Identification and comprehensive structural characterization of serum lipid markers to Type 1 diabetes progression

Type 1 diabetes (T1D) is resulted from a self-destruction of insulin-secreting pancreatic ß-cells, but the exact etiology remains unknown despite evidence indicating interaction between environmental and genetic factors. For the genetically predisposed individuals of T1D, islet autoantibodies are used for predicting the likelihood of T1D in the future, however, neither the appearance nor the titer can indicate the extent of the destruction of ß-cells or quantify the remaining ß-cell mass. Therefore, additional biomarkers are needed to monitor the health status of ß-cell and the development of T1D. Dysregulation of lipid metabolism exists in distinctive disease states. Several studies suggested lipids as a potential biomarker for T1D and the dysregulated profiles of lipids in T1D blood serum could predict the seroconversion of autoantibody positivity. However, many of the potential T1D lipid markers reported to date have not been validated in independent cohorts, and the structural identifications are ambiguous as only the total number of carbon atoms and double bonds in the fatty acyl chains were reported. There is no detailed structural information reported for the lipid species regarding the fatty acyl compositions and the location of C=C double bond- those fine structural details can determine the biological functions of lipids and help to elucidate the pathogenic mechanism of T1D. Based on these, we hypothesize that 1) lipid markers that either shed from diseased pancreatic ß-cells or as a systemic response to autoimmune attack exist in human serum; 2) dysregulation of lipid markers can predate the appearance of islet autoantibodies. Using advanced lipidomics tools and longitudinally collected sera from a well characterized T1D cohort, the primary goal of this project is to identify a panel of serum lipid markers correlated to T1D progression, with unambiguous characterization of their molecular structures. In this dissertation, we are focusing on the following aims: 1) Create a comprehensive human serum lipid library for high throughput LC-MS based lipidomics analysis; 2) Identify candidate lipid markers to T1D progression through quantitative profiling of the temporal changes of serum lipids in T1D cohorts; and 3) Comprehensively characterize the structures of the lipid markers. These aims were addressed in four projects that employed advanced instrumentation, sophisticated data analysis tools and precious human samples longitudinally collected from a T1D cohort. The first project generated a comprehensive library contains LC retention time and accurate mass of each lipid molecular species, and will be used for accurate and speedy identification of serum lipids in T1D subjects. In addition, this library can be implemented for an accurate and high throughput analysis of human serum lipids related to other diseases. The second and third project focused on development of Ozoneinduced dissociation (OzID) on a high resolution MS to determine unambiguously the C=C double bond positions in unsaturated lipids. This technique is based on a highly selective gas phase reaction between C=C and ozone. We achieved high efficiency of OzID in both direct infusion- and RPLC-based workflows to effectively elucidate C=C unsaturation in complex biological samples. Using the methodologies developed in the first three projects, the last project profiled temporal changes of lipidome in a T1D cohort, and identified a list of candidate lipid markers. These lipid markers showed a distinct profile prior to appearance of T1D as compared to healthy controls

Conducting Community Audits to Evaluate Community Resources for Healthful Lifestyle Behaviors: An Illustration From Rural Eastern North Carolina

A community audit is a qualitative and quantitative research technique in which researchers drive through a community to observe its physical and social attributes, primarily through windshield tours and "ground truthing." Ground truthing is a verification process that uses data gathered by direct observation to corroborate data gathered from secondary sources. Community audits have been used for epidemiologic studies and in program planning for health-promotion interventions. Few studies have detailed the methodology for conducting community audits in rural areas or the extent to which community audits can contribute to an accurate assessment of community characteristics (eg, presence of sidewalks) and nutrition and physical activity resources (eg, produce stands, parks) that may promote healthful lifestyle behaviors. The objective of this article is to describe our approach to conducting a community audit (consisting of windshield tours and ground truthing) to enumerate resources, to assess community characteristics, and to inform revisions to a community guide on nutrition and physical activity resources. We conducted an audit in 10 communities in a rural eastern North Carolina county in 2010. We also collected data from secondary sources to make comparisons with community audit data. The initial resource guide included 42 resources; the community audits identified 38 additional resources. There was moderate to high agreement between windshield tour observations and secondary data sources for several community characteristics, such as number of fast-food restaurants (67% agreement) and existence of sidewalks (100% agreement). Community audits improved the description of health-promoting community resources and the context in which people make lifestyle choices

Contribution of Matrix Metalloproteinase-9 to Cerebral Edema and Functional Outcome following Experimental Subarachnoid Hemorrhage

Background: Cerebral edema is an important risk factor for death and poor outcome following subarachnoid hemorrhage (SAH). However, underlying mechanisms are still poorly understood. Matrix metalloproteinase (MMP)-9 is held responsible for the degradation of microvascular basal lamina proteins leading to blood-brain barrier dysfunction and, thus, formation of vasogenic cerebral edema. The current study was conducted to clarify the role of MMP-9 for the development of cerebral edema and for functional outcome after SAH. Methods: SAH was induced in FVB/N wild-type (WT) or MMP-9 knockout (MMP-9(-/-)) mice by endovascular puncture. Intracranial pressure (ICP), regional cerebral blood flow (rCBF), and mean arterial blood pressure (MABP) were continuously monitored up to 30 min after SAH. Mortality was quantified for 7 days after SAH. In an additional series neurological function and body weight were assessed for 3 days after SAH. Subsequently, ICP and brain water content were quantified. Results: Acute ICP, rCBF, and MABP did not differ between WT and MMP-9(-/-) mice, while 7 days' mortality was lower in MMP-9(-/-) mice (p = 0.03; 20 vs. 60%). MMP-9(-/-) mice also exhibited better neurological recovery, less brain edema formation, and lower chronic ICP. Conclusions: The results of the current study suggest that MMP-9 contributes to the development of early brain damage after SAH by promoting cerebral edema formation. Hence, MMP-9 may represent a novel molecular target for the treatment of SAH. Copyright (C) 2011 S. Karger AG, Base

Quantitative model for inferring dynamic regulation of the tumour suppressor gene p53

Background: The availability of various "omics" datasets creates a prospect of performing the study of genome-wide genetic regulatory networks. However, one of the major challenges of using mathematical models to infer genetic regulation from microarray datasets is the lack of information for protein concentrations and activities. Most of the previous researches were based on an assumption that the mRNA levels of a gene are consistent with its protein activities, though it is not always the case. Therefore, a more sophisticated modelling framework together with the corresponding inference methods is needed to accurately estimate genetic regulation from "omics" datasets. Results: This work developed a novel approach, which is based on a nonlinear mathematical model, to infer genetic regulation from microarray gene expression data. By using the p53 network as a test system, we used the nonlinear model to estimate the activities of transcription factor (TF) p53 from the expression levels of its target genes, and to identify the activation/inhibition status of p53 to its target genes. The predicted top 317 putative p53 target genes were supported by DNA sequence analysis. A comparison between our prediction and the other published predictions of p53 targets suggests that most of putative p53 targets may share a common depleted or enriched sequence signal on their upstream non-coding region. Conclusions: The proposed quantitative model can not only be used to infer the regulatory relationship between TF and its down-stream genes, but also be applied to estimate the protein activities of TF from the expression levels of its target genes

Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review.

© 2015 Owiti et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Hepatitis B and C (HBV, HCV) infections are associated with high morbidity and mortality. Many countries with traditionally low prevalence (such as UK) are now planning interventions (screening, vaccination, and treatment) of high-risk immigrants from countries with high prevalence. This review aimed to synthesise the evidence on immigrants' knowledge of HBV and HCV that might influence the uptake of clinical interventions. The review was also used to inform the design and successful delivery of a randomised controlled trial of targeted screening and treatment. METHODS: Five databases (PubMed, CINHAL, SOCIOFILE, PsycINFO & Web of Science) were systematically searched, supplemented by reference tracking, searches of selected journals, and of relevant websites. We aimed to identify qualitative and quantitative studies that investigated knowledge of HBV and HCV among immigrants from high endemic areas to low endemic areas. Evidence, extracted according to a conceptual framework of Kleinman's explanatory model, was subjected to narrative synthesis. We adapted the PEN-3 model to categorise and analyse themes, and recommend strategies for interventions to influence help-seeking behaviour. RESULTS: We identified 51 publications including quantitative (n = 39), qualitative (n = 11), and mixed methods (n = 1) designs. Most of the quantitative studies included small samples and had heterogeneous methods and outcomes. The studies mainly concentrated on hepatitis B and ethnic groups of South East Asian immigrants residing in USA, Canada, and Australia. Many immigrants lacked adequate knowledge of aetiology, symptoms, transmission risk factors, prevention strategies, and treatment, of hepatitis HBV and HCV. Ethnicity, gender, better education, higher income, and English proficiency influenced variations in levels and forms of knowledge. CONCLUSION: Immigrants are vulnerable to HBV and HCV, and risk life-threatening complications from these infections because of poor knowledge and help-seeking behaviour. Primary studies in this area are extremely diverse and of variable quality precluding meta-analysis. Further research is needed outside North America and Australia

TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population

<p>Abstract</p> <p>Background</p> <p>In adults, the <it>TCF7L2 </it>rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance.</p> <p>Methods</p> <p>The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10^thpercentile; n = 764), and AGA (25^th< birth weight < 75^thpercentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees.</p> <p>Results</p> <p>The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78–1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele.</p> <p>Conclusion</p> <p>The <it>TCF7L2 </it>rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA.</p

The Association between Peptic Ulcer Disease and Gastric Cancer: Results from the Stomach Cancer Pooling (StoP) Project Consortium

Background. Gastric cancer (GC) is the fifth most common type of cancer and the fourth most common cause of cancer-related mortality. Although the risk of GC and peptic ulcer disease (PUD) is known to be increased by H. pylori infection, evidence regarding the direct relationship between PUD and GC across ethnicities is inconclusive. Therefore, we investigated the association between PUD and GC in the Stomach cancer Pooling (StoP) consortium. Methods. History of peptic ulcer disease was collected using a structured questionnaire in 11 studies in the StoP consortium, including 4106 GC cases and 6922 controls. The two-stage individual-participant data meta-analysis approach was adopted to generate a priori. Unconditional logistic regression and Firth’s penalized maximum likelihood estimator were used to calculate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gastric ulcer (GU)/duodenal ulcer (DU) and risk of GC. Results. History of GU and DU was thoroughly reported and used in association analysis, respectively, by 487 cases (12.5%) and 276 controls (4.1%), and 253 cases (7.8%) and 318 controls (6.0%). We found that GU was associated with an increased risk of GC (OR = 3.04, 95% CI: 2.07–4.49). No association between DU and GC risk was observed (OR = 1.03, 95% CI: 0.77–1.39). Conclusions. In the pooled analysis of 11 case–control studies in a large consortium (i.e., the Stomach cancer Pooling (StoP) consortium), we found a positive association between GU and risk of GC and no association between DU and GC risk. © 2022 by the authors.This work is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Project no. 21378 (Investigator Grant); Fondazione Italiana per la Ricerca sul Cancro (FIRC); Italian League for the Fight Against Cancer (LILT); European Cancer Prevention (ECP) Organization; and UPMC Start-up Grant (to HNL). P Paragomi was supported by a cancer research training grant from NIH (grant # T32CA186873)