bluuebunny/crossref_metadata_2025_split huggingface dataset:
HES-1 Is Involved in Adaptation of Adult Human β-Cells to Proliferation In Vitro
Authors: Bar Yael , Russ Holger A. , Knoller Sarah , Ouziel-Yahalom Limor , Efrat Shimon 
Published: July 2008

OBJECTIVE—In vitro expansion of β-cells from adult human islets could solve the tissue shortage for cell replacement therapy of diabetes. Culture of human islet cells typically results in &lt;16 cell doublings and loss of insulin expression. Using cell lineage tracing, we demonstrated that the expanded cell population included cells derived from β-cells. Understanding the molecular mechanisms involved in β-cell fate in vitro is crucial for optimizing expansion and redifferentiation of these cells. In the developing pancreas, important cell-fate decisions are regulated by NOTCH receptors, which signal through the hairy and enhancer of split (HES)-1 transcriptional regulator. Here, we investigated the role of the NOTCH signaling pathway in β-cell dedifferentiation and proliferation in vitro.
RESEARCH DESIGN AND METHODS—Isolated human islets were dissociated into single cells. β-Cells were genetically labeled using a Cre-lox system delivered by lentiviruses. Cells were analyzed for changes in expression of components of the NOTCH pathway during the initial weeks in culture. HES-1 expression was inhibited by a small hairpin RNA (shRNA), and the effects on β-cell phenotype were analyzed.
RESULTS—Human β-cell dedifferentiation and entrance into the cell cycle in vitro correlated with activation of the NOTCH pathway and downregulation of the cell cycle inhibitor p57. Inhibition of HES-1 expression using shRNA resulted in significantly reduced β-cell replication and dedifferentiation.
CONCLUSIONS—These findings demonstrate that the NOTCH pathway is involved in determining β-cell fate in vitro and suggest possible molecular targets for induction of β-cell redifferentiation following in vitro expansion.
Mechanism of Oxidative DNA Damage in Diabetes
Authors: Simone Simona , Gorin Yves , Velagapudi Chakradhar , Abboud Hanna E. , Habib Samy L. 
Published: July 2008

OBJECTIVE—To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells.
RESEARCH DESIGN AND METHODS—Phosphorylation of Akt and tuberin, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose.
RESULTS—In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/Akt significantly reduced high glucose–induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant N-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression.
CONCLUSIONS—Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress–mediated DNA damage in diabetes.
Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins
Authors: Kawahara Shuhei , Hata Yasuaki , Kita Takeshi , Arita Ryoichi , Miura Muneki , Nakao Shintaro , Mochizuki Yasutaka , Enaida Hiroshi , Kagimoto Tadahisa , Goto Yoshinobu , Hafezi-Moghadam Ali , Ishibashi Tatsuro 
Published: July 2008

OBJECTIVE—Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.
RESEARCH DESIGN AND METHODS—Human vitreous concentrations of transforming growth factor-β2 (TGF-β2) were measured by enzyme-linked immunosorbent assay. TGF-β2–and vitreous-dependent phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase pathway, and collagen gel contraction simulating cicatrical contraction were analyzed using cultured hyalocytes. Inhibitory effects of simvastatin on cicatrical contraction were assessed both in vitro and in vivo.
RESULTS—Human vitreous concentrations of TGF-β2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-β2–dependent MLC phosphorylation and gel contraction in a dose- and time-dependent manner and was capable of inhibiting translocation of Rho protein to the plasma membrane in the presence of TGF-β2. Vitreous samples from patients with PVD enhanced MLC phosphorylation and gel contraction, whereas simvastatin almost completely inhibited these phenomena. Finally, intravitreal injection of simvastatin dose-dependently prevented the progression of diseased states in an in vivo model of PVR.
CONCLUSIONS—Statins might have therapeutic potential in the prevention of PVDs.
Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype
Authors: Asleh Rabea , Blum Shany , Kalet-Litman Shiri , Alshiek Jonia , Miller-Lotan Rachel , Asaf Roy , Rock Wasseem , Aviram Michael , Milman Uzi , Shapira Chen , Abassi Zaid , Levy Andrew P. 
Published: July 2008

OBJECTIVE—Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.
RESEARCH DESIGN AND METHODS—Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters.
RESULTS—Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.
CONCLUSIONS—Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.
Ser1369Ala Variant in Sulfonylurea Receptor Gene ABCC8 Is Associated With Antidiabetic Efficacy of Gliclazide in Chinese Type 2 Diabetic Patients
Authors: Feng Yan , Mao Guangyun , Ren Xiaowei , Xing Houxun , Tang Genfu , Li Qiang , Li Xueqi , Sun Lirong , Yang Jinqui , Ma Weiqing , Wang Xiaobin , Xu Xiping 
Published: July 2008

OBJECTIVE—The purpose of this study was to investigate whether genetic variants could influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients.
RESEARCH DESIGN AND METHODS—A total of 1,268 type 2 diabetic patients whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic treatment were enrolled from 23 hospitals in China. All of the patients were treated with gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, fasting insulin, and A1C were measured at baseline and after 8 weeks of treatment. We used two independent cohorts to test the associations of 25 single nuclear polymorphisms in 11 candidate genes with the antidiabetic efficacy of gliclazide. A general linear regression model was used to test the association with adjustment for important covariates.
RESULTS—After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was reduced from 11.1 mmol/l at baseline to 7.7 mmol/l. In cohort 1, we genotyped all 25 SNPs (n = 661) and found that Ser1369Ala of the ABCC8 gene and rs5210 of the KCNJ11 gene were significantly associated with decreases in FPG (P = 0.002). We further genotyped Ser1369Ala in cohort 2 (n = 607) and confirmed the association identified in cohort 1. In the pooled analysis, compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a 7.7% greater decrease in FPG (P &lt; 0.001), an 11.9% greater decrease in 2-h plasma glucose (P = 0.003), and a 3.5% greater decrease in A1C (P = 0.06) after 8 weeks of treatment with gliclazide.
CONCLUSIONS—In two independent cohorts of Chinese type 2 diabetic patients, we found consistent evidence that the Ser1369Ala variant in the ABCC8 gene can influence the antidiabetic efficacy of gliclazide.
A1C but Not Serum Glycated Albumin Is Elevated in Late Pregnancy Owing to Iron Deficiency
Authors: Hashimoto Kunihiko , Noguchi Sanai , Morimoto Yasuhiko , Hamada Shinichi , Wasada Kenshi , Imai Shiro , Murata Yuji , Kasayama Soji , Koga Masafumi 
Published: July 2008

OBJECTIVE—A1C levels have been shown to be elevated in relation to glycemia in late pregnancy, although the precise mechanisms remain undetermined. We hypothesized that iron deficiency is involved in the A1C increase in late pregnancy.
RESEARCH DESIGN AND METHODS—In study 1, A1C, serum glycated albumin, erythrocyte indexes, and iron metabolism indexes were determined in 47 nondiabetic pregnant women not receiving iron supplementation who were divided into four groups according to gestational period (group I, 21–24 weeks; group II, 25–28 weeks; group III, 29–32 weeks; and group IV, 33–36 weeks). In study 2, these determinants were obtained at two gestational periods (20–23 weeks and 32–33 weeks) in 17 nondiabetic pregnant women.
RESULTS—In study 1, A1C levels were higher in groups III and IV than those in groups I and II, whereas serum glycated albumin levels were not different among these four groups. Hemoglobin, mean corpuscular hemoglobin (MCH), serum transferrin saturation, and serum ferritin were lower in groups III and IV. A1C levels were negatively correlated with MCH, serum transferrin saturation, and serum ferritin. In study 2, A1C levels were significantly increased at gestational weeks 32–33 from those at weeks 20–23, whereas serum glycated albumin levels did not differ between the two gestational periods. MCH, serum transferrin saturation, and serum ferritin were decreased at gestational weeks 32–33. A1C levels showed a negative correlation with MCH, serum transferrin saturation, and serum ferritin.
CONCLUSIONS—A1C levels were elevated in late pregnancy owing to iron deficiency. Serum glycated albumin may offer a better index for monitoring glycemic control in pregnancy.
Prospective Cohort Study of Type 2 Diabetes and the Risk of Parkinson's Disease
Authors: Driver Jane A. , Smith Ashley , Buring Julie E. , Gaziano J. Michael , Kurth Tobias , Logroscino Giancarlo 
Published: July 2008

OBJECTIVE—To evaluate the association between type 2 diabetes and newly reported Parkinson's disease.
RESEARCH DESIGN AND METHODS—Our study included 21,841 participants in the Physicians’ Health Study, a cohort of U.S. male physicians. Diabetes and Parkinson's disease were self-reported via questionnaire. We used time-varying Cox regression to calculate adjusted relative risk (RR) for Parkinson's disease.
RESULTS—Over 23 years, 556 individuals with Parkinson's disease were identified. Subjects with diabetes had an increased Parkinson's disease risk (multivariable-adjusted RR 1.34 [95% CI 1.01–1.77]). The association remained significant after exclusion of those with known vascular disease. The diagnosis of diabetes was clustered around the diagnosis of Parkinson's disease and was more apparent among men with short diabetes duration and those without complications from diabetes.
CONCLUSIONS—Results of this large prospective study in men do not suggest that diabetes is a preceding risk factor for Parkinson's disease. Whether the positive association may be explained by ascertainment bias or a common underlying biological mechanism remains to be established.
Theory-Based Programme Development and Evaluation in Physiotherapy
Authors: Huijbregts Maria P.J. , Kay Theresa , Klinck Beth 
Published: July 2008

Purpose: Programme evaluation has been defined as “the systematic process of collecting credible information for timely decision making about a particular program.” Where possible, findings are used to develop, revise, and improve programmes. Theory-based programme development and evaluation provides a comprehensive approach to programme evaluation.Summary of key points: In order to obtain meaningful information from evaluation activities, relevant programme components need to be understood. Theory-based programme development and evaluation starts with a comprehensive description of the programme. A useful tool to describe a programme is the Sidani and Braden Model of Program Theory, consisting of six programme components: problem definition, critical inputs, mediating factors, expected outcomes, extraneous factors, and implementation issues. Articulation of these key components may guide physiotherapy programme implementation and delivery and assist in the development of key evaluation questions and methodologies. Using this approach leads to a better understanding of client needs, programme processes, and programme outcomes and can help to identify barriers to and enablers of successful implementation. Two specific examples, representing public and private sectors, will illustrate the application of this approach to clinical practice.Conclusions: Theory-based programme development helps clinicians, administrators, and researchers develop an understanding of who benefits the most from which types of programmes and facilitates the implementation of processes to improve programmes.
Spinal hydatidosis accompanied by a secondary infection
Authors: Kotil Kadir , Tatar Zeynep , Bilge Turgay 
Published: July 2008

✓Spinal hydatid disease is rarely encountered in nonendemic regions. It is a progressive disease that is associated with risks of serious morbidity. The authors report a case of an isolated primary hydatid cyst of the spine in a 34-year-old woman who presented with back pain, which had lasted for 3 months, as well as lower-extremity pain and fatigue, which had persisted for 2 months. A neurological examination yielded findings indicative of upper motor neuron involvement with complete sensory loss below the level of T-11. Magnetic resonance imaging of the spine showed multiple extradural cystic lesions with an abscess formation at T-11 and involvement of the paraspinal muscles. The patient underwent spinal decompression in which stabilization and total excision of the multiple epidural and psoas abscesses and paraspinal multiloculated cysts were performed. The diagnosis of hydatid disease associated with another infection was confirmed by histopathological evaluation. Albendazole was administered during the postoperative period.Previous reports of secondary infections accompanying this disease in extraspinal locations have been published. However, to the best of the authors' knowledge, there have been no publications about a secondary infection associated with hydatidosis in the spinal cord. One should bear in mind that spinal hydatidosis may be accompanied by other infections in endemic regions. Antihelminthic treatment should be administered for a long period following early decompressive surgery and adequate stabilization.
Diurnal fluctuations in borehole water levels: configuration of the drainage system beneath Bench Glacier, Alaska, USA
Authors: Fudge T.J. , Humphrey Neil F. , Harper Joel T. , Tad Pfeffer W. 
Published: July 2008

AbstractWater levels were measured in boreholes spaced along the entire length of Bench Glacier, Alaska, USA, for a period in excess of 2 years. Instrumented boreholes were arranged as nine pairs along the center line of the glacier and an orthogonal grid of 16 boreholes in a 3600 m2 region at the center of the ablation area. Diurnal fluctuations of the water levels were found to be restricted to the late melt season. Pairs of boreholes spaced along the length of the ablation area often exhibited similar fluctuations and diurnal changes in water levels. Three distinct and independent types of diurnal fluctuations in water level were observed in clusters of boreholes within the grid of boreholes. Head gradients suggest water did not flow between clusters, and a single tunnel connecting the boreholes could not explain the observed pattern of diurnal water-level fluctuations. Inter-borehole and borehole-cluster connectivity suggests the cross-glacier width of influence of a segment of the drainage system connected to a borehole was limited to tens of meters. A drainage configuration whereby boreholes are connected to a somewhat distant tunnel by drainage pipes of differing lengths, often hundreds of meters, is shown with a numerical test to be a plausible explanation for the observed borehole behavior.
Snow accumulation rate on Qomolangma (Mount Everest), Himalaya: synchroneity with sites across the Tibetan Plateau on 50–100 year timescales
Authors: Kaspari Susan , Hooke Roger LeB. , Mayewski Paul Andrew , Kang Shichang , Hou Shugui , Qin Dahe 
Published: July 2008

AbstractAnnual-layer thickness data, spanning AD 1534–2001, from an ice core from East Rongbuk Col on Qomolangma (Mount Everest, Himalaya) yield an age–depth profile that deviates systematically from a constant accumulation-rate analytical model. The profile clearly shows that the mean accumulation rate has changed every 50–100 years. A numerical model was developed to determine the magnitude of these multi-decadal-scale rates. The model was used to obtain a time series of annual accumulation. The mean annual accumulation rate decreased from ∼0.8 m ice equivalent in the 1500s to ∼0.3 m in the mid-1800s. From ∼1880 to ∼1970 the rate increased. However, it has decreased since ∼1970. Comparison with six other records from the Himalaya and the Tibetan Plateau shows that the changes in accumulation in East Rongbuk Col are broadly consistent with a regional pattern over much of the Plateau. This suggests that there may be an overarching mechanism controlling precipitation and mass balance over this area. However, a record from Dasuopu, only 125 km northwest of Qomolangma and 700 m higher than East Rongbuk Col, shows a maximum in accumulation during the 1800s, a time during which the East Rongbuk Col and Tibetan Plateau ice-core and tree-ring records show a minimum. This asynchroneity may be due to altitudinal or seasonal differences in monsoon versus westerly moisture sources or complex mountain meteorology.
A novel method for obtaining very large ancient air samples from ablating glacial ice for analyses of methane radiocarbon
Authors: Petrenko Vasilii V. , Severinghaus Jeffrey P. , Brook Edward J. , Mühle Jens , Headly Melissa , Harth Christina M. , Schaefer Hinrich , Reeh Niels , Weiss Ray F. , Lowe Dave , Smith Andrew M. 
Published: July 2008

AbstractWe present techniques for obtaining large (∼100 L STP) samples of ancient air for analysis of 14C of methane (14CH4)and other trace constituents. Paleoatmospheric 14CH4 measurements should constrain the fossil fraction of past methane budgets, as well as provide a definitive test of methane clathrate involvement in large and rapid methane concentration ([CH4]) increases that accompanied rapid warming events during the last deglaciation. Air dating to the Younger Dryas–Preboreal and Oldest Dryas–Bølling abrupt climatic transitions was obtained by melt extraction from old glacial ice outcropping at an ablation margin in West Greenland. The outcropping ice and occluded air were dated using a combination of δ15N of N2, δ18O of O2, δ18Oice and [CH4] measurements. The [CH4] blank of the melt extractions was <4 ppb. Measurements of δ18O and δ15N indicated no significant gas isotopic fractionation from handling. Measured Ar/N2, CFC-11 and CFC-12 in the samples indicated no significant contamination from ambient air. Ar/N2, Kr/Ar and Xe/Ar ratios in the samples were used to quantify effects of gas dissolution during the melt extractions and correct the sample [CH4]. Corrected [CH4] is elevated over expected values by up to 132 ppb for most samples, suggesting some in situ CH4 production in ice at this site.
Termination V in the Vostok (Antarctica) ice core
Authors: Suwa Makoto 
Published: July 2008

AbstractThe age–depth relationship of the Vostok (Antarctica) ice core has been reconstructed in the depth interval 3300–3347 m, by comparing three gas properties in ice (CO2, CH4 and δ18Oatm) with those in the EPICA Dome C (Antarctica) core. Fourteen Vostok depths were examined in this interval, and it was found that nine samples are uniquely dated if candidate ages are restricted to the interval between 400 and 650 kyr. One of these samples is uniquely dated without restriction. The analysis supports previous reports that this section contains ice from Termination V, but that the stratigraphic order of ice is reversed. The top of the overturned layer lies between 3316 and 3319 m. At least one other stratigraphic disturbance was found between 3340 and 3343 m, as indicated by another reversal of the age–depth relationship. Finally, the oldest ice in this section is dated at ≥440 kyr, confirming the existence of ice from the cold marine isotope stage (MIS) 12 interval.