bluuebunny/crossref_metadata_2025 huggingface dataset:
The First Six Years at the National Institute for Longevity Sciences, Japan
Authors: KITANI KENICHI
Published: July 2010

The National Institute for Longevity Sciences (NILS) of Japan opened on July 7, 1995, 15 years after the Science Council of Japan recommended the establishment of the National Center for Aging and Geriatric Illnesses (the provisional name for NILS) in 1980. During the first four years of operation, 8 separate research departments, containing 21 laboratories, were established. NILS has both research departments for biomedical sciences, such as dementia research, molecular genetics, and geriatric research, and also departments of gerontechnology and the care of the elderly, which engage in research directed toward the comprehensive improvement of the health and well‐ being of the elderly. On July 9, 1995, the day of the opening ceremonies, NILS employed only three staff members, including the director general. At the end of fiscal year 2000 (March 31, 2001), the institute comprised a staff of more than 200 people, including 30 senior science staff and about 50 junior scientists. The Japanese government has recently decided to expand NILS to double its present size by the end of fiscal year 2004 (March 2005).
Viruses and Diabetes
Authors: JAECKEL ELMAR , MANNS MICHAEL , VON HERRATH MATTHIAS
Published: July 2010

Abstract: Insulin‐dependent diabetes mellitus (IDDM) is a multifactorial disease. Besides a genetic predisposition environmental factors have been implicated in the pathogenesis of β cell destruction. Among these environmental factors viruses have been the focus of many studies. Some viruses are diabetogenic in animals, and others have been implicated as triggers in human IDDM by temporal and geographical association between IDDM and viral infections, serological evidence of infection in recently diagnosed diabetic patients, and the isolation of viruses from the pancreas of affected individuals. We discuss possible pathomechanisms of viral infections in β cell destruction and review the studies on involvement of enteroviruses, retroviruses, rubella viruses, cytomegaloviruses, and Epstein‐Barr viruses in human IDDM. We also report on studies of diabetogenic viruses in animal models as well as on viral infections protecting from IDDM. Some of the difficulties in linking viral infections to IDDM will be illustrated with data from a transgenic mouse model in which IDDM can be precipitated by infections with certain strains of lymphocytic choriomeningitis virus (LCMV). Emerging treatment concepts that do not rely on defining the initiating autoantigens but involve self‐reactive regulatory lymphocytes such as oral antigen administration, as well as DNA vaccines, will be discussed briefly.
The Gut Immune System and Type 1 Diabetes
Authors: VAARALA OUTI
Published: July 2010

Abstract: Accumulating data suggest that the gut immune system plays a role in the development of autoimmune diabetes: (1) Diet modifies the incidence of autoimmune diabetes and the phenotype of the islet‐infiltrating T cells in the animal models of human type 1 diabetes; (2) gut‐associated homing receptor β7‐integrin is found on the islet‐infiltrating T cells in both human type 1 diabetes and in the animal models of autoimmune diabetes; (3) mesenterial lymphocytes from young NOD mice are able to transfer diabetes to healthy recipients; (4) autoantigen feeding modifies the disease development in the animal models (prevents or accelerates autoimmune diabetes). In humans, a link between the gut immune system and type 1 diabetes has also been suggested. Early introduction of cow milk formulas in infancy may increase the risk of type 1 diabetes. We have demonstrated that primary immunization to a β cell‐specific autoantigen, insulin, occurs in the gut by exposure to cow milk formulas, which contain immunogenic bovine insulin. The induced antibody and T cell responses to bovine insulin cross‐react with human insulin. In children at genetic risk who developed β cell autoimmunity, bovine insulin‐binding antibodies increased during follow‐up in contrast to autoantibody‐negative children. This suggests that insulin‐specific immune response induced by dietary insulin may not be controlled in children prone to β cell autoimmunity. The gut immune system has a key role in controlling insulin‐specific immunity induced by dietary insulin. Indeed, indications for aberrant function of the gut immune system have been reported in type 1 diabetes, such as intestinal immune activation and increased intestinal permeability. Research on the gut immune system in human type 1 diabetes is needed to reveal the role of oral immunity in this disease.
Clinicoepidemiological and Biochemical Profile of Malnutrition‐Modulated Diabetes Mellitus
Authors: SAMAL K. C. , KANUNGO A. , SANJEEVI C. B.
Published: July 2010

Abstract: Malnitrition‐modulated diabetes mellitus ((MMDM) was previously known as protein‐deficient diabetes mellitus (PDDM). Its clinical picture is similar to that of type 1 diabetes, but it develops over a background of chronic malnutrition from childhood. In spite of severe hyperglycemia, ketonuria never occurs. MMDM patients are extremely lean and require high doses of insulin—over 2.0 U/kg/day for good glycemic control. Even when optimally controlled, these patients maintain their leanness. Infections of the skin and soft tissues and pulmonary tuberculosis are often seen, whereas micro‐ and macrovascular complications are rare, even after long‐term follow‐up. Ultrasonographic evaluation of the abdomen clearly differentiates MMDM from fibrocalculous pancreatic diabetes. Absence of ketonuria and ketosis despite very severe hyperglycemia in emaciated young subjects is the most significant marker of MMDM.
Immunogenetic Studies on Malnutrition‐Modulated Diabetes Mellitus
Authors: SANJEEVI C. B. , KANUNGO A. , SAMAL K. C.
Published: July 2010

Abstract: Genetic studies of malnutrition‐related diabetes are few. We have analyzed the HLA class II gene polymorphism in malnutrition‐modulated diabetes mellitus (MMDM), which was previously referred to as protein‐deficient diabetes mellitus (PDDM) in the 1985 WHO classification. Insulin‐dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. Both IDDM and MMDM in eastern Indians are associated with DR3‐DQ2 but not DR4‐DQ8. The presence of autoantibodies to IDDM autoantigens in clinical MMDM either identifies the slow‐onset form of IDDM or suggests autoimmunity different from that in IDDM. Our study demonstrates that the presence of GAD65 antibody and DR3‐DQ2 positivity in MMDM patients identifies the underlying autoimmune mechanism in the etiology in eastern India. In autoantibody‐negative MMDM patients an association with DR7‐DQ2 is identified. The date obtained also indicate the possibility that MMDM can coexist with IDDM in these patients and that malnutrition could be one of the reasons for the slower onset in IDDM‐prone individuals. The association of DR7‐DQ2 suggests that there is a different immunogenetic background to MMDM than to IDDM. MICA is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of MICA gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. We studied the association of MICA alleles with IDDM (n= 52) and MMDM (n= 41) patients and healthy controls (n= 73) from Cuttack, eastern India. MICA was typed by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. Allele 9 of MICA is positively and allele 4 negatively associated with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64, P < 0.05) when compared to controls. Our findings suggest that MMDM is immunogenetically different from IDDM in eastern India and that MIC‐A is important in the pathogenesis of MMDM patients from Cuttack in eastern India.
Induction of Islet Allotolerance in Nonhuman Primates
Authors: GAUR LAKSHMI K. , NITTA Y. , KENNEDY E. , LERNMARK Å. , NELSON K. A. , ALLEN M. , NEPOM G. T.
Published: July 2010

Abstract: Recent clinical trials have pioneered the successful use of a nonsteroidal immunosuppressive regimen and established a basis for application in a routine clinical setting. In this study, a single islet transplant was not sufficient to regulate blood glucose levels, and a second transplant became necessary. A similar observation was made in our macaque islet transplant study, where animals after the second transplantation have shown trends towards normoglycemia in the presence of mycophenolate mofetil. All five animals that received the second transplant have shown an initial rise in C peptide levels, which rapidly decreased as we tapered the MMF dose from 20 mg/kg BID to 5 mg/kg SID. Two animals of the five that were preconditioned with MMF one week prior to transplantation have shown significantly higher C peptide levels. We believe that it is very important to understand the relationship between the first graft failure and subsequent islet allograft success. Since graft success did not correlate with number of transplanted islets, the correction of blood glucose levels toward normoglycemia after the second transplantation suggests a mechanism by which the allotolerance to second transplant is facilitated by the first islet transplantation. These initial observations suggest approaches to “tolerize” the recipient to accept the second‐transplant islets (a) through preconditioning the animal to improve the rate of success for the first transplant or (b) through tolerization to islets in the first transplant to facilitate better engraftment of the second‐transplant islets.
Th2 Dominance of T Helper Cell Response to Preproinsulin in Individuals with Preclinical Type 1 Diabetes
Authors: DURINOVIC‐BELLÓ IVANA , RIEDL MARTINA , ROSINGER SILKE , MAISEL NICOLA , KALBACHER HUBERT , DEEG MARTIN , SCHRECKLING HANS‐JÜRGEN , SCHLOSSER MICHAEL , ZIEGLER MANFRED , KUEHNL PETER , BOEHM BERNHARD O.
Published: July 2010

Abstract: In human type 1 diabetes (T1D) autoantibodies to insulin precede clinical disease, while little is known about the contribution of insulin‐specific T lymphocytes—in particular, T helper (Th) subsets. Here we have studied the in vivo primed cytokine response to preproinsulin in peripheral blood mononuclear cells (PBMCs) and two major Th cell subsets—CD45RO+ memory cells and CD45RA+ naive/resting cells—in 35 individuals with HLA‐DRB1*04, DQB1*0302 diabetes risk marker: 12 patients with T1D, 12 autoantibody‐positive (Ab+) individuals, and 11 healthy controls. Cytokine secretion (TNF‐α, IFN‐γ, IL‐2, IL‐4, IL‐5, and IL‐10) was measured in the supernatants of the cultures stimulated with 21 overlapping preproinsulin peptides as well as proinsulin and insulin. In Ab+ individuals our results reveal higher IL‐4 levels in CD45RO+ memory cells and higher IL‐5 levels in CD45RA+ naive/resting cells, while higher IL‐2 production was found in PBMCs. In contrast, in PBMCs of T1D patients higher IFN‐γ and IL‐10 secretion was found. Our data delineate characteristic cytokine patterns in peripheral T lymphocytes from patients at different stages of the T1D development.
Increased Autoantibodies to SOX13 in Swedish Patients with Type 1 Diabetes
Authors: TÖRN C. , SHTAUVERE‐BRAMEUS A. , SANJEEVI C. B. , LANDIN‐OLSSON M.
Published: July 2010

Abstract: This article aims to estimate the prevalence of SOX13 antibodies in Swedish patients with type 1 diabetes and healthy controls. The patients (n= 102; median age 35 years [range, 9‐89]) were newly diagnosed with type 1 diabetes in a defined area in southern Sweden during 1995‐1998. Islet cell antibodies (ICA) were analyzed with immunofluorescence, while glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase antibodies (IA‐2A), and antibodies against the transcription factor SOX13 (SOX13Ab) were analyzed with radioimmunoprecipitating assays. SOX13Ab were found in 9.8% (10/102) of type 1 patients compared to 2.0% (2/99) in healthy controls (P= 0.033). At least one of the four autoantibodies (ICA, GADA, IA‐2A or SOX13Ab) were identified in 67% (68/102) of the patients. Samples positive for IA‐2A were only in one case positive also for SOX13Ab. IA‐2A‐positive patients were often positive also for ICA and GADA (19/27), and the same combination was also common for SOX13Ab‐positive patients (6/10). Only 2.0% (2/102) were positive for SOX13Ab alone. ICA, GADA and IA‐2A were more frequent in younger patients (≤ 35 years of age) than in older patients, while SOX13Ab showed similar frequency in both groups. We concluded that the frequency of SOX13Ab was significantly increased in Swedish patients with type 1 diabetes, but that the addition of SOX13Ab to the combination of GADA and IA2‐A only increased the sensitivity by 2% for autoimmune diabetes. Therefore, SOX13 could be a minor autoantigen involved in the pathogenesis of type 1 diabetes.
Diabetes Prevention Trial 1
Authors: YU LIPING , CUTHBERTSON DAVID D. , EISENBARTH GEORGE S. , KRISCHER JEFFREY P. ,   DPT‐1 PARTICIPATING INVESTIGATORS
Published: July 2010

Abstract: The Diabetes Prevention Trial Type 1 (DPT‐1) has recruited relatives of patients with type 1 diabetes throughout the United States and Canada. Of the group screened before June 30, 2000, 71,148 initial screening samples of DPT‐1 subjects were tested for GAD65 autoantibodies (GAA) and ICA512 (IA‐2) autoantibodies (ICA512AA). Of 71,148 relatives screened, first‐degree relatives (4.63%, n= 59,752) had a significantly higher prevalence of autoantibodies than did second‐degree relatives (2.61%, n= 9,856) (P < 0.0001 for both autoantibodies). Among first‐degree relatives, siblings (5.47%, n= 27,128) had a significantly higher prevalence of autoantibodies than did offspring (3.98%, n= 17,063) and parents (3.88%, n= 15,561) (P < 0.0001 for both autoantibodies). Among offspring, the offspring (n= 105) of both parents with diabetes had twice (8.57%) the prevalence of autoantibodies than did the offspring (n= 16,901) of a single diabetic parent (3.96%). Interestingly, the offspring (n= 8,777) of diabetic fathers had a significantly higher prevalence of autoantibodies than did the offspring (n= 8,124) of diabetic mothers, but only among those aged 10‐30 years (P < 0.0001). We conclude that the prevalence of anti‐islet cell autoantibodies is affected by multiple levels of relationship to the proband.
Low Frequency of Autoantibodies to Islet Cell, Glutamic Acid Decarboxylase, and Second‐Islet Antigen in Patients with Gestational Diabetes Mellitus
Authors: LAPOLLA A. , FEDELE D. , PEDINI B. , DAL FRÀ M. G. , SANZARI M. , MASIN M. , ZANCHETTA R. , BETTERLE C.
Published: July 2010

Abstract: The aim of the study was to determine the frequency of patients with gestational diabetes mellitus (GDM) who have serological markers typical of autoimmune type 1 DM. The specific pancreatic markers, ICAs, glutamic decarboxylase (GADAbs), and second islet antigen (IA2Abs), were measured in 70 women with GDM during the pregnancy and after delivery. ICAs were measured by indirect immunofluorescence and GADAbs and IA2Abs were determined by a radiobinding assay with recombinant antigens. On entering the study, 1 of 70 (1.4%) patients was positive for both ICAs (80 JDF‐U) and GADAbs (167 U/mL), while another (1.4%) was positive for ICAs (40 JDF‐U). None of the patients was positive for IA2Abs. During follow‐up, positivity was maintained unchanged in the two positive patients. Four previously negative patients had seroconversion: one for both ICAs (20 JDF‐U) and GADAbs (49.3 U/mL) and the other three for GADAbs (1.8, 1.4, and 15.3 U/mL, respectively). The IA2Abs remained negative in all patients. Overall, during the observation period 6 of 70 (8.6%) patients had or developed autoantibodies against endocrine pancreas. During follow‐up 15 patients developed clinical DM (10 type 2, 5 type 1) and 7 demonstrated impaired glucose tolerance (IGT) after OGTT. No correlations were demonstrated between the immunological patterns and the evolution in DM. In patients with GDM, the frequency of pancreatic autoantibodies varies during the pregnancy and after delivery, but a small subgroup of patients bearing these markers is identifiable. GDM is a complex syndrome, constituted by different types of diabetes mellitus where the autoimmune form is very rare.
Pancreatic Autoantibodies in Italian Patients with Newly Diagnosed Type 1 Diabetes Mellitus under the Age of 20 Years
Authors: BETTERLE C. , FUSARI A. , PRESOTTO F. , DAL PRA C. , PEDINI B. , LAZZAROTTO F. , ZANCHETTA R.
Published: July 2010

Abstract: We analyzed 97 children and young persons (< 20 years of age) with newly diagnosed diabetes for antibodies to islet cells (ICAs), glutamic acid decarboxylase (GADAbs), second‐islet antigen (IA2Abs), and insulin (IAAs) in order to evaluate the prevalence of immune‐mediated type 1 diabetes, as well as to recognize which autoantibody combination is better associated with the disease. A positive result for one or more diabetes‐related antibodies evaluated was found in 92 children (94.8%): 41 females (95.3%) and 51 males (94.4%). With regard to single autoantibody testing, ICA levels were found to be positive in 84 patients (86.6%), GADAbs in 71 (73.2%), IA2Abs in 60 (61.8%), and IAAs in 51 (52.6%) patients. Combining the determination of at least two autoantibodies, ICAs and/or GADAbs were more frequently detectable than other antibody combinations, being positive in 89 patients (91.8%). Our data indicate that the vast majority of cases of type 1 diabetes in children may be considered as immune‐mediated, that multiple autoantibody analysis improves identification of the disease, and that first‐level screening is provided by the combined detection of ICAs and GADAbs.
Diabetes‐Related Autoantibodies in Cord Blood from Children of Healthy Mothers Have Disappeared by the Time the Child Is One Year Old
Authors: LUDVIGSSON JOHNNY , WAHLBERG JEANETTE ,   ABIS STUDY GROUP
Published: July 2010

Abstract: Autoantibodies found in cord blood in children who later develop diabetes might be produced by the fetus. If so, continuous autoantibody production would still be expected in these children at one year of age. We decided to determine autoantibodies in cord blood and to see whether they persisted in these children at one year. Autoantibodies against GAD65 (glutamic acid decarboxylase) and IA‐2 (tyrosine phosphatase) in cord blood were determined in 2,518 randomly selected children. Forty‐nine (1.95%) were positive for GAD65 antibodies, 14 (0.56%) were positive for IA‐2 antibodies, and 3 of them were positive for both GAD and IA‐2. Four of the mothers of children with GAD65 autoantibodies in cord blood (8.2%) had type 1 diabetes as did 5 mothers of children with IA‐2 antibodies (35.7 %), but only 0.4% of the mothers had type 1 diabetes in the autoantibody‐negative group (P < 0.001). Information on infections during pregnancy was available in 2,169 pregnancies. In the autoantibody‐positive group, 31.5% had an infection during pregnancy, which was more common than in the autoantibody‐negative group of 500 children with the lowest values (20.1%; P < 0.04). At one year follow‐up nobody of those with positive cord blood had GAD65 or IA‐2 autoantibodies. We conclude that most autoantibodies found in cord blood samples of children are probably passively transferred from mother to child. Antibody screening of cord blood cannot be used to predict diabetes in the general population. Infections during pregnancy may initiate an immune process related to diabetes development.
Molecular Modeling of Eluted Peptides from DQ6 Molecules (DQB1*0602 and DQB1*0604) Negatively and Positively Associated with Type 1 Diabetes
Authors: SANJEEVI C. B. , LYBRAND T. P. , STEVANOVIC S. , RAMMENSEE H. G.
Published: July 2010

Abstract: Insulin‐dependent diabetes mellitus (IDDM) is positively associated with HLA‐DQ8, DQ2, and DQ6 (B*0604) and negatively with DQ6 (B*0602). The mechanisms by which the DQ molecules control the development of IDDM is not known. DQ6 (B*0602) and DQ6 (B*0604) molecules share the same DQα chain but differ in the β chain by six residues at positions 9, 30, 57, 70, 86, and 87. The aim of the study was to sequence the peptides eluted from both DQ6 molecules and to determine the binding motifs and construct peptides for docking them into the DQ6 peptide binding groove by molecular modeling. EBV transformed B cell line homozygous for DQ6 and hybridoma cell line secreting DQ6 specific antibody were grown in large‐scale culture. The DQ6 molecules were precipitated with solid‐phase bound antibodies specific for DQ6. The dissociation of peptides from MHC was done with ultrafiltration and separation of peptides by reversed‐phase HPLC, using Edman degradation. A special application of Edman degradation is pool sequencing. This approach allowed us to determine common characteristics of all peptides associated with a given MHC molecule. The precipitation of DQ6 molecules and the peptide elution were done successfully. The sequencing of the peptides from DQ6 (B*0602) identified three fractions: (1) IINEPTAAAIAYGLD (Bovine HSP70), (2) IINEPTAAAIAGLDR (Human HSP70), and (3) NPRDAKACVVHGSDLK (Na+/K+ ATPase). Peptide eluted from DQ6 (B*0604) had a sequence ADLFRGTLDPVEK with sequence homology to HSP70 (residues 307‐319). We were able to predict the motifs for DQ6 from the ligands eluted. We used molecular modeling as a tool to identify plausible binding motifs for peptides. Our studies show that peptide ADLFRGTLDPVEK and NPRDAKACVVHGSDLK fit well in the respective DQ6 binding grooves. These predicted motifs should then be useful for screening of autoantigens associated with diabetes and identifying the epitopes that are likely to interact with T cells.
Genetic Dissection of Type 1 Diabetes Susceptibility Gene, Idd3, by Ancestral Haplotype Congenic Mapping
Authors: IKEGAMI HIROSHI , FUJISAWA TOMOMI , MAKINO SUSUMU , OGIHARA TOSHIO
Published: July 2010

Abstract: One of the strongest non‐MHC susceptibility genes for type 1 diabetes, Idd3, has been mapped to a 0.15‐cM segment of chromosome 3, where a strong candidate gene, Il2, encoding cytokine IL2, is located. To prove that the NOD allele of Il2 is responsible for the Idd3 effect, it is necessary to find a recombinant chromosome with the NOD allele of Il2, but with different flanking markers from NOD mice, and to demonstrate that NOD mouse strains that are congenic for the recombinant Il2 region develop type 1 diabetes with similar incidence and age at onset of the disease. As a first step in this approach, we searched for recombinant Il2 region in NOD‐related strains derived from the same outbred colony, Jcl:ICR. The same Il2 allele as is found in the NOD mouse was found in four out of seven NOD‐related strains, indicating that the NOD allele of Il2 is common in NOD‐related strains. One of these strains, IIS, was found to have a recombinant Il2 region with the same Il2 allele as the NOD, but different alleles at flanking markers from the NOD mouse. A preliminary study on a NOD strain congenic for the Il2 region of IIS has shown that the Il2 region of IIS confers susceptibility to type 1 diabetes, suggesting that Il2 may be responsible for the Idd3 effect.
Mothers of Children in ABIS, a Population‐Based Screening for Prediabetes, Experience Few Ethical Conflicts and Have a Positive Attitude
Authors: LUDVIGSSON JOHNNY , GUSTAFSSON‐STOLT ULRICA , LISS PER‐ERIK , SVENSSON TOMMY ,   ABIS STUDY GROUP
Published: July 2010

Abstract: Screening is supposed to create less anxiety among first‐degree relatives of diabetic patients where the risk of developing diabetes already is well known. It has also been argued that screening of a general child population should never be performed unless identified high‐risk individuals can be offered intervention to prevent diabetes. However, the empirical data are scarce, especially regarding what opinions patients or their parents have of these matters/issues themselves. We have therefore tried to evaluate mothers' attitudes to and ethical views on participation in a research screening for prediabetes in an unselected birth cohort. All 21,700 mothers of children in southeast Sweden born between 1 October 1997 and 1 October 1999 were asked to participate in ABIS (All Babies in Southeast Sweden). They were given information about the design of the study and that HLA types and autoantibodies will be determined in order to predict diabetes, but that no prevention of diabetes will be offered unless future studies show effective methods. After informed consent, 78.6% of mothers let their babies participate (17,055 children) despite a quite laborious study protocol. Explorative in‐depth semistructured interviews were performed in 21 mothers, of whom 15 were strategically selected to get as many various attitudes as possible and of whom 6 chose not to participate in ABIS. All interviewed mothers were positive to the ABIS project. We conclude that a well‐designed screening program to detect individuals in the general population with high risk of developing diabetes does not evoke anxiety nor severe ethical conflicts.
Immunomodulatory Effect of Tungstate on Streptozotocin‐Induced Experimental Diabetes in Rats
Authors: PALANIVEL R. , SAKTHISEKARAN D.
Published: July 2010

Abstract: Immune dysfunction has been found to be associated with diabetes mellitus. Tungstate treatment restored the number and function of immune cells as well as the immunoglobulin level in STZ diabetic rats. This indicated the immunomodulatory effect of tungstate in diabetics and would be effective in inhibiting diabetic‐induced alterations.
HLA Class I and Class II Association with Ankylosing Spondylitis in a Southern Indian Population
Authors: MADHAVAN RADHA , PARTHIBAN M. , RAJENDRAN C. PANCHAPAKESA , CHANDRASEKARAN A. N. , ZAKE L. , SANJEEVI C. B.
Published: July 2010

Abstract: Ankylosing spondylitis (AS) is a chronic inflammatory condition associated with HLA B27. But the association is not absolute. Hence association with other HLA class I antigens and class II alleles was studied in a southern Indian population. Sixty‐five patients with primary AS were typed serologically for HLA class I antigens. Age‐ and sex‐matched disease controls (37 with enterogenic reactive arthritis [ReA] and 25 with undifferentiated spondyloarthropathy [UnSpA]) and 124 healthy controls were studied. PCR‐based DNA‐SSO typing for DQA1 and DQB1 was performed on 20 patients with AS and 38 healthy controls. Twenty‐three patients with AS and 39 controls were typed for DRB1 alleles. HLA B27 was positive in 76.9 % of the cases of AS (RR 811), 59.5% of those with ReA (RR 9.3), and 40% of the patients with UnSpA (RR 9.3), while none of the controls were B27 positive. The P value for positive association was highly significant for B27 in all the three groups. B27 positivity was associated with earlier age of onset of disease in all the diseases compared to the B27‐negative group. HLA Cw2 was positively associated with AS (P highly significant; OR 52) and ReA (P= 0.0003; OR 14.2). HLA A1 and CW6 were significantly negatively associated only with AS (P= 0.0001 and 0.00004 and OR 0.25 and 0.02, respectively). None of the HLA class II alleles were significantly associated with AS. The apparent association with DRB1*11 (P= 0.03) was lost after Yates correction.
Could Parenting Stress and Lack of Support/Confidence Function as Mediating Mechanisms between Certain Environmental Factors and the Development of Autoimmunity in Children?
Authors: SEPA ANNELI , FRODI ANN , LUDVIGSSON JOHNNY
Published: July 2010

Abstract: Despite extensive research, the etiology of type 1 diabetes is still to a large extent unknown. We would like to propose psychoimmunology as one possible pathway. Psychological mechanisms are directly linked to hormonal and nervous signals, which increase the need for insulin and affect the immune system. Disparate factors of social, environmental, and medical character have been associated with the onset of type 1 diabetes or with the autoimmune process leading to the disease—for instance, parental age, maternal infections, delivery mood, need for neonatal intensive care, and low socioeconomic status. Our results, based on the analyses of 4337 nonselected newborn children and their mothers, show that all these risk factors were also associated with psychological mechanisms (defined as lack of social support/confidence and high parenting stress). These results support the hypothesis of psychological mechanisms as mediating variables between a number of disparate risk factors and the development of type 1 diabetes.
Ferroelectric Molecular Films for Nanoscopic Ultrahigh‐Density Memories
Authors: MATSUSHIGE KAZUMI , YAMADA HIROFUMI
Published: July 2010

Abstract: The formation and visualization of nanometer‐scale polarized domains in ultrathin ferroelectric molecular films by scanning‐probe microscopy are described. These operations to the ferroelectric domains correspond to the “writing” and the “reading” process, respectively, for the data‐storage application. In addition, nanometer‐scale structures and the local electrical properties of the local domains, including the interface effect, are discussed. The achieved minimum diameter of the written ferroelectric domains was 30 nm. The size of the “recording” dot corresponds to the recording density of about 230 Gbit/in.2. The “erasing” process by switching domains was also demonstrated. Furthermore, nanometer‐scale ferroelectric domains using VDF oligomer molecular films were successfully formed, which has opened the way to the control of single molecular dipoles.
Nonlinear Transport Through a Nanoscale Molecule
Authors: HETTLER MATTHIAS H. , SCHOELLER HERBERT
Published: July 2010

Abstract: A simple model of electrical transport through a metal‐aromatic molecule‐metal system that includes charging effects as well as aspects of the electronic structure of the molecule, is presented. The interplay of a large charging energy and an asymmetry of the metal‐molecule coupling can lead to various effects in nonlinear electrical transport. In particular, strong negative differential conductance is observed under certain conditions.
Interplay of Topology and Chemical Stability on the Electronic Transport of Molecular Junctions
Authors: YALIRAKI S. N. , RATNER MARK A.
Published: July 2010

Abstract: The coherent electronic transport through molecular junctions is theoretically modeled. The interplay of geometry, topology, and chemistry is explored within the Landauer picture of elastic scattering and various methods of quantum description of the composite system. The emphasis is on obtaining guiding principles for device optimization. Outstanding problems and future directions are outlined.
Single‐Walled Carbon Nanotubes
Authors: ODOM TERI WANG , HUANG JIN‐LIN , LIEBER CHARLES M.
Published: July 2010

Abstract: Single‐walled carbon nanotubes (SWNTs) are ideal systems for investigating fundamental properties in one‐dimensional electronic systems and have the potential to revolutionize many aspects of nano/molecular electronics. Scanning tunneling microscopy (STM) has been used to characterize the atomic structure and tunneling density of states of individual SWNTs. Detailed spectroscopic measurements showed one‐dimensional singularities in the SWNT density of states for both metallic and semiconducting nanotubes. The results obtained were compared to and agree well with theoretical predictions and tight‐binding calculations. SWNTs were also shortened using the STM to explore the role of finite size, which might be exploited for device applications. Segments less than 10 nm exhibited discrete peaks in their tunneling spectra, which correspond to quantized energy levels, and whose spacing scales inversely with length. Finally, the interaction between magnetic impurities and electrons confined to one dimension was studied by spatially resolving the local electronic density of states of small cobalt clusters on metallic SWNTs. Spectroscopic measurements performed on and near these clusters exhibited a narrow peak near the Fermi level that has been identified as a Kondo resonance. In addition, spectroscopic studies of ultrasmall magnetic nanostructures, consisting of small cobalt clusters on short nanotube pieces, exhibited features characteristic of the bulk Kondo resonance, but also new features due to their finite size.
Neuroblastoma: A Challenge for Pediatric Oncology of the Third Millennium
Authors: MASSIMO LUISA
Published: July 2010

Abstract: Neuroblastoma is the only cancer of childhood considered in this conference on hormone‐related tumors, because the percentage of deaths in children with this rare type of cancer is still very high. Pediatricians feel the need for help from basic researchers to better understand the biological nature of this disease and to improve protocols and the challenge of cure.
New Approaches to Breast Cancer
Authors: LEONARDI V. , SAVIO G. , LAUDANI A. , BLASI L. , AGOSTARA B.
Published: July 2010

Abstract: Oxaliplatin is a platinum compound that inhibits DNA synthesis. This drug has a broad spectrum of antineoplastic activity, and its results in breast cancer are promising. We began a phase II study in pretreated advanced breast cancer patients using oxaliplatin together with 5‐fluorouracil and folinic acid, a combination based on the efficacy of both drugs in breast cancer and their different toxicity profiles. Seventeen patients with advanced breast cancer were treated with oxaliplatin, 5‐fluorouracil, and folinic acid, and preliminary data were analyzed. The mean number of courses per patient was 2.82 (range 1‐8). The main toxicity was gastrointestinal, with nausea and vomiting G2‐3 in 53% of the patients. Hematologic toxicity was moderate with neutropenia G2‐3 in 13% of the patients. Among 10 evaluable patients we obtained partial response in one and stabilized the disease in two patients. No data on survival were evaluated. The small number of enrolled and evaluable patients does not permit any conclusions to be drawn. The study is ongoing.
Modulation of Epidermal Growth Factor Receptor in Endocrine‐Resistant, Estrogen‐Receptor‐Positive Breast Cancer
Authors: NICHOLSON R. I. , HUTCHESON I. R. , HARPER M. E. , KNOWLDEN J. M. , BARROW D. , McCLELLAND R. A. , JONES H. E. , WAKELING A. E. , GEE J.M. W.
Published: July 2010

Abstract: An increasing body of evidence demonstrates that growth factor networks are highly interactive with estrogen receptor signaling in the control of breast cancer growth. As such, tumor responses to antihormones are likely to be a composite of the estrogen receptor and growth factor inhibitory activity of these agents. The modulation of growth factor networks during endocrine response is examined, and in vitro and clinical evidence is presented that epidermal growth factor receptor signaling, maintained in either an estrogen receptor‐dependent or a receptor‐independent manner, is critical to antihormone‐resistant breast cancer cell growth. The considerable potential of the epidermal growth factor receptor‐selective tyrosine kinase inhibitor Iressa (ZD 1839) to efficiently treat, and perhaps even prevent, endocrine‐resistant breast cancer is highlighted.
Objective Response to Treatment as a Potential Surrogate Marker of Survival in Breast Cancer
Authors: BRUZZI PAOLO
Published: July 2010

Abstract: Until recently, objective tumor response to chemotherapy was used as the primary endpoint in phase II trials aimed at assessing the anti‐tumor activity of new drugs. However, it was not accepted as a surrogate endpoint of survival for efficacy trials in solid tumors, and it was not believed to be associated with survival benefit. The recent demonstration that objective response is indeed a valid surrogate endpoint of survival in colorectal cancer, together with strong indirect evidence supporting a similar role of response in breast cancer, opens new possibilities for both the design of trials in metastatic breast cancer and the clinical decision in individual patients with the disease.
Prevention and Treatment of Breast Cancer by Suppressing Aromatase Activity and Expression
Authors: CHEN SHIUAN , ZHOU DUJIN , OKUBO TOMOHARU , KAO YEH‐CHIH , ENG ELIZABETH T. , GRUBE BAIBA , KWON ANNETTE , YANG CHUN , YU BIN
Published: July 2010

Abstract: Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, expression of aromatase is upregulated compared to that of surrounding noncancerous tissue. Tumor aromatase is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A treatment strategy for breast cancer is to abolish in situ estrogen formation with aromatase inhibitors. In addition, aromatase suppression in postmenapausal women is being evaluated as a potential chemopreventive modality against breast cancer. One area of aromatase research in this laboratory is the identification of foods and dietary compounds that can suppress aromatase activity. In vitro and in vivo studies have found that grapes and mushrooms contain chemicals that can inhibit aromatase. Therefore, a diet that includes grapes and mushrooms would be considered preventative against breast cancer. Another area of our aromatase research is the elucidation of the regulatory mechanism of aromatase expression in breast cancer tissue. Increased aromatase expression in breast tumors is attributed to changes in the transcriptional control of aromatase expression. Whereas promoter I.4 is the main promoter that controls aromatase expression in noncancerous breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. Our recent gene regulation studies revealed that in cancerous versus normal tissue, several positive regulatory proteins (e.g., nuclear receptors and CREB1) are present at higher levels and several negative regulatory proteins (e.g., snail and slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is upregulated in cancerous tissue. In addition, our in vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene as a reporter capped with different untranslated exon Is revealed that exon PII‐containing transcripts were translated more effectively than were exon I.3‐containing transcripts. An understanding of the molecular mechanisms of aromatase expression between noncancerous and cancerous breast tissue, at both transcriptional and translational levels, may help in the design of a therapy based on suppressing aromatase expression in breast cancer tissue.
Diet and Breast Cancer
Authors: BRADLOW H. LEON , SEPKOVIC DANIEL W.
Published: July 2010

Abstract: The preponderance of evidence suggests a role for fat and alcohol as risk factors for breast cancer. The role of milk is more controversial with some studies suggesting that milk is a risk factor and others that consumption of milk is protective against breast cancer. No other major nutrient appears to play a significant role in increasing breast cancer risk. On the other hand, there is increasing evidence that a variety of micronutrients and hormones appear to have significant anticancer activity. These range from steroids such as dehydroepiandrosterone (DHEA) and its analysis to indoles, isothiocyanates, and isoflavone derivatives. These compounds act directly by interfering with cyclins and promoting apoptosis as well as indirectly by altering estrogen metabolism in a favorable direction. These effects are not merely theoretical actions in cell culture and tissue explants; they have been demonstrated in human patients as a range of studies have demonstrated.
The Mediet Project
Authors: CASTAGNETTA L. , GRANATA O. M. , CUSIMANO R. , RAVAZZOLO B. , LIQUORI M. , POLITO L. , MIELE M. , DI CRISTINA A. , HAMEL P. , TRAINA A.
Published: July 2010

Abstract: Preliminary evidence from a case control study of healthy postmenopausal women living in Palermo, Sicily, is presented to investigate the potential impact of a traditional Mediterranean diet on the risk of developing breast cancer. Of the 230 women who fulfilled specific eligibility criteria, 115 were enrolled in the study based on serum testosterone values equal to or greater than the median population value (0.14 μg/ml). Women were then individually randomized into a diet intervention (n= 58) and a control (n= 55) group. Women in the intervention group attended a weekly “cooking course” for 1 year, being trained by professional chefs in the correct use of the natural ingredients of the traditional Mediterranean diet, including whole cereals, legumes, seeds, fish, cruciferous vegetables, and many others. The intervention group was subsequently instructed to follow the learned diet at home, while the control group was only advised to increase the consumption of fruits and vegetables, as recommended by WHO. The following measures were taken at the beginning, middle, and end of the study: (a) fasting blood and 12‐hour urine samples to assay defined hormonal endpoints; (b) height, weight, and circumference of the waist and hip; and (c) a food frequency and computerized 24‐hour dietary recall questionnaire. After 1 year, both the control and the intervention groups showed satisfactory compliance rates (81 and 85%, respectively). In addition, preliminary results so far obtained reveal an unequivocal trend towards weight loss, a strong reduction in cholesterol levels, and a psychophysical feeling of well‐being by women adopting the Mediterranean diet. The study is currently ongoing to verify the association of changes in serum and urine hormone levels and breast cancer risk in the intervention group.
Molecular Genetics of Acute Myeloid Leukemia
Authors: BERNASCONI PAOLO , BONI MARINA , CAVIGLIANO PAOLA MARIA , CALATRONI SILVIA , GIARDINI ILARIA , ROCCA BARBARA , CARESANA MARILENA
Published: July 2010

Abstract: Recurring chromosomal abnormalities are detected in most patients with acute myeloid leukemia (AML). They may be associated with a distinct AML FAB subtype or may identify distinct clinicobiological entities within the same FAB subtype. Therefore, cytogenetic investigation has a pivotal role in AML diagnosis. In addition, it is one of the most valuable prognostic determinants of the disease, as recently demonstrated. The development of new molecular techniques, such as reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization, has allowed perfect definition of the chromosome regions containing genes with a crucial role in normal hemopoiesis and leukemia. Understanding the action of such genes provides new insights into AML pathogenesis and has led us to envisage new therapeutic options.
Correlation between Helicobacter pylori Infection and IL‐18 mRNA Expression in Human Gastric Biopsy Specimens
Authors: FERA M. T. , CARBONE M. , BUDA C. , ARAGONA M. , PANETTA S. , GIANNONE M. , LA TORRE F. , GIUDICE A. , LOSI E.
Published: July 2010

Abstract: Our data indicate that H. pylori infection is associated with active interleukin‐18 production in patients with chronic gastritis. Different cell types appear to be involved in this activity and may play a role in the development of immunopathologic damage.
Cytokine Induction in Murine Bladder Tissue by Type 1 Fimbriated Escherichia coli
Authors: CARBONE M. , HASTY D. L. , YI K. C. , RUE J. , FERA M. T. , LA TORRE F. , GIANNONE M. , LOSI E.
Published: July 2010

Abstract: The local cytokine response to uropathogenic phenotype Escherichia coli KBC211 infection exhibits characteristics of both TH1 and TH2 profiles. Interleukin (IL)‐6, MIP‐2, IL‐12, IL‐18, and tumor necrosis factor‐alpha (TNF‐α) are expressed, but IL‐4, IL‐5, and IL‐10 are also present at low levels. This is clearly a complex response that should be explored more fully. The relative contributions of the bladder epithelium and other cells of the bladder wall should also be determined. Epithelial cytokine responses may be considerable, and because these cells are the first to encounter the pathogen, they will be of great importance in the immune response to pathogenic E. coli.
Application of the IFBC/ILSI Allergenicity Assessment Decision Tree
Authors: LAMB IAN C.
Published: July 2010

Abstract: Three case studies are described; each represents a specific application of the IFBC/ILSI decision tree as prescribed by Metcalfe et al.1 to assess the allergenic potential of foods derived from genetically engineered crop plants. The case studies include high methionine soybean, high oleic soybean and Herculex TM 1 Insect Protected Maize, the results of which support/validate the use of the IFBC/ILSI decision tree for the prescribed applications.
Prediction of Allergenicity of Gene‐Modified Foods by Serum‐Based Testing
Authors: POULSEN LARS K.
Published: July 2010

Abstract:On the basis of applying the IFBC/ILSI decision tree in a number of cases, a refinement of the scheme is suggested. Large differences in allergenic potential may be obtained by altering the route of administration of an allergen. Because an inhalation allergen can induce symptoms at different threshold doses depending on whether it is introduced via the inhalation or oral route, we propose that double‐blind, placebo‐controlled food challenges be performed in all cases of inhalation allergens being present in foods. Even proteins never previously ingested may cause IgE binding and elicit clinically relevant symptoms.
Gene Expression Related to Synaptogenesis, Neuritogenesis, and MAP Kinase in Behavioral Sensitization to Psychostimulants
Authors: UJIKE HIROSHI , TAKAKI MANABU , KODAMA MASAFUMI , KURODA SHIGETOSHI
Published: July 2010

Abstract:The most important characteristic of behavioral sensitization to psychostimulants, such as amphetamine and cocaine, is the very long‐lasting hypersensitivity to the drug after cessation of exposure. Rearrangement and structural modification of neural networks in CNS must be involved in behavioral sensitization. Previous microscopic studies have shown that the length of dendrites and density of dendritic spines increased in the nucleus accumbens and frontal cortex after repeated exposure to amphetamine and cocaine, but the molecular mechanisms responsible are not well understood. We investigated a set of genes related to synaptogenesis, neuritogenesis, and mitogen‐activated protein (MAP) kinase after exposure to methamphetamine.SynaptophysinmRNA, but notVAMP2(synaptobrevin 2) mRNA, which are considered as synaptogenesis markers, increased in the accumbens, striatum, hippocampus, and several cortices, including the medial frontal cortex, after a single dose of 4 mg/kg methamphetamine.StathminmRNA, but notneuritinornarpmRNA, which are markers for neuritic sprouting, increased in the striatum, hippocampus, and cortices after a single dose of methamphetamine. The mRNA ofarc, an activity‐regulated protein associated with cytoskeleton, but not ofalpha‐tubulin, as markers for neuritic elongation, showed robust increases in the striatum, hippocampus, and cortices after a single dose of methamphetamine. The mRNAs ofMAP kinase phosphatase‐1 (MKP‐1),MKP‐3, andrheb, a ras homologue abundant in brain, were investigated to assess the MAP kinase cascades.MKP‐1andMKP‐3mRNAs, but notrhebmRNA, increased in the striatum, thalamus, and cortices, and in the striatum, hippocampus, and cortices, respectively, after a single methamphetamine.SynaptophysinandstathminmRNAs did not increase again after chronic methamphetamine administration, whereas the increases inarc,MKP‐1, andMKP‐3mRNAs persisted in the brain regions after chronic methamphetamine administration. These findings indicate that the earlier induction process in behavioral sensitization may require various plastic modifications, such as synaptogenesis, neuritic sprouting, neuritic elongation, and activation of MAP kinase cascades, throughout almost the entire brain. In contrast, later maintenance process of sensitization may require only limited plastic modification in restricted regions.