Effects of Aspergillus-meal prebiotic diet on the growth performance, health status and gut microbiota of Asian seabass, Lates calcarifer.

In this study, the growth performance, health status and intestinal microbiota of juvenile Asian seabass, Lates calcarifer, were assessed after dietary administration of a prebiotic product obtained from fermented Aspergillus orizae, Fermacto®. Asian seabass were fed three diets; control (without Aspergillus-meal prebiotic), 0.2% and 0.3% Aspergillus-meal prebiotic for 56 days. Fish were raised in freshwater with acceptable water quality. No significant differences were found in the growth performance and composition of dorsal fish muscle among all groups. Fish fed diets supplemented with 0.3% of Aspergillus-meal prebiotic had a significantly higher survival rate after being challenged with V. alginolyticus than fish fed with the control diet. Supplementation of the Aspergillus-meal prebiotic significantly improved immune responses by inducing higher respiratory burst, superoxide dismutase, phagocytic and lysozyme activity compared to the control group. In addition, prebiotic doses significantly induced an up-regulation of heat shock cognate 70 kDa protein (hsp70) in the liver compared to the control group. Signaling pathways were also affected with significantly higher gene expression of complement c-3 (c3), mechanistic target of rapamycin (mtor), and mammalian lethal with SEC13 protein 8 (mlst-8) in the liver of fish fed 0.3% Aspergillus prebiotic. The pro-inflammatory gene, tumor necrosis factor (tnf) and anti-inflammatory gene, transforming growth factor beta-1 (tfg-ß1) were significantly higher in the head kidney of fish offered prebiotic diets. Fish receiving Aspergillus-meal prebiotic revealed significantly higher expression of Mx gene 24 h post nervous necrosis virus injection compared to the control. Additionally, the α-diversity of gut microbiota, including genus, Pielou's evenness, Shannon diversity index, and Margalef's species richness were significantly higher in fish fed 0.3% Aspergillus-meal prebiotic than the control group. The principal component analysis eigenvector plots showed that a high abundance of beneficial bacteria, such as Entercoccus faecium, Lactococcus lactis, Macrococcus caseolyticus and Vagococcus fluvialis, along with potentially pathogenic bacteria, such as Staphylococcus sciuri and L. garvieae subsp. garvieae were present in fish treated with Aspergillus-meal prebiotic. Although dietary Aspergillus-meal prebiotic did not improve the growth performance of Asian seabass, 0.3% of Aspergillus-meal prebiotic is recommended to elevate the immunological status of fish.

Dose-Dependent Association between Sarcopenia and Moderate-To-Severe Thoracic Vertebral Fragility Fracture in Older Adults.

INTRODUCTION: Sarcopenia and vertebral fracture affect a large number of older adults and can be debilitating. However, the correlation between sarcopenia and vertebral fracture has not been well studied. Thus, this study investigates the correlation between vertebral fragility fracture and the severity of sarcopenia. METHOD: This cross-sectional study included 300 community-dwelling older adults with risk higher than 10-year probability of 3% for a hip fracture and 20% for a major osteoporotic fracture by FRAX score. Sarcopenia was defined according to the Asian Working Group for Sarcopenia consensus. Bone mineral density (BMD) was classified into normal or abnormal groups (T score ≤ -1.0) according to WHO criteria. Vertebral fracture was graded mild, moderate, and severe by a standardized semi-quantitative method. The association between sarcopenia and vertebral fragility fracture was investigated using a logistic regression model adjusted for confounding factors. RESULTS: Compared with the normal BMD group, the abnormal BMD group had a significantly higher prevalence of sarcopenia (7.4 vs. 26.6%, p < 0.001), poorer muscle mass (p < 0.001), and poorer hand grip (p < 0.001). The prevalence of moderate-to-severe fracture was significantly different (p = 0.006) among severe sarcopenia (16.7%), sarcopenia (6.9%), and non-sarcopenia (3.7%) for thoracic vertebrae. In the logistical regression model adjusted for confounding factors, sarcopenia plus severe sarcopenia was identified as a risk factor for moderate-to-severe thoracic vertebral fragility fracture (odds ratio [OR] = 3.29, 95% CI: 1.23-8.78, p = 0.018). We further classified the participants into normal, sarcopenia, and severe sarcopenia and found that sarcopenia and severe sarcopenia had a dose-dependent association with prevalence of thoracic vertebral fragility fractures with ORs of 2.56 (95% CI: 0.66-9.91) and 4.04 (95% CI: 1.24-13.20), respectively; p for trend = 0.014. CONCLUSION: Sarcopenia is a potential risk factor for and has a dose-dependent association with moderate-to-severe thoracic fragility fracture in older adults at increased risk for fractures.

Sex Differences and Positive Dose-Response Relationships between Serum Osteocalcin Levels and Low Muscle Strength.

INTRODUCTION: Impaired handgrip strength is an indication for sarcopenia and frailty screening, and is associated with increased osteoporotic risks and all-cause mortality. Osteocalcin, secreted by osteoblasts, is a versatile factor that participates in bone turnover and muscle adaptation. The role of osteocalcin in muscle strength has mainly been discussed in animal models and requires more human data. The study aimed to investigate the association between the serum osteocalcin level and handgrip strength in middle-aged individuals and older adults with diabetes. METHODS: Adult participants (aged 40 and above, N = 237) with diabetes were enrolled in a medical center in northern Taiwan. Subjects were divided into normal, low muscle mass without dynapenia, dynapenia without low muscle mass, and groups of low muscle mass with dynapenia according to their handgrip strength and muscle mass measurements. Physical performance, including handgrip strength, repeated sit-to-stand tests, walking speed, and short physical performance batteries, was documented. Body composition was measured by bioelectrical impedance analysis. RESULTS: The median serum osteocalcin level was highest in the dynapenic group without low muscle mass (median [Q1, Q3], 14.1 [11.2, 16.3] ng/mL). Multivariate logistic regression showed that a higher serum osteocalcin level was associated with worse handgrip strength (OR: 3.89, 95% CI: 1.66-9.10) after adjusting for body mass index (adiposity), skeletal muscle mass index (muscle), and medication with dipeptidyl peptidase-4 inhibitor. Further sex stratification revealed a more significant association between serum osteocalcin level and impaired handgrip strength in women but not in men. The female groups showed increases in the risk of impaired handgrip strength: 4.84-fold in the osteocalcin T2 group (11.4 ≤ osteocalcin <15.0 ng/mL) and 4.54-fold in the osteocalcin T3 group (osteocalcin ≥15.0 ng/mL). Moreover, after adjusting for various confounders, 8.41-fold and 8.03-fold increases in the risk of impaired handgrip strength were observed in the osteocalcin T2 group (11.4≤ osteocalcin <15.0 ng/mL) and osteocalcin T3 group (osteocalcin ≥14.5 ng/mL), respectively. CONCLUSION: Higher serum osteocalcin is associated with increased risks of impaired handgrip strength and impaired physical performance. Dose-dependent associations were found especially in postmenopausal women but not in men.

Proteomic Analysis of Skeletal Muscle and White Adipose Tissue after Aerobic Exercise Training in High Fat Diet Induced Obese Mice.

Obesity is associated with excessive fat accumulation in adipose tissue and other organs, such as skeletal muscle, whereas aerobic exercise (AE) plays an important role in managing obesity through profound protein regulation. Our study aimed to investigate the impact of AE on proteomic changes in both the skeletal muscle and the epididymal fat pad (EFP) of high-fat-diet-induced obese mice. Bioinformatic analyses were performed on differentially regulated proteins using gene ontology enrichment analysis and ingenuity pathway analysis. Eight weeks of AE significantly reduced body weight, increased the serum FNDC5 level, and improved the homeostatic model assessment of insulin resistance. A high-fat diet caused alterations in a subset of proteins involved in the sirtuin signaling pathway and the production of reactive oxygen species in both skeletal muscle and EFP, leading to insulin resistance, mitochondrial dysfunction, and inflammation. On the other hand, AE upregulated skeletal muscle proteins (NDUFB5, NDUFS2, NDUFS7, ETFD, FRDA, and MKNK1) that enhance mitochondrial function and insulin sensitivity. Additionally, the upregulation of LDHC and PRKACA and the downregulation of CTBP1 in EFP can promote the browning of white adipose tissue with the involvement of FNDC5/irisin in the canonical pathway. Our study provides insights into AE-induced molecular responses and may help further develop exercise-mimicking therapeutic targets.

Effects of a 12-week walking intervention on circulating lipid profiles and adipokines in normal weight and abdominal obese female college students.

Background/objectives: Regular exercise such as aerobic exercise has been shown to reduce the risk of some diseases such as cardiovascular disease (CVD). However, only few studies have investigated the impact of regular aerobic exercise on non-obese and overweight/obese persons. Therefore, this study was designed to compare the effect of a 12-week 10,000 steps a day walking intervention on the body composition, serum lipids, adipose tissue function, and obesity-associated cardiometabolic risk between normal weight and overweight/obese female college students. Methods: Ten normal weight (NWCG) and 10 overweight/obese (AOG) individuals were recruited in this study. Both groups performed a regular 10,000 steps a day walk for 12 weeks. Their blood pressure, body mass index, waist-to-hip ratio, and blood lipid profiles were evaluated. Moreover, serum leptin and adiponectin levels were measured using an enzyme-linked immunosorbent assay. Results: Our results revealed that triglyceride (TG), TG/high-density lipoprotein cholesterol (HDL-C) ratio and leptin were significantly reduced in the AOG group after the 12-week walking intervention. However, total cholesterol, HDL-C, and adiponectin/leptin ratio were significantly increased in the AOG group. There was little or no change in these variables in the NWCG group after the 12-week walking intervention. Conclusions: Our study demonstrated that a 12-week walking intervention may help improve cardiorespiratory fitness and obesity-associated cardiometabolic risk by decrease resting heart rate, modulating blood lipid profiles, and inducing adipokine alterations in obese individuals. Therefore, our research encourages obese young adults to improve their physical health by participating in a 12-week walking program of 10,000 steps a day.

Ovariectomy Interferes with Proteomes of Brown Adipose Tissue in Rats.

Postmenopausal women exhibit a higher prevalence of obesity due to decreased energy expenditure and increased food intake compared to their premenopausal counterparts. Brown adipose tissue (BAT) plays a key role in energy homeostasis, thus providing us with appealing therapeutic targets in obesity. However, how BAT proteomes are altered in response to low levels of estrogen remains unclear. To better understand the underlying mechanisms between the postmenopausal state and BAT proteomic changes, our study aimed to investigate the effect of ovariectomy on the BAT proteome. In this study, eight-week-old female Sprague Dawley rats were randomly allocated into bilateral ovariectomy (Ovx) and sham operation (Sham) groups. Mass spectrometry was used for proteomics assay and Ingenuity Pathway Analysis was applied to examine the differentially regulated proteins. Of the 1,412 identified proteins, 18 proteins were significantly upregulated, whereas 36 proteins were significantly downregulated in the Ovx group as compared to the Sham group. Our findings demonstrate that the proteins involved in BAT morphology, the browning of white adipose tissue, and metabolic substrates for thermogenesis were regulated by ovariectomy. The dysregulation of proteins by ovariectomy might be related to the disruption of BAT function in the postmenopausal status. Understanding how BAT proteomes are altered in response to ovariectomy may illuminate novel therapeutic strategies for the management of postmenopausal weight gain in the future.

Effects of Vitality Acupunch exercise on functional fitness and activities of daily living among probable sarcopenic older adults in residential facilities.

PURPOSE: To test the effects of a Vitality Acupunch exercise program on the functional fitness and the ability to perform the activities of daily living (ADL) among older adults with probable sarcopenia in residential facilities. DESIGN: This was a cluster-randomized controlled trial. A total of 12 long-term care facilities randomly assigned to the intervention and control groups with 1:1 allocation ratio. Among them, 114 older adults with probable sarcopenia participated at baseline and were allocated to either the intervention or control group according to the facility where they resided in. Of these, 103 older adults completed the study. METHODS: The intervention group (n = 52) underwent the Vitality Acupunch exercise program three times a week, each lasting 40 min, for 6 months while the control group (n = 51) performed its routine daily activities. FINDINGS: The functional fitness and ADL of the intervention group significantly improved at each time point (all p < 0.001), while the control group showed a significant decreasing trend. Except the lower limb muscular endurance, the functional fitness and ADL of the intervention group significantly improved compared to the control group at T1, and the improvements were still significant at T2. CONCLUSIONS: Functional fitness and the ability to perform ADL in older adults with probable sarcopenia were significantly improved after receiving the Vitality Acupunch exercises. CLINICAL RELEVANCE: An exercise that integrates the meridian theory and exercise concepts effectively improves functional fitness in probable sarcopenic older adults. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (NCT04504786). The trial was first posted on August 7, 2020. This part of the data was collected from August 2020 to March 2021.

Exposure of Immunogenic Tumor Antigens in Surrendered Immunity and the Significance of Autologous Tumor Cell-Based Vaccination in Precision Medicine.

The mechanisms by which immune systems identify and destroy tumors, known as immunosurveillance, have been discussed for decades. However, several factors that lead to tumor persistence and escape from the attack of immune cells in a normal immune system have been found. In the process known as immunoediting, tumors decrease their immunogenicity and evade immunosurveillance. Furthermore, tumors exploit factors such as regulatory T cells, myeloid-derived suppressive cells, and inhibitory cytokines that avoid cytotoxic T cell (CTL) recognition. Current immunotherapies targeting tumors and their surroundings have been proposed. One such immunotherapy is autologous cancer vaccines (ACVs), which are characterized by enriched tumor antigens that can escalate specific CTL responses. Unfortunately, ACVs usually fail to activate desirable therapeutic effects, and the low immunogenicity of ACVs still needs to be elucidated. This difficulty highlights the significance of immunogenic antigens in antitumor therapies. Previous studies have shown that defective host immunity triggers tumor development by reprogramming tumor antigenic expressions. This phenomenon sheds new light on ACVs and provides a potential cue to improve the effectiveness of ACVs. Furthermore, synergistically with the ACV treatment, combinational therapy, which can reverse the suppressive tumor microenvironments, has also been widely proposed. Thus, in this review, we focus on tumor immunogenicity sculpted by the immune systems and discuss the significance and application of restructuring tumor antigens in precision medicine.

Community-based multiple screening for metabolic syndrome by innovative theory: A longitudinal study.

The purpose of this research is to elucidate whether metabolic syndrome affects the rate of adoption of a new multiple cancer screening programme, based on the Diffusion of Innovation theory. The time to attend the screening programme, conducted in Keelung, Taiwan, within 10 years was assessed by innovativeness (innovators, early adaptors, early majority, late majority and laggard) using data from 79,303 residents, with the information on metabolic syndrome accrued from routine adult health check-ups. The median time of adopting the programme and the relative rates of early adoption by metabolic syndrome and its severity score were estimated. The results show that the estimated times to adopt the programme ranged from 3 months for innovators to 10 years for the laggard. The rate of early adoption was 34% higher for participants without metabolic syndrome than for those with the disease, and the gradient relationship of disease severity was noted. The adjusted median time to adopt innovativeness was 0.82 years earlier for participants who were disease-free than those with the disease. Meanwhile, the adjusted median time was wider by up to 2.25 years for those with severe disease. The study suggests that innovation should prioritise the potential risk of the metabolic syndrome population.

Bacteriology and mortality of necrotizing fasciitis in a tertiary coastal hospital with comparing risk indicators of methicillin-resistant Staphylococcus aureus and Vibrio vulnificus infections: a prospective study.

BACKGROUND: Vibrio vulnificus has been reported as the leading causative pathogen of necrotizing fasciitis (NF) and related fatality in the coastal area. Necrotizing fasciitis caused by methicillin-resistant Staphylococcus aureus (MRSA) and V. vulnificus have high mortality rates. The purpose of this prospective study was to clarify the clinical characteristics between death and survival NF patients, to investigate bacteriologic profile and mortality of NF patients, and to compare risk indicators of MRSA and V. vulnificus NF patients. METHODS: This prospective study was conducted in 184 consecutive NF patients over a period of three years in a tertiary coastal hospital. Differences in mortality, laboratory findings, microbiology and clinical outcomes were compared between the death and survival groups, and the V. vulnificus and MRSA subgroups. RESULTS: Twenty patients died, resulting in a mortality rate of 10.9%, and there were 108 patients with a monomicrobial infection (58.7%). The death group had a significantly higher incidence of shock at emergency room and bacteremia than did the survival group. Vibrio species (40 cases) and S. aureus (31 cases) were the two major pathogens. Significant differences with respect to hepatic dysfunction, shock, the event with seawater or seafood contact, bacteremia, C-reactive protein, mean platelet counts, and the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score were observes between V. vulnificus and MRSA groups. CONCLUSIONS: NF patients with both hepatic dysfunction and diabetes mellitus, bacteremia and shock have significantly higher mortality. We should be aware of the increasing incidence of monomicrobial NF and higher mortality rates of Gram-negative pathogens in the warm coastal area. LRINEC score is not a suitable diagnostic indicator for V. vulnificus NF, which is more rapidly progressive and fulminant than MRSA NF. NF needed team works by early suspicion, immediate surgical intervention and aggressive care, which can successfully decrease mortality.

Metabolically healthy obesity and risk of non-alcoholic fatty liver disease severity independent of visceral fat.

BACKGROUND AND AIM: Obesity and metabolic conditions may be related to non-alcoholic fatty liver disease (NAFLD). The study assesses the risk of NAFLD according to obesity and metabolic health status in a community-based population. METHODS: A total of 1651 subjects were recruited from the community. Individuals were categorized into four groups according to obesity status (defined as a body mass index ≥ 25 kg/m2 ) and metabolically healthy status: metabolically healthy nonobesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy nonobesity (MUHNO), and metabolically unhealthy obesity (MUHO). NAFLD was diagnosed based on a semiquantitative ultrasonography measurement. Visceral fat was assessed through bioelectrical impedance analysis and is shown by tertile (T1, T2, and T3). A proportional odds model was used to assess the cumulative risk of NAFLD. RESULTS: The NAFLD prevalence was 26.7%, 62.8%, 47.0%, and 76.7% in subjects with MHNO, MHO, MUHNO, and MUHO, respectively (P < 0.0001). After adjustment for age, sex, exercise habits, alcohol consumption, cigarette smoking, and visceral fat, the odds ratios for more severe NAFLD were 2.44 (95% confidence interval [CI]: 1.64-3.65), 2.75 (95% CI: 1.91-3.94), and 7.41 (95% CI: 4.94-11.12) in the MHO, MUHNO, and MUHO groups, respectively, compared with the MHNO group. In addition, the odds ratios for more severe NAFLD significantly increased with the increase in visceral fat level (T2 vs T1: 3.83, 95% CI: 2.65-5.53; T3 vs T1: 9.17, 95% CI: 5.33-15.79). CONCLUSION: Both obesity and metabolically unhealthy status were associated with a higher risk of NAFLD independent of visceral fat level.

Risk factors and modes of failure in the modern dual mobility implant. A systematic review and meta-analysis.

BACKGROUND: The aims of this meta-analysis were to: (1) validate the outcome of modern dual mobility (DM) designs in patients who had undergone primary and revision total hip arthroplasty (THA) procedures and (2) to identify factors that affect the outcome. METHODS: We searched for studies that assessed the outcome of modern DM-THA in primary and revision procedures that were conducted between January, 2000 to August, 2020 on PubMed, MEDLINE, Cochrane Reviews and Embase. The pooled incidence of the most common failure modes and patient reported outcomes were evaluated in patients who have received: (1) primary THA, (2) revision THA for all causes or (3) for recurrent dislocation. A meta-regression analysis was performed for each parameter to determine the association with the outcome. The study design of each study was assessed for potential bias and flaws by using the quality assessment tool for case series studies. RESULTS: A total of 119 studies (N= 30016 DM-THAs) were included for analysis. The mean follow-up duration was 47.3 months. The overall implant failure rate was 4.2% (primary: 2.3%, revision for all causes: 5.5%, recurrent dislocation: 6.0%). The most common failure modes were aseptic loosening (primary: 0.9%, revision for all causes: 2.2%, recurrent dislocation: 2.4%), septic loosening (primary:0.8%, revision for all causes: 2.3%, recurrent dislocation: 2.5%), extra-articular dislocation (primary:0.6%, revision for all causes:1.3%, recurrent dislocation:2.5%), intra-prosthetic dislocation (primary:0.8%, revision for all causes:1.0%, recurrent dislocation:1.6%) and periprosthetic fracture (primary:0.9%, revision for all causes:0.9%, recurrent dislocation:1.3%). The multi-regression analysis identified younger age (ß=-0.04, 95% CI -0.07 - -0.02) and female patients (ß=3.34, 95% CI 0.91-5.78) were correlated with higher implant failure rate. Age, gender, posterolateral approach and body mass index (BMI) were not risk factors for extra-articular or intra-prosthetic dislocation in this cohort. The overall Harris hip score and Merle d'Aubigné score were 84.87 and 16.36, respectively. Level of evidence of this meta-analysis was IV. CONCLUSION: Modern dual-mobility designs provide satisfactory mid-term implant survival and clinical performance. Younger age and female patients might impact the outcome after DM-THA. Future research directions should focus on, (1) long-term outcome of modern dual-mobility design, including specific concerns such as intra-prosthetic dislocation and elevated metal ion, and (2) cost-effectiveness analysis of dual-mobility implant as an alternative to conventional THA for patients who are at high risk of dislocation.

Household transmission but without the community-acquired outbreak of COVID-19 in Taiwan.

BACKGROUND: Household transmission is responsible for the subsequent outbreak of community-acquired COVID-19. The aim of this study was to elucidate the household transmission mode and to further estimate effective and basic reproductive number with and without non-pharmaceutical interventions (NPIs). METHODS: A total of 26 households with 39 family clusters between January, 2020 and February, 2021 in Taiwan were enrolled for analysis. The Becker's chain binomial model was used to analyze the probabilities of being infected and escaping from SARS-COV-2 before and after January 1st, 2021, which were further converted to estimating basic reproductive numbers in the absence of NPIs. The likelihood of leading to the subsequent community-acquired outbreak given NPIs was further assessed. RESULTS: The secondary attack rate was 46.2%. Given the saturated Greenwood model selected as the best fitted model, the probability of being infected and escaping from COVID-19 within household was estimated as 44.4% (95% CI: 5.0%-53.7%) and 55.7% (95% CI: 46.3%-65.0%), respectively. In the second period of early 2021, the infected probability was increased to 58.3% (95% CI: 12.7%-90.0%) and the escape probability was lowered to 41.7% (95% CI: 0.0%-86.9%). The corresponding basic reproductive numbers (R0) increased from 4.29 in the first period to 6.73 in the second period without NPIs. However, none of subsequent community-acquired outbreak was noted in Taiwan given very effective NPIs in both periods. CONCLUSION: The proposed method and results are useful for designing household-specific containment measures and NPIs to stamp out a large-scale community-acquired outbreak as demonstrated in Taiwan.

Effects of Visfatin on Intracellular Mechanics and Catabolism in Human Primary Chondrocytes through Glycogen Synthase Kinase 3ß Inactivation.

Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3ß (GSK3ß) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3ß inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.

Effect of mean HbA1c on the association of HbA1c variability and all-cause mortality in patients with type 2 diabetes.

AIM: To evaluate the effect of mean HbA1c on the correlation between HbA1c variability and all-cause mortality, and the risks associated with different levels of HbA1c and glycaemic control status in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes and at least three HbA1c measurements within 12-24 months were included. HbA1c variability score, coefficient of variation (CV) and standard deviation (SD) were used to evaluate variability. A variability score of 50 was set as a cutoff to define low and high variability. RESULTS: A total of 4216 patients were included, of whom 1196 died during the observation period (11.1 ± 3.2 years). All-cause mortality increased with HbA1c variability score and the quartiles of HbA1c CV and SD. The strength of this association was attenuated after adjustment for mean HbA1c, and the risks associated with HbA1c variability and glycaemic control status were similar. The highest associated risk was observed with an HbA1c variability score of >50 and mean HbA1c of ≥7.5%. Mortality risk was significantly higher with a mean HbA1c of ≤6.0% and >8.5% and of ≤6.0% and >8.0% for low and high HbA1c variability, respectively. CONCLUSIONS: Mean HbA1c contributed to the correlation between HbA1c variability and all-cause mortality. The risks associated with HbA1c variability and glycaemic control status were similar. The relationship between mean HbA1c and mortality presented a J-shaped distribution for both low and high HbA1c variability.

Metabolic profiles and fibrosis of nonalcoholic fatty liver disease in the elderly: A community-based study.

BACKGROUND AND AIMS: There are sparse data on the epidemiology of fatty liver in the elderly Asian population. We evaluated for predictors of fatty liver and high risk of advanced fibrosis in a community-based elderly population. METHODS: A total of 1091 participants (mean age was 74.6 ± 6.3 years) were enrolled from 2017 to 2018. Subjects with age younger than 65 years, alcoholism, and history of hepatitis B and hepatitis C were excluded. Fatty liver was diagnosed with abdominal ultrasound by using ultrasonographic fatty liver indicator, a semi-quantitative measurement grading the severity (normal, mild, and moderate-to-severe). Fibrosis-4 score was used for the prediction of the high risk of advanced fibrosis. Using a multivariable logistic regression model, we identified predictors of fatty liver and high risk of advanced fibrosis. RESULTS: In this ambulatory elderly Asian population, the prevalence of fatty liver is 41.9% and of high risk of advanced fibrosis is 12.3%. The prevalence of fatty liver decreases (44.5% to 31.8%), and the high risk of advanced fibrosis increases (3.9% to 27.0%) with aging significantly (both P < 0.05). Metabolic syndrome is a risk factor for fatty liver (odds ratio [OR], 3.19; 95% CI, 2.41-4.22) but not for high risk of advanced fibrosis (OR, 0.67; 95% CI, 0.41-1.08). Hypertriglyceridemia decreases the risk for high risk of advanced fibrosis (OR, 0.53; 95% CI, 0.33-0.87). CONCLUSION: Fatty liver is prevalent in the ambulatory elderly Asian population, affecting over 40% of this population. Age is a risk factor for high risk of advanced fibrosis, with the disease likely progressing from a steatotic to a fibrotic picture with age.

Doses of hepatitis B revaccination needed for the seronegative youths to be seropositive to antibody against hepatitis B surface antigen.

OBJECTIVES: To determine the required hepatitis B vaccine doses for subjects who were seronegative for three hepatitis B seromarkers during their youth who wish to have seroprotective antibodies against the hepatitis B surface antigen (anti-HBs). METHODS: We conducted a retrospective cohort study. From 2012 to 2015, graduate school students born after 1986 who were seronegative for three hepatitis B virus seromarkers at college entrance (n = 1037) were recruited. Four groups of subjects received zero to three doses of a hepatitis B vaccine booster at their free willingness, and their anti-HBs titre were measured at their graduate school entrance. Very low and extremely low antibody titres against the hepatitis B surface antigen were elucidated by graphic inference to determine the required booster dose cut-off value for seropositivity after revaccination. RESULTS: The anti-HBs seropositive rates in the four groups of subjects receiving the hepatitis B booster vaccine(s) were 17.7%, 52.1%, 78.6% and 90.9% for those receiving zero, one, two and three doses, respectively. In subjects with very low antibody titres against the hepatitis B surface antigen after one dose of the vaccine booster and subjects with an extremely low titre after two doses of the booster, the seropositive rates reached 95% at the cut-off value of 3 mIU/ml. CONCLUSION: A seropositive rate of at least 95% can be reached by the administration of two hepatitis B booster doses to youths with extremely low antibody titres against the hepatitis B surface antigen (<3 mIU/ml) and administering one dose to those with very low titres (3-10 mIU/ml) at college.

Stearoyl-CoA Desaturase-1 Attenuates the High Shear Force Damage Effect on Human MG63 Osteosarcoma Cells.

Mechanical regulation is known as an important regulator in cancer progression and malignancy. High shear force has been found to inhibit the cell cycle progression and result in cell death in various cancer cells. Stearoyl-CoA desaturase (SCD)-1, one of the important lipogenic enzymes, has recently been indicated as a potential pharmaceutical target in cancer therapy. In this study, we determined whether the cell fate control of shear force stimulation is through regulating the SCD-1 expression in cancer cells. Human MG63 osteosarcoma cells were used in this study. 2 and 20 dynes/cm2 shear forces were defined as low and high intensities, respectively. A SCD-1 upregulation in human MG63 osteosarcoma cells under 20, but not 2, dynes/cm2 shear force stimulation was shown, and this induction was regulated by Smad1/5 and peroxisome proliferator-activated receptor δ (PPARδ) signaling. Moreover, gene knockdown of PPARδ and SCD-1 in human MG63 osteosarcoma cells attenuated the differentiation inhibition and resulted in much more cell death of high shear force initiation. The present study finds a possible auto-protective role of SCD-1 upregulation in high shear force-damaged human MG63 osteosarcoma cells. However, its detailed regulation in the cancer fate decision of high shear force should be further examined.

Hyperglycemia inhibits osteoblastogenesis of rat bone marrow stromal cells via activation of the Notch2 signaling pathway.

Background: Bone fragility and related fractures are increasingly being recognized as an important diabetic complication. Mesenchymal progenitors often serve as an important source of bone formation and regeneration. In the present study, we have evaluated the effects of diabetes on osteoblastogenesis of mesenchymal progenitors. Methods: Primary bone marrow stromal cells (BMSCs) were isolated from control and streptozotocin-induced diabetic rats. These cells were evaluated for the effects of in vivo hyperglycemia on the survival and function of mesenchymal progenitors. We concomitantly investigated the effects of different concentrations of glucose, osmolality, and advanced glycation end product (AGE) on osteogenic differentiation and matrix mineralization of rat bone marrow mesenchymal stem cells (RMSC-bm). The relationship between the expression levels of Notch proteins and the corresponding ALP levels was also examined. Results: Our results revealed that in vivo hyperglycemia increased cell proliferation rate but decreased osteogenic differentiation and matrix mineralization of primary rat BMSCs. In vitro high glucose treatment, instead of high AGE treatment, induced a dose-dependent inhibition of osteoblastogenesis of RMSC-bm cells. Activation of the Notch2 signaling pathway, instead of the Notch1 or osmotic response pathways, was associated with these diabetic effects on osteoblastogenesis of mesenchymal progenitors. Conclusions: Hyperglycemia might inhibit osteoblastogenesis of mesenchymal progenitors via activation of the Notch2 signaling pathway.

Zoledronate induces cell cycle arrest and differentiation by upregulating p21 in mouse MC3T3-E1 preosteoblasts.

Background: Increasing research has recently been focused on the supplementary use of drugs such as bisphosphonates that are known to influence bone turnover to prevent and treat periprosthetic bone loss and subsequent implant loosening following total joint replacements. However, there are still concerns about the conflicting effects of bisphosphonate treatment on osteoblastic bone formation in the literature. Methods: In this study, we investigate the role of zoledronate (ZOL) in regulating cell cycle distribution and differentiation in mouse MC3T3-E1 preosteoblasts and also explore the mechanism underlying this effect of ZOL. We examined the expression levels of osteocalcin (OCN) by quantitative polymerase chain reaction (qPCR), the total amount of CDK6, p21 and p27 proteins by Western blot analysis, and the cell cycle distribution by flow cytometric analysis in mouse MC3T3-E1 preosteoblasts to evaluate the effect of ZOL. Small interfering RNAs (siRNAs) were used to assess the individual contributions of genes to specific osteoblast phenotypes. Results: In addition to increased OCN expression, we found that ZOL treatment induces the G0/G1 arrest and results in the increase of p21 and p27 expressions and decrease of CDK6 expression in mouse MC3T3-E1 preosteoblasts. Both p21 and p27 mediates ZOL-induced cell cycle exit; however, p21, but not p27, is responsible for the increase of ZOL-induced OCN expression in these cells. Conclusions: These results endorse that ZOL might have an anabolic effect on osteoblasts. The CDK inhibitor p21 plays a key role in regulating osteoblast differentiation by controlling proliferation-related events in mouse MC3T3-E1 preosteoblasts.