bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous Electrical Oscillations Emerge from a Coupled Network: A Study of the Inferior Olive using Lentiviral Knockdown of Connexin36
Authors: Placantonakis Dimitris G. , Bukovsky Anatoly A. , Aicher Sue A. , Kiem Hans-Peter , Welsh John P.
Published: May 2006

Do continuous subthreshold oscillations in membrane potential within an electrically coupled network depend on gap junctional coupling? For the inferior olive (IO), modeling and developmental studies suggested that the answer is yes, although physiological studies of connexin36 knock-out mice lacking electrical coupling suggested that the answer is no. Here we addressed the question differently by using a lentivirus-based vector to express, in the IO of adult rats, a single amino acid mutation of connexin36 that disrupts the intracellular trafficking of wild-type connexin36 and blocks gap junctional coupling. Confocal microscopy of green fluorescence protein-labeled dendrites revealed that the mutant connexin36 prevented wild-type connexin36 from being expressed in dendritic spines of IO neurons. Intracellular recordings from lentivirally transduced IO networks revealed that robust and continuous subthreshold oscillations require gap junctional coupling of IO neuron somata within 40 μm of one another. Topological studies indicated that the minimal coupled network for supporting such oscillations may be confined to the dendritic arbor of a single IO neuron. Occasionally, genetically uncoupled IO neurons showed transient oscillations; however, these were not sustained longer than 3 s and were 69% slower and 71% smaller than the oscillations of normal IO neurons, a finding replicated with carbenoxolone, a pharmacological antagonist of gap junctions. The experiments provided the first direct evidence that gap junctional coupling between neurons, specifically mediated by connexin36, allows a continuous network oscillation to emerge from a population of weak and episodic single-cell oscillators. The findings are discussed in the context of the importance of gap junctions for cerebellar rhythms involved in movement.
Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3
Authors: Engel Tobias , Hernández Félix , Avila Jesús , Lucas José J.
Published: May 2006

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist after cessation of the initial trigger. Regarding AD, GSK-3 has been shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in PHF (paired helical filament)-tau and GSK-3 activity contributes both to β-amyloid production and to β-amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here, we exploit the conditional system used to generate Tet/GSK-3β mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert after restoration of normal GSK-3 levels. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics.
Dorsomedial Prefrontal Cortex Resolves Response Conflict in Rats
Authors: de Wit Sanne , Kosaki Yutaka , Balleine Bernard Walter , Dickinson Anthony
Published: May 2006

The capacity for goal-directed behavior requires not only the encoding of the response-outcome relationship but also the ability to resolve conflict induced by competing responses. Recent neuroimaging studies have identified the prefrontal cortex as critical for resolving conflict between competing responses. At present, however, much of this evidence is indirect, and the necessity of dorsomedial prefrontal cortex (dmPFC) function for the resolution of conflict in goal-directed behavior has not been assessed. Here, we develop a rodent paradigm to investigate response conflict caused by the concurrent activation of a correct and incorrect response. In this paradigm, the outcome of one response also acts as a discriminative stimulus signaling that the other response is correct. Whereas rats with a functional dmPFC are able to resolve this conflict, inactivation of dmPFC using an infusion of muscimol produced a deficit by selectively interfering with their ability to inhibit the incorrect, competing response.
The Mexican Connection: Another Look at “Perishable” Relationships between Mexico and Points North
Authors: Adovasio J. M.
Published: May 2006

For more than three decades, it has been clearly possible to distinguish a series of prehistoric basket making “traditions” in western North America, specifically including Mexico. While the exact nature of these traditions remains controversial, virtually no one would deny the existence of distinctive and long-lived regional perishable manufacturing trajectories with unique suites of signature artifacts and definite frontiers. Perhaps some of the most intriguing aspects of these entities are their interrelationships both in time and through time. This article reexamines the relationships between basketry production and basket making populations in Mexico, the American Southwest, and points farther afield, and concludes that certain technologies of Mexican genesis are introduced into the Southwest and elsewhere precisely at the time that a package of domesticates of Mesoamerican origin are also spreading northward. The nature of both dispersals is defined and examined and several scenarios are offered to explain these interrelated processes.
Reply: Transfers vs. Economic Costs in the Iraq War
Authors: Stiglitz Joseph
Published: May 2006

Transfers and economic costs are indeed different in the war in Iraq, and transfers may be significant.
Update in Pre-Clinical Regulatory Requirements for Phytomedicines in Latin America
Authors: Remirez Diadelis Caridad
Published: May 2006

The use of herbal medicines or natural health products as alternative medicines for public health use continues to expand rapidly around the world. Pre-clinical assays are essential to guarantee the efficacy and safety of natural products and are commonly requested by regulatory agencies to approve marketing of these products. Different animal models are used to evaluate the pharmacological effects of natural health products and herbal medicines in particular. The main toxicological assays and pharmacological activities to be tested in the evaluation of natural products will be discussed in this presentation. Common pharmacological effects of herbal medicines are: anti inflammatory, antioxidative, hepatoprotective, laxative and analgesic. The importance of using positive and negative controls will be explained and examples will be provided. Animal models currently used in the evaluation of herbal medicines will be presented and the importance of selecting the right model to reproduce human disorders will be highlighted.
Insulin Signaling and Glucose Transport in Skeletal Muscle From First-Degree Relatives of Type 2 Diabetic Patients
Authors: Karlsson Håkan K.R. , Ahlsén Maria , Zierath Juleen R. , Wallberg-Henriksson Harriet , Koistinen Heikki A.
Published: May 2006

Aberrant insulin signaling and glucose metabolism in skeletal muscle from type 2 diabetic patients may arise from genetic defects and an altered metabolic milieu. We determined insulin action on signal transduction and glucose transport in isolated vastus lateralis skeletal muscle from normal glucose-tolerant first-degree relatives of type 2 diabetic patients (n = 8, 41 ± 3 years, BMI 25.1 ± 0.8 kg/m2) and healthy control subjects (n = 9, 40 ± 2 years, BMI 23.4 ± 0.7 kg/m2) with no family history of diabetes. Basal and submaximal insulin-stimulated (0.6 and 1.2 nmol/l) glucose transport was comparable between groups, whereas the maximal response (120 nmol/l) was 38% lower (P < 0.05) in the relatives. Insulin increased phosphorylation of Akt and Akt substrate of 160 kDa (AS160) in a dose-dependent manner, with comparable responses between groups. AS160 phosphorylation and glucose transport were positively correlated in control subjects (R2 = 0.97, P = 0.01) but not relatives (R2 = 0.46, P = 0.32). mRNA of key transcriptional factors and coregulators of mitochondrial biogenesis were also determined. Skeletal muscle mRNA expression of peroxisome proliferator–activated receptor (PPAR) γ coactivator (PGC)-1α, PGC-1β, PPARδ, nuclear respiratory factor-1, and uncoupling protein-3 was comparable between first-degree relatives and control subjects. In conclusion, the uncoupling of insulin action on Akt/AS160 signaling and glucose transport implicates defective GLUT4 trafficking as an early event in the pathogenesis of type 2 diabetes.
l-Cysteine Inhibits Insulin Release From the Pancreatic β-Cell
Authors: Kaneko Yukiko , Kimura Yuka , Kimura Hideo , Niki Ichiro
Published: May 2006

Hydrogen sulfide (H2S) was historically recognized as a toxic gas generated by natural resources. However, its enzymatic production from l-cysteine has recently been demonstrated in mammals. Cystathionine β-synthase and cystathionine γ-lyase, both of which can produce H2S, were expressed in mouse pancreatic islet cells and the β-cell line, MIN6. l-Cysteine and the H2S donor NaHS inhibited glucose-induced insulin release from islets and MIN6 cells. These inhibitory effects were reproduced when insulin release was stimulated by α-ketoisocaproate, tolbutamide, or high K+. l-Cysteine and NaHS inhibited glucose-potentiated insulin release in the copresence of diazoxide and high K+. Real-time imaging of intracellular Ca2+ concentration ([Ca2+]i) demonstrated that both l-cysteine and NaHS reversibly suppressed glucose-induced [Ca2+]i oscillation in a single β-cell without obvious changes in the mean value. These substances inhibited Ca2+- or guanosine 5′-0-3-thiotriphosphate–induced insulin release from islets permeabilized with streptolysin-O. l-Cysteine and NaHS reduced ATP production and attenuated glucose-induced hyperpolarization of the mitochondrial membrane potential. Finally, l-cysteine increased H2S content in MIN6 cells. We suggest here that l-cysteine inhibits insulin release via multiple actions on the insulin secretory process through H2S production. Because the activities of H2S-producing enzymes and the tissue H2S contents are known to increase under diabetic conditions, the inhibition may participate in the deterioration of insulin release in this disease.
Effect of Donor Age on Function of Isolated Human Islets
Authors: Ihm Sung-Hee , Matsumoto Ippei , Sawada Toshiya , Nakano Masahiko , Zhang Hui J. , Ansite Jeffrey D. , Sutherland David E.R. , Hering Bernhard J.
Published: May 2006

This study intended to evaluate the impact of donor age on the function of isolated islets. Analysis of human islets from cadaveric donors (age 16–70 years) was performed using glucose-stimulated insulin release (GSIR) (n = 93), islet ATP content (n = 27), diabetic nude mouse bioassay (n = 72), and the insulin secretory function after single-donor clinical islet allotransplantation (n = 7). The GSIR index was significantly higher in younger donors (age ≤40 years) than in older donors and negatively correlated with the donor age (r = −0.535). Islet ATP was higher in younger donors (115.7 ± 17.7 vs. 75.7 ± 6.6 pmol/μg DNA). The diabetes reversal rate of mice with 2,000 IE was significantly higher in younger donors (96 vs. 68%). C-peptide increment to glucose during intravenous glucose tolerance test at days 90–120 after clinical transplantation showed negative correlation with donor age (r = −0.872) and positive correlation with the islet mass (r = 0.832). On the other hand, acute insulin response to arginine only showed correlation with the islet mass and not with donor age. These results show that insulin secretory response to glucose deteriorates with increasing age and that it may be related to changes in ATP generation in β-cells.
Insulin Resistance and Microalbuminuria
Authors: Parvanova Aneliya I. , Trevisan Roberto , Iliev Ilian P. , Dimitrov Borislav D. , Vedovato Monica , Tiengo Antonio , Remuzzi Giuseppe , Ruggenenti Piero
Published: May 2006

Microalbuminuria is a risk factor for renal and cardiovascular disease. A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested but is still unproven. In this case-control, cross-sectional study, we compared glucose disposal rate (GDR), measured by hyperinsulinemic-euglycemic clamp, in 50 pairs of matched type 2 diabetic patients with micro- or normoalbuminuria (main study) and in 29 matched pairs of diabetic patients with macro- or microalbuminuria (substudy). In the main study, GDR was ∼25% lower in micro- than in normoalbuminuric patients (5.20 ± 1.91 vs. 6.86 ± 2.88 mg · kg−1 · min−1, P < 0.05) and was independently associated with microalbuminuria (P = 0.002), with each 1 mg · kg−1 · min−1 decrease predicting ∼40% increased prevalence (odds ratio 1.37 [95% CI 1.14–1.70]). Microalbuminuria was threefold more frequent in patients with GDR ≤7.50 ± 2.56 mg · kg−1 · min−1 than in those with higher GDR (60% vs. 20%, P < 0.005). In the substudy, GDR in macro- and microalbuminuric patients was comparable (5.52 ± 2.56 vs. 5.16 ± 1.61 mg · kg−1 · min−1) and independent of macroalbuminuria. GDR was significantly correlated with urinary albumin excretion rate in the main study (P = 0.004) but not in the substudy (P = 0.60). In type 2 diabetes, more severe insulin resistance is independently associated with microalbuminuria. Longitudinal studies are needed to clarify the role of insulin resistance in the pathogenesis of microalbuminuria and related complications.
Diabetes as a Tracer Condition in International Benchmarking of Health Systems
Authors: Nolte Ellen , Bain Chris , McKee Martin
Published: May 2006

OBJECTIVE—To assess the performance of health systems using diabetes as a tracer condition.

RESEARCH DESIGN AND METHODS—We generated a measure of “case-fatality” among young people with diabetes using the mortality-to-incidence ratio (M/I ratio) for 29 industrialized countries using published data on diabetes incidence and mortality. Standardized incidence rates for ages 0–14 years were extracted from the World Health Organization DiaMond study for the period 1990–1994; data on death from diabetes for ages 0–39 years were obtained from the World Health Organization mortality database and converted into age-standardized death rates for the period 1994–1998, using the European standard population.

RESULTS—The M/I ratio varied >10-fold. These relative differences appear similar to those observed in cohort studies of mortality among young people with type 1 diabetes in five countries. A sensitivity analysis showed that using plausible assumptions about potential overestimation of diabetes as a cause of death and underestimation of incidence rates in the U.S. yields an M/I ratio that would still be twice as high as in the U.K. or Canada.

CONCLUSIONS—The M/I ratio for diabetes provides a means of differentiating countries on quality of care for people with diabetes. It is solely an indicator of potential problems, a basis for stimulating more detailed assessments of whether such problems exist, and what can be done to address them.
Albumin and Fibrinogen Synthesis and Insulin Effect in Type 2 Diabetic Patients With Normoalbuminuria
Authors: Tessari Paolo , Kiwanuka Edward , Millioni Renato , Vettore Monica , Puricelli Lucia , Zanetti Michela , Gucciardi Antonella , Tosolini Marina , Cogo Paola , Carnielli Virgilio , Tiengo Antonio , Barazzoni Rocco
Published: May 2006

OBJECTIVE—Insulin stimulates albumin synthesis but inhibits that of fibrinogen in both type 1 diabetic and healthy subjects. In type 2 diabetes, fibrinogen production is increased both in the postabsorptive state and in response to hyperinsulinemia. No data exist on the rate of albumin synthesis and its response to insulin in type 2 diabetes.

RESEARCH DESIGN AND METHODS—We measured fractional synthesis rates (FSRs) and absolute synthesis rates (ASRs) of both albumin and fibrinogen in postabsorptive normoalbuminuric type 2 diabetic patients at their spontaneous glucose levels (study A), as well as albumin FSR and ASR before and after a hyperinsulinemic-euglycemic euaminoacidemic clamp (study B), using leucine isotope methods.

RESULTS—In postabsorptive type 2 diabetes (study A), albumin FSR (11.2 ± 0.9%/day) and albumin ASR (15.4 ± 1.2 g/day) were not different from control values (albumin FSR: 9.4 ± 0.7%/day; albumin ASR: 13.8 ± 1.2 g/day, P > 0.1 for both). In contrast, in the type 2 diabetic subjects, both fibrinogen FSR (24.9 ± 2.1%/day) and ASR (2.4 ± 0.2 g/day) were greater (P < 0.025 and P < 0.007, respectively) compared with the control subjects (FSR: 18.6 ± 1.51%/day; ASR: 1.6 ± 0.2 g/day). Worse metabolic control in the type 2 diabetic patients was associated with hyperfibrinogenemia and increased leucine rate of appearance, whereas neither the (increased) fibrinogen ASR nor the (normal) albumin production was affected. In study B, after hyperinsulinemia (raised to ∼860 nmol/l), albumin FSR and ASR increased by ∼25% versus basal (P < 0.04) and to the same extent in both type 2 diabetic and control subjects.

CONCLUSIONS—In normoalbuminuric type 2 diabetic patients, postabsorptive albumin synthesis and its response to insulin were normal, whereas fibrinogen synthesis was increased, irrespective of metabolic control. Furthermore, in normoalbuminuric type 2 diabetic patients, a normal insulin sensitivity with respect to albumin production but a selective hepatic dysregulation of fibrinogen metabolism were present.
Neuropathy Among the Diabetes Control and Complications Trial Cohort 8 Years After Trial Completion
Authors: Martin Catherine L. , Albers James , Herman William H. , Cleary Patricia , Waberski Barbara , Greene Douglas A. , Stevens Martin J. , Feldman Eva L.
Published: May 2006

OBJECTIVE—To evaluate the impact of prior intensive diabetes therapy on neuropathy among former Diabetes Control and Complications Trial (DCCT) participants.

RESEARCH DESIGN AND METHODS—At the conclusion of the DCCT, subjects in the intensive group were encouraged to maintain intensive therapy, and subjects in the conventional group were encouraged to begin intensive therapy. Thereafter, we annually assessed neuropathy as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Neuropathy was defined using the Michigan Neuropathy Screening Instrument (MNSI). We recorded potential adverse consequences of neuropathy.

RESULTS—At the first EDIC examination, 1,257 subjects participated in the neuropathy assessment. Consistent with DCCT results, the former intensive group showed a lower prevalence of neuropathy than the conventional group based on positive questionnaire (1.8 vs. 4.7%; P = 0.003) or examination (17.8 vs. 28.0%; P < 0.0001) results. Despite similar levels of glycemic control, symptoms and signs of neuropathy remained less prevalent among the former intensive group compared with the conventional group. At the beginning of the EDIC study, prior intensive therapy reduced the odds of having symptoms and signs of neuropathy using MNSI criteria by 64% (P = 0.0044) and 45% (P < 0.0001), respectively, with similar odds reductions observed for both neuropathic symptoms (51%, P < 0.0001) and neuropathic signs (43%, P < 0.0001) across 8 years of EDIC follow-up.

CONCLUSIONS—The benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the DCCT, similar to the findings described for diabetic retinopathy and nephropathy.
Mesenteric Fat Thickness Is an Independent Determinant of Metabolic Syndrome and Identifies Subjects With Increased Carotid Intima-Media Thickness
Authors: Liu Kin Hung , Chan Yu Leung , Chan Wing Bun , Chan Juliana Chung Ngor , Chu Chiu Wing Winnie
Published: May 2006

OBJECTIVE—Mesenteric fat, a reflection of visceral adiposity, may play an important role in the pathogenesis of metabolic syndrome and cardiovascular diseases (CVD). In this study, we examined the independent relationship between mesenteric fat thickness and metabolic syndrome and defined its optimal cutoff value to identify high-risk subjects for metabolic syndrome and CVD.

RESEARCH DESIGN AND METHODS—A total of 290 Chinese subjects had an ultrasound examination for measurements of thickness of mesenteric, preperitoneal, and subcutaneous fat as well as carotid intima-media thickness (IMT). Anthropometric measurements and metabolic risk profile were assessed by physical examination and blood taking.

RESULTS—Twenty (6.9%) subjects had metabolic syndrome according to the National Cholesterol Education Panel Adult Treatment Panel III criteria with Asian definitions for central obesity (waist circumference >80 cm in women and >90 cm in men). Mesenteric fat thickness had significant correlations (P < 0.05) with various metabolic variables. On multivariate regression, mesenteric fat thickness was an independent determinant of all components of metabolic syndrome after adjustment for age, sex, homeostasis model assessment of insulin resistance, and other fat deposits. The odds ratio of metabolic syndrome was increased by 1.35 (95% CI 1.10–1.66)-fold for every 1-mm increase in mesenteric fat thickness. On receiver-operating characteristic curve analysis, mesenteric fat thickness of ≥10 mm was the optimal cutoff value to identify metabolic syndrome, with sensitivity of 70% and specificity of 75%. Subjects with mesenteric fat thickness ≥10 mm had higher carotid IMT than those with thickness <10 mm (0.73 ± 0.19 vs. 0.64 ± 0.16 mm, P = 0.001).

CONCLUSIONS—Mesenteric fat thickness was an independent determinant of metabolic syndrome and identified subjects with increased carotid IMT.
The Importance of Waist Circumference in the Definition of Metabolic Syndrome
Authors: Katzmarzyk Peter T. , Janssen Ian , Ross Robert , Church Timothy S. , Blair Steven N.
Published: May 2006

OBJECTIVE—The purpose of this study was to compare the predictive ability of the National Cholesterol Education Panel (NCEP), revised NCEP (NCEP-R), and International Diabetes Federation (IDF) metabolic syndrome criteria for mortality risk, and to examine the effects of waist circumference on mortality within the context of these criteria.

RESEARCH DESIGN AND METHODS—The sample included 20,789 white, non-Hispanic men 20–83 years of age from the Aerobics Center Longitudinal Study. The main outcome measures were all-cause and cardiovascular disease (CVD) mortality over 11.4 years of follow-up.

RESULTS—The proportions of men with the metabolic syndrome were 19.7, 27, and 30% at baseline, respectively, according to NCEP, NCEP-R, and IDF criteria. A total of 632 deaths (213 CVD) occurred. The relative risks (RRs) and 95% CIs of all-cause mortality were 1.36 (1.14–1.62), 1.31 (1.11–1.54), and 1.26 (1.07–1.49) for the NCEP, NCEP-R, and IDF definitions, respectively. The corresponding RRs for CVD mortality were 1.79 (1.35–2.37), 1.67 (1.27–2.19), and 1.67 (1.27–2.20). Additionally, there was a significant trend for a higher risk of CVD mortality across waist circumference categories (<94, 94–102, and >102 cm) among men with at least two additional metabolic syndrome risk factors (P = 0.01).

CONCLUSIONS—The prediction of mortality with IDF and NCEP metabolic syndrome criteria was comparable in men. Waist circumference is a valuable component of metabolic syndrome; however, the IDF requirement of an elevated waist circumference warrants caution given that a large proportion of men with normal waist circumference have multiple risk factors and an increased risk of mortality.
High-Sensitivity C-Reactive Protein and Coronary Heart Disease Mortality in Patients With Type 2 Diabetes
Authors: Soinio Minna , Marniemi Jukka , Laakso Markku , Lehto Seppo , Rönnemaa Tapani
Published: May 2006

OBJECTIVE—To investigate in a follow-up study whether high-sensitivity C-reactive protein (hs-CRP) predicts coronary heart disease (CHD) events in subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS—The original study population consisted of 1,059 patients with type 2 diabetes (age 45–64 years). Mean duration of diabetes was 8 years. CRP values were available from 1,045 subjects, of whom 878 were free of myocardial infarction (MI) at baseline. CHD mortality and the incidence of nonfatal MI were assessed in a 7-year follow-up.

RESULTS—Altogether, 157 patients died from CHD and 254 had a nonfatal or fatal CHD event. Patients with hs-CRP >3 mg/l had a higher risk for CHD death than patients with hs-CRP ≤3 mg/l (19.8 and 12.9%, respectively, P = 0.004). In Cox regression analysis, patients with high hs-CRP had a relative risk of 1.72 for CHD death even after the adjustment for confounding factors (P = 0.002). Among subjects who were free from MI at baseline, those with a high hs-CRP level had relative risks of 1.83 (P = 0.003) and 1.84 (P = 0.004) for CHD death in univariate and multivariate analyses, respectively.

CONCLUSIONS—In this large cohort of type 2 diabetic patients, hs-CRP was an independent risk factor for CHD deaths.
Familial Clustering for Features of the Metabolic Syndrome
Authors: Tang Weihong , Hong Yuling , Province Michael A. , Rich Stephen S. , Hopkins Paul N. , Arnett Donna K. , Pankow James S. , Miller Michael B. , Eckfeldt John H.
Published: May 2006

OBJECTIVE—Metabolic syndrome–related traits (obesity, glucose intolerance/insulin resistance, dyslipidemia, and hypertension) have been shown to be genetically correlated. It is less clear, however, if the genetic correlation extends to novel risk factors associated with inflammation, impaired fibrinolytic activity, and hyperuricemia. We present a bivariate genetic analysis of MetS-related traits including both traditional and novel risk factors.

RESEARCH DESIGN AND METHODS—Genetic correlations were estimated using a variance components procedure in 1,940 nondiabetic white individuals from 445 families in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Twelve MetS-related traits, including BMI, waist circumference, blood pressure, white blood cell count, fasting serum triglycerides, HDL cholesterol, insulin, glucose, plasminogen activator inhibitor-1 antigen, uric acid, and C-reactive protein, were measured and adjusted for covariates, including lifestyle variables.

RESULTS—Significant genetic correlations were detected among BMI, waist circumference, HDL cholesterol, triglycerides, insulin, and plasminogen activator inhibitor-1 antigen and between uric acid and all of the above variables except insulin. C-reactive protein and white blood cell count were genetically correlated with each other, and both showed significant genetic correlations with waist circumference and insulin. Fasting glucose was not significantly genetically correlated with any of the other traits.

CONCLUSIONS—These results suggest that pleiotropic effects of genes or shared family environment contribute to the familial clustering of MetS-related traits.
Patterns of Metabolic Progression to Type 1 Diabetes in the Diabetes Prevention Trial–Type 1
Authors: Sosenko Jay M. , Palmer Jerry P. , Greenbaum Carla J. , Mahon Jeffrey , Cowie Catherine , Krischer Jeffrey P. , Chase H. Peter , White Neil H. , Buckingham Bruce , Herold Kevan C. , Cuthbertson David , Skyler Jay S. ,   the Diabetes Prevention Trial–Type 1 Study Group
Published: May 2006

OBJECTIVE—There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial–Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis.

RESEARCH DESIGN AND METHODS—Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points.

RESULTS—Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P < 0.001 for all indexes). Area under the curve (AUC) C-peptide (P < 0.05) and AUC C-peptide–to–AUC glucose ratio (P < 0.001) values decreased in the oral group; peak C-peptide–to–2-h glucose ratio values decreased in both groups (P < 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P < 0.05) and peak C-peptide (oral group, P < 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide–to–glucose ratio values decreased in both groups (P < 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P < 0.01). Fasting C-peptide–to–fasting glucose ratio values remained constant throughout the 30-month follow-up.

CONCLUSIONS—These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.
Diabetic Cardiomyopathy and Subclinical Cardiovascular Disease
Authors: Bertoni Alain G. , Goff David C. , D’Agostino Ralph B. , Liu Kiang , Hundley W. Gregory , Lima Joao A. , Polak Joseph F. , Saad Mohammed F. , Szklo Moyses , Tracy Russell P. , Siscovick David S.
Published: May 2006

OBJECTIVE—Studies have demonstrated increased left ventricular mass (LVM) and diastolic dysfunction among diabetic patients without clinical cardiovascular disease (CVD), but few have assessed the potential contribution of subclinical CVD to ventricular abnormalities in diabetes. We examined whether diabetic cardiomyopathy is associated with subclinical atherosclerosis and if abnormalities are found with impaired fasting glucose (IFG).

RESEARCH DESIGN AND METHODS—LVM, end-diastolic volume (EDV), and stroke volume were measured by magnetic resonance imaging (MRI), and atherosclerosis was assessed by coronary artery calcium and carotid intima-media wall thickness in 4,991 participants in the Multi-Ethnic Study of Atherosclerosis, a cohort study of adults aged 45–84 without prior CVD. Multivariable linear regression was used to analyze the association between MRI measures and glucose status.

RESULTS—Increased LVM was observed in white, black, and Hispanic participants with diabetes but not among Chinese participants. After adjustment for weight, height, CVD risk factors, and subclinical atherosclerosis, ethnicity-specific differences in ventricular parameters were present. Among whites and Chinese with diabetes, LVM was similar to that in normal subjects; EDV and stroke volume were reduced. In blacks with diabetes, EDV and stroke volume were reduced, and LVM was increased (+5.6 g, P < 0.05). Among Hispanics with diabetes, EDV and stroke volume were similar to normal, but LVM was increased (+5.5 g, P < 0.05). After adjustment, IFG was associated with a decrease in EDV and stroke volume in whites and blacks only; however, no significant differences in LVM were observed.

CONCLUSIONS—Ethnicity-specific differences in LVM, EDV, and stroke volume are associated with abnormal glucose metabolism and are independent of subclinical CVD.
Age at Onset of Childhood-Onset Type 1 Diabetes and the Development of End-Stage Renal Disease
Authors: Svensson Maria , Nyström Lennarth , Schön Staffan , Dahlquist Gisela ,   on behalf of the Swedish Childhood Diabetes Study and the Swedish Registry for Active Treatment of Uraemia
Published: May 2006

OBJECTIVE—To analyze the impact of age at onset on the development of end-stage renal disease (ESRD) due to diabetic nephropathy in a nationwide population-based cohort with childhood-onset type 1 diabetes.

RESEARCH DESIGN AND METHODS—A record linkage between two nationwide registers, the Swedish Childhood Diabetes Registry, including 12,032 cases with childhood-onset diabetes, and the Swedish Registry for Active Treatment of Uraemia was performed. Log-rank test was used to test differences between cumulative risk curves of developing ESRD due to diabetic nephropathy in three different strata of age at onset (0–4, 5–9, and 10–14 years).

RESULTS—At a maximum follow-up of 27 years, 33 patients had developed ESRD due to diabetic nephropathy and all had a diabetes duration >15 years. In total, 4,414 patients had diabetes duration >15 years, and thus the risk in this cohort to develop ESRD was 33 of 4,414 (0.7%). A significant difference in risk of developing ESRD was found between the youngest (0–4 years) and the two older (5–9 and 10–14 years) age-at-onset strata (P = 0.03 and P = 0.001, respectively). A significant difference in the risk of developing ESRD was also found between children with prepubertal (0–4 and 5–9 years, n = 2,424) and pubertal (10–14 years, n = 2000) onset of diabetes (P = 0.002). No patient with onset of diabetes before 5 years of age had developed ESRD.

CONCLUSIONS—With a median duration of 21 years in this population-based Swedish cohort with childhood-onset diabetes, <1% of the patients had developed ESRD due to diabetic nephropathy, and a prepubertal onset of diabetes seems to prolong the time to development of ESRD.
Hyperglycemia and Diabetes in Patients With Schizophrenia or Schizoaffective Disorders
Authors: Cohen Dan , Stolk Ronald P. , Grobbee Diederick E. , Gispen-de Wied Christine C.
Published: May 2006

OBJECTIVE—Pharmacoepidemiological studies have shown an increased prevalence of diabetes in patients with schizophrenia. To address this issue, we decided to assess glucose metabolism in a population of patients with schizophrenia or schizoaffective disorder.

RESEARCH DESIGN AND METHODS—Oral glucose tolerance tests (OGTTs) were performed in 200 unselected in- and outpatients. Insulin sensitivity and β-cell function were assessed using the homeostasis model assessment (HOMA) indexes and 30-min glucose and insulin levels.

RESULTS—The mainly Western European (87.7%) study population had a mean age of 40.8 years, was 70% male, and had a mean fasting glucose of 5.1 mmol/l and a mean fasting insulin of 14.8 mU/l. Hyperglycemia was present in 7% of the population: 1.5% with impaired fasting glucose and 5.5% with impaired glucose tolerance. The prevalence of diabetes was 14.5%, of which 8% was previously known and 6.5% was newly diagnosed. Compared with a 1.5% prevalence of diabetes in the age-matched general Dutch population, the prevalence of identified cases was significantly increased in the study population. Comparable figures on the prevalence of hyperglycemia in the general population are not available. Insulin resistance was increased in the study population as a whole (HOMA of insulin resistance: 3.1–3.5), irrespective of the use of antipsychotic medication and, if used, irrespective of its type (typical or atypical). No indication of β-cell defect was found, whereas a nonsignificant increased insulin resistance was found with antipsychotic medication.

CONCLUSIONS—OGTTs in 200 mainly Caucasian patients with schizophrenia or schizoaffective disorder, mean age 41 years, showed that 7% suffered from hyperglycemia and 14.5% from diabetes. The prevalence of diabetes was significantly increased compared with the general population. No differential effect of antipsychotic monotherapy in diabetogenic effects was found. Therefore, a modification of the consensus statement on antipsychotic drugs, obesity, and diabetes is proposed, i.e., measurement of fasting glucose in all patients with schizophrenia, irrespective of prescribed antipsychotic drug.
The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) Study
Authors: Cheung N. Wah , Wong Vincent W. , McLean Mark
Published: May 2006

OBJECTIVE—There is conflicting evidence regarding the benefit of intravenous insulin therapy on mortality following acute myocardial infarction (AMI). The goal of the current study was to determine whether improved glycemic control, achieved through an insulin/dextrose infusion with a variable rate of insulin, reduces mortality among hyperglycemic patients with AMI.

RESEARCH DESIGN AND METHODS—Subjects suffering AMI with either known diabetes or without diabetes but blood glucose level (BGL) ≥7.8 mmol/l were randomized to receive insulin/dextrose infusion therapy for at least 24 h to maintain a BGL <10 mmol/l or conventional therapy.

RESULTS—A total of 240 subjects were recruited. Insulin/dextrose infusion did not reduce mortality at the inpatient stage (4.8 vs. conventional 3.5%, P = 0.75), 3 months (7.1 vs 4.4%, P = 0.42), or 6 months (7.9 vs. 6.1%, P = 0.62). There was, however, a lower incidence of cardiac failure (12.7 vs. 22.8%, P = 0.04) and reinfarction within 3 months (2.4 vs. 6.1%, P = 0.05). When analyzed by mean BGL achieved during the first 24 h, mortality was lower among subjects with a mean BGL ≤8 mmol/l, compared with subjects with a mean BGL >8 mmol/l (2 vs. 11% at 6 months, P = 0.02).

CONCLUSIONS—We did not find a reduction in mortality among patients who received insulin/dextrose infusion therapy. However, it remains possible that tight glycemic control with insulin therapy following AMI improves outcomes.
The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes
Authors: Sorensen Lea , Molyneaux Lynda , Yue Dennis K.
Published: May 2006

OBJECTIVE—Many individuals with diabetes experience neuropathic pain, often without objective signs of large-fiber neuropathy. We examined intraepidermal nerve fibers (IENFs) to evaluate the role of small nerve fibers in the genesis of neuropathic pain.

RESEARCH DESIGN AND METHODS—Twenty-five diabetic subjects with neuropathic pain and 13 without were studied. The pain was present for at least 6 months for which no other cause could be found. Punch skin biopsies were obtained from the distal leg. IENFs were stained using antibody to protein gene product 9.5 and counted with confocal microscopy. Neuropathy was graded by vibration perception and cold detection thresholds and the Michigan Neuropathy Screening Instrument.

RESULTS—In the total cohort, IENF density was significantly lower in those with pain compared with those without (3 [1–6] vs. 10 [3–19], respectively, P = 0.02). There were significant inverse correlations between IENF and severity of neuropathy, with the pain group having a flatter gradient than their pain-free counterparts (P < 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P ≤ 0.01).

CONCLUSIONS—More severe loss of IENF is associated with the presence of neuropathic pain only in those with little or no objective sign of neuropathy. Thus, loss of IENF cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.
Highly Luminescent CuI Complexes for Light‐Emitting Electrochemical Cells (Adv. Mater. 10/2006)
Authors: Armaroli N. , Accorsi G. , Holler M. , Moudam O. , Nierengarten J.‐F. , Zhou Z. , Wegh R. T. , Welter R.
Published: May 2006

The crystal structure of a Cu(I) complex having two nitrogen (blue) and two phosphor (yellow) coordinating atoms is depicted. This class of complexes exhibits intense green photo‐and electroluminescence as well as triplet lifetimes on the microsecond timescale. These features make them attractive candidates for light‐emitting devices based on cheap, abundant, and environmentally sustainable metal elements, as shown by Armaroli, Nierengarten, Wegh, and co‐workers on p. 1313.
DNA Methylation and Gene Silencing in Cancer
Authors: Baylin Stephen B.
Published: May 2006

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
Myeloperoxidase accumulates at the neutrophil surface and enhances cell metabolism and oxidant release during pregnancy
Authors: Kindzelskii Andrei L. , Clark Andrea J. , Espinoza Jimmy , Maeda Nobuyo , Aratani Yasuaki , Romero Roberto , Petty Howard R.
Published: May 2006

Pregnancy is a unique immunological state. Pregnancy neutrophils differ from those of non‐pregnant women as they cannot be fully activated for oxidant production, but yet have higher levels of unstimulated oxidant production. Although reduced activation is due to decreased hexose monophosphate shunt activity, the mechanism enhancing basal oxidant levels is unknown. We hypothesize that myeloperoxidase (MPO) trafficking affects the basal oxidant release by maternal neutrophils. Immunofluorescence microscopy has demonstrated MPO at the surface of pregnancy neutrophils, whereas non‐pregnancy cells do not exhibit surface MPO. Adherent pregnancy neutrophils were characterized by high‐amplitude metabolic oscillations, which were blocked by MPO inactivation. Conversely, metabolic oscillatory amplitudes of control neutrophils were heightened by incubation with PMA or exogenous MPO. Importantly, MPO decoration of cell surfaces and high‐amplitude metabolic oscillations were observed for neutrophils from pregnant but not from non‐pregnant mice. However, cells from pregnant MPO knockout mice did not exhibit MPO expression or high‐amplitude metabolic oscillations. Unstimulated neutrophils from pregnant women were found to release reactive oxygen metabolites (ROM) and reactive nitrogen intermediates (RNI), but cells from non‐pregnant women did not. MPO inhibition returned ROM and RNI formation to non‐pregnant levels. Hence, MPO trafficking influences metabolic activity and oxidant production in pregnancy.
The Reactivity of Hexa(N‐methylideneimine)CoIII Complexes towards Nucleophiles: Structure and Mechanism
Authors: Kuppert Dirk , Comba Peter , Hegetschweiler Kaspar
Published: May 2006

The reactivity of the hexa(N‐methylideneimine)CoIII complex [Co‐hmi‐(taci)2]3+ (taci = 1,3,5‐triamino‐1,3,5‐trideoxy‐cis‐inositol) towards the nucleophiles ammonia, aniline and cyanide was investigated and the main products were identified by spectroscopic methods and by a crystal structure analysis. The relative energies of the complexes formed and those of possible stereo isomers were analysed by means of molecular mechanics calculations. In the reaction with NH3, two condensation products, [Co(La)]3+ and [Co(Lb)]3+, were identified with the two taci moieties linked by one or two N=CH–N(H)‐CH2–NH bridges, respectively. The reaction with aniline yielded the complex [Co(Lc)(Ld)]3+ (where Lc is a mono‐N‐methylated and Ld a phenylformamidine‐substituted taci), whereas the reaction with cyanide resulted in the formation of [Co(Le)]3+ having an NH–CH2–C(NH2)=N bridge between the two taci subunits. A mechanism that accounts for the different types of products can be suggested as follows: In [Co(La)]3+, [Co(Lb)]3+ and [Co(Lc)(Ld)]3+, N‐methylation was observed and this can be interpreted in terms of an intramolecular Cannizzaro type hydride shift. For [Co(La)]3+ and [Co(Lb)]3+ two subsequent addition steps of the nucleophile to adjacent imino groups must take place prior to the hydride shift, whereas for [Co(Lc)(Ld)]3+ the hydride shift appears to have already occurred after the first addition step of aniline to an imino group. Formation of [Co(Le)]3+ can be explained in terms of a nucleophilic attack of CN– to an imino group and a subsequent attack of a deprotonated amino group (which must have previously been formed by hydrolysis of a methylideneimino group) to the nitrile C‐atom. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Dopamine regulates cell cycle regulatory proteins via cAMP, Ca2+/PKC, MAPKs, and NF‐κB in mouse embryonic stem cells
Authors: Lee Min Young , Heo Jung Sun , Han Ho Jae
Published: May 2006

This study examined the effect of dopamine on DNA synthesis and its related signal cascades in mouse embryonic stem (ES) cells. Dopamine inhibited DNA synthesis in both a dose‐ and time‐dependent manner. Dopamine, SKF 38393 (D1 receptor agonist), and quinpirole (D2 receptor agonist) decreased the level of [3H]‐thymidine incorporation. The level of cyclic adenosine 3, 5‐monophosphate (cAMP) was increased by SKF 38393 but not by quinpirole. The protein kinase C (PKC) protein was translocated from the cytosolic fraction to the membrane compartment by dopamine. Dopamine also increased [Ca2+]i, which was blocked by EGTA (an extracellular Ca2+ chelator), BAPTA‐AM (an intracellular Ca2+ chelator), nifedipine (a L‐type Ca2+ channel blocker), SQ 22536 [an adenylyl cyclase (AC) inhibitor] and neomycin [a phospholipase C (PLC) inhibitor]. Dopamine, SKF 38393, and quinpirole increased the level of p44/42 mitogen‐activated protein kinases (MAPKs), p38 MAPK, and stress‐activated protein kinase/Jun‐N‐terminal kinase (SAPK/JNK) phosphorylation. Dopamine also increased level of H2O2 formation and activated the transcription factor family NF‐κB. Moreover, SKF 38393, quinpirole, and dopamine inhibited cell cycle regulatory proteins, which is consistent with the change in the level of [3H]‐thymidine incorporation observed. The dopamine‐induced decrease in cyclin E, cyclin‐dependent protein kinase‐2 (CDK‐2), and cyclin D1, CDK‐4 were blocked by pertussis toxin (G protein inhibitor), SQ 22536, neomycin, bisindolylmaleimide I (PKC inhibitor), SB 203580 (p38 MAPK inhibitor), PD 98059 (p44/42 inhibitor), and SP 600125 (SAPK/JNK inhibitor). In conclusion, dopamine inhibits DNA synthesis in mouse ES cells via the cAMP, Ca2+/PKC, MAPKs, and NF‐κB signaling pathways. J. Cell. Physiol. 208: 399–406, 2006. © 2006 Wiley‐Liss, Inc.
Targeting cyclooxygenase‐2 for prevention and therapy of colorectal cancer
Authors: Sinicrope Frank A
Published: May 2006

Cyclooxygenase‐2 (COX‐2) is an inducible enzyme that regulates prostaglandin synthesis and is overexpressed at sites of inflammation and in several epithelial cancers. A causal link for COX‐2 in epithelial tumorigenesis was shown in genetically manipulated animal models of colon and breast carcinoma. Studies have elucidated the regulation of COX‐2 expression and have identified EP receptors through which prostanoids exert their biological effects. Mechanistic studies indicated that COX‐2 is involved in apoptosis resistance, angiogenesis, and tumor cell invasiveness, which appear to contribute to its effects in tumorigenesis. Furthermore, forced COX‐2 expression has been shown to suppress apoptosis by modulating the level of death receptor 5 (DR5) and this effect was reversed by a COX inhibitor. COX enzymes are targets for cancer prevention as shown by the observation that nonselective COX and selective COX‐2 inhibitors have been reported to effectively prevent experimental colon cancer and can regress colorectal polyps in patients with familial adenomatous polyposis. This review will focus on the role of COX‐2 as a target for the prevention and treatment of human colorectal cancer. © 2006 Wiley‐Liss, Inc.