bluuebunny/crossref_metadata_2025 huggingface dataset:
Carnitine-Associated Encephalopathy Caused by Long-term Treatment With an Antibiotic Containing Pivalic Acid
Authors: Makino Yasuko , Sugiura Tokio , Ito Tetsuya , Sugiyama Naruji , Koyama Norihisa
Published: August 2007

An 18-month-old boy was treated with an antibiotic containing pivalic acid for 6 months for intractable otitis media and then developed repeated convulsions and loss of consciousness. Laboratory data showed hypoglycemia and hypocarnitinemia. Intravenous administration of glucose was ineffective against the seizures and loss of consciousness. However, the patient regained consciousness and recovered soon after intravenous infusion of carnitine. To our knowledge, intravenous carnitine administration that contributed to marked improvements in neurologic deficit caused by administration of an antibiotic containing pivalic acid has not been reported previously. These findings indicate that long-term use of such antibiotics should be avoided.
Interaction between external debt and equity finance in Hungarian international investment positions
Authors: Kuti M.
Published: August 2007

This study aims to scrutinise the external capital structure in Hungary from the 1970s to recent years. On the one hand, this paper uses a combined analysis of external debt and equity, and, on the other hand, it makes an effort to apply a couple of corporate finance principles to a macro-economic setting, attempting to test the corporate model on a national economy from the perspective of the sources and uses of global funds and their return. At the same time, the corporate analogue has its limitations.
Is convergence rate monotonic?
Authors: Csillik P. , Tarján T.
Published: August 2007

The paper aims to develop a model of nonlinear economic growth — with simple assumptions — which explains both Japan’s
S
-shape convergence path and the UK’s declining path toward the US between 1870–2000, and the development of other countries, as well as post-war reconstruction. According to the model, progress in stock of knowledge is formed by a quadratic formula of the relative development of follower countries.The model draws on four recent theories. Firstly, Romer’s theory, which approaches a country’s level of development by using the number of its products (Romer 1990), secondly, Jones’ idea theory with a slight modification (Jones 2004), third, the theory of quality of institutions, which determines economic performance (North 1993), and finally, the theory of physical and human capital. The first part of the paper sets up the production function, the second determines the growth rate and analyses the reconstruction path, while the third draws up model forecasts.
Prevalence of childhood asthma in Baranya County, Hungary: two surveys over 3 years
Authors: Harangi Ferenc , Lőrinczy Katalin , Lázár Anett , Örkényi Mária , Adonyi Mária , Sebők Béla
Published: August 2007

A gyermekkori asztma, allergiás rhinitis és atópiás dermatitis prevalenciája világszerte folyamatosan emelkedett az elmúlt évtizedekben. A legfrissebb közlések az emelkedő tendencia megváltozásáról, plató kialakulásáról vagy csökkenésről számolnak be. A szerzők 2003 után 2006-ban is meghatározták az asztma és asztmatünetek prevalenciáját Baranya megyei iskolás gyermekek körében, hogy regisztrálják az esetleges változásokat.
Vizsgálati anyag, módszer:
Munkájukhoz az ISAAC (International Study for Asthma and Allergies in Childhood) III. fázisú protokoll magyar nyelvre fordított kérdőívét használták. 2006 februárjában 16 általános iskolában (6 nagyvárosi és 10 kisvárosi, falusi) 2404 (1124 fiú, 1280 lány) 6–7 és 13–14 éves gyermek adatait gyűjtötték össze, és értékelték, illetőleg az adatokat a 2003-ban végzett ISAAC I. fázisú protokoll szerinti felmérés eredményeihez viszonyították.
Eredmények:
A valaha előfordult asztmás nehézlégzés és az orvos által megállapított asztma prevalenciája nem változott szignifikánsan (2006-ban 20,2% és 6,7%, 2003-ban 19,8% és 8,2%), míg a legutóbbi 12 hónapban előforduló asztmás nehézlégzés aránya szignifikánsan emelkedett (2006-ban 9,6% és 2003-ban 6,8%). A várakozásnak megfelelően, 2006-ban éppúgy, mint 2003-ban, a fiúk és a 6–7 évesek körében szignifikánsan magasabb volt a prevalencia, mint a lányok és a 13–14 évesek körében. 2006-ban és 2003-ban nem volt szignifikáns különbség a nagyvárosi és a kisebb települések iskolás gyermekeinek asztma- és asztmatüneti prevalenciájában.
Következtetés:
Baranya megyében az iskolás gyermekek körében a legutóbbi 12 hónapban előforduló asztmás nehézlégzés prevalenciája szignifikánsan emelkedett a vizsgált periódusban, a valaha előforduló asztmás nehézlégzés és az orvos által megállapított asztma prevalenciája nem változott.
Grasping reflex activity in utero is one element of fetal behavior (Grasping activity is a part of fetal ethology)
Authors: Jakobovits Ákos
Published: August 2007

Ismeretes, hogy az újszülöttek, illetve a csecsemők néhány hónapos korig a kezük ügyébe kerülő testrészeket és tárgyakat megfogják. A szerző rutin-ultrahangvizsgálatok során az utolsó trimeszterben lévő magzatok fogóreflexének érvényesülését a méhben véletlenszerűen figyelte meg. Hat magzat a köldökzsinórját, egy a scrotumát és egy a péniszét fogta meg. Színkódolt Doppler ultrahangkészülékkel vizsgálva, az arteria umbilicalis véráramlás-sebesség hullámformáiban a leszorítás másodpercekig tartó átmeneti zavart okozott. Ezután a magzatok a köldökzsinórt elengedték. A napokkal-hetekkel később világra jött újszülöttek egészségesek voltak. A szerző következtetése, hogy a magzat fogóreflexének aktivitása csupán egy ártalmatlan, átmeneti epizód a magzat életében. A fogóreflexnek csupán etológiai jelentősége van, bizonyítja a prae- és postnatalis aktivitás átmenetét. A fogóreflex sztereotip ismétlődése a magzatokban, újszülöttekben és csecsemőkben bizonyíték a genetikailag örökölt mivoltra.
Influences of psychiatric and psychosomatic disorders on patients’ quality of life
Authors: Pikó Bettina , Rudisch Tibor
Published: August 2007

Az életminőség fogalma az utóbbi évtizedekben egyre inkább előtérbe került a krónikus betegek ellátásával kapcsolatban. A jelen tanulmány célja, hogy a fejfájás (tenziós típus), a hangulatzavar (depresszió), a szorongás diagnózisával, valamint a komorbid állapotokkal összefüggésben elemezzük e betegségek életminőségre gyakorolt hatását, bevonva néhány kiemelt pszichológiai jellemzőt, mint például a hosztilitás vagy a társas támogatás.
Módszerek:
A vizsgálatban 157 beteg vett részt, akik a SZTE ÁOK Pszichiátriai Klinika Neuropszichiátriai Rehabilitációs Osztály ambuláns beteganyagából kerültek ki 2005 első félévében. A minta végső elemszáma 151 személy volt, akiket öt fő betegségcsoportba osztottunk be: hangulatzavar (depresszió); szorongásos kórképek; kevert pszichiátriai diagnózis; fejfájás és komorbiditás (fejfájás és pszichiátriai zavar együtt). Az életminőségi skálák pontértékeit nemenként, betegségcsoportonként vizsgáltuk, valamint elemeztük az életminőség pszichológiai hátterét. A kérdőíves felmérés önkitöltéses formában történt, a válaszadás önkéntes volt.
Eredmények:
Faktoranalízis segítségével két életminőségi faktort különítettünk el: az ún. „mindennapi élettevékenység” életminőségi faktort (például munka, anyagi helyzet, táplálkozás, szexuális élet vagy önkifejezés), valamint a „társas aktivitások” életminőségi faktort (például a házastárssal, családdal, egyéb személyekkel való, vallásos és közösségi tevékenységek). A betegségcsoportok szerint elsősorban a mindennapi tevékenységek terén mutatkozott különbség: leginkább a hangulatzavarban szenvedők ezzel kapcsolatos életminősége romlott, hozzájuk képest a fejfájásos betegek kevésbé jeleztek változást. Amennyiben komorbid pszichiátriai zavar előfordul a fejfájás mellett, az életminőség-változás számottevőbb. A mindennapi tevékenységeket érintő életminőség-romláshoz elsősorban a hosztilitás (ellenségesség), valamint a pszichoszomatikus/szorongásos tünetek megléte járul hozzá, és az életkor előrehaladtával a betegek az életminőség-romlást is erőteljesebben élik meg. A betegségcsoportból a hangulatzavar megléte rontja leginkább a betegek életminőségét. A szociális aktivitásokat érintő életminőség-faktor esetében a társas támogatás védőfaktor.
Következtetések:
A jelen tanulmányunkban szeretnénk felhívni a figyelmet a pszichoszomatikus és pszichiátriai zavarok életminőségre gyakorolt hatásaira, amelynek segítségével közelebb juthatunk a betegek viselkedésének mélyebb megértéséhez. Az életminőség-kutatás nemcsak kedvezőtlen hatásokat azonosít, hanem a pozitívakat is feltérképezi. Ez magában foglalja a hatékony alkalmazkodás lehetőségét.
Presidential Address 2006: It Must Change
Authors: Perloff Marjorie
Published: August 2007

This year marks the centennial of Samuel Beckett's birth, and the celebrations around the world have been a wonder to behold. From Buenos Aires to Tokyo, from Rio de Janeiro to Sofia, from South Africa (where Beckett did not permit his plays to be performed until apartheid was ended) to New Zealand, from Florida State University, in Tallahassee, to the University of Reading, from the Barbican Theatre, in London, to the Pompidou Center, in Paris, from Hamburg and Kassel and Zurich to Aix-en-Provence and Lille, from Saint Petersburg to Madrid to Tel Aviv, and of course most notably in Dublin, 2006 has been Beckett's year. Most of the festivals have included not only performances of the plays but also lectures, symposia, readings, art exhibitions, and manuscript displays. Paris Beckett 2006, for example, cosponsored by the French government and New York University's Center for French Civilization and Culture, has featured productions of Beckett's entire dramatic oeuvre, mounted in theaters large and small all over Paris, and lectures by such major figures as the novelist-theorists Philippe Sollers and Hélène Cixous, the playwrights Fernando Arrabal and Israel Horovitz, and the philosopher Alain Badiou. To round things out, in 2007 the Pompidou Center will host a major exhibition of and on Beckett's work.
Identifying Emma Dunham Kelley: Rethinking Race and Authorship
Authors: Jackson Holly
Published: August 2007

Though she has long been considered a pioneer of black women's writing, there is no evidence to suggest that Emma Dunham Kelley-Hawkins, author ofMegdaandFour Girls at Cottage City, was African American. This author considered herself racially white, as did every recorded member of her family before her. Instead of simply asserting her whiteness to correct the “mistake” of her racial categorization in the scholarly reception of her novels, this essay explores the uses of authorial racial identity in critical practice. Reading the obsessive concern with skin color inFour Girls at Cottage Citydemands not only further consideration of Kelley's work alongside African American literature but also attention to issues of white racialization at the turn of the century. However we identify Kelley, the critical history and continued interpretation of her work provide a rare opportunity to observe the consequences of destabilizing an author's identity or, more precisely, recognizing identity as unstable.
Statistical Methods for Evaluating Soil Salinity Spatial and Temporal Variability
Authors: Douaik Ahmed , Van Meirvenne Marc , Tóth Tibor
Published: August 2007

Monitoring soil salinity requires knowledge of its magnitude and its spatial and temporal variability. To characterize the spatiotemporal variability of soil salinity in a native sodic grassland in the east of Hungary, we applied several statistical methods. Within a 25‐ha study area, soil samples were taken repeatedly from 13 to 20 locations at 19 dates between November 1994 and June 2001 (with intervals between 2 and 9 mo). Electrical conductivity was measured both in the laboratory in a 1:2.5 soil/water suspension (EC2.5) and in situ using a four‐electrode probe (ECa). These measurements were converted, via calibration regressions, into predicted EC2.5*, which were compared with EC2.5 in their ability to characterize the spatiotemporal variability of soil salinity. The temporal change in the mean soil salinity level between each subsequent two dates was evaluated using a paired t‐test, a test of significance of the regression parameters based on the concept of temporal stability, and a temporal mean shift test. The static–dynamic (uniform–nonuniform) nature of the temporal change in the spatial pattern of soil salinity between two dates was evaluated using the same concept of temporal stability and a spatial shift test. For either type of temporal change (mean level or spatial pattern), the methods agreed for some pairs of dates and did not for others, but these differences were partly due to differences in data input. The method to use depends on the data availability and the aim of the study. The joint use of temporal stability and temporal mean shift and spatial shift tests could result in a drastically reduced sampling effort.
Significance of Wettability‐Induced Changes in Microscopic Water Distribution for Soil Organic Matter Decomposition
Authors: Goebel Marc-O. , Woche Susanne K. , Bachmann Joerg , Lamparter Axel , Fischer Walter R.
Published: August 2007

The significance of soil water‐repellent properties has been discussed with respect to water dynamics and distribution; however, there are indications of their importance also for C stabilization processes. Water‐repellent aggregates, for example, have been shown to protect soil organic matter (SOM) due to their stability against water slaking. Soil wettability can act as a key factor for SOM decomposition as it controls the microbial availability of water and nutrients. The main objective of this study was therefore to investigate the impact of wettability on C release by linking the wetting properties in terms of the contact angle to soil respiration parameters. For this, the wetting properties of two topsoil samples (an Orthic Luvisol and a Dystric Cambisol) were altered by the addition of particles that were hydrophobized by treatment with dichlorodimethylsilane (DCDMS). Additionally, aggregates were created to assess whether artificial aggregation also can contribute to SOM protection. Environmental scanning electron microscopy revealed a locally confined distribution of water for the DCDMS‐treated material, compared with untreated soil where water was uniformly distributed. Measurements indicated an increasing contact angle with increasing amount of DCDMS‐treated particles in the mixtures. With increasing contact angle, C release decreased, suggesting that wettability‐induced changes in water distribution can significantly affect the decomposition of SOM. Respiration from artificial aggregates, however, was not reduced compared with the corresponding homogeneous material. We conclude that wettability is an important factor for SOM decomposition as it governs the spatial distribution and availability of water necessary for microbial activity.
Soil Carbon and Nitrogen Changes in Forests of Walker Branch Watershed, 1972 to 2004
Authors: Johnson D. W. , Todd D. E. , Trettin C. F. , Sedinger J. S.
Published: August 2007

Changes in soil C and N concentrations and contents in four samplings during a 32‐yr period on Walker Branch watershed in Tennessee were determined and compared with previously measured C and N fluxes and with changes in ecosystem C and N pools during this period. Soils showed significant increases in C and N concentrations in surface horizons from 1972 to 2004, and most of this increase occurred between 1972 and 1982. A previously observed decline in soil C and N contents between 1982 and 1993 was reversed in 2004 such that the latter increased to near 1982 values. The changes in soil C content could be approximately accounted for by previously measured litterfall and soil CO2–C fluxes. Changes in soil N could not be accounted for by leaching, increments in vegetation, or by laboratory bias, changes during sample storage, or reasonable estimates of field sampling errors. We conclude that, although vegetation C and N pools increased steadily during the sampling period in most cases, changes in soil C and N pools on Walker Branch watershed are highly variable in both space and time, and there has been no unidirectional trend during the time period of this study.
Analytical Solution of the Heat Pulse Method in a Parallelepiped Sample Space
Authors: Liu Gang , Li Baoguo , Ren Tusheng , Horton Robert
Published: August 2007

The heat pulse method enables estimation of the thermal diffusivity (k), volumetric heat capacity (C), and thermal conductivity of soils (λ) and soil water content. In this study, analytical solutions were derived by the method of Green's function for a finite pulse cylinder source in a parallelepiped sample of size a by b by c with two kinds of boundary conditions. One is the zero surface temperature (ZST) boundary condition, and the other is the adiabatic boundary condition (ABC). The proposed solutions may be useful for evaluating the errors of a dual‐probe heat pulse (DPHP) system introduced by approximating the finite heater with an infinite line source (ILS) model. Applications of the solution are presented in the context of an air‐dried virtual soil sample to demonstrate how different factors (boundary conditions, soil sample size, heater needle length and radius, probe spacing, heating duration, and strength) can affect the error in k and C caused by using an ILS model. For a given parallelepiped (or soil column), the larger the ratio of lengths of the heater probe and the sample, the smaller the boundary influence on the temperature rise at the mid‐needle temperature sensing location, and the smaller the errors introduced by using the ILS approximation. For various heating strengths, it was found that the errors in both k and C were relatively constant when all other parameters were fixed. These errors increased monotonically and slowly, however, as heat duration increased.
The Vascular Ectonucleotidase ENTPD1 Is a Novel Renoprotective Factor in Diabetic Nephropathy
Authors: Friedman David J. , Rennke Helmut G. , Csizmadia Eva , Enjyoji Keiichi , Robson Simon C.
Published: August 2007

Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39) is the dominant vascular ectonucleotidase. By hydrolyzing ATP and ADP to AMP, ENTPD1 regulates ligand availability to a large family of P2 (purinergic) receptors. Modulation of extracellular nucleotide metabolism is an important factor in several acute and subacute models of vascular injury. We hypothesized that aberrant nucleotide signaling would promote chronic glomerular injury in diabetic nephropathy. Inducing diabetes in ENTPD1-null mice with streptozotocin resulted in increased proteinuria and more severe glomerular sclerosis compared with matched diabetic wild-type mice. Diabetic ENTPD1-null mice also had more glomerular fibrin deposition and glomerular plasminogen activator inhibitor-1 (PAI-1) staining than wild-type controls. In addition, ENTPD1-null mice showed increased glomerular inflammation, in association with higher levels of monocyte chemoattractant protein-1 (MCP-1) expression. Mesangial cell PAI-1 and MCP-1 mRNA expression were upregulated by ATP and UTP but not ADP or adenosine in vitro. The stable nucleotide analog ATPγS stimulated sustained expression of PAI-1 and MCP-1 in vitro, whereas the stable adenosine analog NECA [5′-(N-ethylcarboxamido)adenosine] downregulated expression of both genes. Extracellular nucleotide-stimulated upregulation of MCP-1 is, at least in part, protein kinase C dependent. We conclude that ENTPD1 is a vascular protective factor in diabetic nephropathy that modulates glomerular inflammation and thromboregulation.
Metallothionein Prevents High-Fat Diet–Induced Cardiac Contractile Dysfunction
Authors: Dong Feng , Li Qun , Sreejayan Nair , Nunn Jennifer M. , Ren Jun
Published: August 2007

Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet–induced myocardial, intracellular Ca2+, and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat–fed FVB mice. Cardiomyocytes from high-fat–fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca2+ defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca2+ rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet–fed FVB mice. The peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1α downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat–fed FVB mice. Intriguingly, the high-fat diet–induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet–induced cardiac dysfunction possibly associated with upregulation of PGC-1α and preservation of mitochondrial biogenesis.
Increased Number of Islet-Associated Macrophages in Type 2 Diabetes
Authors: Ehses Jan A. , Perren Aurel , Eppler Elisabeth , Ribaux Pascale , Pospisilik John A. , Maor-Cahn Ranit , Gueripel Xavier , Ellingsgaard Helga , Schneider Marten K.J. , Biollaz Gregoire , Fontana Adriano , Reinecke Manfred , Homo-Delarche Francoise , Donath Marc Y.
Published: August 2007

Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat–fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat–fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1α. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and β-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic α-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes.
Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice
Authors: Grempler Rolf , Zibrova Darya , Schoelch Corinna , van Marle André , Rippmann Joerg F. , Redemann Norbert
Published: August 2007

Type 2 diabetes is characterized by a progressive resistance of peripheral tissues to insulin. Recent data have established the lipid phosphatase SH2 domain–containing inositol phosphatase 2 (SHIP2) as a critical negative regulator of insulin signal transduction. Mutations in the SHIP2 gene are associated with type 2 diabetes. Here, we used hyperglycemic and hyperinsulinemic KKAy mice to gain insight into the signaling events and metabolic changes triggered by SHIP2 inhibition in vivo. Liver-specific expression of a dominant-negative SHIP2 mutant in KKAy mice increased basal and insulin-stimulated Akt phosphorylation. Protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase were significantly reduced, and consequently the liver produced less glucose through gluconeogenesis. Furthermore, SHIP2 inhibition improved hepatic glycogen metabolism by modulating the phosphorylation states of glycogen phosphorylase and glycogen synthase, which ultimately increased hepatic glycogen content. Enhanced glucokinase and reduced pyruvate dehydrogenase kinase 4 expression, together with increased plasma triglycerides, indicate improved glycolysis. As a consequence of the insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis, the liver-specific inhibition of SHIP2 improved glucose tolerance and markedly reduced prandial blood glucose levels in KKAy mice. These results support the attractiveness of a specific inhibition of SHIP2 for the prevention and/or treatment of type 2 diabetes.
Distinct In Vivo Roles of Caspase-8 in β-Cells in Physiological and Diabetes Models
Authors: Liadis Nicole , Salmena Leonardo , Kwan Edwin , Tajmir Panteha , Schroer Stephanie A. , Radziszewska Anna , Li Xie , Sheu Laura , Eweida Mohamed , Xu Shilong , Gaisano Herbert Y. , Hakem Razqallah , Woo Minna
Published: August 2007

Inadequate pancreatic β-cell mass resulting from excessive β-cell apoptosis is a key defect in type 1 and type 2 diabetes. Caspases are the major molecules involved in apoptosis; however, in vivo roles of specific caspases in diabetes are unclear. The purpose of this study is to examine the role of Caspase (Casp)8 in β-cells in vivo. Using the Cre-loxP system, mice lacking Casp8 in β-cells (RIPcre+Casp8fl/fl mice) were generated to address the role of Casp8 in β-cells in physiological and diabetes models. We show that islets isolated from RIPcre+Casp8fl/fl mice were protected from Fas ligand (FasL)–and ceramide-induced cell death. Furthermore, RIPcre+Casp8fl/fl mice were protected from in vivo models of type 1 and type 2 diabetes. In addition to being the central mediator of apoptosis in diabetes models, we show that Casp8 is critical for maintenance of β-cell mass under physiological conditions. With aging, RIPcre+Casp8fl/fl mice gradually develop hyperglycemia and a concomitant decline in β-cell mass. Their islets display decreased expression of molecules involved in insulin/IGF-I signaling and show decreased pancreatic duodenal homeobox-1 and cAMP response element binding protein expression. At the level of individual islets, we observed increased insulin secretory capacity associated with increased expression of exocytotic proteins. Our results show distinct context-specific roles of Casp8 in physiological and disease states; Casp8 is essential for β-cell apoptosis in type 1 and type 2 diabetes models and in regulating β-cell mass and insulin secretion under physiological conditions.
HLA-DPB1*0402 Protects Against Type 1A Diabetes Autoimmunity in the Highest Risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY Population
Authors: Baschal Erin E. , Aly Theresa A. , Babu Sunanda R. , Fernando Maria S. , Yu Liping , Miao Dongmei , Barriga Katherine J. , Norris Jill M. , Noble Janelle A. , Erlich Henry A. , Rewers Marian J. , Eisenbarth George S.
Published: August 2007

OBJECTIVE— A major goal in genetic studies of type 1A diabetes is prediction of anti-islet autoimmunity and subsequent diabetes in the general population, as >85% of patients do not have a first-degree relative with type 1A diabetes. Given prior association studies, we hypothesized that the strongest candidates for enhancing diabetes risk among DR3-DQB1*0201/DR4-DQB1*0302 individuals would be alleles of DP and DRB1*04 subtypes and, in particular, the absence of reportedly protective alleles DPB1*0402 and/or DRB1*0403.

RESEARCH DESIGN AND METHODS— We genotyped 457 DR3-DQB1*0201/DR4-DQB1*0302 Diabetes Autoimmunity Study of the Young (DAISY) children (358 general population and 99 siblings/offspring of type 1 diabetic patients) at the DPB1, DQB1, and DRB1 loci using linear arrays of immobilized sequence-specific oligonucleotides, with direct sequencing to differentiate DRB1*04 subtypes.

RESULTS— By survival curve analysis of DAISY children, the risk of persistently expressing anti-islet autoantibodies is ∼55% for relatives (children with a parent or sibling with type 1 diabetes) in the absence of these two protective alleles vs. 0% (P = 0.02) with either protective allele, and the risk is 20 vs. 2% (P = 0.004) for general population children. Even when the population analyzed is limited to DR3-DQB1*0201/DR4-DQB1*0302 children with DRB1*0401 (the most common DRB1*04 subtype), DPB1*0402 influences development of anti-islet autoantibodies.

CONCLUSIONS— The ability to identify a major group of general population newborns with a 20% risk of anti-islet autoimmunity should enhance both studies of the environmental determinants of type 1A diabetes and the design of trials for the primary prevention of anti-islet autoimmunity.
A CTG Polymorphism in the CNDP1 Gene Determines the Secretion of Serum Carnosinase in Cos-7–Transfected Cells
Authors: Riedl Eva , Koeppel Hannes , Brinkkoetter Paul , Sternik Paula , Steinbeisser Herbert , Sauerhoefer Sibylle , Janssen Bart , van der Woude Fokko J. , Yard Benito A.
Published: August 2007

Recently, we demonstrated that a polymorphism in exon 2 of the serum carnosinase (CNDP1) gene is associated with susceptibility to developing diabetic nephropathy. Based on the number of CTG repeats in the signal peptide, five different alleles coding for 4, 5, 6, 7, or 8 leucines (4L–8L) are known. Diabetic patients without nephropathy are homozygous for the 5L allele more frequently than those with nephropathy. Since serum carnosinase activity correlates with CNDP1 genotype, we hypothesized in the present study that secretion of serum carnosinase is determined by the CNDP1 genotype. To test this hypothesis, we transfected Cos-7 cells with different CNDP1 constructs varying in CTG repeats and assessed the expression of CNDP1 protein in cell extracts and supernatants. Our results demonstrate that CNDP1 secretion is significantly higher in cells expressing variants with more than five leucines in the signal peptide. Hence, our data might explain why individuals homozygous for the 5L allele have low serum carnosinase activity. Because carnosine, the natural substrate for carnosinase, exerts antioxidative effects and inhibits ACE activity and advanced glycation end product formation, our results support the finding that diabetic patients homozygous for CNDP1 5L are protected against diabetic nephropathy.
Congenital Hyperinsulinism–Associated ABCC8 Mutations That Cause Defective Trafficking of ATP-Sensitive K+ Channels
Authors: Yan Fei-Fei , Lin Yu-Wen , MacMullen Courtney , Ganguly Arupa , Stanley Charles A. , Shyng Show-Ling
Published: August 2007

Congenital hyperinsulinism (CHI) is a disease characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K+ (KATP) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Previous studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide. The purpose of this study is to identify additional mutations that cause channel biogenesis/trafficking defects and those that are amenable to rescue by pharmacological chaperones. Fifteen previously uncharacterized CHI-associated missense SUR1 mutations were examined for their biogenesis/trafficking defects and responses to pharmacological chaperones, using a combination of immunological and functional assays. Twelve of the 15 mutations analyzed cause reduction in cell surface expression of KATP channels by >50%. Sulfonylureas rescued a subset of the trafficking mutants. By contrast, diazoxide failed to rescue any of the mutants. Strikingly, the mutations rescued by sulfonylureas are all located in the first transmembrane domain of SUR1, designated as TMD0. All TMD0 mutants rescued to the cell surface by the sulfonylurea tolbutamide could be subsequently activated by metabolic inhibition on tolbutamide removal. Our study identifies a group of CHI-causing SUR1 mutations for which the resulting KATP channel trafficking and expression defects may be corrected pharmacologically to restore channel function.
Impairment of the Ubiquitin-Proteasome Pathway Is a Downstream Endoplasmic Reticulum Stress Response Induced by Extracellular Human Islet Amyloid Polypeptide and Contributes to Pancreatic β-Cell Apoptosis
Authors: Casas Sílvia , Gomis Ramon , Gribble Fiona M. , Altirriba Jordi , Knuutila Sakari , Novials Anna
Published: August 2007

OBJECTIVE—Human islet amyloid polypeptide (hIAPP) aggregation plays a major role in the development of islet amyloidosis in type 2 diabetes. It is known that extracellular hIAPP oligomers are toxic to pancreatic β-cells and associated with apoptosis. We therefore investigated the molecular mechanism by which extracellular hIAPP mediates pancreatic β-cell apoptosis.

RESEARCH DESIGN AND METHODS—MIN6 cells and primary cultures of human pancreatic islets were treated with freshly dissolved hIAPP peptide. Morphology of the cultures was evaluated by electron microscopy. Gene expression was analyzed by microarray, RT-PCR, and immunoblot. Calcium levels were measured in fura-2–loaded cells. Apoptosis was quantified by cytometry.

RESULTS—Increased expression of several heat shock proteins and activation of the spliced form of XBP-1, a transcription factor for overexpression of chaperones during endoplasmic reticulum (ER) stress, were detected together with morphological evidence of ER dysfunction. Intracellular calcium overload was detected in association with this process. Moreover, reduction in the proteasome activity, which was detected over time, contributed to the intracellular accumulation of ubiquitinated proteins, leading to a functional suppression of the ubiquitin-proteasome pathway. In addition, impairment of the proteasome function contributed to apoptosis, while, despite the presence of hIAPP, cell viability improved when a proteasome activator was overexpressed. The key cytotoxic events induced by extracellular hIAPP were also observed in treated human islets.

CONCLUSIONS—Our data suggest that ER stress responses are intracellular signaling mechanisms induced by extracellular hIAPP aggregation and that impairment of the ubiquitin-proteasome pathway is implicated in ER stress–mediated pancreatic β-cell apoptosis.
Absence of CC Chemokine Ligand 2 Does Not Limit Obesity-Associated Infiltration of Macrophages Into Adipose Tissue
Authors: Inouye Karen E. , Shi Hang , Howard Jane K. , Daly Christine H. , Lord Graham M. , Rollins Barrett J. , Flier Jeffrey S.
Published: August 2007

Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2−/− and wild-type mice (n = 11–14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12–16 and 25–29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2−/− mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2−/− mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2−/− mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2−/− mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2−/− mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.
Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes
Authors: Li Ruobing , Perez Nicolas , Karumuthil-Melethil Subha , Vasu Chenthamarakshan
Published: August 2007

OBJECTIVE—The pancreatic microenvironment is considered to be the primary location of autoreactive T-cells in type 1 diabetes. Diabetogenic T-cells have also been detected in the spleens of NOD mice. However, it is not known whether bone marrow also contains T-cells specific for self-antigens in hosts with autoimmunity. In this study, we investigated whether autoreactive diabetogenic T-cells are present in the bone marrow of NOD mice.

RESEARCH DESIGN AND METHODS—Bone marrow and splenic T-cells of female NOD mice were purified and tested for their cytokine secretion and proliferation in response to stimulation with immunodominant peptides of pancreatic β-cells. The diabetogenic nature and homing properties of purified bone marrow T-cells were compared with those of splenic T-cells in NOD-Scid and wild-type mice.

RESULTS—The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with β-cell antigens than T-cells from spleen. Bone marrow T-cells showed rapid expansion and aggressive infiltration into pancreatic islets in NOD-Scid mice and induced hyperglycemia earlier than splenic T-cells. Adoptive transfer of bone marrow T-cells resulted in their trafficking predominantly to bone marrow and pancreatic lymph nodes.

CONCLUSIONS—Our study demonstrates that a large number of diabetogenic T-cells are present in the bone marrow of female NOD mice and that these autoreactive T-cells can be detected long before clinical onset of the disease.
Depression, Self-Care, and Medication Adherence in Type 2 Diabetes
Authors: Gonzalez Jeffrey S. , Safren Steven A. , Cagliero Enrico , Wexler Deborah J. , Delahanty Linda , Wittenberg Eve , Blais Mark A. , Meigs James B. , Grant Richard W.
Published: August 2007

OBJECTIVE—We examined the association between depression, measured as either a continuous symptom severity score or a clinical disorder variable, with self-care behaviors in type 2 diabetes.

RESEARCH DESIGN AND METHODS—We surveyed 879 type 2 diabetic patients from two primary care clinics using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence.

RESULTS—Of the patients, 19% met the criteria for probable major depression (HANDS score ≥9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days' adherent to diet, exercise, and glucose self-monitoring regimens (P < 0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5–3.6, P < 0.001) compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score <9, n = 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P < 0.01).

CONCLUSIONS—These findings challenge the conceptualization of depression as a categorical risk factor for nonadherence and suggest that even low levels of depressive symptomatology are associated with nonadherence to important aspects of diabetes self-care. Interventions aimed at alleviating depressive symptoms, which are quite common, could result in significant improvements in diabetes self-care.
Software for Reading and Grading Diabetic Retinopathy
Authors: Perumalsamy Namperumalsamy , Prasad Noela M. , Sathya Shankar , Ramasamy Kim
Published: August 2007

OBJECTIVE—To evaluate the validity and reproducibility of software for reading digital images and grading diabetic retinopathy.

RESEARCH DESIGN AND METHODS—A prospective, comparative observational study was conducted on a series of patients with type 2 diabetes who presented at the retina clinic of a tertiary care center in India. A total of 210 eyes of 105 patients were allocated to one of three ophthalmologists, who performed dilated indirect and direct ophthalmoscopy and subsequently assessed the digital images of the same group of patients who were masked to the patient's identity. The interobserver and intertest agreement between clinical assessments and grading of diabetic retinopathy using the software was estimated.

RESULTS—Moderate nonproliferative diabetic retinopathy (NPDR) was most frequently diagnosed, both clinically and on evaluating digital images. The overall agreement between the clinical grading of diabetic retinopathy and the grading of images was 81.3% (κ = 0.69, SE 0.04, P < 0.0001); there was good agreement (81.3%) for NPDR (κ = 0.61, SE 0.05, P < 0.0001), but agreement was not as good (54.6%) for proliferative diabetic retinopathy (κ = 0.29, SE 0.11, P = 0.005). Clinically significant macular edema was diagnosed in 33.3% (70 of 210) of eyes clinically and in 40.2% (84 of 209) of eyes by grading images, and there was good agreement (89.5%) between the two (κ = 0.77, SE 0.07, P < 0.0001).

CONCLUSIONS—Aravind Diabetic Retinopathy Screening 3.0 is a simple and valid tool to assist in the detection of sight-threatening retinopathy and could supplement dilated fundus examinations by ophthalmologists on patients to detect diabetic retinopathy.
Insulin Resistance and Hyperinsulinemia Are Related to Plasma Aldosterone Levels in Hypertensive Patients
Authors: Colussi GianLuca , Catena Cristiana , Lapenna Roberta , Nadalini Elisa , Chiuch Alessandra , Sechi Leonardo A.
Published: August 2007

OBJECTIVE—An association between aldosterone and insulin resistance has been demonstrated in obesity and primary aldosteronism and in blacks with the metabolic syndrome. The aim of this study was to evaluate the relationship of plasma aldosterone with insulin sensitivity in white subjects.

RESEARCH DESIGN AND METHODS—In 356 patients with essential hypertension and 102 normotensive control subjects of comparable age and BMI, we measured, after discontinuation of treatment, plasma active renin, aldosterone, cortisol, glucose, insulin, and C-peptide levels and calculated markers of insulin sensitivity. Direct assessment of insulin sensitivity was obtained in a subset of 64 hypertensive patients by a hyperinsulinemic clamp.

RESULTS—Hypertensive patients had significantly greater fasting plasma insulin and C-peptide concentrations and homeostasis model assessment (HOMA) indexes than normotensive control subjects. A positive association with increasing plasma aldosterone concentrations was demonstrated for plasma glucose, insulin, C-peptides, and HOMA. Assessment of insulin sensitivity by clamp showed a significant decrease of the metabolic clearance rate of glucose with increasing aldosterone levels. Significant correlations were found between plasma aldosterone, plasma insulin, and C-peptide levels, HOMA, and glucose metabolic clearance rate. Blood pressure and plasma potassium, plasma cortisol, and renin levels, but not BMI, were also directly correlated with plasma aldosterone. Multiple regression analysis showed that HOMA, together with plasma potassium, cortisol, and renin levels, was independently correlated with plasma aldosterone.

CONCLUSIONS—This study demonstrates a direct relationship between aldosterone, insulin resistance, and hyperinsulinemia in white subjects. In patients with hypertension, this relationship might contribute to maintenance of high blood pressure and increased cardiovascular risk.
Increased Incidence of Gestational Diabetes in Women Receiving Prophylactic 17α-Hydroxyprogesterone Caproate for Prevention of Recurrent Preterm Delivery
Authors: Rebarber Andrei , Istwan Niki B. , Russo-Stieglitz Karen , Cleary-Goldman Jane , Rhea Debbie J. , Stanziano Gary J. , Saltzman Daniel H.
Published: August 2007

OBJECTIVE—Progesterone has a known diabetogenic effect. We sought to determine whether the incidence of gestational diabetes mellitus (GDM) is altered in women receiving weekly 17α-hydroxyprogesterone caproate (17P) prophylaxis for the prevention of recurrent preterm birth.

RESEARCH DESIGN AND METHODS—Singleton gestations in women having a history of preterm delivery were identified from a database containing prospectively collected information from women receiving outpatient nursing services related to a high-risk pregnancy. Included were patients enrolled for outpatient management at <27 weeks' gestation with documented pregnancy outcome and delivery at >28 weeks. Patients with preexisting diabetes were excluded. The incidence of GDM was compared between patients who received prophylactic intramuscular 17P (250-mg weekly injection initiated between 16.0 and 20.9 weeks' gestation) and those who did not.

RESULTS—Maternal BMI and age were similar. The incidence of GDM was 12.9% in the 17P group (n = 557) compared with 4.9% in control subjects (n = 1,524, P < 0.001; odds ratio 2.9 [95% CI 2.1–4.1]).

CONCLUSIONS—The use of 17P for the prevention of recurrent preterm delivery is associated with an increased risk of developing GDM. Early GDM screening is appropriate for women receiving 17P prophylaxis.