Interspecific Differences in Carbon and Nitrogen Metabolism and Leaf Epiphytic Bacteria among Three Submerged Macrophytes in Response to Elevated Ammonia Nitrogen Concentrations.

Submerged macrophytes in eutrophic aquatic environments adapt to changes in ammonia nitrogen (NH4-N) levels by modifying their levels of free amino acids (FAAs) and soluble carbohydrates (SCs). As symbionts of submerged macrophytes, epiphytic bacteria have obvious host specificity. In the present study, the interspecific differences in the FAA and SC contents of Hydrilla verticillata (Linn. f.) Roylep, Vallisneria natans Hara and Chara braunii Gmelin and their leaf epiphytic bacterial communities were assessed in response to increased NH4-N concentrations. The results revealed that the response of the three submerged macrophytes to NH4-N stress involved the consumption of SCs and the production of FAAs. The NH4-N concentration had a greater impact on the variation in the FAA content, whereas the variation in the SC content was primarily influenced by the species. At the phylum level, the relative abundance of Nitrospirota on the leaves exhibited specific differences, with the order H. verticillata > V. natans > C. braunii. The dominant genera of epiphytic bacteria with denitrification effects on V. natans, H. verticillata and C. braunii leaves were Halomonas, Acinetobacter and Bacillus, respectively. When faced with NH4-N stress, the variation in epiphytic bacterial populations associated with ammonia oxidation and denitrification among submerged macrophytes could contribute to their divergent responses to heightened nitrogen levels.

Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-ß signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-ß signaling. Interestingly, blocking SOCE had little effect on TGF-ß-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-ß signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-ß-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-ß signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.

Doxycycline cotherapy with albendazole relieves neural function damage in C57BL/6 and BALB/c mice infected with Angiostrongylus cantonensis.

BACKGROUND: We investigated the effects of combination therapy albendazole and doxycycline in Angiostrongylus cantonensis-infected mice during early and late treatment. MATERIALS AND METHODS: C57BL/6 and BALB/c mice were divided into five groups: (i) uninfected, (ii) infected with A. cantonensis, (iii) infected + 10 mg/kg albendazole, (iv) infected + 25mg/kg doxycycline, and (v) infected + 10 mg/kg albendazole + 25 mg/kg doxycycline. We administered drugs in both early treatments started at 7-day post infections (dpi) and late treatments (14 dpi) to A. cantonensis-infected C57BL/6 and BALB/c mice. To assess the impact of these treatments, we employed the Morris water maze test to evaluate spatial learning and memory abilities, and the rotarod test to measure motor coordination and balance in C57BL/6 mice. Additionally, we monitored the expression of the cytokine IL-33 and GFAP in the brain of these mice using western blot analysis. RESULTS: In this study, A. cantonensis infection was observed to cause extensive cerebral angiostrongyliasis in C57BL/6 mice. This condition significantly affected their spatial learning and memory abilities, as assessed by the Morris water maze test, as well as their motor coordination, which was evaluated using the rotarod test. Early treatment with albendazole led to favorable recovery outcomes. Both C57BL/6 and BALB/c mice express IL-33 and GFAP after co-therapy. The differences of levels and patterns of IL-33 and GFAP expression in mice may be influenced by the balance between pro-inflammatory and anti-inflammatory signals within the immune system. CONCLUSIONS: Combination therapy with anthelmintics and antibiotics in the early stage of A. cantonensis infection, in C57BL/6 and BALB/c mice resulted in the death of parasites in the brain and reduced the subsequent neural function damage and slowed brain damage and neurobehavior impairment. This study suggests a more effective and novel treatment, and drug delivery method for brain lesions that can decrease the neurological damage of angiostrongyliasis patients.

Understanding the human conflict processing network: A review of the literature on direct neural recordings during performance of a modified stroop task.

The Stroop Task is a well-known neuropsychological task developed to investigate conflict processing in the human brain. Our group has utilized direct intracranial neural recordings in various brain regions during performance of a modified color-word Stroop Task to gain a mechanistic understanding of non-emotional human conflict processing. The purpose of this review article is to: 1) synthesize our own studies into a model of human conflict processing, 2) review the current literature on the Stroop Task and other conflict tasks to put our research in context, and 3) describe how these studies define a network in conflict processing. The figures presented are reprinted from our prior publications and key publications referenced in the manuscript. We summarize all studies to date that employ invasive intracranial recordings in humans during performance of conflict-inducing tasks. For our own studies, we analyzed local field potentials (LFPs) from patients with implanted stereotactic electroencephalography (SEEG) electrodes, and we observed intracortical oscillation patterns as well as intercortical temporal relationships in the hippocampus, amygdala, and orbitofrontal cortex (OFC) during the cue-processing phase of a modified Stroop Task. Our findings suggest that non-emotional human conflict processing involves modulation across multiple frequency bands within and between brain structures.

The Causality between Gut Microbiota and Hypertension and Hypertension-related Complications: A Bidirectional Two-Sample Mendelian Randomization Analysis.

BACKGROUND: Recent studies have highlighted a connection between gut microbiota and hypertension, yet the precise nature of this relationship remains unclear. OBJECTIVE: This research aims to analyze the causal link between gut microbiota and hypertension, along with associated complications, utilizing two-sample bidirectional Mendelian randomization (MR). MATERIALS AND METHODS: Summary data from genome-wide association studies (GWAS) meta-analyses, including gut microbiota GWAS data from 24 cohorts, and the latest GWAS data for hypertension-related conditions were acquired. Employing various MR methods, including Inverse-variance weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode, we investigated the association between gut microbiota and hypertension-related conditions. Sensitivity analyses were conducted for result stability, and reverse MR analysis assessed the potential for reverse causality. RESULTS: The Mendelian randomization analysis involving 199 microbial taxa and four phenotypes identified 46 microbial taxa with potential causal links to hypertension and its complications. Following Bonferroni correction, genus.Victivallis showed a robust causal relationship with hypertension (OR = 1.08, 95% CI = 1.04-1.12, P = 9.82e-5). This suggests an 8% increased risk of hypertension with each unit rise in genus.Victivallis abundance. CONCLUSION: In conclusion, this study establishes a causal connection between gut microbiota and hypertension, along with common associated complications. The findings unveil potential targets and evidence for future hypertension and complication treatment through gut microbiota interventions, offering a novel avenue for therapeutic exploration.

Impulse oscillometry and its independent role in the diagnosis of chronic obstructive pulmonary disease.

Background: Pulmonary function test, particularly in patients with COVID-19, is problematic because it involves forced expiration. Impulse oscillometry (IOS) reduces the potential exposure of health-care staff to infectious droplets. In this study, we investigated the correlation between IOS and spirometry and whether IOS can precisely predict spirometry-based diagnoses of chronic obstructive pulmonary disease (COPD). Methods: We retrospectively analyzed the data (January 1 to December 31, 2021) of patients who underwent both spirometry and IOS on the same date. One-way analysis of variance was performed to evaluate the IOS results of patients stratified into two (COPD and non-COPD) groups by spirometry results. IOS results were also analyzed using receiver operator characteristics curves to diagnose advanced COPD, which was indicated by a postbronchodilator (BD) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of <0.6. We further evaluated the accuracy of oscillometry as a predictor of spirometry-based COPD diagnosis. Results: A total of 115 patients were included in the analysis. The best parameters assessed for spirometry-based COPD diagnosis were area under reactance (AX) and airway resistance (predicted R5% × resonant frequency) in relation to body mass index (BMI). However, when the post-BD FEV1/FVC ratio was <0.6, BMI-adjusted airway resistance had an area under curve (0.782; 95 % confidence interval: 0.620-0.945) value larger than the corresponding AX. A BMI-adjusted airway resistance value of >160 moderately predicted spirometry-based COPD diagnosis. Conclusions: BMI-adjusted airway resistance is a potential predictor of spirometry-based COPD diagnosis; the cutoff values of this parameter differ between individuals with and without obesity.

The influence of prior use of inhaled corticosteroids on COVID-19 outcomes: A systematic review and meta-analysis.

The influence of inhaled corticosteroids (ICS) on COVID-19 outcomes remains uncertain. To address this, we conducted a systematic review and meta-analysis, analyzing 30 studies, to investigate the impact of ICS on patients with COVID-19. Our study focused on various outcomes, including mortality risk, hospitalization, admission to the intensive care unit (ICU), mechanical ventilation (MV) utilization, and length of hospital stay. Additionally, we conducted a subgroup analysis to assess the effect of ICS on patients with chronic obstructive pulmonary disease (COPD) and asthma. Our findings suggest that the prior use of ICS did not lead to significant differences in mortality risk, ICU admission, hospitalization, or MV utilization between individuals who had used ICS previously and those who had not. However, in the subgroup analysis of patients with COPD, prior ICS use was associated with a lower risk of mortality compared to non-users (OR, 0.95; 95% CI, 0.90-1.00). Overall, while the use of ICS did not significantly affect COVID-19 outcomes in general, it may have beneficial effects specifically for patients with COPD. Nevertheless, more research is needed to establish a definitive conclusion on the role of ICS in COVID-19 treatment. PROSPERO registration number: CRD42021279429.

Positive Echocardiographic Association between Carotid Artery and Coronary Artery Diameter and Z-Score in a Mouse Model of Kawasaki Disease.

Kawasaki disease (KD) occurs in young children, has an unknown etiology, and can cause such life-threatening complications as coronary artery aneurysm. A mouse model using Lactobacillus casei cell wall extract (LCWE) with intraperitoneal injection was established for KD years ago. Histological examination of coronary artery lesions indicated features similar to those of vascular lesions of patients with KD. Since animals must be sacrificed during histological examination, the longitudinal survey of coronary artery lesions (CALs) is difficult. The aim of this study was to survey the vasculitis status of the coronary artery and the carotid artery in a KD mouse model. METHOD: LCWE was intraperitoneally injected into 5-week-old male C57BL/6 mice to induce CALs. We studied the longitudinal status of the carotid and coronary arteries and analyzed the Z-score of coronary artery diameter. RESULTS: Carotid artery wall thickness (day 7) and diameter (day 14) significantly increased in the LCWE group with a dose-dependent effect (p < 0.05). Aortic diameter and wall thickness demonstrated significant increases on day 28 and day 7, respectively (p < 0.05). Carotid artery outer diameter and wall thickness were positively associated with coronary artery diameter on day 28 (p < 0.01). Coronary artery diameter significantly increased in the LCWE group after day 7 (p < 0.05). The percentage of Z > 3.0 indicated was more than 80% in the high-dose LCWE group and 0% in the control group. CONCLUSIONS: This report is the first to use coronary artery Z-score in a mouse model of KD by echocardiography and to find a positive association between carotid artery and coronary artery diameter.

Changing the standardised obstetric care by expanded carrier screening and counselling: a multicentre prospective cohort study.

BACKGROUND: Expanded genetic screening before conception or during prenatal care can provide a more comprehensive evaluation of heritable fetal diseases. This study aimed to provide a large cohort to evaluate the significance of expanded carrier screening and to consolidate the role of expanded genetic screening in prenatal care. METHODS: This multicentre, retrospective cohort study was conducted between 31 December 2019 and 21 July 2022. A screening panel containing 302 genes and next-generation sequencing were used for the evaluation. The patients were referred from obstetric clinics, infertility centres and medical centres. Genetic counsellors conducted consultation for at least 15 min before and after screening. RESULTS: A total of 1587 patients were screened, and 653 pairs were identified. Among the couples who underwent the screening, 62 (9.49%) had pathogenic variants detected on the same genes. In total, 212 pathogenic genes were identified in this study. A total of 1173 participants carried at least one mutated gene, with a positive screening rate of 73.91%. Among the pathogenic variants that were screened, the gene encoding gap junction beta-2 (GJB2) exhibited the highest prevalence, amounting to 19.85%. CONCLUSION: Next-generation sequencing carrier screening provided additional information that may alter prenatal obstetric care by 9.49%. Pan-ethnic genetic screening and counselling should be suggested for couples of fertile age.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Endoscopic Versus Microscopic Type I Tympanoplasty: An Updated Systematic Review and Meta-analysis.

OBJECTIVE: Our objective was to perform a systematic review and meta-analysis comparing the clinical outcomes after endoscopic and microscopic type I tympanoplasty. STUDY DESIGN: Randomized controlled trials, two-arm prospective studies, and retrospective studies were included. SETTING: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until March 1, 2022 using the combinations of search terms: "endoscopic," "microscopic," and "tympanoplasty." METHODS: Two independent reviewers utilized the abovementioned search strategy to identify eligible studies. If any uncertainty existed regarding eligibility, a third reviewer was consulted. Primary outcome measures were graft success rate, air-bone gap (ABG) improvement, and operative time. Secondary outcomes were the rate of need for canalplasty, the proportion of self-rated excellent cosmetic results, and pain visual analog scale (VAS). RESULTS: Forty-three studies enrolled a total of 3712 patients who were undergoing type I tympanoplasty and were finally included. The pooled result showed endoscopic approach was significantly associated with shorter operative time (difference in means: -20.021, 95% confidence interval [CI]: -31.431 to -8.611), less need for canalplasty (odds ratio [OR]: 0.065, 95% CI: 0.026-0.164), more self-rated excellent cosmetic results (OR: 87.323, 95% CI: 26.750-285.063), and lower pain VAS (difference in means: -2.513, 95% CI: -4.737 to -0.228). No significant differences in graft success rate or ABG were observed between the two procedures. CONCLUSION: Endoscopic type I tympanoplasty provides a similar graft success rate, improvement in ABG, and reperforation rate to microscopic tympanoplasty with a shorter operative time, better self-rated cosmetic results, and less pain. Unless contraindicated, the endoscopic approach should be the procedure of choice in type I tympanoplasty.

Persistent Halogenated Organic Pollutants in Deep-Water-Deposited Particulates from South China Sea.

POP data are limited in the marine environment; thus, this study aimed to investigate background persistent organic pollutant (POP) levels in oceanic deep-water-deposited particulates in the South China Sea (SCS). Six POPs, including polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (DL-PCBs), polybrominated diphenyl ethers (PBDEs), polybrominated dibenzo-p-dioxins/dibenzofurans (PBDD/Fs), polychlorinated diphenyl ethers (PCDEs), and polybrominated biphenyls (PBBs), were investigated in eight pooled samples from the SCS from 20 September 2013 to 23 March 2014 and 15 April 2014 to 24 October 2014 at depths of 2000 m and 3500 m. PBDEs were the most predominant compounds, with the highest mean Σ14PBDE of 125 ± 114 ng/g dry weight (d.w.), followed by Σ17PCDD/F, Σ12PBDD/F, and Σ12DL-PCB (275 ± 1930, 253 ± 216, and 116 ± 166 pg/g d.w., respectively). Most PBDD/F, PBB, and PCDE congeners were below the detection limits. PCDDs had the highest toxic equivalency (TEQ), followed by PBDDs and DL-PCBs. Among the six POPs, PBDEs were the major components of the marine-deposited particles, regarding both concentrations and mass fluxes. Compared to 3500 m, PBDE levels were higher at a depth of 2000 m. PBDE mass fluxes were 20.9 and 14.2 ng/m2/day or 68.2 and 75.9 ng/m2/year at deep-water 2000 and 3500 m, respectively. This study first investigated POP levels in oceanic deep-water-deposited particles from existing global data.

Molecular Hydrogen: Emerging Treatment for Stroke Management.

Ischemic stroke is a major cause of death and disability worldwide. However, only intravenous thrombolysis using mechanical thrombectomy or tissue plasminogen activator is considered an effective and approved treatment. Molecular hydrogen is an emerging therapeutic agent and has recently become a research focus. Molecular hydrogen is involved in antioxidative, anti-inflammatory, and antiapoptotic functions in normal physical processes and may play an important role in stroke management; it has been evaluated in numerous preclinical and clinical studies in several administration formats, including inhalation of hydrogen gas, intravenous or intraperitoneal injection of hydrogen-enriched solution, or drinking of hydrogen-enriched water. In addition to investigation of the underlying mechanisms, the safety and efficacy of using molecular hydrogen have been carefully evaluated, and favorable outcomes have been achieved. All available evidence indicates that molecular hydrogen may be a promising treatment option for stroke management in the future. This review aimed to provide an overview of the role of molecular hydrogen in the management of stroke and possible further modifications of treatment conditions and procedures in terms of dose, duration, and administration route.

Real-World Evidence of Intra-institutional Performance Variation in Indefinite Diagnosis of Pleural Effusion Cytology.

CONTEXT.­: Pleural effusion cytology has been widely used in the investigation of pathologic fluid accumulation in pleural spaces. However, up to one-tenth of the cases were not given a definitive diagnosis. These cases have largely been neglected in the bulk of the literature. OBJECTIVE.­: To provide real-world data on indefinite diagnoses including "atypia of uncertain significance" (AUS) and "suspicious for malignancy" (SFM) in pleural effusion cytology and to investigate pathologists' practice patterns on using these diagnostic categories. DESIGN.­: We reported the diagnoses of 51 675 cases. Descriptive statistics and correlation coefficients were used to analyze the relationships between different diagnostic categories and pathologists' practice patterns and possible explanatory variables. RESULTS.­: The diagnoses AUS and SFM were reported in 4060 cases (7.86%) and 1554 cases (3.01%) in the cohort, respectively. The mean rates for these indefinite diagnoses varied up to 3-fold between pathologists. Correlations were found between AUS and SFM, as well as between indefinite diagnoses and negative for malignancy (NFM). No correlations were found between pathologists' years of experience or case volume and the rates of indefinite diagnosis or diagnostic certainty. CONCLUSIONS.­: A real-world baseline for the rates of indefinite diagnoses in pleural effusion cytology is provided in this large retrospective study. Pathologists show significant variation in their use of indefinite diagnostic categories, and the tendency to use these ambiguous terms was not correlated with individuals' experience or case volume. How to untangle the intertwined relationship between the uncertainty of indefinite diagnoses and that of NFM requires future prospective studies.

Circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis: a two-step bidirectional Mendelian randomization study.

Background: The relationship between gut microbiota and the occurrence of cholecystitis remains unclear. Existing research lacks a clear understanding of how circulating vitamin levels modulate this relationship. Therefore, our study aims to investigate whether circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis using a two-step bidirectional Mendelian randomization approach. Methods: In this study, we initially employed Linkage Disequilibrium Score Regression (LDSC) analysis to assess the genetic correlation of five circulating vitamin level genome-wide association study (GWAS) summary datasets, thereby avoiding potential sample overlap. Subsequently, we conducted a two-step analysis to investigate the causal effects between gut microbiota and cholecystitis. In the second step, we explored the causal relationship between circulating vitamin levels and cholecystitis and identified the mediating role of vitamin D. The primary method used for causal analysis was the inverse variance-weighted approach. We performed additional sensitivity analyses to ensure result robustness, including the cML-MA method and reverse Mendelian randomization (MR) analysis. Results: An increment of one standard deviation in RuminococcaceaeUCG003 was associated with a 25% increased risk of cholecystitis (OR = 1.25, 95%CI = 1.01-1.54, p = 0.04), along with a 3% decrease in 25-hydroxyvitamin D levels (OR = 0.97, 95%CI = 0.944-0.998, p = 0.04). However, following the rigorous Bonferroni correction, every one standard deviation decrease in circulating vitamin D levels was associated with a 33% increased risk of cholecystitis (OR = 0.67, 95%CI = 0.49-0.90, p = 0.008, Padjust = 0.04). Thus, the potential link between gut microbiota and cholecystitis risk might be mediated by circulating vitamin D levels (proportion mediated = 5.5%). Sensitivity analyses provided no evidence of pleiotropy. Conclusion: Our study results suggest that an elevated abundance of specific gut microbiota is associated with an increased susceptibility to cholecystitis, with the causal relationship being mediated by circulating vitamin D levels. Further large-scale randomized controlled trials are necessary to validate the causal effects of gut microbiota on cholecystitis risk. This study provides novel insights into cholecystitis prevention through the regulation of gut microbiota.

Protective effect of benzaldehyde combined with albendazole against brain injury induced by Angiostrongylus cantonensis infection in mice.

Angiostrongylus cantonensis, also known as rat lungworm, is an important food-borne zoonotic parasite that causes severe neuropathological damage and symptoms, including eosinophilic meningitis and eosinophilic meningoencephalitis, in humans. At present, the therapeutic strategy for cerebral angiostrongyliasis remains controversial. Benzaldehyde, an important bioactive constituent of Gastrodia elata (Tianma), reduces oxidative stress by inhibiting the production of reactive oxygen species. This study aimed to evaluate the therapeutic effect of benzaldehyde in combination with albendazole on angiostrongyliasis in animal models. First, the data from body weight monitoring and behavioural analyses demonstrated that benzaldehyde improved body weight and cognitive function changes after A. cantonensis infection. Next, blood‒brain barrier breakdown and pathological changes were reduced after benzaldehyde and albendazole treatment in BALB/c mice infected with A. cantonensis. Subsequently, four RNA-seq datasets were established from mouse brains that had undergone different treatments: normal, infection, infection + albendazole, and infection + albendazole + 3-hydroxybenzaldehyde groups. Ultimately, benzaldehyde was found to regulate cell apoptosis, oxidative stress and Sonic Hedgehog signalling in mouse brains infected with A. cantonensis. This study evaluated the therapeutic effect of benzaldehyde on angiostrongyliasis, and provided a potential therapeutic strategy for human angiostrongyliasis in the clinical setting. Moreover, the molecular mechanism of benzaldehyde in mouse brains infected with A. cantonensis was elucidated.

Dipeptidyl peptidase IV inhibitors and the risk of mycobacterial pulmonary infections in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (DM) is a risk factor for mycobacterial pulmonary infections (MPI), including tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD). Dipeptidyl peptidase IV inhibitor (DPP4i), a common DM medication, has an immune-modulation effect that raises concerns about developing MPI. However, there is scarce research on the topic. METHODS: This retrospective study was conducted in a tertiary-referral center in Taiwan from 2009 to 2016. Patients with type 2 DM who were receiving any DM medication were enrolled. TB and NTM-LD were defined by microbiological criteria. We analyzed the risk of MPI in DPP4i users using Cox proportional hazard regression with adjusted inverse probability of treatment weighting. RESULTS: A total of 9963 patients were included. Among them, 3931 were classified as DPP4i users, and 6032 patients were DPP4i nonusers. DPP4i users had no increase in incidences of MPI (604 vs. 768 per 100,000 person-years, p = 0.776), NTM-LD (174 vs. 255 per 100,000 person-years, p = 0.228), and TB (542 vs. 449 per 100,000 person-years, p = 0.663) relative to those of DPP4i nonusers. After adjustment, the adjusted hazard ratios for MPI (aHR: 1.07, 95% CI: 0.79-1.45), TB (aHR: 1.15, 95% CI: 0.81-1.64) and NTM-LD (aHR: 0.85, 95% CI: 0.49-1.47) were not significantly increased relative to those of nonusers. The subgroup analysis also showed that DPP4i use did not increase the risk of MPI in different DM severities and comorbidities. CONCLUSIONS: According to our large cohort study, DPP4i use is safe for patients with type 2 DM and might not increase the risk of MPI.

Isolation and Biological Evaluation of Alfa-Mangostin as Potential Therapeutic Agents against Liver Fibrosis.

The increased proliferation and activation of hepatic stellate cells (HSCs) are associated with liver fibrosis development. To date, there are no FDA-approved drugs for the treatment of liver cirrhosis. Augmentation of HSCs apoptosis is one of the resolutions for liver fibrosis. In this study, we extracted α-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-9H-xanthen-9-one) from the fruit waste components of mangosteen pericarp. The isolated α-mangostin structure was determined and characterized with nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) and compared with those known compounds. The intracellular signaling pathway activities of α-mangostin on Transforming growth factors-beta 1 (TGF-ß1) or Platelet-derived growth factor subunit B (PDGF-BB) induced HSCs activation and were analyzed via Western blot and Real-time Quantitative Polymerase Chain Reaction (Q-PCR). α-Mangostin-induced mitochondrial dysfunction and apoptosis in HSCs were measured by seahorse assay and caspase-dependent cleavage. The in vivo anti-fibrotic effect of α-mangostin was assessed by carbon tetrachloride (CCl4) treatment mouse model. The data showed that α-mangostin treatment inhibited TGF-ß1-induced Smad2/3 phosphorylation and alpha-smooth muscle actin (α-SMA) expression in HSCs in a dose-dependent manner. Regarding the PDGF-BB-induced HSCs proliferation signaling pathways, α-mangostin pretreatment suppressed the phosphorylation of extracellular-signal-regulated kinase (ERK) and p38. The activation of caspase-dependent apoptosis and dysfunction of mitochondrial respiration (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were observed in α-mangostin-treated HSCs. The CCl4-induced liver fibrosis mouse model showed that the administration of α-mangostin significantly decreased the expression of the fibrosis markers (α-SMA, collagen-a2 (col1a2), desmin and matrix metalloproteinase-2 (MMP-2)) as well as attenuated hepatic collagen deposition and liver damage. In conclusion, this study demonstrates that α-mangostin attenuates the progression of liver fibrosis through inhibiting the proliferation of HSCs and triggering apoptosis signals. Thus, α-mangostin may be used as a potential novel therapeutic agent against liver fibrosis.

HDAC1 is Involved in Neuroinflammation and Blood-Brain Barrier Damage in Stroke Pathogenesis.

Background: Stroke is a common cause of disability and mortality worldwide; however, effective therapy remains limited. In stroke pathogenesis, ischemia/reperfusion injury triggers gliosis and neuroinflammation that further activates matrix metalloproteinases (MMPs), thereby damaging the blood-brain barrier (BBB). Increased BBB permeability promotes macrophage infiltration and brain edema, thereby worsening behavioral outcomes and prognosis. Histone deacetylase 1 (HDAC1) is a repressor of epigenomic gene transcription and participates in DNA damage and cell cycle regulation. Although HDAC1 is deregulated after stroke and is involved in neuronal loss and DNA repair, its role in neuroinflammation and BBB damage remains unknown. Methods: The rats with cerebral ischemia were evaluated in behavioral outcomes, levels of inflammation in gliosis and cytokines, and BBB damage by using an endothelin-1-induced rat model with cerebral ischemia/reperfusion injury. Results: The results revealed that HDAC1 dysfunction could promote BBB damage through the destruction of tight junction proteins, such as ZO-1 and occludin, after stroke in rats. HDAC1 inhibition also increased the levels of astrocyte and microglial gliosis, tumor necrosis factor-alpha, interleukin-1 beta, lactate dehydrogenase, and reactive oxygen species, further triggering MMP-2 and MMP-9 activity. Moreover, modified neurological severity scores for the cylinder test revealed that HDAC1 inhibition deteriorated behavioral outcomes in rats with cerebral ischemia. Discussion: HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.

Smoking cessation and influenza vaccination can reduce the healthcare burden of COPD.

INTRODUCTION: Influenza vaccination (INV) and smoking cessation (SC) have individual positive effects on COPD, but their synergistic impact has yet to be extensively studied. This retrospective study aimed to assess the combined effect of SC and IV on the medical burden of COPD, including medical visits, hospitalization, medical expenses, and the occurrence of respiratory failure. METHODS: Patients with COPD who visited our medical center between January and October 2018 were included in the study. The patients were categorized into four groups: Group I (no SC or INV), Group II (INV only), Group III (SC only), and Group IV (both SC and INV). The outcomes analyzed were emergency utilization, hospital utilization, and occurrence of respiratory failure. Airflow limitation was stratified according to GOLD guidelines, and successful smoking cessation was defined as not smoking for at least one year. RESULTS: A total of 357 patients were included in the study. Group I (119 patients) neither smoking cessation nor influenza vaccination; Group II (66 patients) had only influenza vaccination; Group III (94 patients), had only smoking cessation, Group IV (78 patients), with both smoking cessation and influenza vaccination. Group IV had lower odds of emergency utilization (OR=0.13; 95% CI: 0.07-0.25), hospital utilization (OR=0.13; 95% CI: 0.05-0.30, p<0.001), and occurrence of respiratory failure (OR=0.13; 95% CI: 0.04-0.40, p<0.001). CONCLUSIONS: Combined smoking cessation and influenza vaccination are more effective in reducing the medical burden of COPD compared to either intervention alone or neither. These findings highlight the importance of promoting both smoking cessation and influenza vaccination in the management of COPD.