Accuracy of antigen tests for meningococcal meningitis in cerebrospinal fluid: A diagnostic meta-analysis.

OBJECTIVES: Neisseria meningitidis is one of the major pathogens of meningitis in children worldwide and causes invasive meningococcal disease (IMD), which is a critical illness that mainly presents as meningitis and/or septicemia in children. Identification of N. meningitidis in cerebrospinal fluid (CSF) is the gold standard for the diagnosis of meningococcal meningitis, but antigen tests have advantages such as timely results, relatively low cost, and convenience. Yet, the diagnostic accuracy of antigen tests remains uncertain. Therefore, the aim of this meta-analysis was to evaluate the diagnostic accuracy of antigen tests for N. meningitidis in CSF. METHODS: We searched the PubMed, Embase, and Cochrane Library databases for studies evaluating the diagnostic accuracy of antigen tests for N. meningitidis in CSF. We included studies that provided sufficient data to construct a 2 × 2 table on a per-sample basis. To determine the overall sensitivity and specificity of the antigen tests, we used polymerase chain reaction (PCR) as the reference standard and employed the hierarchical summary receiver operating characteristic model. RESULTS: Nine studies with 4533 CSF samples were included. The meta-analysis yielded a pooled sensitivity of 91.2% (95% confidence interval [CI]: 80.0%-100.0%) and a pooled specificity of 93.8% (95% CI: 83.9%-100.0%). A subgroup analysis of 2 studies that reported the outcomes of MeningoSpeed yielded a pooled sensitivity of 93.4% (95% CI: 90.0%-95.8%) and a pooled specificity of 91.9% (95% CI: 88.6%-94.4%). Antigen testing for the N. meningitidis serogroup X had a pooled sensitivity of 92.4% (95% CI: 85.2%-96.2%) and a pooled specificity of 99.2% (95% CI: 78.7%-100.0%). CONCLUSIONS: The studied antigen tests had high sensitivity and specificity for the diagnosis of meningococcal meningitis in CSF specimens. Antigen testing could serve as an accurate diagnostic method for assessing patients who have a suspected N. meningitidis infection.

TRAX Provides Neuroprotection for Huntington's Disease Via Modulating a Novel Subset of MicroRNAs.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by CAG-repeat expansions (>36) in exon 1 of HTT, which dysregulates multiple cellular machineries. Translin-associated protein X (TRAX) is a scaffold protein with diverse functions, including suppressing the microRNA (miRNA)-mediated silencing by degrading pre-miRNA. To date, the role of TRAX in neurodegenerative diseases remains unknown. OBJECTIVES: We delineated the role of TRAX upregulation during HD progression. METHODS: Expression of TRAX in the brains of humans and three mouse models with HD were analyzed by immunohistochemistry staining, western blot, and quantitative reverse transcription-polymerase chain reaction. Adeno-associated viruses harboring TRAX short hairpin RNA were intrastriatally injected into HD mice to downregulate TRAX. HD-like symptoms were analyzed by behavioral and biochemical assessments. The miRNA-sequencing and RNA-sequencing analyses were used to identify the TRAX- regulated miRNA-messenger RNA (mRNA) axis during HD progression. The identified gene targets were validated biochemically in mouse and human striatal cells. RESULTS: We discovered that TRAX was upregulated in the brains of HD patients and three HD mouse models. Downregulation of TRAX enhanced 83 miRNAs (including miR-330-3p, miR-496a-3p) and subsequently changed the corresponding mRNA networks critical for HD pathogenesis (eg, DARPP-32 and brain-derived neurotrophic factor). Disruption of the TRAX-mediated miRNA-mRNA axis accelerated the progression of HD-like symptoms, including the degeneration of motor function, accumulation of mHTT aggregates, and shortened neurite outgrowth. CONCLUSIONS: We demonstrated that TRAX upregulation is authentic and protective in HD. Our study provides a novel layer of regulation for HD pathogenesis and may lead to the development of new therapeutic strategies for HD. © 2022 International Parkinson and Movement Disorder Society.

A PIAS1 Protective Variant S510G Delays polyQ Disease Onset by Modifying Protein Homeostasis.

BACKGROUND: Polyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ-encoding CAG repeats in the disease-causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). OBJECTIVE: We set out to identify common genetic variant(s) that may affect the AO of polyQ diseases. METHODS: Three hundred thirty-seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin-like modifier) ligase for huntingtin (HTT), the protein linked to HD. RESULTS: Biochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than that of PIAS1WT , resulting in lower SUMOylation of mHTT and lower accumulation of insoluble mHTT. Genetic knock-in of PIAS1S510G in a HD mouse model (R6/2) ameliorated several HD-like deficits (including shortened life spans, poor grip strength and motor coordination) and reduced neuronal accumulation of mHTT. CONCLUSIONS: Our findings suggest that PIAS1 is a genetic modifier of polyQ diseases. The naturally occurring variant, PIAS1S510G , is associated with late AO in polyQ disease patients and milder disease severity in HD mice. Our study highlights the possibility of targeting PIAS1 or pathways governing protein homeostasis as a disease-modifying approach for treating patients with HD. © 2021 International Parkinson and Movement Disorder Society.

Predictors of adherence, contamination and dropout in home-based walking by lung and oesophageal cancer patients from two randomised control trials: An exploratory study.

OBJECTIVES: In this study, we examined predictors of exercise adherence, contamination and dropout in lung and oesophageal cancer patients who participated in two randomised controlled trials. METHODS: We used data on 188 lung and oesophageal cancer patients from two previous studies (intervention: moderate-intensity walking for 12 weeks). Baseline measurements included demographic variables, disease characteristics, Hospital Anxiety and Depression Scale and Bouchard 3-day physical activity (PA) record. We used multiple linear and logistic regressions to analyse predictors of exercise adherence in the walking group, contamination in the control group and dropout in both groups. RESULTS: Pre-intervention exercise habits and baseline depression scores predicted adherence, with an explanatory power of 16.7% (p < 0.0001). Pre-intervention exercise habits (odds ratio [OR] 19.65, 95% confidence interval [CI] 2.76-139.97), baseline moderate PA (min/day) (OR 1.03, 95% CI 1.01-1.05) and baseline vigorous PA (min/day) (OR 1.09, 95% CI 1.01-1.18) predicted contamination. Baseline mild PA (10 min/day) (OR 0.94, 95% CI 0.89-0.99) predicted dropout. CONCLUSIONS: Pre-intervention exercise habits and baseline depression levels predicted exercise adherence in the walking group. In the control group, pre-intervention exercise habits and baseline moderate and vigorous PA predicted contamination. Baseline mild PA predicted dropout rates in both groups.

Effect of Guided Imagery Meditation During Laparoscopic Cholecystectomy on Reducing Anxiety: A Randomized Controlled Trial.

BACKGROUND: Up to 90% of patients still experience pain after abdominal surgery, which also affects their physical recovery and psychological anxiety. AIM: To evaluate the effects of guided imagery meditation on ameliorating anxiety, improving the quality of sleep, and relieving postoperative pain in patients after laparoscopic cholecystectomy surgery. METHOD: In the general surgical ward of a teaching hospital, patients were randomly assigned to usual care (n = 34) and guided imagery meditation intervention (n = 34) groups, using the method. The measuring outcomes included their anxiety score, quality of sleep, and pain control. RESULTS: In terms of the anxiety difference, the experimental group scored 0.42 (standard deviation [SD] = 0.97), while the control group scored 4.79 (SD = 7.56), which indicates a statistically significant difference (F = 8.04, p = .01, partial eta2 = 0.11). In terms of quality of sleep, the mean score of the experimental group was 2.67 (SD = 1.96), while the control group scored 7.55 (SD = 3.81), which indicates a significant difference (F = 39.99, p = .001, partial eta2 = 0.39). The mean of the degree of postoperative pain was 2.11 points (SD = 1.39), and the score of the control group was 4.00 points (SD = 1.62), which indicates a significant difference (p = .001). CONCLUSIONS: Guided imagery meditation is a simple, non-invasive, non-pharmacologic intervention measure. It can reduce anxiety and postoperative pain, and improve the quality of sleep. Thus, it should be promoted in clinical practice.

Effect of patient-centred self-management programme on mental health, self-efficacy and self-management of patients with hypertensive nephropathy: A randomised controlled trial.

AIM AND OBJECTIVES: To evaluate the effect of patient-centred self-management programme on mental health, self-efficacy and self-management of patients with hypertensive nephropathy. BACKGROUND: If the symptoms of hypertension are not well-controlled, deterioration of renal function will accelerate and evolve into hypertensive nephropathy. DESIGN: A randomised single-blind trial. This article follows the requirements of CONSORT statement. METHODS: The experimental group (n = 35) after pre-test used patient-centred self-management programme once a week for a total of 4 weeks and the intervention effect was measured after 3 months for post-test. Contrarily, the traditional care was employed for the control group (n = 35). The measuring outcomes included mental health, self-efficacy and self-management. Trial registry is listed under https://clinicaltrials.gov/ with Identifier No. NCT04633993. RESULTS: After the intervention, the average score of mental health for the experimental group was 20.79 (SD = 0.82) which was higher than the 19.27 points for the control group (SD = 0.77) and showed a significant difference (F = 8.31, p = .005, partial eta2  = 0.133). In terms of self-efficacy, the average score for the experimental group was 214.13 (SD = 6.40), which was higher than the 189.58 points for the control group (SD = 6.03) and exhibited a significant difference (F = 11.82, p = .001, partial eta2  = 0.197). Regarding self-management, the average score of the experimental group was 75.12 (SD = 2.29) which was significantly higher than the 68.80 points of the control group (SD = 2.43) (F = 11.17, p = .001, partial eta2  = 0.190). CONCLUSIONS: In addition to promoting mental health of individual cases, this intervention also increases their self-confidence in disease control and improves their self-management on diseases. RELEVANCE TO CLINICAL PRACTICE: The intervention provides an effective option for clinical care workers as a replacement for or supplement to the traditional care.

Degeneration of ipRGCs in Mouse Models of Huntington's Disease Disrupts Non-Image-Forming Behaviors Before Motor Impairment.

Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are photosensitive neurons in the retina and are essential for non-image-forming functions, circadian photoentrainment, and pupillary light reflexes. Five subtypes of ipRGCs (M1-M5) have been identified in mice. Although ipRGCs are spared in several forms of inherited blindness, they are affected in Alzheimer's disease and aging, which are associated with impaired circadian rhythms. Huntington's disease (HD) is an autosomal neurodegenerative disease caused by the expansion of a CAG repeat in the huntingtin gene. In addition to motor function impairment, HD mice also show impaired circadian rhythms and loss of ipRGC. Here, we found that, in HD mouse models (R6/2 and N171-82Q male mice), the expression of melanopsin was reduced before the onset of motor deficits. The expression of retinal T-box brain 2, a transcription factor essential for ipRGCs, was associated with the survival of ipRGCs. The number of M1 ipRGCs in R6/2 male mice was reduced due to apoptosis, whereas non-M1 ipRGCs were relatively resilient to HD progression. Most importantly, the reduced innervations of M1 ipRGCs, which was assessed by X-gal staining in R6/2-OPN4Lacz/+ male mice, contributed to the diminished light-induced c-fos and vasoactive intestinal peptide in the suprachiasmatic nuclei (SCN), which may explain the impaired circadian photoentrainment in HD mice. Collectively, our results show that M1 ipRGCs were susceptible to the toxicity caused by mutant Huntingtin. The resultant impairment of M1 ipRGCs contributed to the early degeneration of the ipRGC-SCN pathway and disrupted circadian regulation during HD progression.SIGNIFICANCE STATEMENT Circadian disruption is a common nonmotor symptom of Huntington's disease (HD). In addition to the molecular defects in the suprachiasmatic nuclei (SCN), the cause of circadian disruption in HD remains to be further explored. We hypothesized that ipRGCs, by integrating light input to the SCN, participate in the circadian regulation in HD mice. We report early reductions in melanopsin in two mouse models of HD, R6/2, and N171-82Q. Suppression of retinal T-box brain 2, a transcription factor essential for ipRGCs, by mutant Huntingtin might mediate the reduced number of ipRGCs. Importantly, M1 ipRGCs showed higher susceptibility than non-M1 ipRGCs in R6/2 mice. The resultant impairment of M1 ipRGCs contributed to the early degeneration of the ipRGC-SCN pathway and the circadian abnormality during HD progression.

Factors affecting mammography screening behaviour among rural Vietnamese women.

OBJECTIVES: To identify factors associated with mammography screening behaviour and its predictors among rural Vietnamese women. METHOD: A predictive correlational study involving 120 women aged ≥ 40 years was conducted in the suburbs of Hanoi, Vietnam, in July 2018 by using Breast Cancer Awareness Measurement and the Champion Health Beliefs Model Scale. Mammography screening behaviour was assessed by asking participants about their previous mammography experience. RESULTS: Only 16.7% of participants had undergone mammography screening. High education levels, high monthly family income, having family members or friends with breast cancer, and receiving physicians' recommendations increased the likelihood of participants screening for breast cancer. Mean scores on perceived susceptibility and perceived barriers differed significantly between participants who had and those who had not undergone screening (t = 4.31; p < .001; t = -5.05; p < .001, respectively). Perceived susceptibility and perceived barriers significantly increased the predictive power of the hierarchical logistic model (critical value = 6.16; [df = 2]; p = .046). Perceived barriers were the most significant predictors of screening behaviour (odds ratio 0.84; 95% CI, 0.71-0.99; p = .039). CONCLUSION: Efforts are necessary to increase mammography awareness in the community and promote screening rates in Vietnam.

Relationships of exercise timing with sleep, fatigue and rest-activity rhythms of lung cancer patients in Taiwan: An exploratory study.

OBJECTIVE: To explore the relationship of exercise timing (exercising close to bedtime, exercising in daylight and maintaining fixed exercise schedule) with sleep quality, fatigue and rest-activity rhythms among lung cancer patients in Taiwan. METHODS: Results from 43 lung cancer patients who were assigned and adhered to the exercise intervention in a 12-week randomised controlled trial were analysed. The MD Anderson Symptom Inventory and Pittsburgh Sleep Quality Index (PSQI) were administered. Actigraphs were used to assess rest-activity rhythms (in-bed less than out-of-bed dichotomy index, I < O) and objective sleep parameters, including total sleep time (TST) and sleep onset latency (SOL). RESULTS: Patients who exercised >4 hr before bedtime had significant improvement in fatigue (p < .0001), sleep quality (p = .012 for PSQI; p = .037 for TST; p = .017 for SOL) and rest-activity rhythms (p = .048 for I < O). Furthermore, patients who exercised with daylight exposure had a significant improvement in fatigue (p = .037) and sleep quality (p = .039 for PSQI). CONCLUSIONS: Exercising >4 hr before bedtime with daylight exposure is associated with improvement in rest-activity rhythms, sleep quality and fatigue in lung cancer patients. The causal relationship requires further investigation with experimental design.

Foot care knowledge, attitudes and practices among patients with diabetic foot and amputation in St. Kitts and Nevis.

About one-third of admissions to the surgical unit annually are diabetes foot infections in need of amputation In St. Kitts and Nevis. However, the risk factors related to diabetes foot and amputation remain unknown. This study investigated factors associated with diabetic foot and amputation (DFA). Retrospective case control study design, and purposive and quota sampling method was used to recruit the participants. Patients with and without DFA were interviewed at two main hospitals, several primary health centres, and a private doctor's office during July and August 2018. Self-development questionnaires were applied to assess patients' demographic, physical and behaviour, foot care knowledge, attitudes, and practices related to DFA. Chi-square, t-test, and multiple logistic regressions were used to analyse the data. A total of 210 patients were evaluated, 89 had DFA, while 121 did not, with a mean age of 61.10 (SD = 11.85). Participants' responses indicated good knowledge, favourable attitudes, and adequate practices related to foot care. The two items of the questionnaire, ways to maintain blood flow in the lower extremities and wash their feet daily, had significant lower score in DFA group. In multiple logistic regression, knowledge, attitudes, and practices related to foot care were not a significant predictor of DFA. Being male was a predictor of DFA than female (OR = 3.53; 95% CI = 1.65-7.57; P < .01). Participants who were currently unemployed were less likely to have DFA than those who were employed (OR = 0.38; 95% Cl = 0.17-0.86; P < .05). Comparing patients with the longest experience of diabetes mellitus (31 years or more) with those who had diabetes for the shortest period of time (between 1 and 10 years) was less likely to have DFA (OR = 0.38; 95% CI = 0.15-0.97; P = <.05). The combination of these independent variables could explain 29% of the variance in DFA. Based on these findings, strategies to prevent diabetic foot and amputation should focus on male and outdoor heavy worker, and longer duration of diabetes patients which are identified in this study.

Targeting ENT1 and adenosine tone for the treatment of Huntington's disease.

Huntington's disease (HD) is caused by an abnormal CAG expansion in the exon 1 of huntingtin gene. The treatment of HD is an unmet medical need. Given the important role of adenosine in modulating brain activity, in this study, levels of adenosine and adenine nucleotides in the cerebral spinal fluid of patients with HD and in the brain of two mouse models of HD (R6/2 and Hdh150Q) were analysed. The expression and activity of ENT1 in the striatum of mice with HD were measured. Targeting adenosine tone for treating HD was examined in R6/2 mice by genetic removal of ENT1 and by giving an ENT1 inhibitor, respectively. The results showed that the adenosine homeostasis is dysregulated in the brain of patients and mice with HD. In patients, the ratio of adenosine/ATP in the cerebral spinal fluid was negatively correlated with the disease duration, and tended to have a positive correlation with independence scale and functional capacity. In comparison to controls, mRNA level of ENT1 was higher in the striatum of R6/2 and Hdh150Q mice. Intrastriatal administration of ENT1 inhibitors increased extracellular level of adenosine in the striatum of R6/2 mice to a much higher level than controls. Chronic inhibition of ENT1 or by genetic removal of ENT1 enhanced the survival of R6/2 mice. Collectively, adenosine homeostasis and ENT1 expression are altered in HD. The inhibition of ENT1 can enhance extracellular adenosine level and be a potential therapeutic approach for treating HD.

Enhanced Na+ -K+ -2Cl- cotransporter 1 underlies motor dysfunction in huntington's disease.

BACKGROUND: Altered γ-aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na-K-2Cl cotransporter-1 is a key molecule that controls γ-aminobutyric acid-ergic signaling. However, the role of Na-K-2Cl cotransporter-1 and efficacy of γ-aminobutyric acid-ergic transmission remain unknown in Huntington's disease. METHODS: We determined the levels of Na-K-2Cl cotransporter-1 in brain tissue from Huntington's disease mice and patients by real-time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin-perforated patch-clamp recordings were used to measure the Eγ-aminobutyric acid in striatal brain slices. To inhibit Na-K-2Cl cotransporter-1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno-associated virus-mediated delivery of Na-K-2Cl cotransporter-1 short-hairpin RNA into the striatum. Motor behavior assays were employed. RESULTS: Expression of Na-K-2Cl cotransporter-1 was elevated in the striatum of R6/2 and Hdh150Q/7Q mouse models. An increase in Na-K-2Cl cotransporter-1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of Eγ-aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na-K-2Cl cotransporter-1 in HD mice. Notably, pharmacological or genetic inhibition of Na-K-2Cl cotransporter-1 rescued the motor deficits of R6/2 mice. CONCLUSIONS: Our findings demonstrate that aberrant γ-aminobutyric acid-ergic signaling and enhanced Na-K-2Cl cotransporter-1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society.

Vaginal microbiome variances in sample groups categorized by clinical criteria of bacterial vaginosis.

BACKGROUND: One of the most common and recurrent vaginal infections is bacterial vaginosis (BV). The diagnosis is based on changes to the "normal" vaginal microbiome; however, the normal microbiome appears to differ according to reproductive status and ethnicity, and even among individuals within these groups. The Amsel criteria and Nugent score test are widely used for diagnosing BV; however, these tests are based on different criteria, and so may indicate distinct changes in the vaginal microbial community. Nevertheless, few studies have compared the results of these test against metagenomics analysis. METHODS: Vaginal flora samples from 77 participants were classified according to the Amsel criteria and Nugent score test. The microbiota composition was analyzed using 16S ribosome RNA gene amplicon sequencing. Bioinformatics analysis and multivariate statistical analysis were used to evaluate the microbial diversity and function. RESULTS: Only 3 % of the participants diagnosed BV negative using the Amsel criteria (A-) were BV-positive according to the Nugent score test (N+), while over half of the BV-positive patients using the Amsel criteria (A+) were BV-negative according to the Nugent score test (N-). Thirteen genera showed significant differences in distribution among BV status defined by BV tests (e.g., A - N-, A + N- and A + N+). Variations in the four most abundant taxa, Lactobacillus, Gardnerella, Prevotella, and Escherichia, were responsible for most of this dissimilarity. Furthermore, vaginal microbial diversity differed significantly among the three groups classified by the Nugent score test (N-, N+, and intermediate flora), but not between the Amsel criteria groups. Numerous predictive microbial functions, such as bacterial chemotaxis and bacterial invasion of epithelial cells, differed significantly among multiple BV test, but not between the A- and A+ groups. CONCLUSIONS: Metagenomics analysis can greatly expand our current understanding of vaginal microbial diversity in health and disease. Metagenomics profiling may also provide more reliable diagnostic criteria for BV testing.

Gut microbiome changes in overweight male adults following bowel preparation.

BACKGROUND: Human gut microbiome has an essential role in human health and disease. Although the major dominant microbiota within individuals have been reported, the change of gut microbiome caused by external factors, such as antibiotic use and bowel cleansing, remains unclear. We conducted this study to investigate the change of gut microbiome in overweight male adults after bowel preparation, where none of the participants had been diagnosed with any systemic diseases. METHODS: A total of 20 overweight, male Taiwanese adults were recruited, and all participants were omnivorous. The participants provided fecal samples and blood samples at three time points: prior to bowel preparation, 7 days after colonoscopy, and 28 days after colonoscopy. The microbiota composition in fecal samples was analyzed using 16S ribosome RNA gene amplicon sequencing. RESULTS: Our results demonstrated that the relative abundance of the most dominant bacteria hardly changed from prior to bowel preparation to 28 days after colonoscopy. Using the ratio of Prevotella to the sum of Prevotella and Bacteroides in the fecal samples at baseline, the participants were separated into two groups. The fecal samples of the Type 1 group was Bacteroides-dominant, and that of the Type 2 group was Prevotella-dominant with a noticeable presence Bacteroides. Bulleidia appears more in the Type 1 fecal samples, while Akkermensia appears more in the Type 2 fecal samples. Of each type, the gut microbial diversity differed slightly among the three collection times. Additionally, the Type 2 fecal microbiota was temporarily susceptible to bowel cleansing. Predictive functional analysis of microbial community reveals that their activities for the mineral absorption metabolism and arachidonic acid metabolism differed significantly between the two types. Depending on their fecal type, the variance of triglycerides and C-reactive protein also differed between the two types of participants. CONCLUSIONS: Depending upon the fecal type, the microbial diversity and the predictive functional modules of microbial community differed significantly after bowel preparation. In addition, blood biochemical markers presented somewhat associated with fecal type. Therefore, our results might provide some insights as to how knowledge of the microbial community could be used to promote health through personalized clinical treatment.

Diversity and enterotype in gut bacterial community of adults in Taiwan.

BACKGROUND: Gastrointestinal microbiota, particularly gut microbiota, is associated with human health. The biodiversity of gut microbiota is affected by ethnicities and environmental factors such as dietary habits or medicine intake, and three enterotypes of the human gut microbiome were announced in 2011. These enterotypes are not significantly correlated with gender, age, or body weight but are influenced by long-term dietary habits. However, to date, only two enterotypes (predominantly consisting of Bacteroides and Prevotella) have shown these characteristics in previous research; the third enterotype remains ambiguous. Understanding the enterotypes can improve the knowledge of the relationship between microbiota and human health. RESULTS: We obtained 181 human fecal samples from adults in Taiwan. Microbiota compositions were analyzed using next-generation sequencing (NGS) technology, which is a culture-independent method of constructing microbial community profiles by sequencing 16S ribosomal DNA (rDNA). In these samples, 17,675,898 sequencing reads were sequenced, and on average, 215 operational taxonomic units (OTUs) were identified for each sample. In this study, the major bacteria in the enterotypes identified from the fecal samples were Bacteroides, Prevotella, and Enterobacteriaceae, and their correlation with dietary habits was confirmed. A microbial interaction network in the gut was observed on the basis of the amount of short-chain fatty acids, pH value of the intestine, and composition of the bacterial community (enterotypes). Finally, a decision tree was derived to provide a predictive model for the three enterotypes. The accuracies of this model in training and independent testing sets were 97.2 and 84.0%, respectively. CONCLUSIONS: We used NGS technology to characterize the microbiota and constructed a predictive model. The most significant finding was that Enterobacteriaceae, the predominant subtype, could be a new subtype of enterotypes in the Asian population.

Activation of AMP-activated protein kinase α1 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis.

TAR DNA-binding protein-43 (TDP-43) is a nuclear RNA-binding protein involved in many cellular pathways. TDP-43-positive inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). The major clinical presentation of ALS is muscle weakness due to the degeneration of motor neurons. Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early event of ALS. In this study, we demonstrate that cytoplasmic mislocalization of TDP-43 was accompanied by increased activation of AMP-activated protein kinase (AMPK) in motor neurons of ALS patients. The activation of AMPK in a motor neuron cell line (NSC34) or mouse spinal cords induced the mislocalization of TDP-43, recapitulating this characteristic of ALS. Down-regulation of AMPK-α1 or exogenous expression of a dominant-negative AMPK-α1 mutant reduced TDP-43 mislocalization. Suppression of AMPK activity using cAMP-simulating agents rescued the mislocalization of TDP-43 in NSC34 cells and delayed disease progression in TDP-43 transgenic mice. Our findings demonstrate that activation of AMPK-α1 plays a critical role in TDP-43 mislocalization and the development of ALS; thus, AMPK-α1 may be a potential drug target for this devastating disease.

Altered behavioral responses to gamma-aminobutyric acid pharmacological agents in a mouse model of Huntington's disease.

BACKGROUND: Disruptions in gamma-aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease. METHODS: We treated wild-type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABAA receptors) and monitored their locomotor activity. The expression levels of GABAA receptors and a major neuron-specific chloride extruder (potassium-chloride cotransporter-2) were analyzed by real-time quantitative polymerase chain reaction, Western blot, and immunocytochemistry. RESULTS: The R6/2 mice were less sensitive to the sedative effects of both drugs, suggesting reduced function of GABAA receptors. Consistently, the expression levels of α1/α2 and δ subunits were lower in the cortex and striatum of R6/2 mice. Similar results were also found in 2 other mouse models of Huntington's disease and in Huntington's disease patients. Moreover, the interaction and expression levels of potassium-chloride cotransporter-2 and its activator (brain-type creatine kinase) were decreased in Huntington's disease neurons. These findings collectively suggest impaired chloride homeostasis, which further dampens GABAA receptor-mediated inhibitory signaling in Huntington's disease brains. CONCLUSIONS: The dysregulated GABAergic responses and altered expression levels of GABAA receptors and potassium-chloride cotransporter-2 in Huntington's disease mice appear to be authentic and may contribute to the clinical manifestations of Huntington's disease patients. © 2017 International Parkinson and Movement Disorder Society.

Inhibition of soluble tumor necrosis factor is therapeutic in Huntington's disease.

Neuroinflammation is a common feature of many neurodegenerative diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disease caused by an expanded CAG repeat in exon 1 of the huntingtin (HTT) gene. Previous studies demonstrated that levels of several proinflammatory cytokines, including tumor necrosis factor (TNF)-α, were higher in the plasma and brain tissues of mice and patients with HD, suggesting that inflammation may contribute to HD progression. To evaluate the pathological role of TNF-α in HD pathogenesis, we blocked TNF-α signaling using a dominant negative inhibitor of soluble TNF-α (XPro1595). XPro1595 effectively suppressed the inflammatory responses of primary astrocytes-enriched culture isolated from a transgenic mouse model (R6/2) and human astrocytes-enriched culture derived from induced pluripotent stem cells (iPSCs) of HD patients evoked by lipopolysaccharide and cytokines, respectively. Moreover, XPro1595 protected the cytokine-induced toxicity of primary R6/2 neurons and human neurons derived from iPSCs of HD patients. To assess the beneficial effect of XPro1595 in vivo, an intracerebroventricular (i.c.v.) infusion was provided with an osmotic minipump. ELISA analyses showed that i.c.v. infusion of XPro1595 decreased elevated levels of TNFα in the cortex and striatum, improved motor function, reduced caspase activation, diminished the amount of mutant HTT aggregates, increased neuronal density and decreased gliosis in brains of R6/2 mice. Moreover, reducing the peripheral inflammatory response by a systemic injection of XPro1595 improved the impaired motor function of R6/2 mice but did not affect caspase activation. Collectively, our findings suggest that an effective and selective anti-inflammatory treatment targeting the abnormal brain inflammatory response is a potential therapeutic strategy for HD.

Effect of walking on circadian rhythms and sleep quality of patients with lung cancer: a randomised controlled trial.

BACKGROUND: Sleep disturbances and poor rest-activity rhythms, which can reduce the quality of life, are highly prevalent among patients with lung cancer. METHODS: This trial investigated the effects of a 12-week exercise intervention including home-based walking exercise training and weekly exercise counseling on 111 lung cancer patients. Participants were randomly allocated to receive the intervention or usual-care. Outcomes included objective sleep (total sleep time, TST; sleep efficiency, SE; sleep onset latency, SOL; and wake after sleep onset, WASO), subjective sleep (Pittsburgh Sleep Quality Index, PSQI), and rest-activity rhythms (r24 and I

Aberrant astrocytes impair vascular reactivity in Huntington disease.

OBJECTIVE: Huntington disease (HD) is an inherited neurodegenerative disease caused by the mutant huntingtin gene (mHTT), which harbors expanded CAG repeats. We previously reported that the brain vessel density is higher in mice and patients with HD than in controls. The present study determines whether vascular function is altered in HD and characterizes the underlying mechanism. METHODS: The brain vessel density and vascular reactivity (VR) to carbogen challenge of HD mice were monitored by 3D ΔR2 -mMRA and blood oxygenation level-dependent (BOLD)/flow-sensitive alternating inversion recovery (FAIR) magnetic resonance imaging (MRI), respectively. The amount of vascular endothelial growth factor (VEGF)-A and the pericyte coverage were determined by immunohistochemistry and enzyme-linked immunosorbent assay in human and mouse brain sections, primary mouse astrocytes and pericytes, and human astrocytes derived from induced pluripotent stem cells. RESULTS: Expression of mHTT in astrocytes and neurons is sufficient to increase the brain vessel density in HD mice. BOLD and FAIR MRI revealed gradually impaired VR to carbogen in HD mice. Astrocytes from HD mice and patients contained more VEGF-A, which triggers proliferation of endothelial cells and may be responsible for the augmented neurovascular changes. Moreover, an astrocytic inflammatory response, which reduces the survival of pericytes through an IκB kinase-dependent pathway, mediates the low pericyte coverage of blood vessels in HD brains. INTERPRETATION: Our findings suggest that the inflammation-prone HD astrocytes provide less pericyte coverage by promoting angiogenesis and reducing the number of pericytes and that these changes can explain the inferior VR in HD mice. The resultant impaired VR might hinder cerebral hemodynamics and increase brain atrophy during HD progression.