Altered microbiome of serum exosomes in patients with acute and chronic cholecystitis.

BACKGROUND: This study aimed to investigate the differences in the microbiota composition of serum exosomes from patients with acute and chronic cholecystitis. METHOD: Exosomes were isolated from the serum of cholecystitis patients through centrifugation and identified and characterized using transmission electron microscopy and nano-flow cytometry. Microbiota analysis was performed using 16S rRNA sequencing. RESULTS: Compared to patients with chronic cholecystitis, those with acute cholecystitis exhibited lower richness and diversity. Beta diversity analysis revealed significant differences in the microbiota composition between patients with acute and chronic cholecystitis. The relative abundance of Proteobacteria was significantly higher in exosomes from patients with acute cholecystitis, whereas Actinobacteria, Bacteroidetes, and Firmicutes were significantly more abundant in exosomes from patients with chronic cholecystitis. Furthermore, functional predictions of microbial communities using Tax4Fun analysis revealed significant differences in metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and membrane transport between the two patient groups. CONCLUSIONS: This study confirmed the differences in the microbiota composition within serum exosomes of patients with acute and chronic cholecystitis. Serum exosomes could serve as diagnostic indicators for distinguishing acute and chronic cholecystitis.

Association between inflammatory bowel disease and risk of stroke: a systematic review and meta-analysis of cohort studies.

Background/objectives: Recently, four meta-analyses have explored the association between inflammatory bowel disease (IBD) and the risk of stroke. These studies have demonstrated that people with IBD may be at an increased risk of stroke. However, some limitations such as high heterogeneity and the lack of uniformity in the types of research, especially the reuse of some sample sizes, cannot be neglected. These factors reduce the credibility of their research conclusions. Therefore, we conducted a meta-analysis to explore this possible association. Methods: PubMed, Embase, and Web of Science were searched from inception to 30 June 2023. A random effects model with the generic inverse variance method was used in this meta-analysis. The Review Manager software was used to obtain all relative risks (RRs) and their 95% confidence intervals (CIs). Publication bias was tested, and sensitivity and subgroup analyses were conducted to explore possible heterogeneities. Results: This meta-analysis included 12 cohort studies (involving 4,495,055 individuals). Meta-analysis of these data has shown that IBD was associated with an increased risk of stroke (RR = 1.19, 95%CI:1.14-1.24, p < 0.00001). Our results were stable and robust in subgroup and sensitivity analyses. Conclusions: Our results suggest that IBD is associated with an increased risk of stroke. To reduce the incidence of stroke, patients with IBD are encouraged to undergo stroke risk assessments, especially for young female patients; assessing the risk of ischemic stroke is of particular importance. Prospective studies considering stroke subtypes, IBD severity and treatments, regions, and other confounding factors are needed to further explore the nature of each association. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022373656.

Effect of rScO2-Guided Blood Pressure Management on Postoperative Complications in Elderly Patients After Major Noncardiac Surgery: Protocol for a Randomized Controlled Trial.

Background: Postoperative complications are common after major surgical procedures, leading to increased morbidity and mortality. Regional cerebral oxygen saturation (rScO2) reflects cerebral and global perfusion, and thus it can be used to guide hemodynamic management. We aim to explore the effect of rScO2-guided blood pressure management strategy on postoperative major complications in older adults who undergo major noncardiac surgery. Methods: This randomized controlled clinical trial includes a total of 400 elderly patients receiving major noncardiac surgery and general anesthesia. Patients will be randomized (1:1) to one of two blood pressure management groups: a standard care group (targeting mean arterial pressure >65 mmHg or within 20% of baseline value), and a rScO2-guided group (absolute value of rScO2 >60% or decrease in rScO2 <10% of baseline). The primary outcome is the composite outcome of major complications (including infectious, respiratory, neurologic, cardiovascular, renal, thromboembolic gastrointestinal, and surgical complications) and deaths within the first 7 days after surgery. Secondary outcomes include the individual components of the primary outcome by day 7 after surgery and 30-day mortality. Data will be analyzed in the modified intention-to-treat population. Discussion: This study will provide evidence for improving postoperative outcomes using the rScO2-guided blood pressure management among older adults who undergo major noncardiac surgery. Trial Registration: Chinese Clinical Trial Registry (Identifier: ChiCTR2200060816).

This is a protocol for a prospective, randomized, controlled clinical trial to evaluate the use of intraoperative individualized regional cerebral oxygen saturation (rScO₂) optimization for blood pressure management in older adults undergoing major noncardiac surgery. The primary focus of this trial is the composite outcome of major complications (including infectious, respiratory, neurologic, cardiovascular, renal, thromboembolic gastrointestinal, and surgical complications) and deaths within the first 7 days after surgery. The secondary outcomes are the individual components of the primary outcome by day 7 after surgery and 30-day mortality. The findings of this trial will provide clinical evidence for the rScO₂-guided blood pressure management to improve postoperative outcomes in older patients who are scheduled for major noncardiac surgery.

Simvastatin inhibits the inflammation and oxidative stress of human neutrophils in sepsis via autophagy induction.

Simvastatin exerts a protective effect during sepsis (SP) in animal models; however, the underlying mechanism is not completely understood, particularly in human SP. Neutrophils are a critical effector in the host inflammatory response to SP. Therefore, the present study aimed to investigate the effect of simvastatin on neutrophils in human SP. Neutrophils were isolated from the peripheral venous blood of adult patients with SP and healthy volunteers (HP). Cell viability was analyzed using the MTT assay. Intracellular reactive oxygen species (ROS) generation and the concentrations of inflammatory mediators were also assessed using flow cytometry and ELISA. The results demonstrated that the cell viability of neutrophils from the SP group was significantly decreased compared with that in the HP group, and that treatment with simvastatin partly reversed the reduced cell viability. Furthermore, simvastatin administration significantly decreased ROS production and the concentrations of TNF­α and IL­6, which were significantly increased in neutrophils isolated from the SP group. Simvastatin also enhanced autophagy induction, as indicated by the promotion of the conversion of LC3I to LC3II and the increased expression levels of Beclin 1 in SP neutrophils. Treatment with 3­methyladenine, an autophagy inhibitor, completely blocked the protective effects of simvastatin on neutrophils from SP, including the effects of simvastatin on the inhibition of inflammation, oxidative stress and improving cell viability. Collectively, the present study provided evidence for the simvastatin­induced autophagic process of neutrophils involved in human SP, which protects neutrophils and partially attenuates the inflammatory response and oxidative stress. Therefore, the augmentation of neutrophil autophagy may serve as a potential therapeutic target for patients with SP.

Association between glaucoma and risk of stroke: A systematic review and meta-analysis.

Background/objectives: Recently, several studies explored the association between glaucoma and the risk of stroke, but these results were inconsistent. Therefore, we conducted a meta-analysis to examine this possible association. Methods: We conducted a systematic literature search of PubMed, Embase, and Web of Science from inception until February 28, 2022. Random-effects meta-analysis was conducted by generic inverse variance method. Sensitivity and subgroup analyses were performed. The review protocol has been registered with PROSPERO (CRD42022312797). Results: Seven studies (involving 362,267 participants) have been published from 2004 to 2017 and included in the meta-analysis. These studies included four retrospective cohort studies, two cross-sectional studies, and one case-control study. Meta-analysis of these data has shown that glaucoma was associated with an increased risk of stroke (OR = 1.94, 95% CI = 1.45-2.59). Most of the subgroup analyses demonstrated similar results. These findings were stable in sensitivity analyses. Conclusions: We found that glaucoma was associated with an increased risk of stroke. The result suggests that patients with glaucoma need to be assessed the risk of stroke to reduce the incidence of stroke. To better explore the nature of any association, prospective studies that consider the stroke subtypes, sample size, district, and other confounding factors are needed.

Discovery of new tranylcypromine derivatives as highly potent LSD1 inhibitors.

Tranylcypromine (TCP)-based structural modifications lead to the discovery of new LSD1 inhibitors, of which compounds 26b and 29b effectively inhibit LSD1 with the IC50 values of 17 and 11 nM, respectively and also show good selectivity over MAO-B. Mechanistic studies showed that compound 29b concentration-dependently induced H3K4me1/2 accumulation in LSD1 overexpressed MGC-803 cells and also inhibited metastasis of MGC-803 cells. Collectively, both compounds could be promising lead compounds for further investigation.

Long-term prognosis in patients with end-stage renal disease after coronary artery bypass grafting.

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Coronary artery bypass grafting (CABG) is beneficial in selected patients with ESRD. This study investigates the survival outcomes and prognostic factors in ESRD patients who underwent CABG. METHODS: A retrospective analysis was performed for 149 patients with ESRD who underwent isolated CABG between 2006 and 2015. RESULTS: Mean age was 59.4±8.7 years and 106 patients (71.1%) were male. Operative mortality occurred in 20 patients (13.4%). Overall survival was 81.1%±3.2% at 1 year, 41.5%±4.3% at 5 years and 19.2%±4.2% at 10 years. Median survival was 4.3 years. Multivariable analysis identified age [P=0.001, odds ratio (OR): 1.15 per 1-year increase, 95% confidence interval (CI): 1.06-1.25], preoperative left ventricular ejection fraction (LVEF) (P=0.020, OR: 0.94, 95% CI: 0.89-0.99) and non-elective status of operation (P=0.049, OR: 3.34, 95% CI: 1.00-11.1) as predictors of operative mortality. Cox regression analysis identified age [P<0.001, hazard ratio (HR): 1.05 per 1-year increase, 95% CI: 1.03-1.08], New York Heart Association (NYHA) class III or IV status (P=0.010, HR: 1.75, 95% CI: 1.15-2.67) and the use of a left internal mammary artery (LIMA) to left anterior descending artery (LIMA-LAD) graft (P=0.029, HR: 0.42, 95% CI: 0.19-0.92) as factors influencing long-term survival. CONCLUSIONS: CABG is associated with high operative mortality and poor long-term survival in ESRD patients. Age and NYHA class influenced late survival. LIMA-LAD grafting conferred a long-term survival advantage.

Targeting histone demethylase KDM5B for cancer treatment.

KDM5B (Lysine-Specific Demethylase 5B) erases the methyl group from H3K4me2/3, which performs wide regulatory effects on chromatin structure, and represses the transcriptional function of genes. KDM5B functions as an oncogene and associates with human cancers closely. Targeting KDM5B has been a promising direction for curing cancer since the emergence of potent KDM5B inhibitor CPI-455. In this area, most reported KDM5B inhibitors are Fe (Ⅱ) chelators, which also compete with the cofactor 2-OG in the active pockets. Besides, Some KDM5B inhibitors have been identified through high throughput screening or biochemical screening. In this reviewing article, we summarized the pioneering progress in KDM5B to provide a comprehensive realization, including crystal structure, transcriptional regulation function, cancer-related functions, development of inhibitors, and SAR studies. We hope to provide a comprehensive overview of KDM5B and the development of KDM5B inhibitors.

Synthesis and anti-gastric cancer activity evaluation of novel triazole nucleobase analogues containing steroidal/coumarin/quinoline moieties.

A series of novel triazole nucleobase analogues containing steroidal/coumarin/quinoline moieties have been synthesized based on copper-catalyzed azide-alkyne cycloaddition (CuAAC). The anti-cancer activity of the new triazole nucleobase analogues was studied in gastric cancer cell lines (MGC-803, SGC-7901) and normal gastric epithelial cells (GES-1) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells. Among the tested compounds, compound 20c demonstrated good anti-proliferation activity against MGC-803 cells (IC50 = 1.48 µM) and SGC-7901 (IC50 = 2.28 µM) cells as well as the best selectivity between the cancer and normal cells. Further mechanistic studies indicated that compound 20c could down-regulate the expression of TGF ß1 both in the tested gastric cancer cell lines and inhibit the cell migration and invasion. The results of the study indicate that compound 20c could be used as a promising skeleton for anti-gastric cancer agents with improved efficacy and less side effects.

Design, synthesis and biological evaluation of new steroidal ß-triazoly enones as potent antiproliferative agents.

ß-Triazoly enones are biologically interesting scaffolds, incorporation of such scaffolds into the steroid nucleus may generate new bioactive steroids and further enrich structural types of steroids. In this work, a series of new steroidal ß-triazoly enones were synthesized based on click chemistry and Claisen-Schmidt condensation reaction and further evaluated for their antiproliferative activity against a panel of cancer cells. Most of these compounds showed better potency against PC-3 and MGC-803 cells. Particularly, compound 5a inhibited PC-3 and MGC-803 cells potently with the IC50 values of 1.61 and 1.16 µM, respectively, and was less toxic toward GES-1 with an IC50 value of 20.72 µM. Further mechanistic studies showed that compound 5a inhibited migration and invasion of MGC-803 and PC-3 dose-dependently. Treatment with compound 5a varied mRNA levels and protein expression of EMT markers in both cells. Collectively, the steroidal ß-triazoly enones could be potentially utilized to develop new anticancer agents with the ability of inhibiting cell migration and invasion.

Restrictive mitral valve annuloplasty for chronic ischaemic mitral regurgitation: outcomes of flexible versus semi-rigid rings.

BACKGROUND: Restrictive mitral annuloplasty is the mainstay of surgical correction of chronic ischaemic mitral regurgitation (CIMR). Long-term data on the various types of annuloplasty rings is limited. The aim of this study was to investigate the clinical and echocardiographic outcomes of restrictive mitral annuloplasty in patients with CIMR, comparing the use of flexible versus semi-rigid annuloplasty rings. METHODS: A retrospective review was conducted for 133 patients with CIMR who underwent restrictive mitral annuloplasty at our institution between 1999 and 2015. Patient demographics and postoperative outcomes were analyzed. RESULTS: Mean age was 61.9±9.2 years and 103 patients (77.4%) were male. All patients underwent coronary artery bypass grafting, with a mean of 3.3±0.8 grafts. Flexible rings was implanted in 39 patients (29.3%, group F) and semi-rigid rings in 94 (70.7%, group R). Preoperative New York Heart Association class was III/IV in 104 patients (78.2%). Mean preoperative left ventricular ejection fraction was 28.8%±10.2%. Preoperative mitral regurgitation was moderate in 51 patients (38.3%) and severe in 82 (61.7%). In-hospital mortality occurred in 11 patients (8.3%). Overall survival at 1, 5 and 10 years were, respectively, 86.4%, 69.7% and 45.9%. At 10 years, overall survival (group F 53.1%, group R 40.0%, P=0.330) and freedom from moderate to severe MR (group F 53.1%, group R 53.8%, P=0.725) did not differ significantly. Freedom from hospitalization for heart failure was 59.3%. Left ventricular reverse remodelling, defined as a reduction of left ventricular end-systolic volume index >15%, occurred more commonly in Group R (51.1%) compared to Group F (23.1%), P=0.003. CONCLUSIONS: Restrictive mitral annuloplasty was associated with an operative mortality of 8.3%. Heart failure symptoms and significant MR recur in approximately 40% of patients after 10 years. Survival remained suboptimal and was not influenced by the type of annuloplasty ring.

Therapeutic Hypothermia May Improve Neurological Outcomes in Extracorporeal Life Support for Adult Cardiac Arrest.

BACKGROUND: Limited data exists on patients receiving therapeutic hypothermia during extracorporeal life support (ECLS). We investigated outcomes and prognostic factors in these patients. METHODS: A retrospective review was conducted for 225 consecutive adult patients treated with ECLS between July 2003 and January 2016. Extracorporeal life support was initiated for refractory cardiac arrest (>10 mins) in 79 patients (35.1%). Patient demographics, ECLS-related complications, in-hospital mortality and neurological outcomes were analysed. RESULTS: The mean age was 49.9±12.4 years. Sixty-two patients (78.5%) were male. The mean duration of CPR and ECLS were respectively, 32.0±23.3 mins and 5.4±4.0 days. Therapeutic hypothermia (34oC) was maintained for 24hours in 14 patients (17.7%). Thirty-five patients (44.3%) were weaned off ECLS. Twenty-one patients (26.6%) survived to hospital discharge with 16 (20.3%) recovering good neurological function. Compared to ECLS at normothermia, neurologically favourable survival was higher in the hypothermia group (42.9% vs 15.4%, p=0.020). Multivariable analysis identified a non-shockable rhythm [odds ratio (OR) 5.1, confidence interval (CI) 1.5-16.8], ischaemic hepatitis (OR 6.2, CI 1.1-33.6) and hypoxic ischaemic encephalopathy (OR 5.1, CI 1.5-17.1) as predictors of in-hospital mortality. Therapeutic hypothermia (OR 4.9, CI 1.2-20.4) and acute renal failure (OR 0.19, CI 0.05-0.70) were predictors of neurologically favourable survival. CONCLUSIONS: In this report of patients treated with ECLS, in-hospital survival and survival with good neurological performance were 26.6% and 20.3% respectively. A non-shockable rhythm, ischaemic hepatitis and hypoxic ischaemic encephalopathy were predictors of in-hospital mortality. Therapeutic hypothermia during ECLS was associated with improved neurological outcomes.

[Plasma fibroblast growth factor-21 and abdominal obesity].

OBJECTIVE: To investigate the association of plasma fibroblast growth factor-21 (FGF-21) with abdominal obesity and other metabolic indicators. METHODS: Sixty one people with abdominal obesity and 113 healthy controls were recruited. The stature, avoirdupois, waist circumference and blood pressure of the participants were measured. Serum lipid, glucose, insulin and plasma FGF-21 levels of those participants were also determined. RESULTS: 1) The participants with abdominal obesity had significantly higher FGF-21 levels than the healthy controls [(1.91 +/- 0.40) ng/mL vs. (1.75 +/- 0.45) ng/mL, P = 0.020]. 2) Plasma FGF-21 levels were positively associated with BMI (r = 0.24, P = 0.001), waist circumference (r = 0.16, P = 0.033), body fat contents (r = 0.24, P = 0.001), and triglycerides (r = 0.16, P = 0.036) after adjustment for age and sex. The multiple liner regression analysis identified BMI, waist circumference, body fat contents, and triglycerides as factors associated with FGF-21 (P < 0.05). 3) Plasma FGF-21 levels were found to be independently associated with abdominal obesity (OR = 2.413, 95% CI 1.115-5.221, P = 0.025). CONCLUSION: FGF-21 is an independent risk factor for abdominal obesity. It is perhaps an important factor in the occurrence and development of abdominal obesity.

[Relationship of 25(OH)VD with bone mass and other indicators in male patients with diabetes mellitus].

OBJECTIVE: To investigate the relationship of serum 25- Hydroxy D with bone mass density and other indicators in male patients with diabetes. METHODS: Bone mass density (BMD), serum 25- HydroxyD (25 (OH)VD) and several other biochemical indicators were measured in 82 male patients with diabetes, among whom 49 had osteoporosis. RESULTS: The diabetic patients with osteoporosis had higher tartrate-resistant acid phosphatase-5b (TRCAP-5b) and lower 25(OH)VD, testosterone (T), Dehydroepiandrosterone sulfate (DHEA-S), and bone-specific alkaline phosphatase (B-ALP) than those without osteoporosis (P < 0.05). The Parathormone (PTH) and albumin-creatinine ratio (UAlb/Cr) also increased in the diabetic patients with osteoporosis, but with no statistical significance. No difference was observed in glycosylated hemoglobin (HBA1c) between the diabetic patients with and without osteoporosis. The serum 25(OH)VD was negatively correlated with the duration of diabetes in both groups (P < 0.05), which was independent from the increase of age. The serum 25(OH)VD was positively correlated with T score of neck, ward, greater trochanter of femur and vertebrae lumbales, and T and DHEA-S in both patients with and without osteoporosis (P < 0.05). The 25(OH)VD was also positively correlated with PTH in the patients with osteoporosis. Negative correlation was noted between 25(OH)VD and B-ALP. There were no correlations between 25(OH)VD and TRCAP-5b, HBA1c and UAlb/Cr. CONCLUSION: Serum 25(OH)VD, T and DHEA-S may play an important role in the development of osteoporosis in male patients with diabetes mellitus.

[The response of serum ghrelin and PYY to oral glucose and steamed-bread tolerance test in nonobese and obese patients with type 2 diabetes].

OBJECTIVE: To investigate the response of serum ghrelin and PYY to oral glucose and steamed-bread load and their relationships to insulin and glucose in nonobese and obese patients with type 2 diabetes. METHODS: Ten obese subjects (Male: waist > or =90 cm, Female: waist > or =80 cm) and eleven nonobese subjects with type 2 diabetes were given oral glucose load and steamed-bread challenge in 2 consecutive days after blood glucose was controlled. The serum levels of ghrelin, PYY, insulin and glucose were measured with routine methods. RESULTS: (1) Either in oral glucose or steamed-bread load tests, both fasting serum PYY and ghrelin levels of obese subjects were significantly lower than those of nonobese subjects. After taking glucose or steamed-bread, all subjects were observed the increase of PYY and ghrelin levels, which reached the peak at 30 min and 60 min respectively. However, there were no significant difference found between nonobese and obese group at 30 min, 60 min and 120 min (P=NS). (2) In all subjects, fasting serum PYY, ghrelin concentrations were inversely associated with waist circumferences and BMI but not WHR. (3) No correlations were observed between serum PYY and insulin, glucose at any time points. The ghrelin and insulin levels showed a correlation at 0 min (r = -0.591, P = 0.005), however, no correlations were found at any other time points. When comparing PYY, ghrelin AUC with the AUC of insulin and glucose, no correlations were found. (4) Ghrelin level was positively correlated with QUICKI, however, no correlation between PYY concentrations and QUICKI was noted. CONCLUSIONS: In the subjects with type 2 diabetes, both PYY and ghrelin respond differently to glucose and bread, athough the calories are similar. PYY and ghrelin levels are inversely related to waist and BMI but not WHR. It is fasting ghrelin not PYY negatively associated with fasting insulin and positively with QUICKI.

[Impact of human isophane insulin on the evaluation of beta cell functions].

OBJECTIVE: To evaluate the beta cell functions with and without human Isophane insulin treatments. METHODS: Thirty patients with type 2 diabetes mellitus who followed the human Isophane insulin therapeutic regimen at bedtime were given 100 g steamed bread tests in two consecutive days. Then the human Isophane insulin treatments were stopped and the 100 g steamed bread tests were repeated in the next day. The fasting and 1, 2, 3 h after meal plasma glucose, serum insulin, C-peptide and proinsulin were measured. RESULTS: (1) The fasting and 1,2,3 h after meal plasma glucose increased while the serum insulin decreased after the human Isophane insulin treatments were stopped (P<0.05). (2) The fasting and 1, 2 h after meal C peptide increased (P<0.05) after the human Isophane insulin treatments were stopped. (3) The fasting and 1, 2, 3 h after meal proinsulin increased after the human isophane insulin treatments were stopped (P<0.05). (4) The area under the insulin curve decreased, while, the area under the C peptide increased after the human Isophane insulin treatments were stopped (P<0.05). CONCLUSION: Human Isophane insulin treatments should not be stopped to evaluate the beta cell functions of the patients who are undergoing Isophane insulin treatment.