bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Determinants of Type 1 Diabetes Across Populations
Authors: JAHROMI MOHAMED M. , EISENBARTH GEORGE S.
Published: November 2006

Abstract:  T1D results from autoimmune‐mediated destruction of the pancreatic β cells, a process that is conditioned by multiple genes and environmental factors. The main genetic determinants map to the major histocompatibility complex (MHC), and in particular DR and DQ, although, genes outside the MHC contribute, including the insulin gene, PTPN22, and CTLA‐4. There are remarkable differences in genetic susceptibility to T1D between populations. We believe this variation reflects differing frequencies of diabetes causative and protective alleles and haplotypes, and thus remains a major genetic influence linked to the MHC region not accounted for by DR and DQ alleles. In this article, we discuss global variations in genetic susceptibility to T1D in view of current genetic understanding.
TNFa‐e Microsatellite, HLA‐DRB1 and ‐DQB1 Alleles and Haplotypes in Brazilian Patients Presenting Recently Diagnosed Type 1 Diabetes Mellitus
Authors: RASSI DIANE M. , WASTOWSKI ISABELA J. , SIMÕES RENATA T. , RODRIGUES SANDRA , DEGHAIDE NEIFE N.H.S. , MENDES‐JUNIOR CELSO T. , SIMÕES AGUINALDO L. , SOARES C.P. , PASSOS GERALDO A.S. , DONADI EDUARDO A.
Published: November 2006

Abstract:  TNF microsatellite and HLA class II polymorphisms were studied in 28 recently diagnosed Brazilian patients presenting type 1 diabetes mellitus (T1DM) and in 120 healthy controls. TNFa‐e and HLA‐DRB1/DQB1 alleles were identified using sets of sequence‐specific primers. Compared to controls, the DRB1*03 and DQB1*02 allele groups, TNFa1 allele, and the TNFa4‐b5‐c1‐d4‐e3 and TNFa10‐b5‐c1‐d4‐e3 haplotypes were overrepresented in patients. TNF microsatellite together with HLA polymorphisms is associated with type 1 diabetes in Brazilian patients, corroborating the participation of the MHC genes in disease susceptibility.
Is HLA Class II Profile Relevant for the Study of Large‐Scale Differentially Expressed Genes in Type 1 Diabetes Mellitus Patients?
Authors: RASSI DIANE M. , JUNTA CRISTINA M. , FACHIN ANA L. , SANDRIN‐GARCIA PAULA , MELLO STEPHANO S. , FERNANDES ANA P.M. , DEGHAIDE NEIFE N.H.S. , FOSS‐FREITAS MARIA C. , FOSS MILTON C. , SAKAMOTO‐HOJO ELZA T. , PASSOS GERALDO A.S. , DONADI EDUARDO A.
Published: November 2006

Abstract:  We have previously identified 30 differentially expressed genes when comparing recently diagnosed type 1 diabetes mellitus (DM‐1) patients and controls paired for sex, age, and ethnic background. In this article we performed the hierarchical clustering of these genes taking into account the human‐leukocyte‐antigen (HLA)‐DRB1/DQB1 profile. The dendrogram obtained using the Cluster program grouped patients and controls into three clusters, one including individuals with no susceptibility alleles, another including individuals with at least three susceptibility alleles, and a third intermingling susceptibility/protective alleles. In addition to other variables, the results of the present article suggest that the major histocompatibility complex (MHC) class II profile may be of relevance for the study of a large‐scale differentially expressed genes.
Interleukin‐10 Plasmid Construction and Delivery for the Prevention of Type 1 Diabetes
Authors: LEE MINHYUNG , PARK HYEWON , YOUN JEEHEE , OH EUN TAEX , KO KYUNGSOO , KIM SUNGWAN , PARK YONGSOO
Published: November 2006

Abstract:  Studies of animals with spontaneous autoimmune diabetes have revealed that autoreactive T cells that mediate islet β cell destruction can be manipulated by the administration of Th2 cytokines. In this article, the effect of interleukin‐10 (IL‐10) gene delivery was evaluated in vitro and in vivo with a novel IL‐10 plasmid, pSI‐IL‐10‐NFκB. In pSI‐IL‐10‐NFκB, the expression of the IL‐10 gene was driven by the SV40 promotor/enhancer. The nuclear factor κB (NFκB) binding sites were also introduced to facilitate nuclear transport of the plasmid in the cell. In vitro transfection assay with pSI‐IL‐10‐NFκB showed a similar expression level of IL‐10 to the plasmid without NFκB binding sites (pSI‐IL‐10). pSI‐IL‐10‐NFκB and pSI‐IL‐10 were intravenously injected into 5‐week‐old nonobese diabetic (NOD) mice using polyethylenimine (PEI) as a gene carrier. Both groups had persistent gene expression, longer than 5 weeks, and secreted the similarly high IL‐10 serum levels. Interestingly, the degree of insulitis in the pSI‐IL‐10‐NFκB group was improved over the pSI‐IL‐10 group, PEI‐only group, and noninjected controls. The serum glucose levels showed that single injection of pSI‐IL‐10‐NFκB prevented the development of diabetes in 100% of the pSI‐IL‐10‐NFκB–injected animals (5/5), while that of pSI‐IL‐10 prevented diabetes in 40% of the treated animals (2/5). These results suggest that pSI‐IL‐10‐NFκB with PEI can effectively reduce the incidence of insulitis and type 1 diabetes in NOD mice.
Living Donor Islet Transplantation, the Alternative Approach to Overcome the Obstacles Limiting Transplant
Authors: IWANAGA YASUHIRO , MATSUMOTO SHINICHI , OKITSU TERU , NOGUCHI HIROFUMI , NAGATA HIDEO , YONEKAWA YUKIHIDE , YAMADA YUICHIRO , FUKUDA KAZUHITO , TSUKIYAMA KATSUSHI , TANAKA KOICHI
Published: November 2006

Abstract:  We performed the world's first successful living donor islet transplantation for unstable diabetes. A total of 408,114 islet equivalents were isolated from half a living pancreas and transplanted immediately to the recipient who was a 27‐year‐old female. The donor was a 56‐year‐old female in good health, mother of the recipient. The islets functioned immediately, and the recipient was weaned completely from insulin on the 22nd posttransplant day, and has maintained excellent glycemic control since. The donor was discharged on the 18th postoperative day with normal oral glucose tolerance test and without complications. Living donor islet transplantation could cure one insulin‐dependent diabetes mellitus patients with a single donor. There are some advantages in the living donor islet transplantation: (a) living donor can alleviate the issue of donor shortage; (b) highly potent islets can be isolated from a living donor; and (c) the recipient can be treated with immunosuppressant and controlled blood glucose level tightly prior to the transplantation. These are important factors in overcoming the obstacles limiting islet transplantation. We believe that the living donor islet transplantation may become an additional option in treating insulin‐dependent diabetes.
Probiotics for the Prevention of Beta Cell Autoimmunity in Children at Genetic Risk of Type 1 Diabetes—the PRODIA Study
Authors: LJUNGBERG MARTIN , KORPELA RIITA , ILONEN JORMA , LUDVIGSSON JOHNNY , VAARALA OUTI
Published: November 2006

Abstract:  The final aim of the PRODIA study is to determine whether the use of probiotics during the first 6 months of life decreases the appearance of type 1 diabetes mellitus (T1DM)‐associated autoantibodies in children with genetic risk for T1DM. A pilot study including 200 subjects was planned to show whether the use of probiotics during the first 6 months of life is safe and feasible. The prevalence of autoantibodies among the study subjects at 6, 12, and 24 months of age was at levels close to the expected and the clinical follow‐up did not either indicate problems in the feasibility of the study.
Thiazolidinediones May Not Reduce Diabetes Incidence in Type 1 Diabetes
Authors: SHIGIHARA TOSHIKATSU , OKUBO YOSHIAKI , KANAZAWA YASUHIKO , OIKAWA YOICHI , SHIMADA AKIRA
Published: November 2006

Abstract:  Thiazolidinediones improve glycemic control by reducing insulin resistance. Some studies have demonstrated that troglitazone had a preventative effect on diabetes in NOD (non‐obese diabetic) mice. One of the mechanisms proposed for the prevention of diabetes by thiazolidinediones is an effect on T‐helper 1/T‐helper 2 (Th1/Th2) balance. In this article, we attempted to clarify whether pioglitazone is also effective in preventing diabetes as compared to metformin, which has no immunological effect. Female NOD mice were administered pioglitazone or metformin orally, and the insulitis score, cytokines secreted from splenocytes, cytokine expression levels in the pancreas, and the incidence of diabetes after acceleration by cyclophosphamide were analyzed. We could not find any advantage of pioglitazone in preventing Th1 skewing and the development of diabetes over metformin. Therefore, further research should take place before the application of thiazolidinediones to human slowly progressive insulin‐dependent diabetes mellitus (SPIDDM) patients.
Mechanisms Mediating Anti‐CD3 Antibody Efficacy
Authors: YOUNG DANIEL L. , RAMANUJAN SAROJA , KREUWEL HUUB T.C. , WHITING CHAN CHUNG , GADKAR KAPIL G. , SHODA LISL K.M.
Published: November 2006

Abstract:  Anti‐CD3 antibody therapy, a promising clinical approach for the treatment of type 1 diabetes (T1D), was investigated using a mathematical model of T1D in the female nonobese diabetic (NOD) mouse. Analyses of model simulation results indicate that, in addition to the known direct effects of anti‐CD3 antibody on T lymphocytes, two additional mechanisms are required for sustained disease remission: (a) rapid regrowth of healthy β cells following clearance of islet inflammation and (b) enhanced regulatory T cell activity and/or phenotypic changes in antigen presenting cells (APCs) that promote a stable regulatory environment in the pancreas.
Cell‐Based Approaches for Cardiac Repair
Authors: RUBART MICHAEL , FIELD LOREN J.
Published: November 2006

Abstract:  Many forms of cardiovascular disease are associated with cardiomyocyte loss via necrosis and/or apoptosis. The cumulative loss of contractile cells ultimately results in diminished cardiac function. Numerous approaches have been employed to reduce the rate of cardiomyocyte loss, or alternatively, to repopulate the heart with new cardiomyocytes. Strategies aimed at repopulating the heart include cardiomyocyte cell therapy, myogenic stem cell therapy, and cell cycle activation therapy. All three approaches are based on the assumption that the de novo cardiomyocytes will participate in a functional syncytium with the surviving myocardium. This review will discuss the current status of interventions aimed at repopulating the heart with functional cardiomyocytes.
The Unstoppable Connexin43 Carboxyl‐Terminus
Authors: GOURDIE ROBERT G. , GHATNEKAR GAUTAM S. , O'QUINN MICHAEL , RHETT MATTHEW J. , BARKER RALPH J. , ZHU CHING , JOURDAN JANE , HUNTER ANDREW W.
Published: November 2006

Abstract:  Intercellular connectivity mediated by gap junctions (GJs) composed of connexin43 (C×43) is critical to the function of excitable tissues such as the heart and brain. Disruptions to C×43 GJ organization are thought to be a factor in cardiac arrhythmias and are also implicated in epilepsy. This article is based on a presentation to the 4th Larry and Horti Fairberg Workshop on Interactive and Integrative Cardiology and summarizes the work of Gourdie and his lab on C×43 GJs in the heart. Background and perspective of recently published studies on the function of C×43‐interacting protein zonula occludens‐(ZO)‐1 in determining the organization of GJ plaques are provided. In addition how a peptide containing a PDZ‐binding sequence of C×43, developed as part of the work on cardiac GJ organization is also described, which has led to evidence for novel and unexpected roles for C×43 in modulating healing following tissue injury.
Dynamic Interactions between Myocytes, Fibroblasts, and Extracellular Matrix
Authors: BANERJEE INDRONEAL , YEKKALA KRISHNA , BORG THOMAS K. , BAUDINO TROY A.
Published: November 2006

Abstract:  Cardiac function is determined by the coordinated and dynamic interaction of several cell types together with components of the extracellular matrix (ECM). This interaction is regulated by mechanical, chemical, and electrical signals between the cellular and noncellular components of the heart. Recent studies using fluorescence‐activated cell sorting indicate that the number of myocytes remains relatively constant during development and disease, whereas the number of fibroblasts and other cell types can change dramatically. Cardiac fibroblasts appear to have different origins at different stages of development and fluctuate in response to a variety of physiological signals. Fibroblasts form a network of cells that are connected to each other via specific cadherins and connexins, to the ECM via integrins, and to myocytes by a variety of receptors, including connexins. Examples of the integration of signals include the role of angiotensin II (Ang II), which stimulates mechanical contraction of fibroblasts, as well as cytokine signaling. Cytokine signaling alters connexin and K+ channel activation, which in turn is regulated by Ang II, essentially forming a feedback loop. Quantitative changes in mechanical, chemical, and electrical signals that can alter the overall cardiac form and function will be discussed here.
The Integration of Spontaneous Intracellular Ca2+ Cycling and Surface Membrane Ion Channel Activation Entrains Normal Automaticity in Cells of the Heart's Pacemaker
Authors: LAKATTA EDWARD G. , VINOGRADOVA TATIANA , LYASHKOV ALEXEY , SIRENKO SYEVDA , ZHU WEIZONG , RUKNUDIN ABDUL , MALTSEV VICTOR A.
Published: November 2006

Abstract:  Although the ensemble of voltage‐ and time‐dependent rhythms of surface membrane ion channels, the membrane “Clock”, is the immediate cause of a sinoatrial nodal cell (SANC) action potential (AP), it does not necessarily follow that this ion channel ensemble is the formal cause of spontaneous, rhythmic APs. SANC also generates intracellular oscillatory spontaneous Ca2+ releases that ignite excitation (SCaRIE) of the surface membrane via Na+/Ca2+ exchanger activation. The idea that a rhythmic intracellular Ca2+ Clock might keep time for normal automaticity of SANC, however, has not been assimilated into mainstream pacemaker dogma. Recent experimental evidence, derived from simultaneous, confocal imaging of submembrane Ca2+ and membrane potential of SANC, and supported by numerical modeling, indicates that normal automaticity of SANC is entrained and stabilized by the tight integration of the SR Ca2+ Clock that generates rhythmic SCaRIE, and the surface membrane Clock that responds to SCaRIE to immediately produce APs of an adequate shape. Thus, tightly controlled, rhythmic SCaRIE does not merely fine tune SANC AP firing, but is the formal cause of the basal and reserve rhythms, insuring pacemaker stability by rhythmically integrating multiple Ca2+‐dependent functions, and effects normal automaticity by rhythmic ignition of the surface membrane Clock.
Calcium Handling in Embryonic Stem Cell–Derived Cardiac Myocytes
Authors: ITZHAKI ILANIT , SCHILLER JACKIE , BEYAR RAFAEL , SATIN JONATHAN , GEPSTEIN LIOR
Published: November 2006

Abstract:  Excitation–contraction (EC) coupling is fundamental to the function of cardiac myocytes (CMs). In mature myocytes plasma membrane (PM) L‐type Ca2+ channels function in close juxtaposition to ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) membrane. Action potentials (APs) cause the opening of PM L‐type Ca2+ channels, which in turn provide trigger Ca2+ for a larger RyR‐mediated SR Ca2+ release. In contrast, developing myocytes have a less well‐developed SR. This incomplete development is observed in early stage and mid‐maturation stages of murine embryonic stem cell–derived cardiac myocytes (ESC‐CMs). Despite the absence of a well‐developed t‐tubule system, murine ESC‐CMs use internal Ca2+ stores for EC coupling. Direct measures of Ca2+ handling, including pharmacological studies and investigation of genetically modified mouse ESC‐CMs, established an important contribution of RyR‐mediated internal Ca2+ store to cell function. Similarly, early‐stage human ESC‐CMs use internal Ca2+ store and partially share Ca2+ handling characteristics with murine ESC‐CMs. For example, elementary Ca2+ release events are present in both murine and human ESC‐CMs, and it is likely that Ca2+ handling contributes to automatic rhythm generation in these cells. However, in human ESC‐CMs, a unique voltage‐gated Na+ channel window current is critical for spontaneous, rhythmic depolarization. The advent of the murine and human ES cardiomyocyte differentiating systems has provided initial insights into the early steps of development of excitability and electromechanical coupling in the mammalian heart, including patterns of gene expression, myofibrillogenesis, ion channel development and function, and Ca2+ handling. Here we discuss the information gained from these models to describe the nexus of voltage‐gated channel currents and Ca2+ handling on rhythmic activity.
Cardiac Defibrillation and the Role of Mechanoelectric Feedback in Postshock Arrhythmogenesis
Authors: GUREV VIATCHESLAV , MALECKAR MARY M. , TRAYANOVA NATALIA A.
Published: November 2006

Abstract:  Ventricular dilatation increases the defibrillation threshold (DFT). In order to elucidate the mechanisms responsible for this increase, the present article investigates changes in the postshock behavior of the myocardium upon stretch. A two‐dimensional electro‐mechanical model of cardiac tissue incorporating heterogeneous fiber orientation was used to explore the effect of sustained stretch on postshock behavior via (a) recruitment of mechanosensitive channels (MSC) and (b) tissue deformation and concomitant changes in tissue conductivities. Recruitment of MSC had no influence on vulnerability to electric shocks as compared to control, but increased the complexity of postshock VF patterns. Stretch‐induced deformation and changes in tissue conductivities resulted in a decrease in vulnerability to electric shocks.
Modeling Cardiac Electrical Activity at the Cell and Tissue Levels
Authors: AUSTIN TRAVIS M. , HOOKS DARREN A. , HUNTER PETER J. , NICKERSON DAVID P. , PULLAN ANDREW J. , SANDS GREGORY B. , SMAILL BRUCE H. , TREW MARK L.
Published: November 2006

Abstract:  Significant tissue structures exist in cardiac ventricular tissue, which are of supracellular dimension. It is hypothesized that these tissue structures contribute to the discontinuous spread of electrical activation, may contribute to arrhythmogenesis, and also provide a substrate for effective cardioversion. However, the influences of these mesoscale tissue structures in intact ventricular tissue are difficult to understand solely on the basis of experimental measurement. Current measurement technology is able to record at both the macroscale tissue level and the microscale cellular or subcellular level, but to date it has not been possible to obtain large volume, direct measurements at the mesoscales. To bridge this scale gap in experimental measurements, we use tissue‐specific structure and mathematical modeling. Our models, which can incorporate ion channel models at the cell level into the reaction–diffusion equations at the tissue level, have enabled us to consider key hypotheses regarding discontinuous activation.
Nonlinear Dynamics of Paced Cardiac Cells
Authors: SHIFERAW YOHANNES , QU ZHILIN , GARFINKEL ALAN , KARMA ALAIN , WEISS JAMES N.
Published: November 2006

Abstract:  When a cardiac cell is rapidly paced it can exhibit a beat‐to‐beat alternation in the action potential duration (APD) and the intracellular calcium transient. This dynamical instability at the cellular level has been shown to correlate with the genesis of cardiac arrhythmias and has motivated the application of nonlinear dynamics in cardiology. In this article, we review mathematical approaches to describe the underlying mechanisms for alternans using beat‐to‐beat iterated maps. We explain the development and properties of these maps, and show that they provide a fruitful framework to understand dynamical instabilities of voltage and calcium in paced cardiac cells.
Endogenous anti-inflammatory substances, inter-α-inhibitor and bikunin
Authors: Kobayashi Hiroshi
Published: November 2006

There have been new developments in the elucidation of the biological functions of the inter-α-inhibitor (IαI) family. The anti-proteolytic activity of the IαI family originates from bikunin (also known as urinary trypsin inhibitor). Growing evidence indicates that bikunin is not just an anti-proteolytic agent, but can also be considered an anti-inflammatory agent that suppresses lipopolysaccharide (LPS)-induced cytokine synthesis. Bikunin functions to inhibit calcium influx and extracellular signal-regulated kinase (ERK) signaling via LPS receptors and/or as yet unidentified bikunin signaling receptors. By signaling via the LPS receptor, LPS increases calcium influx and yields phosphorylated ERK, which activates multiple transcription factors, such as nuclear factor κB (NF-κB) or early growth response-1 (Egr-1), which in turn promote cytokine expression. Deficits in the signaling cascades caused by free or cell-bound bikunin are predicted to down-regulate cytokine expression, render macrophages/neutrophils more inactive, and impair inflammatory processes. This brief review largely focuses on our current understanding of the apparent functions of bikunin, its ligands, the effector molecules with which it interacts, and its regulation.
The human malaria parasite Plasmodium falciparum expresses an atypical N-terminally extended pyrophosphokinase with specificity for thiamine
Authors: Eschbach Marie-Luise , Müller Ingrid B. , Gilberger Tim-Wolf , Walter Rolf D. , Wrenger Carsten
Published: November 2006

Vitamin B1is an essential cofactor for key enzymes such as 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase. Plants, bacteria and fungi, as well asPlasmodium falciparum, are capable of synthesising vitamin B1de novo, whereas mammals have to take up this cofactor from their diet. Thiamine, a B1vitamer, has to be pyrophosphorylated by thiamine pyrophosphokinase (TPK) to the active form. The human malaria parasiteP. falciparumexpresses an N-terminally extended pyrophosphokinase throughout the entire erythrocytic life cycle, which was analysed by Northern and Western blotting. The recombinant enzyme shows a specific activity of 27 nmol min-1mg-1protein and specificity for thiamine with aKmvalue of 73 μM, while thiamine monophosphate is not accepted. Mutational analysis of the N-terminal extension of the plasmodial TPK showed that it influences thiamine binding as well as metal dependence, which suggests N-terminal participation in the conformation of the active site. Protein sequences of various plasmodial TPKs were analysed for their phylogeny, which classified thePlasmodiumTPKs to a group distinct from the mammalian TPKs. To verify the location of the parasite TPK within the cell, immunofluorescence analyses were performed. Co-staining ofPfTPK with a GFP marker visualised its cytosolic localisation.
Fes1p acts as a nucleotide exchange factor for the ribosome-associated molecular chaperone Ssb1p
Authors: Dragovic Zdravko , Shomura Yasuhito , Tzvetkov Nikolay , Hartl F. Ulrich , Bracher Andreas
Published: November 2006

The HspBP1 homolog Fes1p was recently identified as a nucleotide exchange factor (NEF) of Ssa1p, a canonical Hsp70 molecular chaperone in the cytosol of Saccharomyces cerevisiae. Besides the Ssa-type Hsp70s, the yeast cytosol contains three additional classes of Hsp70, termed Ssb, Sse and Ssz. Here, we show that Fes1p also functions as NEF for the ribosome-bound Ssb Hsp70s. Sequence analysis indicated that residues important for interaction with Fes1p are highly conserved in Ssa1p and Ssb1p, but not in Sse1p and Ssz1p. Indeed, Fes1p interacts with Ssa1p and Ssb1p with similar affinity, but does not form a complex with Sse1p. Functional analysis showed that Fes1p accelerates the release of the nucleotide analog MABA-ADP from Ssb1p by a factor of 35. In contrast to the interaction between mammalian HspBP1 and Hsp70, however, addition of ATP only moderately decreases the affinity of Fes1p for Ssb1p. Point mutations in Fes1p abolishing complex formation with Ssa1p also prevent the interaction with Ssb1p. The ATPase activity of Ssb1p is stimulated by the ribosome-associated complex of Zuotin and Ssz1p (RAC). Interestingly, Fes1p inhibits the stimulation of Ssb1p ATPase by RAC, suggesting a complex regulatory role of Fes1p in modulating the function of Ssb Hsp70s in co-translational protein folding.
How players manage moral concerns to make video game violence enjoyable
Authors: Klimmt Christoph , Schmid Hannah , Nosper Andreas , Hartmann Tilo , Vorderer Peter
Published: November 2006

Research on video game violence has focused on the impact of aggression, but has so far neglected the processes and mechanisms underlying the enjoyment of video game violence. The present contribution examines a specific process in this context, namely players' strategies to cope with moral concern that would (in real-life settings) arise from violent actions. Based on Bandura's (2002) theory of moral disengagement, we argue that in order to maintain their enjoyment of game violence, players find effective strategies to avoid or cope with the moral conflict related to their violent behaviors in the game world (‘moral management’). Exploratory interviews with ten players of violent video games revealed some relevance of moral reasoning to their game enjoyment, and several strategies that help players to ‘manage’ moral concern. Most importantly, respondents referred to the game-reality distinction and their focus on winning the game when explaining how violent action is a by-product of good performance. Findings are discussed in light of further theorizing on ‘moral management’ and potential links to the media violence debate.
Looking back: Joke comprehension and the space structuring model
Authors: Coulson Seana , Urbach Thomas P , Kutas Marta
Published: November 2006

We describe the space structuring model, a model of language comprehension inspired by ideas in cognitive linguistics, focusing on its capacity to explain the sorts of inferences needed to understand one-line jokes. One process posited in the model is frame-shifting, the semantic and pragmatic reanalysis in which elements of the existing message-level representation are mapped into a new frame retrieved from long-term memory. To test this model, we recorded participants' eye movements with a headband-mounted eye-tracker while they read sentences that ended either as a joke, or as nonfunny controls (“She read so much about the bad effects of smoking she decided to give up the reading/habit.”) . Only jokes required frame-shifting; nonjoke endings were consistent with the contextually evoked frame. Though initial gaze durations were the same for jokes and non-jokes, total viewing duration was longer for the jokes and participants were more likely to make regressive (leftward) eye movements after reading the “punch word” of a joke. Results are consistent with the psychological reality of some process like frame-shifting, suggesting readers literally revisit aspects of the prior context while apprehending one-line jokes.
Reinterpretation and viewpoints
Authors: Ritchie Graeme
Published: November 2006

It has often been observed that many jokes rely on the audience reinterpreting the initial part of the joke once the punchline is encountered. In order to elaborate on this account, we outline how these reinterpretations may happen in various ways. The examples we consider suggest that the generalization is best stated not in terms of syntactic or even semantic forms, since the same mechanism seems to occur in jokes presented visually or partly verbally, partly visually. We sketch an analysis using separate but related viewpoints (expressible in terms of mental spaces), concluding that the revised interpretation may occur in any nested viewpoint, and need not be adopted by the audience as a factually correct interpretation.
Heavy Duty Diesel Engine Coolant Technology: Past, Present, and Future
Authors: DeBaun HJ , Alverson FC
Published: November 2006

Significant advances have been made in heavy duty diesel engine technology to meet increasingly stringent environmental regulations for emissions. Today's heavy duty diesel engines are being designed with lighter and softer metals, greater turbocharging, increased combustion controls, and new emission reduction equipment. The cooling systems contained in these vehicles are similarly being impacted by smaller designs, new cooling system configurations, and increased usage of lighter, softer metals. Vehicle thermal loads have significantly increased due to increased power densities, higher engine temperatures, and greater metal-coolant fluxes which places greater emphasis on oxidation/thermal stability, and high temperature corrosion protection performance of the coolant. Other operating conditions (coolant flow rates, turbulence, pressure drops, deaeration) are also becoming more severe calling for improved erosion-corrosion protection, cavitation protection, and elastomer, seal, hose compatibility. This paper reviews the changes in heavy duty diesel engine technology and provides information on coolant performance in 2002-4 emission compliant engines. Predictions are also made on future engine technology and next generation engine coolants.
Associations of remission status and lanreotide treatment with quality of life in patients with treated acromegaly
Authors: Hua Shih-Che , Yan Yuan-Horng , Chang Tien-Chun
Published: November 2006

Objective: Acromegaly has an important impact on quality of life (QOL). The aim of this study was to evaluate the associations of remission status and lanreotide treatment with QOL in patients with treated acromegaly, by the newly developed disease-generated acromegaly QOL questionnaire (ACROQOL).

Design: Cross-sectional study.

Methods: Fifty-two patients with treated acromegaly were recruited to complete the Chinese version of the ACROQOL translated and validated from the English version. These patients were divided into controlled and uncontrolled groups based on the latest remission criteria and further subdivided into four groups according to the present treatment with lanreotide or not. Comparisons between groups were analyzed.

Results: There was no difference between controlled and uncontrolled groups in the ACROQOL scores of total score, both scales and psychological subscales. However, in the controlled group, present treatment with lanreotide, in comparison with no treatment, showed worse ACROQOL scores in total score (P = 0.021), psychological scale (P = 0.011), psychological subscale ‘appearance’ (P = 0.032) and ‘personal relations’ (P = 0.010).

Conclusions: The lanreotide treatment was negatively associated with QOL in biochemically controlled acromegalic patients, especially in the psychological aspect.
The incidence of second primary tumors in thyroid cancer patients is increased, but not related to treatment of thyroid cancer
Authors: Verkooijen Robbert B T , Smit Jan W A , Romijn Johannes A , Stokkel Marcel P M
Published: November 2006

Objective: The aim of the present study is to assess the prevalence of second primary tumors in patients treated for thyroid cancer. Furthermore, we wanted to assess the standardized risk rates for all second primary tumors, but especially for breast cancer, as data in the literature indicate an excessive risk in differentiated thyroid cancer (DTC) patients for this tumor.

Materials and methods: We included consecutive patients, who received ablation treatment with I-131 at the Leiden University Medical Center between January 1985 and December 1999 (n = 282). The mean period of follow-up was 10.6 ± 4.1 years.

Results: Thirty-five of the 282 patients (12.4%) had a second primary tumor (SPT), either preceding or following the diagnosis of thyroid cancer. Five other patients had three primary tumors, including DTC. As a result, 40 additional tumors were found in this group, revealing an overall prevalence of 14.2%. Twenty tumors (7.1%) preceded the thyroid cancer with a mean interval of 5.7 years (range: 0.5–22.0 years), whereas 20 tumors (7.1%) occurred after this tumor with a mean interval of 6.7 years (range: 1.0–15.0 years). In 13 female patients, breast cancer was found as SPT. The standardized incidence rate (SIR) for all cancers after the diagnosis of DTC in this study population was not increased (1.13; confidence interval (CI): 0.68–1.69). However, we found an increased SIR of 2.26 (CI: 1.60–3.03) for all cancers either following or preceding DTC, which is mainly caused by a SIR of 3.95 (CI: 2.06–6.45) for breast cancer.

Conclusion: Patients with DTC have an overall increased standardized incidence rate for second primary tumors, but not for second primary tumors following I-131 therapy. These findings suggest a common etiologic and/or genetic mechanism instead of a causal relation.
Thiamine transporter mutation: an example of monogenic diabetes mellitus
Authors: Alzahrani Ali S , Baitei Essa , Zou Minging , Shi Yufei
Published: November 2006

Objective: Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome.

Case: The patient is an 18-year-old girl whowas born to non-consanguous parents. She was noted to be deaf-mute in the first year of life. She was diagnosed with DM at the age of 9 months and with severe anemia at the age of 2 years. An extensive work up could not identify the cause. She was treated with blood transfusions every 3–4 weeks for the past 16 years. A diagnosis of TRMAwas suspected and the patient was treated with thiamine hydrochloride. Hemoglobin and platelets increased to normal values after a few weeks of thiamine therapy. Diabetic control significantly improved but she had no noticeable changes in the deafness.

Methods: Peripheral blood DNAwas extracted from the patient, her mother, aunt, and a healthy sister. Exons and exon–intron boundaries of the thiamine transporter gene SLC19A2 were PCR amplified and directly sequenced.

Results: A G515C homozygous mutation was identified in the SLC19A2 gene of the patient. This mutation changes Gly to Arg at codon 172 (G172R). The mother, an aunt, and a sister had a heterozygous G172R mutation.

Conclusions: Mutations in thiamine transporter gene, SLC19A2, causes a rare form of monogenic diabetes, anemia, and sensorineural deafness. Thiamine induces a remarkable hematological response and improvement in the diabetic control but has no effect on deafness.
The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies
Authors: O’Toole Dermot , Saveanu Alexandru , Couvelard Anne , Gunz Ginette , Enjalbert Alain , Jaquet Philippe , Ruszniewski Philippe , Barlier Anne
Published: November 2006

Objective: Somatostatin (sst) are present in the majority of gastro-entero-pancreatic (GEP) tumours. Effects of somatostatin receptor (sst) analogues are partial and of limited duration. Cell lines derived from GEP express dopaminergic receptors D2. New chimeric analogues simultaneously recognising sst2 and sst5 or sst2 and D2 have additive effects in inhibition of GH and prolactin secretion in pituitary adenomas. Our aim was to quantify the expression of sst and D2 mRNA in human GEP tumours.

Design and methods: mRNA expression of sst1, sst2, sst3 and sst5 as well as D2, was analysed using real-time PCR (TaqMan probe) in a series of 35 patients with GEP tumours (pancreas (n = 19) and intestinal (n = 16)). Levels of expression were compared with a group of 13 somatotroph adenomas.

Results: All GEP tumours express sst1, sst2 and D2. Expression of sst3 and sst5 was observed in 89 and 76% of tumours respectively with highly variable levels. sst2 mRNA expression was higher in nonfunctional tumours (P < 0.009) and sst5 was higher in pancreatic than in intestinal tumours (P < 0.02). Whereas sst2 levels were similar between GEP and somatotroph tumours, levels of sst5 and D2 were higher in the former (394.9 ± 156.1 × 10−2 vs 69.7 ± 19.5 × 10−2 copy/copy β-Gus (P < 0.0036) and 519.6 ± 121.2 × 10−2 vs 50.0 ± 21.6 × 10−2 copy/copy β-Gus (P < 0.0001) respectively). In small tumours ( < 30 mm), sst2 density appeared as a crucial parameter in somatostatin receptor scintigraphy results, whereas in big tumours, a consistent bias in SRS results was introduced by the size. In pancreatic GEP, high-level sst3 expression was found in tumours with more active angiogenesis (higher microvessel density and vascular endothelial growth factor expression (P < 0.03)).

Conclusions: GEP tumours co-express sst2 and D2 in 100% of cases and sst5 in 89% thus supporting the testing of bi-specific agonists (sst2/sst5 or sst2/D2) in these tumours.
Protein Inhibitor of Neuronal Nitric Oxide Synthase (PIN) Is a New Regulator of Glucose-Induced Insulin Secretion
Authors: Lajoix Anne-Dominique , Badiou Stéphanie , Péraldi-Roux Sylvie , Chardès Thierry , Dietz Samuel , Aknin Cindy , Tribillac Florence , Petit Pierre , Gross René
Published: November 2006

We previously showed that pancreatic β-cells express neuronal nitric oxide synthase (nNOS) that controls insulin secretion through two catalytic activities: nitric oxide (NO) production and cytochrome c reductase activity. We now provide evidence that the endogenous protein inhibitor of nNOS (PIN) is expressed in rat pancreatic islets and INS-1 cells. Double-immunofluorescence studies showed a colocalization of PIN with both nNOS and myosin Va in insulin-secreting β-cells. Electron microscopy studies confirmed that PIN is mainly associated with insulin secretory granules and colocated with nNOS in the latter. In addition, PIN overexpression in INS-1 cells enhanced glucose-induced insulin secretion, which is only partly reversed by addition of an NO donor, sodium nitroprusside (SNP), and unaffected by the inhibitor of cytochrome c reductase activity, miconazole. In contrast, the pharmacological inhibitor of nNOS, Nω-nitro-l-arginine methyl ester, amplified glucose-induced insulin secretion, an effect insensitive to SNP but completely normalized by the addition of miconazole. Thus, PIN insulinotropic effect could be related to its colocalization with the actin-based molecular motor myosin Va and as such be implicated in the physiological regulation of glucose-induced insulin secretion at the level of the exocytotic machinery.
Pathogenesis of Pre-Diabetes
Authors: Bock Gerlies , Dalla Man Chiara , Campioni Marco , Chittilapilly Elizabeth , Basu Rita , Toffolo Gianna , Cobelli Claudio , Rizza Robert
Published: November 2006

Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (Rd) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (Si) and insulin-stimulated glucose disposal (Si*) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial Rd since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG.
OXPAT/PAT-1 Is a PPAR-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization
Authors: Wolins Nathan E. , Quaynor Benjamin K. , Skinner James R. , Tzekov Anatoly , Croce Michelle A. , Gropler Matthew C. , Varma Vijayalakshmi , Yao-Borengasser Aiwei , Rasouli Neda , Kern Philip A. , Finck Brian N. , Bickel Perry E.
Published: November 2006

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as “OXPAT.” Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid–induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse adipose tissue, striated muscle, and liver by physiological (fasting), pathophysiological (insulin deficiency), pharmacological (peroxisome proliferator–activated receptor [PPAR] agonists), and genetic (muscle-specific PPARα overexpression) perturbations that increase fatty acid utilization. In humans with impaired glucose tolerance, PPARγ agonist treatment induces adipose OXPAT mRNA. Further, adipose OXPAT mRNA negatively correlates with BMI in nondiabetic humans. Our collective data in cells, mice, and humans suggest that OXPAT is a marker for PPAR activation and fatty acid oxidation. OXPAT likely contributes to adaptive responses to the fatty acid burden that accompanies fasting, insulin deficiency, and overnutrition, responses that are defective in obesity and type 2 diabetes.
Diabetes Alters Sphingolipid Metabolism in the Retina
Authors: Fox Todd E. , Han Xianlin , Kelly Samuel , Merrill Alfred H. , Martin Rex E. , Anderson Robert E. , Gardner Thomas W. , Kester Mark
Published: November 2006

Dysregulated sphingolipid metabolism causes neuronal cell death and is associated with insulin resistance and diseases. Thus, we hypothesized that diabetes-induced changes in retinal sphingolipid metabolism may contribute to neuronal pathologies in diabetic retinopathy. ESI-MS/MS was used to measure ceramide content and ceramide metabolites in whole retinas after 2, 4, and 8 weeks of streptozotocin-induced diabetes. After 4 and 8 weeks of diabetes, a ∼30% decrease in total ceramide content was observed, concomitant with a significant ∼30% increase in glucosylceramide levels in fed diabetic rats compared with their age-matched controls. Acute insulin therapy as well as a short-term lowering of glucose via fasting did not affect the increase in glucosylceramide composition. To assess the putative biological consequences of the increase in glucosylceramide composition, R28 retinal neurons were treated with glucosylceramide synthase inhibitors. Inhibiting glycosphingolipid metabolism increased insulin sensitivity in retinal neurons. Glycosphingolipid inhibitors augmented insulin-stimulated p70 S6kinase activity in the presence of inhibitory concentrations of high glucose or glucosamine. Inhibition of glycosphingolipid synthesis also suppressed glucosamine- and interleukin-1β–induced death. Consistent with these inhibitor studies, pharmacological accumulation of glycosphingolipids increased activation of the endoplasmic reticulum stress response, a putative modulator of insulin resistance and neuronal apoptosis. It is speculated that an increase in glucosylceramide, and possibly higher-order glycosphingolipids, could contribute to the pathogenesis of diabetic retinopathy by contributing to local insulin resistance, resulting in neuronal cell death. Thus, dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes, and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy.
Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene
Authors: Gray Juliette , Yeo Giles S.H. , Cox James J. , Morton Jenny , Adlam Anna-Lynne R. , Keogh Julia M. , Yanovski Jack A. , El Gharbawy Areeg , Han Joan C. , Tung Y.C. Loraine , Hodges John R. , Raymond F. Lucy , O’Rahilly Stephen , Farooqi I. Sadaf
Published: November 2006

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.
The Effect of Intensive Glycemic Treatment on Coronary Artery Calcification in Type 1 Diabetic Participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
Authors: Cleary Patricia A. , Orchard Trevor J. , Genuth Saul , Wong Nathan D. , Detrano Robert , Backlund Jye-Yu C. , Zinman Bernard , Jacobson Alan , Sun Wanjie , Lachin John M. , Nathan David M. ,   for the DCCT/EDIC Research Group
Published: November 2006

The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ∼7–9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT.