AKI. Secondary outcomes included frequency of AKI identification, nephrotoxic medication use, hospital length of stay, renal replacement therapy, and death. Fisher exact test or Pearson's chi-square test was used to calculate odds ratio (OR) with 95% confidence intervals (CIs); multivariable analyses were performed using logistic regression. Results In 2015 there were 119,151 PED visits; 15,486 met inclusion criteria. CA-AKI was present in 239 of 15,486 (1.5%) encounters. AKI was identified by PED clinicians in 46 of 239 (19%) of encounters and by the inpatient team in 123 of 199 (62%) of the encounters admitted. AKI was never recognized by a PED or inpatient clinician in 74 of 199 (37%) encounters. Encounters with AKI correctly diagnosed were older (13 years old vs. 10 years old, p = 0.0114), had more severe (stage 2 or 3) AKI (OR = 5.5, 95% CI = 2.6-11.8), and were more likely to be admitted (OR = 10.3, 95% CI = 1.38-77.4) than encounters with missed AKI. Conclusions CA-AKI remains an underrecognized entity in the PED. Better tools for early recognition of AKI in the busy PED environment are needed.

Peanut oral immunotherapy dose variations do not result in allergic reactions.

Abstract: 1. Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update2014. J Allergy Clin Immunol. 2014;134:1016-1025. 2. Nowak-Węgrzyn A. Food proteininduced enterocolitis syndrome and allergic proctocolitis. Allergy Asthma Proc. 2015;36:172-184. 3. Dello Iacono I, Martelli A, Miniello V. Manifestazioni gastrointestinali di allergia alimentare non IgE-mediate. In: Editeam, ed. Allergie Alimentari. Guida alle allergie. Cento, Italy; 2015:78-80. 4. Arvola T, Ruuska T, Keränen J, Hyöty H, Salminen S, Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination. Pediatrics. 2006;117:e760-e768. 5. Elizur A, Cohen M, Goldberg MR, et al. Cow’s milk associated rectal bleeding: a population based prospective study. Pediatr Allergy Immunol. 2012;23:766-770. 6. Nowak-Wegrzyn A, Assa’ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS. Work group report: oral food challenge testing. J Allergy Clin Immunol. 2009;123:S365-S383.

Optimization of oestradiol assays to improve utility in an in vitro fertilization setting.

Abstract: BackgroundThe measurement of oestradiol is an integral component for the management of ovarian stimulation for in vitro fertilization. Automated immunoassays offer fast assay times and high throughput, with less sensitivity and specificity. The aim of this study is to optimize the oestradiol assay in patients undergoing ovarian stimulation for in vitro fertilization via comparison of oestradiol values obtained using two immunoassays compared with mass spectrometry.MethodsPatients undergoing ovarian stimulation were prospectively recruited. Serum samples were analysed with ADVIA Centaur® CP Immunoassay, Abbott Architect i1000® immunoassay and AB Sciex 5500 liquid chromatography-tandem mass spectrometry (LC-MS/MS) systems. Per cent bias was determined for each system to report the average tendency of the values to be larger or smaller than the LC-MS/MS value. Linear regression of total follicular volume and oestradiol was computed.ResultsThe ADVIA Centaur® CP assay had a positive bias of 20% compared with L...

The effect of increasing tertiles of waist circumference on cardio-metabolic risk, adipokines and biomarkers of inflammation and oxidative stress in nascent metabolic syndrome.

Abstract: Aims The effect of waist circumference (WC) on cardio-metabolic features and biomarkers of oxidative stress and inflammation and adipose tissue dysregulation is poorly defined in Metabolic Syndrome (MetS). Hence the aim of this study was to examine the effect of increasing tertiles of WC on the cardio metabolic risk profile, pro-oxidant state, pro-inflammatory state and adipose tissue dysregulation in nascent MetS patients (n = 59) without diabetes or CVD. Methods and results None of the main cardio-metabolic features including blood pressure, blood glucose, HDL-cholesterol, triglycerides, HOMA-IR, and free fatty acids increased with increasing WC tertiles except for hsCRP. In addition, none of the biomarkers of oxidative stress increased with increasing WC. Other circulating and cellular bio-mediators of inflammation and adipokines did not show significant increase with increasing WC. Using the waist to height ratio (WHtR) also did not reveal any major findings with increasing tertiles. Conclusion In conclusion, in a well-defined cohort of MetS we failed to show any superiority of either WC or WHtR compared to BMI in capturing the cardio-metabolic cluster, adipose tissue dysregulation and the increased burden of oxidative stress and inflammation in this pilot study. These observations need confirmation in larger studies.

Accuracy of Two Progesterone Immunoassays for Monitoring In Vitro Fertilization.

Abstract: Background: Progesterone concentrations are routinely monitored during in vitro fertilization cycles. Immunoassay-based platforms are used most often in this setting because they are simple to use and amenable to same-day sample collection and result-reporting. However, immunoassay methods are subject to variation in specificity between different assay manufacturers. In this study, a set of unexpectedly high progesterone concentrations led to a method comparison between two in-house immunoassay platforms relative to the reference method. Methods: Progesterone was measured in 28 serum samples from women undergoing IVF cycles using the Siemens ADVIA Centaur Immunoassay system and the Abbott Architect i1000SR analyzer. A subset of these samples was selected for progesterone measurement by liquid chromatography–tandem mass spectrometry to define the accuracy of each immunoassay. Results: The Siemens ADVIA Centaur immunoassay system overestimated progesterone concentrations by 19% and the Abbott Architect overestimated progesterone concentrations by 5%. Conclusions: The Abbott Architect progesterone immunoassay provides a more accurate measurement of serum progesterone than the Centaur immunoassay at concentrations relevant for monitoring in vitro fertilization populations.

Kidney Injury Detection and Prevention in Children (KIDPIC)

Abstract: BACKGROUND Acute kidney injury (AKI) increases morbidity and mortality, yet remains difficult to diagnose in clinical practice even in the inpatient setting, where fewer than 0.4% of inpatients are correctly diagnosed with AKI. Multiple AKI definitions, the lack of baseline creatinine data in many children, and age-related creatinine changes make recognition of AKI in the fast-paced clinical environment, such as the emergency department (ED), especially challenging. …

Adolescent Female with Jaundice and Edema.

Abstract: An 18-year-old female presented to the emergency department at Texas Children's Hospital with intermittent symptoms of fever, nausea, poor food intake, fatigue, and shortness of breath in the past 3 months. The patient reported excessive weight loss of 10 lbs in the last month. On physical examination, her weight was 40.6 kg (89 lbs, 8.1 oz) and height was 153.4 cm, with a body mass index of 17.30 kg/m2. Other significant physical examination findings included scleral icterus, edema (4+ in bilateral lower extremities), and tachycardia. Abdominal examination was remarkable for the presence of distension and ascites, with tenderness in the left lower quadrant. Patient had a history of Crohn disease with several failed therapies and at presentation was on Cimzia®, an antitumor necrosis factor α (TNF-α) monoclonal antibody therapy, and prednisone. Initial laboratory results at the emergency department showed concentrations of sodium of 130 mmol/L, potassium of 3.4 mmol/L, chloride of 101 mmol/L, and albumin of 1.7 g/dL. She was then admitted to the intensive care unit (ICU)3 for intensive monitoring and correction of her electrolyte abnormalities. Further laboratory tests demonstrated hyperbilirubinemia (mainly conjugated bilirubin) and increased liver enzymes, including aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase, and increased prothrombin time and partial thromboplastin time (Table 1). Her …

Correction to: Inflammation, Atherosclerosis, and Psoriasis

Abstract: Following publication of this article [1] it came to our attention that we neglected to reference an article by Ishwarlal Jialal published in Critical Pathways in Cardiology [2].