bluuebunny/crossref_metadata_2025_split huggingface dataset:
RANTES/CCL5 gene polymorphisms, serum concentrations, and incident type 2 diabetes: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002
Authors: Herder Christian , Illig Thomas , Baumert Jens , Müller Martina , Klopp Norman , Khuseyinova Natalie , Meisinger Christa , Poschen Ulrike , Martin Stephan , Koenig Wolfgang , Thorand Barbara 
Published: April 2008

ObjectiveRegulated on activation, normal T-cell expressed and secreted (RANTES)/chemokine(C-C motif) ligand (CCL5) is expressed by adipocytes, and serum levels of RANTES are increased in obesity and type 2 diabetes. The aim of this study was to test the hypothesis that RANTES is involved in the pathogenesis of type 2 diabetes by analyzing the triangular association between CCL5 gene polymorphisms, systemic RANTES concentrations, and incident type 2 diabetes in a large prospective study.Subjects and methodsThe study is based on 502 individuals (293 men and 209 women) and 1632 individuals (859 men and 773 women) with and without incident type 2 diabetes from the population-based MONItoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) case–cohort study respectively (mean follow-up time±s.d. 10.1±4.9 years). CCL5 genotypes and RANTES serum concentrations were determined and associations between genotypes, haplotypes, serum levels, and incident type 2 diabetes were assessed.ResultsMinor alleles of four single nucleotide polymorphisms were associated with lower RANTES levels (Padditive between 1.2×10−9 and 3.1×10−8), but neither genotypes, haplotypes, nor serum levels were associated with incident type 2 diabetes.ConclusionsOur data suggest that RANTES/CCL5 gene variants and serum levels are not causally related with type 2 diabetes and that elevated RANTES levels in patients with type 2 diabetes may be a consequence of hyperglycemia. However, our findings cannot preclude a local role in adipose tissue where RANTES expression may contribute to leukocyte infiltration and a proinflammatory state.
Retinol, retinol-binding protein 4, abdominal fat mass, peak bone mineral density, and markers of bone metabolism in men: the Northern Osteoporosis and Obesity (NO2) Study
Authors: Högström Magnus , Nordström Anna , Nordström Peter 
Published: April 2008

ContextThe association between retinol and bone mineral density (BMD) in males after puberty has not been fully investigated previously.ObjectiveTo investigate the association between retinol, retinol-binding protein-4 (RBP-4), BMD (g/cm2), abdominal fat mass, and markers of bone metabolism in young men.DesignLongitudinal study.ParticipantsSeventy-eight healthy males with a mean age of 22.6±0.7 years at baseline. A follow-up was conducted in 73 of the participants 2.0±0.4 years later.Main outcome measuresAssociations between serum concentrations of retinol and RBP-4, and BMD of the total body, lumbar spine, and hip, serum concentrations of osteocalcin, and carboxy terminal telopeptide of type 1 collagen (CTX), were investigated.ResultsBoth retinol and RBP-4 showed an inverse relationship with that of osteocalcin (r=−0.23 to −0.25, P<0.05). Levels of RBP-4 (r=0.26, P=0.02) and osteocalcin (r=−0.23, P=0.04) were also related to abdominal fat mass, and the relationship between RBP-4, retinol, and osteocalcin disappeared after adjusting for this influence of abdominal fat mass. Neither retinol nor RBP-4 concentrations were associated with BMD at any site, CTX as baseline, or changes in BMD during the 2-year follow-up period. Levels of RBP-4 showed a strong association with levels of retinol (r=0.61, P<0.001).ConclusionWe found a negative association between the bone formation marker osteocalcin with retinol and RBP-4. The association disappeared when adjusting for the influence of abdominal fat mass. Neither retinol nor RBP-4 were associated with peak BMD in young men.
Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas
Authors: Fusco Alessandra , Gunz Ginette , Jaquet Philippe , Dufour Henry , Germanetti Anne Laure , Culler Michael D , Barlier Anne , Saveanu Alexandru 
Published: April 2008

ObjectiveTen percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas.Design and methodsThe efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR.ResultsThe mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3±47.3, 2.2±1.4, 1.1±0.7, and 1.6±0.6 copy/copy β-glucuronidase (β-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [3H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC50 (0.5±0.1 vs 2.5±1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19±6 and 21±3% respectively).ConclusionAlthough the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.
Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes
Authors: Lund Søren S , Tarnow Lise , Stehouwer Coen D A , Schalkwijk Casper G , Teerlink Tom , Gram Jørgen , Winther Kaj , Frandsen Merete , Smidt Ulla M , Pedersen Oluf , Parving Hans-Henrik , Vaag Allan A 
Published: April 2008

ObjectiveIn patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients.Design and methodsSingle-centre, double-masked, double-dummy, crossover study during 2×4 months involving 96 non-obese (body mass index≤27 kg/m2) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions.ResultsLevels of tumour necrosis factor-α, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects.ConclusionsIn non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.
Elevated serum parathyroid hormone predicts impaired survival prognosis in a general aged population
Authors: Björkman Mikko P , Sorva Antti J , Tilvis Reijo S 
Published: April 2008

ObjectiveShort-term studies on selected patients have indicated that elevated serum parathyroid hormone (PTH) is an independent risk factor of death. However, long-term data on unselected populations are lacking, thus far. In order to evaluate the predictive value of elevated serum PTH during the last years of life, random persons of age cohorts of 75, 80 and 85 years were followed for 17 years.DesignA prospective cohort study.MethodsSubjects (n=567) were investigated for calcaemic status including serum intact PTH, serum total calcium (CaT) and ionized calcium (Ca2+). Thorough clinical examinations included an assessment of co-morbidity. Mortality data were collected from National Census Records.ResultsUp to 93% of the subjects died within the follow-up. In contrast to Ca2+ levels, high serum PTH (≥63 ng/l, IV quartile cut point) was associated with significant over-mortality (HR=1.56, 95% CI: 1.29–1.88) and a 2.3-year reduction of median life expectancy. After controlling for age, gender, co-morbidity and creatinine, the prognostic impact of elevated serum PTH was still significant (HR=1.24, 95% CI: 1.01–1.53). The tendency for over-mortality was consistent in both genders, in all age groups as well as in subjects with varying co-morbidity, renal function, body mass index categories and Ca2+ levels.ConclusionsElevated serum PTH level is an independent predictor of impaired long-term survival prognosis in unselected aged population. Serum Ca2+ did not emerge as a significant prognostic indicator. The long-term prognostic impact of vitamin D deficiency, the most common cause of elevated PTH levels in the elderly, remains to be investigated.
Increased Nε-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus
Authors: van Deutekom A W , Niessen H W M , Schalkwijk C G , Heine R J , Simsek S 
Published: April 2008

ObjectiveNon-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, Nε-(carboxymethyl)-lysine (CML), in cerebral vessels.Research design and methodsBrain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels.ResultsStaining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm2 in the diabetic group of 0.85 (interquartile range (IQR) 0.66–1.52) vs 0.63 in the control group (IQR 0.44–0.70); P=0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm2 in the diabetic group of 1.08 (IQR 0.73–1.43) vs 0.23 in the control group (IQR 0.12–0.43); P=0.003).ConclusionsAccumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGE-blocking and/or breaking compounds is indicated.
Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults.
Authors: Reis Jared P , von Mühlen Denise , Miller Edgar R 
Published: April 2008

ObjectivePrevious research on the combined association of 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) with metabolic syndrome may have been limited by restricted age variability and a lack of representation of the general population. This study examined the combined association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetSyn among a nationally representative sample of US adults.Design and methodsThis population-based cross-sectional study included 834 men and 820 women aged ≥20 years without diagnosed diabetes who completed a physical examination as part of the 2003–2004 US National Health and Nutrition Examination Survey.ResultsAfter adjusting for age, sex, race/ethnicity, income, lifestyle factors, total calcium, and energy intake, the odds ratio (OR) for MetSyn in the highest quintile of 25(OH)D (median 88.0 nmol/l) compared with the lowest quintile (median 26.8 nmol/l) was 0.27 (0.15, 0.46;Ptrend<0.001). This relation was unchanged after additional adjustment for PTH level (OR, 0.26; 0.15, 0.44;Ptrend<0.001) and did not differ by sex (Pinteraction 0.6) or age (< or ≥50 years;Pinteraction 0.2). In contrast, the multivariable-adjusted odds for MetSyn increased with increasing PTH among older men (Ptrend0.004), but not younger men (Ptrend0.4) or women regardless of age (Ptrend0.4 in younger and older women).ConclusionsThese data suggest an inverse association of 25(OH)D with MetSyn, independent of potential confounding factors, calcium intake, and PTH, and a positive association of PTH with MetSyn among older men.
Heterogeneity in the molecular basis of ACTH resistance syndrome.
Authors: Collares Cristhianna Viesti Advincula , Antunes-Rodrigues Jose , Moreira Ayrton Custodio , Franca Suzana Nesi , Pereira Luiz Alberto , Soares Maria Marta Sarquis , Elias Junior Jorge , Clark Adrian J , de Castro Margaret , Elias Lucila Leico Kagohara 
Published: April 2008

ObjectiveACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis ofMC2R,MRAP, andAAASgenes in five Brazilian patients with ACTH resistance syndrome.Design and methodsGenomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R.ResultsAll five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in theMC2Rgene in one patient and p.Met1Ile mutation in theMRAPgene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of theAAASgene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation inMC2R,MRAP, orAAASgene.ConclusionsIn conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.
High Diversity of Genes for Nonhost Resistance of Barley to Heterologous Rust Fungi
Authors: Jafary Hossein , Albertazzi Giorgia , Marcel Thierry C , Niks Rients E 
Published: April 2008

Abstract
Inheritance studies on the nonhost resistance of plants would normally require interspecific crosses that suffer from sterility and abnormal segregation. Therefore, we developed the barley–Puccinia rust model system to study, using forward genetics, the specificity, number, and diversity of genes involved in nonhost resistance. We developed two mapping populations by crossing the line SusPtrit, with exceptional susceptibility to heterologous rust species, with the immune barley cultivars Vada and Cebada Capa. These two mapping populations along with the Oregon Wolfe Barley population, which showed unexpected segregation for resistance to heterologous rusts, were phenotyped with four heterologous rust fungal species. Positions of QTL conferring nonhost resistance in the three mapping populations were compared using an integrated consensus map. The results confirmed that nonhost resistance in barley to heterologous rust species is controlled by QTL with different and overlapping specificities and by an occasional contribution of an R-gene for hypersensitivity. In each population, different sets of loci were implicated in resistance. Few genes were common between the populations, suggesting a high diversity of genes conferring nonhost resistance to heterologous pathogens. These loci were significantly associated with QTL for partial resistance to the pathogen Puccinia hordei and with defense-related genes.
Quantitative Genetic Analysis of Sleep inDrosophila melanogaster
Authors: Harbison Susan T , Sehgal Amita 
Published: April 2008

AbstractAlthough intensively studied, the biological purpose of sleep is not known. To identify candidate genes affecting sleep, we assayed 136 isogenic P-element insertion lines of Drosophila melanogaster. Since sleep has been negatively correlated with energy reserves across taxa, we measured energy stores (whole-body protein, glycogen, and triglycerides) in these lines as well. Twenty-one insertions with known effects on physiology, development, and behavior affect 24-hr sleep time. Thirty-two candidate insertions significantly impact energy stores. Mutational genetic correlations among sleep parameters revealed that the genetic basis of the transition between sleep and waking states in males and females may be different. Furthermore, sleep bout number can be decoupled from waking activity in males, but not in females. Significant genetic correlations are present between sleep phenotypes and glycogen stores in males, while sleep phenotypes are correlated with triglycerides in females. Differences observed in male and female sleep behavior in flies may therefore be related to sex-specific differences in metabolic needs. Sleep thus emerges as a complex trait that exhibits extensive pleiotropy and sex specificity. The large mutational target that we observed implicates genes functioning in a variety of biological processes, suggesting that sleep may serve a number of different functions rather than a single purpose.
The Rate and Spectrum of Microsatellite Mutation in Caenorhabditis elegans and Daphnia pulex
Authors: Seyfert Amanda L , Cristescu Melania E A , Frisse Linda , Schaack Sarah , Thomas W Kelley , Lynch Michael 
Published: April 2008

Abstract
The effective use of microsatellite loci as tools for microevolutionary analysis requires knowledge of the factors influencing the rate and pattern of mutation, much of which is derived from indirect inference from population samples. Interspecific variation in microsatellite stability also provides a glimpse into aspects of phylogenetic constancy of mutational processes. Using long-term series of mutation-accumulation lines, we have obtained direct estimates of the spectrum of microsatellite mutations in two model systems: the nematode Caenorhabditis elegans and the microcrustacean Daphnia pulex. Although the scaling of the mutation rate with the number of tandem repeats is highly consistent across distantly related species, including yeast and human, the per-cell-division mutation rate appears to be elevated in multicellular species. Contrary to the expectations under the stepwise mutation model, most microsatellite mutations in C. elegans and D. pulex involve changes of multiple repeat units, with expansions being much more common than contractions.
Fraction of Informative Recombinations: A Heuristic Approach to Analyze Recombination Rates
Authors: Lefebvre J-F , Labuda D 
Published: April 2008

Abstract
In this article we present a new heuristic approach (informative recombinations, InfRec) to analyze recombination density at the sequence level. InfRec is intuitive and easy and combines previously developed methods that (i) resolve genotypes into haplotypes, (ii) estimate the minimum number of recombinations, and (iii) evaluate the fraction of informative recombinations. We tested this approach in its sliding-window version on 117 genes from the SeattleSNPs program, resequenced in 24 African-Americans (AAs) and 23 European-Americans (EAs). We obtained population recombination rate estimates (ρobs) of 0.85 and 0.37 kb−1 in AAs and EAs, respectively. Coalescence simulations indicated that these values account for both the recombinations and the gene conversions in the history of the sample. The intensity of ρobs varied considerably along the sequence, revealing the presence of recombination hotspots. Overall, we observed ∼80% of recombinations in one-third and ∼50% in only 10% of the sequence. InfRec performance, tested on published simulated and additional experimental data sets, was similar to that of other hotspot detection methods. Fast, intuitive, and visual, InfRec is not constrained by sample size limitations. It facilitates understanding data and provides a simple and flexible tool to analyze recombination intensity along the sequence.
AMutatorTransposon Insertion Is Associated With Ectopic Expression of a Tandemly Repeated MulticopyMybGenepericarp color1of Maize
Authors: Robbins Michael L , Sekhon Rajandeep S , Meeley Robert , Chopra Surinder 
Published: April 2008

AbstractThe molecular basis of tissue-specific pigmentation of maize carrying a tandemly repeated multicopy allele of pericarp color1 (p1) was examined using Mutator (Mu) transposon-mediated mutagenesis. The P1-wr allele conditions a white or colorless pericarp and a red cob glumes phenotype. However, a Mu-insertion allele, designated as P1-wr-mum6, displayed an altered phenotype that was first noted as occasional red stripes on pericarp tissue. This gain-of-pericarp-pigmentation phenotype was heritable, yielding families that displayed variable penetrance and expressivity. In one fully penetrant family, deep red pericarp pigmentation was observed. Several reports on Mu suppressible alleles have shown that Mu transposons can affect gene expression by mechanisms that depend on transposase activity. Conversely, the P1-wr-mum6 phenotype is not affected by transposase activity. The increased pigmentation was associated with elevated mRNA expression of P1-wr-mum6 copy (or copies) that was uninterrupted by the transposons. Genomic bisulfite sequencing analysis showed that the elevated expression was associated with hypomethylation of a floral-specific enhancer that is ∼4.7 kb upstream of the Mu1 insertion site and may be proximal to an adjacent repeated copy. We propose that the Mu1 insertion interferes with the DNA methylation and related chromatin packaging of P1-wr, thereby inducing expression from gene copy (or copies) that is otherwise suppressed.