Diabetes and Cognitive Deficits in Chronic Schizophrenia: A Case-Control Study

Cognitive impairment occurs in both schizophrenia and diabetes. There is currently limited understanding whether schizophrenia with diabetes has more serious cognitive deficits than schizophrenia without diabetes or diabetes only. This study assessed cognitive performance in 190 healthy controls, 106 diabetes only, 127 schizophrenia without diabetes and 55 schizophrenia with diabetes. This study was conducted from January 2008 to December 2010. Compared to healthy controls, all patient groups had significantly decreased total and five index RBANS scores (all p<0.01–p<0.001), except for the visuospatial/constructional index. Schizophrenia with diabetes performed worse than schizophrenia without diabetes in immediate memory (p<0.01) and total RBANS scores (<0.05), and showed a trend for decreased attention (p = 0.052) and visuospatial/constructional capacity (p = 0.063). Schizophrenia with diabetes performed worse than diabetes only in immediate memory (p<0.001) and attention (p<0.05), and showed a trend for decreased total RBANS scores (p = 0.069). Regression analysis showed that the RBANS had modest correlations with schizophrenia’ PANSS scores, their duration of current antipsychotic treatment, and diagnosis of diabetes. Schizophrenia with co-morbid diabetes showed more cognitive impairment than schizophrenia without diabetes and diabetes only, especially in immediate memory and attention.     

Regulation of Glucose Metabolism in Thiobacillus intermedius

Glucose-yeast extract or glucose-casein hydrolysate-grown Thiobacillus intermedius cells, which use glucose for energy generation, possess high specific activities of the Entner-Doudoroff pathway and related enzymes, 6-phosphogluconate dehydrase, 2-keto-3-deoxy-6-phosphogluconate aldolase, glucokinase, and glucose-6-phosphate dehydrogenase, but low activities of enzymes unique to the pentose shunt and Embden-Meyerhof pathways. Although the synthesis of the latter enzymes remains largely unaffected by the growth environment, that of the former is stimulated by glucose. Radiorespirometric measurements demonstrate an early and parallel respiration of glucose carbon atoms one and four in glucose-casein hydrolysate broth. It is concluded that the Entner-Doudoroff pathway performs an energetic role in glucose metabolism by T. intermedius with the pentose shunt and Embden-Meyerhof pathways functioning mainly in biosynthesis. The presence of thiosulfate in the growth medium inhibits the synthesis of the Entner-Doudoroff pathway and related enzymes. In addition, both thiosulfate and glucose inhibit the synthesis of the Krebs cycle enzymes, nicotinamide adenine dinucleotide phosphate-linked isocitrate and alpha-ketoglutarate dehydrogenases. Thus, repression of enzymes is of significance in the adaptation of T. intermedius to its nutritional environment. The activity of glucose-6-phosphate dehydrogenase of T. intermedius is inhibited by adenosine triphosphate. Such a control could afford the organism a mechanism to regulate the flow of glucose into major energetic and biosynthetic routes.     

Serum Taurine and Stroke Risk in Women: A Prospective,Nested Case-Control Study

Background

Taurine (2-aminoethanesulfonic acid), a conditionally essential sulfur-containing amino acid, is mainly obtained from diet in humans. Experimental studies have shown that taurine’s main biological actions include bile salt conjugation, blood pressure regulation, anti-oxidation, and anti-inflammation.

Methods

We conducted a prospective case-control study nested in the New York University Women’s Health Study, a cohort study involving 14,274 women enrolled since 1985. Taurine was measured in pre-diagnostic serum samples of 241 stroke cases and 479 matched controls.

Results

There was no statistically significant association between serum taurine and stroke risk in the overall study population. The adjusted ORs for stroke were 1.0 (reference), 0.87 (95% CI, 0.59–1.28), and 1.03 (95% CI, 0.69–1.54) in increasing tertiles of taurine (64.3–126.6, 126.7–152.9, and 153.0–308.5 nmol/mL, respectively). A significant inverse association between serum taurine and stroke risk was observed among never smokers, with an adjusted OR of 0.66 (95% CI, 0.37–1.18) and 0.50 (95% CI, 0.26–0.94) for the second and third tertile, respectively (p for trend = 0.01), but not among past or current smokers (p for interaction < 0.01).

Conclusions

We observed no overall association between serum taurine and stroke risk, although a protective effect was observed in never smokers, which requires further investigation.Taurine, Stroke, Epidemiology, Prospective, Case-control study, NYUWHS.     

Evidence for Central Regulation of Glucose Metabolism

Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K_ATP) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.     

蛋白质精氨酸甲基化修饰在糖代谢调节中的作用

蛋白质精氨酸甲基化是重要的细胞翻译后修饰方式,参与众多生命过程. 精氨酸的甲基化修饰与糖代谢相关疾病如糖尿病、糖耐量异常密切相关. 蛋白质精氨酸甲基化转移酶(protein arginine methyltransferases, PRMTs)活性下降及表达异常是糖代谢疾病的重要发病基础. 目前研究表明,PRMT1、PRMT4、PRMT5在糖代谢调节中均扮演重要角色,与糖代谢关键酶如磷酸烯醇式丙酮酸羧基激酶、葡萄糖6磷酸酶,胰岛素受体 胰岛素受体配体1 磷脂酰肌醇3激酶通道及其它通路密切相关. 给予甲基化抑制剂MTA及siRNA干扰甲基化则可引发糖代谢紊乱,进而诱发糖代谢疾病. 糖尿病药物罗格列酮、氨基胍与蛋白质精氨酸甲基化也有一定联系. 深入研究蛋白质精氨酸甲基化与糖代谢调节之间的联系及机制,可为防治糖代谢疾病及相关并发症提供更多的理论依据.     

Propofol-Induced Sleep: Efficacy and Safety in Patients with Refractory Chronic Primary Insomnia

Insomnia, defined as difficulty in falling asleep and/or staying asleep, short sleep duration, or poor quality sleep, is a common sleep disorder affecting 30-40% of adult population. We have conducted a randomized, double-blind, placebo-controlled study to test if anesthesia is therapeutically beneficial in patients with refractory chronic primary insomnia. We have assessed the efficacy and safety of propofol-induced sleep in these patients. This study comprised of 103 patients with refractory chronic primary insomnia (including 59 non-pregnant, non-lactating women; 28-60 years) and the participants were randomized to receive either physiological saline (placebo) (n = 39) or 3.0 g/l propofol (n = 64) in a 2-h continuous intravenous infusion for five consecutive nights. The Leeds Sleep Evaluation Questionnaire was used for the subjective assessment of sleep, and polysomnography was used for the objective measurement of sleep architecture and patterns. The assessments were done prior to and at the end of the 5-day treatment and 6 months after treatment period. The adverse effects of the treatment were also recorded. A 2-h continuous intravenous infusion of 3.0 g/l propofol for five consecutive nights improved the subjective and objective assessments of sleep in 64 patients with refractory chronic primary insomnia. This improvement occurred immediately after the therapy and persisted for 6 months. No serious adverse events were noticed during the period of drug administration or 6 months after the treatment. Propofol therapy is an efficacious and safe choice for restoring normal sleep in patients with refractory chronic primary insomnia.     

Rosiglitazone Improves Glucose Metabolism in Obese Adolescents With Impaired Glucose Tolerance: A Pilot Study

Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor β‐cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and β‐cell function. In a small randomized, double‐blind, placebo (PLA)‐controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z‐score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z‐score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic‐euglycemic clamp, magnetic resonance imaging, and ¹H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short‐term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and β‐cell function, two principal pathophysiological abnormalities of IGT.     

Chronic Liver Disease and Hepatitis-B Antigen: A Prospective Study

A long-term follow-up of 45 patients with chronic hepatitis and 41 with cirrhosis is reported. Hepatitis-B antigen (HBAg) was present in 19 (42%) of the chronic hepatitis patients and in 20 (49%) of those with cirrhosis. The clinical course and biochemical and histological findings in the HBAg-positive and the HBAg-negative cases were similar, suggesting that HBAg-positive chronic liver disease is not a distinct clinical entity. The presence of antigen and autoantibodies was not found to be mutually exclusive. In HBAg-positive cases antigen tended to persist for months and years. When no irreversible lesions exist disappearance of the antigen may be a sign that the liver disease will resolve.     

Microbial Regulation of Glucose Metabolism and Cell-Cycle Progression in Mammalian Colonocytes

A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, ¹³C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO₂ production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G₁-to-S-phase transition that was rescued by a butyrate-fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells.     

非编码RNA与肝脏糖脂代谢调控

随着经济的迅速发展、人们饮食习惯的改变和身体活动的减少,糖尿病成为了现代社会的非传染性的流行病,给家庭和社会造成了极大的危害和经济负担。其中以全身性胰岛素抵抗及胰岛功能衰竭为主要发病特征的2型糖尿病(type 2 diabetes,T2D)已在世界范围引起广泛关注。T2D的发生发展涉及许多组织及糖代谢的各个环节,遗传因素和环境因素共同引起的糖脂代谢通路任一环节的失调均可导致T2D的发生。近年来,包括microRNA(miRNA)及长非编码RNA(LncRNA)在内的非编码RNA(ncRNA)的发现及其在人体生理和病理生理过程中的重要调控作用不断被揭示,为进一步了解T2D的发病机制注入了新理念和信息。miRNAs及LncRNAs的表达具有组织特异性,其表达水平的异常通常与疾病相关。本文主要对miRNAs和LncRNAs在肝脏糖脂代谢调控及T2D的发生发展中的作用及机制的最新研究进展作简要综述。     

非编码RNA在肿瘤细胞糖代谢中的调控作用

非编码RNA(non-coding RNA,ncRNA)是一类不具有蛋白质编码潜能的RNA,可分为管家ncRNA和调控性ncRNA。微RNA(microRNA,miRNA)是研究得比较清楚的一类调控性ncRNA,不仅可调控细胞分化、增殖和凋亡,还可通过调节糖酵解途径中的限速酶［如己糖激酶(hexokinase,HK)、磷酸果糖激酶(phosphofructokinase, PFK)和丙酮酸激酶(pyruvate kinase, PK)］来调控肿瘤细胞的糖代谢。长链非编码RNA(long non-coding RNA, lncRNA)是另一类近年来引起重视的调控性ncRNA,它们可通过调节癌基因c Myc、葡糖转运蛋白(glucose transporter, GLUT)、HK和缺氧诱导因子等来调控肿瘤细胞的糖代谢。深入了解miRNA和lncRNA等调控性ncRNA调控肿瘤细胞糖代谢的机制不仅可以使我们更加深入地了解肿瘤的发生机制,而且可能为肿瘤的预防、诊断和治疗提供新方向。     

Insomnia,Daytime Sleepiness and Cardio-Cerebrovascular Diseases in the Elderly: A 6-Year Prospective Study

Objective

To examine 1) the associations between history of cardio-cerebrovascular diseases (CVD) and insomnia complaints and excessive daytime sleepiness (EDS), and 2) the relationships between sleep complaints and future CVD in persons over 65.

Methods

CVD was assessed at baseline and during two, four, and six-year follow-up in 5494 non-demented subjects. Self-reported insomnia complaints (poor sleep quality, difficulty in initiating sleep, difficulty in maintening sleep, and early morning awakening), EDS and sleep medication use were evaluated at baseline. Logistic regression models and Cox proportional hazard models, with delayed entry and age of participants as the time scale, were adjusted for socio-demographic, lifestyle and clinical variables.

Results

At baseline, 748 participants had a past-history of CVD. A past-history of CVD was associated with EDS (OR = 1.28 95%CI = [1.05–1.57]) and the number of insomnia complaints (OR = 1.26 95%CI = [1.03–1.55] for 1–2 insomnia complaints; OR = 1.32 95%CI = [1.03–1.71] for ≥3 complaints). In longitudinal analyses, neither the four components of insomnia nor the number of insomnia complaints were significantly associated with first or recurrent CVD events (n = 391 events). EDS was independently associated with future CVD events even after adjusting for prescribed sleep medication and past-history of CVD (HR = 1.35 95%CI = [1.06–1.71]).

Conclusion

Our results suggest that the relationships between sleep complaints and CVD could be complex. Insomnia complaints are more likely a consequence of CVD, whereas EDS appears to be a determinant of CVD independently of past-history of CVD. EDS screening may thus constitute a means of detecting persons at high risk of CVD.     

Diurnal Regulation of Peripheral Glucose Metabolism: Potential Effects of Exercise Timing

Diurnal oscillations in energy metabolism are linked to the activity of biological clocks and contribute to whole‐body glucose homeostasis. Postprandially, skeletal muscle takes up approximately 80% of circulatory glucose and hence is a key organ in maintenance of glucose homeostasis. Dysregulation of molecular clock components in skeletal muscle disrupts whole‐body glucose homeostasis. Next to light‐dark cycles, nonphotic cues such as nutrient intake and physical activity are also potent cues to (re)set (dys)regulated clocks. Physical exercise is one of the most potent ways to improve myocellular insulin sensitivity. Given the role of the biological clock in glucose homeostasis and the power of exercise to improve insulin sensitivity, one can hypothesize that there might be an optimal time for exercise to maximally improve insulin sensitivity and glucose homeostasis. In this review, we aim to summarize the available information related to the interaction of diurnal rhythm, glucose homeostasis, and physical exercise as a nonphotic cue to correct dysregulation of human glucose metabolism.     

脂联素对肝脏糖脂代谢调节作用的研究进展

脂联素因其具有抗糖尿病作用而备受关注,它能控制血糖,并且在肝脏、脂肪和胰腺中能影响脂质代谢。脂联素通过刺激脂肪细胞,对抗炎症、控制脂质过氧化和脂肪分解的速率来调控脂质流入非脂肪组织。肝脏是脂联素发挥作用的重要靶器官;在肝脏中,脂联素与脂联素受体1、2或T-钙黏着蛋白结合,激活下游的AMPK、APPL1、神经酰胺酶等发挥其调节作用。我们总结了脂联素改善肝脏胰岛素敏感性和糖脂代谢的相关机制。     

Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study

BackgroundChronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance.ConclusionsManagement of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD.     

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.     

Etiology and Factors Associated with Pneumonia in Children under 5 Years of Age in Mali: A Prospective Case-Control Study

Background

There are very limited data on children with pneumonia in Mali. The objective was to assess the etiology and factors associated with community-acquired pneumonia in hospitalized children <5 years of age in Mali.

Methods

A prospective hospital-based case-control study was implemented in the Pediatric department of Gabriel Touré University Hospital at Bamako, Mali, between July 2011-December 2012. Cases were children with radiologically-confirmed pneumonia; Controls were hospitalized children without respiratory features, matched for age and period. Respiratory specimens, were collected to identify 19 viruses and 5 bacteria. Whole blood was collected from cases only. Factors associated with pneumonia were assessed by multivariate logistic regression.

Results

Overall, 118 cases and 98 controls were analyzed; 44.1% were female, median age was 11 months. Among pneumonia cases, 30.5% were hypoxemic at admission, mortality was 4.2%. Pneumonia cases differed from the controls regarding clinical signs and symptoms but not in terms of past medical history. Multivariate analysis of nasal swab findings disclosed that S. pneumoniae (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.6–7.0), human metapneumovirus (aOR = 17.2, 95% CI: 2.0–151.4), respiratory syncytial virus [RSV] (aOR = 7.4, 95% CI: 2.3–23.3), and influenza A virus (aOR = 10.7, 95% CI: 1.0–112.2) were associated with pneumonia, independently of patient age, gender, period, and other pathogens. Distribution of S. pneumoniae and RSV differed by season with higher rates of S. pneumoniae in January-June and of RSV in July-September. Pneumococcal serotypes 1 and 5 were more frequent in pneumonia cases than in the controls (P = 0.009, and P = 0.04, respectively).

Conclusions

In this non-PCV population from Mali, pneumonia in children was mainly attributed to S. pneumoniae, RSV, human metapneumovirus, and influenza A virus. Increased pneumococcal conjugate vaccine coverage in children could significantly reduce the burden of pneumonia in sub-Saharan African countries.     

Regulation of Glycogen Metabolism in Primary and Transformed Astrocytes In Vitro

Glycogen metabolism was studied in primary and Herpesvirus-transformed cultures of neonatal rat brain astrocytes. A small fraction of the glucose consumed was conserved in glycogen in both the primary and the transformed astrocytic cell cultures. After addition of culture medium containing 5.5 mM glucose, glycogen increased to maximal levels within 2.5 h, the approximate time at which half of the medium glucose was consumed, and rapidly declined thereafter in both the primary and transformed astrocytic cultures. Maximum levels of glycogen were apparently related to the cell density of the Herpesvirus-transformed cultures, but primary cultures did not show this behavior. At any given cell density, maximal levels of glycogen were dependent on the concentration of extracellular glucose. Administration of glucose caused a transient activation of glycogen synthase alpha and a rapid inactivation of glycogen phosphorylase alpha.