Poor Sleep in Patients with Multiple Sclerosis

Background

Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). Sleep may be influenced by MS-related symptoms and adverse effects from immunotherapy and symptomatic medications. We aimed to study the prevalence of poor sleep and the influence of socio-demographic and clinical factors on sleep quality in MS- patients.

Methods

A total of 90 MS patients and 108 sex-and age- matched controls were included in a questionnaire survey. Sleep complaints were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a global PSQI score was used to separate good sleepers (≤5) from poor sleepers (>5). Excessive daytime sleepiness, the use of immunotherapy and antidepressant drugs, symptoms of pain, depression, fatigue and MS-specific health related quality of life were registered. Results were compared between patients and controls and between good and poor sleepers among MS patients.

Results

MS patients reported a higher mean global PSQI score than controls (8.6 vs. 6.3, p = 0.001), and 67.1% of the MS patients compared to 43.9% of the controls (p = 0.002) were poor sleepers. Pain (p = 0.02), fatigue (p = 0.001), depression (p = 0.01) and female gender (p = 0.04) were associated with sleep disturbance. Multivariate analyses showed that female gender (p = 0.02), use of immunotherapy (p = 005) and a high psychological burden of MS (p = 0.001) were associated with poor sleep among MS patients.

Conclusions

Poor sleep is common in patients with MS. Early identification and treatment of modifiable risk factors may improve sleep and quality of life in MS.     

Altered Plasma Apolipoprotein Modifications in Patients with Pancreatic Cancer: Protein Characterization and Multi-Institutional Validation

Background

Among the more common human malignancies, invasive ductal carcinoma of the pancreas has the worst prognosis. The poor outcome seems to be attributable to difficulty in early detection.

Methods

We compared the plasma protein profiles of 112 pancreatic cancer patients with those of 103 sex- and age-matched healthy controls (Cohort 1) using a newly developed matrix-assisted laser desorption/ionization (oMALDI) QqTOF (quadrupole time-of-flight) mass spectrometry (MS) system.

Results

We found that hemi-truncated apolipoprotein AII dimer (ApoAII-2; 17252 m/z), unglycosylated apolipoprotein CIII (ApoCIII-0; 8766 m/z), and their summed value were significantly decreased in the pancreatic cancer patients [P = 1.36×10⁻²¹, P = 4.35×10⁻¹⁴, and P = 1.83×10⁻²⁴ (Mann-Whitney U-test); area-under-curve values of 0.877, 0.798, and 0.903, respectively]. The significance was further validated in a total of 1099 plasma/serum samples, consisting of 2 retrospective cohorts [Cohort 2 (n = 103) and Cohort 3 (n = 163)] and a prospective cohort [Cohort 4 (n = 833)] collected from 8 medical institutions in Japan and Germany.

Conclusions

We have constructed a robust quantitative MS profiling system and used it to validate alterations of modified apolipoproteins in multiple cohorts of patients with pancreatic cancer.     

Susceptibility to Declarative Memory Interference is Pronounced in Primary Insomnia

Sleep has been shown to stabilize memory traces and to protect against competing interference in both the procedural and declarative memory domain. Here, we focused on an interference learning paradigm by testing patients with primary insomnia (N = 27) and healthy control subjects (N = 21). In two separate experimental nights with full polysomnography it was revealed that after morning interference procedural memory performance (using a finger tapping task) was not impaired in insomnia patients while declarative memory (word pair association) was decreased following interference. More specifically, we demonstrate robust associations of central sleep spindles (in N3) with motor memory susceptibility to interference as well as (cortically more widespread) fast spindle associations with declarative memory susceptibility. In general the results suggest that insufficient sleep quality does not necessarily show up in worse overnight consolidation in insomnia but may only become evident (in the declarative memory domain) when interference is imposed.     

Timing and Intensity of Light Correlate with Body Weight in Adults

Light exposure can influence sleep and circadian timing, both of which have been shown to influence weight regulation. The goal of this study was to evaluate the relationship between ambient light, sleep and body mass index. Participants included 54 individuals (26 males, mean age 30.6, SD = 11.7 years). Light levels, sleep midpoint and duration were measured with wrist actigraphy (Actiwatch-L) for 7 days. BMI was derived from self-reported height and weight. Caloric intake was determined from 7 days of food logs. For each participant, light and activity data were output in 2 minute epochs, smoothed using a 5 point (10 minute) moving average and then aggregated over 24 hours. The mean light timing above 500 lux (MLiT⁵⁰⁰) was defined as the average clock time of all aggregated data points above 500 lux. MLiT⁵⁰⁰ was positively correlated with BMI (r = 0.51, p<0.001), and midpoint of sleep (r = 0.47, p<0.01). In a multivariable linear regression model including MLiT⁵⁰⁰ and midpoint of sleep, MLiT⁵⁰⁰ was a significant predictor of BMI (B = 1.26 SE = 0.34, β = 0.53 p = 0.001, r ² _Δ = 0.22). Adjusting for covariates, MLiT⁵⁰⁰ remained an independent predictor of BMI (B = 1.28 SE = 0.36, β = 0.54, p = 0.002, r ² _Δ = 0.20). The full model accounted for 34.7% of the variance in BMI (p = 0.01). Exposure to moderate levels of light at biologically appropriate times can influence weight, independent of sleep timing and duration.     

Prevalence and Risk Factors of Poor Sleep Quality among Chinese Elderly in an Urban Community: Results from the Shanghai Aging Study

Background

Sleep disorders causes a significant negative effect on mental and physical health, particularly among the elderly. The disease burden and risk factors of poor sleep quality of the elderly need to be verified using a validated form of measurement in urban mainland China.

Methods

This study included 1086 community residents aged ≥60 years who completed the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). Poor sleeper was defined by a CPSQI global score of >5. Subjects also accepted the neurological and neuropsychological assessments, including the Mini-Mental State Examination, Center for Epidemiological Studies Depression Scale, and Zung Self-Rating Anxiety Scale (ZSAS). A history of chronic diseases was confirmed by the medical records of each participant.

Results

The prevalence of poor sleep quality in this population was 41.5% (95% confidence interval (CI) = 38.6–44.5%), with a higher rate observed in elderly females (45.8% [95% CI = 41.9–49.7%]) than that in elderly males (35.8% [95% CI = 31.4–40.1%]). The prevalence rate increased with age, from 32.1% (95% CI = 27.8–36.4%) in those aged 60–69 years to 52.5% (95% CI = 45.9–59.1%) in those aged ≥80 years (p value for trend<0.001). Multivariate logistic regression analysis indicated that age (OR = 1.03[95% CI = 1.01–1.05], p<0.001), less education duration (OR = 1.04 [95% CI = 1.01–1.08, p = 0.014), living alone (OR = 1.62 [95% CI = 1.02–2.58], p = 0.04), anxiety (ZSAS score: OR = 1.09 [95% CI = 1.05–1.12], p<0.001), number of chronic disease (OR = 1.18 [95% CI = 1.07–1.30], p = 0.14) and arthritis (OR = 1.45[95% CI = 1.05–2.01], p = 0.025) were risk factors of poor sleep quality.

Conclusions

Poor sleep quality is highly prevalent among elderly Chinese residents in urban Shanghai. Growing attention and comprehensive countermeasures involving psycho-social and personal activities might alleviate the sleep problem in the elderly.     

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     

Sleep Disturbances and Health-Related Quality of Life in Adults with Steady-State Bronchiectasis

Background

Sleep disturbances are common in patients with chronic lung diseases, but little is known about the prevalence in patients with bronchiectasis. A cross sectional study was conducted to investigate the prevalence and determinants associated with sleep disturbances, and the correlation between sleep disturbances and quality of life (QoL) in adults with steady-state bronchiectasis.

Methods

One hundred and forty-four bronchiectasis patients and eighty healthy subjects were enrolled. Sleep disturbances, daytime sleepiness, and QoL were measured by utilizing the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and St. George Respiratory Questionnaire (SGRQ), respectively. Demographic, clinical indices, radiology, spirometry, bacteriology, anxiety and depression were also assessed.

Results

Adults with steady-state bronchiectasis had a higher prevalence of sleep disturbances (PSQI>5) (57% vs. 29%, P<0.001), but not daytime sleepiness (ESS≥10) (32% vs. 30%, P = 0.76), compared with healthy subjects. In the multivariate model, determinants associated with sleep disturbances in bronchiectasis patients included depression (OR, 10.09; 95% CI, 3.46–29.37; P<0.001), nocturnal cough (OR, 1.89; 95% CI, 1.13–3.18; P = 0.016), aging (OR, 1.04; 95% CI, 1.01–1.07; P = 0.009) and increased 24-hour sputum volume (OR, 2.01; 95% CI, 1.22–3.33; P = 0.006). Patients with sleep disturbances had more significantly impaired QoL affecting all domains than those without. Only 6.2% of patients reported using a sleep medication at least weekly.

Conclusions

In adults with steady-state bronchiectasis, sleep disturbances are more common than in healthy subjects and are related to poorer QoL. Determinants associated with sleep disturbances include depression, aging, nighttime cough and increased sputum volume. Assessment and intervention of sleep disturbances are warranted and may improve QoL.     

Impaired Glucose Tolerance in Sleep Disorders

Background

Recent epidemiological and experimental data suggest a negative influence of shortened or disturbed night sleep on glucose tolerance. Due to the high prevalence of sleep disorders this might be a major health issue. However, no comparative studies of carbohydrate metabolism have been conducted in clinical sleep disorders.

Methodology/Principal Findings

We performed oral glucose tolerance tests (OGTT) and assessed additional parameters of carbohydrate metabolism in patients suffering from obstructive sleep apnea syndrome (OSAS, N = 25), restless legs syndrome (RLS, N = 18) or primary insomnia (N = 21), and in healthy controls (N = 33). Compared to controls, increased rates of impaired glucose tolerance were found in OSAS (OR: 4.9) and RLS (OR: 4.7) patients, but not in primary insomnia patients (OR: 1.6). In addition, HbA1c values were significantly increased in the same two patient groups. Significant positive correlations were found between 2-h plasma glucose values measured during the OGTT and the apnea-arousal-index in OSAS (r = 0.56; p<0.05) and the periodic leg movement-arousal-index in RLS (r = 0.56, p<0.05), respectively. Sleep duration and other quantitative aspects of sleep were similar between patient groups.

Conclusions/Significance

Our findings suggest that some, but not all sleep disorders considerably compromise glucose metabolism. Repeated arousals during sleep might be a pivotal causative factor deserving further experimental investigations to reveal potential novel targets for the prevention of metabolic diseases.     

Sleepiness,Long Distance Commuting and Night Work as Predictors of Driving Performance

Few studies have examined the effect of working night shift and long distance commuting. We examined the association between several sleep related and demographic variables, commuting distance, night work and use of mobile phones on driving performance. We used a prospective design to recruit participants and conducted a telephone survey (n = 649). The survey collected demographic and journey details, work and sleep history and driving performance concerning the day the participant was recruited. Participants also completed the Karolinska Sleepiness Scale and the Epworth Sleepiness Scale. Night workers reported significantly more sleepiness, shorter sleep duration and commuting longer distances. Seven variables were significant predictors of lane crossing. The strongest predictor was acute sleepiness (OR = 5.25, CI, 1.42–19.49, p<0.01) followed by driving ≥150 kms (OR = 3.61, CI, 1.66–7.81, p<0.001), obtaining less than 10 hours sleep in the previous 48 hours (OR = 2.58, CI, 1.03–6.46, p<0.05), driving after night shift (OR = 2.19, CI, 1.24–3.88, p<0.001), being <43 years old (OR = 1.95, CI, 1.11–3.41, p<0.05) and using mobile phones during the journey (OR = 1.90, CI, 1.10–3.27, p<0.05). Sleep related variables, long-distance commuting and night work have a major impact on lane crossing. Several interventions should be considered to reduce the level of sleepiness in night workers.     

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description,Validation of Severity Scale,and Exploration of BMI Effects on Disease Course

Objectives

To assess the potential of an online platform, PatientsLikeMe.com (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform.

Methods

First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM’s patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure.

Results

Compared with 4,039 MS Center patients, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center patients revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between patient and physician scores. Additionally, there were good correlations between the patient-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course.

Conclusions

The PLM population is comparable to a clinic population, and its patient-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting.     

Associations between Rice,Noodle, and Bread Intake and Sleep Quality in Japanese Men and Women

Background

Previous studies have shown that a diet with a high-glycemic index is associated with good sleep quality. Therefore, we investigated the association of sleep quality with the intake of 3 common starchy foods with different glycemic indexes–rice, bread, and noodles–as well as the dietary glycemic index in a Japanese population.

Methods

The participants were 1,848 men and women between 20 and 60 years of age. Rice, bread, and noodle consumption was evaluated using a self-administered diet history questionnaire. Sleep quality was evaluated by using the Japanese version of the Pittsburgh Sleep Quality Index, and a global score >5.5 was considered to indicate poor sleep.

Results

Multivariate-adjusted odds ratios (95% confidence intervals) for poor sleep across the quintiles of rice consumption were 1.00 (reference), 0.68 (0.49–0.93), 0.61 (0.43–0.85), 0.59 (0.42–0.85), and 0.54 (0.37–0.81) (p for trend = 0.015); those for the quintiles of noodle consumption were 1.00 (reference), 1.25 (0.90–1.74), 1.05 (0.75–1.47), 1.31 (0.94–1.82), and 1.82 (1.31–2.51) (p for trend = 0.002). Bread intake was not associated with sleep quality. A higher dietary glycemic index was significantly associated with a lower risk of poor sleep (p for trend = 0.020).

Conclusion

A high dietary glycemic index and high rice consumption are significantly associated with good sleep in Japanese men and women, whereas bread intake is not associated with sleep quality and noodle consumption is associated with poor sleep. The different associations of these starchy foods with sleep quality might be attributable to the different glycemic index of each food.     

Iterative Structure-Based Peptide-Like Inhibitor Design against the Botulinum Neurotoxin Serotype A

The botulinum neurotoxin serotype A light chain (BoNT/A LC) protease is the catalytic component responsible for the neuroparalysis that is characteristic of the disease state botulism. Three related peptide-like molecules (PLMs) were designed using previous information from co-crystal structures, synthesized, and assayed for in vitro inhibition against BoNT/A LC. Our results indicate these PLMS are competitive inhibitors of the BoNT/A LC protease and their K_i values are in the nM-range. A co-crystal structure for one of these inhibitors was determined and reveals that the PLM, in accord with the goals of our design strategy, simultaneously involves both ionic interactions via its P1 residue and hydrophobic contacts by means of an aromatic group in the P2′ position. The PLM adopts a helical conformation similar to previously determined co-crystal structures of PLMs, although there are also major differences to these other structures such as contacts with specific BoNT/A LC residues. Our structure further demonstrates the remarkable plasticity of the substrate binding cleft of the BoNT/A LC protease and provides a paradigm for iterative structure-based design and development of BoNT/A LC inhibitors.     

Shift Work Disorder in a Random Population Sample – Prevalence and Comorbidities

Few studies have investigated the presence of shift work disorder (SWD) in the general community. We addressed many of the limitations in this literature and present new findings. SWD has been treated as an ‘all or none’ construct but we propose the need to consider the ‘severity’ of the disorder. Using random digit dialling, we randomly recruited 1163 participants. Participants completed an extensive battery of scales and questions concerning work, health and individual differences. Three questions based on the criteria from the International Classification for Sleep Disorders were used to categorise participants with SWD (n = 176). In addition, we asked participants whether SWD interfered with aspects of their life and high ratings were used to define severe shift work disorder (SSWD). The prevalence of SWD was 32.1% among night workers and 10.1% in day workers (p<.001). SSWD was present in 9.1% of night workers and 1.3% of day workers (p<.001). Adjusted logistic regression analyses found significant associations between SWD and night work (OR  = 3.35, CI 2.19-5.12), weekly work hours (OR  = 1.02, CI 1.00–1.04), short sleep (≤6 h; OR  = 2.93, CI 1.94–4.41), languidity (OR  = 1.11, CI 1.06–1.16) and resilience (OR  = 0.56, CI 0.43–0.81). Night work, short sleep, languidity, and hypertension were significantly associated with SSWD. Overall, participants with SSWD slept 0.80 h less than other participants (p<.001). Night work, short sleep and languidity were associated with both SWD and SSWD. Day workers with SWD symptoms reported significantly shorter sleep duration, higher levels of languidity and worked longer working hours compared to day workers without SWD.     

Genome-Wide Association Analyses for Fatty Acid Composition in Porcine Muscle and Abdominal Fat Tissues

Fatty acid composition is an important phenotypic trait in pigs as it affects nutritional, technical and sensory quality of pork. Here, we reported a genome-wide association study (GWAS) for fatty acid composition in the longissimus muscle and abdominal fat tissues of 591 White Duroc×Erhualian F₂ animals and in muscle samples of 282 Chinese Sutai pigs. A total of 46 loci surpassing the suggestive significance level were identified on 15 pig chromosomes (SSC) for 12 fatty acids, revealing the complex genetic architecture of fatty acid composition in pigs. Of the 46 loci, 15 on SSC5, 7, 14 and 16 reached the genome-wide significance level. The two most significant SNPs were ss131535508 (P = 2.48×10⁻²⁵) at 41.39 Mb on SSC16 for C20∶0 in abdominal fat and ss478935891 (P = 3.29×10⁻¹³) at 121.31 Mb on SSC14 for muscle C18∶0. A meta-analysis of GWAS identified 4 novel loci and enhanced the association strength at 6 loci compared to those evidenced in a single population, suggesting the presence of common underlying variants. The longissimus muscle and abdominal fat showed consistent association profiles at most of the identified loci and distinct association signals at several loci. All loci have specific effects on fatty acid composition, except for two loci on SSC4 and SSC7 affecting multiple fatness traits. Several promising candidate genes were found in the neighboring regions of the lead SNPs at the genome-wide significant loci, such as SCD for C18∶0 and C16∶1 on SSC14 and ELOVL7 for C20∶0 on SSC16. The findings provide insights into the molecular basis of fatty acid composition in pigs, and would benefit the final identification of the underlying mutations.     

Deficient Beta-Mannosylation of Candida albicans Phospholipomannan Affects the Proinflammatory Response in Macrophages

Candida albicans produces a complex glycosphingolipid called phospholipomannan (PLM), which is present on the cell-wall surface of yeast and shed upon contact with host cells. The glycan moiety of PLM is composed of β-mannosides with degrees of polymerization up to 19 in C. albicans serotype A. PLM from serotype B strains displays a twofold decrease in the length of the glycan chains. In this study we compared the proinflammatory activities of PLMs purified from C. albicans serotype A and serotype B strains and from a bmt6Δ mutant of C. albicans, whose PLM is composed of short truncated oligomannosidic chain. We found that PLMs activate caspase-1 in murine macrophage cell line J774 independent of the glycan chain length although IL-1β secretion is more intense with long glycan chain. None of the tested PLMs stimulate ROS production, indicating that caspase-1 activation may occur through a ROS-independent pathway. On the other hand, only long-chain oligomannosides present on PLM from serotype A strain (PLM-A) are able to induce TNF-α production in macrophages, a property that is not affect by blocking endocytosis through latrunculin A treatment. Finally, we demonstrate that soluble and not cell surface-bound galectin-3, is able to potentiate PLM-A-induced TNF-α production in macrophages. PLMs from C. albicans serotype B and from bmt6∆ mutant are not able to induce TNF-α production and galectin-3 pretreatment does not interfere with this result. In conclusion, we show here that PLMs are able to evoke a proinflammatory state in macrophage, which is in part dependent on their glycosylation status. Long-glycan chains favor interaction with soluble galectin-3 and help amplify inflammatory response.     

Genetic manipulation of the biosynthetic process leading to phoslactomycins, potent protein phosphatase 2A inhibitors

Phoslactomycins (PLMs) represent an unusual structural class of natural products secreted by various streptomycetes, containing an α,β-unsaturated δ-lactone, an amino group, phosphate ester, conjugated diene and a cyclohexane ring. Phosphazomycins, phospholines and leustroducsins contain the same structural moieties, varying only in the acyl substituent at the C-18 hydroxyl position. These compounds possess either antifungal or antitumor activities or both. The antitumor activity of the PLM class of compounds has been attributed to a potent and selective inhibition of protein phosphatase 2A (PP2A). The cysteine-269 residue of PP2Ac-subunit has been shown to be the site of covalent modification by PLMs. In this article, we review previous work on the isolation, structure elucidation and biological activities of PLMs and related compounds and current status of our work on both PLM stability and genetic manipulation of the biosynthetic process. Our work has shown that PLM B is surprisingly stable in solution, with a pH optimum of 6. Preliminary biosynthetic studies utilizing isotopically labeled shikimic acid and cyclohexanecarboxylic acid (CHC) suggested PLM B to be a polyketide-type antibiotic synthesized using CHC as a starter unit. Using a gene (chcA) from a set of CHC-CoA biosynthesis genes from Streptomyces collinus as a probe, a 75 kb region of 29 ORFs encoding PLM biosynthesis was located in the genome of Streptomyces sp. strain HK803. Analysis and subsequent manipulation of plmS ₂ and plmR ₂ in the gene cluster has allowed for rational engineering of a strain that produces only one PLM analog, PLM B, at ninefold higher titers than the wild type strain. A strain producing PLM G (the penultimate intermediate in PLMs biosynthesis) has also been generated. Current work is aimed at selective in vitro acylation of PLM G with various carboxylic acids and a precursor-directed biosynthesis in a chcA deletion mutant with the aim of generating novel PLM analogs.     

Longer Sleep – Slimmer Kids: The ENERGY-Project

Background

Few studies have differentiated between weekday and weekend day sleep duration in their association with indicators of weight status in children. Therefore, we examined the association of week and weekend day sleep duration with indicators of body composition in 10–12 year old European school children.

Methods and Findings

Multi-level linear regression analysis was performed to examine the association between parent-reported week and weekend day sleep duration and objectively assessed child BMI and WC, adjusting for socio-demographic variables and energy balanced related behaviours EBRBs (i.e. dietary, physical and sedentary behaviour). Compared to sleeping 10 hrs/night or more, sleeping on average less than 10 hrs/night during weekdays was associated with higher BMI (for example, B = 0.86 and CI = [0.27;1.45] when sleeping ≤7 hrs) and WC (for example, B = 1.99 and CI = [0.32;3.65] when sleeping ≤7 hrs). Sleeping 9 hrs/night during weekend days, but not ≤8 hrs, was associated with higher WC (B = 0.66; CI = [0.04;1.28]) compared to sleeping more than 10 hrs/night. Average (week and weekend) sleep duration less than 10 hrs/night was associated with higher values for BMI (B = 0.98; CI = [0.24;1.73] and WC (B = 2.35; CI = [0.08;4.31]).

Conclusions

Weekday sleep duration seems more strongly associated with body composition in European school children than weekend day sleep duration. Promoting adequate sleep duration may contribute to healthy weight in children.     

Sleep Deprivation Impairs Consolidation of Cued Fear Memory in Rats

Post-learning sleep facilitates negative memory consolidation and also helps preserve it over several years. It is believed, therefore, that sleep deprivation may help prevent consolidation of fearful memory. Its effect, however, on consolidation of negative/frightening memories is not known. Cued fear-conditioning (CuFC) is a widely used model to understand the neural basis of negative memory associated with anxiety disorders. In this study, we first determined the suitable circadian timing for consolidation of CuFC memory and changes in sleep architecture after CuFC. Thereafter, we studied the effect of sleep deprivation on CuFC memory consolidation. Three sets of experiments were performed in male Wistar rat (n = 51). In experiment-I, animals were conditioned to cued-fear by presenting ten tone-shock paired stimuli during lights-on (7 AM) (n = 9) and lights-off (7 PM) (n = 9) periods. In experiment-II, animals were prepared for polysomnographic recording (n = 8) and changes in sleep architecture after CuFC was determined. Further in experiment-III, animals were cued fear-conditioned during the lights-off period and were randomly divided into four groups: Sleep-Deprived (SD) (n = 9), Non-Sleep Deprived (NSD) (n = 9), Stress Control (SC) (n = 9) and Tone Control (n = 7). Percent freezing amount, a hallmark of fear, was compared statistically in these groups. Rats trained during the lights-off period exhibited significantly more freezing compared to lights-on period. In CuFC trained animals, total sleep amount did not change, however, REM sleep decreased significantly. Further, out of total sleep time, animals spent proportionately more time in NREM sleep. Nevertheless, SD animals exhibited significantly less freezing compared to NSD and SC groups. These data suggest that sleep plays an important role in the consolidation of cued fear-conditioned memory.     

FGFR1OP tagSNP but Not CCR6 Polymorphisms Are Associated with Vogt-Koyanagi-Harada Syndrome in Chinese Han

Background

Polymorphisms of the CC chemokine receptor 6 (CCR6) and FGFR10P tagSNP (locus close to CCR6) at 6q27 have recently been reported to be associated with the susceptibility to several immune-related diseases. This study was designed to determine the association of CCR6 and FGFR10P (tag)SNPs with Vogt-Koyanagi-Harada (VKH) syndrome, an autoimmune disease directed against melanocytes, in two independent Chinese Han populations.

Methodology/Principal Findings

A total of 601 VKH patients and 725 healthy controls from two Chinese Han populations were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Hardy-Weinberg equilibrium was tested using the χ² test. Genotype frequencies were estimated by direct counting. Allele and genotype frequencies were compared between patients and controls using the χ² test. The frequency of the A allele of rs2301436 was significantly higher both in Cohort 1 and Cohort 2 as compared with two separate controls (P = 0.044; P = 0.049, respectively). The significance was lost after Bonferroni correction in both cohorts (Pc = 0.516; Pc = 0.392, respectively). The frequency of the A allele was significantly higher in the combined patient group as compared with all controls before and after Bonferroni correction (P = 0.005, Pc = 0.025). The genotype and allele frequencies of rs3093024, rs6902119, rs3093023 and rs968334 were not different between patients with VKH and healthy controls based on analysis either for both cohorts or for the patients and controls in total. Analysis according to extra ocular clinical findings including headache, alopecia and poliosis, vitiligo and tinnitus did not show any association of the five polymorphisms with these parameters.

Conclusion

These results suggest that the rs2301436 tagSNP of FGFR10P is positively associated with susceptibility to VKH syndrome in the tested Chinese Han populations. No association was found for the tested CCR6 SNPs.