bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower insulin sensitivity differentiates hirsute from non-hirsute Sicilian women with polycystic ovary syndrome
Authors: Amato Marco C , Galluzzo Aldo , Merlino Simona , Mattina Antonina , Richiusa Pierina , Criscimanna Angela , Giordano Carla
Published: November 2006

Objective: It is well known that hyperandrogenism and insulin-resistance with or without compensatory hyperinsulinism are closely associated, but the Rotterdam Consensus has concluded that principally obese women with polycystic ovary syndrome (PCOS) should be evaluated for the metabolic syndrome. Our aim was to study insulin sensitivity in PCOS women with hirsutism regardless of obesity.

Methods: Clinical characteristics, sex hormones and fasting- and after OGTT-glycemia and insulinemia, homeostatic model of insulin resistance (HOMA IR), and Matsuda index of insulin sensitivity were analyzed in 130 women with PCOS. Hirsutism has been evaluated through the Ferriman–Gallwey (FG) map scoring system.

Results: PCOS women with hirsutism (57.7% of participants) showed significant higher values of total testosterone levels (P = 0.016), free testosterone (P = 0.027), DHEA sulfate (P = 0.017), and Δ4androstenedione (P = 0.018). They had similar body mass index (BMI) (P = 0.073) and were significantly less insulin sensitive (P = 0.002) than those without hirsutism (42.3% of participants). In women with PCOS and hirsutism, there was a significant correlation between FG score and insulin-sensitivity indexes (HOMA IR, ρ = 0.33, P = 0.005; Matsuda index, ρ = −0.34, P = 0.003) but not with the androgen levels. Moreover, women with hirsutism showed a significantly greater insulin (P = 0.019), C-peptide (P = 0.002), and glucose (P = 0.024) areas under the curve (auc2h).

Conclusions: Our study suggests that the increased responsiveness of the pilo-sebaceous unit to androgens seems to be influenced by insulin sensitivity and that insulin resistance should be assessed in all hirsute women with PCOS regardless of their BMI, as insulin resistance was found in hirsute women irrespective of whether they were overweight or obese.
Selenium and goiter prevalence in borderline iodine sufficiency
Authors: Brauer Volker F H , Schweizer Ulrich , Köhrle Josef , Paschke Ralf
Published: November 2006

Design: Selenium (Se) is required for the biosynthesis of selenocysteine-containing proteins. Several selenoenzymes, e.g. glutathione peroxidases and thioredoxin reductases, are expressed in the thyroid. Selenoenzymes of the deiodinase family regulate the levels of thyroid hormones. For clinical investigators, it is difficult to determine the role of Se in the etiology of (nodular-)goiter, because there are considerable variations of Se concentrations in different populations as reflected by dietary habits, bioavailability of Se compounds, and racial differences. Moreover, most previous clinical trials which investigated the influence of Se on thyroid volume harbored a bias due to the coexistence of severe iodine deficiency in the study populations.

Methods: Therefore, we investigated the influence of Se on thyroid volume in an area with borderline iodine sufficiency. First, we investigated randomly selected probands for urinary iodine (UI) and creatinine excretion in spot urine samples and determined the prevalence of goiter and thyroid nodules by high-resolution ultrasonography. After this, we determined urinary Se excretion (USe) in probands with goiter as well as in matched probands without goiter. Adjustments between the two compared groups were made for age, gender, history of thyroid disorders, smoking, and UI excretion.

Results: The mean USe and UI rates of all 172 probands were 24 μg Se/l or 27 μg Se/g creatinine and 96 μg I/l or 113 μg I/g creatinine indicating borderline selenium (20–200 μg/l) and iodine (100–200 μg/l) sufficiency of the study population. Probands with goiter (n=89) showed significantly higher USe levels than probands with normal thyroid volume (n=83; P < 0.05). USe rates were not influenced by present smoking or pregnancy.

Conclusions: In our investigation, USe was not an independent risk factor for the development of goiter. The higher USe in probands with goiter in comparison with probands with normal thyroid volume is most likely a coincidence. Se does not significantly influence thyroid volume in borderline iodine sufficiency because the iodine status is most likely the more important determinant.
Testosterone and cognitive function: current clinical evidence of a relationship
Authors: Beauchet Olivier
Published: November 2006

Background: Testosterone levels decline as men age, as does cognitive function. Whether there is more than a temporal relationship between testosterone and cognitive function is unclear. Chemical castration studies in men with prostate cancer suggest that low serum testosterone may be associated with cognitive dysfunction. Low testosterone levels have also been observed in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This paper reviews the current clinical evidence of the relationship between serum testosterone levels and cognitive function in older men.

Methods: A systematic literature search was conducted using PubMed and EMBASE to identify clinical studies and relevant reviews that evaluated cognitive function and endogenous testosterone levels or the effects of testosterone substitution in older men.

Results: Low levels of endogenous testosterone in healthy older men may be associated with poor performance on at least some cognitive tests. The results of randomized, placebo-controlled studies have been mixed, but generally indicate that testosterone substitution may have moderate positive effects on selective cognitive domains (e.g. spatial ability) in older men with and without hypogonadism. Similar results have been found in studies in patients with existing AD or MCI.

Conclusions: Low endogenous levels of testosterone may be related to reduced cognitive ability, and testosterone substitution may improve some aspects of cognitive ability. Measurement of serum testosterone should be considered in older men with cognitive dysfunction. For men with both cognitive impairment and low testosterone, testosterone substitution may be considered. Large, long-term studies evaluating the effects of testosterone substitution on cognitive function in older men are warranted.
Clinical Disease in Children Associated With Newly Described Coronavirus Subtypes
Authors: Kuypers Jane , Martin Emily T. , Heugel Judson , Wright Nancy , Morrow Rhoda , Englund Janet A.
Published: November 2006

OBJECTIVES. Coronaviruses cause upper respiratory illness and occasionally lower tract disease in susceptible populations. In this study we examined the prevalence of 4 human coronaviruses, including subtypes OC43, 229E, and the recently described NL63 and HKU1 in a pediatric population presenting to a children's hospital.

PATIENTS AND METHODS. Specimens collected over a 1-year period from pediatric patients presenting with acute respiratory illness were analyzed for the presence of 4 coronavirus subtypes using consensus and subtype-specific real-time reverse-transcription polymerase chain reaction assays. The demographic and clinical characteristics associated with coronavirus infection were examined retrospectively.

RESULTS. Coronaviruses were detected in 66 of 1043 children. Eight, 11, 19, and 28 specimens were positive for subtypes 229E, NL63, OC43, and HKU1, respectively. Coronaviruses were detected throughout the study period; all 4 of the subtypes were present simultaneously in December. The acute clinical features were similar across subtypes. Of 32 children infected with a coronavirus as the sole respiratory pathogen, 13 had lower respiratory tract disease. Children whose only detectable respiratory virus was a coronavirus were more likely to have underlying chronic disease than were children coinfected with another respiratory virus.

CONCLUSIONS. Although 4 subtypes of coronavirus were detected, the recently discovered coronavirus subtypes NL63 and HKU1 accounted for the majority of coronaviruses detected in our cohort of mostly hospitalized children with respiratory symptoms. New subtypes likely represent a substantial portion of previously unexplained respiratory illnesses.
Recovery of Islet β-Cell Function in Streptozotocin- Induced Diabetic Mice
Authors: Yin Dengping , Tao Jing , Lee David D. , Shen Jikun , Hara Manami , Lopez James , Kuznetsov Andrey , Philipson Louis H. , Chong Anita S.
Published: November 2006

Limitations in islet β-cell transplantation as a therapeutic option for type 1 diabetes have prompted renewed interest in islet regeneration as a source of new islets. In this study we tested whether severely diabetic adult C57BL/6 mice can regenerate β-cells. Diabetes was induced in C57BL/6 mice with high-dose streptozotocin (160−170 mg/kg). In the absence of islet transplantation, all diabetic mice remained diabetic (blood glucose >400 mg/dl), and no spontaneous reversal of diabetes was observed. When syngeneic islets (200/mouse) were transplanted into these diabetic mice under a single kidney capsule, stable restoration of euglycemia for ≥120 days was achieved. Removal of the kidney bearing the transplanted islets at 120 days posttransplantation revealed significant restoration of endogenous β-cell function. This restoration of islet function was associated with increased β-cell mass, as well as β-cell hypertrophy and proliferation. The restoration of islet cell function was facilitated by the presence of a spleen; however, the facilitation was not due to the direct differentiation of spleen-derived cells into β-cells. This study supports the possibility of restoring β-cell function in diabetic individuals and points to a role for the spleen in facilitating this process.
Insulin-Mediated Phosphorylation of the Proline-Rich Akt Substrate PRAS40 Is Impaired in Insulin Target Tissues of High-Fat Diet–Fed Rats
Authors: Nascimento Emmani B.M. , Fodor Mariann , van der Zon Gerard C.M. , Jazet Ingrid M. , Meinders A. Edo , Voshol Peter J. , Vlasblom Ronald , Baan Bart , Eckel Jürgen , Maassen J. Antonie , Diamant Michaela , Ouwens D. Margriet
Published: November 2006

Clinical insulin resistance is associated with decreased activation of phosphatidylinositol 3′-kinase (PI3K) and its downstream substrate protein kinase B (PKB)/Akt. However, its physiological protein substrates remain poorly characterized. In the present study, the effect of in vivo insulin action on phosphorylation of the PKB/Akt substrate 40 (PRAS40) was examined. In rat and mice, insulin stimulated PRAS40-Thr246 phosphorylation in skeletal and cardiac muscle, the liver, and adipose tissue in vivo. Physiological hyperinsulinemia increased PRAS40-Thr246 phosphorylation in human skeletal muscle biopsies. In cultured cell lines, insulin-mediated PRAS40 phosphorylation was prevented by the PI3K inhibitors wortmannin and LY294002. Immunohistochemical and immunofluorescence studies showed that phosphorylated PRAS40 is predominantly localized to the nucleus. Finally, in rats fed a high-fat diet (HFD), phosphorylation of PRAS40 was markedly reduced compared with low-fat diet–fed animals in all tissues examined. In conclusion, the current study identifies PRAS40 as a physiological target of in vivo insulin action. Phosphorylation of PRAS40 is increased by insulin in human, rat, and mouse insulin target tissues. In rats, this response is reduced under conditions of HFD-induced insulin resistance.
Decreased Hepatic Futile Cycling Compensates for Increased Glucose Disposal in the Pten Heterodeficient Mouse
Authors: Xu Jun , Gowen Lori , Raphalides Christian , Hoyer Katrina K. , Weinger Jason G. , Renard Mathilde , Troke Joshua J. , Vaitheesyaran Bhavapriya , Lee W.N. Paul , Saad Mohammed F. , Sleeman Mark W. , Teitell Michael A. , Kurland Irwin J.
Published: November 2006

Despite altered regulation of insulin signaling, Pten+/− heterodeficient standard diet–fed mice, ∼4 months old, exhibit normal fasting glucose and insulin levels. We report here a stable isotope flux phenotyping study of this “silent” phenotype, in which tissue-specific insulin effects in whole-body Pten+/−-deficient mice were dissected in vivo. Flux phenotyping showed gain of function in Pten+/− mice, seen as increased peripheral glucose disposal, and compensation by a metabolic feedback mechanism that 1) decreases hepatic glucose recycling via suppression of glucokinase expression in the basal state to preserve hepatic glucose production and 2) increases hepatic responsiveness in the fasted-to-fed transition. In Pten+/− mice, hepatic gene expression of glucokinase was 10-fold less than wild-type (Pten+/+) mice in the fasted state and reached Pten+/+ values in the fed state. Glucose-6-phosphatase expression was the same for Pten+/− and Pten+/+ mice in the fasted state, and its expression for Pten+/− was 25% of Pten+/+ in the fed state. This study demonstrates how intra- and interorgan flux compensations can preserve glucose homeostasis (despite a specific gene defect that accelerates glucose disposal) and how flux phenotyping can dissect these tissue-specific flux compensations in mice presenting with a “silent” phenotype.
Maintenance of Hepatic Nuclear Factor 6 in Postnatal Islets Impairs Terminal Differentiation and Function of β-Cells
Authors: Tweedie Elizabeth , Artner Isabella , Crawford Laura , Poffenberger Greg , Thorens Bernard , Stein Roland , Powers Alvin C. , Gannon Maureen
Published: November 2006

The Onecut homeodomain transcription factor hepatic nuclear factor 6 (Hnf6) is necessary for proper development of islet β-cells. Hnf6 is initially expressed throughout the pancreatic epithelium but is downregulated in endocrine cells at late gestation and is not expressed in postnatal islets. Transgenic mice in which Hnf6 expression is maintained in postnatal islets (pdx1PBHnf6) show overt diabetes and impaired glucose-stimulated insulin secretion (GSIS) at weaning. We now define the mechanism whereby maintenance of Hnf6 expression postnatally leads to β-cell dysfunction. We provide evidence that continued expression of Hnf6 impairs GSIS by altering insulin granule biosynthesis, resulting in a reduced response to secretagogues. Sustained expression of Hnf6 also results in downregulation of the β-cell–specific transcription factor MafA and a decrease in total pancreatic insulin. These results suggest that downregulation of Hnf6 expression in β-cells during development is essential to achieve a mature, glucose-responsive β-cell.
Insulin Treatment in Patients With Type 1 Diabetes Induces Upregulation of Regulatory T-Cell Markers in Peripheral Blood Mononuclear Cells Stimulated With Insulin In Vitro
Authors: Tiittanen Minna , Huupponen Johanna T. , Knip Mikael , Vaarala Outi
Published: November 2006

Patients with type 1 diabetes are treated with daily injections of human insulin, an autoantigen expressed in thymus. Natural CD4+CD25high regulatory T-cells are derived from thymus, and accordingly human insulin–specific regulatory T-cells should exist. We had a chance to study peripheral blood mononuclear cells (PBMCs) from children with type 1 diabetes both before and after starting insulin treatment, and thus we could analyze the effects of insulin treatment on regulatory T-cells in children with type 1 diabetes. PBMCs were stimulated for 72 h with bovine/human insulin. The mRNA expression of regulatory T-cell markers (transforming growth factor-β, Foxp3, cytotoxic T-lymphocyte antigen-4 [CTLA-4], and inducible co-stimulator [ICOS]) or cytokines (γ-interferon [IFN-γ], interleukin [IL]-5, IL-4) was measured by quantitative RT-PCR. The secretion of IFN-γ, IL-2, IL-4, IL-5, and IL-10 was also studied. The expression of Foxp3, CTLA-4, and ICOS mRNAs in PBMCs stimulated with bovine or human insulin was higher in patients on insulin treatment than in patients studied before starting insulin treatment. The insulin-induced Foxp3 protein expression in CD4+CD25high cells was detectable in flow cytometry. No differences were seen in cytokine activation between the patient groups. Insulin stimulation in vitro induced increased expression of regulatory T-cell markers, Foxp3, CTLA-4, and ICOS only in patients treated with insulin, suggesting that treatment with human insulin activates insulin-specific regulatory T-cells in children with newly diagnosed type 1 diabetes. This effect of the exogenous autoantigen could explain the difficulties to detect in vitro T-cell proliferation responses to insulin in newly diagnosed patients. Furthermore, autoantigen treatment–induced activation of regulatory T-cells may contribute to the clinical remission of the disease.
Endogenous ApoE Expression Modulates Adipocyte Triglyceride Content and Turnover
Authors: Huang Zhi Hua , Reardon Catherine A. , Mazzone Theodore
Published: November 2006

Apolipoprotein E (apoE) is highly expressed in adipose tissue and adipocytes in which its expression is regulated by peroxisome proliferator–activated receptor (PPAR)-γ agonists and tumor necrosis factor–α. There is, however, no information regarding a role for endogenous apoE in differentiated adipocyte function. In this report, we define a novel role for apoE in modulating adipocyte lipid metabolism. ApoE−/− mice have less body fat and smaller adipocytes compared with wild-type controls. Freshly isolated adipose tissue from apoE−/− mice contains lower levels of triglyceride and free fatty acid, and these differences are maintained in cultured adipocytes derived from preadipocytes. Adenoviral expression of apoE in apoE−/−-cultured adipocytes increases triglyceride and fatty acid content. During incubation with apoE-containing triglyceride-rich lipoproteins, apoE−/− adipose tissue accumulates less triglyceride than wild type. The absence of apoE expression in primary cultured adipocytes also leads to changes in the expression of genes involved in the metabolism/turnover of fatty acids and the triglyceride droplet. Markers of adipocyte differentiation were lower in freshly isolated and cultured apoE−/− adipocytes. Importantly, PPAR-γ–mediated changes in lipid content and gene expression are markedly altered in cultured apoE−/− adipocytes. These results establish a novel role for endogenous apoE in adipocyte lipid metabolism and have implications for constructing an integrated model of adipocyte physiology in health and disease.
CHRM3 Gene Variation Is Associated With Decreased Acute Insulin Secretion and Increased Risk for Early-Onset Type 2 Diabetes in Pima Indians
Authors: Guo Yan , Traurig Michael , Ma Lijun , Kobes Sayuko , Harper Inge , Infante Aniello M. , Bogardus Clifton , Baier Leslie J. , Prochazka Michal
Published: November 2006

The muscarinic acetylcholine receptor subtype M3 (CHRM3) gene is expressed in islet β-cells and has a role in stimulating insulin secretion; therefore, CHRM3 was analyzed as a candidate gene for type 2 diabetes in Pima Indians. Ten variants were genotyped in a family-based sample (n = 1,037), and 1 variant (rs3738435) located in the 5′ untranslated region of an alternative transcript was found to be modestly associated with both early-onset type 2 diabetes and the acute insulin response in a small subset of these subjects. To better assess whether this variant has a role in acute insulin secretion, which could affect risk for early-onset type 2 diabetes, rs3738435 was genotyped in a larger group of normal glucose-tolerant Pima Indians who had measures of acute insulin secretion (n = 282) and a larger case-control group of Pima Indians selected for early-onset type 2 diabetes (n = 348 case subjects with age of onset <25 years; n = 392 nondiabetic control subjects aged >45 years). Genotyping in these larger sets of subjects confirmed that the C allele of rs3738435 was associated with a reduced acute insulin response (adjusted P = 0.00006) and was also modestly associated with increased risk of early-onset type 2 diabetes (adjusted P = 0.02).
Contribution of Calcium Influx in Mediating Glucose-Stimulated Oxygen Consumption in Pancreatic Islets
Authors: Sweet Ian R. , Gilbert Merle
Published: November 2006

In brain, muscle, and pancreatic islets, depolarization induces an increase in respiration, which is dependent on calcium influx. The goal of this study was to assess the quantitative significance of this effect in islets relative to glucose-stimulated ATP turnover, to examine the molecular mechanism mediating the changes, and to investigate the functional implications with respect to insulin secretion. Glucose (3–20 mmol/l) increased steady-state levels of cytochrome c reduction (32–66%) in isolated rat islets, reflecting an increased production of NADH, and oxygen consumption rate (OCR) by 0.32 nmol/min/100 islets. Glucose-stimulated OCR was inhibited 30% by inhibitors of calcium influx (diazoxide or nimodipine), whereas a protein synthesis inhibitor (emetine) decreased it by only 24%. None of the inhibitors affected cytochrome c reduction, suggesting that calcium’s effect on steady-state OCR is mediated by changes in ATP usage rather than the rate of NADH generation. 3-isobutyl-1-methylxanthine increased insulin secretion but had little effect on OCR, indicating that the processes of movement and exocytosis of secretory granules do not significantly contribute to ATP turnover. At 20 mmol/l glucose, a blocker of sarcoendoplasmic reticulum calcium ATPase (SERCA) had little effect on OCR despite a large increase in cytosolic calcium, further supporting the notion that influx of calcium, not bulk cytosolic calcium, is associated with the increase in ATP turnover. The glucose dose response of calcium influx–dependent OCR showed a remarkable correlation with insulin secretion, suggesting that the process mediating the effect of calcium on ATP turnover has a role in the amplification pathway of insulin secretion.
Altered Monocyte Cyclooxygenase Response to Lipopolysaccharide in Type 1 Diabetes
Authors: Beyan Huriya , Goodier Martin R. , Nawroly Niga S. , Hawa Mohammed I. , Bustin Stephen A. , Ogunkolade William B. , Londei Marco , Yousaf Nasim , Leslie R. David G.
Published: November 2006

Type 1 diabetes is caused by adaptive immune responses, but innate immunity is important because monocytes infiltrate islets. Activated monocytes express cyclooxygenase (COX)-2, promoting prostaglandin-E2 (PGE2) secretion, whereas COX-1 expression is constitutive. We aimed to define monocyte COX expression in type 1 diabetes basally and after lipopolysaccharide (LPS) stimulation. Isolated CD14+ monocytes were analyzed for COX mRNA and protein expression from identical twins (discordant for type 1 diabetes) and control subjects. Basal monocyte COX mRNA, protein expression, and PGE2 secretion were normal in type 1 diabetic subjects. After LPS, twins and control subjects showed a COX mRNA isoform switch with decreased COX-1 mRNA (P < 0.01), increased COX-2 mRNA (P < 0.01), and increased COX-2 protein expression (P < 0.01). Compared with control subjects, both diabetic and nondiabetic twins showed greater LPS-induced downregulation of monocyte COX-1 mRNA (P = 0.02), reduced upregulation of COX-2 mRNA and protein (P < 0.03), and greater inhibition by the COX-2 inhibitor di-isopropylfluorophosphate (DFP) of monocyte PGE2 (P < 0.007). We demonstrate an alteration in monocyte COX mRNA expression as well as monocyte COX-2 and PGE2 production after LPS in type 1 diabetic patients and their nondiabetic twins. Because COX-2 response to LPS is proinflammatory, an inherited reduced response would predispose to chronic inflammatory diseases such as type 1 diabetes.
Effects of Sex and Hormone Replacement Therapy Use on the Prevalence of Isolated Impaired Fasting Glucose and Isolated Impaired Glucose Tolerance in Subjects With a Family History of Type 2 Diabetes
Authors: van Genugten Renate E. , Utzschneider Kristina M. , Tong Jenny , Gerchman Fernando , Zraika Sakeneh , Udayasankar Jayalakshmi , Boyko Edward J. , Fujimoto Wilfred Y. , Kahn Steven E. ,   and the American Diabetes Association GENNID Study Group
Published: November 2006

Impaired fasting glucose (IFG) is more prevalent in men and impaired glucose tolerance (IGT) more prevalent in women. To explore whether this sex difference is related to female sex hormones, we performed a cross-sectional analysis of data from 2,164 (1,329 women and 835 men) first-degree relatives of individuals with type 2 diabetes. Subjects were categorized based on a 75-g oral glucose tolerance test. Sex and hormone replacement therapy (HRT) effects on the distribution of glucose tolerance were assessed using multinomial logistic regression corrected for familial clustering. Compared with men, women were more likely to have isolated IGT (relative risk 1.8 [95% CI 1.3–2.5]) and less likely to have isolated IFG (0.5 [0.3–0.7]) adjusted for ethnicity, age, waist, fasting insulin, and early insulin release (ΔI0–30/ΔG0–30). To evaluate HRT effects, postmenopausal women using (n = 238) or not using (n = 378) HRT were compared. HRT users were more likely to have isolated IGT (2.2 [1.2–4.0]) after adjustment, but the prevalence of isolated IFG did not differ by HRT status. Based on the influence of sex and HRT on the prevalence of isolated IFG and isolated IGT, we conclude that female sex hormones may play an important role in the pathogenesis of IFG and IGT.
Modulation of Insulin Secretion by Fatty Acyl Analogs
Authors: Las Guy , Mayorek Nina , Dickstein Kobie , Bar-Tana Jacob
Published: November 2006

The secretagogue, the incretin-like, and the suppressive activities of long-chain fatty acids (LCFAs) in modulating insulin secretion in vivo and in cultured islets were simulated here by β,β′-tetramethyl-hexadecanedioic acid (M16) and α,α′-tetrachloro-tetradecanedioic acid (Cl-DICA). M16, but not Cl-DICA, serves as a substrate for ATP-dependent CoA thioesterification but is not further metabolized. M16, but not Cl-DICA, acted as a potent insulin secretagogue in islets cultured in basal but not high glucose. Short-term exposure to M16 or Cl-DICA resulted in activation of glucose- but not arginine-stimulated insulin secretion. Long-term exposure to M16, but not to Cl-DICA, resulted in suppression of glucose-, arginine-, and K+-stimulated insulin secretion; inhibition of glucose-induced proinsulin biosynthesis; and depletion of islets insulin. β-Cell mass and islet ATP content remained unaffected. Hence, nonmetabolizable LCFA analogs may highlight discrete LCFA metabolites and pathways involved in modulating insulin secretion, which could be overlooked due to the rapid turnover of natural LCFA.
Introgression of F344 Rat Genomic DNA on BB Rat Chromosome 4 Generates Diabetes-Resistant Lymphopenic BB Rats
Authors: Fuller Jessica M. , Kwitek Anne E. , Hawkins Tyson J. , Moralejo Daniel H. , Lu Wen , Tupling Terry D. , MacMurray Armand J. , Borchardt Gretta , Hasinoff Michael , Lernmark Åke
Published: November 2006

Failure to express the Gimap5 protein is associated with lymphopenia (lyp) and linked to spontaneous diabetes in the diabetes-prone BioBreeding (BBDP) rat. Gimap5 is a member of seven related genes located within 150 Kb on rat chromosome 4. Congenic DR.lyp/lyp rats, where BBDP lyp was introgressed onto the diabetes-resistant BBDR background (BBDR.BBDP.lyp/lyp), all develop diabetes between 46 and 81 days of age (mean ± SE, 61 ± 1), whereas DR.lyp/+ and DR.+/+ rats are nonlymphopenic and diabetes resistant. In an intercross between F1(BBDP x F344) rats, we identified a rat with a recombination event on chromosome 4, allowing us to fix 33 Mb of F344 between D4Rat253 and D4Rhw6 in the congenic DR.lyp rat line. Gimap1 and Gimap5 were the only members of the Gimap family remaining homozygous for the BBDP allele. Offspring homozygous for the F344 allele (f/f) between D4Rat253 and D4Rhw6 were lymphopenic (85 of 85, 100%) but did not develop diabetes (0 of 85). During rescue of the recombination, 102 of 163 (63%) rats heterozygous (b/f) for the recombination developed diabetes between 52 and 222 days of age (88 ± 3). Our data demonstrate that introgression of a 33-Mb region of the F344 genome, proximal to the mutated Gimap5 gene, renders the rat diabetes resistant despite being lymphopenic. Spontaneous diabetes in the BB rat may therefore be controlled, in part, by a diabetogenic factor(s), perhaps unrelated to the Gimap5 mutation on rat chromosome 4.
The Idd4 Locus Displays Sex-Specific Epistatic Effects on Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice
Authors: Ivakine Evgueni A. , Mortin-Toth Steven M. , Gulban Omid M. , Valova Aneta , Canty Angelo , Scott Christopher , Danska Jayne S.
Published: November 2006

The nonobese diabetic (NOD) mouse recapitulates many aspects of the pathogenesis of type 1 diabetes in humans, including inheritance as a complex trait. More than 20 Idd loci have been linked to type 1 diabetes susceptibility in NOD mice. Previously, we used linkage analysis of NOD crossed to the nonobese diabetes-resistant (NOR) strain and NOD congenic strains to map susceptibility to both spontaneous and cyclophosphamide-accelerated type 1 diabetes to the Idd4 locus on chromosome 11 that displayed a sex-specific effect on diabetes susceptibility. Here, we elucidate the complex genetic architecture of Idd4 by analysis of congenic strains on the NOD and NOR backgrounds. We previously refined Idd4.1 to 1.4 Mb and demonstrated an impact of this interval on type 1 interferon pathways in antigen-presenting cells. Here, we identify a second subregion, the 0.92 Mb Idd4.2 locus located telomeric to Idd4.1. Strikingly, Idd4.2 displayed a sex-specific, epistatic interaction with Idd4.1 in NOR.NOD congenic females that was not observed in syngenic males. Idd4.2 contains 29 genes, and promising candidates for the Idd4.2 effect on type 1 diabetes are described. These data demonstrate sex-dependent interaction effects on type 1 diabetes susceptibility and provide a framework for functional analysis of Idd4.2 candidate genes.
A Genome-Wide Linkage Scan for Genes Controlling Variation in Renal Function Estimated by Serum Cystatin C Levels in Extended Families With Type 2 Diabetes
Authors: Placha Grzegorz , Poznik G. David , Dunn Jonathon , Smiles Adam , Krolewski Bozena , Glew Timothy , Puppala Sobha , Schneider Jennifer , Rogus John J. , Rich Stephen S. , Duggirala Ravindranath , Warram James H. , Krolewski Andrzej S.
Published: November 2006

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h2) in diabetic (h2 = 0.45, P < 1 × 10−5) and nondiabetic (h2 = 0.36, P < 1 × 10−3) relatives. Genetic correlation (rG = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.
Nutrient Control of Insulin Secretion in Isolated Normal Human Islets
Authors: Henquin Jean-Claude , Dufrane Denis , Nenquin Myriam
Published: November 2006

Pancreatic islets were isolated from 16 nondiabetic organ donors and, after culture for ∼2 days in 5 mmol/l glucose, were perifused to characterize nutrient-induced insulin secretion in human islets. Stepwise increases from 0 to 30 mmol/l glucose (eight 30-min steps) evoked concentration-dependent insulin secretion with a threshold at 3–4 mmol/l glucose, Km at 6.5 mmol/l glucose, and Vmax at 15 mmol/l glucose. An increase from 1 to 15 mmol/l glucose induced biphasic insulin secretion with a prominent first phase (peak increase of ∼18-fold) and a sustained, flat second phase (∼10-fold increase), which were both potentiated by forskolin. The central role of ATP-sensitive K+ channels in the response to glucose was established by abrogation of insulin secretion by diazoxide and reversible restoration by tolbutamide. Depolarization with tolbutamide or KCl (plus diazoxide) triggered rapid insulin secretion in 1 mmol/l glucose. Subsequent application of 15 mmol/l glucose further increased insulin secretion, showing that the amplifying pathway is operative. In control medium, glutamine alone was ineffective, but its combination with leucine or nonmetabolized 2-amino-bicyclo [2,2,1]-heptane-2-carboxylic acid (BCH) evoked rapid insulin secretion. The effect of BCH was larger in low glucose than in high glucose. In contrast, the insulin secretion response to arginine or a mixture of four amino acids was potentiated by glucose or tolbutamide. Palmitate slightly augmented insulin secretion only at the supraphysiological palmitate-to-albumin ratio of 5. Inosine and membrane-permeant analogs of pyruvate, glutamate, or succinate increased insulin secretion in 3 and 10 mmol/l glucose, whereas lactate and pyruvate had no effect. In conclusion, nutrient-induced insulin secretion in normal human islets is larger than often reported. Its characteristics are globally similar to those of insulin secretion by rodent islets, with both triggering and amplifying pathways. The pattern of the biphasic response to glucose is superimposable on that in mouse islets, but the concentration-response curve is shifted to the left, and various nutrients, in particular amino acids, influence insulin secretion within the physiological range of glucose concentrations.
Kinetics and mechanism of hydroboration of oct-1-and-4-ene by dimeric dialkylboranes
Authors: Jaganyi D. , Govender J.
Published: November 2006

The kinetics and mechanism of hydroboration of oct-1-and-4-ene with a series of dimeric dialkylboranes was investigated. The kinetic results showed that the hydroboration of terminal olefins proceeds via a three-halves-order mechanism, first-order with respect to the olefin and one-half-order with respect to the dimer. Using dicyclohexylborane, diisopinocamphenylborane, and 3,6-dimethylborepane the observed rate constants for the hydroboration of oct-4-ene were approximately 6 times smaller than those for oct-1-ene. Supporting computations showed that both steric and electronic effects influence the rate of hydroboration of both internal and terminal olefins. A model computational study of the isomerization of oct-4-ene with di(prop-2-yl)borane showed that formation of the terminal hydroborated complex is thermodynamically favored over the internal complex.
Reaction sites of N,N′-substituted p-phenylenediamine antioxidants
Authors: Kortišová I. , Breza M. , Cibulková Z.
Published: November 2006

The geometries of N,N′-diphenylbenzene-1,4-diamine (DPPD), N-phenyl-N′-(1-phenylethyl)benzene-1,4-diamine (SPPD), N-(4-methylpentan-2-yl)-N′-phenylbenzene-1,4-diamine (6PPD), N-propan-2-yl-N′-phenylbenzene-1,4-diamine (IPPD), N-(2-methoxybenzyl)-N′-phenylbenzene-1,4-diamine (MBPPD), and N-phenyl-N′-(2-phenylpropan-2-yl)benzene-1,4-diamine (CPPD) as well as of their dehydrogenation products were optimized by the semiempirical AM1 method. The results support the idea of stable NB=CX structures formation during the consecutive dehydrogenation of SPPD, 6PPD, IPPD, and MBPPD antioxidants. The biradicals formed during the second step of dehydrogenation of substituted phenylenediamines might be important for their antioxidant effectiveness.
Determinants of the Innovation Process: An Empirical Test for the Portuguese Manufacturing Industry
Authors: Susana Marques Carla , Monteiro‐Barata José
Published: November 2006

The aim of this paper is to analyze the determinants of the main phases of the innovation process in Portuguese manufacturing firms. The analysis will adopt as its main frame of reference an interactive model of the innovation process, on which empirical tests will be carried out, making use of tobit and probit models and simultaneous equation systems. It is broadly concluded that the relationships shown between the main variables that are typical of the innovation process in the context of Portuguese manufacturing firms are tenuous and unsystematic.
Proline‐Catalyzed Imino‐Diels–Alder Reactions: Synthesis of meso‐2,6‐Diaryl‐4‐piperidones
Authors: Aznar Fernando , García Ana‐Belén , Cabal María‐Paz
Published: November 2006

Amine‐catalyzed imino‐Diels–Alder reactions of acyclic α,β‐unsaturated ketones with imines have been developed. L‐Proline catalyzed the in situ generation of 2‐amino‐1,3‐butadienes to provide a stereoselective synthesis of meso‐2,6‐diaryl‐4‐piperidones in one direct step.
Enantioselective Diels–Alder Reaction of α‐Acyloxyacroleins Catalyzed by Chiral 1,1′‐Binaphthyl‐2,2′‐diammonium Salts
Authors: Sakakura Akira , Suzuki Kenji , Ishihara Kazuaki
Published: November 2006

A diammonium salt of chiral 1,1′‐binaphthyl‐2,2′‐diamine (2a) and trifluoromethanesulfonimide (Tf2NH) shows excellent catalytic activity and enantioselectivity for the Diels–Alder reaction of α‐acyloxyacroleins. For example, in the presence of 5 mol % of 2a and 9.5 mol % of Tf2NH, the Diels–Alder reaction of α‐(cyclohexanecarbonyloxy)acrolein with cyclopentadiene proceeded in EtCN at −75 °C to give the adducts in 88 % yield with 92 % exo and 91 % ee. The electron‐donating property of the acyl group of the α‐acyloxyacroleins increases the enantioselectivity due to the formation of strong intramolecular hydrogen bonding of the acyl group with a proton of the ammonium group in the transition state. This catalyst can be easily prepared in situ by mixing the commercially available chiral diamine and Tf2NH.
Nickel‐Catalyzed Intermolecular [3+2+2] and [2+2+2] Cocyclizations of Bicyclopropylidene and Alkynes
Authors: Zhao Ligang , de Meijere Armin
Published: November 2006

Under the catalysis of bis(1,5‐cyclooctadiene)nickel(0), Ni(cod)2, in the presence of triphenylphosphane, two molecules of bicyclopropylidene (1) and one molecule of a terminal alkyne 2 at ambient temperature undergo an intermolecular [3+2+2] cocyclization to furnish the bis‐spirocyclopropanated cyclopropylidenecycloheptene derivatives 3 in 45–93 % yield (15 examples plus 2 examples with 8 and 25 % yield, respectively). With the same catalyst system, [2+2+2] cocyclizations of two molecules of an arylmethyl (aryl=phenyl, furyl) propargyl ether and one molecule of bicyclopropylidene (1) occur to provide regioisomeric dispiro[2.0.2.4]deca‐7,9‐diene derivatives 9/10 (2 examples, 57 and 44 % yield, respectively).
A Simple, Efficient, and Highly Enantioselective Synthesis of MS‐153 Employing a Chiral Silane Lewis Acid‐Promoted Acylhydrazone‐Enol Ether [3+2] Cycloaddition
Authors: Tran Kristy , Leighton James L.
Published: November 2006

Our previously reported chiral silane‐promoted enol ether‐acylhydrazone [3+2] cycloaddition reaction has been applied to a brief and efficient synthesis of the neuroprotective agent MS‐153. Unsatisfactory and variable levels of efficiency and enantioselectivity with the requisite acetaldehyde‐derived acylhydrazone occasioned a modification to the chiral silane Lewis acid, which led to the key cycloaddition step proceeding with excellent efficiency (85 % yield) and enantioselectivity (≥98 % ee).
Formal Enantioselective [4+3] Cycloaddition by a Tandem Diels–Alder Reaction/Ring Expansion
Authors: Dai Xing , Davies Huw M. L.
Published: November 2006

The tandem Diels–Alder reaction/ring expansion between cyclopentadiene and unsaturated aldehydes is a highly stereoselective process for the synthesis of bicyclo[3.2.1]octenones, the formal products of a [4+3] cycloaddition. When the initial cycloaddition was conducted in the presence of the chiral Lewis acid catalyst 14, the bicyclo[3.2.1]octenones were obtained in two steps in 72–85 % yields with up to 96 % ee and>98 % de.
Gold Catalysis: Dihydroisobenzofurans and Isochromanes by the Intramolecular Furan/Alkyne Reaction
Authors: Hashmi A. Stephen K. , Wölfle M. , Ata Filiz , Hamzic Melissa , Salathé Ralph , Frey Wolfgang
Published: November 2006

A series of furyl alcohols and homofuryl alcohols was synthesized by reduction of furfurals or reaction of furyllithium compounds with epoxides and subsequent propargylation. The gold‐catalyzed cycloisomerization of these products furnished dihydroisobenzofurans and isochromanes. Crystal structure analyses proved the sequence of the substituents for both classes of products. Unsaturated dicarbonyl compounds as side‐products show the mechanistic relationship to the analogous platinum‐catalyzed reactions. Neither ester groups, even on the 4‐position of the furan ring, nor aryl bromides hinder the catalysis by gold. In the case of a substrate with an allyl ether in the side chain, a side‐product, which provides evidence for a reaction of the alkyne with an inverse regioselectivity, was observed.
Variable adhesion of different red blood cell products to activated vascular endothelium under flow conditions
Authors: Anniss Angela M. , Sparrow Rosemary L.
Published: November 2006

Red blood cells (RBCs) that have been stored prior to transfusion show increased adherence to vascular endothelium in vitro, which suggests a potential for stored blood transfusion to impede blood flow in some patients. Transfusion is often required in patients with sepsis or inflammation; however, whether activation of endothelium affects stored RBC–endothelial cell (EC) interactions is unknown. We investigated whether storage time and leukocyte content of RBC products influences the adhesion of RBCs to activated ECs. RBCs from nonleukocyte‐reduced (S‐RBCs), buffy‐coat‐poor (BCP‐RBCs), and leukocyte‐filtered (LF‐RBCs) products and cultured EC layers were pretreated with endotoxin, tumor necrosis factor‐α (TNF‐α), or medium alone prior to perfusion of the RBCs across the EC layer in a continuous flow microchamber. After a single day of RBC storage, the number of adherent RBCs was increased in the endotoxin and TNF‐α pretreated groups compared to the unactivated‐control group. These differences were statistically significant for S‐RBCs and LF‐RBC products (P < 0.05). In contrast, there was no significant difference in RBC adherence to activated and unactivated endothelium at other time‐points of RBC product storage. The strength of adhesion of stored RBCs from S‐RBC products to activated ECs was not altered following treatment; however, endotoxin significantly increased the adhesive strength of LF‐RBCs to endothelium. These results demonstrate that while fresh RBCs show increased adhesion to activated endothelium, storage of RBCs did not promote increased adhesion to activated endothelium. However, inflammatory conditions promote stronger adhesion of stored RBCs to ECs, which may contribute to impaired tissue perfusion in some transfusion recipients. Am. J. Hematol., 2007. © 2006 Wiley‐Liss, Inc.
Biodistance analysis of the Moche sacrificial victims from Huaca de la Luna plaza 3C: Matrix method test of their origins
Authors: Sutter Richard C. , Verano John W.
Published: November 2006

The purpose of this study is to test two competing models regarding the origins of Early Intermediate Period (AD 200–750) sacrificial victims from the Huacas de Moche site using the matrix correlation method. The first model posits the sacrificial victims represent local elites who lost competitions in ritual battles with one another, while the other model suggests the victims were nonlocal warriors captured during warfare with nearby polities. We estimate biodistances for sacrificial victims from Huaca de la Luna Plaza 3C (AD 300–550) with eight previously reported samples from the north coast of Peru using both the mean measure of divergence (MMD) and Mahalanobis' distance (d2). Hypothetical matrices are developed based upon the assumptions of each of the two competing models regarding the origins of Moche sacrificial victims. When the MMD matrix is compared to the two hypothetical matrices using a partial‐Mantel test (Smouse et al.: Syst Zool 35 (1986) 627–632), the ritual combat model (i.e. local origins) has a low and nonsignificant correlation (r = 0.134, P = 0.163), while the nonlocal origins model is highly correlated and significant (r = 0.688, P = 0.001). Comparisons of the d2 results and the two hypothetical matrices also produced low and nonsignificant correlation for the ritual combat model (r = 0.210, P = 0.212), while producing a higher and statistically significant result with the nonlocal origins model (r = 0.676, P = 0.002). We suggest that the Moche sacrificial victims represent nonlocal warriors captured in territorial combat with nearby competing polities. Am J Phys Anthropol, 2007. © 2006 Wiley‐Liss, Inc.
Hormones and body size evolution in papionin primates
Authors: Bernstein Robin M. , Leigh Steven R. , Donovan Sharon M. , Monaco Marcia H.
Published: November 2006

This study examines the evolution of size differences among papionin primates by measuring hormones that regulate size growth during ontogeny and influence ultimate adult size (insulin‐like growth factor‐I (IGF‐I), insulin‐like growth factor binding protein‐3 (IGFBP‐3), growth hormone binding protein (GHBP), dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol). The analyses assess longstanding ideas about circulating hormone levels and body size. Importantly, because the consensus papionin molecular phylogeny implies at least two episodes of size increase, this study offers opportunities to determine whether or not similar hormone profiles regulate this apparent evolutionary convergence (i.e., do larger‐bodied papionins have higher levels of growth‐related hormones than smaller‐bodied papionins?). Five hundred and sixty serum samples (from 161 individuals) from 11 papionin species were analyzed using a two‐level approach to address this issue. One used mixed longitudinal samples from two papionin species to test whether, during growth, large‐ and small‐bodied species have higher and lower hormone levels, respectively. The second compared multiple papionin species to assess whether or not hormone levels covary with size in adult animals. Result show that size and hormone levels do not covary consistently across papionins, either during growth or in adulthood. Specifically, some smaller‐bodied papionin species have higher absolute hormone levels than larger‐bodied species. Differences in some hormone levels appear to track phylogeny more closely than body size. In contrast to studies based on single species, we demonstrate that, while the hormones analyzed affect growth, absolute circulating hormone levels either during growth or adulthood may be decoupled from interspecific differences in body size. Am J Phys Anthropol, 2007. © 2006 Wiley‐Liss, Inc.
Rheological behavior of hydrophilic silica dispersion in polyethylene glycol
Authors: Park Jong‐Hwan , Kim Ho‐gyum , Han Dong‐Hee , Lim Jeong‐Cheol , Oh Dae‐Hee , Min Kyung‐Eun
Published: November 2006

The rheological properties of hydrophilic fumed silica dispersed in polyethylene glycol (PEG) were investigated. The dispersion was prepared by dispersing the fumed silica in PEG with various concentrations. The reversible sol–gel transition was observed over 5 wt % of silica concentration as a function of temperature. The gelation temperature was found to depend on the applied shear stress and silica concentration, and the high shear stress was found to lead to the decrease of sol–gel transition temperature of the dispersion with the same silica concentration. As the silica concentration increases, the sol–gel transition shifts to the lower temperature. © 2006 Wiley Periodicals, Inc. J Apple Polly Sci 103: 2481–2486, 2007