Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness.

Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis revealed a predominant decrease in expression of genes linked to mitochondrial and oxidative metabolism in DKO versus WT muscles. DKO muscles exhibit marked repression of oxidative enzymatic capacity, as well as mitochondrial number and size compared to WT muscles. Mitochondrial function is also impaired in single myofibers isolated from DKO versus WT muscles. In addition, mutant muscles exhibit reduced angiogenic gene expression and decreased capillarity. Consequently, DKO mice have a significantly reduced exercise capacity, further reflected in poor fatigue resistance of DKO mice in in vivo contraction assays. These results show that ERRα and ERRγ together are a critical link between muscle aerobic capacity and exercise tolerance. The ERRα/γ mutant mice could be valuable for understanding the long-term impact of impaired mitochondria and vascular supply on the pathogenesis of muscle-linked disorders.

The dorsal hippocampal protein targeting to glycogen maintains ionotropic glutamate receptor subunits expression and contributes to working and short-term memories in mice.

Brain glycogen metabolism is known to be involved in the learning and memory processes. Protein targeting to glycogen (PTG) is a crucial molecule for glycogenesis, and its expression level is shown to be increased in the dorsal hippocampus during fear memory acquisition and recall, suggesting that PTG may contribute to the memory process. However, its detailed role in the dorsal hippocampus remains unclear. Therefore, we knocked down the expression of PTG in the dorsal hippocampus and attempted to analyze its function behaviorally. PTG expression was found to be enriched in astrocytes. Furthermore, short hairpin RNA against PTG suppressed the expression of PTG in astrocytes. Mice with knockdown of PTG in the dorsal hippocampus showed suppressed alternation behavior in the Y-maze test and reduced memory recall at the first hour after acquisition in the passive avoidance test. Knockdown of mouse dorsal hippocampal astrocyte-specific PTG also impaired working memory in the Y-maze test. GluR1, GluR2, and NR2a subunits expressions were significantly down-regulated in the dorsal hippocampus of mice in which PTG was knocked down. These results indicate that PTG in the dorsal hippocampal astrocytes may contribute to working and short-term memories by maintaining the expression of glutamate receptor subunits.

Carotane sesquiterpenes from Peperomia pellucida and their anti-infective activities.

Owing to the challenges of antimicrobial resistance, investigations of new antibiotics from medicinal plants are continuously being conducted. Peperomia pellucida is a pantropical plant used in traditional medicine for the treatment of various disorders. From the ethanol extract of a whole P. pellucida plant, one previously undescribed carotane sesquiterpene (pellucarotine), one known carotane sesquiterpene (daucol), and one phenylpropanoid (dillapiol) were isolated and structurally elucidated. Their structures were determined based on 1D and 2D NMR, HR-ESI-Mass, experimental, and computational electronic circular dichroism spectroscopic data and compared with those reported in the literature. Antimicrobial assay results showed that pellucarotine had an anti-infective effect on Candida albicans with an MIC of 512 µg/mL.

Recurrent paradoxical cerebral embolism caused by a thrombus entrapped in a patent foramen ovale: a case report.

Introduction: A thrombus straddling the patent foramen ovale (PFO) is a very rare clinical entity. Optimal management remains unclear due to the availability of various therapeutic options; thus, an individualized approach is recommended. Case presentation: The authors describe a case presenting with recurrent cerebral embolism and a large and mobile thrombus straddled in the PFO. Historically, cardiac surgery, thrombolysis or anticoagulation were possible management options for this patient. However, there are no guidelines on what the optimal treatment is. Our patient was a poor surgical candidate because of advanced age and multiple comorbidities. Furthermore, she had a recent ischaemic stroke which was a relative contraindication to thrombolysis. After consulting the Heart Team, medical treatment alone with systemic anticoagulation was administered. Subsequent transthoracic echocardiography (TTE) after 1 week showed complete thrombus resolution. After 4 months, the PFO was successfully occluded with an Amplatzer device. The patient received rehabilitation therapy and had good functional recovery. Clinical discussion: Anticoagulant therapy alone was chosen because of high risk for surgery. Complete thrombus resolution was achieved after 1 week although the initial thrombus size was quite large. Nevertheless, this approach may not be applicable to every patient. In addition to TTE, multimodality imaging using transesophageal echocardiography and cardiac magnetic resonance is helpful to identify the mechanism of stroke, which in our case is a thrombus-straddled PFO, and to make early treatment decisions. Serial TTEs help assess the response to anticoagulation. An individualized approach should be made with a multidisciplinary Heart Team. Conclusion: Echocardiography plays an important role in the diagnosis and treatment evaluation for patients with a thrombus straddling a PFO. An individualized approach to manage the patient should be made with a multidisciplinary Heart Team.

Cost-Effectiveness of Ticagrelor Compared with Clopidogrel in Patients with Acute Coronary Syndrome from Vietnamese Healthcare Payers' Perspective.

INTRODUCTION: The PLATelet inhibition and patient Outcomes (PLATO) trial (NCT00391872) demonstrated that ticagrelor compared to clopidogrel significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke in patients with acute coronary syndrome (ACS). The aim of this study is to analyze the long-term cost-effectiveness of ticagrelor compared to clopidogrel in ACS patients from a Vietnamese healthcare payers' perspective. METHODS: A two-part cost-effectiveness model was developed to estimate long-term costs and quality-adjusted life-years (QALY). Cardiovascular event rates, hospital bed days, interventions, investigations, study drug utilization and EuroQol 5 Dimension (EQ-5D) data were derived from the PLATO trial. Unit costs of medical services were derived from the Vietnamese governmental price list, and drug costs were based on the weighted average price from the Vietnamese social security report (in VND; 10.000 VND = 0.405 USD). An annual discount rate of 3% was used. Probabilistic and deterministic sensitivity analyses were conducted to evaluate uncertainty of the results. RESULTS: Ticagrelor was associated with an incremental cost of VND 5.34 million (USD 216.49) and a QALY gain of 0.11. This resulted in a cost per QALY gained of VND 49.58 million (USD 2009.96) from the Vietnamese healthcare payers' perspective. Probabilistic sensitivity analysis indicates that ticagrelor has 59% probability of being cost-effective compared with clopidogrel when using a willingness-to-pay threshold of one gross domestic products (GDP) per capita. Deterministic sensitivity analysis using clinical outcomes from the Asian sub-population of PLATO resulted in a cost per QALY of VND 42.25 million (USD 1712.80). CONCLUSION: Ticagrelor can be considered a cost-effective treatment for ACS compared with clopidogrel from a Vietnamese healthcare payers' perspective.

Evaluation of urinary L-FABP as an early marker for diabetic nephropathy in type 2 diabetic patients.

BACKGROUND: Albuminuria is the standard biomarker for the diagnosis of diabetic nephropathy (DN). However, some patients with persistent microalbuminuria still progress to chronic kidney disease, raising the question of finding a better biomarker. This study aimed to evaluate the correlation of urinary liver-type fatty acid-binding protein (L-FABP) levels with renal function and to compare the role of urinary albumin-to-creatinine ratio (ACR) with urinary L-FABP in early detection of DN in type 2 diabetic patients. METHODS: The cross-sectional study was done on 106 type 2 diabetic patients and 30 non-diabetic people. L-FABP was measured with the Latex enhanced immunoturbidimetric technique. RESULTS: There was a strong and negative correlation between the urine L-FABP levels and eGFR (r = -0.606, p<0.001). The urinary L-FABP levels were significantly higher (p<0.001) in the normoalbuminuria diabetic group than the non-diabetic control group. The ROC-curve analyses in the diabetic patients and the normoalbuminuria diabetic patients showed that the AUCL-FABP was remarkably higher (p<0.001) than the AUCACR. An optimal cutoff value of 5 mg L-FABP/g Cr (with the sensitivity of 98.1% and specificity of 90%) and of 4.3 mg L-FABP/g Cr (with the sensitivity of 100% and specificity of 86.67%) was set to detect DN in the diabetic patients and the normoalbuminuria diabetic patients, respectively. CONCLUSIONS: The change in urinary L-FABP levels happened earlier than in urinary albumin during renal function impairment. Urinary L-FABP can be used as a better indicator than ACR for early detection of DN in type 2 diabetes.

Metabolic Reprogramming by c-MET Inhibition as a Targetable Vulnerability in Glioblastoma.

The elucidation of better treatments for solid tumors and especially malignant glial tumors is a priority. Better understanding of the molecular underpinnings of treatment response and resistance are critical determinants in the success for this endeavor. Recently, a battery of novel tools have surfaced that allow to interrogate tumor cell metabolism to more precise extent than this was possible in the earlier days. At the forefront of these developments are the extracellular flux and carbon tracing analyses. Through utilization of these techniques our group made the recent observation that acute and chronic c-MET inhibition drives fatty acid oxidation that in turn can be therapeutically targeted for drug combination therapies. Herein, we summarize and comment on some of our key findings related to this study.

Association Between Serum 25-Hydroxyvitamin D Concentrations and Chronic Pain: Effects of Drinking Habits.

PURPOSE: Although the explanation for inconsistencies in the reported association between serum 25-hydroxyvitamin D [25(OH)D] levels and chronic pain (CP) has not yet been determined, understanding this discrepancy is necessary for the development of vitamin D supplementation as an effective treatment for CP. The aim of this cross-sectional study was to examine the relationship between 25(OH)D concentrations and CP according to drinking habits in Japanese subjects. PATIENTS AND METHODS: We distributed invitation letters to 2314 individuals older than 40 years in Shika town, a rural area in Japan, and 724 subjects (386 females; mean age: 63.9 ± 10.4 years) were recruited. CP was defined as persistent pain lasting at least 3 months in any part of the body. Serum concentrations of 25(OH)D, a biomarker of the vitamin D status, were measured using a radioimmunoassay. A serum 25(OH)D level <20 ng/mL was defined as serum 25(OH)D deficiency. Drinking habits were assessed using a self-administered questionnaire. There were three choices, "rarely drink", "sometimes" and "everyday". Respondents who answered "rarely drink" were labelled as non-drinkers and the others as drinkers. RESULTS: The prevalence of CP was 40.6%. A significant interaction between CP and drinking habits on 25(OH)D concentrations was observed (p = 0.098). A one-way analysis of covariance was performed to compare 25(OH)D concentrations between the subjects with and without CP in each drinking group, and the serum 25(OH)D levels of subjects with CP were significantly lower than those without CP among drinkers (p = 0.007). A logistic regression analysis revealed a correlation between serum 25(OH)D deficiency and CP in drinkers after adjustments for several confounding factors (odds ratio: 0.499; 95% confidence interval: 0.268 - 0.927; p = 0.028). CONCLUSION: The present results suggest that low serum 25(OH)D concentrations are associated with the development of CP in drinkers.

Social and behavioral determinants of attitudes towards and practices of hepatitis B vaccine birth dose in Vietnam.

BACKGROUND: Hepatitis B virus (HBV) infection is a significant public health issue in Vietnam. Our goal was to understand the determinants of attitudes towards and practices of hepatitis B vaccine birth dose (HepB-BD) in certain regions of Vietnam. METHOD: A rapid qualitative assessment was conducted in three geographically diverse provinces that reported low coverage (<50%) of HepB-BD. Using purposive sampling of participants, 29 focus group discussions and 20 in-depth interviews were held with caregivers (n = 96), healthcare providers (n = 75), and healthcare administrators (n = 16). Summary notes from these were translated, and inductive coding was used to derive themes. The SAGE Vaccine Hesitancy Determinants Matrix was used as a theoretical framework to organize barriers and facilitators associated with the themes into three levels of influence. RESULTS: At the individual and group level, caregivers who had higher levels of knowledge about HepB-BD sought the vaccine proactively, while others with lower knowledge faced barriers to the vaccine. Some caregivers reported a negative attitude toward health services because of a language barrier or had generalized concerns about HepB-BD due to media reporting of the past adverse events. Distress arising from potential adverse events was equally common among healthcare providers. At the contextual level, the physical environment made it difficult for caregivers to access healthcare facilities and for providers to conduct outreach. Home births posed a challenge for timely administration of HepB-BD, while health facility births facilitated it. Vaccination-specific barriers included misinterpretation of pre-vaccination screening criteria and asking for the consent of caregivers. Inadequate resources for service delivery negatively influenced HepB-BD attitudes and practices. CONCLUSION: Given the diversity of barriers associated with attitudes towards and practices of HepB-BD in the three provinces, tailored interventions will be necessary for both demand- and supply-side factors. Rural areas, often with more home births and geographic barriers, may require focused attention.

Characterization of chitosan/alginate/lovastatin nanoparticles and investigation of their toxic effects in vitro and in vivo.

In this study, chitosan and alginate were selected to prepare alginate/chitosan nanoparticles to load the drug lovastatin by the ionic gelation method. The synthesized nanoparticles loaded with drug were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), laser scattering and differential scanning calorimetry (DSC) methods. The FTIR spectrum of the alginate/chitosan/lovastatin nanoparticles showed that chitosan and alginate interacted with lovastatin through hydrogen bonding and dipolar-dipolar interactions between the C-O, C=O, and OH groups in lovastatin, the C-O, NH, and OH groups in chitosan and the C-O, C=O, and OH groups in alginate. The laser scattering results and SEM images indicated that the alginate/chitosan/lovastatin nanoparticles have a spherical shape with a particle size in the range of 50-80 nm. The DSC diagrams displayed that the melting temperature of the alginate/chitosan/lovastatin nanoparticles was higher than that of chitosan and lower than that of alginate. This result means that the alginate and chitosan interact together, so that the nanoparticles have a larger crystal degree when compared with alginate and chitosan individually. Investigations of the in vitro lovastatin release from the alginate/chitosan/lovastatin nanoparticles under different conditions, including different alginate/chitosan ratios, different solution pH values and different lovastatin contents, were carried out by ultraviolet-visible spectroscopy. The rate of drug release from the nanoparticles is proportional to the increase in the solution pH and inversely proportional to the content of the loaded lovastatin. The drug release process is divided into two stages: a rapid stage over the first 10 hr, then the release becomes gradual and stable. The Korsmeyer-Peppas model is most suitable for the lovastatin release process from the alginate/chitosan/lovastatin nanoparticles in the first stage, and then the drug release complies with other models depending on solution pH in the slow release stage. In addition, the toxicity of alginate/chitosan/lovastatin (abbreviated ACL) nanoparticles was sufficiently low in mice in the acute toxicity test. The LD50 of the drug was higher than 5000 mg/kg, while in the subchronic toxicity test with treatments of 100 mg/kg and 300 mg/kg ACL nanoparticles, there were no abnormal signs, mortality, or toxicity in general to the function or structure of the crucial organs. The results show that the ACL nanoparticles are safe in mice and that these composite nanoparticles might be useful as a new drug carrier.

Food knowledge of patients at the first access to a Diabetology center. / Conoscenze alimentari in pazienti afferenti ad un centro di diabetologia

Il diabete rappresenta una patologia in costante aumento: familiarità, età e stili di vita rappresentano i principali fattori di rischio per questa malattia e per le complicanze ad essa correlate. Considerando l'importanza del regime alimentare per la prevenzione e il trattamento di questa patologia, scopo del presente studio è stato quello di valutare le conoscenze alimentari di pazienti al primo accesso presso un centro di Diabetologia e di indagare sulla loro eventuale influenza su alcuni parametri ematici. È stato somministrato il questionario di Moynihan. La relazione tra i punteggi ottenuti e le variabili emoglobina glicata, BMI, glicemia a digiuno, è stata analizzata attraverso regressione multipla basata sul metodo dei minimi quadrati ordinari (modello OLS). Il response rate è stato del 73,3%. Il punteggio medio totale ottenuto dal questionario è stato di 23,61 ed è stata osservata una correlazione statisticamente significativa (p<0,0473) tra i migliori punteggi del questionario e i valori di Hb1Ac. Questo studio è il primo passo di un'indagine più ampia che verrà condotta nell'ottica di promuovere una formazione del paziente volta a verificare nel tempo le ricadute positive sulle scelte alimentari e sui parametri clinici.

Association between Lower Intake of Minerals and Depressive Symptoms among Elderly Japanese Women but Not Men: Findings from Shika Study.

The aim of this cross-sectional study was to examine the relationship of mineral intake, including sodium, potassium, calcium, magnesium, phosphorus, iron, zinc, copper and manganese, with depressive symptoms in both genders in the Japanese elderly population. A total of 1423 participants who were older than 65 years old were recruited in this study. Mineral intake was analyzed using a validated and brief self-administered diet history questionnaire. Depressive symptoms were assessed with a short version of the Geriatric Depression Scale. A logistic regression model was applied to determine the relationship between mineral intake and depressive symptoms. The prevalence of depressive symptoms was 20%. Except for sodium and manganese, mineral intake was significantly lower in the depressive symptoms group. There was no difference of mineral intake between male participants with depressive symptoms and those without such symptoms. However, in female participants, mineral intake was significantly lower in participants with depressive symptoms compared to those without such symptoms. Potassium, calcium, magnesium, phosphorus, iron, zinc, and copper were significantly and negatively correlated with depressive symptoms among female participants, but not male participants. Our results suggest that the deficiencies in mineral intake may be related to depressive symptoms, especially in women.

Relationship between the Intake of n-3 Polyunsaturated Fatty Acids and Depressive Symptoms in Elderly Japanese People: Differences According to Sex and Weight Status.

n-3 polyunsaturated fatty acids (PUFAs) have been shown to have preventive effects against depression. In this study, we aimed to investigate the associations between the intake of n-3 PUFAs and depression among people according to sex and weight status. We utilized cross-sectional data from the Shika study in Japan. The study was conducted between 2013 and 2016. Data were collected from adults older than 65 years. Invitation letters were distributed to 2677 individuals, 2470 of whom participated in the study (92.3%). We assessed depressive states using the Japanese short version of the Geriatric Depression Scale (GDS-15). We assessed the intake of n-3 PUFAs using the validated food frequency questionnaire. One thousand six hundred thirty-three participants provided data, among which 327 (20.0%) exhibited depressive symptoms. When we performed the stratified analysis by sex and weight status, there were significant inverse relationships between total n-3 PUFAs, individual n-3 PUFAs, and n-3/n-6 PUFAs ratio and depressive symptoms in overweight/obese females. No correlations were observed between n-3 PUFAs intake and depressive states in males. The results demonstrated a relationship between n-3 PUFAs deficiencies and depressive states, particularly in overweight/obese females. Dietary modifications may help to prevent depressive symptoms in overweight/obese females.

Knowledge and Determinants of Health Consequences of Cigarette Smoking Among Vietnamese Adults, 2015.

Background. Vietnam was one of 16 countries that implemented the second round of the GATS (Global Adult Tobacco Survey) in 2015. Aims. To assess knowledge and determinants of health consequences of different types of cigarette smoking among Vietnamese adults. Methods. A cross-sectional study among adults aged 15 years combined with using 15% of the master sample from the national sampling frame of the population and housing census was conducted. Multilevel analysis using Poisson regression was undertaken. Results. Knowledge on the health consequences of cigarette smoking has not significantly improved in the GATS-2015. Adults believe that active smoking had more of an impact on health than secondhand smoking and 24.5% and 43% of them answered that smoking light and e-cigarettes, respectively, causes less harm than regular cigarettes, and 17.3% and 18.1% of adults are not aware of the difference between them, respectively. Conclusion. Household and community's role had little impact in the adult knowledge of smoking health consequences. It is necessary to disseminate information on the "other tobacco product" and to improve public knowledge on specific health consequences, to enhance household and community's role in conveying health education messages to individuals.

Relationship between Dietary n-6 Fatty Acid Intake and Hypertension: Effect of Glycated Hemoglobin Levels.

The relationship between dietary n-6 fatty acids and hypertension is not clear. The metabolic products of n-6 fatty acids include those that control blood pressure, such as prostaglandin and thromboxane, and that differ depending on the extent of glucose tolerance. This cross-sectional study investigated the association of dietary n-6 fatty acid intake on hypertension, and the effects of glycated hemoglobin (HbA1c) value in 633 Japanese subjects aged 40 years and older. Dietary intake was measured using a validated brief self-administered diet history questionnaire. We defined hypertension as the use of antihypertensive medication or a blood pressure of 140/90 mmHg. The prevalence of hypertension was 55.3%. A high n-6 fatty acids intake inversely correlated with hypertension in subjects with HbA1c values less than 6.5% (odds ratio, 0.857; 95% confidence interval, 0.744 to 0.987). On the contrary, in subjects with an HbA1c value of 6.5% or higher, the n-6 fatty acids intake was significantly associated with hypertension (odds ratio, 3.618; 95% confidence interval, 1.019 to 12.84). Regular dietary n-6 fatty acid intake may contribute to the prevention and treatment of hypertension in a healthy general population. By contrast, in subjects with diabetes, regular n-6 fatty acids intake may increase the risk of hypertension.

Diagnostic accuracy of microscopic Observation Drug Susceptibility (MODS) assay for pediatric tuberculosis in Hanoi, Vietnam.

INTRODUCTION: Microscopic [corrected] Observation Drug Susceptibility (MODS) has been shown to be an effective and rapid technique for early diagnosis of tuberculosis (TB). Thus far only a limited number of studies evaluating MODS have been performed in children and in extra-pulmonary tuberculosis. This study aims to assess relative accuracy and time to positive culture of MODS for TB diagnosis in children admitted to a general pediatric hospital in Vietnam. METHODS/PRINCIPAL FINDINGS: Specimens from children with suspected TB were tested by smear, MODS and Lowenstein-Jensen agar (LJ). 1129 samples from 705 children were analyzed, including sputum (n=59), gastric aspirate (n=775), CSF (n=148), pleural fluid (n=33), BAL (n=41), tracheal fluid (n=45), other (n=28). 113 TB cases were defined based on the "clinical diagnosis" (confirmed and probable groups) as the reference standard, in which 26% (n=30) were diagnosed as extra-pulmonary TB. Analysis by patient shows that the overall sensitivity and specificity of smear, LJ and MODS against "clinical diagnosis" was 8.8% and 100%, 38.9% and 100%, 46% and 99.5% respectively with MODS significantly more sensitive than LJ culture (P=0.02). When analyzed by sample type, the sensitivity of MODS was significantly higher than LJ for gastric aspirates (P=0.004). The time to detection was also significantly shorter for MODS than LJ (7 days versus 32 days, P<0.001). CONCLUSION: MODS [corrected] is a sensitive and rapid culture technique for detecting TB in children. As MODS culture can be performed at a BSL2 facility and is inexpensive, it can therefore be recommended as a routine test for children with symptoms suggestive of TB in resource-limited settings.