bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional consequence of a novel Y129C mutation in a patient with two contradictory melanocortin-2-receptor mutations
Authors: Chan Li F , Chung Teng-Teng , Massoud Ahmed F , Metherell Louise A , Clark Adrian J L 
Published: January 2009

ContextFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease, characterised by isolated glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Inactivating mutations in the ACTH receptor (melanocortin-2-receptor, MC2R) are well described and account for ∼25% of cases. By contrast, activating MC2R mutations are extremely rare.PatientWe report a child of Saudi Arabian origin who was diagnosed with FGD following hypoglycaemic episodes that resulted in spastic quadriplegia.Methods and resultsMC2R gene analysis revealed an unusual combination of two homozygous missense mutations, consisting of the novel mutation Y129C and the previously described F278C activating mutation. Parents were heterozygous at both of these sites. In vitro analysis of the Y129C mutation using a fluorescent cell surface assay showed that this mutant was unable to reach the cell surface in CHO cells stably transfected with MC2R accessory protein (MRAP), despite the demonstration of an interaction with MRAP by co-immunoprecipitation. The double mutant Y129C-F278C also failed to traffic to the cell surface.ConclusionThe tyrosine residue at position 129 in the second intracellular loop is critical in MC2R folding and/or trafficking to the cell surface. Furthermore, the absence of cell surface expression of MC2R would account for the lack of activation of the receptor due to the F278C mutation located at the C-terminal tail. We provide a novel molecular explanation for a child with two opposing mutations causing severe FGD.
Selective Genotyping and Phenotyping Strategies in a Complex Trait Context
Authors: Sen Śaunak , Johannes Frank , Broman Karl W 
Published: January 2009

AbstractSelective genotyping and phenotyping strategies are used to lower the cost of quantitative trait locus studies. Their efficiency has been studied primarily in simplified contexts—when a single locus contributes to the phenotype, and when the residual error (phenotype conditional on the genotype) is normally distributed. It is unclear how these strategies will perform in the context of complex traits where multiple loci, possibly linked or epistatic, may contribute to the trait. We also do not know what genotyping strategies should be used for nonnormally distributed phenotypes. For time-to-event phenotypes there is the additional question of choosing follow-up time duration. We use an information perspective to examine these experimental design issues in the broader context of complex traits and make recommendations on their use.
GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes After Experimental Myocardial Infarction in Mice
Authors: Noyan-Ashraf Mohammad Hossein , Momen M. Abdul , Ban Kiwon , Sadi Al-Muktafi , Zhou Yu-Qing , Riazi Ali M. , Baggio Laurie L. , Henkelman R. Mark , Husain Mansoor , Drucker Daniel J. 
Published: January 2009

OBJECTIVE
Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation before ischemic myocardial injury remain unclear.

RESEARCH DESIGN AND METHODS
We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-1R agonist liraglutide.

RESULTS
Male C57BL/6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Liraglutide reduced cardiac rupture (12 of 60 versus 46 of 60; P = 0.0001) and infarct size (21 ± 2% versus 29 ± 3%, P = 0.02) and improved cardiac output (12.4 ± 0.6 versus 9.7 ± 0.6 ml/min; P = 0.002). Liraglutide also modulated the expression and activity of cardioprotective genes in the mouse heart, including Akt, GSK3β, PPARβ-δ, Nrf-2, and HO-1. The effects of liraglutide on survival were independent of weight loss. Moreover, liraglutide conferred cardioprotection and survival advantages over metformin, despite equivalent glycemic control, in diabetic mice with experimental MI. The cardioprotective effects of liraglutide remained detectable 4 days after cessation of therapy and may be partly direct, because liraglutide increased cyclic AMP formation and reduced the extent of caspase-3 activation in cardiomyocytes in a GLP-1R–dependent manner in vitro.

CONCLUSIONS
These findings demonstrate that GLP-1R activation engages prosurvival pathways in the normal and diabetic mouse heart, leading to improved outcomes and enhanced survival after MI in vivo.
Mice With Hyperghrelinemia Are Hyperphagic and Glucose Intolerant and Have Reduced Leptin Sensitivity
Authors: Bewick Gavin A. , Kent Aysha , Campbell Daniel , Patterson Michael , Ghatei Mohammed A. , Bloom Stephen R. , Gardiner James V. 
Published: January 2009

OBJECTIVE
Ghrelin is the only known peripheral hormone to increase ingestive behavior. However, its role in the physiological regulation of energy homeostasis is unclear because deletion of ghrelin or its receptor does not alter food intake or body weight in mice fed a normal chow diet. We hypothesized that overexpression of ghrelin in its physiological tissues would increase food intake and body weight.

RESEARCH DESIGN AND METHODS
We used bacterial artificial chromosome transgenesis to generate a mouse model with increased ghrelin expression and production in the stomach and brain. We investigated the effect of ghrelin overexpression on food intake and body weight. We also measured energy expenditure and determined glucose tolerance, glucose stimulated insulin release, and peripheral insulin sensitivity.

RESULTS
Ghrelin transgenic (Tg) mice exhibited increased circulating bioactive ghrelin, which was associated with hyperphagia, increased energy expenditure, glucose intolerance, decreased glucose stimulated insulin secretion, and reduced leptin sensitivity.

CONCLUSIONS
This is the first report of a Tg approach suggesting that ghrelin regulates appetite under normal feeding conditions and provides evidence that ghrelin plays a fundamental role in regulating β-cell function.
Rapamycin Prevents and Breaks the Anti-CD3–Induced Tolerance in NOD Mice
Authors: Valle Andrea , Jofra Tatiana , Stabilini Angela , Atkinson Mark , Roncarolo Maria-Grazia , Battaglia Manuela 
Published: January 2009

OBJECTIVENon–Fc-binding anti-CD3–specific antibodies represent a promising therapy for preserving C-peptide production in subjects with recent-onset type 1 diabetes. However, the mechanisms by which anti-CD3 exerts its beneficial effect are still poorly understood, and it is questionable whether this therapeutic approach will prove durable with regard to its ability to impart metabolic preservation without additional actions designed to maintain immunological tolerance. We used the NOD mouse model to test whether rapamycin, a compound well-known for its immunomodulatory activity in mice and humans, could increase the therapeutic effectiveness of anti-CD3 treatment in type 1 diabetes.RESEARCH DESIGN AND METHODSRapamycin was administered to diabetic NOD mice simultaneously with anti-CD3 or to NOD mice cured by anti-CD3 therapy. The ability of this combined therapy to revert type 1 diabetes and maintain a state of long-term tolerance was monitored and compared with that of anti-CD3 therapy alone.RESULTSRapamycin inhibited the ability of anti-CD3 to revert disease without affecting the frequency/phenotype of T-cells. Rapamycin also reinstated diabetes in mice whose disease was previously reversed by anti-CD3. Withdrawal of rapamycin in these latter animals promptly restored a normoglycemic state.CONCLUSIONSOur findings indicate that, when combined with anti-CD3, rapamycin exerts a detrimental effect on the disease outcome in NOD mice for as long as it is administered. These results suggest strong caution with regard to combining these treatments in type 1 diabetic patients.
Successful Versus Failed Adaptation to High-Fat Diet–Induced Insulin Resistance
Authors: Matveyenko Aleksey V. , Gurlo Tatyana , Daval Marie , Butler Alexandra E. , Butler Peter C. 
Published: January 2009

OBJECTIVE
Obesity is a known risk factor for type 2 diabetes. However, most obese individuals do not develop diabetes because they adapt to insulin resistance by increasing β-cell mass and insulin secretion. Islet pathology in type 2 diabetes is characterized by β-cell loss, islet amyloid derived from islet amyloid polypeptide (IAPP), and increased β-cell apoptosis characterized by endoplasmic reticulum (ER) stress. We hypothesized that IAPP-induced ER stress distinguishes successful versus unsuccessful islet adaptation to insulin resistance.

RESEARCH DESIGN AND METHODS
To address this, we fed wild-type (WT) and human IAPP transgenic (HIP) rats either 10 weeks of regular chow or a high-fat diet and prospectively examined the relations among β-cell mass and turnover, β-cell ER stress, insulin secretion, and insulin sensitivity.

RESULTS
A high-fat diet led to comparable insulin resistance in WT and HIP rats. WT rats compensated with increased insulin secretion and β-cell mass. In HIP rats, in contrast, neither β-cell function nor mass compensated for the increased insulin demand, leading to diabetes. The failure to increase β-cell mass in HIP rats was the result of ER stress–induced β-cell apoptosis that increased in proportion to diet-induced insulin resistance.

CONCLUSIONS
IAPP-induced ER stress distinguishes the successful versus unsuccessful islet adaptation to a high-fat diet in rats. These studies are consistent with the hypothesis that IAPP oligomers contribute to increased β-cell apoptosis and β-cell failure in humans with type 2 diabetes.
Central Nervous System Function in Youth With Type 1 Diabetes 12 Years After Disease Onset
Authors: Northam Elisabeth A. , Rankins Debbie , Lin Ashleigh , Wellard R. Mark , Pell Gaby S. , Finch Sue J. , Werther George A. , Cameron Fergus J. 
Published: January 2009

OBJECTIVE—In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis.
RESEARCH DESIGN AND METHODS—We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis.
RESULTS—Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P &lt; 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P &lt; 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P &lt; 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P &lt; 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia.
CONCLUSIONS—This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.
Diet Soda Intake and Risk of Incident Metabolic Syndrome and Type 2 Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Nettleton Jennifer A. , Lutsey Pamela L. , Wang Youfa , Lima João A. , Michos Erin D. , Jacobs David R. 
Published: January 2009

OBJECTIVE
We determined associations between diet soda consumption and risk of incident metabolic syndrome, its components, and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis.

RESEARCH DESIGN AND METHODS
Diet soda consumption was assessed by food frequency questionnaire at baseline (2000–2002). Incident type 2 diabetes was identified at three follow-up examinations (2002–2003, 2004–2005, and 2005–2007) as fasting glucose &gt;126 mg/dl, self-reported type 2 diabetes, or use of diabetes medication. Metabolic syndrome (and components) was defined by National Cholesterol Education Program Adult Treatment Panel III criteria. Hazard ratios (HRs) with 95% CI for type 2 diabetes, metabolic syndrome, and metabolic syndrome components were estimated, adjusting for demographic, lifestyle, and dietary confounders.

RESULTS
At least daily consumption of diet soda was associated with a 36% greater relative risk of incident metabolic syndrome and a 67% greater relative risk of incident type 2 diabetes compared with nonconsumption (HR 1.36 [95% CI 1.11–1.66] for metabolic syndrome and 1.67 [1.27–2.20] for type 2 diabetes). Of metabolic syndrome components, only high waist circumference (men ≥102 cm and women ≥88 cm) and high fasting glucose (≥100 mg/dl) were prospectively associated with diet soda consumption. Associations between diet soda consumption and type 2 diabetes were independent of baseline measures of adiposity or changes in these measures, whereas associations between diet soda and metabolic syndrome were not independent of these factors.

CONCLUSIONS
Although these observational data cannot establish causality, consumption of diet soda at least daily was associated with significantly greater risks of select incident metabolic syndrome components and type 2 diabetes.
Iran and the Boomeranging Cartoon Wars: Can Public Spheres at Risk Ally with Public Spheres Yet to Be Achieved?
Authors: Fischer Michael M.J 
Published: January 2009

Twelve cartoons, published in the Danish newspaper Jyllands-Posten in September 2005, nine cartoons published in the Tehran newspaper Iran in May 2006, and 282 cartoons curated in Tehran in September 2006 provide a useful case study in the experimentation with new and old media in the transnational circuitry.
At stake are the agons, polemos (Greek terms of reference), or luti-jahel-darvish, “Karbala paradigm,” and jumhuri-ye moral struggles (Persian terms of reference) in Iran and the West over creating and protecting robust public spheres and civil societies. Four perspectives are probed: cultural politics; cultural media histories; the emotional excess (jouissance, petit à) of cultural politics; and the deep play mode of aesthetic judgement formed between the practical and ethical, between political economy and expressive art (including political drama), and between individual self-fashioning on the one hand, and on the other hand changing symbolic and social orders.
Assessing factors influencing the space use of a woodland caribou Rangifer tarandus caribou population using an individual‐based model
Authors: Metsaranta Juha M. 
Published: January 2009

AbstractSimilar to earlier studies, a population of woodland caribou Rangifer tarandus caribou in west‐central Manitoba, Canada, showed preference for mature coniferous forests and fidelity to seasonal home ranges. However, because preferred forest types were common in the study area, these findings could not determine what would happen if these home ranges were disturbed because the relative importance of preference for these forest types and home‐range fidelity in determining the space use of this population was not known. This question was explored using an individual‐based space‐use model that incorporates a random movement component, a habitat value function that considers these two factors individually or together, and a decision optimisation component. Four possible forms of the model were used to conduct Monte‐Carlo simulations of space‐use patterns, which were compared to true range‐use patterns over an annual cycle. True range use could not be simulated without including a home‐range fidelity factor in the model. This suggests that there is some factor about the selected home ranges that is not quantified by the forest type which is currently present that causes animals in this population to show fidelity to them. The explanation most consistent with the general understanding of the factors limiting this species is that these home ranges are refuges from predation. This suggests that the appropriate conservation action is to protect these ranges from disturbance unless the animals themselves demonstrate the presence of other suitable areas by dispersing to them.
The clinical impact of identifying metabolic syndrome in patients with diabetes: a cross-sectional study
Authors: Bulugahapitiya Uditha , Siyambalapitiya Sajith , Sithole Jabulani , Fernando Devaka J , Idris Iskandar 
Published: January 2009

The objectives of the study were to determine whether identifying patients with metabolic syndrome (MetS) (as defined by International Diabetes Federation [IDF] criteria) among patients with diabetes would affect the decision to prescribe statin for primary prevention of cardiovascular disease (CVD), based on currently available public health guidelines. We analysed the most recent recorded CVD risk profiles obtained from electronic patient files from 304 general practices in England and Wales. Of 60,258 patients with diabetes, 11,005 men and women aged 30–74 years fulfilled criteria for primary CVD prevention and were not on lipid-lowering drugs. Outcome data were extrapolated to an estimated national diabetes prevalence of 3.6%. Identifying MetS in this group of patients would produce an additional 29,536 (8.4%; 95% CI: 7.7, 9.0), 104,288 (29.6%; 95% CI: 28.5, 30.7) and 147, 328 (41.9%; 95% CI: 40.8, 43.0) patients nationally who would not have been eligible otherwise for primary CVD prevention strategies with statins, based on the Joint British Societies’, the National Institute for Health and Clinical Excellence and the General Medical Services contract guidelines, respectively. The sensitivity and positive predictive value of these different strategies to detect metabolic syndrome were 87.5% and 69.1%; 57.3% and 76.8%; and 37.8% and 70.2%, respectively. In conclusion, among individuals with diabetes, identifying patients with MetS may further increase the use of statin therapy for primary CVD prevention.
Long-term hyperglycaemia impairs vascular smooth muscle cell function in women with type 1 diabetes mellitus
Authors: Bjarnegård Niclas , Arnqvist Hans J , Lindströ;m Torbjö;rn , Jonasson Lena , Länne Toste 
Published: January 2009

Observations of increased stiffness in the elastic aorta in women with diabetes, but not men, emphasise the need for further analysis regarding early abnormalities in arterial wall properties of women with type 1 diabetes mellitus (DM). Ultrasound was used to study the wall properties of the distal brachial artery (BA) in 37 type 1 diabetic women (aged 22–45 years) without evident complications and in 53 controls (C). Blood samples were drawn for later analysis. Flow-mediated dilatation (FMD) was slightly lower in DM than C, 8.1±4.3% vs. 10.3±4.9% (p<0.05), and nitrate-mediated dilatation (NMD) was markedly lower, 21.7±6.6% vs. 31.4±5.7% (p<0.001). Lumen diameter, intima-media thickness and distensibility were similar in DM and C. Insulin-like growth factor (IGF-1) was lower in DM than C, 231±65 vs. 349±68 ng/ml (p<0.001). Glycosylated haemoglobin (HbA1C) and matrix metalloproteinase (MMP-9) were independent predictors of the reduced NMD in the DM. Brachial artery responsiveness to an exogenous donor of nitric oxide (NO) was markedly reduced in type 1 diabetic women despite only limited reduction in endothelium-dependent dilatation. The negative association between NMD and HbA1C suggests that long-term hyperglycaemia impairs vascular smooth muscle cell function in DM.
Metabolic syndrome and its single traits as risk factors for diabetes in people with impaired glucose tolerance: the STOP-NIDDM trial
Authors: Hanefeld Markolf , Karasik Avraham , Koehler Carsta , Westermeier Torsten , Chiasson Jean-Louis 
Published: January 2009

The STOP-NIDDM trial was an international, double-blind, placebo-controlled randomised study in people with impaired glucose tolerance (IGT). They were treated with an α-glucosidase inhibitor, acarbose, to prevent diabetes; the overall number needed to treat (NNT) was 11. In a secondary analysis, we considered the impact of single traits and overall metabolic syndrome (MetS) respectively on risk of diabetes and NNT respectively. In all, there were 1,368 patients. They were followed up for 3.3 years, and the prevalence of MetS was 61%. Multivariate analysis revealed treatment group 2-hour (post-challenge) plasma glucose, glycosylated haemoglobin (HbA1C), triglycerides and leukocyte count as independent predictors. The annual incidence of diabetes in the placebo group with MetS was 18.7% vs. 11.2% in patients without MetS; the corresponding figures in the acarbose group were 13.5% and 9.4%, respectively. The NNT in patients was 5.8 in patients with MetS and 16.5 in those without MetS. In conclusion, most single traits and overall MetS label a very high-risk group in people with IGT. People with MetS reach a NNT to prevent development of new diabetes with acarbose of 5.8. Trial-Number: NCT00629213//ClinicalTrials.gov
The effect of rosiglitazone on integrated cardiovascular performance, cardiac structure, function and myocardial triglyceride: trial design and rationale
Authors: Mcguire Darren K , See Raphael , Abdullah Shuaib M , Snell Peter G , Mcgavock Jonathan M , Ayers Colby R , Szczepaniak Lidia S 
Published: January 2009

The thiazolidinedione (TZD) class of medications has been associated with increased risk for peripheral oedema, as well as incident and worsening heart failure (HF). The mechanism of these observed effects remains unclear. Here we present the rationale and study design for a randomised clinical trial designed to evaluate the cardiac effects of rosiglitazone on integrated cardiovascular performance, cardiac structure and function. The study is a randomised, single-centre, double-blind, placebo-controlled, parallel-group clinical trial to evaluate the effect of rosiglitazone on integrated cardiovascular performance in a cohort of patients with type 2 diabetes mellitus (T2DM) at increased risk for developing heart failure (HF). Participants will be randomised to receive rosiglitazone or matching placebo for six months. All subjects will undergo maximal treadmill cardiopulmonary exercise testing at baseline and after six months on study drug, with the primary trial end point of peak oxygen uptake indexed to fat-free mass (VO2peak-FFM). Approximately two-thirds of the study cohort will undergo cardiac magnetic resonance imaging (MRI) and spectroscopy (MRS) at baseline and after six months of study therapy to assess cardiac structure, function and myocardial triglyceride content. While concerns for peripheral oedema and HF continue to confound clinical use of TZD medications, the direct cardiac effects of these drugs remain poorly understood and the clinical relevance of these clinical observations remains unclear. The present study will combine a series of state-of-the-art assessments to evaluate the cardiac effects of rosiglitazone treatment. (ClinicalTrials.gov NCT00424762).