CiteULike: omalbam's library [224 articles]

High Prevalence of Central Adrenal Insufficiency in Patients with Prader-Willi Syndrome

de Lind — 2008-05-11T23:51:05-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1649-1654.

Context: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. Objective: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Design: Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessed on a different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. Setting: The study was conducted in a pediatric intensive care unit. Patients: Patients included 25 randomly selected PWS patients. Main Outcome Measure: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. Results: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions. Conclusions: Strikingly, 60% of our PWS patients had CAI. The high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test. 10.1210/jc.2007-2294

A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

Marc Berna — 2008-05-11T23:45:51-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1582-1591.

Context: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. Objectives: Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. Setting and Patients: Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. Interventions and Outcome Measures: Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. Results: ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. Conclusions: Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies. 10.1210/jc.2007-2279

Approach to the Patient with a Positive Serum Thyroglobulin and a Negative Radioiodine Scan after Initial Therapy for Differentiated Thyroid Cancer

Richard Kloos — 2008-05-09T19:55:08-00:00

J Clin Endocrinol Metab, Vol. 93, No. 5. (1 May 2008), pp. 1519-1525.

The 10-yr survival of differentiated thyroid cancer is about 76-93%, and at least 10% of patients manifest tumor persistence or recurrence, depending on their disease stage, after initial therapy, which typically includes total thyroidectomy and 131I ablation. Previously the realization of their residual/recurrent cancer often presented simultaneously with the additional surprise that they lacked pathological uptake on their diagnostic whole-body radioiodine image despite their elevated stimulated serum thyroglobulin (Tg) level, a scenario referred to as the scan-negative, Tg-positive patient. Now that serum Tg and neck ultrasonography have supplanted the diagnostic whole-body scan because of its inferior sensitivity, patients are often recognized to harbor residual disease without radioiodine imaging, and a new challenging scenario has emerged: the ultrasonography-negative, Tg-positive patient. Similarities and differences of these two patient populations aside, these Tg-positive patients are frequently encountered, and some are considered for additional 131I therapy, although now typically after negative anatomic +/- 18F-fluorodeoxyglucose positron emission tomography imaging or in the setting of known or suspected distant metastases already localized by anatomic imaging. Thus, the scan-negative, Tg-positive patient of today differs from those of the past, but the term still has relevance to current practice. The optimal evaluation and treatment of these patients remain controversial, partly because many of these patients will not die from thyroid cancer, and there are no randomized trials to demonstrate that intervention could have prevented the deaths that do occur. Here a case is presented that adds the complexity of advanced age, and one approach to these challenging patients is offered. 10.1210/jc.2007-2357

Long-term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes.

V Martina — 2008-05-09T19:38:39-00:00

Diabetes care, Vol. 31, No. 5. (May 2008), pp. 940-944.

OBJECTIVE: Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of l-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation. RESEARCH DESIGN AND METHODS: A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months. RESULTS: The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed. CONCLUSIONS: NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.

Metformin versus Insulin for the Treatment of Gestational Diabetes

Janet Rowan — 2008-05-08T02:04:07-00:00

N Engl J Med, Vol. 358, No. 19. (8 May 2008), pp. 2003-2015.

Background Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking. Methods We randomly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin (with supplemental insulin if required) or insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity. The trial was designed to rule out a 33% increase (from 30% to 40%) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin. Secondary outcomes included neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment. Results Of the 363 women assigned to metformin, 92.6% continued to receive metformin until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32.0% in the group assigned to metformin and 32.2% in the insulin group (relative risk, 1.00; 95% confidence interval, 0.90 to 1.10). More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P<0.001). The rates of other secondary outcomes did not differ significantly between the groups. There were no serious adverse events associated with the use of metformin. Conclusions In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment. (Australian New Zealand Clinical Trials Registry number, 12605000311651.) 10.1056/NEJMoa0707193

Whole Grain Consumption and Body Mass Index in Adult Women: An Analysis of NHANES 1999-2000 and the USDA Pyramid Servings Database

Carolyn Good — 2008-05-06T19:57:55-00:00

J Am Coll Nutr, Vol. 27, No. 1. (1 February 2008), pp. 80-87.

Objective: To examine the relationship between whole grain consumption and body mass index (BMI) in a sample of American adult women. Methods: Dietary intake data from the National Health and Nutrition Examination Survey 1999-2000 were linked to the USDA Pyramid Servings Database. Women 19 years of age and older (n = 2,092) were classified into groups based on their average whole grain (WG) intake: 0 servings, more than 0 but less than 1 serving, and [≥]1 servings per day. Within these classifications, mean BMI, mean waist circumference and percent overweight/obese (BMI [≥] 25) were identified as primary dependent variables. Regression and logistic regression analyses were used to assess associations between BMI, waist circumference and percent of the population overweight/obese (BMI [≥]25) and WG consumption. Results: Women consuming at least one serving of WG had a significantly lower mean BMI and waist circumference than women with no WG consumption (p < 0.05). Multiple regression analysis showed a significant inverse relationship between BMI and whole grain intake after adjustment for age, energy intake, dietary fiber and alcohol intake (p = 0.004). This effect was mildly attenuated but remained significant after further adjustment for level of physical activity, smoking status, ethnicity and education (p = 0.018). The odds ratio for having a BMI [≥] 25 was 1.47 (95% CI 1.12-1.94; p for trend 0.013) for women consuming no WG compared to those consuming at least one serving, after adjustment for all covariates. Conclusions: These data support other research suggesting increased WG intake may contribute to a healthy body weight in adult women.

The Effects of 6-Week Low Glycemic Load Diet Based on Low Glycemic Index Foods in Overweight/Obese Children - Pilot Study

Zsuzsanna Fajcsak — 2008-05-06T19:53:40-00:00

J Am Coll Nutr, Vol. 27, No. 1. (1 February 2008), pp. 12-21.

Objective: To evaluate the effectiveness of a 6-week low Glycemic Load (GL) diet intervention based on low Glycemic Index (GI) foods on body weight, body composition, metabolic risk factors and satiety in overweight/obese pre-pubertal children. Methods: Following a pediatric examination 8 healthy, average age 11 year old, Caucasian, pre-pubertal overweight/obese (BMI = 24, 7 +/- 3.8 kg/m2) children participated in the study. The Low GL diet intervention was based on the replacement of at least 50% of the high GI foods with Low-GI foods. The children with one of their parents participated in weekly nutrition consultations. Body composition, fasting glucose, insulin, cholesterol and triglyceride were measured before and after the study. Dietary changes were made based on weekly 4-day food-diaries. Results: Despite no change in body weight, there was a significant (p < 0.05) reduction in % body fat (29.4 +/- 4.2 vs. 25.4 +/- 5.3), Waist-to-Hip Ratio (WHR 0.87 +/- 0.053 vs. 0.86 +/- 0.05), decrease in self-reported hunger level (4.37 +/- 0.74 vs. 1.75 +/- 0.75) and the total number of risk factors (28 vs. 15). There was a strong negative correlation between fasting glucose and insulin levels at baseline and in the magnitude of change after the study (r = -0.93 and r = -0.85 respectively; p < 0.01). Conclusions: A 6 week study demonstrated the practicality and effectiveness of this Low GL dietary approach. Despite of the unchanged body weight, Low GL diet consultations positively modified body fat content and cardiovascular risk factors in overweight or obese children.

N of 1 trials in diabetes: making individual therapeutic decisions

A Tsapas — 2008-05-05T01:38:55-00:00

Diabetologia, Vol. 51, No. 6. (1 June 2008), pp. 921-925.

Abstract N of 1 trials are single-subject, randomised, crossover studies, in which the patient serves as their own control to compare the efficacy of a treatment. They offer an alternative to large, randomised clinical trials, which have limited applicability, and empirical testing, which is arbitrary in nature. N of 1 trials are regarded as providing the highest strength of evidence for individual subject decisions. They rely upon the patient expressing preferences and making shared decisions for determining the future therapy, and may therefore lead to the successful implementation of lifestyle interventions. N of 1 trials are an optimal approach for making therapeutic decisions in chronic diseases like diabetes mellitus, where decision-making is often reliant upon arbitrary criteria and clinical judgement.

Reduction in Blood Pressure With Statins: Results From the UCSD Statin Study, a Randomized Trial.

BA Golomb — 2008-04-29T20:42:00-00:00

Archives of internal medicine, Vol. 168, No. 7. (14 April 2008), pp. 721-727.

BACKGROUND: Some studies have suggested reductions in blood pressure (BP)with statin treatment, particularly in persons with hypertension. Randomized trial evidence is limited. METHODS: We performed a randomized, double-blind, placebo-controlled trial with equal allocation to simvastatin, 20 mg; pravastatin sodium,40 mg; or placebo for 6 months. Nine hundred seventy-three men and women without known cardiovascular disease or diabetes mellitus, with low-density lipoprotein cholesterol screening levels of 115 to 190mg/dL, had assessment of systolic and diastolic BP (SBP and DBP, respectively). Blood pressure values were compared for placebo vs statins by intention-to-treat (ITT) analysis. Additional analyses were performed that (1) were confined to subjects with neither high baseline BP (SBP >140 mm Hg or DBP >90mm Hg) nor receiving BP medications, to exclude groups in whom BP medications or medication changes may have influenced results, and (2) separately evaluated simvastatin and pravastatin (vs placebo). The time course of BP changes after statin initiation and the effect of stopping statins on BP were examined. RESULTS: Statins modestly but significantly reduced BP relative to placebo,by 2.2 mm Hg for SBP (P = .02) and 2.4mm Hg for DBP (P < .001) in ITT analysis.Blood pressure reductions ranged from 2.4 to 2.8 mm Hg for both SBP and DBP with both simvastatin and pravastatin, in those subjects with full follow-up, and without potential for influence by BP medications (ie, neither receiving nor meriting BP medications). CONCLUSIONS: Reductions in SBP and DBP occurred with hydrophilic and lipophilic statins and extended to normotensive subjects. These modest effects may contribute to the reduced risk of stroke and cardiovascular events reported on statins. Trial Registration clinicaltrials.gov Identifier: NCT00330980.

Variations in the uncoupling protein-3 gene are associated with specific obesity phenotypes

Annet van Abeelen — 2008-04-21T19:09:45-00:00

Eur J Endocrinol, Vol. 158, No. 5. (1 May 2008), pp. 669-676.

ObjectiveUncoupling protein 3 (UCP-3) uncouples oxidative metabolism from ATP synthesis, resulting in the production of heat instead of energy storage. Single nucleotide polymorphisms (SNPs) in UCP-3 might result in a reduced function or expression of UCP-3 and therefore lead to an increased capacity to store energy as fat. DesignWe conducted a population-based, cross-sectional single-center study among 400 Dutch men between 40 and 80 years. MethodsSeven SNPs in the UCP-3 gene were genotyped by means of an allele-specific real-time TaqMan PCR. Linear regression analyses were performed to examine the independent effects of these SNPs on obesity phenotypes. ResultsWe found a significant association between homozygosity for the minor allele of rs647126, rs1685356, and rs2075577 and an increase in body mass index (BMI; P=0.033, P=0.016, and P=0.019 respectively). Heterozygosity for rs1685354 was associated with a significant decrease in visceral fat mass (P=0.030). ConclusionsOur results suggest that genetic variations in the UCP-3 gene are associated with an increase in BMI. A plausible mechanism by which these SNPs lead to an increase in BMI is that due to these SNPs, the UCP-3 activity might be decreased. As a result, uncoupling activity may also decrease, which will lead to an increase in body weight and BMI. 10.1530/EJE-07-0834

Antiandrogens for the Treatment of Hirsutism: A Systematic Review and Metaanalyses of Randomized Controlled Trials

Brian Swiglo — 2008-04-21T17:04:06-00:00

J Clin Endocrinol Metab, Vol. 93, No. 4. (1 April 2008), pp. 1153-1160.

Context: The relative efficacy of antiandrogens for the treatment of hirsutism remains unclear. Objective: We performed a systematic review and metaanalyses of randomized controlled trials (RCTs) evaluating the effect of antiandrogens on hirsutism. Data Sources: We used librarian-designed search strategies for MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006), review of reference lists, and contact with hirsutism experts to identify eligible RCTs. Study Selection: Eligible studies were RCTs of at least 6 months of antiandrogen use in women with hirsutism. Reviewers, with acceptable chance-adjusted agreement (kappa = 0.72), independently assessed eligibility. Data Extraction: Reviewers used structured forms to assess and collect methodological quality (allocation concealment, blinding, and loss to follow-up) and study data. Data Synthesis: Of 348 candidate studies, 12 were eligible (18 comparisons). Their methodological quality was low. Random-effects metaanalyses showed that compared with placebo, antiandrogens reduce Ferriman-Gallwey scores by 3.9 [95% confidence interval (CI), 2.35.4; inconsistency (I2) = 0%]. When compared with metformin, spironolactone reduced hirsutism scores by 1.3 (CI, 0.032.6) and flutamide by 5.0 (CI, 3.07.0; I2 = 0%). For these interventions, two to five women need to receive treatment for one to notice improvement. Spironolactone or finasteride in combination with contraceptives (1.7; CI, 0.13.3; I2 = 0%) or flutamide with metformin (4.6; CI, 1.37.9; I2 = 40%) appear superior to monotherapy with contraceptives and metformin, respectively. Only three RCTs reported patient self-assessments of hirsutism. Conclusions: Weak evidence suggests antiandrogens are mildly effective agents for the treatment of hirsutism. 10.1210/jc.2007-2430

Evaluation of Gene Expression Profiles in Thyroid Nodule Biopsy Material to Diagnose Thyroid Cancer

Stephanie Durand — 2008-04-21T17:03:02-00:00

J Clin Endocrinol Metab, Vol. 93, No. 4. (1 April 2008), pp. 1195-1202.

Context: Detection of thyroid cancer among benign nodules on fine-needle aspiration biopsies (FNAB), which presently relies on cytological examination, is expected to be improved by new diagnostic tests set up from genomic data. Objective: The aim of the study was to use a set of genes discriminating benign from malignant tumors, on the basis of their expression levels, to build tumor classifiers and evaluate their capacity to predict malignancy on FNAB. Design: We analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon macroarrays. Gene expression data were subjected to a weighted voting algorithm to generate tumor classifiers. The performances of the classifiers were evaluated on a series of 26 sham FNAB, i.e. FNAB carried out on thyroid nodules after surgical resection. Results: A series of 19 genes with a similar expression in follicular adenomas and normal tissue and discriminating follicular adenomas+normal tissue from the following: 1) follicular thyroid carcinomas (FTCs), 2) papillary thyroid carcinomas (PTCs), or 3) both FTCs and PTCs. These were used to generate four classifiers, the FTCs, PTCs, common (FTC+PTCs), and global classifiers. In 23 of the 26 sham FNAB, the four classifiers yielded a diagnosis in agreement with the diagnosis of the pathologist used as reference; in the three other cases, the correct diagnosis was given by three of four classifiers. Conclusions: We developed a procedure of molecular diagnosis of benign vs. malignant tumors applicable to the material collected by FNAB. The molecular test complied with a preclinical validation stage; it must be now evaluated on ultrasound-guided FNAB in a large-scale prospective study. 10.1210/jc.2007-1571

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial.

SE Nissen — 2008-04-17T16:02:25-00:00

JAMA : the journal of the American Medical Association, Vol. 299, No. 13. (2 April 2008), pp. 1547-1560.

CONTEXT: Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. OBJECTIVE: To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. DESIGN, SETTING, AND PATIENTS: Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. INTERVENTIONS: Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676). MAIN OUTCOME MEASURES: The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). RESULTS: In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm3 (-4.09 to -0.24) vs an increase of 0.88 mm3 (-1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (-35.4 to -17.3) (20.5%) vs 8.9 mg/dL (-14.2 to -1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001). CONCLUSIONS: After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00124332.

Height velocity targets from the national cooperative growth study for first-year growth hormone responses in short children.

B Bakker — 2008-04-15T20:45:58-00:00

The Journal of clinical endocrinology and metabolism, Vol. 93, No. 2. (February 2008), pp. 352-357.

CONTEXT: Although GH has been used to treat short stature in GH deficiency (GHD) and other conditions for more than 40 yr, criteria for satisfactorily defining targets for GH responsiveness have never been developed. OBJECTIVE: The objective of this study was to present the first-year growth expressed as height velocity (HV) for prepubertal boys and girls with idiopathic GHD, organic GHD, idiopathic short stature, or Turner syndrome from Genentech's National Cooperative Growth Study to derive age-specific targets for GH responsiveness for each etiology and gender. DESIGN AND POPULATION: Using data from the National Cooperative Growth Study, we constructed curves of response to GH during the first year of treatment with standard daily doses in naive-to-treatment prepubertal children with idiopathic GHD (2323 males, 842 females), organic GHD (582 males, 387 females), idiopathic short stature (1392 males, 465 females), or Turner syndrome (1367 females). MAIN OUTCOME MEASURE: For each category, mean pretreatment and mean +/-1 and +/-2 sd for the first-year HV on GH were assessed. Mean and mean +/- 1 sd for HV were plotted vs. age at baseline (initiation of GH treatment) and compared with mean pretreatment HV. RESULTS: HV plots for each category as a factor of age at baseline are presented. Mean - 2 sd HV plots approximated the pretreatment HV. CONCLUSION: Using baseline age- and gender-specific targets will assist clinicians in assessing a patient's first-year growth response. We propose that HV below the mean - 1 sd on these plots be considered a "poor" response. These curves may be used to identify patients who may benefit from GH dose adjustment, to assess compliance issues, or to challenge the original diagnosis.

Measurement of basal growth hormone (GH) is a useful test of disease activity in treated acromegalic patients

Jayasena — 2007-12-14T09:35:44-00:00

Clinical Endocrinology, Vol. 68, No. 1. (January 2008), pp. 36-41.

Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials

Robin Christensen — 2008-02-18T04:17:32-00:00

The Lancet, Vol. 370, No. 9600., pp. 1706-1713.

SummaryBackground Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.Methods We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo.Findings Patients given rimonabant had a 4[middle dot]7 kg (95% CI 4[middle dot]1-5[middle dot]3 kg; p<0[middle dot]0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1[middle dot]4; p=0[middle dot]0007; number needed to harm=25 individuals [95% CI 17-58]), and 1[middle dot]4 times more serious adverse events (OR=1[middle dot]4; p=0[middle dot]03; number needed to harm=59 [27-830]). Patients given rimonabant were 2[middle dot]5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2[middle dot]5; p=0[middle dot]01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3[middle dot]0; p=0[middle dot]03; number needed to harm=166 [47-3716]).Interpretation Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety--despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Usefulness of statin pretreatment to prevent contrast-induced nephropathy and to improve long-term outcome in patients undergoing percutaneous coronary intervention.

G Patti — 2008-04-15T20:33:19-00:00

The American journal of cardiology, Vol. 101, No. 3. (1 February 2008), pp. 279-285.

Contrast-induced nephropathy (CIN) is an important cause of mortality and morbidity in patients undergoing angiography. This study investigated whether statins decrease incidence of CIN in the setting of percutaneous coronary intervention (PCI) and evaluated the influence of such potential benefit on long-term outcome. Four-hundred thirty-four patients undergoing PCI were prospectively enrolled and followed up to 4 years. Patients were stratified according to preprocedural statin therapy (260 statin treated, 174 statin naive). CIN was defined as a postprocedural increase in serum creatinine of >or=0.5 mg/dl or>25% from baseline. Follow-up assessment included 4-year occurrence of major adverse cardiac events. Statin-treated patients had a significantly lower incidence of CIN (3% vs 27%, p<0.0001; 90% risk decrease) and had better postprocedural creatinine clearance (80+/-20 vs 65+/-16 ml/min, p<0.0001). Benefit of statin before treatment was observed in all subgroups, except in patients with a pre-existing creatinine clearance<40 ml/min. During follow-up, CIN was a predictor of poorer outcome; 4-year survival free of major adverse cardiac events was highest in statin-treated patients without CIN (95%, p<or=0.015) and lowest in statin-naive patients with CIN (53%, p<or=0.018). In conclusion, patients receiving statins before PCI have a significant decrease of CIN; this early protective effect translates into better long-term event-free survival. These results may lend further support to utilization of statins as adjuvant pharmacologic therapy before PCI.

Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results.

LM Ruilope — 2008-04-15T20:30:25-00:00

Journal of hypertension, Vol. 26, No. 2. (February 2008), pp. 357-367.

OBJECTIVE: Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme. METHODS: RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment. RESULTS: After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%). CONCLUSIONS: Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events

Sekar Kathiresan — 2008-03-20T07:22:21-00:00

N Engl J Med, Vol. 358, No. 12. (20 March 2008), pp. 1240-1249.

Background Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease. Methods We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score. Results All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score. Conclusions A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors. 10.1056/NEJMoa0706728

Vitamin D deficiency and risk of cardiovascular disease.

TJ Wang — 2008-04-07T17:56:32-00:00

Circulation, Vol. 117, No. 4. (29 January 2008), pp. 503-511.

BACKGROUND: Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. METHODS AND RESULTS: We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (< 15 ng/mL, < 10 ng/mL). Multivariable Cox regression models were adjusted for conventional risk factors. Overall, 28% of individuals had levels < 15 ng/mL, and 9% had levels < 10 ng/mL. During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Individuals with 25-OH D < 15 ng/mL had a multivariable-adjusted hazard ratio of 1.62 (95% confidence interval 1.11 to 2.36, P=0.01) for incident cardiovascular events compared with those with 25-OH D > or = 15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to < 15 ng/mL and 1.80 (95% confidence interval 1.05 to 3.08) for levels < 10 ng/mL (P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. CONCLUSIONS: Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study.

PL Lutsey — 2008-04-07T17:53:31-00:00

Circulation, Vol. 117, No. 6. (12 February 2008), pp. 754-761.

BACKGROUND: The role of diet in the origin of metabolic syndrome (MetSyn) is not well understood; thus, we sought to evaluate the relationship between incident MetSyn and dietary intake using prospective data from 9514 participants (age, 45 to 64 years) enrolled in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS: Dietary intake was assessed at baseline via a 66-item food frequency questionnaire. We used principal-components analysis to derive "Western" and "prudent" dietary patterns from 32 food groups and evaluated 10 food groups used in previous studies of the ARIC cohort. MetSyn was defined by American Heart Association guidelines. Proportional-hazards regression was used. Over 9 years of follow-up, 3782 incident cases of MetSyn were identified. After adjustment for demographic factors, smoking, physical activity, and energy intake, consumption of a Western dietary pattern (P(trend)=0.03) was adversely associated with incident MetSyn. After further adjustment for intake of meat, dairy, fruits and vegetables, refined grains, and whole grains, analysis of individual food groups revealed that meat (P(trend)<0.001), fried foods (P(trend)=0.02), and diet soda (P(trend)=< 0.001) also were adversely associated with incident MetSyn, whereas dairy consumption (P(trend)=0.006) was beneficial. No associations were observed between incident MetSyn and a prudent dietary pattern or intakes of whole grains, refined grains, fruits and vegetables, nuts, coffee, or sweetened beverages. CONCLUSIONS: These prospective findings suggest that consumption of a Western dietary pattern, meat, and fried foods promotes the incidence of MetSyn, whereas dairy consumption provides some protection. The diet soda association was not hypothesized and deserves further study.

Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial.

LP Svetkey — 2008-04-07T17:50:47-00:00

JAMA : the journal of the American Medical Association, Vol. 299, No. 10. (12 March 2008), pp. 1139-1148.

CONTEXT: Behavioral weight loss interventions achieve short-term success, but re-gain is common. OBJECTIVE: To compare 2 weight loss maintenance interventions with a self-directed control group. DESIGN, SETTING, AND PARTICIPANTS: Two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). Enrollment at 4 academic centers occurred August 2003-July 2004 and randomization, February-December 2004. Data collection was completed in June 2007. INTERVENTIONS: After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology-based intervention, or self-directed control. Main Outcome Changes in weight from randomization. RESULTS: Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, -1.5 kg; 95% confidence interval [CI], -2.4 to -0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology-based (5.2 kg) and self-directed groups (5.5 kg; mean difference -0.3 kg; 95% CI, -1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology-based than in the self-directed group at 18 months (mean difference, -1.1 kg; 95% CI, -1.9 to -0.4 kg; P = .003) and at 24 months (mean difference, -0.9 kg; 95% CI, -1.7 to -0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology-based group was -1.2 kg (95% CI -2.1 to -0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight. CONCLUSIONS: The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive technology-based intervention provided early but transient benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054925.

Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia

John Kastelein — 2008-04-01T08:03:47-00:00

N Engl J Med (30 March 2008), NEJMoa0800742.

Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. Methods We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intimamedia thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intimamedia thickness, which was defined as the average of the means of the far-wall intimamedia thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. Results The primary outcome, the mean (+/-SE) change in the carotid-artery intimamedia thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intimamedia thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. Conclusions In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intimamedia thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 .) 10.1056/NEJMoa0800742

Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders.

JL Akerblom — 2008-04-04T19:27:43-00:00

Age and ageing, Vol. 37, No. 2. (March 2008), pp. 207-213.

OBJECTIVES: to investigate the relation of plasma lipids to all-cause mortality in a multi-ethnic cohort of non-demented elderly. SETTING: community-based sample of Medicare recipients, 65 years and older, residing in Northern Manhattan. PARTICIPANTS: about two thousand five hundred and fifty-six non-demented elderly, 65-103 years. Among participants, 66.1% were women, 27.6% were White/non-Hispanic, 31.2% were African-American and 41.2% were Hispanic. METHODS: a standardised assessment, including functional ability, medical history, physical and neurological examination and a neuropsychological battery was conducted. Vital status was ascertained through the National Death Index (NDI). We used survival analyses stratified by race and ethnicity to examine the relation of plasma lipids to subsequent all-cause mortality. RESULTS: hispanics had the best overall survival, followed by African-Americans and Whites. Whites and African-Americans in the lowest quartiles of total cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) were approximately twice as likely to die as those in the highest quartile (White HR: 2.2, for lowest total cholesterol quartile; HR: 2.3, for lowest non-HDL cholesterol quartile; and HR: 1.8, for lowest LDL cholesterol quartile. African-American HR: 1.9, for lowest total cholesterol, HR: 2.0, for lowest non-HDL cholesterol and HR: 1.9, for lowest LDL cholesterol). In contrast, plasma lipid levels were not related to mortality risk among Hispanics. CONCLUSIONS: hispanic ethnicity modifies the associations between lipid levels and all-cause mortality in the elderly.

Does thoracic or lumbar spine bone architecture predict vertebral failure strength more accurately than density?

EM Lochmüller — 2008-03-24T21:21:13-00:00

Osteoporosis International, Vol. 19, No. 4. (14 April 2008), pp. 537-545.

Abstract Summary Trabecular bone microstructure was studied in 6 mm bone biopsies taken from the 10th thoracic and 2nd lumbar vertebra of 165 human donors and shown to not differ significantly between these sites. Microstructural parameters at the locations examined provided only marginal additional information to quantitative computed tomography in predicting experimental failure strength. Introduction It is unknown whether trabecular microstructure differs between thoracic and lumbar vertebrae and whether it adds significant information in predicting the mechanical strength of vertebrae in combination with QCT-based bone density. Methods Six mm cylindrical biopsies taken at mid-vertebral level, anterior to the center of the thoracic vertebra (T) 10 and the lumbar vertebra (L) 2 were studied with micro-computed tomography (μCT) in 165 donors (age 52 to 99 years). The segment T11-L1 was examined with QCT and tested to failure using a testing machine. Results The correlation of microstructural properties was moderate between T10 and L2 (r ≤ 0.5). No significant differences were observed in the microstructural properties between the thoracic and lumbar spine, nor were sex differences at T10 or L2 observed. Cortical/subcortical density of T12 (r 2 = 48%) was more strongly correlated with vertebral failure stress than trabecular density (r 2 = 32%). BV/TV (of T10) improved the prediction by 52% (adjusted r 2) in a multiple regression model. Conclusion Microstructural properties of trabecular bone biopsies displayed a high degree of heterogeneity between vertebrae but did not differ significantly between the thoracic and lumbar spine. At the locations examined, bone microstructure only marginally improved the prediction of structural vertebral strength beyond QCT-based bone density.

Metabolic effects of time-released garlic powder tablets in type 2 diabetes mellitus: the results of double-blinded placebo-controlled study

Igor Sobenin — 2008-03-24T21:08:56-00:00

Acta Diabetologica, Vol. 45, No. 1. (March 2008), pp. 1-6.

Abstract Late complications in type 2 diabetic patients are commonly associated with accelerated development of atherosclerosis. In type 2 diabetes mellitus, non-enzymatic glycosylation of apo-B that is a function of hyperglycaemia is an efficient biochemical way of low-density lipoprotein atherogenic modification. So, proper metabolic control is needed to prevent late complications of diabetes. The study was performed to estimate the effects of time-released garlic powder tablet Allicor on the parameters of metabolic control and plasma lipids in type 2 diabetes mellitus. The metabolic action of Allicor was investigated in the 4-week double-blinded placebo-controlled study in 60 type 2 diabetic patients. Fasting blood glucose was measured daily, and serum fructosamine as well as cholesterol and triglyceride levels were determined at the baseline, after 1, 2, 3 and 4 weeks. It has been demonstrated that treatment with Allicor resulted in better metabolic control due to the lowering of fasting blood glucose, serum fructosamine and serum triglyceride levels. The results of this study may allow recommending garlic powder tablets Allicor for the treatment of type 2 diabetes mellitus along with dietary treatment and/or sulfonylurea derivatives to achieve better metabolic control. The benefits from garlic preparations may lead to the reduction of cardiovascular risk in diabetic patients.

Morbidity and GH deficiency: a nationwide study.

Kirstine Stochholm — 2008-03-24T21:03:35-00:00

Eur J Endocrinol, Vol. 158, No. 4. (1 April 2008), pp. 447-457.

ObjectiveTo estimate morbidity in Denmark in all patients with GH deficiency (GHD). DesignMorbidity was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in the GHD patients were studied and additional morbidity noted. Diagnoses and dates of admissions were identified in the National Patient Registry. Lag time until first admission was used as a measure of morbidity. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cut-off of 18 years at onset of GHD. MethodSex- and cause-specific hazard ratios (HRs) in CO and AO GHD compared with controls. ResultsTotal morbidity was significantly increased in the GHD patients. HR for CO males: 3.1 (95% confidence interval (CI): 2.73.7), CO females: 3.2 (95% CI: 2.63.9), AO males: 2.9 (95% CI: 2.63.2), and AO females: 3.2 (95% CI: 2.83.6). In 18 out of 20 chapters from the International Classification of Diseases-10, a significantly increased morbidity was identified for at least one of the four subgroups of patients. Morbidity was significantly increased in all the four subgroups due to infectious, endocrine, pulmonary, urogenital, and neurological diseases; cancer; diseases of the eye, ear, and circulatory diseases; and traumas. Fractures were significantly increased in AO females, not in males. ConclusionsMorbidity was significantly increased in the GHD patients. The increased morbidity was due to a variety of disorders, some of which can readily be explained by GHD and other pituitary deficiencies, while others cannot be easily explained. 10.1530/EJE-07-0523

Effects of GH treatment in GH-deficient adults on adiponectin, leptin and pregnancy-associated plasma protein-A.

C Joaquin — 2008-03-24T21:00:32-00:00

Eur J Endocrinol, Vol. 158, No. 4. (1 April 2008), pp. 483-490.

ObjectiveGH deficiency (GHD) in adults is associated with adverse effects on metabolism and increased cardiovascular risk. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that promotes IGF-I availability in vascular tissues. PAPP-A levels appear to correlate with carotid intima-media thickness and have been proposed as an early predictor of cardiac events. The aim of our study was to evaluate PAPP-A levels in GHD adults at baseline and after GH replacement and correlate them with changes in body composition, lipid profile, glucose homeostasis, inflammatory markers and in leptin and adiponectin. Patients and methodsFourteen GHD adults were evaluated at baseline and after 1 year of GH therapy. All patients were compared at baseline with 28 age-, sex- and body mass index (BMI)-matched control subjects. ResultsAt baseline, GHD adults showed higher PAPP-A levels (P=0.03) and higher leptin (P=0.04), fibrinogen (P=0.002) and highly sensitive C-reactive protein (P=0.01) values than controls. Therapy with GH reduced PAPP-A (P=0.03) and fibrinogen levels (P=0.002) while increased BMI (P=0.01) and reduced waist-hip ratio (WHR; P=0.05) were observed. Insulin and homeostasis model assessment of insulin resistance index increased after treatment (P<0.004/P=0.007), without changes in leptin or adiponectin levels. PAPP-A values correlated positively with BMI and WHR and negatively with adiponectin before and after treatment, with no correlation with glucose homeostasis parameters, lipid profile or leptin. ConclusionsOur study suggests that PAPP-A expression is increased in GHD adults, and that 1 year of GH replacement therapy is able to reduce PAPP-A levels in this population. However, further studies are required to determine whether this decrease correlates with an improvement in atherosclerosis. 10.1530/EJE-07-0554

Intensive glucose lowering arm of diabetes trial is stopped after excess deaths

Susan Mayor — 2008-03-24T20:46:38-00:00

BMJ, Vol. 336, No. 7641. (23 February 2008), 407.

10.1136/bmj.39496.527384.DB

Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials

Giovanni Strippoli — 2008-03-22T20:38:36-00:00

BMJ, Vol. 336, No. 7645. (22 March 2008), pp. 645-651.

Objective To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations). Design Meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006). Study selection Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease. Data extraction and analysis Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model. Results Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference 42.28 mg/dl (1.10 mmol/l), 95% confidence interval 47.25 to 37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; 43.12 mg/dl (1.12 mmol/l), 47.85 to 38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; 0.73 g/24 hour, 0.95 to 0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), 2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only. Conclusion Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias. 10.1136/bmj.39472.580984.AE

Hyperthyroidism and pregnancy

Helen Marx — 2008-03-24T20:29:51-00:00

BMJ, Vol. 336, No. 7645. (22 March 2008), pp. 663-667.

10.1136/bmj.39462.709005.AE

Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study

Rakesh Amin — 2008-03-19T15:57:22-00:00

BMJ (18 March 2008), bmj.39478.378241.BE.

Objectives To describe independent predictors for the development of microalbuminuria and progression to macroalbuminuria in those with childhood onset type 1 diabetes. Design Prospective observational study with follow-up for 9.8 (SD 3.8) years. Setting Oxford regional prospective study. Participants 527 participants with a diagnosis of type 1 diabetes at mean age 8.8 (SD 4.0) years. Main outcome measures Annual measurement of glycated haemoglobin (HbA1c) and assessment of urinary albumin:creatinine ratio. Results Cumulative prevalence of microalbuminuria was 25.7% (95% confidence interval 21.3% to 30.1%) after 10 years of diabetes and 50.7% (40.5% to 60.9%) after 19 years of diabetes and 5182 patient years of follow-up. The only modifiable adjusted predictor for microalbuminuria was high HbA1c concentrations (hazard ratio per 1% rise in HbA1c 1.39, 1.27 to 1.52). Blood pressure and history of smoking were not predictors. Microalbuminuria was persistent in 48% of patients. Cumulative prevalence of progression from microalbuminuria to macroalbuminuria was 13.9% (12.9% to 14.9%); progression occurred at a mean age of 18.5 (5.8) years. Although the sample size was small, modifiable predictors of macroalbuminuria were higher HbA1c levels and both persistent and intermittent microalbuminuria (hazard ratios 1.42 (1.22 to 1.78), 27.72 (7.99 to 96.12), and 8.76 (2.44 to 31.44), respectively). Conclusion In childhood onset type 1 diabetes, the only modifiable predictors were poor glycaemic control for the development of microalbuminuria and poor control and microalbuminuria (both persistent and intermittent) for progression to macroalbuminuria. Risk for macroalbuminuria is similar to that observed in cohorts with adult onset disease but as it occurs in young adult life early intervention in normotensive adolescents might be needed to improve prognosis. 10.1136/bmj.39478.378241.BE

Genetic tests for common diseases: new insights, old concerns

David Melzer — 2008-03-14T20:01:07-00:00

BMJ, Vol. 336, No. 7644. (15 March 2008), pp. 590-593.

10.1136/bmj.39506.601053.BE

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels.

Richa Saxena — 2007-05-07T08:53:58-00:00

Science (26 April 2007)

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single nucleotide polymorphisms (SNPs) in 1,464 patients with T2D and 1,467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D) we identify and confirm three loci associated with T2D -- in a non-coding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 -- and replicate associations near HHEX and in SLC30A8 found by a recent whole genome association study. We identify and confirm association of a SNP in an intron of glucokinase regulatory protein with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues into the pathogenesis of common diseases.

Studies of Association of Variants Near the HHEX, CDKN2A/B, and IGF2BP2 Genes With Type 2 Diabetes and Impaired Insulin Release in 10,705 Danish Subjects: Validation and Extension of Genome-Wide Association Studies

Niels Grarup — 2008-03-14T19:12:33-00:00

Diabetes, Vol. 56, No. 12. (1 December 2007), pp. 3105-3111.

OBJECTIVE In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed to characterize quantitative metabolic risk phenotypes of the four variants. RESEARCH DESIGN AND METHODS The variants were genotyped in the population-based Inter99 cohort (n = 5,970), the ADDITION Study (n = 1,626), a population-based sample of young healthy subjects (n = 377), and in additional type 2 diabetic case (n = 2,111) and glucose-tolerant (n = 521) subjects. The case-control studies involved a total of 4,089 type 2 diabetic patients and 5,043 glucose-tolerant control subjects. RESULTS We validated association of variants near HHEX/KIF11/IDE, CDKN2A/B, and IGF2BP2 with type 2 diabetes. Interestingly, in middle-aged people, the rs1111875 C-allele of HHEX/KIF11/IDE strongly associated with lower acute insulin response during an oral glucose tolerance test (P = 6 x 107). In addition, decreased insulin release following intravenous tolbutamide injection was observed in young healthy subjects (P = 0.02). Also, a reduced insulin release was observed for the CDKN2A/B rs10811661 T-allele after both oral and intravenous glucose challenges (P = 0.001 and P = 0.009, respectively). CONCLUSIONS We validate that variants in the proximity of the HHEX/KIF11/IDE, CDKN2A/B, and IFG2BP2 loci associate with type 2 diabetes. Importantly, variations within the HHEX/KIF11/IDE and CDKN2A/B loci confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects, suggesting a role for these variants in the pathogenesis of pancreatic beta-cell dysfunction. 10.2337/db07-0856

Anastrozole Increases Predicted Adult Height of Short Adolescent Males Treated with Growth Hormone: A Randomized, Placebo-Controlled, Multicenter Trial for One to Three Years

Nelly Mauras — 2008-03-12T16:21:11-00:00

J Clin Endocrinol Metab, Vol. 93, No. 3. (1 March 2008), pp. 823-831.

Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8 +/- 0.1 vs. +2.7 +/- 0.1 yr, P < 0.0001) and after 3 yr (+2.5 +/- 0.2 vs. +4.1 +/- 0.1 yr, P < 0.0001). This resulted in a net increase in predicted adult height of +4.5 +/- 1.2 cm in the anastrozole group at 24 months and +6.7 +/- 1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 23 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach. 10.1210/jc.2007-1559

Should Nonalcoholic Fatty Liver Disease Be Included in the Definition of Metabolic Syndrome?: A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects

Giovanni Musso — 2008-03-11T20:45:30-00:00

Diabetes Care, Vol. 31, No. 3. (1 March 2008), pp. 562-568.

OBJECTIVEThe ability of the Adult Treatment Panel III (ATP III) criteria of metabolic syndrome to identify insulin-resistant subjects at increased cardiovascular risk is suboptimal, especially in the absence of obesity and diabetes. Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and is emerging as an independent cardiovascular risk factor. We compared the strength of the associations of ATP III criteria and of NAFLD to insulin resistance, oxidative stress, and endothelial dysfunction in nonobese nondiabetic subjects. RESEARCH DESIGN AND METHODSHomeostasis model assessment of insulin resistance (HOMA-IR) >2, oxidative stress (nitrotyrosine), soluble adhesion molecules (intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), and circulating adipokines (tumor necrosis factor-alpha, leptin, adiponectin, and resistin) were cross-sectionally correlated to ATP III criteria and to NAFLD in 197 unselected nonobese nondiabetic subjects. RESULTSNAFLD more accurately predicted insulin resistance than ATP III criteria: sensitivity 73 vs. 38% (P = 0.0001); positive predictive value: 81 vs. 62% (P = 0.035); negative predictive value 87 vs. 74% (P = 0.012); positive likelihood ratio 4.39 vs. 1.64 (P = 0.0001); and negative likelihood ratio 0.14 vs. 0.35 (P = 0.0001). Adding NAFLD to ATP III criteria significantly improved their diagnostic accuracy for insulin resistance. Furthermore, NAFLD independently predicted HOMA-IR, nitrotyrosine, and soluble adhesion molecules on logistic regression analysis; the presence of NAFLD entailed more severe oxidative stress and endothelial dysfunction, independent of adiposity or any feature of the metabolic syndrome in insulin-resistant subjects. CONCLUSIONSNAFLD is more tightly associated with insulin resistance and with markers of oxidative stress and endothelial dysfunction than with ATP III criteria in nonobese nondiabetic subjects and may help identify individuals with increased cardiometabolic risk in this population. 10.2337/dc07-1526

Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study.

P Cohen — 2008-03-11T17:01:22-00:00

J Clin Endocrinol Metab, Vol. 92, No. 7. (July 2007), pp. 2480-2486.

CONTEXT: Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. OBJECTIVE: The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. DESIGN: This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) -2.64] with low IGF-I levels (mean IGF-I SDS -3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF((low)) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF((high)) group, n = 68] or to a comparison group of conventional GH dose of 40 microg/kg/d (n = 34). SETTING: The study was conducted in a multicenter, outpatient setting. PRIMARY OUTCOME MEASURE: Change in HT-SDS over 2 yr was measured. RESULTS: One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF((low)), and IGF((high)), respectively, with IGF((high)) showing significantly greater linear growth response (P < 0.001, compared with the other two groups). The IGF((high)) arm required higher doses (>2.5 times) than the IGF((low)) arm, and these GH doses were highly variable (20-346 microg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. CONCLUSION: IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.