bluuebunny/crossref_metadata_2025 huggingface dataset:
3‐D GROWTH PATTERNS OF TREES: EFFECTS OF CARBON ECONOMY, MERISTEM ACTIVITY, AND SELECTION
Authors: Sterck Frank J. , Schieving Feike
Published: July 2007

A functional–structural plant growth model was used to explore how selection might influence the ontogenetic patterns in three‐dimensional (3‐D) growth of trees. The 3‐D plant structure is defined by the orientation of metamers. The dynamics in the 3‐D plant structure depend on the production of metamers and/or leaf pipes and the loss of such plant components. In the simulations, metamer and leaf‐pipe traits were kept constant, so all ontogenetic changes depended on the spatial arrangement of metamers and/or leaf pipes. This study explores the consequences of three new assumptions for ontogenetic changes in 3‐D plant structure: (1) meristems are produced at the positions where branches fall, thus enabling a tree to maintain a viable meristem population within the crown; (2) metamers are placed at meristem positions in the 3‐D structure where the carbon benefit over the expected life span of a leaf pipe is maximized; (3) the carbon allocation to reproduction maximizes the long‐term reproductive output. In combination with the constraints set by the morphology of metamer and leaf pipe, the carbon economy, and light conditions, these assumptions explain how selection may cause a sigmoid expansion phase and a stable steady‐state phase; adaptive responses in 3‐D structure during ontogeny; limits to tree size (including height); constant allometric scaling during the expansion phase; different scaling for trees in different light environments; and responses in optimal reproductive allocation to forest light environments. These results support the idea that selection for maximizing the net carbon gain determines how trees change in 3‐D tree structure during ontogeny and, at the same time, how they acclimate in 3‐D structure in response to light gradients.
ONGOING ADAPTATION TO MEDITERRANEAN CLIMATE EXTREMES IN A CHEMICALLY POLYMORPHIC PLANT
Authors: Thompson John D. , Gauthier Perrine , Amiot Justin , Ehlers Bodil K. , Collin Christian , Fossat Julia , Barrios Violeta , Arnaud-Miramont François , Keefover-Ring Ken , Linhart Yan B.
Published: July 2007

Although extreme climatic events may have profound effects on ecological systems, there is a marked lack of information on adaptation to such events. In this study, we employed reciprocal transplantation on both a geographic scale (experimental sites 200 km apart in different parts of the range of the study species) and a local landscape scale (reciprocal populations separated by 2–8 km) to study the performance of different chemical forms of Thymus vulgaris which naturally occur in different climatic environments. Survival and growth were analyzed in relation to long‐term and contemporary climate data in natural populations and our experimental sites. The reciprocal transplants involved a period of six years for clones transplanted in experimental field sites on a geographic scale and three years for seedlings transplanted among natural populations at the local landscape level. Cloned transplants on a geographic scale produced evidence for local adaptation to either summer drought, primarily following the extreme summer drought of 2003, or severe early‐winter freezing. Chemotypes that show high survival after intense summer drought showed poor survival after intense early‐winter freezing and vice versa, results which directly accord with climate data for their original sites. On the local landscape scale, we found further evidence for local adaptation to summer drought but not to winter freezing (probably due to the absence of extreme freezing during the three years of this study). Future modifications to the occurrence and frequency of extreme climate events may have a profound influence on the spatial distribution of thyme chemotypes.
Transfusion of Apoptotic β-Cells Induces Immune Tolerance to β-Cell Antigens and Prevents Type 1 Diabetes in NOD Mice
Authors: Xia Chang-Qing , Peng Ruihua , Qiu Yushi , Annamalai Mani , Gordon David , Clare-Salzler Michael J.
Published: July 2007

In vivo induction of β-cell apoptosis has been demonstrated to be effective in preventing type 1 diabetes in NOD mice. Based on the notion that steady-state cell apoptosis is associated with self-tolerance and the need for developing a more practical approach using apoptotic β-cells to prevent type 1 diabetes, the current study was designed to investigate apoptotic β-cells induced ex vivo in preventing type 1 diabetes. The NIT-1 cell line serves as a source of β-cells. Apoptotic NIT-1 cells were prepared by ultraviolet B (UVB) irradiation. Three weekly transfusions of UVB-irradiated NIT-1 cells (1 × 105/mouse) or PBS were used to determine whether transfusions of UVB-irradiated NIT-1 cells induce immune tolerance to β-cell antigens in vivo and prevent type 1 diabetes. The suppression of anti–β-cell antibodies, polarization of T-helper (Th) cells, and induction of regulatory T-cells by UVB-irradiated NIT-1 cell treatment were investigated. The transfusions of apoptotic NIT-1 cells suppress anti–β-cell antibody development and induce Th2 responses and interleukin-10–producing regulatory type 1 cells. Importantly, this treatment significantly delays and prevents the onset of diabetes when 10-week-old NOD mice are treated. Adoptive transfer of splenocytes from UVB-irradiated NIT-1 cell–treated mice prevents diabetes caused by simultaneously injected diabetogenic splenocytes in NOD-Rag−/− mice. Moreover, the proliferation of adoptively transferred carboxyfluorescein diacetate succinimidyl ester–labeled β-cell antigen–specific T-cell receptor–transgenic T-cells in UVB-irradiated NIT-1–cell treated mice is markedly suppressed. The transfusion of apoptotic β-cells effectively protects against type 1 diabetes in NOD mice by inducing immune tolerance to β-cell antigens. This approach has great potential for immune intervention for human type 1 diabetes.
Association of the Estrogen Receptor-α Gene With the Metabolic Syndrome and Its Component Traits in African-American Families
Authors: Gallagher Carla J. , Langefeld Carl D. , Gordon Candace J. , Campbell Joel K. , Mychalecky Josyf C. , Bryer-Ash Michael , Rich Stephen S. , Bowden Donald W. , Sale Michèle M.
Published: July 2007

OBJECTIVE— We previously detected an association between a region of the estrogen receptor-α (ESR1) gene and type 2 diabetes in an African-American case-control study; thus, we investigated this region for associations with the metabolic syndrome and its component traits in African-American families from the Insulin Resistance Atherosclerosis Family Study.

RESEARCH DESIGN AND METHODS— A total of 17 single nucleotide polymorphisms (SNPs) from a contiguous 41-kb intron 1–intron 2 region of the ESR1 gene were genotyped in 548 individuals from 42 African-American pedigrees. Generalized estimating equations were computed using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation.

RESULTS— Significant associations were detected between ESR1 SNPs and the metabolic syndrome (P = 0.005 to P = 0.029), type 2 diabetes (P = 0.001), insulin sensitivity (P = 0.0005 to P = 0.023), fasting insulin (P = 0.022 to P = 0.033), triglycerides (P = 0.021), LDL (P = 0.016 to P = 0.034), cholesterol (P = 0.046), BMI (P = 0.016 to P = 0.035), waist circumference (P = 0.012 to P = 0.023), and subcutaneous adipose tissue area (P = 0.016).

CONCLUSIONS— It appears likely that ESR1 contributes to type 2 diabetes and CVD risk via pleiotropic effects, leading to insulin resistance, a poor lipid profile, and obesity.
Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice
Authors: Cha Dae Ryong , Zhang Xiaoyan , Zhang Yahua , Wu Jing , Su Dongming , Han Jee Young , Fang Xuefen , Yu Bo , Breyer Matthew D. , Guan Youfei
Published: July 2007

Peroxisome proliferator–activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPARα and -γ are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPARα/γ dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-β1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPARα and -γ were expressed, tesaglitazar treatment abolished high glucose–induced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treatment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPARα/γ agonists in treating type 2 diabetes and diabetic nephropathy.
Inhibition of Autoimmune Diabetes by Oral Administration of Anti-CD3 Monoclonal Antibody
Authors: Ishikawa Hiroki , Ochi Hirofumi , Chen Mei-Ling , Frenkel Dan , Maron Ruth , Weiner Howard L.
Published: July 2007

Anti-CD3 monoclonal antibody (mAb) has been shown to induce tolerance and to be an effective treatment for diabetes both in animal models and in human trials. We have shown that anti-CD3 mAb given orally is biologically active in the gut and suppresses experimental autoimmune encephalitis by the induction of a regulatory T-cell that expresses latency-associated peptide (LAP) on its surface. In the present study, we investigated the effect of oral anti-CD3 mAb on the prevention of autoimmune diabetes in AKR mice in which the low-dose streptozocin (STZ) model induces autoimmunity to the β-cells of the islets. We found that oral anti-CD3 mAb given at doses of 50 and 250 μg/feeding suppressed the incidence of diabetes in this model with the best effects seen at the 50 μg/dose. Associated with suppression, we observed decreased cell proliferation in the spleen and conversion of T-helper (Th)1 responses into Th2/Th3 responses in the periphery, including the pancreatic lymph nodes. Oral anti-CD3 mAb increased the expression of LAP on CD4+ T-cells, and these cells could adoptively transfer protection. Protection by oral anti-CD3 was transforming growth factor-β dependent. Our results demonstrate that oral anti-CD3 is effective in the model of STZ-induced diabetes and may be a useful form of therapy for type 1 diabetes in humans.
Effects of Endurance Exercise Training on Insulin Signaling in Human Skeletal Muscle
Authors: Frøsig Christian , Rose Adam J. , Treebak Jonas T. , Kiens Bente , Richter Erik A. , Wojtaszewski Jørgen F.P.
Published: July 2007

The purpose of this study was to investigate the mechanisms explaining improved insulin-stimulated glucose uptake after exercise training in human skeletal muscle. Eight healthy men performed 3 weeks of one-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was ∼60% higher (P < 0.01) in the trained compared with the untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies were obtained before and after training as well as after 10 and 120 min of insulin stimulation in both legs. Protein content of Akt1/2 (55 ± 17%, P < 0.05), AS160 (25 ± 8%, P = 0.08), GLUT4 (52 ± 19%, P < 0.001), hexokinase 2 (HK2) (197 ± 40%, P < 0.001), and insulin-responsive aminopeptidase (65 ± 15%, P < 0.001) increased in muscle in response to training. During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)–associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P < 0.005), and glycogen synthase (GS) (percent I-form, P < 0.05) increased similarly in both trained and untrained muscle, consistent with increased phosphorylation of Akt Thr308, Akt Ser473, AS160, glycogen synthase kinase (GSK)-3α Ser21, and GSK-3β Ser9 and decreased phosphorylation of GS site 3a+b (all P < 0.005). Interestingly, training improved insulin action on thigh blood flow, and, furthermore, in both basal and insulin-stimulated muscle tissue, activities of Akt1 and GS and phosphorylation of AS160 increased with training (all P < 0.05). In contrast, training reduced IRS-1–associated PI3-K activity (P < 0.05) in both basal and insulin-stimulated muscle tissue. Our findings do not support generally improved insulin signaling after endurance training; rather it seems that improved insulin-stimulated glucose uptake may result from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism.
Progression to Type 2 Diabetes Characterized by Moderate Then Rapid Glucose Increases
Authors: Mason Clinton C. , Hanson Robert L. , Knowler William C.
Published: July 2007

OBJECTIVE—The transition of an individual from normoglycemia to diabetes has generally been thought to involve either moderate or rapid changes in glucose over time, although few studies have analyzed these changes. We sought to determine whether a general pattern of glucose change exists in most individuals who become diabetic.

RESEARCH DESIGN AND METHODS—We examined longitudinal data from Pima Indians who developed diabetes after several biennial examinations to characterize changes in 2-h plasma glucose. A distinct pattern of glucose change was apparent in the time course of most individuals, an initial linear trend followed by a steeper rise in glucose values. A model consisting of additive linear and exponential functions was hypothesized to account for this pattern and was tested for goodness of fit on 55 individuals who became diabetic after at least 10 previous examinations.

RESULTS—The combined linear and exponential model provided a significantly better fit than linear or exponential models alone in 40 of the 55 cases (P < 10−38). Using this model, the timeframe over which glucose values rose suddenly was estimated, having a median time to onset of <4.5 years from the time at which the exponential effect had contributed a modest increase of 10 mg/dl to the initial linear trend.

CONCLUSIONS—We conclude that there are two distinct processes affecting glucose levels in most individuals who progress to type 2 diabetes and that the rapid glucose rise identified in these people may be an important period for physiologic and preventive research.
Reduced Incretin Effect in Type 2 Diabetes
Authors: Knop Filip K. , Vilsbøll Tina , Højberg Patricia V. , Larsen Steen , Madsbad Sten , Vølund Aage , Holst Jens J. , Krarup Thure
Published: July 2007

We aimed to investigate whether the reduced incretin effect observed in patients with type 2 diabetes is a primary event in the pathogenesis of type 2 diabetes or a consequence of the diabetic state. Eight patients with chronic pancreatitis and secondary diabetes (A1C mean [range] of 6.9% [6.2–8.0]), eight patients with chronic pancreatitis and normal glucose tolerance (NGT; 5.3 [4.9–5.7]), eight patients with type 2 diabetes (6.9 [6.2–8.0]); and eight healthy subjects (5.5 [5.1–5.8]) were studied. Blood was sampled over 4 h on 2 separate days after a 50-g oral glucose load and an isoglycemic intravenous glucose infusion, respectively. The incretin effect (100% × [β-cell secretory response to oral glucose tolerance test − intravenous β-cell secretory response]/β-cell secretory response to oral glucose tolerance test) was significantly (P < 0.05) reduced (means ± SE) in patients with chronic pancreatitis and secondary diabetes (31 ± 4%) compared with patients with chronic pancreatitis and NGT (68 ± 3) and healthy subjects (60 ± 4), respectively. In the type 2 diabetes group, the incretin effect amounted to 36 ± 6%, significantly (P < 0.05) lower than in chronic pancreatitis patients with NGT and in healthy subjects, respectively. These results suggest that the reduced incretin effect is not a primary event in the development of type 2 diabetes, but rather a consequence of the diabetic state.
Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy
Authors: Lindegaard Birgitte , Frøsig Christian , Petersen Anne Marie W. , Plomgaard Peter , Ditlevsen Susanne , Mittendorfer Bettina , Van Hall Gerrit , Wojtaszewski Jørgen F.P. , Pedersen Bente K.
Published: July 2007

HIV-infected patients with lipodystrophy (HIV lipodystrophy) are insulin resistant and have elevated plasma free fatty acid (FFA) concentrations. We aimed to explore the mechanisms underlying FFA-induced insulin resistance in patients with HIV lipodystrophy. Using a randomized, placebo-controlled, cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFAs on glucose and FFA metabolism by using stable isotope–labeled tracer techniques during basal conditions and a two-stage euglycemic-hyperinsulinemic clamp (20 and 50 mU insulin/m2 per min, respectively) in nine patients with nondiabetic HIV lipodystrophy. All patients received antiretroviral therapy. Biopsies from the vastus lateralis muscle were obtained during each stage of the clamp. Acipimox treatment reduced basal FFA rate of appearance by 68.9% (95% CI 52.6–79.5) and decreased plasma FFA concentration by 51.6% (42.0–58.9) (both, P < 0.0001). Endogenous glucose production was not influenced by acipimox. During the clamp, the increase in glucose uptake was significantly greater after acipimox treatment compared with placebo (acipimox: 26.85 μmol · kg−1 · min−1 [18.09–39.86] vs. placebo: 20.30 μmol · kg−1 · min−1 [13.67–30.13]; P < 0.01). Insulin increased phosphorylation of Akt Thr308 and glycogen synthase kinase-3β Ser9, decreased phosphorylation of glycogen synthase (GS) site 3a + b, and increased GS activity (percent I-form) in skeletal muscle (P < 0.01). Acipimox decreased phosphorylation of GS (site 3a + b) (P < 0.02) and increased GS activity (P < 0.01) in muscle. The present study provides direct evidence that suppression of lipolysis in patients with HIV lipodystrophy improves insulin-stimulated peripheral glucose uptake. The increased glucose uptake may in part be explained by increased dephosphorylation of GS (site 3a + b), resulting in increased GS activity.
Selective Downregulation of the High–Molecular Weight Form of Adiponectin in Hyperinsulinemia and in Type 2 Diabetes
Authors: Basu Rita , Pajvani Utpal B. , Rizza Robert A. , Scherer Philipp E.
Published: July 2007

OBJECTIVE—Adiponectin is an adipocyte-specific secretory protein found in circulation in several different forms and is present at significantly lower levels in the plasma of diabetic patients compared with that of insulin-sensitive individuals. We wanted to test whether insulin per se is a contributing factor toward lower plasma adiponectin concentrations and, if so, whether the splanchnic bed contributes to this phenomenon.

RESEARCH DESIGN AND METHODS—We sampled femoral artery and hepatic venous samples and measured the high–molecular weight (HMW) and low–molecular weight (LMW) fractions of adiponectin in 11 type 2 diabetic and 7 nondiabetic subjects matched for age, sex, and BMI during basal conditions and during a hyperglycemic (∼9.5 mmol/l) hyperinsulinemic (∼700 pmol/l) clamp.

RESULTS—Under these conditions, total arterial adiponectin, HMW, and the ratio of HMW to total adiponectin all were lower (P < 0.01) in the diabetic versus nondiabetic subjects, whereas the LMW form did not significantly differ. Under hyperinsulinemic conditions, total adiponectin levels dropped, primarily due to a reduction of the HMW form, whereas LMW forms were not significantly affected.

CONCLUSIONS—HMW adiponectin and the ratio of HMW to total adiponectin are lower in individuals with diabetes than in nondiabetic subjects. We conclude that HMW adiponectin is downregulated in hyperinsulinemia and type 2 diabetes.
High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes
Authors: Huang Chang-jiang , Lin Chia-yu , Haataja Leena , Gurlo Tatyana , Butler Alexandra E. , Rizza Robert A. , Butler Peter C.
Published: July 2007

OBJECTIVE—Endoplasmic reticulum (ER) stress–induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased β-cell apoptosis. We questioned the following: 1) whether IAPP-induced β-cell apoptosis is mediated by ER stress and 2) whether β-cells in type 2 diabetes are characterized by ER stress.

RESEARCH DESIGN AND METHODS—The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IAPP (HIP) transgenic rats. ER stress in humans was investigated by β-cell C/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes.

RESULTS—IAPP induces β-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 ± 2.0%) and more frequent in obese nondiabetic (14.6 ± 3.0%) and obese diabetic (18.5 ± 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 ± 0.04%) but six times higher (P < 0.01) in obese diabetic (0.49 ± 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 ± 2.3%) and nuclear CHOP not detected.

CONCLUSIONS—ER stress is a mechanism by which IAPP induces β-cell apoptosis and is characteristic of β-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in β-cell apoptosis in type 2 diabetes.
Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy
Authors: Quattrini Cristian , Tavakoli Mitra , Jeziorska Maria , Kallinikos Panagiotis , Tesfaye Solomon , Finnigan Joanne , Marshall Andrew , Boulton Andrew J.M. , Efron Nathan , Malik Rayaz A.
Published: July 2007

Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy.
Islet Surface Heparinization Prevents the Instant Blood-Mediated Inflammatory Reaction in Islet Transplantation
Authors: Cabric Sanja , Sanchez Javier , Lundgren Torbjörn , Foss Aksel , Felldin Marie , Källen Ragnar , Salmela Kaija , Tibell Annika , Tufveson Gunnar , Larsson Rolf , Korsgren Olle , Nilsson Bo
Published: July 2007

OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.

RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.

RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.

CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
Variation in TCF7L2 Influences Therapeutic Response to Sulfonylureas
Authors: Pearson Ewan R. , Donnelly Louise A. , Kimber Charlotte , Whitley Adrian , Doney Alex S.F. , McCarthy Mark I. , Hattersley Andrew T. , Morris Andrew D. , Palmer Colin N.A.
Published: July 2007

OBJECTIVE— There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased β-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response.

RESEARCH DESIGN AND METHODS— The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3–12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755).

RESULTS— Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23–3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21–3.86], P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C.

CONCLUSIONS— TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.
Characterization of oriented protein-ceramic and protein-polymer-composites for cartilage tissue engineering using synchrotron μ-CT
Authors: Zehbe Rolf , Haibel Astrid , Brochhausen Christoph , Gross Ulrich , Kirkpatrick C. James , Schubert Helmut
Published: July 2007

In this paper we report on the synthesis of three different gelatine based scaffold materials for the reconstruction of articular cartilage defects. The first scaffold design is based on an unmodified, oriented gelatine network, while the second design further comprises an attached inorganic hydroxyapatite layer and the third design includes poly(l-lactide) microspheres as a model material for future drug-release applications.

All three scaffold designs were characterized and imaged using synchrotron μ-CT, obtaining a complete volumetric reconstruction of a previously defined sample region.

Furthermore, two unmodified scaffolds were cultivated for one week with porcine chondrocytes. Afterwards the attached cells were labelled using a combination of Au-lysine and silver enhancer. In synchrotron μ-CT analysis we were thus able to map the cell distribution due to the difference in X-ray absorption of the labelled cells and the non labelled scaffolds in a volume of several millimetres.
Methane conversion rate into structure H hydrate crystals from ice
Authors: Susilo Robin , Ripmeester John A. , Englezos Peter
Published: July 2007

The methane uptake and conversion rate to structure H (sH) hydrates was measured and compared to crystallization kinetics models. Three large molecule guest substances (LMGS) were used as sH hydrate formers: neohexane (NH), methylcyclohexane (MCH), and tert‐butyl methyl ether ( TBME). The initial crystallization occurred quickly at the LMGS liquid‐ice interface until ∼20–30% of ice was converted into hydrate (hydrate growth stage I). Slower hydrate crystal growth was observed after a hydrate film covered the ice surface at a rate of 3–400 nm2/h (hydrate growth stage II). The TBME system showed the fastest kinetics at the beginning of the reaction followed by NH and MCH system. However the trend changed when the temperature was increased (“reaction” stage III). Surprisingly, the conversion rate achieved with the TBME system upon melting the ice was the smallest. This was attributed to the strong interaction of TBME with water molecules that increased the energy barrier for water molecules to form hydrate cages. The conversion rates were well correlated with the Avrami equation and the shrinking core model. Finally, NH was found to be the best LMGS in this study to obtain full conversion within a short reaction time and achieving high methane gas storage in the hydrate. © 2007 American Institute of Chemical Engineers AIChE J, 2007
Overweight and obesity in a rural amerindian population in Oaxaca, Southern Mexico, 1968–2000
Authors: Malina Robert M. , Reyes Maria Eugenia Peña , Tan Swee Kheng , Buschang Peter H. , Little Bertis B.
Published: July 2007

The purpose of this study was to evaluate secular change in the prevalence of overweight and obesity in a rural Zapotec Indian community in southern Mexico between 1968 and 2000. Cross‐sectional surveys of children 6–13 years, adolescents 13–17 years, and adults 19 years of age and older resident in a rural community in Oaxaca were conducted in 1968/1971, 1978, and 2000. Individuals present in the 1968, 1978, and 2000 surveys provided a small longitudinal component. Height and weight were measured; the BMI was calculated. International criteria for overweight and obesity were used. Overweight and obesity were virtually absent in school children 6–13 years in 1968 and 1978 and in adolescents in 1978. Small proportions of children (boys, 5%; girls, 8%) and adolescents (boys, 3%; girls, 15%) were overweight in 2000; two children (1%) and no adolescents were obese. Among adults, 7% of males and 19% of females were overweight and <1% of males and 4% of females were obese in 1971/1978, but 46% of males and 47% of females were overweight; and 5% of males and 14% of females were obese in 2000. The trends for children, adolescents, and adults were confirmed in the longitudinal subsamples. In conclusion, overweight and obesity are not presently a major problem in children and adolescents in this rural Zapotec community. Overweight, in particular, and to a lesser extent obesity have increased in prevalence among adults since the late 1970s. The results suggest adulthood as a critical period for onset of overweight and obesity in this sample. Am. J. Hum. Biol., 2007. © 2007 Wiley‐Liss, Inc.
Preparation of resistant starch/poly(vinyl alcohol) blend films with added plasticizer and crosslinking agents
Authors: Yoon Soon‐Do , Chough Sung‐Hyo , Park Hye‐Ryoung
Published: July 2007

We report on the physical properties of films synthesized with native corn starch (NCS) and resistant starch (RS4) prepared with NCS. NCS and RS4/poly(vinyl alcohol) (PVA) blend films were synthesized with a mixing process and casting method. Glycerol (GL) and citric acid (CA) were used as additives. Glutaraldehyde (GLU) was used as a crosslinking agent of the films. RS4 was synthesized with sodium trimetaphosphate and sodium tripolyphosphate as a crosslinker. Then, the RS4 thus synthesized was confirmed by the pancreatin–gravimetry method, swelling power, differential scanning calorimetry, and X‐ray diffraction. The tensile strength, elongation, swelling behavior, and solubility of the films were measured. The results of the measurements indicated that the RS4‐added film was better than the NCS‐added film. In particular, the RS4/PVA blend film with CA as an additive showed physical properties superior to those of the other films. Also, the physical properties with GLU added as a crosslinking agent to the films were investigated. With increasing GLU contents, the tensile strength increased but the elongation, swelling behavior, and solubility values of the GL‐added and CA‐added films decreased. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007
Zur Adhäsion von Wärmedämmverbundsystemen auf Holzwerkstoffplatten
Authors: Röder Jörg
Published: July 2007

Bei der Verklebung von Wärmedämmverbundsystemen auf Holzwerkstoffplatten im Holzrahmenbau kam es in der Vergangenheit zu Adhäsionsversagen. Die Schadensursachen waren bisher mangels systematischer Untersuchungen unklar. In diesem Beitrag wird der versuchstechnisch nachgewiesene Zusammenhang zwischen der Topografieänderung der Holzwerkstoffoberflächen bedingt durch den Feuchteeintrag nach dem Aufbringen des Klebemörtels und der Adhäsionsfestigkeit der Klebemörtel in Abhängigkeit von deren Rezeptur dargestellt und erläutert. Auf der Grundlage dieser Untersuchungen werden normierte Adhäsionsprognosen abgeleitet, mit denen die Haftzugfestigkeit auf den gängigen Holzwerkstoffoberflächen prognostiziert werden kann.

In weiteren im Beitrag dargestellten Untersuchungen stellt sich die klimatisch bedingte jahreszeitliche Feuchtegehaltsschwankung des Holzwerkstoffs als maßgebliche Beanspruchung des Haftverbundes heraus. Abhängig von der Klebemörtelrezeptur wird daher eine zulässige Feuchteamplitude für Holzwerkstoffe abgeleitet. Die gewonnenen Erkenntnisse ermöglichen eine wissenschaftlich begründete Beurteilung des Haftverbundes zwischen Klebemörteln und Holzwerkstoffen und münden in Empfehlungen für die Ausführung von Wärmedämmverbundsystemen im Holzrahmenbau.
The Swedish rectal cancer registry
Authors: Påhlman L , Bohe M , Cedermark B , Dahlberg M , Lindmark G , Sjödahl R , Öjerskog B , Damber L , Johansson R
Published: July 2007

Background

An audit of all patients with rectal cancer in Sweden was launched in 1995. This is the first report from the Swedish Rectal Cancer Registry (SRCR).

Methods

Between 1995 and 2003, 13 434 patients treated for adenocarcinoma of the rectum were registered with the SRCR; there were approximately 1500 new patients annually.

Results

Approximately half had an anterior resection, a quarter an abdominoperineal resection and 15 per cent a Hartmann's procedure. The median 30-day postoperative mortality rate was 2·4 per cent and the overall postoperative morbidity rate was 35·0 per cent. The 5-year cancer-specific survival rate was 62·3 per cent. The 5-year relative survival rate was 70·1 per cent after anterior resection, 59·8 per cent after abdominoperineal resection and 39·8 per cent after a Hartmann's procedure. The crude 5-year local recurrence rate was 9·5 per cent overall, 6·1 per cent after preoperative radiotherapy and 11·4 per cent after surgery alone. For 3868 patients who had a locally curative procedure the local recurrence rate was 7·4 per cent overall, 5·9 per cent for those who had radiotherapy and 10·2 per cent for those who did not. The local recurrence rate was 2·9 per cent (28 of 968) for stage I disease, 7·9 per cent (112 of 1418) for stage II, 13·9 per cent (188 of 1357) for stage III and 8·5 per cent (45 of 532) for stage IV.

Conclusion

These good population-based results are due, in part, to the nationwide prospective quality assurance registration.
Urodynamic outcome of waterjet-assisted total mesorectal excision
Authors: Geers P , Moesta K T , Yildirim C , Thon W F , Köckerling F
Published: July 2007

Background

Waterjet dissection has been proposed for total mesorectal excision. The present study investigated its impact on urodynamic function and oncological outcome.

Methods

Thirty patients with rectal cancer were recruited to this prospective study, of whom 25 underwent urodynamic evaluation both before and after surgery.

Results

All patients were capable of spontaneous micturition at a median of 5 months after surgery. Urodynamic measurements revealed a decrease in detrusor pressure of more than 30 mmHg, and residual urine volumes of between 100 and 200 ml, in three patients. No patient had a complete neurogenic voiding disorder. Local recurrences developed in two of 22 patients.

Conclusion

The extent of micturition disorders observed after total mesorectal excision using the waterjet method in this small series is encouraging.
Strong Magnetic Interactions through Weak Bonding Interactions in Organometallic Radicals: Combined Experimental and Theoretical Study
Authors: Cauchy Thomas , Ruiz Eliseo , Jeannin Olivier , Nomura Mitsushiro , Fourmigué Marc
Published: July 2007

The magnetic properties of a series of three neutral radical organometallic complexes of general formula [CpNi(dithiolene)]. have been investigated by a combination of X‐ray crystal structure analysis and magnetic susceptibility measurements, while the assignment of the exchange coupling constants to the possible exchange pathways has been accomplished with the help of calculations based on density functional theory (DFT). The syntheses and X‐ray structures of [CpNi(adt)] (adt=acrylonitrile‐2,3‐dithiolate) and [CpNi(tfd)] (tfd=1,2‐bis(trifluoromethyl)ethene‐1,2‐dithiolate) complexes are described, while [CpNi(mnt)] (mnt=maleonitriledithiolate) was reported earlier. In the three complexes, we observed strong antiferromagnetic coupling that could not be explained solely by short S⋅⋅⋅S intermolecular contacts. Our calculations indicated that spin density in these complexes is strongly delocalized on the NiS2 moiety, with up to 20 % on the Cp ring. As a consequence, Cp⋅⋅⋅Cp and Cp⋅⋅⋅dithiolene overlap interactions have been identified as responsible for antiferromagnetic couplings. The [CpNi(adt)] complex thus has a value J=−369.5 cm−1 for an exchange interaction through a π stacking due to the Cp⋅⋅⋅Cp overlap.
Gas‐Phase Reactivity of Metavanadate [VO3]− towards Methanol and Ethanol: Experiment and Theory
Authors: Waters Tom , Wedd Anthony G. , O'Hair Richard A. J.
Published: July 2007

The gas‐phase reactivity of the metavanadate anion [VO3]− towards methanol and ethanol was examined by a combination of ion–molecule reaction and isotope labelling experiments in a quadrupole ion‐trap mass spectrometer. The experimental data were interpreted with the aid of density functional theory calculations. [VO3]− dehydrated methanol to eliminate water and form [VO2(η2‐OCH2)]−, which features an [η2‐C,O‐OCH2]2− ligand formed by formal removal of two protons from methanol and which is isoelectronic with peroxide. [VO3]− reacted with ethanol in an analogous manner to form [VO2(η2‐OCHCH3)]−, as well as by loss of ethene to form [VO2(OH)2]−. The calculations predicted that important intermediates in these reactions were the hydroxo alkoxo anions [VO2(OH)(OCH2R)]− (R: H, CH3). These were predicted to undergo intramolecular hydrogen‐atom transfer to form [VO(OH)2(η1‐OCHR)]− followed by η1‐O→η2‐C,O rearrangements to form [VO(OH)2(η2‐OCHR)]−. The latter reacted further to eliminate water and generate the product [VO2(η2‐OCHR)]−. This major product observed for [VO3]− is markedly different from that observed previously for [NbO3]− containing the heavier Group 5 congener niobium. In that case, the major product of the reaction was an ion of stoichiometry [Nb, O3, H2]− arising from the formal dehydrogenation of methanol to formaldehyde. The origin of this difference was examined theoretically and attributed to the intermediate alkoxo anion [NbO2(OH)(OCH3)]− preferring hydride transfer to form [HNbO2(OH)]− with loss of formaldehyde. This contrasts with the hydrogen‐atom‐transfer pathway observed for [VO2(OH)(OCH3)]−.
Prognostic significance of p16INK4a alteration for Ewing sarcoma
Authors: Honoki Kanya , Stojanovski Elizabeth , McEvoy Mark , Fujii Hiromasa , Tsujiuchi Toshifumi , Kido Akira , Takakura Yoshinori , Attia John
Published: July 2007

BACKGROUND.

Despite findings from individual studies regarding prognostic factors for Ewing sarcoma, no conclusive results have been produced, partly because of small sample sizes. The objective of the current study was to evaluate whether the presence of p16INK4a alteration is associated with a poorer prognosis in patients with Ewing sarcomas.

METHODS.

A review was conducted of publications that assessed associations between p16INK4a status and 2‐year survival among patients with Ewing sarcoma. The association between metastatic disease at initial diagnosis and 2‐year survival was evaluated by synthesizing data in the form of risk ratios.

RESULTS.

Of 11 studies that were identified in the initial search strategy, 6 studies, representing 188 patients, met the inclusion criteria and, consequently, were pooled for quantitative analyses. The estimated pooled risk ratio of p16INK4a aberration was 2.17 (95% confidence interval [95% CI], 1.55–3.03; P < .001), whereas the estimated pooled risk ratio of metastasis at diagnosis among the 164 eligible patients was 2.60 (95% CI, 1.71–3.97; P < .001). There was no statistically significant difference in the pooled estimated risk ratios of p16INK4a aberration for a poor prognosis between patients with and without metastasis at diagnosis (1.86 and 2.21, respectively; P > .59).

CONCLUSIONS.

The presence of p16INK4a alteration was a statistically significant predictor of prognosis for patients with Ewing sarcoma. Along with other prognostic factors, such as metastasis, the p16INK4a alteration may be a potential candidate for improving the risk‐stratifying strategy for patients with these tumors. © 2007 American Cancer Society.
Micelle–Vesicle Transition of Fatty Acid Based Ion‐Pair Surfactants: Interfacial Evidence and Influence of the Ammonium Counterion Structure
Authors: Bordes Romain , Vedrenne Marc , Coppel Yannick , Franceschi Sophie , Perez Emile , Rico‐Lattes Isabelle
Published: July 2007

We describe the synthesis and the physicochemical study of new ion‐pair amphiphiles from a mixture of bicyclic, cyclic, linear or branched amines and fatty acids of three chain lengths. Surface‐tension measurements of bicyclic, cyclic and branched structures of ammonium/alkanoate acid ion pairs show a phase transition, with two plateaux in the plot of surface tension versus log(c) (c=concentration). Such behaviour is related to the structure of the counterion, the alkyl chain length and the temperature. Pulsed gradient spin echo NMR spectroscopy experiments were performed to demonstrate the existence of micelles on the first plateau and to confirm the phase transition. The existence of vesicles on the second plateau of the surface tension was proved by CryoTEM observation and dynamic light scattering (DLS) measurements. Mainly, according to the structure of the counterion, there is either a strong association and a positioning along the chain leading to vesicles or a less strong association leading to external positioning and the formation of micelles at low concentrations or vesicles at higher concentrations.
Enhanced purification of cell‐permeant Cre and germline transmission after transduction into mouse embryonic stem cells
Authors: Peitz Michael , Jäger Richard , Patsch Christoph , Jäger Andrea , Egert Angela , Schorle Hubert , Edenhofer Frank
Published: July 2007

Continuous expression of Cre recombinase has the potential to yield toxic side effects in various cell types, thereby limiting applications of the Cre/loxP system for conditional mutagenesis. In this study, we investigate the potential of Cre protein transduction to overcome this limitation. COS‐7, CV1‐5B, and mouse embryonic stem (ES) cells treated with cell‐permeant Cre (HTNCre) maintain a normal growth behavior employing Cre concentrations sufficient to induce recombination in more than 90% of the cells, whereas continuous application of high doses resulted in markedly reduced proliferation. HTNCre‐treated ES cells maintain a normal karyotype and are still able to contribute to the germline. Moreover, we present an enhanced HTNCre purification protocol that allows the preparation of a concentrated glycerol stock solution, thereby enabling a considerable simplification of the Cre protein transduction procedure. The protocol described here allows rapid and highly efficient conditional mutagenesis of cultured cells. genesis 45:508–517, 2007. © 2007 Wiley‐Liss, Inc.
η1‐Vinylidene Formation from Internal Alkynones by C–C Bond Migration
Authors: Shaw Michael J. , Bryant Steven W. , Rath Nigam
Published: July 2007

The [μ2‐N2{CpRu(PPh3)2}2]2+ (12+) dication is a source of the formal 16‐electron [CpRu(PPh3)2]+ fragment, and it reacts with internal alkynes such as 1,3‐diphenylpropynone, 4‐phenyl‐3‐butyn‐2‐one, and 3‐cyclopropyl‐1‐phenylpropynone to yield η1‐vinylidene complexes 2a+–2c+ by C–C bond activation. In the case of 1,3‐diphenylpropynone, the η1‐ketone complex [CpRu(PPh3)2{PhC(η1‐O)C≡CPh}]+ (3a+) was isolated as its PF6– salt, and it is apparently an intermediate in the formation of the vinylidene complex. Complexes 2a+–2c+ were characterized as their BArF4– [ArF = 3,5‐bis(trifluoromethyl)phenyl] salts by NMR and IR spectroscopic methods, ESI‐MS, and EA. The single crystal X‐ray diffraction structure of 2aBArF4 is presented. These reactions represent the first examples where an internal alkyne undergoes C–C bond migration to form an η1‐vinylidene complex. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)