bluuebunny/crossref_metadata_2025 huggingface dataset:
Transition to Turbulence Under Low‐Pressure Turbine Conditions
Authors: Simon Terrence W. , Kaszeta Richard W.
Published: July 2010

Abstract: In this paper, the topic of laminar to turbulent flow transition, as applied to the design of gas turbines, is discussed. Transition comes about when a flow becomes sufficiently unstable that the orderly vorticity structure of the laminar layer becomes randomly oriented. Vorticity with a streamwise component leads to rapid growth of eddies of a wide range of sizes and eventually to turbulent flow. Under “natural” transition, infinitesimal disturbances of selected frequencies grow. “Bypass transition” is a term coined to describe a similar process, but one driven by strong external disturbances. Transition proceeds so rapidly that the processes associated with “natural” transition seem to be “bypassed.” Because the flow environment in the turbine is disturbed by wakes from upstream airfoils, eddies from combustor flows, jets from film cooling, separation zones on upstream airfoils and steps in the duct walls, transition is of the bypass mode. In this paper, we discuss work that has been done to characterize and model bypass transition, as applied to the turbine environment.
STUDIES ON FREE STREAM TURBULENCE AS RELATED TO GAS TURBINE HEAT TRANSFER
Authors: YAVUZKURT SAVAS , IYER GANESH R.
Published: July 2010

Abstract: A review of the past work done on free stream turbulence (FST) as applied to gas turbine heat transfer and its implications for future studies are presented. It is a comprehensive approach to the results of many individual studies in order to derive the general conclusions that could be inferred from all rather than discussing the results of each individual study. Three experimental and four modeling studies are reviewed. The first study was on prediction of heat transfer for film cooled gas turbine blades. An injection model was devised and used along with a 2‐D low Reynolds number k‐ε model of turbulence for the calculations. Reasonable predictions of heat transfer coefficients were obtained for turbulence intensity levels up to 7%. Following this modeling study a series of experimental studies were undertaken. The objective of these studies was to gain a fundamental understanding of mechanisms through which FST augments the surface heat transfer. Experiments were carried out in the boundary layer and in the free stream downstream of a gas turbine combustor simulator, which produced initial FST levels of 25.7% and large length scales (About 5‐10 cm for a boundary layer 4‐5 cm thick). This result showed that one possible mechanism through which FST caused an increase in heat transfer is by increasing the number of ejection events. In a number of modeling studies several well‐known k‐ε models were compared for their predictive capability of heat transfer and skin friction coefficient under moderate and high FST. Two data sets, one with moderate levels of FST (about 7%) and one with high levels of FST (about 25%) were used for this purpose. Although the models did fine in their predictions of cases with no FST (baseline cases) they failed one by one as FST levels were increased. Under high FST (25.7% initial intensity) predictions of Stanton number were between 35‐100% in error compared to the measured values. Later a new additional production term indicating the interaction between the turbulent kinetic energy (TKE) and mean velocity gradients was introduced into the TKE equation. The predicted results of skin friction coefficient and Stanton number were excellent both in moderate and high FST cases. In fact these model also gave good predictions of TKE profiles whereas earlier unmodified models did not predict the correct TKE profiles even under moderate turbulence intensities. Although this new production term seems to achieve the purpose, it is the authors' belief that it is the diffusion term of the TKE equation, which needs to be modified in order to fit the physical events in high FST boundary layer flows. The results of these studies are currently being used to come up with new diffusion model for the TKE equation.
A Novel Digital Image Processing System for the Transient Liquid Crystal Technique applied for Heat Transfer and Film Cooling Measurements
Authors: VOGEL GREGORY , BOELCS ALBIN
Published: July 2010

Abstract: This paper is dedicated to the transient liquid crystal technique measurements for multiple view access by using a novel digital recording and image processing system.

The transient liquid crystal technique is widely used for heat transfer investigations in turbomachinery. It has been applied in our laboratory in several test facilities such as a linear cascade for external film cooling measurements or on a ribbed squared duct for internal cooling measurements.

The data analysis as well as the measurement equipment is described, with a special focus on the newly developed computerized image processing system suitable to capture the liquid crystal signal.
NUMERICAL INVESTIGATION OF HEAT TRANSFER ON FILM‐COOLED TURBINE BLADES
Authors: Ginibre P. , Lefebvre M. , Liamis N.
Published: July 2010

Abstract: The accurate heat transfer prediction of film‐cooled blades is a key issue for the aerothermal turbine design. For this purpose, advanced numerical methods have been developed at Snecma Moteurs. The goal of this paper is the assessment of a three‐dimensional Navier‐Stokes solver, based on the ONERA CANARI‐COMET code, devoted to the steady aerothermal computations of film‐cooled blades. The code uses a multidomain approach to discretize the blade to blade channel with overlapping structured meshes for the injection holes. The turbulence closure is done by means of either Michel mixing length model or Spalart‐Allmaras one transport equation model. Computations of thin 3D slices of three film‐cooled nozzle guide vane blades with multiple injections are performed. Aerothermal predictions are compared to experiments carried out by the von Karman Institute. The behavior of the turbulence models is discussed, and velocity and temperature injection profiles are investigated.
Analyses of Heat Transfer in Stationary and Rotating Ribbed Blade Cooling Passages using Computational Fluid Dynamics
Authors: BREWSTER R.A. , VITHULA S. JONNA
Published: July 2010

Abstract: Computational fluid dynamics (CFD) predictions of the flow patterns and heat transfer in simplified ribbed‐wall turbine blade cooling passages were performed for representative stationary and rotating conditions. Analyses have been performed with different mesh densities and using different turbulence models to assess the sensitivity of predictions to these variables. Computed local heat transfer results are compared to measurements available in the literature to assess their accuracy. The results generally agree well with experiment, although the peak values of the heat transfer coefficients were under‐predicted in the first leg of the channel. Some sensitivity to mesh density was seen, while the choice of near‐wall turbulence model appeared to have little effect.
Cell Senescence in Human Aging and Disease
Authors: FOSSEL MICHAEL
Published: July 2010

The most common causes of death and suffering, even in most underdeveloped nations, are age‐related diseases. These diseases share fundamental and often unappreciated pathology at the cellular and genetic levels, through cell senescence. In cancer, enforcing cell senescence permits us to kill cancer cells without significantly harming normal cells. In other age‐related diseases, cell senescence plays a direct role, and we may be able to prevent and reverse much of the pathology. While aging is attributed to “wear and tear,” genetic studies show that these effects are avoidable (as is the case in germ cell lines) and occur only when cells down‐regulate active (and sufficient) repair mechanisms, permitting degradation to occur. Aging occurs when cells permit accumulative damage by wear and tear, by altering their gene expression rather than vice versa. Using telomerase in laboratory settings, we can currently reset this pattern and its consequences both within cells and between cells. Doing so resets not only cell behavior but the pathological consequences within tissues comprising such cells. We can currently grow histologically young, reconstituted human skin using old human skin cells (keratinocytes and fibroblasts). Technically we could now test this approach in joints, vessels, the immune system, and other tissues. This model is consistent with all available laboratory data and known aging pathology. Within the next decade, we will be able to treat age‐related diseases more effectively than ever before.
Can Exercise Training Improve Immune Function in the Aged?
Authors: WOODS JEFFREY A. , LOWDER THOMAS W. , KEYLOCK K. TODD
Published: July 2010

Many strategies have been used to improve immune function in the aged. Unfortunately, many of these interventions have been disappointing, impractical, costly to develop and administer, or accompanied by adverse side effects. Aside from dietary manipulation (caloric restriction without malnutrition or antioxidant supplementation), research involving behavioral preventative or restorative therapies has been lacking. Moderate exercise training has been shown to elicit beneficial outcomes in both the prevention and rehabilitation of many diseases of the elderly. It has been hypothesized that moderate levels of exercise improves, whereas strenuous exercise or overtraining suppresses, various immune function measures. Three general approaches have been implemented to study the impact of exercise on immune functioning in the elderly: (1) cross‐sectional studies, (2) longitudinal studies, and (3) animal studies. In general, cross‐sectional studies examining highly active elderly have demonstrated improved in vitro T cell responses to polyclonal stimulation when compared to sedentary elderly. This is corroborated by several animal studies that have shown improved splenic T cell responses in vitro. Unfortunately, human prospective studies have failed to demonstrate consistent improvements in various measures of immune function in older adults. However, it should be cautioned that these studies have included small samples followed over a short duration, measuring a limited number of in vitro immune parameters, with some failing to account for potential confounding influences. Although such findings have the potential to be of substantial public health importance, very few systematic studies have been conducted.
Human Aging and Global Function of Coenzyme Q10
Authors: LINNANE ANTHONY W. , ZHANG CHUNFANG , YAROVAYA NATALIA , KOPSIDAS GEORGE , KOVALENKO SERGEY , PAPAKOSTOPOULOS PENNY , EASTWOOD HAYDEN , GRAVES STEPHEN , RICHARDSON MARTIN
Published: July 2010

In this paper, we review two parts of our recent work on human skeletal muscle. The first part mainly describes changes occurring during aging, whereas the second part discusses the functions of coenzyme Q10 (CoQ10), particularly in relation to the aging process. During the lifetime of an individual, mtDNA undergoes a variety of mutation events and rearrangements. These mutations and their consequent bioenergenic decline, together with nuclear DNA damage, contribute to the reduced function of cells and organs, especially in postmitotic tissues. In skeletal muscle, this functional decline can be observed by means of changes with age in fiber type profile and the reduction in the number and size of the muscle fibers. In addition to the functions of coenzyme Q10 as an electron carrier in the respiratory chain and as an antioxidant, CoQ10 has been shown to regulate global gene expression in skeletal muscle. We hypothesize that this regulation is achieved via superoxide formation with H2O2 as a second messenger to the nucleus.
Beta Cell Rest and Recovery—Does It Bring Patients with Latent Autoimmune Diabetes in Adults to Euglycemia?
Authors: PALMER JERRY P.
Published: July 2010

Abstract: Diabetes mellitus in humans is a heterogeneous disorder classified clinically into two main types. The diagnosis of type 1 versus type 2 diabetes is made phenotypically using criteria such as age at onset, abruptness of hyperglycemic symptoms, presence of ketosis, degree of obesity and the perceived need for insulin replacement. The pathogeneses of type 1 and type 2 diabetes are believed to be different. Type 1 diabetes is an autoimmune disease mediated by cellular effector mechanisms; whereas classic type 2 diabetes is not autoimmune but results from insulin resistance and a nonautoimmune insulin secretory defect. Most type 1 diabetes patients are diagnosed in childhood or young adulthood before the age of 35 years. However, there is clearly a subgroup of patients clinically diagnosed with type 2 diabetes who are greater than 35 years of age and have evidence of autoimmunity. The disease of these autoantibody‐positive type 2 diabetics is often termed latent autoimmune diabetes in adults (LADA), slowly progressive type 1 diabetes, latent type 1 diabetes, and type 1.5 diabetes. This group of patients comprises approximately 10‐15% of Caucasian type 2 diabetes patients. Type 1.5 diabetes patients tend to present with islet cell autoantibodies, islet‐reactive T cells, higher HbA1c levels, lower C peptide, and a propensity toward insulin dependency compared to autoantibody‐negative classic type 2 diabetes subjects.
Insulin Intervention to Preserve β Cells in Slowly Progressive Insulin‐Dependent (Type 1) Diabetes Mellitusa
Authors: KOBAYASHI TETSURO , MARUYAMA TARO , SHIMADA AKIRA , KASUGA AKIRA , KANATSUKA AZUMA , TAKEI IZUMI , TANAKA SHOICHIRO , YOKOYAMA JUNICHI
Published: July 2010

Abstract: Slowly progressive insulin‐dependent (type 1) diabetes mellitus (SPIDDM) is characterized by (1) late age of onset, with initial features of NIDDM and subsequent progression to insulin‐dependent stage; (2) high predictive value of autoantibodies against glutamic acid decarboxylase (GADAb) and islet cell antibodies (ICA) for progression of β cell failure; (3) less predominant T cell response, which may attack and eventually destroy β‐cells in affected pancreas. These findings may suggest a rationale for intervention to prevent slowly progressive β cell dysfunction in this type of diabetes. We identified three independent risk factors for progression of β cell failure in SPIDDM: (1) sulfonylurea treatment; (2) ICA‐positive periods; and (3) initial body weight. We hypothesized that removal of the risk factors for further progression of β cell dysfunction will have beneficial effects on intervention strategy in treating SPIDDM. In our pilot study, we used a small dose of insulin instead of sulfonylurea in the early stage of treatment of patients with SPIDDM. Insulin‐treated SPIDDM patients had a sustained C peptide response (CPR), while most of sulfonylurea‐treated patients progressed to an insulin‐dependent state. We organized a randomized multicenter clinical trial to study early treatment to prevent the progression of β cell dysfunction in SPIDDM (the Tokyo Study). It was demonstrated that early intervention with insulin therapy is an effective treatment modality in the early stage of SPIDDM patients who had preserved β cell function at entry (integrated value of serum C peptide values at 0, 30, 60, 90, and 120 minutes; Sigma CPR ≥ 10 ng/mL) and high GADAb (>10 U/mL). Preventive insulin treatment was ineffective in the patients who had diminished insulin reserve at entry (Sigma CPR < 10 ng/mL). Insulin intervention to preserve β cell dysfunction in SPIDDM is effective and safe in patients with preserved β cell function and high GADAb titers at the initiation of insulin.
Role of Donor MHC Class III Genes in the Destruction of Transplanted Islets in NOD Mice
Authors: JEVNIKAR ANTHONY M. , PRANGE SEAN , ZUCKER PETER , SINGH BHAGIRATH
Published: July 2010

Abstract: MHC class III genes are important in immune regulation and inflammation, and the gene products of this region are well conserved between species. Their role in diabetes is, however, unknown. We used islets from NOD mice that lacked expression of both MHC class I and class II molecules to test the effect of class III differences on the injury of transplanted NOD islets. Loss of islet MHC class I was highly protective, while deletion of MHC class II had no benefit on islet survival. However the combined absence of both MHC class I and class II expression by NOD islets resulted in a delayed form of injury, when islets were transplanted to NOD mice. As neither MHC class I or II molecules were expressed by donor islet tissue, these results suggest a previously unrecognized and important contribution of MHC class III differences on islet injury following transplantation.
Autoantibodies to IA‐2 in Type 1 Diabetes
Authors: KAWASAKI EIJI , YAMAGUCHI HIROKAZU , HATTORI HIROAKI , EGASHIRA TORU , EGUCHI KATSUMI
Published: July 2010

Abstract: The tyrosine phosphatase‐like protein IA‐2 is an important islet autoantigen in type 1 diabetes. Although the radioligand binding assay with in vitro synthesized 35S‐labeled antigen has been used extensively for measuring autoantibodies to IA‐2, disadvantages of both assays with respect to synthesis and handling of the radioactive antigen limit their use in routine laboratories. Therefore, we attempted to develop a nonradioactive ELISA for the simple detection of IA‐2 autoantibodies. The biotinylated cytoplasmic domain of IA‐2 expressed in Escherichia coli was used as an antigen. We evaluated two kinds of ELISA: ELISA with biotin‐IA‐2 directly captured on streptavidine‐coated plates (solid phase) and ELISA with antigen‐antibody preincubation in solution in which serum samples were reacted first with biotin‐IA‐2 and the mixture was transferred to streptavidine‐coated plates (liquid phase). We compared their disease sensitivity and specificity with a conventional radioligand binding assay in 52 patients with recent‐onset type 1 diabetes and 138 normal individuals. The radioligand binding assay had 61.5% sensitivity and 99.3% specificity. The liquid‐phase ELISA showed relatively higher sensitivity (55.8%) and specificity (99.3%) than the solid‐phase ELISA (sensitivity 53.8% and specificity 97.1%). Furthermore, the mean SD score in IA‐2 autoantibody‐positive serum samples measured by liquid‐phase ELISA was significantly higher than the SD score obtained by solid‐phase ELISA (P < 0.0001). We concluded that this liquid‐phase ELISA is suitable for detecting IA‐2 autoantibodies in patients with type 1 diabetes with a similar sensitivity and specificity to those of conventional radioligand binding assay.
Anti‐Insulin‐like Growth Factor‐1 Autoantibodies in Type 1 Diabetes
Authors: MARUYAMA TARO , MURAYAMA HIROSHI , NAGATA ATSUO , SHIMADA AKIRA , KASUGA AKIRA , SARUTA TAKAO
Published: July 2010

Abstract: Insulin‐like growth factor‐1 (IGF‐1) reportedly suppresses the development of type 1 diabetes in NOD mice, suggesting that IGF‐1 is possibly a candidate for the autoantigens in type 1 diabetes. We therefore examined the anti‐IGF‐1 autoantibodies (IGF‐1 Ab) in sera from patients with type 1 diabetes using radioimmunoassay. However, we were unable to demonstrate the existence of anti‐IGF‐1 autoantibodies in type 1 diabetes with our method. Further study is necessary to clarify whether anti‐IGF‐1 autoantibodies are existent in human type 1 diabetes and to determine the significance of IGF‐1 in the pathogensesis of type 1 diabetes.
The Number of Markers of Pancreatic Autoimmunity Is Proportional to the Risk for Type 1 Diabetes Mellitus in Italian and English Patients with Organ‐Specific Autoimmune Diseases
Authors: BETTERLE C. , SPADACCINO A. C. , PRESOTTO F. , ZANCHETTA R. , PEDINI B. , LAI M. , GREGGIO N. A. , BOTTAZZO G. F.
Published: July 2010

Abstract: An 11‐year prospective study was carried out in 226 patients with organ‐specific autoimmune disease (OSAD) coming from northern Italy and southern England. Patients were investigated for diabetes‐related autoantibodies (ICAs, GADAbs, and IA2Abs) in order to evaluate the best immunological combination in predicting type 1 DM. One hundred twenty‐eight patients were ICA positive (77 Italian and 51 English), and 98 were ICA negative. ICAs were detected by immunofluorescence technique on human pancreas, whereas GADAbs and IA2Abs were found by immunoprecipitation assay. During follow‐up, 33 of 128 (25.8%) ICA+ (26% of Italian and 25.5% of English) and 2 of 98 (2%) ICA− patients developed type 1 DM (17 with acute‐onset, and 18 with non‐acute‐onset disease). Among ICA+ patients, three subgroups were considered: ICA+ alone; ICA and GADAb+; ICA, GADAb, and IA2Ab+. Patients who were only ICA+ had a predictive value for type 1 DM of 4.7%, with an annual incidence of 0.7%, and a cumulative risk of 6%. ICA and GADAb+ patients had a predictive value of 17.5%, with an annual incidence of 2%, and a cumulative risk of 20%. ICA, GADAb, and IA2Ab+ patients had a predictive value of 72, with an annual incidence of 13%, and a cumulative risk of 87%. Patients having three immunological markers revealed a prevalence increased in HLA‐DR3 and/or ‐DR4, but reduced in HLA‐DR2 haplotypes. The risk for type 1 DM increased proportionally with the number of diabetes‐related antibodies, which were also related to the presence of genetic markers of disease susceptibility.
Autoimmune Diabetes in 26 Villages outside Madras
Authors: DATTA MANJULA , SHTAUVERE‐BRAMEUS A. , GUPTA V. , MANI M. K. , SANJEEVI C. B.
Published: July 2010

Abstract: Autoimmune diabetes is one of the most common chronic diseases in the world. Autoantibodies against major antigens GAD65 and IA‐2 as well as some minor antibodies are markers for autoimmune diabetes already several years before clinical onset in most populations. Screening the population for these autoantibodies can help identify subjects at risk for developing type 1 diabetes. In our study we screened 20,903 inhabitants in 26 villages outside Madras for diabetes. Among them 3.64% were detected to be diabetic. The aim of our study was to detect the presence of glutamic acid decarboxylase (GAD65), tyrosine phosphates (IA‐2) and tissue transglutaminase (TTG) antibodies. We studied 169 individuals from this population, 75 of them were diagnosed as diabetics, based on presence of sugar in the urine and an elevated blood sugar, 58 had hypertension, and 36 were healthy subjects. We used radioimmunoassay with in vitro translated and transcribed human recombinant 35S‐GAD65, IA‐2 and TTG antigens. We observed presence of GAD65Ab in 10%, IA‐2Ab in 5%, and TTGAb in 5% in diabetic subjects, while the healthy subjects and people with hypertension didn't carry any of these antibodies. We conclude that prevalence of autoimmune diabetes mellitus based on antibody screening in this population is significantly high.
HLA‐DRB1, DQB1, and DQA1 Allele Profile in Brazilian Patients with Type 1 Diabetes Mellitus
Authors: FERNANDES A. P. M. , LOUZADA‐JÚNIOR P. , FOSS M. C. , DONADI E. A.
Published: July 2010

Abstract: HLA class II profile was evaluated in 64 Brazilian patients presenting with type 1 diabetes mellitus. Although the Brazilian population is highly miscegenated, HLA‐DRB1*301, DRB1*04, DQB1*0302, and DQB1*0201 alleles, which are associated with the development of type 1 diabetes in several Western populations, were also overrepresented in Brazilian patients. In addition to HLA‐DRB1*15 and DQB1*0602 alleles, DRB1*11, DRB1*13, and DQA1*01 allele groups were associated with protection against the development of type 1 diabetes in Brazilian patients.
CTLA‐4 Gene Polymorphism Contributes to the Genetic Risk for Latent Autoimmune Diabetes in Adults
Authors: COSENTINO ANNA , GAMBELUNGHE GIOVANNI , TORTOIOLI CRISTINA , FALORNI ALBERTO
Published: July 2010

Abstract: Latent autoimmune diabetes in adults (LADA) is identified by the presence of GAD65 autoantibodies in diabetic patients who do not require insulin treatment for at least six months after the diagnosis. Previous studies have shown that the risk for LADA, similarly to type 1 diabetes mellitus (T1DM), is increased in subjects carrying the HLA‐DRB1*03‐DQA1*0501‐DQB1*0201 and/or HLA‐DRB1*04‐DQA1*0301‐DQB1*0302 haplotypes. In the present study, we investigated the association between LADA and the CTLA‐4 A/G polymorphism, another gene polymorphism associated with T1DM and other autoimmune diseases. The heterozygous A/G genotype was significantly more frequent among 80 LADA (69%) than among 85 healthy subjects of similar age and geographical provenience (47%) (OR = 2.47, corrected P= 0.023). Conversely, the homozygous A/A genotype was significantly less frequent in LADA subjects than in healthy controls (26% vs. 47%, OR = 0.4, corrected P= 0.028). The results of our study show that LADA is positively associated with the CTLA‐4 A/G genotype, similarly to T1DM, thus providing further supporting evidence of the autoimmune origin of this form of diabetes mellitus of the adult.
DR3 Is Associated with Type 1 Diabetes and Blood Group ABO Incompatibility
Authors: BERZINA L. , LUDVIGSSON J. , SADAUSKAITE‐KUEHNE V. , NELSON N. , SHTAUVERE‐BRAMEUS A. , SANJEEVI C. B.
Published: July 2010

Abstract: Type 1 diabetes is associated with autoimmunity against pancreatic β cells. ABO incompatibility is associated with ABO immunization during pregnancy. Type 1 diabetes is associated with certain HLA DR and DQ haplotypes. The mechanism by which blood group incompatibility is associated with the risk of type 1 diabetes is not known. We propose that certain HLA alleles contribute to the development of both type 1 diabetes and ABO blood group incompatibility. We studied 57 children with ABO blood group incompatibility, 118 children with type 1 diabetes, and 98 age‐ and sex‐matched unrelated healthy controls from Linköping. Typing of HLA DQA1, DQB1, and DRB1 was done on DNA extracted from peripheral blood, by PCR amplification, manual dot‐blotting onto nylon membranes, synthetic sequence‐specific oligonucleotide (SSO) probe 3′ end‐labeling with 32P‐dCTP, and hybridization followed by stringency washes and autoradiography. We observed that DR3 allele was more frequent in patients with ABO incompatibility when compared to healthy controls (OR = 2.7, Pc < 0.05). Patients with type 1 diabetes had significantly higher frequency of DR3, DQ2, DR4, and DQ8 alleles when compared to healthy controls. No significant difference was observed in frequency of DR3 between ABO blood group incompatibility and type 1 diabetes patients. We conclude that DR3 is associated with both the development of type 1 diabetes and ABO incompatibility.
Microsatellite Allele A5.1 of MHC Class I Chain‐Related Gene A Is Associated with Latent Autoimmune Diabetes in Adults in Latvia
Authors: BERZINA L. , SHTAUVERE‐BRAMEUS A. , RUMBA I. , SANJEEVI C. B.
Published: July 2010

Abstract: NIDDM is one of the most common forms of diabetes. The diagnosis is based on WHO classification, which is a clinical classification and misses the autoimmune diabetes in adults. Therefore, among the clinically diagnosed NIDDM cases, there can be a certain number of patients with latent autoimmune diabetes in adults (LADA). The MICA gene is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MICA gene identifies trinucleotide repeat (GCT) microsatellite polymorphism, which identifies 5 alleles with 4, 5, 6, and 9 repetitions of GCT (A4, A5, A6, and A9) or 5 repetitions of GCT with 1 additional G insertion for allele A5.1. From our previous studies, we have shown that microsatellite allele A5 of MICA is associated with IDDM. The aim of this study was to test the hypothesis that certain MICA alleles are associated with LADA among clinically diagnosed NIDDM. Out of 100 clinically diagnosed NIDDM patients, 49 tested positive for GAD65 and IA‐2 antibodies by use of 35S RIA. Samples from these 49 patients and 96 healthy controls were analyzed for MICA by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. Our results show that MICA allele A5.1 is significantly increased in antibody‐positive (GAD65 or IA‐2) NIDDM patients [35/49 (72%)] when compared to healthy controls [22/96 (23%)] (OR = 8.4; P < 0.0001). However, we do not see any association with each of the antibodies separately. From our study, we conclude that (a) MICA allele A5.1 is associated with LADA and (b) MICA may play an important role in the etiopathogenesis of LADA.
First‐Principles Simulations of Molecular Electronics
Authors: PANTELIDES SOKRATES T. , DI VENTRA MASSIMILIANO , LANG NORTON D.
Published: July 2010

Abstract: This paper gives an overview of recent work by the authors in first‐principles, parameter‐free calculations of electronic transport in molecules in the context of experimental measurements of current‐voltage (I‐V) characteristics of several molecules by Reed et al. The results show that the shape of I‐V characteristics is determined by the electronic structure of the molecule in the presence of the external voltage, whereas the absolute magnitude of the current is determined by the chemistry of individual atoms at the contacts. A three‐terminal device has been simulated, showing gain. Finally, recent data that show large negative differential resistance and a peak that shifts substantially as a function of temperature have been accounted for in terms of rotations of ligands attached to the main molecule, a phenomenon that is not present in semiconductor nanostructures.
Epidemiology, Risk Factors, and Natural History of Hepatocellular Carcinoma
Authors: MONTALTO GIUSEPPE , CERVELLO MELCHIORRE , GIANNITRAPANI LYDIA , DANTONA FABIO , TERRANOVA ANGELA , CASTAGNETTA LUIGI A. M.
Published: July 2010

Abstract: The incidence of hepatocellular carcinoma is increasing in many countries. The estimated number of new cases annually is over 500,000, and the yearly incidence comprises between 2.5 and 7% of patients with liver cirrhosis. The incidence varies between different geographic areas, being higher in developing areas; males are predominantly affected, with a 2:3 male/female ratio. The heterogeneous geographic distribution reflects the epidemiologic impact of the main etiologic factors and environmental risk, which are the hepatitis B (HBV) and hepatitis C (HCV) viruses. The percentage of cases of hepatocellular carcinoma attributable to HBV worldwide is 52.3% and is higher in Asia where the seroprevalence of HBsAg in the population is high. However, the vaccination campaign against this virus in some eastern countries has tended to lower the incidence of new cases of hepatocellular carcinoma. The percentage of cases of hepatocellular carcinoma attributable to HCV is 25%, and it is more prevalent in Japan, Spain, and Italy where the association between hepatocellular carcinoma and antibodies to HCV ranges between 50 and 70%. In most cases hepatocellular carcinoma develops in cirrhotic livers, where the persistent proliferation of liver cells represents the key factor of progression to hepatocellular carcinoma independent of the etiology. Another minor risk factor is aflatoxin B1 consumption, which is responsible for most cases of hepatocellular carcinoma in Africa, where the consumption of contaminated foods is common. Other known risk factors are some hereditary diseases, such as hemochromatosis, porphyria cutanea tarda, hereditary tyrosinemia, and α1 anti‐trypsin deficiency. The natural history of hepatocellular carcinoma is heterogeneous and is influenced by nodule dimension, the mono‐ or plurifocality of lesions at diagnosis, the growth rate of the tumor, and the stage of the underlying cirrhosis. Available data to date suggest that tumor growth in a cirrhotic liver is variable and that the time in which a lesion in undetectable until it becomes 2 cm is between 4 and 12 months. Therefore, the suggested interval for surveillance screening with ultrasound in patients with liver cirrhosis has been set at 6 months. Patients who should benefit from screening programs are those who would be treated with curative therapy if diagnosed with hepatocellular carcinoma. Thus, the ideal target population should be limited to Child‐Pugh's class A cirrhotic patients without significant comorbidity.
Expression of HIP/PAP mRNA in Human Hepatoma Cell Lines
Authors: CERVELLO M. , GIANNITRAPANI L. , LA ROSA M. , NOTARBARTOLO M. , D'ALESSANDRO N. , VIRRUSO L. , IOVANNA J. L. , MONTALTO G.
Published: July 2010

Abstract: The present study attempts to shed more light on the role of hepatocarcinoma‐intestine‐pancreas/pancreatic associated protein (HIP/PAP) in hepatoma cells. We initially examined, by reverse transcription‐polymerase chain reaction (RT‐PCR), the HIP/PAP transcripts present in human hepatoma cell lines of different origins and with different grades of differentiation and genetic profiles. We also used DNA sequencing analysis to investigate the structure of the HIP/PAP gene. Further investigation is necessary to define the role of HIP/PAP during the development of human hepatocellular carcinoma and to ascertain whether the use of different transcripts is helpful in regulating HIP/PAP expression in transformed liver cells.
Amplified MYCN in Human Neuroblastoma
Authors: SCHWAB MANFRED
Published: July 2010

Abstract: Increase in the dosage of cellular oncogenes by DNA amplification is a frequent genetic alteration of cancer cells. In neuroblastoma, amplification of the gene MYCN has been associated with aggressively growing cancers and is an indicator for poor prognosis. MYCN amplification is of predictive value in identifying patients with neuroblastoma who require specific therapeutic regimens and those who do not benefit from chemotherapy.
Connexin Expression in Nonneoplastic Human Prostate Epithelial Cells
Authors: SALADINO FRANCESCA , CARRUBA GIUSEPPE , QUADER SALMAAN T.A. , AMOROSO MARIA , DI CRISTINA ANTONIETTA , WEBBER MUKTA M. , CASTAGNETTA LUIGI A.M.
Published: July 2010

Abstract: Expression of gap‐junction proteins connexins (Cx), specifically Cx43, Cx32, and Cx26, in both nontumorigenic (RWPE‐1) and tumorigenic (RWPE‐2) human prostate epithelial cells as well as in two cell clones (WPEI‐7 and WPEI‐10) originating from the RWPE‐1 cell line was investigated. The aim was to determine whether individual connexins are differentially expressed in cultured cells. Western blot analysis revealed striking differences in the expression of individual connexins in the cell lines studied. In particular, Cx43 is largely expressed in RWPE‐1 and WPEI‐10 cells, whereas Cx32 is expressed predominantly in RWPE‐2 and WPEI‐7 cells. In addition, both forskolin and estrone increase Cx43 expression levels in WPEI‐10 cells, with no apparent effect on WPEI‐7 cells. Conversely, forskolin and especially estrone induce a marked increase of Cx32 in WPEI‐7 cells, whereas Cx32 expression is limitedly affected by both agents in WPEI‐10 cells. Overall, expression levels of Cx43 and Cx32 appear to be inversely related, with RWPE‐1 and WPEI‐10 cells having a significantly higher Cx43 to Cx32 ratio than that observed in RWPE‐2 and WPEI‐7 cells. We recently reported that junctional communication could be rescued in RWPE‐1 cells by either forskolin or estrone and that restoration of GJIC is associated with an increase of Cx43 or a decrease of Cx32, or both, eventually leading to a marked rise of the Cx43 to Cx32 ratio. Studies are currently ongoing in our laboratories to assess the potential effect of agents increasing the Cx43 to Cx32 ratio on GJIC activity in these systems.
From Genes to Therapy: The Case of Philadelphia Chromosome‐Positive Leukemias
Authors: CILLONI DANIELA , GUERRASIO ANGELO , GIUGLIANO EMILIA , SCARAVAGLIO PATRIZIA , VOLPE GISELLA , REGE‐CAMBRIN GIOVANNA , SAGLIO GIUSEPPE
Published: July 2010

Abstract: The Philadelphia chromosome (Ph‐chromosome) has long represented the only cytogenetic abnormality known to be associated with a specific malignant disease in humans, being present in more than 95% of patients with chronic myelogenous leukemia. This abnormality is the result of a reciprocal translocation between the long arms of chromosome 9 and 22, t(9;22)(q34;q11), and its presence is not restricted to chronic myelogenous leukemia, but can also be found in 30% of cases of acute lymphoblastic leukemia in adults. In the 1980s, the molecular counterpart of the chromosomal rearrangement was identified to consist of the juxtaposition of parts of the BCR and ABL genes to form a BCR‐ABL hybrid gene. The resulting chimeric proteins (P210 and P190), which retain constitutively activated tyrosine kinase activity, have demonstrated a causative role in the genesis of the leukemic process. Although many aspects of the BCR‐ABL driven transformation remain unsolved, great advances in understanding the molecular pathology of Ph‐positive leukemias resulted in meaningful improvement in the clinical setting. Molecular tools to diagnose disease (PCR, FISH, and southern blot) and to monitor minimal residual disease after potential curative treatment are now in current practice, and new powerful therapeutic tools have emerged that target the molecular oncogenic pathways activated in Ph‐positive cells. Among them, specific ABL tyrosine kinase inhibitors recently obtained extraordinary results in many clinical protocols. This review summarizes the most recent advances in this field with special focus on the putative mechanisms of the transformation and progression of chronic myelogenous leukemia and on the major impact that understanding the molecular biology of these diseases is having in clinical practice.
Androgen Receptor Status in Nontumoral and Malignant Human Colorectal Tissues
Authors: CASTAGNETTA L. , TRAINA A. , CAMPISI I. , CALABRÒ M. , MARATTA A. , SAETTA A. , AGOSTARA B. , MEZZATESTA N.
Published: July 2010

Abstract: Data on androgen receptor (AR) status of nontumoral and malignant human colorectal tissues are compared using ligand binding assay in 22 patients who underwent surgery for colorectal cancer at the “M. Ascoli” Cancer Hospital Centre in Palermo, Sicily. In nontumoral tissues, ARs were predominantly (67%) positive, with 25% of cases having a 0/+ status. Conversely, malignant tissues showed only 32% of cases with a positive (+/+) AR status, with a proportional increase of 0/+ cases (from 25% to 55%); the extent of AR‐negative (0/0) cases remained fairly constant (8‐9%). Overall, our evidence indicates that nontumoral colorectal tissues have a predominantly positive (+/+) AR status and that this condition shifts towards a significant decrease of AR‐positive cases in cancer tissues. Studies on the relation between status of sex steroid receptors and specific biomolecular markers in human colorectal tumors are currently being carried out in our laboratories.
Prenatal Exposure to Methamphetamine in the Rat
Authors: GOMES‐DA‐SILVA JOANA , PÉREZ‐ROSADO ALBERTO , DE MIGUEL ROSARIO , FERNÁNDEZ‐RUIZ JAVIER , SILVA M. CAROLINA , TAVARES M. AMÉLIA
Published: July 2010

Abstract: Methamphetamine (Meth) is an illicit substance known to interfere with catecholaminergic systems and a popular recreational drug among young adult women, that is, in gestational age. Tyrosine hydroxylase (TH), the rate‐limiting enzyme of the synthetic pathway of catecholamines, is a good marker to assess potential effects of Meth in catecholaminergic (particularly in dopaminergic) systems. In the rat, prolonged neonatal Meth exposure altered several dopaminergic markers (TH activity and gene expression) in substantia nigra pars compacta (SN) and in caudate‐putamen (TH activity) when animals matured. However, it was never verified whether gestational exposure to Meth might compromise TH enzyme in the pups during the neonatal immature periods. The present study was designed to address this issue by analyzing TH gene expression, measured by in situ hybridization in SN and ventral tegmental area (VTA), dopaminergic areas that are well characterized as target areas for Meth, and in rats prenatally exposed to this psychostimulant. To this end, dated pregnant Wistar rat dams received 5 mg Meth hydrochloride/kg body weight/day. It was administered subcutaneously from gestational day 8 until 22. The control group was pair‐fed and saline injected, using the same experimental protocol as for Meth‐treated dams. On the day of birth (postnatal day 0, PND 0), litters were culled to 8 pups, sex‐balanced whenever possible, and were followed until the day of sacrifice (PND 7, 14, or 30). Meth treatment differentially affected TH mRNA levels in VTA and SN, in an age‐ and gender‐dependent manner. Thus, TH mRNA levels were decreased in the VTA of PND 7 and PND 14 females gestationally exposed to Meth; this effect was not evident in males or on PND 30. TH mRNA levels also tend to decrease in SN of PND 14 females gestationally exposed to Meth. Collectively, the present results indicated that gestational Meth exposure affects TH gene expression in the postnatal life, a phenomenon that appears to be transient, since it is no longer evident by the end of the first month of life in the rat.
Environmental Chemical Compounds Could Induce Sensitization to Drugs of Abuse
Authors: DUFFARD RICARDO , DE DUFFARD ANA MARÍA EVANGELISTA
Published: July 2010

Abstract: Chemical environment should be considered as an additional factor that influences drugs of abuse. Besides, maternal exposure to environmental chemicals has increased, and fetuses as well as neonates may be at greater risk than adults. Studies from our laboratory have described a permanent effect of the worldwide use of the herbicide 2,4‐dichlorophenoxyacetic acid (2,4‐D) on serotonin and dopamine content in total brain and specific brain areas of adult rats born of mothers treated during lactation and fed with 2,4‐D‐treated diet after weaning. These animals show a modified neurotransmitter‐related behavioral pattern in their developmental young and in adult age. Drugs that could be used to challenge the dopaminergic or serotoninergic systems include amphetamine or haloperidol, a postsynaptic dopamine receptor blocker. 2,4‐D‐exposed animals showed exacerbated response to challenges. Postnatal alterations in central dopaminergic and serotoninergic systems due to environmental chemical exposure may contribute to the enhanced/reduced behavioral sensitization to drugs of abuse.
Insulin Stimulation of Hepatic Triacylglycerol Secretion in the Insulin‐Replete State
Authors: ZAMMIT VICTOR A.
Published: July 2010

Abstract: Observations on humans, on rats in vivo, and on isolated perfused rat livers indicate that insulin stimulates hepatic very‐low‐density lipoprotein (VLDL)‐TAG secretion when the liver is chronically exposed to the hormone. They suggest that frequent stimulation of insulin secretion throughout the diurnal cycle may result in a chronic stimulation of VLDL secretion and increased delivery of acyl moieties to the periphery, particularly to muscle, the most important site of insulin‐sensitive glucose disposal. If acyl groups are provided in excess of the oxidative needs of the tissue, this may lead to induction of insulin resistance, irrespective of whether obesity is established concomitantly. Dietary factors that stimulate hepatic VLDL secretion may have the same effect and contribute to the induction of a vicious spiral leading to the development of the full‐blown Metabolic Syndrome and its pathological consequences, including type‐2 diabetes, stroke, and cardiovascular disease.
Enhanced Diabetogenic Effect of Streptozotocin in Mice Overexpressing UCP‐3 in Skeletal Muscle
Authors: WANG STEVEN , CAWTHORNE MICHAEL A. , CLAPHAM JOHN C.
Published: July 2010

Abstract: Diabetic patients exhibit varying degrees of increased muscle UCP‐3 expression in skeletal muscle and, in rodents, the pancreatoxin streptozotocin (STZ) upregulates UCP‐3 mRNA in skeletal and cardiac muscles. We have investigated the development of STZ‐induced diabetes in transgenic mice overexpressing UCP‐3 in skeletal muscle in order to provide further insight on the functional role of muscle UCP‐3. UCP‐3 transgenic mice treated with STZ (UCP3‐STZ) showed a significant increase in blood glucose concentration 3 days after the last dose of STZ with a progressive induction of diabetes, attaining blood glucose concentrations of 24.7 ± 1.5 mmol/L on day 17. Wild‐type mice treated with STZ (WT‐STZ) only started to show an increase in blood glucose concentration 6 days after the last dose of STZ and peaked on day 17 at a lower concentration than in the UCP‐STZ mice. The pancreatic insulin content of UCP‐3 control mice (UCP3‐CON) was decreased relative to wild‐type control mice (WT‐CON), and STZ reduced the total pancreatic insulin content by 72% in WT‐STZ mice and by 88% in UCP3‐STZ mice. In an insulin tolerance test, blood glucose concentrations declined more in the UCP‐3 transgenic mice than in the wild‐type mice. Mice overexpressing UCP‐3 in skeletal muscle have a lower pancreatic insulin content, but tend to be more insulin‐sensitive. These twin actions result in an increased susceptibility to STZ‐induced diabetes in UCP‐3 transgenic mice.
Positional Cloning of an Obesity/Diabetes Susceptibility Gene(s) on Chromosome 11 in Pima Indians
Authors: BAIER LESLIE , KOVACS PETER , WIEDRICH CHRISTOPHER , CRAY KIMBERLY , SCHEMIDT AMY , SHEN GONG‐QING , SUTHERLAND JEFFREY , THUILLEZ PAMELA , MULLER YUNHUA LI , TRAURIG MICHAEL , BOGARDUS CLIFTON
Published: July 2010

Abstract: Prior results from our genomic scan in Pima Indians indicated an obesity locus in a region on chromosome 11q23‐24 that was also linked to diabetes. Bivariate linkage analysis for the combined phenotype “diabesity” gave the strongest evidence for linkage (LOD = 5.2). Our aim is to positionally clone the gene(s) responsible for the linkage. Linkage disequilibrium mapping is being used to narrow the chromosomal region. Single nucleotide polymorphisms (SNPs) are being systematically identified and genotyped at 50‐kb intervals across the region of linkage. To date, 455 SNPs have been genotyped in 1229 Pimas. A region containing a cluster of SNPs strongly associated with BMI and a second region, approximately 2 Mb telomeric, containing a cluster of SNPs associated with diabetes have been preliminarily identified.
Uncoupling Proteins, Leptin, and Obesity
Authors: GIACOBINO JEAN‐PAUL
Published: July 2010

Abstract: The hypothesis that the novel uncoupling protein UCP3 is thermogenic and/or thermoregulatory is discussed. In vitro, ex vivo, and in vivo models are presented. The β3‐adrenoceptors are crucial for the appearance of UCP1‐expressing cells in the white adipose tissue. These cells might differ from classical brown adipocytes. Besides its well‐known effect on brown adipose tissue UCP1, leptin might stimulate indirectly muscle UCP3 expression.