bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mesenchyme Controls the Timing of Pancreatic β-Cell Differentiation
Authors: Duvillié Bertrand , Attali Myriam , Bounacer Ali , Ravassard Philippe , Basmaciogullari Annie , Scharfmann Raphael
Published: May 2006

The importance of mesenchymal-epithelial interactions in the proliferation of pancreatic progenitor cells is well established. Here, we provide evidence that the mesenchyme also controls the timing of β-cell differentiation. When rat embryonic pancreatic epithelium was cultured without mesenchyme, we found first rapid induction in epithelial progenitor cells of the transcription factor neurogenin3 (Ngn3), a master gene controlling endocrine cell-fate decisions in progenitor cells; then β-cell differentiation occurred. In the presence of mesenchyme, Ngn3 induction was delayed, and few β-cells developed. This effect of the mesenchyme on Ngn3 induction was mediated by cell-cell contacts and required a functional Notch pathway. We then showed that associating Ngn3-expressing epithelial cells with mesenchyme resulted in poor β-cell development via a mechanism mediated by soluble factors. Thus, in addition to its effect upstream of Ngn3, the mesenchyme regulated β-cell differentiation downstream of Ngn3. In conclusion, these data indicate that the mesenchyme controls the timing of β-cell differentiation both upstream and downstream of Ngn3.
AMP-Activated Protein Kinase Activation by Adrenoceptors in L6 Skeletal Muscle Cells
Authors: Hutchinson Dana S. , Bengtsson Tore
Published: May 2006

AMP-activated protein kinase (AMPK), which functions as a sensor of cellular energy homeostasis, was phosphorylated after norepinephrine stimulation in L6 skeletal muscle cells. This effect was mediated by α1-adrenoceptors, with no stimulatory effects due to interactions at α2- or β-adrenoceptors. α1-Adrenoceptors are Gq-coupled receptors, and calcium but not phorbol esters could mimic the effect of α1-adrenergic stimulation; and we show that protein kinase C is not involved as an upstream signal to AMPK by α1-adrenergic stimulation and that the AMP-to-ATP ratio is unaltered after α1-adrenergic stimulation. We further show that glucose uptake mediated by α1- but not by β-adrenoceptors can be inhibited by AMPK inhibition. Acetyl-CoA carboxylase (ACC) is phosphorylated at Ser218 by AMPK, and α1- but not β-adrenoceptor stimulation results in phosphorylation of ACC at this residue. These results suggest a novel pathway where α1-adrenoceptor activation, independent of protein kinase C, leads to activation of AMPK in skeletal muscle, which contributes to α1-adrenoceptor–mediated increases in glucose uptake.
Metformin Restores Leptin Sensitivity in High-Fat–Fed Obese Rats With Leptin Resistance
Authors: Kim Yong-Woon , Kim Jong-Yeon , Park Yong-Hoon , Park So-Young , Won Kyu-Chang , Choi Kwang-Hae , Huh Jung-Yoon , Moon Ki-Hak
Published: May 2006

To evaluate whether metformin enhances leptin sensitivity, we measured leptin sensitivity after 4 weeks of metformin treatment (300 mg/kg daily) in both standard chow and high-fat–fed obese rats. Anorexic and fat-losing responses after intracerebroventricular leptin infusion for 7 days (15 μg daily per rat) in standard chow rats were enhanced by metformin treatment, and these responses to leptin were attenuated in high-fat–fed obese rats compared with age-matched standard chow rats. However, these responses to leptin were corrected by metformin treatment in high-fat–fed obese rats. Moreover, serum concentrations of leptin and insulin were decreased dramatically by leptin in metformin-treated standard chow and high-fat–fed obese rats. The hypothalamic phosphorylated AMP-activated protein kinase level was decreased by lower leptin dose in metformin-treated rats than in untreated rats. In an acute study, metformin treatment also increased the anorexic effect of leptin (5 μg), and this was accompanied by an increased level of phosphorylated signal transducer and activator of transcription 3 in the hypothalamus. These results suggest that metformin enhances leptin sensitivity and corrects leptin resistance in high-fat–fed obese rats and that a combination therapy including metformin and leptin would be helpful in the treatment of obesity.
Novel Mechanism for Plasma Glucose–Lowering Action of Metformin in Streptozotocin-Induced Diabetic Rats
Authors: Cheng Juei-Tang , Huang Ching-Chiu , Liu I-Min , Tzeng Thing-Fong , Chang Chih Jen
Published: May 2006

To better understand the insulin-independent plasma glucose–lowering action of metformin, we used streptozotocin (STZ)-induced diabetic rats to investigate the possible mechanisms. Oral intake of metformin decreased the plasma glucose of STZ-induced diabetic rats with a parallel increase of plasma β-endorphin–like immunoreactivity (BER). Mediation of opioid μ-receptors in the action of metformin was identified by the blockade of receptors with antagonist in STZ-induced diabetic rats and the failure of action in opioid μ-receptor knockout diabetic mice. Release of BER from adrenal glands by metformin was characterized, using bilateral adrenalectomy and the release of BER from isolated adrenal medulla of STZ-induced diabetic rats. Repeated treatment with metformin in STZ-induced diabetic rats increased the mRNA and protein levels of GLUT-4 in soleus muscle that was blocked by naloxonazine. Reduction of the mRNA or protein levels of hepatic PEPCK was also impeded in the same group of STZ-induced diabetic rats. In conclusion, our results provide novel mechanisms for the plasma glucose–lowering action of metformin, via an increase of β-endorphin secretion from adrenal glands to stimulate opioid μ-receptor linkage, leading to an increase of GLUT-4 gene expression and an attenuation of hepatic PEPCK gene expression in STZ-induced diabetic rats.
Necdin and E2F4 Are Modulated by Rosiglitazone Therapy in Diabetic Human Adipose and Muscle Tissue
Authors: Goldfine Allison B. , Crunkhorn Sarah , Costello Maura , Gami Hiral , Landaker Edwin J. , Niinobe Michio , Yoshikawa Kazuaki , Lo David , Warren Amy , Jimenez-Chillaron Jose , Patti Mary Elizabeth
Published: May 2006

To identify novel pathways mediating molecular mechanisms of thiazolidinediones (TZDs) in humans, we assessed gene expression in adipose and muscle tissue from six subjects with type 2 diabetes before and after 8 weeks of treatment with rosiglitazone. mRNA was analyzed using Total Gene Expression Analysis (TOGA), an automated restriction-based cDNA display method with quantitative analysis of PCR products. The expression of cell cycle regulatory transcription factors E2F4 and the MAGE protein necdin were similarly altered in all subjects after rosiglitazone treatment. E2F4 expression was decreased by 10-fold in muscle and 2.5-fold in adipose tissue; necdin was identified in adipose tissue only and increased 1.8-fold after TZD treatment. To determine whether changes were related to an effect of the drug or adipogenesis, we evaluated the impact of rosiglitazone and differentiation independently in 3T3-L1 adipocytes. While treatment of differentiated adipocytes with rosiglitazone did not alter E2F4 or necdin, expression of both genes was significantly altered during differentiation. Differentiation was associated with increased cytosolic localization of E2F4. Moreover, necdin overexpression potently inhibited adipocyte differentiation and cell cycle progression. These data suggest that changes in necdin and E2F4 expression after rosiglitazone exposure in humans are associated with altered adipocyte differentiation and may contribute to improved insulin sensitivity in humans treated with TZDs.
Pancreatic β-Cells Secrete Insulin in Fast- and Slow-Release Forms
Authors: Michael Darren J. , Ritzel Robert A. , Haataja Leena , Chow Robert H.
Published: May 2006

Insulin vesicles contain a chemically rich mixture of cargo that includes ions, small molecules, and proteins. At present, it is unclear if all components of this cargo escape from the vesicle at the same rate or to the same extent during exocytosis. Here, we demonstrate through real-time imaging that individual rat and human pancreatic β-cells secrete insulin in heterogeneous forms that disperse either rapidly or slowly. In healthy pancreatic β-cells maintained in culture, most vesicles discharge insulin in its fast-release form, a form that leaves individual vesicles in a few hundred milliseconds. The fast-release form of insulin leaves vesicles as rapidly as C-peptide leaves vesicles. Healthy β-cells also secrete a slow-release form of insulin that leaves vesicles more slowly than C-peptide, over times ranging from seconds to minutes. Individual β-cells make vesicles with both forms of insulin, though not all vesicles contain both forms of insulin. In addition, we confirm that insulin vesicles store their cargo in two functionally distinct compartments: an acidic solution, or halo, and a condensed core. Thus, our results suggest two important features of the condensed core: 1) It exists in different states among the vesicles undergoing exocytosis and 2) its dissolution determines the availability of insulin during exocytosis.
Variation in the Adiponutrin Gene Influences Its Expression and Associates With Obesity
Authors: Johansson Lovisa E. , Hoffstedt Johan , Parikh Hemang , Carlsson Emma , Wabitsch Martin , Bondeson Anne-Greth , Hedenbro Jan , Tornqvist Hans , Groop Leif , Ridderstråle Martin
Published: May 2006

Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess.
The PPARG Pro12Ala Polymorphism Is Associated With a Decreased Risk of Developing Hyperglycemia Over 6 Years and Combines With the Effect of the APM1 G-11391A Single Nucleotide Polymorphism
Authors: Jaziri Riphed , Lobbens Stephane , Aubert Roberte , Péan Franck , Lahmidi Saida , Vaxillaire Martine , Porchay Isabelle , Bellili Naïma , Tichet Jean , Balkau Beverley , Froguel Philippe , Marre Michel , Fumeron Frédéric ,   for the DESIR Study Group
Published: May 2006

Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44–0.99], P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44–0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D′ = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOMA-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested.
Protection of INS-1 Cells From Free Fatty Acid–Induced Apoptosis by Targeting hOGG1 to Mitochondria
Authors: Rachek Lyudmila I. , Thornley Nancy P. , Grishko Valentina I. , LeDoux Susan P. , Wilson Glenn L.
Published: May 2006

Chronic exposure to elevated levels of free fatty acids (FFAs) impairs pancreatic β-cell function and contributes to the decline of insulin secretion in type 2 diabetes. Previously, we reported that FFAs caused increased nitric oxide (NO) production, which damaged mitochondrial DNA (mtDNA) and ultimately led to apoptosis in INS-1 cells. To firmly establish the link between FFA-generated mtDNA damage and apoptosis, we stably transfected INS-1 cells with an expression vector containing the gene for the DNA repair enzyme human 8-oxoguanine DNA glycosylase/apurinic lyase (hOGG1) downstream of the mitochondrial targeting sequence (MTS) from manganese superoxide dismutase. Successful integration of MTS-OGG1 into the INS-1 cellular genome was confirmed by Southern blot analysis. Western blots and enzyme activity assays revealed that hOGG1 was targeted to mitochondria and the recombinant enzyme was active. MTS-OGG1 cells showed a significant decrease in FFA-induced mtDNA damage compared with vector-only transfectants. Additionally, hOGG1 overexpression in mitochondria decreased FFA-induced inhibition of ATP production and protected INS-1 cells from apoptosis. These results indicate that mtDNA damage plays a pivotal role in FFA-induced β-cell dysfunction and apoptosis. Therefore, targeting DNA repair enzymes into β-cell mitochondria could be a potential therapeutic strategy for preventing or delaying the onset of type 2 diabetes symptoms.
Genistein Acutely Stimulates Insulin Secretion in Pancreatic β-Cells Through a cAMP-Dependent Protein Kinase Pathway
Authors: Liu Dongmin , Zhen Wei , Yang Zandong , Carter Jeffery D. , Si Hongwei , Reynolds Kathryn A.
Published: May 2006

Although genistein, a soy isoflavone, has beneficial effects on various tissues, it is unclear whether it plays a role in physiological insulin secretion. Here, we present evidence that genistein increases rapid glucose-stimulated insulin secretion (GSIS) in both insulin-secreting cell lines (INS-1 and MIN6) and mouse pancreatic islets. Genistein elicited a significant effect at a concentration as low as 10 nmol/l with a maximal effect at 5 μmol/l. The effect of genistein on GSIS was not dependent on estrogen receptor and also not related to an inhibition of protein tyrosine kinase (PTK). Consistent with its effect on GSIS, genistein increases intracellular cAMP and activates protein kinase A (PKA) in both cell lines and the islets by a mechanism that does not involve estrogen receptor or PTK. The induced cAMP by genistein, at physiological concentrations, may result primarily from enhanced adenylate cyclase activity. Pharmacological or molecular intervention of PKA activation indicated that the insulinotropic effect of genistein is primarily mediated through PKA. These findings demonstrated that genistein directly acts on pancreatic β-cells, leading to activation of the cAMP/PKA signaling cascade to exert an insulinotropic effect, thereby providing a novel role of soy isoflavones in the regulation of insulin secretion.
The Natural Course of β-Cell Function in Nondiabetic and Diabetic Individuals
Authors: Festa Andreas , Williams Ken , D’Agostino Ralph , Wagenknecht Lynne E. , Haffner Steven M.
Published: May 2006

Data from the UKPDS (U.K. Prospective Diabetes Study) indicate a continuous decline in β-cell function in patients with type 2 diabetes. We studied longitudinal changes in β-cell function (follow-up of 5.2 years) in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes, using acute insulin response (AIR) and insulin sensitivity index (Si) from a frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years. At baseline, decreasing levels of both Si and AIR (either unadjusted or adjusted for Si) mirrored deteriorating glucose tolerance status at baseline and at follow-up. A different pattern was found with respect to longitudinal changes; Si declined in each glucose tolerance category, ranging from −0.81 ×10−4 min−1 · μU−1 · ml−1 in NGT at baseline and NGT at follow-up (NGT/NGT) to −1.06 ×10−4 in NGT/diabetes, whereas the directional change in AIR principally determined the glucose tolerance status at follow-up. In NGT/NGT Si decreased by 35% and AIR increased by 34%. Results were similar in each of the three ethnic groups. These data shed light on the natural course of β-cell function; over 5.2 years, mean insulin sensitivity declined in each glucose tolerance category. The change in AIR, however, principally determined glucose tolerance status at follow-up; NGT was maintained by a compensatory increase in insulin secretion. Failure to increase insulin secretion led to IGT, and a decrease in insulin secretion led to overt diabetes. This data may have important implications for the prevention and treatment of type 2 diabetes.
Combined Interleukin-6 and Interleukin-1 Deficiency Causes Obesity in Young Mice
Authors: Chida Dai , Osaka Toshimasa , Hashimoto Okito , Iwakura Yoichiro
Published: May 2006

Proinflammatory cytokines including interleukin (IL)-1 and IL-6 exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that IL-1 receptor antagonist–deficient (IL-1Ra−/−) mice show a lean phenotype due to an abnormal lipid metabolism. On the contrary, it was reported that IL-6−/− mice exhibit obesity after 6 months of age. This study sought to assess the roles of IL-1 and IL-6 in body weight homeostasis. We generated mice deficient in IL-6 and IL-1Ra (IL-6−/− IL-1Ra−/−) and IL-6, IL-1α, and IL-1β (IL-6−/− IL-1−/−). IL-6−/− IL-1Ra−/− mice exhibited a lean phenotype, similar to IL-1Ra−/− mice. On the other hand, IL-6−/− IL-1−/− mice became obese as early as 10 weeks of age, while IL-1−/− mice and IL-6−/− mice were normal at this age. The daily food intake was significantly higher in IL-6−/− IL-1−/− mice than in IL-6−/− IL-1+/− mice, while energy expenditure was comparable in these two strains. Acute anorexia induced by peripheral administration of IL-1 was significantly suppressed in IL-6−/− IL-1−/− mice, but not in IL-1−/− mice or IL-6−/− mice compared with wild-type mice. These results indicate that IL-1 and IL-6 are both involved in the regulation of body fat in a redundant manner in young mice.
Atorvastatin Fails to Prevent the Development of Autoimmune Diabetes Despite Inhibition of Pathogenic β-Cell–Specific CD8 T-Cells
Authors: Lozanoska-Ochser Biliana , Barone Francesca , Pitzalis Costantino , Peakman Mark
Published: May 2006

Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins’ protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes. Mice were treated with 0, 1, 10, or 50 mg · kg−1 · day−1 oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration, or islet major histocompatibility complex class II expression. However, there was clear evidence of a disease-relevant immunological effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (γ-interferon–producing) CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting that atorvastatin loses efficiency in inhibiting autoantigen-specific T-cells over time. This observation may explain the discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous model of autoimmune disease and has implications for the adoption of such therapy in humans.
Group 1B Phospholipase A2–Mediated Lysophospholipid Absorption Directly Contributes to Postprandial Hyperglycemia
Authors: Labonté Eric D. , Kirby R. Jason , Schildmeyer Nicholas M. , Cannon April M. , Huggins Kevin W. , Hui David Y.
Published: May 2006

Postprandial hyperglycemia is an early indicator of abnormality in glucose metabolism leading to type 2 diabetes. However, mechanisms that contribute to postprandial hyperglycemia have not been identified. This study showed that mice with targeted inactivation of the group 1B phospholipase A2 (Pla2g1b) gene displayed lower postprandial glycemia than that observed in wild-type mice after being fed a glucose-rich meal. The difference was caused by enhanced postprandial glucose uptake by the liver, heart, and muscle tissues as well as altered postprandial hepatic glucose metabolism in the Pla2g1b−/− mice. These differences were attributed to a fivefold decrease in the amount of dietary phospholipids absorbed as lysophospholipids in Pla2g1b−/− mice compared with that observed in Pla2g1b+/+ mice. Elevating plasma lysophospholipid levels in Pla2g1b−/− mice via intraperitoneal injection resulted in glucose intolerance similar to that exhibited by Pla2g1b+/+ mice. Studies with cultured hepatoma cells revealed that lysophospholipids dose-dependently suppressed insulin-stimulated glycogen synthesis. These results demonstrated that reduction of lysophospholipid absorption enhances insulin-mediated glucose metabolism and is protective against postprandial hyperglycemia.
Survival Benefits of Intensive Insulin Therapy in Critical Illness
Authors: Ellger Björn , Debaveye Yves , Vanhorebeek Ilse , Langouche Lies , Giulietti Annapaula , Van Etten Evelyne , Herijgers Paul , Mathieu Chantal , Van den Berghe Greet
Published: May 2006

Tight blood glucose control with insulin reduces morbidity and mortality of critically ill patients. However, the relative impact of maintaining normoglycemia and of glycemia-independent actions of insulin remains unknown. We therefore independently manipulated blood glucose and plasma insulin levels in burn-injured, parentally fed rabbits over 7 days to obtain four study groups: two normoglycemic groups with either normal or elevated insulin levels and two hyperglycemic groups with either normal or elevated insulin levels. We studied the relative impact of glycemia and glycemia-independent effects of insulin on survival; myocardial contractility in an open chest preparation; endothelial function in isolated aortic rings; and liver, kidney, and leukocyte function in a rabbit model of critical illness. Mortality was significantly lower in the two normoglycemic groups independent of insulin levels. Maintaining normoglycemia, independent of insulin levels, prevented endothelial dysfunction as well as liver and kidney injury. To increase myocardial systolic function, elevated insulin levels and prevention of hyperglycemia were required concomitantly. Leukocyte dysfunction was present in the two hyperglycemic groups, which could in part be rescued by insulin. The results suggest that the observed benefits of intensive insulin therapy required mainly maintenance of normoglycemia; whereas glycemia-independent actions of insulin exerted only minor, organ-specific impact.
Mechanisms of Time-Dependent Potentiation of Insulin Release
Authors: Gunawardana Subhadra C. , Rocheleau Jonathan V. , Head W. Steven , Piston David W.
Published: May 2006

Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pHi) associated with elevated NADPH+H+ (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum. To determine the role of nNOS in the suppression of TDP in mouse islets, glucose-induced TDP was monitored in mouse islets in which nNOS activity had been genetically removed or chemically inhibited and compared with the TDP response in wild-type mouse islets with and without forced intracellular acidification. Genetic deletion of nNOS was provided by an nNOS knockout (NOS-KO) mouse model, B6–129S4-Nos1tm1Plh/J. To explore how nNOS inhibits TDP, we compared pHi and NADPH levels in wild-type and NOS-KO islets and monitored TDP with various components of the nNOS reaction added. Glucose normally does not produce TDP in wild-type mouse islets except under forced intracellular acidification. Remarkably, glucose produced strong TDP in NOS-KO islets and in wild-type islets treated with nNOS inhibitors. TDP in NOS-KO islets was not inhibited by the addition of NO, and NOS-KO islets exhibited a lower pHi than wild-type islets. The addition of arginine to wild-type islets also enabled glucose to induce TDP. Our results show that nNOS activity contributes to the absence of TDP in mouse islets putatively through depletion of intracellular arginine.
Evaluation of genetic and metabolic predispositions and nutritional risk factors for pasture-associated laminitis in ponies
Authors: Treiber Kibby H. , Kronfeld David S. , Hess Tanja M. , Byrd Bridgett M. , Splan Rebecca K. , Staniar W. Burton
Published: May 2006

Objective—To evaluate genetic and metabolic predis-positions and nutritional risk factors for development of pasture-associated laminitis in ponies.

Design—Observational cohort study.

Animals—160 ponies.

Procedures—A previous diagnosis of laminitis was used to differentiate 54 ponies (PL group) from 106 nonlaminitic ponies (NL group). Pedigree analysis was used to determine a mode of inheritance for ponies with a previous diagnosis of laminitis. In early March, ponies were weighed and scored for body condition and basal venous blood samples were obtained. Plasma was analyzed for glucose, insulin, triglycerides, nonesterified fatty acids, and cortisol concentrations. Basal proxies for insulin sensitivity (reciprocal of the square root of insulin [RISQI]) and insulin secretory response (modified insulin-to-glucose ratio [MIRG]) were calculated. Observations were repeated in May, when some ponies had signs of clinical laminitis.

Results—A previous diagnosis of laminitis was consistent with the expected inheritance of a dominant major gene or genes with reduced penetrance. A prelaminitic metabolic profile was defined on the basis of body condition, plasma triglyceride concentration, RISQI, and MIRG. Meeting ≥ 3 of these criteria differentiated PL-from NL-group ponies with a total predictive power of 78%. Determination of prelaminitic metabolic syndrome in March predicted 11 of 13 cases of clinical laminitis observed in May when pasture starch concentration was high.

Conclusions and Clinical Relevance—Prelaminitic metabolic syndrome in apparently healthy ponies is comparable to metabolic syndromes in humans and is the first such set of risk factors to be supported by data in equids. Prelaminitic metabolic syndrome identifies ponies requiring special management, such as avoiding high starch intake that exacerbates insulin resistance.
Messages in Molecules: Ligand/Cation Coding and Self‐Recognition in a Constitutionally Dynamic System of Heterometallic Double Helicates
Authors: Marquis Annie , Smith Virginia , Harrowfield Jack , Lehn Jean‐Marie , Herschbach Haiko , Sanvito Rossella , Leize‐Wagner Emmanuelle , Van Dorsselaer Alain
Published: May 2006

Double helicates are known to exhibit self‐recognition characteristics determined by the coordination geometry of the metal involved as well as by the topicity of the ligands. Combining tridentate (terpyridine, T) or bidentate (bipyridine, B) subunits in a tritopic strand affords a set of ligands able to assemble by pairs to form double helicates, homo‐ or heterostranded, homo‐ or heterotopic, depending on the coordination properties of the metals involved. The four ligand strands, BBB, TTT, BBT, and TBT form constitutionally dynamic sets of double helicates with the metal ions CuI, CuII, and ZnII; these helicates correspond to the correct coding of the BB, BT, and TT pairs for tetra‐, penta‐, and hexacoordinate CuI, CuII, and ZnII cations, respectively.
Water‐Soluble Sal2en‐ and Reduced Sal2en‐Type Ligands: Study of Their CuII and NiII Complexes in the Solid State and in Solution
Authors: Correia Isabel , Dornyei Agnes , Jakusch Tamás , Avecilla Fernando , Kiss Tamás , Costa Pessoa João
Published: May 2006

The CuII and NiII complexes of the Schiff base pyr2en [N,N′‐ethylenebis(pyridoxyliminato)] and reduced Schiff bases Rpyr2en [N,N′‐ethylenebis(pyridoxylaminato)] and R(SO3–sal)2en (SO3–sal = salicylaldehyde‐5‐sulfonate) were prepared and characterized by elemental analysis, IR, UV/Vis, and EPR spectroscopy. The structure of Ni(pyr2en)·3H2O was determined by single‐crystal X‐ray diffraction. The pyr2en2– ligand is coordinated through two phenolate‐O and imine‐N atoms, in a distorted square‐planar geometry. The complexation of CuII and NiII with Rpyr2en in aqueous solution is studied by pH‐potentiometry, UV/Vis spectroscopy, as well as by EPR spectroscopy for the CuII system, and 1H NMR spectroscopy for the NiII system. Complex formation constants were determined and binding modes proposed. While for the CuII system all complexes present a 1:1 stoichiometry with different protonation states, for the NiII system the 2:1 (L/M) complexes become important in the basic pH range at a higher ligand excess. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Assessment of carcinogenic potential of repeated fish fried oil in mice
Authors: Pandey Manoj K. , Das Mukul
Published: May 2006

Our prior studies have shown that single topical treatment of repeated fish fried oil extract (RFFE), containing various polycyclic aromatic hydrocarbons (PAHs), to the dorsal epidermis of mice caused enhancement of DNA damage along with higher expression of p53 and p21WAF1 proteins and cell‐cycle arrest. In the present study carcinogenic potential of repeated fish fried oil (RFFO) and RFFE was assessed. Single topical application of RFFO (100 µL/animal) and RFFE (100–500 µg/animal) to Swiss albino female mice resulted in significant induction (1.8‐ to 7.4‐fold) of ornithine decarboxylase activity. Twice weekly topical application of methylcholanthrene (MCA) for 24 wk or single topical application of 7,12‐dimethylbenzanthracene (DMBA) or RFFO or RFFE, as initiator followed by twice weekly application of 12‐O‐tetradecanoyl phorbol myristate acetate (TPA) as promoter for 24 wk, resulted in development of skin papillomas after 6, 7, 18, and 9 wk, respectively. The cumulative number of tumors in MCA, DMBA/TPA, RFFE (200 µg)/TPA, and RFFE (500 µg)/TPA groups were 276, 168, 34, and 58 after 24 wk while negligible or minimal initiating activity was noticed in RFFO/TPA group. No tumors were found in animals either given twice weekly topical application of RFFO or a single initiating dose of DMBA followed by twice weekly application of RFFO. Histopathology of skin of animals treated with RFFE/TPA showed marked proliferation of epidermal layers along with abnormal mitosis and multinucleated tumor appearance. Skin of animals in groups RFFO/TPA and DMBA/RFFO showed sloughing and regeneration of epidermal layers, oedema along with proliferation of fibroblasts. Histochemical localization of γ‐glutamyl transpeptidase was found to be substantially higher in skin of mice treated with RFFO/TPA and RFFE/TPA. Animals treated with RFFO/TPA, DMBA/RFFO, and RFFE/TPA resulted in significant induction of cutaneous aryl hydrocarbon hydroxylase (AHH) (421–432%), ethoxyresorufin‐O‐deethylase (252–316%), and glutathione S‐transferase (133–245%) activities. Animals treated with RFFO/TPA, DMBA/RFFO, and RFFE/TPA led to significant reduction in glutathione content (39–44%) with a concomitant increase in lipid peroxidation (254–492%). Animals treated with RFFO/TPA and RFFE/TPA led a significant decrease in catalase (43–69%) and superoxide dismutase (20–31%) activities while glutathione reductase activity was found to be diminished (23–51%) in RFFO, RFFO/TPA, DMBA/RFFO, and RFFE/TPA treated groups. These results suggest that RFFE possess skin tumor initiating activity and that it may have weak promoting activity as well, which may involve free radicals. © 2006 Wiley‐Liss, Inc.
Three‐dimensional analysis, real‐time visualization, and automated post‐earthquake damage assessment of buildings
Authors: Naeim F. , Lee H. , Hagie S. , Bhatia H. , Alimoradi A. , Miranda E.
Published: May 2006

A set of methodologies for visualization, analysis, and automated post‐earthquake damage assessment of instrumented buildings is presented. These methods can be used immediately after an earthquake to assess the probability of various damage states in the N–S and E–W directions and throughout the height of each building. The methods have been applied to more than 80 instrumented buildings which have recordings from more than one earthquake. The results indicate that the proposed methods, when used in combination, can provide very useful information regarding the status of a building immediately after an earthquake by simple and rapid analysis of sensor data and prior to any building inspections. The methodologies and applications explained in this paper illustrate more than ever that seismic instrumentation of buildings is vital for damage assessment, learning from performance of buildings during earthquakes, enhancing engineering practice, and further development of seismic code provisions. Copyright © 2006 John Wiley & Sons Ltd.
A two-dimensional analysis of the compressible flow near a reconnection site at the dayside magnetopause
Authors: WESTERBERG LARS G. , ÅKERSTEDT HANS O.
Published: May 2006

A compressible model of the magnetosheath plasma flow is considered. Magnetic reconnection is assumed to occur in a region stretching from the sub-Solar point to the north. Two locations of the reconnection site are treated: two and four Earth radii from the sub-Solar point, respectively. By treating the transition layer as very thin, we solve the governing equations approximately using the method of matched asymptotic expansions. The behavior of the magnetic field and the plasma velocity close to a reconnection site during the transition from the magnetosheath to the magnetosphere is investigated. We also obtain the development of the transition layer thickness north and south of the reconnection point. The magnetopause transition layer is represented by a large-amplitude Alfvén wave implying that the density is approximately the same across the magnetopause boundary. In order to match the solutions we consider a compressible ideal magnetohydrodynamic model describing density, velocity and magnetic field variations along the outer magnetopause boundary. We also compare the analytical results with solutions from a numerical simulation. The compressible effects on the structure of the magnetic field and the total velocity evolution are visible but not dramatic. It is shown that the transition layer north of the reconnection point is thinner than to the south. The effect is stronger for reconnection at higher latitudes.
The Costs of Crime: Unemployment and Poverty
Authors: Fadaei‐Tehrani Reza
Published: May 2006

The tremendous and highly complex industrial development which went
on with ever‐accelerating rapidity during the latter half of the
nineteenth century brought the USA face‐to‐face at the beginning of the
twentieth century with the very serious social problem of crime. This
article examines whether there was any relationship at all between
crime, unemployment and sales of alcohol and, if there was a
relationship, whether the two domains shared two, as opposed to only one
dimension and what the pattern of relationships were relating variables
in one domain with those in the other.
Smith's Invisible Hand and Hegel's Cunning of Reason
Authors: Davis John B.
Published: May 2006

The affinities of Smith′s invisible hand notion and Hegel′s cunning
of reason are examined through a study of all the key locations in which
the invisible hand and cunning of reason are introduced. Despite their
differences in orientation and philosophy, both writers reach similar
conclusions regarding the play of self‐interest and the emergence of the
social good. Specifically, each requires a deus ex machina
– Providence or Geist – to generate the necessary
telosthat supplements their respective logical arguments
concerning the concrete play of interest. At the same time, each view
provides little to explain how individualism creates the greater social
good, so that recourse in each argument to an extra‐social entity
obscures the actual functioning of the social order. The common
approaches of the two very different thinkers thus reflects on the
general requirements and dilemmas of arguments concerning the social
good and individual interest.
Advertising in Saudi Arabia: Content and Regulation
Authors: Luqmani Mushtaq , Yavas Ugur , Quraeshi Zahir
Published: May 2006

More competitive now than a few years ago, the Saudi Arabian market
has changed considerably into one marked by more vigorous advertising.
Advertising content and regulation in this influential, conservative
Middle East country is discussed. The commentary emphasises that since
religion has such a pervasive and abiding influence, it is imperative
that advertising should be compatible with religious standards. In
addition, advertising should be sensitive to other cultural norms and
responsive to changing governmental priorities.
An Assessment of Channel Behaviour in an Alternative Structural Arrangement: The International Joint Venture
Authors: Habib Ghazi M. , Burnett John J.
Published: May 2006

This article tests a number of channel behaviour hypotheses in a unique structural arrangement – the joint venture. The results indicate that goal disparity is a significant predictor of conflict and that perceived conflict is related to member satisfaction, manifest conflict, and desire for change. Managerial and theoretical implications are discussed.
Feasibility and usefulness of self‐assessment of bleeding in patients with haematological malignancies, and the association between platelet count and bleeding
Authors: Stanworth S. J. , Dyer C. , Casbard A. , Murphy M. F.
Published: May 2006

Background and Objectives  The aim of this study was to evaluate the collection of daily prospective information about bleeding outcomes in patients with thrombocytopenia, including information obtained by patient self‐assessment.

Materials and Methods  Consecutive patients with haematological malignancies were enrolled in a study of bleeding data collection during the period of thrombocytopenia. A short educational session and information sheet was designed for self‐assessment. Platelet counts and all transfusions were recorded daily. Bleeding scores were translated into World Health Organization (WHO) bleeding grades.

Results  Nineteen patients were included in the study. Four‐hundred and ten days of thrombocytopenia were eligible for assessment of bleeds. Self‐assessment was feasible, as defined by the total proportion of days on which self‐assessment was completed (70%, 288 thrombocytopenic days). There was 86% agreement between bleeding data collected by self‐assessment and by medical examination using a structured assessment form. Examples of discrepancies included the duration of petechiae/bruises and the reporting of minor bleeding. There was no evidence for an association between patients’ morning platelet count and daily WHO bleeding grade. The incidences of WHO grade 1 and grade 2 bleeding on days with platelet counts ≤ 10 × 109/l, 11–20 × 109/l, and > 20 × 109/l were similar and did not reveal higher rates of bleeding at lower counts.

Conclusions  Patient self‐assessment can help to support comprehensive daily prospective monitoring of bleeding, specifically facilitating data collection following hospital discharge. The discrepancies between self‐assessment and medical examination highlight the need to develop a validated international assessment tool. The association among platelet count, risk of bleeding and role of prophylactic platelet transfusions needs further evaluation in larger prospective trials.
Localization of Fibroblast Growth Factor I (Acid Fibroblast Growth Factor) and Its mRNA in the Bovine Mammary Gland During Mammogenesis, Lactation and Involution
Authors: Sinowatz F. , Schams D. , Habermann F. , Berisha B. , Vermehren M.
Published: May 2006

Growth factors are involved in development and function of the mammary gland. The aim of this study was the localization of fibroblast growth factor 1 (FGF‐1) and its mRNA in the bovine mammary gland during different developmental and functional stages. Mammary tissue was obtained from German Brown Swiss cows (n = 23) during defined stages of mammogenesis (before and during pregnancy), lactogenesis, peak lactation and involution. The distribution of FGF‐1 mRNA was studied using non‐radioactive in situ hybridization, the corresponding FGF‐protein was analysed using immunohistochemistry [avidin–biotin peroxidase complex (ABC)‐method]. A moderate to distinct staining for FGF‐mRNA was found in the epithelium of ducts and developing alveoli during mammogenesis. Post‐partum at the same cellular locations, a considerable amount of FGF‐1 mRNA, was seen that decreased during lactation. Also during early involution clear staining for FGF‐mRNA could still be observed. Immunoreactive FGF‐1 was found in considerable concentration in the epithelium of the mammary gland in heifers. The staining intensity generally decreased somewhat during mammogenesis and lactation, but could be always clearly demonstrated in the secretory epithelial cells of alveoli and glandular ducts. Also during the first day after the end of milking, the epithelium displayed a moderate to distinct epithelial immunostaining. Notably, After 4 weeks of involution, in many alveoli a shedding of the FGF‐1 positive luminal cell layer was found. In our localization studies, no strict correlation between FGF‐1 mRNA and its corresponding protein was found. The various reasons for this finding are discussed.
6q Terminal Deletion Syndrome Associated with a Distinctive EEG and Clinical Pattern: A Report of Five Cases
Authors: Elia Maurizio , Striano Pasquale , Fichera Marco , Gaggero Roberto , Castiglia Lucia , Galesi Ornella , Malacarne Michela , Pierluigi Mauro , Amato Carmelo , Musumeci Sebastiano A. , Romano Corrado , Majore Silvia , Grammatico Paola , Zara Federico , Striano Salvatore , Faravelli Francesca
Published: May 2006

Summary:  Purpose: Mental retardation, facial dysmorphisms, and neurologic and brain abnormalities are features of 6q terminal deletions. Epilepsy is frequently associated with this chromosome abnormality, but electroclinical findings are not well delineated. We report five unrelated patients with 6q terminal deletions and a peculiar clinical, EEG, and neuroradiologic picture of epilepsy, mental retardation, and colpocephaly.

Methods: These three male and two female patients underwent general and neurologic examinations, repeated awake and sleep EEGs, and brain magnetic resonance imaging (MRI). A cytogenetic study and fluorescent in situ hybridization (FISH) with chromosome‐specific subtelomeric probes were carried out in all cases.

Results: All subjects had seizures characterized by vomiting, cyanosis, and head and eye version, with and without loss of consciousness. In four cases, EEGs showed posterior spike‐and‐wave complexes, which were activated by sleep. No patient had status epilepticus or prolonged seizures. Brain MRI revealed colpocephaly and dysgenesis of the corpus callosum and brainstem in four patients; three of them also had hypertrophic massa intermedia. FISH analysis revealed a 6q terminal deletion in all patients, which ranged between 9 Mb (cases 2 and 3) and 16 Mb (case 4).

Conclusions: We suggest that epilepsy associated with 6q terminal deletions is a new entity. Patients with dysmorphic features associated with focal occipital epilepsy, colpocephaly, and dysgenesis of the corpus callosum, thalami, and brainstem should be considered candidates for testing for 6q subtelomere deletions.
Solid‐State Reactive Sintering of Transparent Polycrystalline Nd:YAG Ceramics
Authors: Lee Sang‐Ho , Kochawattana Sujarinee , Messing Gary L. , Dumm John Q. , Quarles Gregory , Castillo Vida
Published: May 2006

Transparent polycrystalline Nd:YAG ceramics were fabricated by solid‐state reactive sintering a mixture of commercial Al2O3, Y2O3, and Nd2O3 powders. The powders were mixed in methanol and doped with 0.5 wt% tetraethoxysilane (TEOS), dried, and pressed. Pressed samples were sintered from 1700° to 1850°C in vacuum without calcination. Transparent fully dense samples with average grain sizes of ∼50 μm were obtained at 1800°C for all Nd2O3 levels studied (0, 1, 3, and 5 at.%). The sintering temperature was little affected by Nd concentration, but SiO2 doping lowered the sintering temperature by ∼100°C. Abnormal grain growth was frequently observed in samples sintered at 1850°C. The Nd concentration was determined by energy‐dispersive spectroscopy to be uniform throughout the samples. The in‐line transmittance was >80% in the 350–900 nm range regardless of the Nd concentration. The best 1 at.% Nd:YAG ceramics (2 mm thick) achieved 84% transmittance, which is equivalent to 0.9 at.% Nd:YAG single crystals grown by the Czochralski method.
Orthodontic movement after periodontal regeneration of class II furcation: a pilot study in dogs
Authors: Da Silva Vanessa Camila , Cirelli Carolina Chan , Ribeiro Fernando Salimon , Costa Maurício Ribeiro , Comelli Lia Raphael Carlos , Cirelli Joni Augusto
Published: May 2006

Purpose: The effect of orthodontic movement on the periodontal tissues of maxillary second pre‐molars, after regenerative treatment for class II furcations, was evaluated in four mongrel dogs.

Material and Methods: Class II furcation lesions were created. After 75 days they were treated with bovine bone mineral matrix and guided tissue regeneration with absorbable membrane. After 2 months of daily plaque control, each of the dog's furcation pre‐molars was randomly assigned to a test or control group. Orthodontic appliances were placed on both sides of the maxilla using third pre‐molars and canines as anchorages. In the test group, bodily orthodontic movement of the second pre‐molars was performed in the mesial direction for 3 months while control pre‐molars remained unmoved. The dogs were sacrificed for histometric and histologic analyses.

Results: There were no statistically significant differences between the two groups in total bone and biomaterial areas or linear extension of periodontal regeneration on the radicular surfaces. In the test group, however, there was a tendency to a greater quantity of bone and a lesser quantity of biomaterial.

Conclusion: The orthodontic movement was not pre‐judicial to the results obtained with the regenerative periodontal treatment.