Combined analyses of 20 common obesity susceptibility variants

OBJECTIVE: Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes. RESEARCH DESIGN AND METHODS: In this study we investigate the combined effect of these variants and their ability to discriminate between normal weight and overweight/obese individuals. We applied receiver operating characteristics (ROC) curves, and estimated the area under the ROC curve (AUC) as a measure of the discriminatory ability. The analyses were performed cross-sectionally in the population-based Inter99 cohort where 1,725 normal weight, 1,519 overweight, and 681 obese individuals were successfully genotyped for all 20 variants. RESULTS: When combining all variants, the 10% of the study participants who carried more than 22 risk-alleles showed a significant increase in probability of being both overweight with an odds ratio of 2.00 (1.47–2.72), P = 4.0 × 10(−5), and obese with an OR of 2.62 (1.76–3.92), P = 6.4 × 10(−7), compared with the 10% of the study participants who carried less than 14 risk-alleles. Discrimination ability for overweight and obesity, using the 20 single nucleotide polymorphisms (SNPs), was determined to AUCs of 0.53 and 0.58, respectively. When combining SNP data with conventional nongenetic risk factors of obesity, the discrimination ability increased to 0.64 for overweight and 0.69 for obesity. The latter is significantly higher (P < 0.001) than for the nongenetic factors alone (AUC = 0.67). CONCLUSIONS: The discriminative value of the 20 validated common obesity variants is at present time sparse and too weak for clinical utility, however, they add to increase the discrimination ability of conventional nongenetic risk factors

The composition of T cell subtypes in duodenal biopsies are altered in coeliac disease patients

One of the hallmarks of Celiac disease (CD) is intraepithelial lymphocytosis in the small intestine. Until now, investigations to characterize the T cell subpopulations within the epithelial layer have not discriminated between the heterodimeric co-receptor molecule, CD8αβ, and the possibly immunoregulatory CD8αα homodimer molecule. Besides TCRαβ+ CD4+ cells, no other phenotypes have been shown to be gluten-reactive. Using flow cytometry on lymphocytes from duodenal biopsies, we determined that the number of B cells (CD3- CD19+) and the number of CD3+ CD4- CD8- double-negative (DN) T cells were elevated 6-7 fold in children with CD. We next isolated and quantified intraepithelial lymphocytes (IELs) from biopsies obtained from patients (both children and adults) with CD, potential CD and non-CD controls. Flow cytometric analysis of the duodenal T cell subpopulations was performed including the markers TCRαβ, TCRγδ, CD4, CD8α and CD8β. Proportions of γδ T cells and CD8αβ+ cells among IELs were increased in CD patients, whereas proportions of CD4+ CD8αα+ and CD4+ single-positive T cells were decreased. Additionally, two gluten-reactive T cell lines (TCLs) derived from CD biopsies were analyzed for changes in proportions of T cell subsets before and after gluten stimulation. In a proliferation assay, dividing cells were tracked with carboxyfluorescein succinimidyl ester (CFSE), and both αβ and γδ T cells proliferated in response to gluten. Changes in duodenal T cell subpopulations in potential CD patients followed the same pattern as for CD patients, but with less pronounced effect

Subjective sleep assessment compared to polysomnography in mechanically ventilated critically ill ICU patients

Sleep deprivation is expected in the intensive care unit (ICU) and is associated with delirium and increased mortality. Polysomnography (PSG) is the gold standard for sleep assessment, but practical issues limit the method. Hence, many ICUs worldwide use subjective sleep assessment (SSA) for sleep monitoring, but the agreement between SSA and PSG is unknown. The hypothesis was that the level of agreement between SSA and PSG was low and that total sleep time (TST) assessed with SSA would be overestimated compared to PSG in this existing cohort database. In this sub-analysis, 30 consecutive study participants underwent 15-h PSG recordings during two consecutive nights. The attending nurse performed an hourly subjective observer rating of sleep quantity during both nights, and the agreement between SSA and PSG was determined along with mean TST. Primary outcome: The level of agreement between SSA and PSG determined by Bland–Altman analysis. Secondary outcome: (1) The overall mean TST estimated by SSA compared to PSG in all study participants enrolled in the main study during both study nights, (2) TST for all study participants evaluated hourly during both study nights, (3) TST assessed with SSA compared to PSG in study participants sedated with dexmedetomidine during the second night and for study participants treated with placebo or non-sedation the first and second nights. The level of agreement between SSA and PSG was low. Mean TST estimated by SSA during the time interval 4.00 p.m. to 7.00 a.m. was 481 min (428;534, 95% CI) vs. PSG at 437 min (386;488, 95% CI) (p =.05). When sedated with dexmedetomidine, TST estimated using SSA was 650 min (571;729, 95% CI) versus PSG which was 588 min (531;645, 95% CI) (p = 0.56). For participants treated with placebo or non-sedation TST estimated with SSA was 397 min (343;450, 95% CI) versus PSG at 362 min (302;422, 95% CI) versus (p = 0.17). In mechanically ventilated critically ill ICU patients, the level of agreement between SSA and PSG was low, and there was a significant overestimation of mean TST. SSA should only be used under awareness that it is imprecise and overestimates TST.</p

Sleep quality and quantity determined by polysomnography in mechanically ventilated critically ill patients randomized to dexmedetomidine or placebo

Background: Abnormal sleep is commonly observed in the ICU and is associated with delirium and increased mortality. If sedation is necessary, it is often performed with gamma-aminobutyric acid agonists such as propofol or midazolam leading to an absence of restorative sleep. We aim to evaluate the effect of dexmedetomidine on sleep quality and quantity. Methods: Thirty consecutive patients were included. The study was conducted as a double-blinded, randomized, placebo-controlled trial with two parallel groups: 20 patients were treated with dexmedetomidine, and 10 with placebo. Two 16 h of polysomnography recordings were done for each patient on two consecutive nights. Patients were randomized to dexmedetomidine or placebo after the first recording, thus providing a control recording for all patients. Dexmedetomidine was administered during the second recording (6 p.m.–6 a.m.). Objective: To compare the effect of dexmedetomidine versus. placebo on sleep - quality and quantity. Primary outcome: Sleep quality, total sleep time (TST), Sleep efficiency (SE), and Rapid Eye Movement (REM) sleep determined by Polysomnography (PSG). Secondary outcome: Delirium and daytime function determined by Confusion Assessment Method of the Intensive Care Unit and physical activity. Alertness and wakefulness were determined by RASS (Richmond Agitation and Sedation Scale). Results: SE were increased in the dexmedetomidine group by; 37.6% (29.7;45.6 95% CI) versus 3.7% (−11.4;18.8 95% CI) (p &lt;.001) and TST were prolonged by 271 min. (210;324 95% CI) versus 27 min. (−82;135 95% CI), (p &lt;.001). No significant difference in REM sleep, delirium physical activity, or RASS score was found except for RASS night two. Conclusion: Total sleep time and sleep efficiency were significantly increased, without elimination of REM sleep, in mechanically ventilated ICU patients randomized to dexmedetomidine, when compared to a control PSG recording performed during non-sedation/standard care.</p

Enoxaparin, effective dosage for intensive care patients: double-blinded, randomised clinical trial

Udgivelsesdato: 2010-Mar-18ABSTRACT: INTRODUCTION: Intensive care unit (ICU) patients are predisposed to thromboembolism. Routine prophylactic anticoagulation is widely recommended. Low-molecular-weight heparins, such as enoxaparin, are increasingly used because of predictable pharmacokinetics. This study aims to determine the subcutaneous (SC) dose of enoxaparin that would give the best anti-factor Xa levels in ICU patients. METHODS: The 72 patients admitted to a mixed ICU at Odense University Hospital (OUH) in Denmark were randomised into four groups to receive 40, 50, 60, or 70 mg SC enoxaparin for a period of 24 hours. Anti-factor Xa activity (aFXa) was measured before, and at 4, 12, and 24 hours after administration. An AFXa level between 0.1 to 0.3 IU/ml was considered evidence of effective antithrombotic activity. RESULTS: Median peak (4 hours after administration), aFXa levels increased significantly with an increase in enoxaparin dose, from 0.13 IU/ml at 40 mg, to 0.14 IU/ml at 50 mg, 0.27 IU/ml at 60 mg, and 0.29 IU/ml at 70 mg (P = 0.002). At 12 hours after administration, median aFXa levels were still within therapeutic range for those patients who received 60 mg (P = 0.02). CONCLUSIONS: Our study confirmed that a standard dose of 40 mg enoxaparin yielded subtherapeutic levels of aFXa in critically ill patients. Higher doses resulted in better peak aFXa levels, with a ceiling effect observed at 60 mg. The present study seems to suggest inadequate dosage as one of the possible mechanisms for the higher failure rate of enoxaparin in ICU patients. TRIAL REGISTRATION: ISRCTN03037804