Targeting the nuclear long noncoding transcript LSP1P5 abrogates extracellular matrix deposition by trans-upregulating CEBPA in keloids.

Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global health care burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort. Therapeutically, the attenuation of LSP1P5 significantly decreased the expression of ECM markers (COL1, COL3, and FN1) both in vitro and in vivo. Intriguingly, an antifibrotic gene, CCAAT enhancer binding protein alpha (CEBPA), is a functional downstream candidate of LSP1P5. Mechanistically, LSP1P5 represses CEBPA expression by hijacking Suppressor of Zeste 12 to the promoter of CEBPA, thereby enhancing the polycomb repressive complex 2-mediated H3K27me3 and changing the chromosomal opening status of CEBPA. Taken together, these findings indicate that targeting LSP1P5 abrogates fibrosis in keloids through epigenetic regulation of CEBPA, revealing a novel antifibrotic therapeutic strategy that bridges our current understanding of lncRNA regulation, histone modification and ECM remodeling in keloids.

Routine single-incision laparoscopic common bile duct exploration with concomitant cholecystectomy for elderly patients: a 6-year retrospective comparative study.

BACKGROUND: While single-incision laparoscopic cholecystectomy (SILC) has gained more popularity in recent years, its application to elderly patients needs further evaluation. Few SILC studies regarded this rapidly growing vulnerable population, and single-incision laparoscopic common bile duct exploration (SILCBDE) was never mentioned. We conducted an observational study of 146 routine SILCBDE to address this issue. METHODS: One hundred forty-six consecutive patients underwent SILCBDE with concomitant cholecystectomies during a period of 6 years (July 2012-June 2016 and July 2018-July 2020). Forty patients with an age of 65 years or older were the study target. Characteristics and operative outcomes were compared with the remaining 106 younger patients by retrospective chart review. The primary outcomes include complications and mortality, while the secondary outcomes contain intraoperative blood loss, operative time, procedural conversions, postoperative length of hospital stay, and bile duct stone recurrence. RESULTS: There was no mortality. The bile duct stone clearance rate was 98.6%. The elderly group had higher American Society of Anesthesiologists (ASA) scores, higher comorbidity rate, higher acute cholangitis rate, lower completion intraoperative cholangiography (IOC) rate, longer operative time, more blood loss, longer postoperative hospital stay (p < .001), longer total hospital stay (p < .001), higher procedural conversion rate (p < .05), higher complication rate (p < .001), and the exclusive open conversion (2.5%). The difference in complications derived from Clavien-Dindo grade I. CONCLUSION: Routine SILCBDE with concomitant cholecystectomy by experienced surgeons is safe and efficacious for elderly patients as for younger patients. Randomized controlled trials are anticipated.

Large-scale fabrication of structurally coloured cellulose nanocrystal films and effect pigments.

Cellulose nanocrystals are renewable plant-based colloidal particles capable of forming photonic films by solvent-evaporation-driven self-assembly. So far, the cellulose nanocrystal self-assembly process has been studied only at a small scale, neglecting the limitations and challenges posed by the continuous deposition processes that are required to exploit this sustainable material in an industrial context. Here, we addressed these limitations by using roll-to-roll deposition to produce large-area photonic films, which required optimization of the formulation of the cellulose nanocrystal suspension and the deposition and drying conditions. Furthermore, we showed how metre-long structurally coloured films can be processed into effect pigments and glitters that are dispersible, even in water-based formulations. These promising effect pigments are an industrially relevant cellulose-based alternative to current products that are either micro-polluting (for example, non-biodegradable microplastic glitters) or based on carcinogenic, unsustainable or unethically sourced compounds (for example, titania or mica).

Inhibition of pathogenic bacterial carbonic anhydrases by monothiocarbamates.

Carbonic anhydrases (CAs) from the pathogenic bacteria Nesseria gonorrhoeae and vancomycin-resistant enterococci (VRE) have recently been validated as antibacterial drug targets. Here we explored the inhibition of the α-CA from N. gonorrhoeae (α-NgCA), of α- and γ-class enzymes from Enterococcus faecium (α-EfCA and γ-EfCA) with a panel of aliphatic, heterocyclic and aryl-alkyl primary/secondary monothiocarbamates (MTCs). α-NgCA was inhibited in vitro with KIs ranging from 0.367 to 0.919 µM. The compounds inhibited the α-EfCA and γ-EfCA with KI ranges of 0.195-0.959 µM and of 0.149-1.90 µM, respectively. Some MTCs were also investigated for their inhibitory effects on the growth of clinically-relevant N. gonorrhoeae and VRE strains. No inhibitory effects on the growth of VRE were noted for all MTCs, whereas one compound (13) inhibited the growth N. gonorrhoeae strains at concentrations ranging from 16 to 64 µg/mL. This suggests that compound 13 may be a potential antibacterial agent against N. gonorrhoeae.

Effect of extended field-of-view approaches on the accuracy of stopping power ratio estimation for single-energy computed tomography simulators.

BACKGROUND: Extended field-of-view (eFOV) methods have been proposed to generate larger demonstration FOVs for computed tomography (CT) simulators with a limited scanning FOV (sFOV) size in order to ensure accurate dose calculation and patient collision avoidance. Although the efficacy of these strategies has been evaluated for photon applications, the effect of stopping power ratio (SPR) estimation on proton therapy has not been studied. This study investigated the effect of an eFOV approach on the accuracy of SPR to water estimation in homogeneous and heterogeneous phantoms. MATERIALS AND METHODS: To simulate patient geometries, tissue-equivalent material (TEM) and customized extension phantoms were used. The TEM phantom supported various rod arrangements through predefined holes. Images were reconstructed to three FOV sizes using a commercial eFOV technique. A single-energy CT stoichiometric method was used to generate Hounsfield unit (HU) to SPR (HU-to-SPR) conversion curves for each FOV. To investigate the effect of rod location in the sFOV and eFOV regions, eight TEM rods were placed at off-center distances in the homogeneous phantom and scanned individually. Similarly, 16 TEM rods were placed in the heterogeneous TEM phantom and scanned simultaneously. RESULTS: The conversion curves derived from the sFOV and eFOV data were identical. The average SPR differences of soft-tissue, bone, and lung materials for rods placed at various off-center locations were 3.3%, 4.8%, and 39.6%, respectively. In the heterogeneous phantom, the difference was within 1.0% in the absence of extension. However, in the presence of extension, the difference increased to 2.8% for all rods, except for lung materials, whose difference was 4.8%. CONCLUSIONS: When an eFOV method is used, the SPR variation in phantoms considerably increases for all TEM rods, especially for lung TEM rods. This phenomenon may substantially increase the uncertainty of HU-to-SPR conversion. Therefore, image reconstruction with a standard FOV size is recommended.

Method Development for Determination of Doripenem in Human Plasma via Capillary Electrophoresis Coupled with Field-Enhanced Sample Stacking and Sweeping.

In this study, we established a novel capillary electrophoresis method for monitoring the concentration of doripenem in human plasma. As a time-dependent antibiotic, doripenem maximizes its antibacterial effects and minimizes the potential for antibiotic resistance through careful therapeutic drug monitoring. Two online preconcentration techniques, field-enhanced sample stacking (FESS) and sweeping, were coupled to enhance the detection sensitivity. Briefly, an uncoated fused silica capillary (40 cm × 50 µm i.d) was rinsed with a high conductivity buffer (HCB) composed of 150 mM phosphate buffer (NaH2PO4, pH 2.5) and 20% methanol. A large sample plug prepared in a low-conductivity phosphate buffer (50 mM NaH2PO4, pH 2.5) was then hydrodynamically injected (5 psi, 80 s) into the capillary. Under an applied voltage of -30 kV, the analyte was accumulated at the FESS boundary and swept by the negatively charged micelles toward the UV detector. Plasma samples were pretreated by solid-phase extraction (SPE) to eliminate endogenous interferences. The validation results demonstrated a high coefficient of determination (r2 > 0.9995) for the regression curve with impressive precision and accuracy: relative standard deviation (RSD) <5.86% and relative error <4.63%. The limit of detection (LOD, S/N = 3) for doripenem was determined to be 0.4 µg/mL. Compared to the conventional micellar electrokinetic chromatography method, our developed method achieved a sensitivity enhancement of up to 488-fold for doripenem. Furthermore, the newly developed method successfully quantified doripenem concentrations in plasma samples obtained from patients accepting doripenem regimens, proving its application potential in the clinical realm.

Early Experience of Patients with left Bundle Branch Block Corrected through Left Bundle Branch Area Pacing Compared with Conventional Right Ventricular Pacing: A Single-Center Retrospective Study.

Background: Left bundle branch area pacing (LBBAP) has the advantages of narrow QRS duration, rapid peak left ventricular (LV) activation, and LV dyssynchrony correction with a low, stable pacing output. Here we report our experience with patients undergoing LBBAP with a left bundle branch block (LBBB) for clinically indicated pacemaker or cardiac resynchronization therapy implantation. We compared the initial follow-up data of these patients and patients undergoing conventional right ventricular pacing (RVP). Methods: This retrospective study was performed between January 2017 and December 2020 and recruited 19 consecutive patients (mean age: 63 years; 8 women, 11 men) who underwent LBBAP (13 LBBAP only and 6 LBBAP + LV pacing), and 14 consecutive patients (mean age: 75 years; 8 women, 6 men) who underwent RVP. Demographic data, QRS durations, and echocardiographic parameters were compared before and after the procedures. Results: LBBAP substantially shortened the QRS duration and improved LV dyssynchrony echocardiographic parameters. However, RVP was not significantly associated with prolonged QRS duration and worse LV dyssynchronization. LBBAP improved cardiac contractility in selected patients. We did not find adverse effects of LBBAP on patients with preserved systolic function, possibly due to the limited number of patients and follow-up time. However, two of the 11 patients with preserved systolic function at baseline who underwent conventional RVP developed heart failure after implantation. Conclusions: In our experience, LBBAP improves LBBB-related ventricular dyssynchrony. However, LBBAP requires greater skill, and doubts remain about lead extraction. LBBAP may be an option for patients with LBBB when performed by an experienced operator, however further studies are needed to verify our findings.

Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance.

The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.

Pre-germinated brown rice alleviates non-alcoholic fatty liver disease induced by high fructose and high fat intake in rat.

In past researches, we had been proved the action mechanism of pre-germinated brown rice (PGBR) to treat metabolic syndrome and diabetes mellitus. This study was to investigate the protective effect of PGBR in high fructose and high fat-induced non-alcoholic fatty liver disease (NAFLD) in rodents. WKY rats were divided into: Control group was fed normal drinking water and diet; FLD group was fed 10% high-fructose-water (HFW) and high-fat-diet (HFD); PGBR group was given HFW, and HFD mixed PGBR. After four weeks, the body, hepatic and cardiac weight gains of FLD group had significant increases than that of Control group. The enhanced blood pressure and heart rate, hypertriglyceridemia, hyperuricemia, and higher liver function index (GPT levels) were observed; meanwhile, the IL-6 and TNF-α levels of serum, and TG level of liver were also elevated in FLD group. The related protein expressions of lipid synthesis, inflammation, cardiac fibrosis, and hypertrophy were deteriorated by HFW/HFD. However, in treatment group, PGBR decreased all above influenced parameters, additionally GOT; and related protein expressions. PGBR treated HFW/HFD-induced NAFLD and cardiac complications might be via improving lipid homeostasis, and inhibiting inflammation. Together, PGBR could be used as a healthy food for controlling NAFLD and its' cardiac dysfunction.

Mulberry leaves extract ameliorates alcohol-induced liver damages through reduction of acetaldehyde toxicity and inhibition of apoptosis caused by oxidative stress signals.

Mulberry leaves (Morus alba L.), which are traditional Chinese herbs, exert several biological functions, such as antioxidant, anti-inflammation, antidiabetic, and antitumor. Alcohol intake increases inflammation and oxidative stress, and this increase causes liver injury and leads to liver steatosis, cirrhosis, and hepatocellular carcinoma, which are major health problems worldwide. Previous report indicated that mulberry leaf extract (MLE) exited hepatoprotection effects against chronic alcohol-induced liver damages. In this present study, we investigated the effects of MLE on acute alcohol and liver injury induced by its metabolized compound called acetaldehyde (ACE) by using in vivo and in vitro models. Administration of MLE reversed acute alcohol-induced liver damages, increased acetaldehyde (ACE) level, and decreased aldehyde dehydrogenase activity in a dose-dependent manner. Acute alcohol exposure-induced leukocyte infiltration and pro-inflammation factors, including cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were blocked by MLE in proportion to MLE concentration. MLE prevented alcohol-induced liver apoptosis via enhanced caveolin-1 expression and attenuated EGFR/STAT3/iNOS pathway using immunohistochemical analysis. ACE induced proteins, such as iNOS, COX-2, TNF-α, and IL-6, and inhibited superoxide dismutase expression, whereas co-treated with MLE reversed these proteins expression. MLE also recovered alcohol-induced apoptosis in cultured Hep G2 cells. Overall, our findings indicated that MLE ameliorated acute alcohol-induced liver damages by reducing ACE toxicity and inhibiting apoptosis caused by oxidative stress signals. Our results implied that MLE might be a potential agent for treating alcohol liver disease.

Living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria: outcome of expanded criteria in tumor size.

BACKGROUND: The Milan criteria are the universal standard of liver transplantation for hepatocellular carcinoma (HCC). Numerous expanded criteria have shown outcomes as good as the Milan criteria. In Taiwan, living donor liver transplant (LDLT) accounts for the majority of transplantations due to organ shortages. METHODS: We retrospectively enrolled 155 patients who underwent LDLT for HCC from July 2005 to June 2017 and were followed up for at least 2 years. Patients beyond the Milan criteria (n = 78) were grouped as recurrent or nonrecurrent, and we established new expanded criteria based on these data. RESULTS: Patients beyond the Milan criteria with recurrence (n = 31) had a significantly larger maximal tumor diameter (4.13 ± 1.96 cm versus 6.10 ± 3.41 cm, p = 0.006) and total tumor diameter (7.19 ± 4.13 cm versus 10.21 ± 5.01 cm, p = 0.005). Therefore, we established expanded criteria involving maximal tumor diameter ≤ 6 cm and total tumor diameter < 10 cm. The 5-year survival rate of patients who met these criteria (n = 134) was 77.3%, and the 5-year recurrence rate was 20.5%; both showed no significant differences from those of the Milan criteria. Under the expanded criteria, the pool of eligible recipients was 35% larger than that of the Milan criteria. CONCLUSION: Currently, patients with HCC who undergo LDLT can achieve good outcomes even when they are beyond the Milan criteria. Under the new expanded criteria, patients can achieve outcomes as good as those with the Milan criteria and more patients can benefit.

Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific.

Foam cells are lipid-laden macrophages that contribute to the inflammation and tissue damage associated with many chronic inflammatory disorders. Although foam cell biogenesis has been extensively studied in atherosclerosis, how these cells form during a chronic infectious disease such as tuberculosis is unknown. Here we report that, unlike the cholesterol-laden cells of atherosclerosis, foam cells in tuberculous lung lesions accumulate triglycerides. Consequently, the biogenesis of foam cells varies with the underlying disease. In vitro mechanistic studies showed that triglyceride accumulation in human macrophages infected with Mycobacterium tuberculosis is mediated by TNF receptor signaling through downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1). These features are distinct from the known biogenesis of atherogenic foam cells and establish a new paradigm for non-atherogenic foam cell formation. Moreover, they reveal novel targets for disease-specific pharmacological interventions against maladaptive macrophage responses.

Management of Pulmonary Arterial Hypertension Patients with World Health Organization Functional Class II.

Pulmonary arterial hypertension (PAH) is an incurable chronic and progressive debilitating disease associated with significant morbidity and mortality. The World Health Organization functional class (WHO FC) at diagnosis and at follow-up remains one of the strongest predictors of survival in PAH. Studies have shown improved long-term outcomes in PAH patients who received PAH-specific treatment, as monotherapy or as combination therapy, early in their disease course. Studies have also shown that without treatment, PAH rapidly deteriorates even in patients with less advanced (low risk) disease state. In this article, we review evidence from randomized controlled clinical trials to support our position on the importance of early PAH management in WHO FC II patients. The growing importance of combination therapy in the early treatment of PAH and recommendations by the most recent guidelines for the diagnosis and treatment of pulmonary hypertension are also discussed in this article.

Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations.

Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of "universal" drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.

Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis.

OBJECTIVES: Autism spectrum disorder (ASD) refers to a group of conditions variably affecting communicative and social interactive abilities presenting alongside behaviors with various restricted and repetitive patterns. In addition to genetic factors that influence the onset of the symptoms, there is growing interest in the potential involvement of non-genetic environmental factors. Some aspects of breastfeeding practices, including rates, timing, or optimality, have been put forward as environmental risk factors for autism. However, previous studies showed a controversial relationship between ASD and breastfeeding. METHODS: A meta-analysis on the association between maternal breastfeeding and ASD in children was conducted. We also explored potential moderating factors which might influence this association. Articles reporting the association between breastfeeding and a diagnosis of ASD were included. RESULTS: Seven articles were included in the meta-analysis. Cumulatively, children with ASD (n = 1463), either in the form of clinical diagnosis or self-report, were significantly less likely to have been breastfed than children without ASD (n = 1180) (OR = 0.61, 95% CI = 0.45-0.83, P = 0.002). Subgroup analyses revealed that results remained significant for children who were breastfed with additional supplementation. DISCUSSION: This meta-analysis provides evidence that breastfeeding (exclusively or including additional supplements) may protect against ASD. Prospective longitudinal research is required to disentangle the complex relationships and to explore potential pathophysiological mechanisms.

Maternal breastfeeding and attention-deficit/hyperactivity disorder in children: a meta-analysis.

Previous studies have suggested environmental factors may contribute to the risk of attention-deficit/hyperactivity disorder (ADHD). The current meta-analysis examined (1) the difference in the duration of maternal breastfeeding between children with and without ADHD, and (2) the association between maternal breastfeeding and ADHD in children. The data of individual studies were synthesized with a random-effects model. Eleven articles were included in this meta-analysis. Children with ADHD had significantly less breastfeeding duration than controls (Hedges' g = - 0.36, 95% confidence intervals (CIs) = - 0.61 to - 0.11, p = 0.005; difference in means: - 2.44 months, 95% CIs = - 3.17 to - 1.71, p < 0.001). In addition, the rates of non-exclusive breastfeeding in children with ADHD is significantly higher in "under 3 months" (odds ratio (OR) = 1.90, 95% CIs = 1.45 to 2.48, p < 0.001) but lower in "6 to 12 months" (OR = 0.69, 95% CIs = 0.49 to 0.98, p = 0.039) and "over 12 months" (OR = 0.58, 95% CIs = 0.35 to 0.97, p = 0.038) than controls. Children with ADHD received significantly higher rate of exclusive breastfeeding duration "under 3 months" (OR = 1.51, 95% CIs = 1.20 to 1.89, p < 0.001) but lower in "over 3 months" (OR = 0.52, 95% CIs = 0.29 to 0.95, p = 0.033) than controls. Furthermore, an association was found between non-breastfeeding and ADHD children (adjusted OR = 3.71, 95% CI = 1.94 to 7.11, p < 0.001). Our results suggest maternal breastfeeding is associated with a lower risk of ADHD in children. Future longitudinal research is required to confirm/refute these findings and to explore possible mechanisms underlying this association.

The Effects of Ergosta-7,9(11),22-trien-3ß-ol from Antrodia camphorata on the Biochemical Profile and Exercise Performance of Mice.

Antrodia camphorata (AC) is a rare and unique mushroom that is difficult to cultivate. Previous studies have demonstrated the bioactivity of the compound Ergosta-7,9(11),22-trien-3ß-ol (EK100) from AC in submerged culture. The purpose of this study is to evaluate the potential beneficial effects of EK100 on fatigue and ergogenic functions following physiological challenge. Male ICR (Institute of Cancer Research) mice were randomly divided into three groups (n = 8 per group) and orally administered EK100 for six weeks at 0 (Vehicle), 10 (EK100-1X), and 20 (EK100-2X) mg/kg/day. The six-week Ek100 supplementation significantly increased grip strength (P = 0.0051) in trend analysis. Anti-fatigue activity was evaluated using 15-min. acute exercise testing and measuring the levels of serum lactate, ammonia, glucose, blood urea nitrogen (BUN), and creatine kinase (CK) after a 15-min. swimming exercise. Our results indicate that AC supplementation leads to a dose-dependent decrease in serum lactate, ammonia, BUN, and CK activity after exercise and significantly increases serum glucose and glycogen content in liver tissues. Biochemical and histopathological data demonstrated that long term daily administration of EK100 for over six weeks (subacute toxicity) was safe. EK100's anti-fatigue properties appear to be through the preservation of energy storage, increasing blood glucose and liver glycogen content, and decreasing the serum levels of lactate, ammonia, BUN, and CK. EK100 could potentially be used to improve exercise physiological adaptation, promote health, and as a potential ergogenic aid in combination with different nutrient strategies.

Dosage of methylphenidate and traumatic brain injury in ADHD: a population-based study in Taiwan.

Preventive effect of stimulants on the risk of brain injuries had been reported. The aim of this study is to determine the extent to which methylphenidate (MPH) prescription moderates the risk of traumatic brain injuries (TBI) in individuals with attention-deficit/hyperactivity disorder (ADHD). Individuals with a recent diagnosis of ADHD between January 1997 and December 2013 (n = 163,618) were identified from Taiwan's National Health Insurance Research Database. A total of 124,438 adolescents and children with ADHD and without prior TBI diagnoses were included and evaluated for subsequent TBI. Methylphenidate prescription duration was subgrouped by the annual average cumulative defined daily dose (DDD): 0, >0 to ≤28, > 28 to ≤84, and >84. We identified 11,463 diagnoses of TBI among 124,438 adolescents and children with ADHD. A Cox regression model was used to investigate whether MPH prescription influenced the risk for TBI after adjusting for sex, age, level of urbanization, seizure, autism and sedative-anxiolytics use. A reduced TBI incidence was observed with MPH prescription DDDs > 84. The protective effect of MPH against TBI persisted after adjusting for confounding factors [hazard ratio (HR) = 0.49; 95% confidence interval (CI): 0.47-0.51]. There was also statistically significant difference in risk for TBI in subjects receiving > 0 to ≤28 or >28 to ≤84 DDDs of MPH treatment (HR = 0.88, 95% CI = 0.83-0.92; HR = 0.76, 95% CI = 0.72-0.80, respectively) when compared with subjects not receiving treatment with MPH. Treatment with MPH for greater than 84 DDDs reduced the risk for TBI among children with ADHD.

Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells.

The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ERα) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ERα regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ERα in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ERα/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ERα/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co-immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ERα reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ERα binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ERα attenuated the activity of the BNIP3 promoter by binding to SP-1 or NFκB sites.