bluuebunny/crossref_metadata_2025_split huggingface dataset:
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes
Authors: Trégouet David-Alexandre , Groop Per-Henrik , McGinn Steven , Forsblom Carol , Hadjadj Samy , Marre Michel , Parving Hans-Henrik , Tarnow Lise , Telgmann Ralph , Godefroy Tiphaine , Nicaud Viviane , Rousseau Rachel , Parkkonen Maikki , Hoverfält Anna , Gut Ivo , Heath Simon , Matsuda Fumihiko , Cox Roger , Kazeem Gbenga , Farrall Martin , Gauguier Dominique , Brand-Herrmann Stefan-Martin , Cambien François , Lathrop Mark , Vionnet Nathalie ,   for the EURAGEDIC Consortium
Published: July 2008

OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.
RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.
RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) (P = 1.0 × 10−4). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30–2.05], P = 2.3 × 10−5).
CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.
Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity
Authors: Cabou Cendrine , Campistron Gérard , Marsollier Nicolas , Leloup Corinne , Cruciani-Guglielmacci Celine , Pénicaud Luc , Drucker Daniel J. , Magnan Christophe , Burcelin Rémy 
Published: July 2008

OBJECTIVE— To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.RESEARCH DESIGN AND METHODS— Awake free-moving mice were infused with the GLP-1 receptor agonist exendin-4 (Ex4) into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu-/hyperglycemic clamps. Arterial femoral blood flow, whole-body insulin-stimulated glucose utilization, and heart rates were continuously recorded.RESULTS— A continuous 3-h brain infusion of Ex4 decreased femoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemic-hyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) antagonist exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4-infused mice, which disappeared in Ex9 and GLP-1R knockout mice. Moreover, hypothalamic nitric oxide synthase activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R–dependent manner, whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity, and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.CONCLUSIONS— Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.
Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo
Authors: Maile Laura A. , Capps Byron E. , Miller Emily C. , Aday Ariel W. , Clemmons David R. 
Published: July 2008

OBJECTIVE—Smooth muscle cell (SMC) maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I, whereas cells maintained in medium containing 25 mmol/l glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of SMC growth were regulated by glucose concentrations in vivo.
RESEARCH DESIGN AND METHODS—We compared IGF-I–stimulated signaling events and growth in the aortic smooth muscle cells from normal and hyperglycemic mice.
RESULTS—We determined that, in mice, hyperglycemia was associated with an increase in formation of the integrin-associated protein (IAP)/Src homology 2 domaine containing tyrosine phosphatase substrate 1 (SHPS-1) complex. There was a corresponding increase in Shc recruitment to SHPS-1 and Shc phosphorylation in response to IGF-I. There was also an increase in mitogen-activated protein kinase activation and SMC proliferation. The increase in IAP association with SHPS-1 in hyperglycemia appeared to be due to the protection of IAP from cleavage that occurred during exposure to normal glucose. In addition, we demonstrated that the protease responsible for IAP cleavage was matrix metalloprotease-2. An anti-IAP antibody that disrupted the IAP–SHPS-1 association resulted in complete inhibition of IGF-I–stimulated proliferation.
CONCLUSIONS—Taken together, our results support a model in which hyperglycemia is associated with a reduction in IAP cleavage, thus allowing the formation of the IAP–SHPS-1 signaling complex that is required for IGF-I–stimulated proliferation of SMC.
Impaired Glucose Tolerance and Insulin Resistance Are Associated With Increased Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Elevated Hepatic 5α-Reductase Activity
Authors: Tomlinson Jeremy W. , Finney Joanne , Gay Christopher , Hughes Beverly A. , Hughes Susan V. , Stewart Paul M. 
Published: July 2008

OBJECTIVE—The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active cortisol from cortisone, and 5α-reductase (5αR), which inactivates cortisol, has been implicated.
RESEARCH DESIGN AND METHODS—A total of 101 obese patients (mean age 48 ± 7 years, BMI 34.4 ± 4.3 kg/m2, 66 women, 35 men) underwent 75-g oral glucose tolerance testing (OGTT), body composition analysis (dual-energy X-ray absorptiometry), assessment of glucocorticoid metabolism (24-h urine steroid metabolite analysis by gas chromatography/mass spectrometry), and subcutaneous abdominal adipose tissue biopsies.
RESULTS—A total of 22.7% of women had IGT compared with 34.2% of men. Two women and five men were diagnosed with type 2 diabetes. In women, adipose 11β-HSD1 expression was increased in patients with IGT and correlated with glucose levels across the OGTT (R = 0.44, P &lt; 0.001) but was independent of fat mass. Total glucocorticoid secretion was higher in men with and without IGT (normal 13,743 ± 863 vs. 7,453 ± 469 μg/24 h, P &lt; 0.001; IGT 16,871 ± 2,113 vs. 10,133 ± 1,488 μg/24 h, P &lt; 0.05), and in women, it was higher in those with IGT (7,453 ± 469 vs. 10,133 ± 1,488 μg/24 h, P &lt; 0.001). In both sexes, 5αR activity correlated with fasting insulin (men R = 0.53, P = 0.003; women R = 0.33, P = 0.02), insulin secretion across an OGTT (men R = 0.46, P = 0.01; women R = 0.40, P = 0.004), and homeostasis model assessment of insulin resistance (men R = 0.52, P = 0.004; women R = 0.33, P = 0.02).
CONCLUSIONS—Increased adipose 11β-HSD1 expression in women may contribute to glucose intolerance. Enhanced 5αR activity in both sexes is associated with insulin resistance but not body composition. Augmented glucocorticoid inactivation may serve as a compensatory, protective mechanism to preserve insulin sensitivity.
Effect of Aging on A1C Levels in Individuals Without Diabetes
Authors: Pani Lydie N. , Korenda Leslie , Meigs James B. , Driver Cynthia , Chamany Shadi , Fox Caroline S. , Sullivan Lisa , D’Agostino Ralph B. , Nathan David M. 
Published: July 2008

OBJECTIVE—Although glycemic levels are known to rise with normal aging, the nondiabetic A1C range is not age specific. We examined whether A1C was associated with age in nondiabetic subjects and in subjects with normal glucose tolerance (NGT) in two population-based cohorts.RESEARCH DESIGN AND METHODS—We performed cross-sectional analyses of A1C across age categories in 2,473 nondiabetic participants of the Framingham Offspring Study (FOS) and in 3,270 nondiabetic participants from the National Health and Nutrition Examination Survey (NHANES) 2001–2004. In FOS, we examined A1C by age in a subset with NGT, i.e., after excluding those with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Multivariate analyses were performed, adjusting for sex, BMI, fasting glucose, and 2-h postload glucose values.RESULTS—In the FOS and NHANES cohorts, A1C levels were positively associated with age in nondiabetic subjects. Linear regression revealed 0.014- and 0.010-unit increases in A1C per year in the nondiabetic FOS and NHANES populations, respectively. The 97.5th percentiles for A1C were 6.0% and 5.6% for nondiabetic individuals aged &lt;40 years in FOS and NHANES, respectively, compared with 6.6% and 6.2% for individuals aged ≥70 years (Ptrend &lt; 0.001). The association of A1C with age was similar when restricted to the subset of FOS subjects with NGT and after adjustments for sex, BMI, fasting glucose, and 2-h postload glucose values.CONCLUSIONS—A1C levels are positively associated with age in nondiabetic populations even after exclusion of subjects with IFG and/or IGT. Further studies are needed to determine whether age-specific diagnostic and treatment criteria would be appropriate.
Risk Factors Related to Inflammation and Endothelial Dysfunction in the DCCT/EDIC Cohort and Their Relationship With Nephropathy and Macrovascular Complications
Authors: Lopes-Virella Maria F. , Carter Rickey E. , Gilbert Gregory E. , Klein Richard L. , Jaffa Miran , Jenkins Alicia J. , Lyons Timothy J. , Garvey W. Timothy , Virella Gabriel ,   and the DCCT/EDIC Cohort Study Group
Published: July 2008

OBJECTIVE—Because endothelial cell dysfunction and inflammation are key contributors to the development of complications in type 1 diabetes, we studied risk factors related to endothelial dysfunction and inflammation (C-reactive protein and fibrinogen, soluble vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin, and fibrinolytic markers) in a subgroup of patients from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study cohort.
RESEARCH DESIGN AND METHODS—We determined which of these risk factors or clusters thereof are associated with the presence of and subsequent development of nephropathy and macrovascular complications (reflected by carotid intima-media thickness [IMT]).
RESULTS—After adjustment for conventional risk factors (age, sex, DCCT treatment group, diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, total and HDL cholesterol, and smoking status), fibrinogen remained strongly associated with progression of internal and common carotid IMT (P &lt; 0.01) and soluble E-selectin had a strong association with nephropathy (P &lt; 0.01).
CONCLUSIONS—The best predictor for IMT progression in the DCCT/EDIC cohort was plasma fibrinogen, and the levels of soluble E-selectin discriminate patients with albuminuria better than conventional risk factors.
Alcohol Consumption, Mediating Biomarkers, and Risk of Type 2 Diabetes Among Middle-Aged Women
Authors: Beulens Joline W.J. , Rimm Eric B. , Hu Frank B. , Hendriks Henk F.J. , Mukamal Kenneth J. 
Published: July 2008

OBJECTIVE—The purpose of this study was to investigate whether adiponectin concentrations and biomarkers of inflammation, endothelial dysfunction, and insulin resistance mediate the association between alcohol consumption and diabetes.
RESEARCH DESIGN AND METHODS—In a nested case-control study of 705 women with incident diabetes and 787 matched control subjects, we examined the adjusted relationship between baseline alcohol consumption and risk of diabetes before and after adjustment for markers of inflammation/endothelial dysfunction (C-reactive protein, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, tumor necrosis factor-α receptor 2, and interleukin-6), fasting insulin, and adiponectin concentrations.
RESULTS—Alcohol consumption was associated with a decreased risk of diabetes (odds ratio per 12.5 g/day increment in alcohol use 0.58; 95% CI 0.49–0.69; P &lt; 0.001). Adjustment for BMI attenuated the association by 25%. None of the markers of inflammation or fasting insulin appeared to account for &gt;2% of the observed relationship. Without adjustment for BMI, these biomarkers individually explained slightly more of the association, but &lt;10% in all cases. Adiponectin accounted for 25% in a fully adjusted model and for 29% without adjustment for BMI.
CONCLUSIONS—In this population of women, alcohol consumption was inversely associated with risk of type 2 diabetes. Adiponectin appeared to be a mediator of this association, but circulating biomarkers of inflammation, endothelial dysfunction, and fasting insulin did not explain this association. These results suggest that further research is needed into the potentially mediating roles of other biomarkers affected by alcohol consumption.
Changes in Risk Variables of Metabolic Syndrome Since Childhood in Pre-Diabetic and Type 2 Diabetic Subjects
Authors: Nguyen Quoc Manh , Srinivasan Sathanur R. , Xu Ji-Hua , Chen Wei , Berenson Gerald S. 
Published: July 2008

OBJECTIVE—That type 2 diabetes is associated with the metabolic syndrome is known. However, information is lacking regarding the long-term and adverse changes of metabolic syndrome variables in the development of type 2 diabetes from childhood to adulthood.
RESEARCH DESIGN AND METHODS—Observations were examined, retrospectively, in a community-based cohort of normoglycemic (n = 1,838), pre-diabetic (n = 90), and type 2 diabetic (n = 60) subjects followed serially for cardiovascular risk factors during childhood (4–11 years), adolescence (12–18 years), and adulthood (19–44 years).
RESULTS—Diabetic subjects versus normoglycemic subjects had significantly higher levels of subscapular skinfold, BMI, triglycerides, glucose, insulin, and homeostasis model assessment of insulin resistance and lower levels of HDL cholesterol beginning in childhood and higher levels of mean arterial pressure (MAP) in adolescence and adulthood. In a multivariate model including BMI, MAP, HDL cholesterol, LDL cholesterol, triglycerides, glucose, and insulin, adjusted for age, age2, race, sex, and race × sex interaction, adverse changes in glucose and LDL cholesterol were independently associated with pre-diabetic subjects, whereas adverse changes in BMI, glucose, and HDL cholesterol were associated with diabetic subjects. As young adults, pre-diabetic and diabetic groups displayed a significantly higher prevalence of obesity, hypertension, dyslipidemia, hyperinsulinemia, and metabolic syndrome.
CONCLUSIONS—These findings indicate that adverse levels of risk variables of metabolic syndrome, adiposity, and measures of glucose homeostasis accelerating since childhood characterize the early natural history of type 2 diabetes and underscore the importance of early prevention and intervention on risk factors beginning in childhood.
Diabetes and Obesity-Related Risks for Pelvic Reconstructive Surgery in a Cohort of Swedish Twins
Authors: Forsman Mats , Iliadou Anastasia , Magnusson Patrik , Falconer Christian , Altman Daniel 
Published: July 2008

OBJECTIVE—To determine the diabetes- and obesity-related risks for surgically managed stress urinary incontinence and pelvic organ prolapse.
RESEARCH DESIGN AND METHODS—This twin cohort study used the Swedish Twin Register to identify 8,443 female twin pairs born from 1926 through 1958. The association between diabetes and pelvic floor surgery was estimated while taking into account the correlated (twin) structure of the data.
RESULTS—For type 1 and type 2 diabetes, no significant associations were observed for stress urinary incontinence (odds ratio [OR] 1.0 [95% CI 0.1–9.2] and 2.0 [1.0–4.0], respectively). There were no cases of prolapse surgery in type 1 diabetic subjects, and for type 2 diabetes the risk estimate was nonsignificant (1.6 [1.0–2.7]). BMI &gt;25 kg/m2, age ≥60 years, and childbirth were the strongest risk factors for having incontinence surgery.
CONCLUSIONS—Our data suggest that diabetes is not associated with stress urinary incontinence or pelvic organ prolapse surgery.
Validité et utilité clinique d'une grille d'observation (PACSLAC-F) pour évaluer la douleur chez des aînés atteints de démence vivant en milieu de soins de longue durée
Authors: Aubin Michèle , Verreault René , Savoie Maryse , LeMay Sylvie , Hadjistavropoulos Thomas , Fillion Lise , Beaulieu Marie , Viens Chantal , Bergeron Rénald , Vézina Lucie , Misson Lucie , Fuchs-Lacelle Shannon 
Published: July 2008

ABSTRACTThis study presents the validation of the French Canadian version (PACLSAC-F) of the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC). Unlike the published validation of the English version of the PACSLAC, which was validated retrospectively, the French version was validated prospectively. The PACSLAC-F was completed by nurses working in long-term care facilities after observing 86 seniors, with severe cognitive impairment, in calm, painful or distressing but non-painful situations. The test-retest and inter-observer reliability, the internal consistency, and the discriminent validity were found to be satisfactory. To evaluate the convergent validity with the DOLOPLUS-2 and the clinical relevance of the PACSLAC, it was also completed by nurses during their work shift, with 26 additional patients, for three days per week during a period of four weeks. These results encourage us to test the PACSLAC in a comprehensive program of pain management targeting this population.
Culture of Postnatal Mesencephalic Dopamine Neurons on an Astrocyte Monolayer
Authors: Fasano Caroline , Thibault Dominic , Trudeau Louis‐Éric 
Published: July 2008

AbstractThis unit presents a protocol for primary culture of postnatal mesencephalic dopamine neurons grown on an astrocyte monolayer, which can be used to investigate cellular and molecular mechanisms regulating dopamine neuron function. Using this in vitro approach, dopamine neurons survive for an extended period of time and establish functional axon terminals and dendrites that display properties similar to those observed in vivo and in brain slices. An alternate protocol is provided for a microculture system in which astrocytes are grown on a spatially limited surface where single or small groups of dopamine neurons develop. Under such conditions, isolated neurons establish synaptic contacts, or autapses, onto their own somatodendritic compartment, thus facilitating morphological and physiological experiments. Curr. Protoc. Neurosci. 44:3.21.1‐3.21.19. © 2008 by John Wiley & Sons, Inc.
Conditional Gene Expression and Targeting in Neuroscience Research
Authors: Morozov Alexei 
Published: July 2008

AbstractRecently developed techniques for spatially and temporally controlled genetic manipulations based on regulated homologous recombination and/or transcription are extensively used in brain research. In addition to being important for testing the role of specific proteins in the central nervous system, these techniques allow analysis of brain functions at the neuronal circuit level. This overview discusses principles of conditional inactivation and expression of genes, and their specific applications to studies of the mammalian brain. Curr. Protoc. Neurosci. 44:4.31.1‐4.31.10. © 2008 by John Wiley & Sons, Inc.
Vapor Inhalation of Alcohol in Rats
Authors: Gilpin Nicholas W. , Richardson Heather N. , Cole Maury , Koob George F. 
Published: July 2008

AbstractAlcohol dependence constitutes a neuroadaptive state critical for understanding alcoholism, and various methods have been utilized to induce alcohol dependence in animals, one of which is alcohol vapor exposure. Alcohol vapor inhalation provides certain advantages over other chronic alcohol exposure procedures that share the ultimate goal of producing alcohol dependence in rats. Chronic alcohol vapor inhalation allows the experimenter to control the dose, duration, and pattern of alcohol exposure. Also, this procedure facilitates testing of somatic and motivational aspects of alcohol dependence. Chronic exposure to alcohol vapor produces increases in alcohol‐drinking behavior, increases in anxiety‐like behavior, and reward deficits in rats. Alcohol vapor inhalation as a laboratory protocol is flexible, and the parameters of this procedure can be adjusted to accommodate the specific aims of different experiments. This unit describes the options available to investigators using this procedure for dependence induction, when different options are more or less appropriate, and the implications of each. Curr. Protoc. Neurosci. 44:9.29.1‐9.29.19. © 2008 by John Wiley & Sons, Inc.
Disease Associations and Family‐Based Tests
Authors: Ewens Warren J. , Spielman Richard S. , Kaplan Norman L. , Gao Xiaoyi , Morris Richard W. , Martin Eden R. 
Published: July 2008

AbstractThis unit describes the statistical techniques necessary for performing family‐based association studies (such as the TDT) for genetic polymorphisms. Such studies have become increasingly important in the identification of genes that confer an increased risk to disease, particularly for common diseases with a complex etiology. The family‐based approach avoids some of the problems often encountered when applying the traditional case‐control design to genetic studies. The unit includes the Sib TDT (S‐TDT) method, which allows application of the principle of the TDT to sibships without parental data, and several related tests.Curr. Protoc. Hum. Genet. 58:1.12.1‐1.12.24. © 2008 by John Wiley & Sons, Inc.
High‐Throughput Quantitative Real‐Time PCR
Authors: Arany Zoltan P. 
Published: July 2008

AbstractRecent technical advances in quantitative real‐time PCR (qRT‐PCR) have allowed for extensive miniaturization, thereby rendering the technique amenable to high‐throughput assays. Large numbers of different nucleic acids can now rapidly be measured quantitatively. Many investigations can benefit from this approach, including determination of gene expression in hundreds of samples, determination of hundreds of genes in a few samples, or even quantification of nucleic acids other than mRNA. A simple technique is described here to quantify 1880 transcripts of choice from any number of starting RNA samples. Curr. Protoc. Hum. Genet. 58:11.10.1–11.10.11. © 2008 by JohnWiley & Sons, Inc.