bluuebunny/crossref_metadata_2025 huggingface dataset:
Viruses Cause Type 1 Diabetes in Animals
Authors: YOON JI‐WON , JUN HEE‐SOOK
Published: November 2006

Abstract:  More than 10 viruses have been reported to be associated with the development of type 1 diabetes‐like symptoms in animals, with the best evidence coming from studies on the D variant of encephalomyocarditis (EMC‐D) virus in mice and Kilham rat virus (KRV) in rats. A high titer of EMC‐D viral infection results in the development of diabetes within 3 days, primarily due to the rapid destruction of β cells by viral replication within the cells. A low titer of EMC‐D viral infection results in the recruitment of macrophages to the islets. Soluble mediators produced by activated macrophages play a critical role in the destruction of residual β cells. A single amino acid at position 776 of the EMC viral genome controls the diabetogenicity of the virus. In contrast, KRV causes autoimmune type 1 diabetes in diabetes‐resistant BioBreeding (DR‐BB) rats without direct infection of β cells. Macrophages play an important role in the development of diabetes in KRV‐infected DR‐BB rats. As well, KRV infection preferentially activates effector T cells, such as Th1‐like CD45RC+CD4+ T cells and CD8+ T cells, and downregulates regulatory T cells, such as Th2‐like CD45RC−CD4+ T cells. This results in the breakdown of the immune balance, contributing to the development of diabetes in KRV‐infected DR‐BB rats.
Metabolism Genes Are among the Differentially Expressed Ones Observed in Lymphomononuclear Cells of Recently Diagnosed Type 1 Diabetes Mellitus Patients
Authors: RASSI DIANE M. , JUNTA CRISTINA M. , FACHIN ANA LÚCIA , SANDRIN‐GARCIA PAULA , MELLO STEFANO , MARQUES MÁRCIA M.C. , FERNANDES ANA PAULA M. , FOSS‐FREITAS MARIA CRISTINA , FOSS MILTON C. , SAKAMOTO‐HOJO ELZA T. , PASSOS GERALDO A.S. , DONADI EDUARDO A.
Published: November 2006

Abstract:  The large‐scale differential gene expression in lymphomononuclear cells of six patients with recently diagnosed type
), and six normal individuals matched to patients for sex and age were studied. Glass slides containing 4608 cDNAs from the IMAGE library were spotted using robotic technology. Statistical analysis was carried out by the SAM program, and gene function assessed by the FATIGO program. Thirty differentially expressed genes (21 induced and 9 repressed) were disclosed when DM‐1 patients were compared with controls. Although presenting with distinct biological function, most of the induced or repressed genes were related with protein, phosphate, DNA, RNA, carboxylic acid, and fatty acid metabolism. Although some of these genes have been previously associated with the pathogenesis of T1DM, many other genes were identified for further studies.
Upregulation of Foxp3 Expression in Mouse and Human Treg Is IL‐2/STAT5 Dependent
Authors: MURAWSKI MATTHEW R. , LITHERLAND SALLY A. , CLARE‐SALZLER MICHAEL J. , DAVOODI‐SEMIROMI ABDOREZA
Published: November 2006

Abstract:  Regulatory T cells (Treg), characterized as CD4+/CD25+hi T cells, are critical for sustaining and promoting immune tolerance. Treg are highly dependent on IL‐2 and IL‐2 signaling to maintain their numbers and function and interruption of this pathway promotes autoimmunity. The transcription factor, Foxp3, is also required for Treg function as defective Foxp3 promotos autoimmunity in both mice and humans. We previously reported a point mutation in the DNA‐binding domain of the NOD STAT5B gene that limits DNA binding when compared to wild‐type STAT5 mice. Based on the presence of five STAT5B consensus sequences in the Foxp3 promotor, we hypothesized a critical linkage between IL‐2 signaling/STAT5B and Foxp3 expression in Treg. Our data show IL‐2 activates long‐form (LF) STAT5 and sustains Foxp3 expression in Treg. In contrast, CD4+/CD25− T cells do not active LF STAT5 and do not express Foxp3 under the same conditions. In addition, blocking LF STAT5 activation with a Jak inhibitor (AG‐490) significantly reduced Foxp3 expression in Treg. Examination of human Treg using flow cytometry and intracellular staining for Foxp3 expression likewise demonstrates that IL‐2 maintains Foxp3 expression through LF STAT5 signaling. These studies reveal a critical link between IL‐2 mediated JAK‐STAT5 signaling and the maintenance of Foxp3 expression in Treg of mice and humans.
TSH Receptor Antibodies in Subjects with Type 1 Diabetes Mellitus
Authors: UNNIKRISHNAN AMBIKA G. , KUMARAVEL VELAYUTHAM , NAIR VASANTHA , RAO ANANTH , JAYAKUMAR ROHINI V. , KUMAR HARISH , SANJEEVI CARANI B.
Published: November 2006

Abstract:  The research was undertaken to study the prevalence of TSH receptor antibody positivity in patients with type 1 diabetes. A total of 74 subjects with type 1 diabetes were enrolled in this cross‐sectional study. Thyroid function test and assessment of thyroid autoimmunity with anti‐TPO and TSH receptor antibody were done in all patients. A total of 33 males and 41 females with type 1 diabetes were studied. The prevalence of TSH receptor antibody positivity alone was 18%. The prevalence of thyroid autoimmunity with anti‐TPO as a marker was 28%; the prevalence increased to 43% when TSH receptor antibody was also measured. Majority of the subjects with antithyroid antibody positivity were also positive for GAD65 antibodies. As a significant proportion of type 1 di abetic subjects have positivity to TSH receptor antibody, we suggest that larger studies should be conducted to study the benefits of TSH receptor antibody‐based screening for thyroid dysfunction in type 1 diabetic subjects. As the TSH receptor antibodies could be of the stimulating or of the blocking type, subjects with antibody positivity could be at risk of developing hyperthyroidism or hypothyroidism.
TEDDY–The Environmental Determinants of Diabetes in the Young
Authors: HAGOPIAN WILLIAM A. , LERNMARK ÅKE , REWERS MARIAN J. , SIMELL OLLI G. , SHE JIN‐XIONG , ZIEGLER ANETTE G. , KRISCHER JEFFREY P. , AKOLKAR BEENA
Published: November 2006

Abstract:  The aim of the TEDDY study is to identify infectious agents, dietary factors, or other environmental agents, including psychosocial factors, which may either trigger islet autoimmunity, type 1 diabetes mellitus (T1DM), or both. The study has two end points: (a) appearance of islet autoantibodies and (b) clinical diagnosis of T1DM. Six clinical centers screen newborns for high‐risk HLA genotypes. As of December 2005 a total of 54,470 newborns have been screened. High‐risk HLA genotypes among 53,560 general population (GP) infants were 2576 (4.8%) and among 910 newborns with a first‐degree relative (FDR) were 194 (21%). A total of 1061 children have been enrolled. The initial enrollment results demonstrate the feasibility of this complex and demanding a prospective study.
Protection From Type 1 Diabetes by Vitamin D Receptor Haplotypes
Authors: RAMOS‐LOPEZ ELIZABETH , JANSEN THOMAS , IVASKEVICIUS VYTAUTAS , KAHLES HEINRICH , KLEPZIG CHRISTIAN , OLDENBURG JOHANNES , BADENHOOP KLAUS
Published: November 2006

Abstract:  Vitamin D has been involved in the modulation of calcium and bone metabolism as well as in the immune system, where it suppresses the proliferation of activated T cells. These effects are exerted via the vitamin D receptor (VDR). Polymorphisms within this gene have been exhaustively studied in diverse autoimmune diseases but with inconsistent results. We previously reported a positive association of polymorphisms within the VDR gene (Apa I, Taq I, Bsm I, and Fok I). In the present article we extended our previous reports to seven additional polymorphisms (rs757343, rs9729, rs2853559, rs1989969, rs3847987, rs2238135, and rs4516035) in a larger set of German simplex type 1 diabetes families. Additionally we correlated serum levels of 25(OH)D3 and 1,25(OH)2D3 with VDR genotypes and haplotypes. The haplotypes “CG” (Taq I‐Apa I), “CGG” (Taq I‐Apa I‐Tru I), “CGC” (Taq I‐Apa I‐Fok I), “GCTG” (rs9729‐Taq I‐Apa I‐Tru I), and “CGGC”(Taq I‐Apa I, Tru I, Fok I) were less often transmitted, thus negatively associated with type 1 diabetes. Patients who carried the genotype “CC” of the rs3847987 polymorphism had higher median serum levels of 25(OH)D3. Furthermore, the majority of patients with this genotype possessed normal serum levels of 25(OH)D3. We conclude that variants of the VDR may confer a genetic protection from type 1 diabetes. Furthermore, normal serum levels of 25(OH)D3 appear to correlate with a VDR genotype. This supports a role of vitamin D in the immune pathogenesis of type 1 diabetes.
DiaPep277® Preserves Endogenous Insulin Production by Immunomodulation in Type 1 Diabetes
Authors: ELIAS DANA , AVRON ANN , TAMIR MERANA , RAZ ITAMAR
Published: November 2006

Abstract:  DiaPep277 is an immunomodulatory peptide that arrests β cell destruction in mouse models of type 1 diabetes mellitus (T1DM). This article extends an original pilot observation to two studies of 61 patients (age > 16 years), diagnosed with T1DM within 6 months, and with measurable β cell function. Patients were treated with placebo (n= 27) or 1.0 mg DiaPep277 (n= 34). After 13 months, 1.0 mg Dia Pep277 treatment significantly (P= 0.02) preserved β cell function as compared to the control with a trend for reduced HbA1c. This was achieved without an increase in insulin dose in the DiaPep277 group and with excellent safety. DiaPep277‐treated patients also had fewer Th1 DiaPep277‐specific T cells.
Is It Dietary Insulin?
Authors: VAARALA OUTI
Published: November 2006

Abstract:  In humans the primary trigger of insulin‐specific immunity is a modified self‐antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self‐insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk‐derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin‐specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect β cells, may release autoantigens and potentiate their presentation by an infection‐associated “danger signal.” This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin‐reactive T cells to the pancreatic islets.
The Developing Cardiac Myocyte
Authors: SCHRODER ELIZABETH A. , WEI YIDONG , SATIN JONATHAN
Published: November 2006

Abstract:  The study of cardiac myocyte (CM) differentiation, development, and maturation is of interest for several compelling reasons. First, mechanisms of development are of fundamental biological interest. Second, congenital malformation of the heart may be related to CM dysfunction during embryonic/fetal development. Third, adult myocardium in a variety of diseased states re‐expresses a fetal‐like gene program. Fourth, the mature heart cannot readily regenerate itself. Thus, cell replacement therapy is an emerging treatment paradigm. Among the obstacles for the realization of cell replacement therapy is our incomplete understanding of the function during CM maturation. This is crucial in the potential use of embryonic stem (ES) cell‐derived CMs as a cell source. Although much progress has been realized with mouse ES‐CMs, our understanding of human counterparts is scant. Here we discuss key molecular underpinnings of excitability and excitation–contraction coupling in developing mouse heart. We focus on the Ca channel multimeric complex and Ca handling. We compare mouse embryonic physiology to that previously described in mouse ES‐CMs and draw parallels and highlight distinctions to human ES‐CMs. During mouse embryonic and fetal maturation, the L‐type Ca channel current (ICa,L) predominates, but embryonic/fetal ICa,L has distinct properties from mature ICa,L. In addition T‐type Ca current (ICa,T) present in the fetus is not present in the adult. It is neither ethical nor practical to experiment with live human embryonic/fetal CMs for ICa and Ca handling studies, but we can draw inferences from human heart cell function based on studies of human ES‐CMs, using the parallels noted between mouse embryonic heart cells and mouse ES‐CMs.
Genetic Engineering and Therapy for Inherited and Acquired Cardiomyopathies
Authors: DAY SHARLENE , DAVIS JENNIFER , WESTFALL MARGARET , METZGER JOSEPH
Published: November 2006

Abstract:  The cardiac myofilaments consist of a highly ordered assembly of proteins that collectively generate force in a calcium‐dependent manner. Defects in myofilament function and its regulation have been implicated in various forms of acquired and inherited human heart disease. For example, during cardiac ischemia, cardiac myocyte contractile performance is dramatically downregulated due in part to a reduced sensitivity of the myofilaments to calcium under acidic pH conditions. Over the last several years, the thin filament regulatory protein, troponin I, has been identified as an important mediator of this response. Mutations in troponin I and other sarcomere genes are also linked to several distinct inherited cardiomyopathic phenotypes, including hypertrophic, dilated, and restrictive cardiomyopathies. With the cardiac sarcomere emerging as a central player for such a diverse array of human heart diseases, genetic‐based strategies that target the myofilament will likely have broad therapeutic potential. The development of safe vector systems for efficient gene delivery will be a critical hurdle to overcome before these types of therapies can be successfully applied. Nonetheless, studies focusing on the principles of acute genetic engineering of the sarcomere hold value as they lay the essential foundation on which to build potential gene‐based therapies for heart disease.
Modelling and measurements of a composite microcantilever beam for chemical sensing applications
Authors: Voiculescu I R , Zaghloul M E , McGill R A , Vignola J F
Published: November 2006

A resonant microcantilever beam gas sensor was designed and fabricated in Carnegie Mellon University using complementary metal oxide semiconductor (CMU-CMOS) technology. The cantilever beam modified with a suitable sorbent coating was demonstrated as a chemical transducer for monitoring hazardous vapours and gases at trace concentrations. The design of the cantilever beam included interdigitated fingers to allow electrostatic actuation of the device and a piezoresistive Wheatstone bridge design to read out the deflection signal. The cantilever beam resonant frequency was modelled using the Euler-Bernoulli beam theory and ANSYS. The beam resonant frequency was measured with an optical laser Doppler vibrometer. Good agreement was obtained among the measured, simulated, and modelled resonant frequencies. A custom sorbent polymer layer was coated on the surface of the cantilever beam to allow its operation as a gas-sensing device. The frequency response as a function of exposure to the nerve agent simulant dimethylmethylphosphonate (DMMP) at different concentrations was measured, which allowed a demonstrated detection at a concentration of 20 ppb or 0.1 mg/m3. The air-polymer partition coefficient K, for DMMP was estimated and compared favourably with the known values for related polymers.
A method for the simultaneous derivation of tensile and compressive behaviour of materials under Bauschinger effect using bend tests
Authors: Urriolagoitia-Sosa G , Durodola J F , Lopez-Castro A , Fellows N A
Published: November 2006

Some materials exhibit Bauschinger effect as a consequence of strain hardening. The effect leads to asymmetric tensile and compressive stress-strain behaviour. If the hardening behaviour in either tension or compression is known, combined isotropic/kinematic hardening rules can be used to estimate the hardening behaviour in the other. These rules are, however, only approximate empirical relationships that are derived from the analysis of separate tensile and compressive test results. This article presents a method for the simultaneous derivation of tensile and compressive stress-strain behaviour from bending tests only. The information required is strains at the top and bottom surfaces of beams and moment as load is incrementally applied. The derivation of the method is based on the application of tensile and moment equilibrium conditions. The proposed method is tested on theoretical data obtained from finite-element analysis and as well as on data from actual experimental testing. The agreement between the results obtained is very good.
Numerical and experimental investigation on backward fitting effect on valve flow coefficient
Authors: Kang S-K , Yoon J-Y , Kang S-H , Lee B-H
Published: November 2006

This study investigates the effect of the attached fitting on the valve flow coefficient. Four types of fittings were mounted on the downstream of a valve. It is concluded that the valve flow coefficient must be corrected by a piping geometric factor around 0.81, regardless of the type of the fitting attached.
The Second International Vortex Flow Experiment (VFE-2): Objectives and first results
Authors: Hummel D
Published: November 2006

This paper presents the objectives for the new International Vortex Flow Experiment (VFE-2), and its organization within an RTO Task Group is outlined. The available wind tunnel models as well as the applied experimental techniques are described briefly. Results of Pressure-Sensitive Paint (PSP) measurements at DLR Goettingen showed a first insight into the flow mechanisms. Additional CFD results from numerical solutions of the RANS equations as calculated by EADS Munich led to an initial understanding of the flow details and allowed a proper wind tunnel set-up for the Particle Image Velocimetry (PIV) experiments at DLR Goettingen. These measurements showed the details of the flow field in the vicinity of the wing in excellent agreement with the CFD results.
Real-Time RT-PCR Quantification of Human Telomerase Reverse Transcriptase Splice Variants in Tumor Cell Lines and Non–Small Cell Lung Cancer
Authors: Mavrogiannou Eleni , Strati Areti , Stathopoulou Aliki , Tsaroucha Emily G , Kaklamanis Loukas , Lianidou Evi S
Published: November 2006

Background: We developed and validated a real-time reverse transcription (RT)–PCR for the quantification of 4 individual human telomerase reverse transcriptase (TERT) splice variants (α+β+, α−β+, α+β−, α−β−) in tumor cell lines and non–small cell lung cancer (NSCLC).

Methods: We used in silico designed primers and a common TaqMan probe for highly specific amplification of each TERT splice variant, PCR transcript–specific DNA external standards as calibrators, and the MCF-7 cell line for the development and validation of the method. We then quantified TERT splice variants in 6 tumor cell lines and telomerase activity and TERT splice variant expression in cancerous and paired noncancerous tissue samples from 28 NSCLC patients.

Results: In most tumor cell lines, we observed little variation in the proportion of TERT splice variants. The α+β− splice variant showed the highest expression and α−β+ and α−β− the lowest. Quantification of the 4 TERT splice variants in NSCLC and surrounding nonneoplastic tissues showed the highest expression percentage for the α+β− variant in both NSCLC and adjacent nonneoplastic tissue samples, followed by α+β+, with the α−β+ and α−β− splice variants having the lowest expression. In the NSCLC tumors, the α+β+ variant had higher expression than other splice variants, and its expression correlated with telomerase activity, overall survival, and disease-free survival.

Conclusions: Real-time RT-PCR quantification is a specific, sensitive, and rapid method that can elucidate the biological role of TERT splice variants in tumor development and progression. Our results suggest that the expression of the TERT α+β+ splice variant may be an independent negative prognostic factor for NSCLC patients.
The role of human tissue kallikreins 7 and 8 in intracranial malignancies
Authors: Prezas Panagiotis , Scorilas Andreas , Yfanti Christina , Viktorov Petar , Agnanti Niki , Diamandis Eleftherios , Talieri Maroulio
Published: November 2006

Recent evidence suggests that many tissue kallikreins are implicated in carcinogenesis. Kallikrein 8 (KLK8) plays a role in the physiology of the central nervous system. Kallikrein 7 (KLK7) takes part in skin desquamation. Both show altered expression in ovarian and breast cancer. In this study, we examined the level of mRNA expression of theKLK7andKLK8genes in 73 intracranial tumors using qualitative RT-PCR. The results were correlated with clinical and histomorphological variables and patient outcome. The expression of both genes was also examined in the brain cancer cell lines U-251 MG, D54 and SH-SY5Y and the invasive capacity of glioblastoma cells U-251 MG overexpressing hK7 or hK8 was also investigated in anin vitroMatrigel assay. Follow-up analysis revealed that expression ofKLK7mRNA was associated with shorter overall survival (OS) compared to patients with noKLK7expression, as determined by Cox proportional hazard regression analysis. Overexpression of hK7 protein by cultivated brain tumor cells significantly enhanced the invasive potential in the Matrigel invasion assay, in contrast to cells overexpressing hK8 protein. Our data suggest that hK7 protein overexpression is associated with a more aggressive phenotype in brain cancer cells.
Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men
Authors: Katznelson Laurence , Robinson Mara W , Coyle Caryn L , Lee Hang , Farrell Christina E
Published: November 2006

Objective: One of the factors that may promote deterioration in quality of life and body composition in elderly men is the relative decline in serum testosterone levels with aging. In this study, we assessed the effects of modest doses of testosterone and a home-based strengthening program on quality of life and body composition in elderly men with relative testosterone insufficiency.

Design: Double-blind, placebo-controlled randomized study (testosterone), and additional randomization to a resistance exercise program or no additional exercise for 12 weeks in men between ages of 65 and 85 years with relative testosterone insufficiency.

Methods: Seventy sedentary, community dwelling men were randomized to a 5 mg testoderm transdermal system applied daily vs placebo system, and additionally randomized to a home-based resistance exercise program. Subjects were randomized to Group 1 (testosterone plus exercise), Group 2 (testosterone plus no exercise), Group 3 (placebo plus exercise), and Group 4 (placebo plus no exercise). Endpoints included quality of life (assessed by the short form-36 questionnaire) and body composition (measured by dual x-ray absorptiometry scan).

Results: Serum testosterone increased by a mean of 10.0 ± 1.9, 6.6 ± 1.6, 0.52 ± 0.6, and 0.5 ± 0.6 nmol/l in Groups 1, 2, 3, and 4 respectively. There was a significant interaction of testosterone and exercise on quality of life in the domains of physical functioning (P = 0.03), role physical (P = 0.01), general health (P = 0.049), and social functioning (P = 0.04). There were no effects of testosterone or exercise on quality of life alone, nor in body composition parameters.

Conclusions: Modest testosterone supplementation to elderly men with relative testosterone insufficiency improved quality of life when accompanied by an exercise program. The combination of testosterone and exercise may be an important strategy in the elderly, though further studies are necessary to determine the long-term impact on body composition and function and for analysis of risk/benefit ratios as well.
The Effects of Oxandrolone and Exercise on Muscle Mass and Function in Children With Severe Burns
Authors: Przkora Rene , Herndon David N. , Suman Oscar E.
Published: November 2006

OBJECTIVES. Severe burns are associated with a significant loss of muscle and strength. Studies have reported that oxandrolone improves lean body mass in muscle-wasting conditions. Also shown previously in burned children is that an exercise program increases lean body mass and muscle strength. We hypothesized that oxandrolone, in combination with exercise, would increase lean body mass and muscle strength in severely burned children more than oxandrolone alone or exercise alone.

METHODS AND PATIENTS. Fifty-one burned children (≥40% total body surface area burned) were randomly assigned to receive oxandrolone alone (0.1 mg/kg per day orally; n = 9), oxandrolone and exercise (n = 14), placebo and no exercise (n = 11), or placebo and exercise (n = 17). Administration of oxandrolone was started at discharge and continued until 1 year after burn. The 12-week exercise training program was started 6 months after burn. Serum hormones, lean body mass, muscle strength, and peak cardiopulmonary capacity were assessed at 6 (baseline) and 9 months after burn. Data were analyzed using a 1-way analysis of variance, and significance was set at P < .05.

RESULTS. The mean percentage of change or increase in weight and lean body mass in the oxandrolone and exercise group was significant compared with placebo and exercise, as well as with the oxandrolone alone group or placebo and no exercise group. Furthermore, lean body mass was significantly improved in the oxandrolone and exercise, oxandrolone alone, and placebo and exercise group compared with the group only receiving placebo. Muscle strength significantly increased in oxandrolone and exercise, placebo and exercise, and the oxandrolone alone group when compared with the placebo and no exercise group. The peak cardiopulmonary capacity was significantly higher in both exercise groups. Insulin-like growth factor 1 was significantly increased in the oxandrolone alone group compared with placebo and exercise and placebo and no exercise. Both exercise groups showed significant changes in insulin-like binding-protein-3 when compared with groups without exercise.

CONCLUSIONS. Oxandrolone, in combination with exercise, is beneficial in severely burned children, thus improving their rehabilitation.
The Role ofCYP2A6in the Emergence of Nicotine Dependence in Adolescents
Authors: Audrain-McGovern Janet , Koudsi Nael Al , Rodriguez Daniel , Wileyto E. Paul , Shields Peter G. , Tyndale Rachel F.
Published: November 2006

OBJECTIVES. The objectives of our study were to evaluate whether genetic variation in nicotine metabolic inactivation accounted for the emergence of nicotine dependence from mid- to late adolescence and whether initial smoking experiences mediated this effect.

METHODS. Participants were 222 adolescents of European ancestry who participated in a longitudinal cohort study of the biobehavioral determinants of adolescent smoking. Survey data were collected annually from grade 9 to the end of grade 12. Self-report measures included nicotine dependence, smoking, age first smoked, initial smoking experiences, peer and household member smoking, and alcohol and marijuana use. DNA collected via buccal swabs was assessed for CYP2A6 alleles that are common in white people and are demonstrated to decrease enzymatic function (CYP2A6*2, *4, *9, *12).

RESULTS. Latent growth-curve modeling indicated that normal metabolizers (individuals with no detected CYP2A6 variants) progressed in nicotine dependence at a faster rate and that these increases in nicotine dependence leveled off more slowly compared with slower metabolizers (individuals with CYP2A6 variants). Initial smoking experiences did not account for how CYP2A6 genetic variation impacts nicotine dependence.

CONCLUSIONS. These findings may help to promote a better understanding of the biology of smoking behavior and the emergence of nicotine dependence in adolescents and inform future work aimed at understanding the complex interplay between genetic, social, and psychological factors in adolescent smoking behavior.
Almost periodic functions, constructively
Authors: Spitters Bas
Published: November 2006

The almost periodic functions form a natural example of a non-separable
normed space. As such, it has been a challenge for constructive mathematicians
to find a natural treatment of them. Here we present a simple proof of Bohr's
fundamental theorem for almost periodic functions which we then generalize to
almost periodic functions on general topological groups.
Efficient Open World Reasoning for Planning
Authors: Babaian Tamara , Schmolze James G.
Published: November 2006

We consider the problem of reasoning and planning with incomplete knowledge
and deterministic actions. We introduce a knowledge representation scheme
called PSIPLAN that can effectively represent incompleteness of an agent's
knowledge while allowing for sound, complete and tractable entailment in
domains where the set of all objects is either unknown or infinite. We present
a procedure for state update resulting from taking an action in PSIPLAN that is
correct, complete and has only polynomial complexity. State update is performed
without considering the set of all possible worlds corresponding to the
knowledge state. As a result, planning with PSIPLAN is done without direct
manipulation of possible worlds. PSIPLAN representation underlies the PSIPOP
planning algorithm that handles quantified goals with or without exceptions
that no other domain independent planner has been shown to achieve. PSIPLAN has
been implemented in Common Lisp and used in an application on planning in a
collaborative interface.
From Proof Nets to the Free *-Autonomous Category
Authors: Lamarche Francois , Strassburger Lutz
Published: November 2006

In the first part of this paper we present a theory of proof nets for full
multiplicative linear logic, including the two units. It naturally extends the
well-known theory of unit-free multiplicative proof nets. A linking is no
longer a set of axiom links but a tree in which the axiom links are subtrees.
These trees will be identified according to an equivalence relation based on a
simple form of graph rewriting. We show the standard results of
sequentialization and strong normalization of cut elimination. In the second
part of the paper we show that the identifications enforced on proofs are such
that the class of two-conclusion proof nets defines the free *-autonomous
category.
Hyperglycemia Inhibits Retinoic Acid–Induced Activation of Rac1, Prevents Differentiation of Cortical Neurons, and Causes Oxidative Stress in a Rat Model of Diabetic Pregnancy
Authors: Guleria Rakeshwar S. , Pan Jing , DiPette Donald , Singh Ugra S.
Published: November 2006

Diabetes is a risk factor for neuronal dysfunction. Impairment in signaling mechanisms that regulate differentiation of neurons is hypothesized to be one of the main causes of neuronal dysfunction. Retinoic acid, a physiologically active retinoid synthesized from vitamin A, regulates neuronal differentiation during embryonic development and is required for maintenance of plasticity in differentiated neurons. To date, little is known about the molecular events underlying hyperglycemia-induced complications in the central nervous system (CNS). Here, we provide evidence, in a diabetes rat model, of hyperglycemia-induced oxidative stress along with apoptotic stress in developing cortical neurons isolated from 16-day-old rat embryos. We also demonstrate impaired retinoic acid signaling that is involved in neuronal differentiation. Retinoic acid–induced neurite outgrowth and expression of neuronal markers were reduced in this model. The activation of small–molecular weight G-protein, Rac1, that mediates these effects was also reduced. Retinoic acid applied at a physiological concentration significantly decreased hyperglycemia-induced oxidative stress and thus supported the antioxidant defense system. These results suggest that diabetes-induced neuronal complications during pregnancy might be due to impaired retinoic acid signaling, and exogenously administered retinoic acid may be useful against CNS complications associated with diabetes.
Expression of IGF-I in Pancreatic Islets Prevents Lymphocytic Infiltration and Protects Mice From Type 1 Diabetes
Authors: Casellas Alba , Salavert Ariana , Agudo Judith , Ayuso Eduard , Jimenez Veronica , Moya Marta , Muñoz Sergio , Franckhauser Sylvie , Bosch Fatima
Published: November 2006

Type 1 diabetic patients are diagnosed when β-cell destruction is almost complete. Reversal of type 1 diabetes will require β-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. IGF-I expression in β-cells of streptozotocin (STZ)-treated transgenic mice regenerates the endocrine pancreas by increasing β-cell replication and neogenesis. Here, we examined whether IGF-I also protects islets from autoimmune destruction. Expression of interferon (IFN)-β in β-cells of transgenic mice led to islet β2-microglobulin and Fas hyperexpression and increased lymphocytic infiltration. Pancreatic islets showed high insulitis, and these mice developed overt diabetes when treated with very-low doses of STZ, which did not affect control mice. IGF-I expression in IFN-β–expressing β-cells of double-transgenic mice reduced β2-microglobulin, blocked Fas expression, and counteracted islet infiltration. This was parallel to a decrease in β-cell death by apoptosis in islets of STZ-treated IGF-I+IFN-β–expressing mice. These mice were normoglycemic, normoinsulinemic, and showed normal glucose tolerance. They also presented similar pancreatic insulin content and β-cell mass to healthy mice. Thus, local expression of IGF-I prevented islet infiltration and β-cell death in mice with increased susceptibility to diabetes. These results indicate that pancreatic expression of IGF-I may regenerate and protect β-cell mass in type 1 diabetes.
Downregulation of EGF Receptor Signaling in Pancreatic Islets Causes Diabetes Due to Impaired Postnatal β-Cell Growth
Authors: Miettinen Päivi J. , Ustinov Jarkko , Ormio Päivi , Gao Ru , Palgi Jaan , Hakonen Elina , Juntti-Berggren Lisa , Berggren Per-Olof , Otonkoski Timo
Published: November 2006

Epidermal growth factor receptor (EGF-R) signaling is essential for proper fetal development and growth of pancreatic islets, and there is also evidence for its involvement in β-cell signal transduction in the adult. To study the functional roles of EGF-R in β-cell physiology in postnatal life, we have generated transgenic mice that carry a mutated EGF-R under the pancreatic duodenal homeobox-1 promoter (E1-DN mice). The transgene was expressed in islet β- and δ-cells but not in α-cells, as expected, and it resulted in an ∼40% reduction in pancreatic EGF-R, extracellular signal–related kinase, and Akt phosphorylation. Homozygous E1-DN mice were overtly diabetic after the age of 2 weeks. The hyperglycemia was more pronounced in male than in female mice. The relative β-cell surface area of E1-DN mice was highly reduced at the age of 2 months, while α-cell surface area was not changed. This defect was essentially postnatal, since the differences in β-cell area of newborn mice were much smaller. An apparent explanation for this is impaired postnatal β-cell proliferation; the normal surge of β-cell proliferation during 2 weeks after birth was totally abolished in the transgenic mice. Heterozygous E1-DN mice were glucose intolerant in intraperitoneal glucose tests. This was associated with a reduced insulin response. However, downregulation of EGF-R signaling had no influence on the insulinotropic effect of glucagon-like peptide-1 analog exendin-4. In summary, our results show that even a modest attenuation of EGF-R signaling leads to a severe defect in postnatal growth of the β-cells, which leads to the development of diabetes.
Feasibility of Automating Insulin Delivery for the Treatment of Type 1 Diabetes
Authors: Steil Garry M. , Rebrin Kerstin , Darwin Christine , Hariri Farzam , Saad Mohammed F.
Published: November 2006

An automated closed-loop insulin delivery system based on subcutaneous glucose sensing and subcutaneous insulin delivery was evaluated in 10 subjects with type 1 diabetes (2 men, 8 women, mean [±SD] age 43.4 ± 11.4 years, duration of diabetes 18.2 ± 13.5 years). Closed-loop control was assessed over ∼30 h and compared with open-loop control assessed over 3 days. Closed-loop insulin delivery was calculated using a model of the β-cell’s multiphasic insulin response to glucose. Plasma glucose was 160 ± 66 mg/dl at the start of closed loop and was thereafter reduced to 71 ± 19 by 1:00 p.m. (preprandial lunch). Fasting glucose the subsequent morning on closed loop was not different from target (124 ± 25 vs. 120 mg/dl, respectively; P > 0.05). Mean glucose levels were not different between the open and closed loop (133 ± 63 vs. 133 ± 52 mg/dl, respectively; P > 0.65). However, glucose was within the range 70–180 mg/dl 75% of the time under closed loop versus 63% for open loop. Incidence of biochemical hypoglycemia (blood glucose <60 mg/dl) was similar under the two treatments. There were no episodes of severe hypoglycemia. The data provide proof of concept that glycemic control can be achieved by a completely automated external closed-loop insulin delivery system.
The Cell Cycle Inhibitory Protein p21cip Is Not Essential for Maintaining β-Cell Cycle Arrest or β-Cell Function In Vivo
Authors: Cozar-Castellano Irene , Haught Marcia , Stewart Andrew F.
Published: November 2006

p21cip1, a regulatory molecule upstream of the G1/0 checkpoint, is increased in β-cells in response to mitogenic stimulation. Whereas p21cip1 can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21cip1 acts as an inhibitor in the pancreatic β-cell. To determine the functional role of p21cip1 in vivo, we studied p21-null mice. Surprisingly, islet mass, β-cell replication rates, and function were normal in p21-null mice. We next attempted to drive β-cell replication in p21-null mice by crossing them with rat insulin II promoter–murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21-null islets showed no additional stimulation. A G1/S proteome scan demonstrated that p21cip1 loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21cip1 loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal β-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain β-cell replication.
Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility
Authors: Ge Xinhui , Piganelli Jon D. , Tse Hubert M. , Bertera Suzanne , Mathews Clayton E. , Trucco Massimo , Wen Li , Rudert William A.
Published: November 2006

This study addressed an important biological question, namely how certain HLA molecules modulate the disease risk conferred by other HLA molecules. The HLA molecules under investigation were HLA-DQ8 and -DR4, the two most prevalent HLA class II alleles found in Caucasian type 1 diabetic patients. A panel of human GAD (hGAD65)-specific CD4 T-cell lines and hybridomas was generated to serve as detection reagents for evaluating the peptide occupancy of DQ8 and DR4. Results indicated that DQ8 and DR4 (0401) were able to bind the same hGAD65 peptides. The coexpression of DR4 (0401) diminished DQ8-restricted T-cell responses. In addition, we also demonstrated that the diminished T-cell response varied according to the specific DRB1*04 alleles. Taken together, this study provides evidence that DR4 is able to modulate DQ8-restricted T-cell responses, possibly by competing for peptides. Given that DQ8 is a primary genetic determinant of type 1 diabetes, the decreased DQ8-restricted CD4 T-cell activity due to peptide competition may be the mechanism explaining the modulation effect of DR4 to type 1 diabetes susceptibility.
The Krüppel-Like Factor 11 (KLF11) Q62R Polymorphism Is Not Associated With Type 2 Diabetes in 8,676 People
Authors: Florez Jose C. , Saxena Richa , Winckler Wendy , Burtt Noël P. , Almgren Peter , Bengtsson Boström Kristina , Tuomi Tiinamaija , Gaudet Daniel , Ardlie Kristin G. , Daly Mark J. , Altshuler David , Hirschhorn Joel N. , Groop Leif
Published: November 2006

Krüppel-like factor 11 is a pancreatic transcription factor whose activity induces the insulin gene. A common glutamine-to-arginine change at codon 62 (Q62R) in its gene KLF11 has been recently associated with type 2 diabetes in two independent samples. Q62R and two other rare missense variants (A347S and T220M) were also shown to affect the function of KLF11 in vitro, and insulin levels were lower in carriers of the minor allele at Q62R. We therefore examined their impact on common type 2 diabetes in several family-based and case-control samples of northern-European ancestry, totaling 8,676 individuals. We did not detect the rare A347S and T220M variants in our samples. With respect to Q62R, despite >99% power to detect an association of the previously published magnitude, Q62R was not associated with type 2 diabetes (pooled odds ratio 0.97 [95% CI 0.88–1.08], P = 0.63). In a subset of normoglycemic individuals, we did not observe significant differences in various insulin traits according to genotype at KLF11 Q62R. We conclude that the KLF11 A347S and T220M mutations do not contribute to increased risk of diabetes in European-derived populations and that the Q62R polymorphism has, at best, a minor effect on diabetes risk.
Blockade of Pancreatic Islet–Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet–Induced Glucose Intolerance
Authors: Dezaki Katsuya , Sone Hideyuki , Koizumi Masaru , Nakata Masanori , Kakei Masafumi , Nagai Hideo , Hosoda Hiroshi , Kangawa Kenji , Yada Toshihiko
Published: November 2006

The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet–induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet–induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes.
Evaluation and interlaboratory validation of a GC-MS method for analysis of pesticide residues in teas
Authors: Peng C. , Kuang H. , Li X. , Xu C.
Published: November 2006

A method was described for simultaneous determination of nine organic heterocyclic pesticide residues by gas chromatography-mass spectrometry-selected ion monitoring. Atrazine, vinclozolin, procymidone, triflumizole, imazalil, buprofezin, propiconazole, fenarimol, and pyridaben were clearly separated from each other, extracted with acetone—hexane mixture, purified with graphitized carbon black cartridge and neutral Al2O3 cartridge, eluted with acetone—hexane mixture, simultaneously determined by GC-MS, and then quantified with an external standard method. Recoveries of pesticides ranged from 73 % to 116 % at the spiked level of 0.01–30 mg kg−1, while the relative standard deviation was between 3 % and 27 %. In addition, the limits of determination (0.01 mg kg−1 to 5.0 mg kg−1) and linearity (0.02–40 μg mL−1) revealed that simultaneous determination of multi-residues in Chinese teas (like Oolong tea, green tea, red tea, etc.) was possible. Furthermore, an interlaboratory study among 5 labs was conducted to further validate the method, and the results were satisfactory.
Influence of composition on corroding process of Na2O-K2O-CaO-ZrO2-SiO2 glasses
Authors: Staňová I. , Plško A. , Pagáčová J. , Šibíková K.
Published: November 2006

The corroding process of six glasses of the Na2O-K2O-CaO-ZrO2-SiO2 system with ZrO2content 0–2.13 mass % by water was observed during static tests at 121°C and pressure of 0.25 MPa in steam sterilizer. Significant increase of Na+ and K+ content in leachates was observed after the addition of ZrO2 into glass. Further increase of the content of ZrO2 in glasses slowed down the rate of Na+ and K+ leaching. The leaching process of SiO2 as well as Na+, K+, and Ca2+ ions was evaluated on the basis of comparison with model leaching processes. Variation of the concentrations of Na+, K+, Ca2+, and SiO2 in leachates with time was described by empirical equation. Observed changes in the initial leaching rates of Na+, K+, Ca2+, and SiO2 can be ascribed to the content of ZrO2 in glasses. The presence of ZrO2 in glasses reduced the overall rate of glass dissolution.
Comparison of chemical properties of food products processed by conventional and ohmic heating
Authors: Pereira R. , Pereira M. , Teixeira J. , Vicente A.
Published: November 2006

The effect of ohmic and conventional heat processing of different food products on their chemical and physical parameters was studied. Depending on the food being analysed, parameters such as pH, total solids, ash, titratable acidity, ascorbic acid, total sugars, total fatty acids, total phenolic compounds, and anthocyanins content were determined before and after ohmic and conventional pasteurization techniques and the results were compared using one-way analysis of variance. In goat milk samples treated by ohmic technology the pH value (6.58) and total fatty acids content in milk fat (86.5 mass %) were comparable to those found in milk treated by conventional process, however, ohmically treated samples presented a lower content of lactic acid, 0.13 %. In cloudberry jam samples treated by ohmic technology the results of some of the main parameters tested, such as total sugar content 46.1 mass %, ascorbic acid content 2.83 mass %, and titratable acidity 6.01 mass % (as citric acid) did not show significant differences when compared with samples treated by conventional technology.