bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Intensive Diabetes Treatment on Resting Heart Rate in Type 1 Diabetes
Authors: Paterson Andrew D. , Rutledge Brandy N. , Cleary Patricia A. , Lachin John M. , Crow Richard S. ,   for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group
Published: July 2007

OBJECTIVE—Cardiovascular disease is a major cause of morbidity and mortality in individuals with type 1 diabetes. Resting heart rate (RHR) is a risk factor for cardiovascular disease in the general population, and case-control studies have reported a higher RHR in individuals with type 1 diabetes. In individuals with type 1 diabetes, there is a positive correlation between A1C and RHR; however, no prospective studies have examined whether a causal relationship exists between A1C and RHR. We hypothesized that intensive diabetes treatment aimed to achieve normal A1C levels has an effect on RHR in individuals with type 1 diabetes.

RESEARCH DESIGN AND METHODS—A total of 1,441 individuals with type 1 diabetes who participated in the Diabetes Control and Complications Trial (DCCT) had their RHR measured biennially by an electrocardiogram during the DCCT and annually for 10 years during the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study.

RESULTS—During the DCCT, intensive treatment was associated with lower mean RHR than conventional treatment, both in adolescents (69.0 vs. 72.0 bpm [95% CI 62.8–75.7 and 65.7–78.9, respectively], P = 0.013) and adults (66.8 vs. 68.2 [65.3–68.4 and 66.6–69.8, respectively], P = 0.0014). During follow-up in the EDIC, the difference in RHR between the treatment groups persisted for at least 10 years (P < 0.0001).

CONCLUSIONS—Compared with conventional therapy, intensive diabetes management is associated with lower RHR in type 1 diabetes. The lower RHR with intensive therapy may explain, in part, its effect in reducing cardiovascular disease, recently demonstrated in type 1 diabetes.
Prevalence and Risk Factors of Diabetic Nephropathy in an Urban South Indian Population
Authors: Unnikrishnan Ranjit , Rema Mohan , Pradeepa Rajendra , Deepa Mohan , Shanthirani Coimbatore Subramaniam , Deepa Raj , Mohan Viswanathan
Published: July 2007

OBJECTIVE—The aim of this study was to determine the prevalence of diabetic nephropathy among urban Asian-Indian type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS—Type 2 diabetic subjects (n = 1,716), inclusive of known diabetic subjects (KD subjects) (1,363 of 1,529; response rate 89.1%) and randomly selected newly diagnosed diabetic subjects (NDD subjects) (n = 353) were selected from the Chennai Urban Rural Epidemiology Study (CURES). Microalbuminuria was estimated by immunoturbidometric assay and diagnosed if albumin excretion was between 30 and 299 μg/mg of creatinine, and overt nephropathy was diagnosed if albumin excretion was ≥300 μg/mg of creatinine in the presence of diabetic retinopathy, which was assessed by stereoscopic retinal color photography.

RESULTS—The prevalence of overt nephropathy was 2.2% (95% CI 1.51–2.91). Microalbuminuria was present in 26.9% (24.8–28.9). Compared with the NDD subjects, KD subjects had greater prevalence rates of both microalbuminuria with retinopathy and overt nephropathy (8.4 vs. 1.4%, P < 0.001; and 2.6 vs. 0.8%, P = 0.043, respectively). Logistic regression analysis showed that A1C (odds ratio 1.325 [95% CI 1.256–1.399], P < 0.001), smoking (odds ratio 1.464, P = 0.011), duration of diabetes (1.023, P = 0.046), systolic blood pressure (1.020, P < 0.001), and diastolic blood pressure (1.016, P = 0.022) were associated with microalbuminuria. A1C (1.483, P < 0.0001), duration of diabetes (1.073, P = 0.003), and systolic blood pressure (1.031, P = 0.004) were associated with overt nephropathy.

CONCLUSIONS—The results of the study suggest that in urban Asian Indians, the prevalence of overt nephropathy and microalbuminuria was 2.2 and 26.9%, respectively. Duration of diabetes, A1C, and systolic blood pressure were the common risk factors for overt nephropathy and microalbuminuria.
Maternal Obesity and Risk of Gestational Diabetes Mellitus
Authors: Chu Susan Y. , Callaghan William M. , Kim Shin Y. , Schmid Christopher H. , Lau Joseph , England Lucinda J. , Dietz Patricia M.
Published: July 2007

OBJECTIVE—Numerous studies in the U.S. and elsewhere have reported an increased risk of gestational diabetes mellitus (GDM) among women who are overweight or obese compared with lean or normal-weight women. Despite the number and overall consistency of studies reporting a higher risk of GDM with increasing weight or BMI, the magnitude of the association remains uncertain. This meta-analysis was conducted to better estimate this risk and to explore differences across studies.

RESEARCH DESIGN AND METHODS—We identified studies from three sources: 1) a PubMed search of relevant articles published between January 1980 and January 2006, 2) reference lists of publications selected from the PubMed search, and 3) reference lists of review articles on obesity and maternal outcomes published between January 2000 and January 2006. We used a Bayesian model to perform the meta-analysis and meta-regression. We included cohort-designed studies that reported obesity measures reflecting pregnancy body mass, that had a normal-weight comparison group, and that presented data allowing a quantitative measurement of risk.

RESULTS—Twenty studies were included in the meta-analysis. The unadjusted ORs of developing GDM were 2.14 (95% CI 1.82–2.53), 3.56 (3.05–4.21), and 8.56 (5.07–16.04) among overweight, obese, and severely obese compared with normal-weight pregnant women, respectively. The meta-regression analysis found no evidence that these estimates were affected by selected study characteristics (publication date, study location, parity, type of data collection [retrospective vs. prospective], and prevalence of GDM among normal-weight women).

CONCLUSIONS—Our findings indicate that high maternal weight is associated with a substantially higher risk of GDM.
Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome
Authors: Rosenson Robert S. , Wolff David A. , Huskin Anna L. , Helenowski Irene B. , Rademaker Alfred W.
Published: July 2007

OBJECTIVE—The aim of this study was to determine the effects of fenofibrate (160 mg/day) on fasting and postprandial lipoproteins, oxidized fatty acids, and inflammatory mediators in subjects with hypertriglyceridemia and the metabolic syndrome.

RESEARCH DESIGN AND METHODS—Fifty-nine subjects with fasting hypertriglyceridemia (≥1.7 and <6.9 mmol/l) and two or more of the Adult Treatment Panel III criteria for the metabolic syndrome were randomly assigned to fenofibrate (160 mg/day) or placebo in a double-blind, controlled clinical trial.

RESULTS—Fenofibrate treatment lowered fasting triglycerides (−46.1%, P < 0.0001) and postprandial (area under the curve) triglycerides (−45.4%, P < 0.0001) due to significant reductions in postprandial levels of large (−40.8%, P < 0.0001) and medium (−49.5%, P < 0.0001) VLDL particles. The number of fasting total LDL particles was reduced in fenofibrate-treated subjects (−19.0%, P = 0.0033) primarily due to reductions in small LDL particles (−40.3%, P < 0.0001); these treatment differences persisted postprandially. Fasting and postprandial oxidized fatty acids were reduced in fenofibrate-treated subjects compared with placebo-administered subjects (−15.3%, P = 0.0013, and 31.0%, P < 0.0001, respectively), and fenofibrate therapy lowered fasting and postprandial soluble vascular cell adhesion molecule-1 (VCAM-1) (−10.9%, P = 0.0005, and −12.0%, P = 0.0001, respectively) as well as fasting and postprandial soluble intercellular adhesion molecule-1 (ICAM-1) (−14.8%, P < 0.0001, and −15.3%, P < 0.0001, respectively). Reductions in VCAM-1 and ICAM-1 were correlated with reductions in fasting and postprandial large VLDL particles (P < 0.0001) as well as postprandial oxidized fatty acids (P < 0.0005).

CONCLUSIONS—Triglyceride-lowering therapy with fenofibrate reduced fasting and postprandial free fatty acid oxidation and inflammatory responses, and these antiatherosclerotic effects were most highly correlated with reductions in large VLDL particles.
End-Digit Preference and the Quality of Blood Pressure Monitoring in Diabetic Adults
Authors: Kim Esther S.H. , Samuels T. Alafia , Yeh Hsin-Chieh , Abuid Marcela , Marinopoulos Spyridon S. , McCauley Jeanne M. , Brancati Frederick L.
Published: July 2007

OBJECTIVE—Although tight blood pressure (BP) control is proven to reduce diabetes-related cardiovascular risk, it has been difficult to achieve in practice, perhaps in part because of low-quality monitoring data. We hypothesized that low-quality BP data, reflected in end-digit preference (EDP), remains common in primary care of diabetic adults.

RESEARCH DESIGN AND METHODS—Data were abstracted from the charts of 404 adults with type 2 diabetes seen at 16 academically affiliated clinics from 1999 to 2001. End-digits of systolic and diastolic BPs taken with nonautomated sphygmomanometers were extracted, and prevalence of EDP for zero was calculated. Associations between EDP and selected patient characteristics were determined using multiple logistic regressions.

RESULTS—EDP was highly prevalent in the BP measurements taken by nonphysicians (4,333 BPs; 50% of systolic, 50% of diastolic readings ended in zero; P < 0.001) and physicians (1,347 BPs; 69% of systolic, 64% of diastolic readings ended in zero; P < 0.001). In multivariate analysis, nonphysicians showed greater EDP for systolic BP in older patients (odds ratio [OR] 1.07 per 5 years) and women (OR 1.36 vs. men) and for diastolic BP in African-Americans (OR 1.25 vs. whites; all P < 0.05); physicians showed greater EDP for diastolic BP in less obese patients (OR 0.97 per 5 kg/m2 increment in BMI; P = 0.02).

CONCLUSIONS—Low-quality BP measurement is common in primary care of diabetic adults. Procedural and technological improvements to BP measurement deserve attention as part of an overall strategy to tighten BP control and reduce cardiovascular risk.
Incidence and Risk Factors of Prolonged QTc Interval in Type 1 Diabetes
Authors: Giunti Sara , Bruno Graziella , Lillaz Emma , Gruden Gabriella , Lolli Valentina , Chaturvedi Nish , Fuller John H. , Veglio Massimo , Cavallo-Perin Paolo ,   The EURODIAB IDDM Complications Study Group
Published: July 2007

OBJECTIVE—Corrected QT (QTc) prolongation is predictive of cardiovascular mortality in both the general and diabetic populations. As part of the EURODIAB Prospective Complication Study, we have assessed the 7-year incidence and risk factors of prolonged QTc in people with type 1 diabetes.

RESEARCH DESIGN AND METHODS—A total of 1,415 type 1 diabetic subjects, who had normal QTc at baseline, were reanalyzed after the 7-year follow-up period. QTc >0.44 s was considered abnormally prolonged.

RESULTS—Cumulative incidence of prolonged QTc was 18.7%, which is twofold higher in women than in men (24.5 vs. 13.9%, P < 0.0001). At the baseline examination, incident cases were older and less physically active than nonincident cases, had higher mean values of systolic blood pressure and HDL cholesterol, and had higher frequencies of hypertension, coronary heart disease, and distal symmetrical polyneuropathy. In multivariate logistic regression analyses, female sex and higher values of A1C and systolic blood pressure were associated with the risk of prolonged QTc, whereas physical activity and BMI within the range of 21.5–23.2 kg/m2 were protective factors. In women, association with modifiable factors, particularly BMI, was stronger than in men.

CONCLUSIONS—In type 1 diabetic subjects from the EURODIAB cohort, female sex, A1C, and systolic blood pressure are predictive of prolonged QTc, whereas physical activity and BMI within the range of 21.5–23.2 kg/m2 play a protective role. These findings are clinically relevant, as they may help to identify subjects at higher risk for prolonged QTc, as well as provide potential targets for risk-lowering strategies.
Hypoglycemia During Sleep Impairs Consolidation of Declarative Memory in Type 1 Diabetic and Healthy Humans
Authors: Jauch-Chara Kamila , Hallschmid Manfred , Gais Steffen , Schmid Sebastian M. , Oltmanns Kerstin M. , Colmorgen Caterina , Born Jan , Schultes Bernd
Published: July 2007

OBJECTIVE—Early nocturnal sleep enhances the consolidation of declarative memories acquired during prior wakefulness. Patients with type 1 diabetes frequently experience hypoglycemic episodes during sleep. We investigated whether short-lasting hypoglycemia during early nocturnal sleep affects the sleep-associated consolidation of declarative memories.

RESEARCH DESIGN AND METHODS—Sixteen type 1 diabetic patients and 16 healthy subjects matched for age and BMI were tested. On one condition, a linear fall of plasma glucose to 2.2 mmol/l was induced within 60 min by infusing insulin during early sleep. On the control condition, euglycemia (>3.86 mmol/l) was maintained throughout the night. In the morning, subjects recalled word pairs learned in the preceding evening. To assess mood and attention, a symptom questionnaire, an adjective check list, and the Stroop test were applied. Also, auditory event-related brain potentials were recorded.

RESULTS—After euglycemia, subjects recalled 1.5 ± 0.5 more word pairs than after hypoglycemia (P < 0.01), remembering 2.0 ± 0.6 more word pairs than at immediate recall before sleep (P = 0.002). Across the hypoglycemic night, no such gain occurred (+0.5 ± 0.6 words; P = 0.41). Hypoglycemia during sleep also impaired mood (P < 0.05) but did not affect attention. Effects compared well between type 1 diabetic patients and healthy control subjects.

CONCLUSIONS—Our findings indicate specific sensitivity of declarative memory consolidation during sleep to rather short episodes of mild hypoglycemia. This effect may disable memory processing in type 1 diabetic patients prone to nocturnal hypoglycemic episodes and underlines the importance of considering sleep as a critical period in the treatment of these patients.
Bone Size Normalizes With Age in Children and Adolescents With Type 1 Diabetes
Authors: Bechtold Susanne , Putzker Stefanie , Bonfig Walter , Fuchs Oliver , Dirlenbach Isa , Schwarz Hans Peter
Published: July 2007

OBJECTIVE—The aim of this study was to establish whether type 1 diabetes has a long-term effect on bone development in children and adolescents.

RESEARCH DESIGN AND METHODS—Bone characteristics and muscle cross-sectional area (CSA) were analyzed cross-sectionally in 41 (19 female and 22 male) patients and were reevaluated after 5.56 ± 0.4 years using peripheral quantitative computed tomography (pQCT). We hypothesize that bone size and muscle mass normalize with age.

RESULTS—At the first evaluation, mean ± SD age was 9.87 ± 2.3 years and disease duration was 4.31 ± 2.9 years. Height was −0.36 ± 1.9 SD, and BMI was 0.39 ± 0.9 SD. Parameters of bone size were low in the whole patient group (corrected for patient's height). At reevaluation, age was 15.44 ± 2.3 years, and patients had a mean height of −0.12 ± 0.8 SD. BMI SD had increased to 0.57 ± 1.1. Total and cortical CSA had normalized. Those patients with an increase in total CSA had a significant younger age at disease manifestation and a younger age at initial pQCT measurement. Bone size was well adapted to muscle mass expressed as the ratio of bone mineral content per muscle mass, and a close correlation was shown between the increase in bone size and in muscle CSA (r = 0.46, P = 0.03).

CONCLUSIONS—Patients with manifestation of type 1 diabetes at an early age had transient impaired bone development. Within the follow-up period, the greatest increase in bone size was found in these patients. In adolescence, all patients had a normal bone size and appropriate adaptation of bone on muscle.
Defining the Metabolic Syndrome Construct
Authors: Vaidya Dhananjay , Szklo Moyses , Liu Kiang , Schreiner Pamela J. , Bertoni Alain G. , Ouyang Pamela
Published: July 2007

OBJECTIVE—It is controversial whether the clustering of certain metabolic abnormalities should be separately designated as the metabolic syndrome. We operationalized the “syndrome” concept and tested whether the metabolic syndrome was compatible with these operational constructs.

RESEARCH DESIGN AND METHODS—The baseline cross-section of the Multi-Ethnic Study of Atherosclerosis recruited a population-based cohort of 6,781 individuals, aged 45–84 years, from six communities in the U.S. Metabolic syndrome components (waist circumference, blood pressure, fasting serum HDL cholesterol, triglycerides, and plasma glucose), homeostasis model assessment (HOMA) of insulin resistance (fasting glucose × insulin), and intimal-medial thickness (IMT) in the common and internal carotid arteries by B-mode ultrasound were measured.

RESULTS—Higher syndrome component count is associated with higher HOMA levels (trend P < 0.001). Given the prevalence of individual components, the nonprevalence of any component or the co-prevalence of four or five components is greater than expected (χ2 P < 0.001). After accounting for the additive association of each component, the current definition of metabolic syndrome (co-prevalence of three or more components) does not have supra-additive association with thicker IMT in the common carotid (men: P = 0.075, women: P = 0.949) or internal carotid artery (men: P = 0.106, women: P = 0.121).

CONCLUSIONS—The metabolic syndrome did not have supra-additive association with IMT, but its components clustered greater than chance expectation and a higher component count was associated with greater insulin resistance. The metabolic syndrome was compatible with two of three “syndrome” constructs tested.
Presence of GAD Antibodies During Gestational Diabetes Mellitus Predicts Type 1 Diabetes
Authors: Nilsson Charlotta , Ursing Dag , Törn Carina , Åberg Anders , Landin-Olsson Mona
Published: July 2007

OBJECTIVE—We sought to study the frequency of β-cell–specific autoantibody markers in women with gestational diabetes mellitus (GDM) and to follow these women to estimate the risk of later development of type 1 diabetes.

RESEARCH DESIGN AND METHODS—Of 385 pregnant women with GDM during 1995–2005 in the district of Lund, 24 (6%) women were found positive for at least one of the following: islet cell antibody (ICA), GAD antibody (GADA), or tyrosine phosphatase antibody (IA-2A). The women were followed and autoantibodies reanalyzed. Those who had not developed diabetes did an oral glucose tolerance test. The frequencies of known risk factors for GDM were compared in women with GDM with and without pancreatic autoantibodies.

RESULTS—Among the autoantibody-positive women, 50% had developed type 1 diabetes compared with none among the GDM control subjects (P = 0.001), 21% had impaired fasting glucose or impaired glucose tolerance compared with 12.5% among control subjects (P = 0.3), and none had developed type 2 diabetes compared with 12.5% among control subjects (P = 0.1).

CONCLUSIONS—Autoantibody screening in pregnant women with GDM and follow-up after delivery should be considered for early recognition of type 1 diabetes.
Combining Population Health and Baseline Risk Strategy by Determining an Age Cutoff for Initiating Statins in Patients With Diabetes
Authors: Siyambalapitiya Sajith , Bulugahapitiya Uditha , Sithole Jabulani , Song Soon , Fernando Devaka J.S. , Idris Iskandar
Published: July 2007

OBJECTIVE—Strategies for initiating statin use among adult patients with diabetes for primary cardiovascular disease (CVD) prevention include treating all patients (assuming diabetes is a coronary risk equivalent) or treating patients who are at risk of developing CVD. The aim of the study was to combine both strategies to derive an appropriate age cutoff for prescribing statins. By considering different strategies, we also aim to assess the effectiveness and efficiency of different strategies to reduce CVD events.

RESEARCH DESIGN AND METHODS—This was a cross-sectional primary care population study using electronic patient files from 304 general practitioner practices in England and Wales. Of 60,258 patients with diabetes, 11,005 men and women aged 30–74 years fullfilled criteria for primary CVD prevention. Model outcomes were extrapolated to an estimated national diabetes prevalence of 3.6%.

RESULTS—The age transition from a low-risk to a moderate-risk category for diabetic men and women occurred at ages 40.6 and 44.2 years, respectively, and sensitivity and specificity for fulfilling moderate CVD risk criteria were 97.9 and 61.8% for men and 92.0 and 77.0% for women. When applied to the national population, the age cutoff strategies were an effective and efficient strategy, potentially avoiding 11,094 events with a number needed to treat of 25.1.

CONCLUSIONS—A strategy to treat all men and women with diabetes aged >40 and 45 years, respectively, with statins showed good compromise between high effectiveness and high efficiency for reducing CVD events. Strategy to intervene if cholesterol was >5 mmol/l was the least effective and efficient in preventing CVD events.
Validation of the WHO-5 Well-Being Index in Adolescents With Type 1 Diabetes
Authors: de Wit Maartie , Pouwer Frans , Gemke Reinoud J.B.J. , Delemarre-van de Waal Henriette A. , Snoek Frank J.
Published: July 2007

OBJECTIVE—It is recommended that the psychological status of adolescents with diabetes be assessed periodically as part of ongoing care. The World Health Organization-Five Well-Being Index (WHO-5) is a short self-report instrument that appears suitable for this purpose. This study is the first to assess the reliability and validity of the WHO-5 in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Ninety-one adolescents with type 1 diabetes (aged 13–17 years) from four pediatric clinics completed the WHO-5, along with other psychological measures: the Center for Epidemiologic Studies Depression Scale (CES-D), the Diabetes Family Conflict Scale (DFCS), and the mental health and self-esteem subscales of the Child Health Questionnaire (CHQ-CF87). Confirmatory factor analysis (CFA) and exploratory factor analysis were conducted. Readability, homogeneity, and item-total and inter-item correlations were determined. Concurrent validity was examined by calculating correlation coefficients among all measures. Sensitivity and specificity of the WHO-5 were tested against those for the CES-D using receiver operating characteristic (ROC) curves.

RESULTS—CFA confirmed the one-factor structure; Cronbach's α of this 5-item scale was 0.82. The WHO-5 showed a moderate to strong correlation with the CES-D (r = −0.67), with the mental health (r = 0.60) and self-esteem (r = 0.43) subscales of the CHQ-CF87, and with the DFCS (r = −0.34), confirming concurrent validity. ROC curve analysis confirmed the WHO-5 cutoff point of <50 for identification of mild to severe depressive affect (sensitivity 89% and specificity 86%).

CONCLUSIONS—The WHO-5 is a brief, patient-friendly measure of positive well-being with good psychometric properties that appears suitable for routine use in adolescents with type 1 diabetes.
Relationships Between Estimates of Adiposity, Insulin Resistance, and Nonalcoholic Fatty Liver Disease in a Large Group of Nondiabetic Korean Adults
Authors: Sung Ki Chul , Ryan Marno C. , Kim Bum Soo , Cho Yong Kyun , Kim Byung Ik , Reaven Gerald M.
Published: July 2007

OBJECTIVE—Nonalcoholic fatty liver disease (NAFLD) is emerging as a major health problem in parallel with an increasing prevalence of obesity. Insulin resistance and abdominal and overall adiposity are closely associated with NAFLD; however, the interplay between them in the relationship with NAFLD is unclear, especially in nondiabetic individuals.

RESEARCH DESIGN AND METHODS—Abdominal ultrasound, hepatitis serology, and measurements of fasting plasma insulin (FPI), lipid concentrations, overall obesity (BMI), and abdominal obesity (waist circumference) were performed in 56,249 Korean subjects.

RESULTS—After rigorous exclusion criteria, 36,654 nondiabetic subjects (54% male) were enrolled. Subjects were divided into control (no fatty liver on ultrasound, serum alanine aminotransferase [ALT] <30 units/l [men] or <19 units/l [women]), fatty liver with normal ALT (FL-NALT), and fatty liver with a high ALT (FL-HALT) groups. After adjusting for age, BMI, and waist circumference, FPI and ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) were significantly higher in the FL-NALT than in the control group and even higher in the FL-HALT group. Odds ratios for the presence of FL-HALT with increasing quartiles of FPI and TG/HDL-C ratio were increased five- to sevenfold over those of the control group, independent of age, BMI, and waist circumference.

CONCLUSIONS—In this large population of individuals of Korean ancestry, results indicate that while overall (BMI) and abdominal (waist circumference) overweight/obesity are associated with features of NAFLD, surrogate estimates of insulin resistance, FPI concentration, and TG/HDL-C ratio predict NAFLD independently of age, BMI, and waist circumference.
Effect of Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin on Glycemic Control in Patients With Type 2 Diabetes
Authors: Goldstein Barry J. , Feinglos Mark N. , Lunceford Jared K. , Johnson Jeremy , Williams-Herman Debora E. ,   for the Sitagliptin 036 Study Group
Published: July 2007

OBJECTIVE—To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise.

RESEARCH DESIGN AND METHODS—In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5–11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C >11% or a fasting glucose value >280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks.

RESULTS—The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was −2.07% (S100/M2000), −1.57% (S100/M1000), −1.30% (M2000), −0.99% (M1000), and −0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was −2.9%. The incidence of hypoglycemia was low (0.5–2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy.

CONCLUSIONS—The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.
Increase in Physical Activity Energy Expenditure Is Associated With Reduced Metabolic Risk Independent of Change in Fatness and Fitness
Authors: Ekelund Ulf , Franks Paul W. , Sharp Stephen , Brage Søren , Wareham Nicholas J.
Published: July 2007

OBJECTIVE—We sought to examine whether change in physical activity energy expenditure (PAEE) is associated with change in metabolic risk factors and whether this association is independent of change in fat mass and aerobic fitness.

RESEARCH DESIGN AND METHODS—In a population-based sample of 176 men and 217 women followed prospectively for 5.6 years, we measured PAEE by individually calibrated heart rate monitoring, aerobic fitness, total body fat (fat mass), and metabolic risk factors (blood pressure, fasting triglycerides, HDL cholesterol, insulin, and 2-h glucose) at baseline and follow-up.

RESULTS—A 100 J · kg fat-free mass (FFM)−1 · min−1 increase in PAEE from baseline to follow-up reduced triglycerides by 3.5% (95% CI 0.03–5.7) in men and 3.2% (0.02–5.4) in women, fasting insulin by 5.3% (1.0–7.5) in men and women, and 2-h glucose by 3.2% (0.3–5.3) in men and 3.1% (0.3–5.2) in women, after adjustment for sex, age, smoking status, aerobic fitness, baseline phenotype, and change in fat mass. In general, the magnitudes of association for change in fat mass with metabolic risk factors were two to three times stronger than for PAEE.

CONCLUSIONS—Increasing levels of physical activity may protect against metabolic disease even in the absence of improved aerobic fitness and reduced body fatness. Therefore, the combination of increasing levels of physical activity and avoidance of gain in fat mass is likely to be the most successful approach for preventing cardiovascular and metabolic disease.
Improving coaxial measurements in laser welding by correcting distortions of a laser focus lens with a wide field of view
Authors: Entzinger Jorg , Iakovou Dimitrios , Aarts Ronald , Meijer Johan
Published: July 2007

A compact, lightweight, and multifunctional head for robotic laser welding applications has been equipped with a camera to provide a real time image stream of the work piece for seam teaching, tracking, and inspection purposes [D. Iakovou, R. G. K. M. Aarts, and J. Meijer, “Integrated sensors for robotic laser welding,” in Proceedings of the Third International WLT Conference on Lasers in Manufacturing, Munich, Germany (AT-Fachverlag GmBH, Stuttgart, 2005), pp. 121–126; D. Iakovou, R. G. K. M. Aarts, and J. Meijer “Sensor integration for robotic laser welding processes,” (paper No. 2301), in Proceedings of the International Congress on Applications of Lasers and Electro-Optics (ICALEO), Miami, 2005 (unpublished)]. The camera uses part of the laser focusing optics. Research has been done to identify and correct for positioning errors introduced by the optical system. A robust camera and lens calibration method has been developed. Calibration and seam detection experiments have been performed and the results were used for seam tracking.
Femtosecond pulsed laser microfabrication of SiC MEMS microgripper
Authors: Vendan Monica , Molian Pal
Published: July 2007

We report the capability of an ultrafast laser to pattern an electrostatic-comb-drive microgripper in the chemically difficult-to-etch 3C-SiC thin films. A microgripper with overall dimensions 1.2 mm×0.35 mm and a gap of 20 μm was designed and fabricated for the purpose of grasping and transporting microscale objects in hostile and harsh environments. Atmospheric pressure chemical vapor deposition was used to deposit thin films (∼2 μm) of 3C-SiC on 〈100〉 silicon substrates. A Ti:sapphire laser with 120 fs pulse width, 800 nm wavelength, and 1 kHz repetition rate was then used to perform “nonthermal” micromachining of thin films. Subsequent KOH anisotropic etching was used to dissolve the silicon substrate and release the gripper structures. The influence of laser pulse energy on the etch rate and quality of microfabricated grippers was examined and illustrated.
Nanoscale self-assembled surface structures of silicon at femtosecond excitation
Authors: El-Bandrawy M. , Bugayev A. A.
Published: July 2007

The results are presented for single picosecond and femtosecond pulse ablation of silicon which creates a continuum of the dominant filament structures with periods as small as 200 nm. It is assumed that the instability of the capillary waves is responsible for the phenomenon observed. Also it is shown that for single pulse femtosecond excitation the filament structure formation is accompanied by a fine substructure generation with a period of 60 nm. The mechanism of this substructure remains obscure.
Locomotor Behavior
Authors: Pierce R. Christopher , Kalivas Peter W.
Published: July 2007

The study of locomotor activation in rodents does not involve extensive learning or conditioning, and so this dependent measure is often used as the initial screen for pharmacological effects predictive of therapeutic efficacy of a drug class in humans. Methods for evaluating locomotor behavior in rodents fall into two general categories: automated monitoring of behavior and direct observational techniques. This unit presents protocols for measurement of locomotor activity using photocell‐based automated monitoring systems, and direct observation using interval and ordinal scales. Other methods used to quantify locomotor activity include video‐based systems, rotometers, and running wheels; these are discussed in the commentary. The protocols provided are designed for rats, although they can easily be adapted for use with mice and other rodents. Curr. Protoc. Neurosci. 40:8.1.1‐8.1.9. © by John Wiley & Sons, Inc.
In Situ Hybridization and Detection Using Nonisotopic Probes
Authors: Knoll Joan H.M. , Lichter Peter , Bakdounes Khldoun , Eltoum Isam‐Eldin A.
Published: July 2007

Nonisotopic in situ hybridization can be used to determine the cellular location and relative levels of expression for specific transcripts within cells and tissues. RNA in specimen preparations is hybridized with a biotin‐ or digoxigenin‐labeled probe, which is generally detected by fluorescence or enzymatic methods. Fluorescence in situ hybridization (FISH), probably the most widely used method, is described here, along with amplification of weak FISH signals. Nonisotopic probes can also be detected by enzymatic reactions using horseradish peroxidase or alkaline phosphatase, as described here. Curr. Protoc. Mol. Biol. 79:14.7.1‐14.7.17. © 2007 by John Wiley & Sons, Inc.
ChIP‐chip for Genome‐Wide Analysis of Protein Binding in Mammalian Cells
Authors: Kim Tae Hoon , Barrera Leah O. , Ren Bing
Published: July 2007

ChIP‐chip combines chromatin immunoprecipitation (ChIP) with microarrays (chip) to determine protein‐DNA interactions occurring in living cells. The high throughput nature of this method makes it an ideal approach for identifying transcription factor targets or chromatin modification sites along the genome. UNIT 21.9 describes a protocol for analysis of protein‐DNA interactions in yeast cells. This unit introduces an alternative protocol developed for mammalian cells. Curr. Protoc. Mol. Biol. 79:21.13.1‐21.13.22. © 2007 by John Wiley & Sons, Inc.
Production and Titration of Lentiviral Vectors
Authors: Salmon Patrick , Trono Didier
Published: July 2007

Lentiviral vectors have emerged over the last decade as powerful, reliable and safe tools for stable gene transfer in a wide variety of mammalian cells. Unlike other vectors derived from oncoretroviruses, they allow for stable gene delivery into most nondividing primary cells. This is why LVs are becoming useful and promising tools for future gene and cell therapy approaches. Lentivectors (LVs) derived from HIV‐1 have gradually evolved to display many desirable features aimed at increasing both their safety and their versatility. These latest designs are reviewed in this unit. This unit also describes protocols for production and titration of LVs that can be implemented in a research laboratory setting, with an emphasis on standardization to improve transposability of results between laboratories Curr. Protoc. Hum. Genet. 54:12.10.1‐12.10.24. © 2007 by John Wiley & Sons, Inc.
Detection of Hypo‐N‐Glycosylation Using Mass Spectrometry of Transferrin
Authors: O'Brien John F. , Lacey Jean M. , Bergen H. Robert
Published: July 2007

Many congenital disorders of glycosylation (CDG) can be diagnosed by observing the extent of glycosylation of the abundant serum glycoprotein transferrin (Trf). Trf is an N‐glycosylated protein with two asparagine glycation sites. CDG types I are those genetic defects which occur prior to transfer of the complex oligosaccharide to the acceptor asparagine in the cotranslated polypeptide chain. CDG Ia constitutes by far the most frequent form of CDG and is the result of mutations in the phosphomannomutase gene. CDG Ia and the Ib subtype (Phosphomannoisomerase deficiency) result in low cellular mannose‐1‐phosphate levels, a required precursor for oligosaccharide assembly in the endoplasmic reticulum. The deficiency in oligosaccharides with branched mannose structures is thereafter expressed by the appearance of glycoproteins with unoccupied N‐glycosylation sites (hypoglycosylation). Currently, there have been at least 11 Type I defects, type Ia being by far the most frequently occurring. Most, if not all type I defects result in unoccupied N‐glycation sites. Hypoglycosylated Trf, also known as carbohydrate‐deficient Trf (CDT), can be detected using mass spectrometry (MS) to measure the masses of the serum Trf. The methods for sample preparation using affinity chromatography and MS analysis are described in this unit. Curr. Protoc. Hum. Genet. 54:17.4.1‐17.4.9 © 2007 by John Wiley & Sons, Inc.
The Differentiation of Distal Lung Epithelium from Embryonic Stem Cells
Authors: Van Vranken Benjamin E. , Rippon Helen J. , Samadikuchaksaraei Ali , Trounson Alan O. , Bishop Anne E.
Published: July 2007

The potential for embryonic stem (ES) cells to differentiate into cells with a distal lung epithelial phenotype has been demonstrated using different in vitro culture methods. Three separate protocols are described here that utilize both murine and human ES cells. The distal lung epithelial phenotype is induced through the use of embryonic distal lung mesenchyme in coculture systems with differentiating embryoid bodies or the use of soluble factors in defined media to maximize definitive endoderm formation and select and maintain the desired phenotype. Phenotypic analysis is demonstrated using immunocytochemistry and SP‐C promoter‐eGFP reporter gene expression in transgenic ES cells. These methods provide an increased efficiency of distal lung epithelial derivation from ES cells and, therefore, they provide the foundation for the development of a cell replacement product to treat chronic lung disease or a useful in vitro model for the study of lung disease and development. Curr. Protoc. Stem Cell Biol. 2:1G.1.1‐1G.1.22. © 2007 by John Wiley & Sons, Inc.
The relationship between impulsive verbal aggression and intermittent explosive disorder
Authors: McCloskey Michael S. , Lee Royce , Berman Mitchell E. , Noblett Kurtis L. , Coccaro Emil F.
Published: July 2007

Intermittent explosive disorder (IED) is the sole psychiatric diagnostic category for which aggression is a cardinal symptom. IED focuses on physical aggression, but researchers have argued for the inclusion of verbal aggression (VA) (e.g., arguing, threatening) as a part of the IED criteria set. The utility of VA in identifying clinically relevant aggression, however, is unknown. IED participants were compared to individuals without a marked history of physical aggression, but who report frequent (two or more times a week) VA, and non‐aggressive personality‐disorder individuals on behavioral and self‐report measures of aggression, self‐report measures of related constructs (e.g., anger, affective lability), and a clinician assessment of psychosocial impairment. Both the IED and VA groups were more aggressive, angry, and clinically impaired than personality‐disorder individuals, while the IED and VA groups did not differ from each other on these measures. These results support the clinical importance of frequent VA for future iterations of the IED criteria set. Aggr. Behav. 34:51–60, 2008. © 2007 Wiley‐Liss, Inc.
Impulsive and premeditated subtypes of aggression in conduct disorder: differences in time estimation
Authors: Dougherty Donald M. , Dew Rachel E. , Mathias Charles W. , Marsh Dawn M. , Addicott Merideth A. , Barratt Ernest S.
Published: July 2007

Research aimed at identifying and studying subtypes of aggression have historically dichotomized aggressive subtypes, although specific nomenclature has varied; one approach has been to classify aggressive behavior as predominantly impulsive or predominantly premeditated. There are a number of behavioral and cognitive differences between those exhibiting these different forms of aggression. This study was designed to extend understanding of the impulsive/premeditated aggression dichotomy by comparing time estimation among adolescents exhibiting predominantly impulsive or predominantly premeditated forms of physical aggression who have a psychiatric diagnosis of conduct disorder (CD). Time estimation has previously been shown to be disrupted in impulsive and some aggressive individuals. Time estimation was compared between healthy Controls (n = 37) and two groups of adolescents with CD, those with histories of either predominantly impulsive (CD‐Impulsive, n = 26) or predominantly premeditated (CD‐Premeditated, n = 38) aggressive behaviors. Participants completed five computerized trials during which they estimated when 1 min had passed. Among aggressive adolescents with CD, the misperception of time was specific to those with histories of impulsive aggression, although time estimates improved with repeated testing and performance feedback. This study confirms the importance of considering the role and type of physical aggression when studying heterogeneous diagnostic groups like CD and supports the relevance of time estimation to certain subgroups of adolescents with CD. Aggr. Behav. 33:574–582, 2007. © 2007 Wiley‐Liss, Inc.
Biomimetic Hydroxyapatite–Drug Nanocrystals as Potential Bone Substitutes with Antitumor Drug Delivery Properties
Authors: Palazzo B. , Iafisco M. , Laforgia M. , Margiotta N. , Natile G. , Bianchi C. L. , Walsh D. , Mann S. , Roveri N.
Published: July 2007

This Full Paper investigates the adsorption and desorption of the anticancer drugs cis‐diamminedichloroplatinum(II) (CDDP, cisplatin) and the new platinum(II) complex di(ethylenediamineplatinum)medronate (DPM), as well as the clinically relevant bisphosphonate alendronate, towards two biomimetic synthetic HA nanocrystalline materials with either plate‐shaped (HAps) or needle‐shaped (HAns) morphologies and different chemico‐physical properties. The adsorption and desorption kinetics are dependent on the specific properties of the drugs and the morphology of the HA nanoparticles. Adsorption of the platinum complexes occurs with retention of the nitrogen ligands but the chloride ligands of cisplatin are displaced. Despite their opposite charges, the negatively charged alendronate bisphosphonate and the positively charged aquated cisplatin are strongly adsorbed, while the neutral DPM complex shows lower affinity towards the negatively charged apatitic surface. The data suggest that adsorption of the two platinum complexes is driven by electrostatic attractions, while interaction between the alendronate and the HA surface takes place by ligand exchange in which the two phosphonate groups of the drug molecule replace two surface phosphate groups. Significantly, adsorption of positively charged hydrolysis species of cisplatin is more favored on the phosphate‐rich HAns surface while adsorption of negatively charged alendronate is more favored on the calcium‐rich HAps surface. The latter type of short‐range electrostatic interactions also appear to dominate the desorption kinetics; consequently, drug release is greater for neutral DPM than for charged alendronate and aquated cisplatin. Moreover, while the release per unit area of charged species is the same for the two types of HAs, the release of DPM is faster from HAns, which is lower in surface calcium, than for HAps. Overall, this work demonstrates that the properties of HA nanocrystals can be modulated in such a way to produce HA/biomolecule conjugates tailored for specific therapeutic applications.
Heat Treatment of Polyelectrolyte Multilayer Capsules: A Versatile Method for Encapsulation
Authors: Köhler K. , Sukhorukov G. B.
Published: July 2007

A simple and generally applicable method of encapsulation in polyelectrolyte multilayer microcapsules based on temperature‐induced rearrangements within the shells is introduced. Using capsules consisting of eight layers of poly(diallyldimethylammonium chloride) (PDADMAC) and poly(styrene sulfonate) (PSS) as a model system, it is demonstrated that the permeability for different molecules decreases dramatically after heat incubation by using a combination of confocal laser scanning microscopy (CLSM) and fluorescence recovery after photobleaching (FRAP) measurements. The decreased permeability results from capsule shrinkage with accompanying wall thickening and densification of the shells. These morphological changes upon heating can be utilized to encapsulate molecules of varying hydrodynamic radius as well as substances bearing different charges as shown for fluorescein isothiocyanate‐labeled dextran (FITC dextran) 10 and 70 kDa and poly(acrylic) acid (PAA) 30 kDa. The encapsulated amount of dextran was quantified by fluorescence measurements and exhibits a nearly linear increase with the initial probe concentration. Furthermore we show that encapsulation by heat‐shrinkage works also for biodegradable capsules consisting of poly(arginine) (PArg) and dextransulfate (DS) indicating the versatility of the new method.
Mechanical Reinforcement of Polyethylene Using Polyethylene‐Grafted Multiwalled Carbon Nanotubes
Authors: Yang B.‐X. , Pramoda K. P. , Xu G. Q. , Goh S. H.
Published: July 2007

The incorporation of carbon nanotubes to a polymer generally improves the stiffness and strength of the polymer, but the ductility and toughness of the polymer are compromised in most cases. Here we report the mechanical reinforcement of polyethylene (PE) using polyethylene‐grafted multiwalled carbon nanotubes (PE‐g‐MWNTs). The stiffness, strength, ductility and toughness of PE are all improved by the addition of PE‐g‐MWNTs. The grafting of PE onto MWNTs enables the well‐dispersion of nanotubes in the PE matrix and improves MWNT/PE interfacial adhesion. The grafting was achieved by a reactive blending process through melt blending of PE containing 0.85 wt % of maleic anhydride and amine‐functionalized MWNTs. The reaction between maleic anhydride and amine groups, as evidenced by X‐ray photoelectron spectroscopy and Raman spectroscopy, leads to the grafting of PE onto the nanotubes.
Treatment options in skeletal localizations of hairy cell leukemia: A systematic review on the role of radiation therapy
Authors: Filippi Andrea R. , Franco Pierfrancesco , Marinone Carlo , Tarella Corrado , Ricardi Umberto
Published: July 2007

Skeletal localizations are a rare complication in hairy cell leukaemia patients, with an extimated incidence of 3%. These lesions, mainly osteolytic, can occur at various sites and are almost always symptomatic. Localized radiation therapy (RT) has been extensively used as effective palliative treatment in such cases, with different total doses and fractionation schedules. In this article, a systematic review of all reported cases with osseous complications is presented, to underline the role of RT and to define the most appropriate approach in this subset of patients. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.