Sleep Extension Improves Neurocognitive Functions in Chronically Sleep-Deprived Obese Individuals

Background

Sleep deprivation and obesity, are associated with neurocognitive impairments. Effects of sleep deprivation and obesity on cognition are unknown, and the cognitive long-term effects of improvement of sleep have not been prospectively assessed in short sleeping, obese individuals.

Objective

To characterize neurocognitive functions and assess its reversibility.

Design

Prospective cohort study.

Setting

Tertiary Referral Research Clinical Center.

Patients

A cohort of 121 short-sleeping (<6.5 h/night) obese (BMI 30–55 kg/m²) men and pre-menopausal women.

Intervention

Sleep extension (468±88 days) with life-style modifications.

Measurements

Neurocognitive functions, sleep quality and sleep duration.

Results

At baseline, 44% of the individuals had an impaired global deficit score (t-score 0–39). Impaired global deficit score was associated with worse subjective sleep quality (p = 0.02), and lower urinary dopamine levels (p = 0.001). Memory was impaired in 33%; attention in 35%; motor skills in 42%; and executive function in 51% of individuals. At the final evaluation (N = 74), subjective sleep quality improved by 24% (p<0.001), self-reported sleep duration increased by 11% by questionnaires (p<0.001) and by 4% by diaries (p = 0.04), and daytime sleepiness tended to improve (p = 0.10). Global cognitive function and attention improved by 7% and 10%, respectively (both p = 0.001), and memory and executive functions tended to improve (p = 0.07 and p = 0.06). Serum cortisol increased by 17% (p = 0.02). In a multivariate mixed model, subjective sleep quality and sleep efficiency, urinary free cortisol and dopamine and plasma total ghrelin accounted for 1/5 of the variability in global cognitive function.

Limitations

Drop-out rate.

Conclusions

Chronically sleep-deprived obese individuals exhibit substantial neurocognitive deficits that are partially reversible upon improvement of sleep in a non-pharmacological way. These findings have clinical implications for large segments of the US population.

Trail registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00261898","term_id":"NCT00261898"}}NCT00261898. NIDDK protocol 06-DK-0036     

Instrumental and Non-Instrumental Evaluation of 4-Meter Walking Speed in Older Individuals

BackgroundManual measurement of 4-meter gait speed by a stopwatch is the gold standard test for functional assessment in older adults. However, the accuracy of this technique may be biased by several factors, including intra- and inter-operator variability. Instrumental techniques of measurement using accelerometers may have a higher accuracy. Studies addressing the concordance between these two techniques are missing. The aim of the present community-based observational study was to compare manual and instrumental measurements of 4-meter gait speed in older individuals and to assess their relationship with other indicators of physical performance.MethodsOne-hundred seventy-two (69 men, 103 women) non-disabled community-dwellers aged ≥65 years were enrolled. They underwent a comprehensive geriatric assessment including physical function by Short Physical Performance Battery (SPPB), hand grip strength, and 6-minute walking test (6MWT). Timed usual walking speed on a 4-meter course was assessed by using both a stopwatch (4-meter manual measurement, 4-MM) and a tri-axial accelerometer (4-meter automatic measurement, 4-MA). Correlations between these performance measures were evaluated separately in men and women by partial correlation coefficients.ResultsIn both genders, 4-MA was associated with 4-MM (men r = 0.62, p<0.001; women r = 0.73, p<0.001), handgrip strength (men r = 0.40, p = 0.005; women r = 0.29, p = 0.001) and 6MWT (men r = 0.50, p = 0.0004; women r = 0.22, p = 0.048). 4-MM was associated with handgrip strength and 6MWT in both men and women. Considering gait speed <0.6 m/s as diagnostic of dismobility syndrome, the two methods of assessment disagreed, with a different categorization of subjects, in 19% of men and 23% of women. The use of accelerometer resulted in 29 (13 M, 16 F) additional diagnoses of dismobility, compared with the 4-MM.ConclusionsIn an older population, the concordance of gait speeds manually or instrumentally assessed is not optimal. The results suggest that manual measures might lead to misclassification of a substantial number of subjects. However, longitudinal studies using standardized and validated procedures aimed at the comparison of different techniques are needed before recommending the use of accelerometers in comprehensive geriatric assessment.     

Gender Differences in the Response of Plasma Leptin Concentrations to Weight Loss in Obese Older Individuals

Plasma leptin concentration is directly related to the degree of obesity and is higher in women than in men of the same body mass index (BMI). We hypothesized that fasting plasma leptin concentrations and the response of leptin to weight loss would differ in older men and women of a similar fat mass. Plasma leptin concentrations (radioimmunoassay) and fat mass (DXA) were measured in 47 older, obese (BMI=30 ± 4 kg/m²) women and 23 older, obese (BMI=31 ± 3 kg/m²) men after a 2 to 4 week period of weight and dietary stabilization, and then in 22 of the women and 18 of the men after a 6-month weight loss intervention (250–350 kcal/d deficit). Leptin correlated with fat mass in men and women (r=0.75 and r=0.77, respectively; p values<0.0001), but women had 3-fold higher leptin levels for a given fat mass than men (p=0.01). In response to the 6-month hypocaloric diet, men and women lost a similar percentage of fat mass (?13% and ?16%, respectively), but the relative decline in circulating leptin was greater in women than men (-45% and ?21%, respectively; p<0.0001). In addition, when leptin was normalized for fat mass using the ratio method, the decrease in leptin per kilogram of fat mass was greater in women than men (-0.37 ± 0.34 vs. ?0.04 ± 0.06 ng/mL/kg; p<0.01). After weight loss, the change in leptin concentrations correlated positively with the change in fat mass in men (r=0.60; p<0.01), but not in women (r=0.31; p=0.17). Furthermore, the loss in fat mass correlated negatively with baseline leptin levels in women (r=-0.47; p<0.05), but not in men (r=0.03, p=NS). These results indicate that the decline in leptin concentration with weight loss correlates with the loss in fat mass in men; but, in women, other factors affect the decrease in leptin concentration. This suggests that the role of leptin in the regulation of obesity is gender-specific and may account for gender differences in response to hypocaloric treatment and maintenance of lost weight.     

Shorter Telomere Length - A Potential Susceptibility Factor for HIV-Associated Neurocognitive Impairments in South African Woman

The neuropathogenesis of the human immunodeficiency virus (HIV) may manifest as various neurocognitive impairments (NCI). HIV-positive individuals also have significantly shorter telomere length (TL) in peripheral blood mononuclear cells (PBMCs) and CD8+ T cells compared to HIV-negative individuals. Additionally, reduced TL has been found to be associated with chronic psychological stress. This study focused on the effects of HIV-infection and chronic stress associated with childhood trauma on telomere length, and investigated whether leukocyte TL (LTL), in particular, represents a risk factor for NCI. Eighty-three HIV-positive and 45 HIV-negative women were assessed for childhood trauma and were subjected to detailed neurocognitive testing. Blood from each participant was used to extract Deoxyribonucleic acid (DNA). Relative LTL were determined by performing real time quantitative PCR reactions as described by Cawthon et al. (2002). As expected, relative LTL in the HIV-positive individuals was significantly shorter than that of HIV-negative individuals (F = 51.56, p = <0.01). Notably, a significant positive correlation was evident between relative LTL and learning performance in the HIV-positive group. In addition, a significant negative correlation was observed between relative LTL and verbal fluency, but this association was only evident in HIV-positive individuals who had experienced trauma. Our results suggest that reduced LTL is associated with worse learning performance in HIV-positive individuals, indicating that TL could act as a susceptibility factor in increasing neurocognitive decline in HIV-infected individuals.     

ADP核糖基化因子的结构及其功能机制

ADP核糖基化因子(ADP-ribosylation factor,ARF)是Ras基因超家族的成员,它们是大小约20kDa的鸟嘌呤核苷酸结合蛋白。ARF最初发现作为霍乱毒素ADP-核糖转移酶的辅助因子共同作用于G蛋白α亚基,促使其ADP-核糖基化。近来人们发现ARF还参与囊泡运输、调节磷脂酶D的活性,在细胞内物质运输和信号转导过程中具有更加重要的生理功能。现就ARF的发现、分类、结构和功能、表达以及生理功能作一综述。     

Domain Structure of the Prokaryotic Selenocysteine-specific Elongation Factor SelB

Incorporation of the non-canonical amino acid selenocysteine into proteins requires the activity of the elongation factor SelB which substitutes for the function of EF-Tu. In contrast to EF-Tu, SelB binds selenocystylated tRNA^Secand an mRNA secondary structure adjacent to the UGA selenocysteine codon. To gain information on the domain structure of this specialized translation factor, theselBgenes from two bacteria unrelated toEscherichia coli(Clostridium thermoaceticumandDesulfomicrobium baculatum) were cloned and sequenced. The derived amino acid residue sequences were compared to those of SelB fromE. coliandHaemophilus influenzaeand to EF-Tu sequences. The alignment revealed that SelB contains all three domains characterized for EF-Tu. A fourth, C-terminally located domain shows only limited sequence conservation within the four SelB proteins. To elucidate the function of this C-terminal part a structure-function analysis of SelB fromE. coliwas performed. It showed that a C-terminal 17 kDa subdomain of the translation factor, when expressed separately, specifically binds the mRNA secondary structure. The recognition motif itself could be reduced to a 17 nucleotide minihelix without loss of binding affinity and specificity. A truncated SelB lacking the mRNA binding domain was still able to interact with selenocysteyl-tRNA^Sec. Expression of the mRNA binding domain alone suppressed selenocysteine insertionin vivoby competing with SelB for its binding site at the mRNA. The results indicate that SelB can be considered as an EF-Tu homolog hooked to the mRNAviaits C-terminal domain.     

Feasibility and Inter-Rater Reliability of Physical Performance Measures in Acutely Admitted Older Medical Patients

ObjectivePhysical performance measures can be used to predict functional decline and increased dependency in older persons. However, few studies have assessed the feasibility or reliability of such measures in hospitalized older patients. Here we assessed the feasibility and inter-rater reliability of four simple measures of physical performance in acutely admitted older medical patients.DesignDuring the first 24 hours of hospitalization, the following were assessed twice by different raters in 52 (≥ 65 years) patients admitted for acute medical illness: isometric hand grip strength, 4-meter gait speed, 30-s chair stand and Cumulated Ambulation Score. Relative reliability was expressed as weighted kappa for the Cumulated Ambulation Score or as intra-class correlation coefficient (ICC_1,1) and lower limit of the 95%-confidence interval (LL_95%) for grip strength, gait speed, and 30-s chair stand. Absolute reliability was expressed as the standard error of measurement and the smallest real difference as a percentage of their respective means (SEM% and SRD%).ResultsThe primary reasons for admission of the 52 included patients were infectious disease and cardiovascular illness. The mean± SD age was 78±8.3 years, and 73.1% were women. All patients performed grip strength and Cumulated Ambulation Score testing, 81% performed the gait speed test, and 54% completed the 30-s chair stand test (46% were unable to rise without using the armrests). No systematic bias was found between first and second tests or between raters. The weighted kappa for the Cumulated Ambulation Score was 0.76 (0.60–0.92). The ICC1,1 values were as follows: grip strength, 0.95 (LL_95% 0.92); gait speed, 0.92 (LL_95% 0.73), and 30-s chair stand, 0.82 (LL_95% 0.67). The SEM% values for grip strength, gait speed, and 30-s chair stand were 8%, 7%, and 18%, and the SRD_95% values were 22%, 17%, and 49%.ConclusionIn acutely admitted older medical patients, grip strength, gait speed, and the Cumulated Ambulation Score measurements were feasible and showed high inter-rater reliability when administered by different raters. The feasibility and inter-rater reliability of the 30-s chair stand were moderate, complicating the use of the 30-s chair stand in acutely admitted older medical patients. However, the predefined modified version of the chair stand test was both feasible and with high inter-rater reliability in this population.     

Structure and Functions of the Prokaryotic Elongation Factor G

Structural and functional data on elongation factor G (EF-G) are reviewed with regard to nucleotide exchange, GTP hydrolysis, mechanism of action of fusidic acid, and functional roles of the EF-G structural domains in translocation. Biochemical data are correlated with structural dynamics of the EF-G molecule on interaction with various ligands. Data on EF-Tu are also considered, as EF-G and EF-Tu share certain structural and functional features.     

Factor Analysis as a Technique for Exploring Patterned Variability in Archaeological Remains

Abstract

The utility of factor analysis for exploring underlying patterns of variation in a data-set was assessed by means of a factor analytic arrangement of provenience units from the Medicine Crow Site (39BF2), South Dakota, based on similarities in the formal qualities of the ceramic vessels contamed within each provenience. Results indicate that two patterns, interpreted as relating to temporal and spatial variation at Medicine Crow, may be Isolated.     

神经生长因子结构与功能研究进展

神经生长因子(NGF)是神经营养因子家族的典型代表, 它控制着脊椎动物周围和中枢神经系统中部分神经元的发育和存活.NGF的三维结构是以“胱氨酸结”和β折叠为基础,它以二聚体的形式结合细胞表面的受体从而发生生物学效应.参与这些反应的氨基酸残基已通过化学修饰和定点突变法加以确定,这有助于更进一步理解其结构与功能的关系.     

Retinal Thickness and the Structure/Function Relationship in the Eyes of Older Adults with Glaucoma

Glaucoma is common and shows high prevalence in older adults. However, there are few studies on the structure/function relationship in older adults with glaucoma. This prospective, cross-sectional study (conducted between February and August 2014), enrolled 102 eyes of 102 subjects aged over 75 years, including 57 eyes with primary open angle glaucoma (POAG), 15 eyes with pseudoexfoliation glaucoma (PXG), and 30 healthy eyes. Multiple regression analysis was used to determine the correlation of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and macular parameters to mean deviation (MD) to and standard automated perimetry (SAP)-measured sensitivity, assessed with the 30–2 and 10–2 programs. In each 10–2 SAP test point, Spearman’s rank correlation coefficient was used to compare macular retinal nerve fiber layer thickness (mRNFLT), macular ganglion cell-inner plexiform layer thickness (GCIPLT), and mRNFL+GCIPL thickness (GCCT) with sensitivity after adjusting for retinal ganglion cell (RGC) displacement. In eyes with POAG and PXG, cpRNFLT was significantly correlated with 30–2 MD and 30–2 sensitivity. Multiple regression analysis revealed that the POAG had significantly lower cpRNFLT, mRNFLT, GCIPLT, and GCCT according to the severity of disease than control eyes after adjusting for sensitivity, age, sex, and axial length. The PXG eyes had significantly lower cpRNFLT, mRNFLT, and GCCT when compared with the early to moderate POAG eyes. GCCT was significantly correlated with 10–2 sensitivity, except in one juxtafoveal point, (r = 0.338–0.778) in the POAG eyes. The periphery of the central 10° area showed a good correlation between sensitivity and mRNFLT, while the central 5.8° showed a good correlation between sensitivity and GCIPLT. The correlation between structure and function was significant, and objective and quantitative method with OCT assessing glaucoma that does not require patient ability could be a possible parameter to assess diagnosis and progression in older patients with glaucoma.     

Factor Structure Underlying Components of Allostatic Load

Allostatic load is a commonly used metric of health risk based on the hypothesis that recurrent exposure to environmental demands (e.g., stress) engenders a progressive dysregulation of multiple physiological systems. Prominent indicators of response to environmental challenges, such as stress-related hormones, sympatho-vagal balance, or inflammatory cytokines, comprise primary allostatic mediators. Secondary mediators reflect ensuing biological alterations that accumulate over time and confer risk for clinical disease but overlap substantially with a second metric of health risk, the metabolic syndrome. Whether allostatic load mediators covary and thus warrant treatment as a unitary construct remains to be established and, in particular, the relation of allostatic load parameters to the metabolic syndrome requires elucidation. Here, we employ confirmatory factor analysis to test: 1) whether a single common factor underlies variation in physiological systems associated with allostatic load; and 2) whether allostatic load parameters continue to load on a single common factor if a second factor representing the metabolic syndrome is also modeled. Participants were 645 adults from Allegheny County, PA (30–54 years old, 82% non-Hispanic white, 52% female) who were free of confounding medications. Model fitting supported a single, second-order factor underlying variance in the allostatic load components available in this study (metabolic, inflammatory and vagal measures). Further, this common factor reflecting covariation among allostatic load components persisted when a latent factor representing metabolic syndrome facets was conjointly modeled. Overall, this study provides novel evidence that the modeled allostatic load components do share common variance as hypothesized. Moreover, the common variance suggests the existence of statistical coherence above and beyond that attributable to the metabolic syndrome.     

Predicting Cognitive Function from Clinical Measures of Physical Function and Health Status in Older Adults

Introduction

Current research suggests that the neuropathology of dementia—including brain changes leading to memory impairment and cognitive decline—is evident years before the onset of this disease. Older adults with cognitive decline have reduced functional independence and quality of life, and are at greater risk for developing dementia. Therefore, identifying biomarkers that can be easily assessed within the clinical setting and predict cognitive decline is important. Early recognition of cognitive decline could promote timely implementation of preventive strategies.

Methods

We included 89 community-dwelling adults aged 70 years and older in our study, and collected 32 measures of physical function, health status and cognitive function at baseline. We utilized an L1–L2 regularized regression model (elastic net) to identify which of the 32 baseline measures were strongly predictive of cognitive function after one year. We built three linear regression models: 1) based on baseline cognitive function, 2) based on variables consistently selected in every cross-validation loop, and 3) a full model based on all the 32 variables. Each of these models was carefully tested with nested cross-validation.

Results

Our model with the six variables consistently selected in every cross-validation loop had a mean squared prediction error of 7.47. This number was smaller than that of the full model (115.33) and the model with baseline cognitive function (7.98). Our model explained 47% of the variance in cognitive function after one year.

Discussion

We built a parsimonious model based on a selected set of six physical function and health status measures strongly predictive of cognitive function after one year. In addition to reducing the complexity of the model without changing the model significantly, our model with the top variables improved the mean prediction error and R-squared. These six physical function and health status measures can be easily implemented in a clinical setting.     

Serum Levels of Fibroblast Growth Factor 19 Are Inversely Associated with Coronary Artery Disease in Chinese Individuals

Background

The fibroblast growth factor 19 (FGF19) has been implicated in recent studies as a potential regulator of glucose and lipid metabolism, which may lead to atherosclerosis. Here, we investigated the association of FGF19 with the presence and severity of coronary artery disease (CAD) in a Chinese population.

Methods

A total of 315 patients with suspected or established CAD, including 205 males and 110 postmenopausal females, were enrolled and assessed by coronary angiography. CAD severity was determined by the Gensini score. Serum FGF19 was measured by quantitative sandwich ELISA.

Results

FGF19 levels were not significantly different between male and female patients (median [interquartile range], 143.40 [87.96–250.80] vs. 141.60 [87.13–226.32] pg/mL, P = 0.773). CAD patients had lower levels of FGF19 than those without CAD (128.20 [80.62–226.58] vs. 188.00 [105.10–284.70] pg/mL, P = 0.007). FGF19 was negatively correlated with 2hPG (r = –0.150, P = 0.008), FINS (r = –0.169, P = 0.004), HOMA-IR (r = –0.171, P = 0.004), and the Gensini score (r = –0.141, P = 0.012), but positively correlated with HDL-c (r = 0.116, P = 0.041) and adiponectin (r = 0.128, P = 0.024). Moreover, FGF19 was found to be independently correlated with 2hPG (β = –0.146, P = 0.022) and adiponectin (β = 0.154, P = 0.016). After adjusting for other CAD risk factors, FGF19 was demonstrated to be an independent factor for Gensini score (β = –0.140, P = 0.019) and the presence of CAD (β = –1.248, P = 0.036).

Conclusions

Serum FGF19 is associated with the presence and severity of CAD in a Chinese population.     

Uric Acid as a Risk Factor for Cardiovascular Disease and Mortality in Overweight/Obese Individuals

Background

The predictive value of serum uric acid (SUA) for adverse cardiovascular events among obese and overweight patients is not known, but potentially important because of the relation between hyperuricaemia and obesity.

Methods

The relationship between SUA and risk of cardiovascular adverse outcomes (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality, respectively, was evaluated in a post-hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Participants enrolled in SCOUT were obese or overweight with pre-existing diabetes and/or cardiovascular disease (CVD). Cox models were used to assess the role of SUA as an independent risk factor.

Results

9742 subjects were included in the study; 83.6% had diabetes, and 75.1% had CVD. During an average follow-up time of 4.2 years, 1043 subjects had a primary outcome (myocardial infarction, resuscitated cardiac arrest, stroke, or cardiovascular death), and 816 died. In a univariate Cox model, the highest SUA quartile was associated with an increased risk of cardiovascular adverse outcomes compared with the lowest SUA quartile in women (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.20–2.10). In multivariate analyses, adjusting for known cardiovascular risk factors the increased risk for the highest SUA quartile was no longer statistically significant among women (HR: 0.99; 95% CI: 0.72–1.36) nor was it among men. Analyses of all-cause mortality found an interaction between sex and SUA. In a multivariate Cox model including women only, the highest SUA quartile was associated with an increased risk in all-cause mortality compared to the lowest SUA quartile (HR: 1.51; 95% CI: 1.08–2.12). No relationship was observed in men (HR: 1.06; 95% CI: 0.82–1.36).

Conclusion

SUA was not an independent predictor of cardiovascular disease and death in these high-risk overweight/obese people. However, our results suggested that SUA was an independent predictor of all-cause mortality in women.     

Depression as a Risk Factor for Mortality in Individuals with Diabetes: A Meta-Analysis of Prospective Studies

Objective

To quantify the impact of depression measured by self-reports and depression measured by clinical interview on all-cause mortality in individuals with diabetes and to analyze the strength of both associations, the influence of covariates, and possible differences between studies assessing self-rated depressive symptoms and those using a clinical interview to measure depression as predictors of mortality.

Research Design and Methods

PUBMED and PsycINFO were searched up to July 2013 for prospective studies assessing depression, diabetes and mortality. The pooled hazard ratios were calculated using random-effects models.

Results

Sixteen studies met the inclusion criteria. After adjustment for demographic variables depression measured by self-reports was associated with an increased all-cause mortality risk (pooled HR = 2.56, 95% CI 1.89–3.47), and the mortality risk remained high after additional adjustment for diabetes complications (HR = 1.76, 95% CI 1.45–2.14,). Six studies reporting adjusted HRs for depression measured by clinical interviews supported the results of the other models (HR = 1.49, 95% CI 1.15–1.93).

Conclusions

Both depression measured by self-report and depression measured by clinical interview have an unfavorable impact on mortality in individuals with diabetes. The results, however, are limited by the heterogeneity of the primary studies. It remains unclear whether self-reports or clinical interviews for depression are the more precise predictor.