Autophagy inhibitors 3-MA and BAF may attenuate hippocampal neuronal necroptosis after global cerebral ischemia-reperfusion injury in male rats by inhibiting the interaction of the RIP3/AIF/CypA complex.

Our previous study found that receptor interacting protein 3 (RIP3) and apoptosis-inducing factor (AIF) were involved in neuronal programmed necrosis during global cerebral ischemia-reperfusion (I/R) injury. Here, we further studied its downstream mechanisms and the role of the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 (BAF). A 20-min global cerebral I/R injury model was constructed using the 4-vessel occlusion (4-VO) method in male rats. 3-MA and BAF were injected into the lateral ventricle 1 h before ischemia. Spatial and activation changes of proteins were detected by immunofluorescence (IF), and protein interaction was determined by immunoprecipitation (IP). The phosphorylation of H2AX (γ-H2AX) and activation of mixed lineage kinase domain-like protein (p-MLKL) occurred as early as 6 h after reperfusion. RIP3, AIF, and cyclophilin A (CypA) in the neurons after I/R injury were spatially overlapped around and within the nucleus and combined with each other after reperfusion. The survival rate of CA1 neurons in the 3-MA and BAF groups was significantly higher than that in the I/R group. Autophagy was activated significantly after I/R injury, which was partially inhibited by 3-MA and BAF. Pretreatment with both 3-MA and BAF almost completely inhibited nuclear translocation, spatial overlap, and combination of RIP3, AIF, and CypA proteins. These findings suggest that after global cerebral I/R injury, RIP3, AIF, and CypA translocated into the nuclei and formed the DNA degradation complex RIP3/AIF/CypA in hippocampal CA1 neurons. Pretreatment with autophagy inhibitors could reduce neuronal necroptosis by preventing the formation of the RIP3/AIF/CypA complex and its nuclear translocation.

Cauchy combination methods for the detection of gene-environment interactions for rare variants related to quantitative phenotypes.

The characterization of gene-environment interactions (GEIs) can provide detailed insights into the biological mechanisms underlying complex diseases. Despite recent interest in GEIs for rare variants, published GEI tests are underpowered for an extremely small proportion of causal rare variants in a gene or a region. By extending the aggregated Cauchy association test (ACAT), we propose three GEI tests to address this issue: a Cauchy combination GEI test with fixed main effects (CCGEI-F), a Cauchy combination GEI test with random main effects (CCGEI-R), and an omnibus Cauchy combination GEI test (CCGEI-O). ACAT was applied to combine p values of single-variant GEI analyses to obtain CCGEI-F and CCGEI-R and p values of multiple GEI tests were combined in CCGEI-O. Through numerical simulations, for small numbers of causal variants, CCGEI-F, CCGEI-R and CCGEI-O provided approximately 5% higher power than the existing GEI tests INT-FIX and INT-RAN; however, they had slightly higher power than the existing GEI test TOW-GE. For large numbers of causal variants, although CCGEI-F and CCGEI-R exhibited comparable or slightly lower power values than the competing tests, the results were still satisfactory. Among all simulation conditions evaluated, CCGEI-O provided significantly higher power than that of competing GEI tests. We further applied our GEI tests in genome-wide analyses of systolic blood pressure or diastolic blood pressure to detect gene-body mass index (BMI) interactions, using whole-exome sequencing data from UK Biobank. At a suggestive significance level of 1.0 × 10-4, KCNC4, GAR1, FAM120AOS and NT5C3B showed interactions with BMI by our GEI tests.

Oxytocin infusion for maintenance of uterine tone under prophylactic phenylephrine infusion for prevention of post-spinal hypotension in cesarean delivery: a prospective randomised double-blinded dose-finding study.

BACKGROUND: Prior studies have shown that, when administered as an intravenous bolus to prevent uterine atony, prophylactic phenylephrine infusion increased the dose requirement of oxytocin and second-line uterotonics. For the prevention of uterine atony, oxytocin should be delivered by continuous infusion. Here, we aimed to determine the ED50 and ED90 parameters (the effective doses for 50 and 90% patients without uterine atony) of oxytocin for co-infusion with prophylactic phenylephrine during cesarean delivery. METHODS: In this prospective randomized double-blinded dose-finding study, one hundred patients were divided into four groups to receive 2.5, 5.0, 7.5, or 10 IU/h oxytocin infusion, after the umbilical cord was clamped during the study period. The uterine tone was evaluated and defined as either adequate or inadequate. Probit regression analysis was applied to calculate the ED50 and ED90 of oxytocin infusion. Uterine tone, the percentage of patients who needed additional oxytocin bolus, second-line uterotonics, side effects, estimated blood loss, and neonatal outcomes were monitored. RESULTS: The estimated ED50 and ED90 values of the oxytocin infusion doses for the prevention of uterine atony were 1.9 IU/h (95% CI -4.6-3.8) IU/h and 9.3 IU/h (95% CI 7.3-16.2) IU/h, respectively. Across groups, there was a significant linear trend between the infusion dose and the percentage of patients who required additional oxytocin (p-value = 0.002). No differences were observed in the incidence of side effects and neonatal outcomes. CONCLUSION: Under the conditions of this study, the ED90 of oxytocin infusion for the prevention of uterine atony was 9.3 IU/h, which is higher than the current recommendation. This finding is helpful for clinical practice, because of the routine use of phenylephrine in cesarean delivery. Further studies are needed to determine the appropriate initial bolus of oxytocin after neonatal delivery. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial Register (register no. ChiCTR2200059556 ).

Resveratrol suppresses microglial activation and promotes functional recovery of traumatic spinal cord via improving intestinal microbiota.

Spinal cord injury (SCI) can change the intestinal microbiota pattern and corresponding metabolites, which in turn affect the prognosis of SCI. Among many metabolites, short-chain fatty acids (SCFAs) are critical for neurological recovery after SCI. Recent research has shown that resveratrol exerts anti-inflammatory properties. But it is unknown if the anti-inflammatory properties of resveratrol are associated with intestinal microbiota and metabolites. We thus investigate the alteration in gut microbiota and the consequent change of SCFAs following resveratrol treatment. The SCI mouse models with retention of gut microbiota (donor) and depletion of gut microbiota (recipient) were established. Fecal microbiota transplantation from donors to recipients was performed with intragastrical administration. Spinal cord tissues of mice were examined by H&E, Nissl, and immunofluorescence stainings. The expressions of the inflammatory profile were examined by qPCR and cytometric bead array. Fecal samples of mice were collected and analyzed with 16S rRNA sequencing. The results showed that resveratrol inhibited the microglial activation and promoted the functional recovery of SCI. The analysis of intestinal microbiota and metabolites indicated that SCI caused dysbiosis and the decrease in butyrate, while resveratrol restored microbiota pattern, reversed intestinal dysbiosis, and increased the concentration of butyrate. Both fecal supernatants from resveratrol-treated donors and butyrate suppressed the expression of pro-inflammatory genes in BV2 microglia. Our result demonstrated that fecal microbiota transplantation from resveratrol-treated donors had beneficial effects on the functional recovery of SCI. One mechanism of resveratrol effects was to restore the disrupted gut microbiota and butyrate.

Association of CHA2DS2-VASC Score with in-Hospital Cardiovascular Adverse Events in Patients with Acute ST-Segment Elevation Myocardial Infarction.

Background: Acute ST-elevation myocardial infarction (STEMI) is a common clinical critical illness, and accurate, reliable, simple, and easy-to-remember tools are needed in clinical practice to quickly identify the risk of this condition in STEMI patients. This study investigates the predictive value of the admission CHA2DS2-VASc score for in-hospital MACE in STEMI patients. Methods: A total of 210 STEMI patients who visited the Chest Pain Center of the Second People's Hospital of Hefei from December 2019 to December 2021 were retrospectively analyzed. They were divided into MACE and non-MACE groups. The receiver operating characteristic curve (ROC) was used to assess the predictive value of the CHA2DS2-VASc score for MACE events during hospitalization. Results: The CHA2DS2-VASc score was higher in the MACE group than in the non-MACE group (P < 0.05), and multivariate logistic regression analysis showed that the CHA2DS2-VASc score was an independent risk factor for MACE events during hospitalization in STEMI patients (OR = 1.391, 95%CI 1.044-1.853, P=0.024); ROC curve analysis showed that the area under the curve (AUC) of the CHA2DS2-VASc score was 0.744, the sensitivity was 0.64, the specificity was 0.694, and the optimal cutoff value was 3.5 in predicting the risk of MACE events during hospitalization in STEMI patients. There were no significant differences between the GRACE score (0.744 VS.0.827) and TIMI score (0.744VS.0.745) (P > 0.05). Conclusion: The CHA2DS2-VASc score can successfully predict the occurrence of in-hospital MACE events in STEMI patients.

A machine-learning approach to discerning prevalence and causes of myopia among elementary students in Hubei.

OBJECTIVE: Our aim is to establish a machine-learning model that will enable us to investigate the key factors influencing the prevalence of myopia in students. METHODS: We performed a cross-sectional study that included 16,653 students from grades 1-3 across 17 cities in Hubei Province. We used questionnaires to discern levels of participation in potential factors contributing to the development of myopia. The relative importance of potential contributors was ranked using machine-learning methods. The students' visual acuity (VA) was measured and those with logMAR VA of > 0.0 underwent a autorefraction test to determine students' refraction status. RESULTS: The prevalence of myopia in grades 1, 2, and 3 was 14.70%, 20.54% and 28.93%, respectively. Myopia rates among primary school students in provincial capital city (32.35%) were higher than those in other urban (23.03%) and rural (14.82%) areas. Children with non-myopic parents, only one myopic parent, or both parents having myopia exhibited myopic rates of 16.36%, 25.18%, and 41.37%, respectively. Myopia prevalence was higher in the students who continued to use their eyes at close range for a long time and lower in those engaged longer in outdoor activities. The machine-learning model determined that the top three contributing factors were the students' age (0.36), followed by place of residence (0.34), starting age of education (0.21). CONCLUSION: The overall prevalence of myopia was 21.52%. Children's age and place of residence were the important influencing factors, but genetics and environmental were also played key roles in myopia development.

Surgical management of Helveston syndrome (Triad exotropia).

PURPOSE: To evaluate and compare different surgical approaches for the treatment of Helveston syndrome and provide further information for preoperative planning. METHODS: From February 2008 to December 2018, data of 52 patients with Helveston syndrome were retrospectively reviewed. Different surgical approaches were selected based on the extent of A-pattern exotropia, dissociated vertical deviation (DVD), and both superior oblique muscle overaction (SOOA) with fundus photograph intorsion. Eye position, A-pattern, DVD, superior oblique muscle function, and binocular vision function were evaluated pre- and postoperatively. The average follow-up duration was 20.5 months. RESULTS: Nine cases underwent simultaneous horizontal deviation correction with bilateral superior rectus recession, 24 underwent simultaneous horizontal deviation correction with bilateral superior oblique muscle lengthening, and 19 underwent two stages of horizontal deviation correction with superior oblique muscle lengthening, and later bilateral superior rectus recession. A-pattern, DVD, SOOA, and fundus intorsion were all collapsed in all patients postoperatively. Forty-five patients had an orthophoric eye position with considerably aligned ocular movements postoperatively. The total success rate was 86.5%. Postoperatively, eight of the 10 patients with diplopia experienced a recovery of binocular single vision and three had a recovery of rudimentary stereopsis (Titmus 3000-400 s of arc). The compensatory head posture of patients improved significantly postoperatively. CONCLUSIONS: The surgical planning of Helveston syndrome should be designed based on the degree of the A-pattern, SOOA, DVD, and the intorsion in fundus photographs, and the appropriate approach should be selected to improve patient satisfaction.

Expression and localization of Sox10 during hair follicle morphogenesis and induced hair cycle.

Sox transcription factors play many diverse roles during development, including regulating stem cell states, directing differentiation, and influencing the local chromatin landscape. Sox10 has been implicated in the control of stem/progenitor activity and epithelial-mesenchymal transition, yet it has not been studied in relation to the hair follicle cycle or hair follicle stem cell (HFSC) control. To elucidate the role of Sox10 in hair follicle cycle control, we performed immunohistochemical and immunofluorescence analysis of its expression during hair morphogenesis, the postnatal hair cycle, and the depilation-induced murine hair follicle cycle. During hair follicle morphogenesis, Sox10 was expressed in the hair germ and peg. In telogen, we detected nuclear Sox10 in the hair bulge and germ cell cap, where HFSCs reside, while in anagen and catagen, Sox10 was detected in the epithelial portion, such as the strands of keratinocytes, the outer root sheath (ORS) in anagen, and the regressed epithelial strand of hair follicle in catagen. These results suggest that Sox10 may be involved in early hair follicle morphogenesis and postnatal follicular cycling.

Active Transportation of Liposome Enhances Tumor Accumulation, Penetration, and Therapeutic Efficacy.

Liposomes are the first and mostly explored nanocarriers for cancer drug delivery, which have shown great promise in clinical applications, but their limited accumulation and penetration into the tumor interstitial space, significantly reduce the therapeutic efficacy. Here, a γ-glutamyltranspeptidase (GGT)-triggered charge-switchable approach is reported that can trigger the fast endocytosis and transcytosis of the liposome in tumor microenvironments to overcome the harsh biological barriers in tumor tissues. The active transporting liposomal nanocarrier (GCSDL) is prepared by surface modification with a glutathione (GSH) moiety and encapsulated with doxorubicin (DOX). When the GCSDL contacts with tumor vascular endothelial cells, the overexpressed GGT enzyme on cytomembrane catalyzes the hydrolysis of GSH to generate cationic primary amines. The cationic GCSDL triggers fast caveolae-mediated endocytosis and vesicle-mediated transcytosis, resulting in sequential transcytosis to augment its tumor accumulation and penetration. Along with continual intercellular transportation, GCSDL can release DOX throughout the tumor to induce cancer cell apoptosis, resulting in complete eradication of hepatocellular carcinoma and cessation of pancreatic ductal adenocarcinoma's progression. This study develops an efficient strategy to realize high tumor accumulation and deep penetration for the liposomal drug delivery system via active transcytosis.

A sensitive LC-MS/MS method to determine ginkgolide B in human plasma and urine: application in a pharmacokinetics and excretion study of healthy Chinese subjects.

1. Ginkgolide B (GB), the most active of the ginkgolides, has been developed as a new drug for the treatment of vascular insufficiency; however, the pharmacokinetics of GB remain unclear. Here, we investigated the pharmacokinetics and urine excretion properties of GB in healthy Chinese subjects administered single- and multiple-dose injectable GB based on a new LC-MS/MS method.2. GB pharmacokinetics were found to be dose-dependent from 20 to 60 mg. GB reached a steady state by day 6 with once-daily dosing at 40 mg. Systemic exposure to GB, as characterised by AUC0-∞, indicated accumulation following repeated once-daily dosing for seven consecutive days. The mean urinary cumulative excretion rate of GB in response to 20, 40, and 60 mg GB was 41.9 ± 18.5%, 32.9 ± 12.2%, and 43.9 ± 8.5%, respectively.3. Dose-proportional pharmacokinetics of GB were observed after intravenous administration in healthy subjects. A gradual reduction in the volume of distribution and slight change in mean resistance time led us to conjecture the limited accumulation of GB based on distribution equilibrium in vivo.4. This comprehensive study of the clinical pharmacokinetics of GB will provide useful information for its application and further development.

Upregulating MicroRNA-203 Alleviates Myocardial Remodeling and Cell Apoptosis Through Downregulating Protein Tyrosine Phosphatase 1B in Rats With Myocardial Infarction.

Myocardial infarction (MI) is one of cardiovascular diseases with high incidence and mortality. MicroRNAs, as posttranscriptional regulators of genes, are involved in many diseases, including cardiovascular diseases. The aim of the present study was to determine whether miR-203 was functional in MI therapy and how it worked. Left anterior descending artery ligation and hypoxia/reoxygenation (H/R) treatment were, respectively, performed to obtain MI rats and hypoxia-injured H9c2 cells. Western blot and quantitative real-time polymerase chain reaction were used to determine protein levels and messenger RNA of relevant genes, respectively. Lentivirus-mediated overexpression of miR-203 was performed to study the miR-203 functions on left ventricular remodeling, infarct size, and cardiomyocyte apoptosis. Compared with the sham group, miR-203 levels were significantly decreased in MI and H/R groups. However, overexpressing miR-203 greatly improved the cardiac function, reduced infarct size in rats after MI and weakened infarction-induced apoptosis by increasing Bcl-2 and reducing decreasing Bax, cleaved caspase-3, and cleaved caspase-9. In addition, Protein tyrosine phosphatase 1B (PTP1B) was proved as a target of miR-203 in cardiomyocytes, and it was negatively regulated by miR-203. Further experiments indicated that PTP1B overexpression could remarkably inhibit miR-203-mediated antiapoptosis of cardiomyocytes and alleviate protective effects of miR-203 on mitochondria after H/R treatment. Altogether, miR-203 prevented infarction-induced apoptosis by regulating PTP1B, including reducing proapoptosis proteins, inactivating caspase pathway, and protecting mitochondria. In conclusion, miR-203 had abilities to alleviate MI-caused injury on myocardium tissues and reduce mitochondria-mediated apoptosis, which might be a potential target used for MI therapy.

Determination of lacidipine in human plasma by LC-MS/MS: Application in a bioequivalence study
.

OBJECTIVE: This study aimed to conduct a sensitive, simple, and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of lacidipine in human plasma. MATERIALS AND METHODS: In this method, the plasma samples were extracted from human plasma using methanol as the precipitant and nisoldipine as internal standard (IS). The analytes were separated on a Phenomenex Luna C18 column (150 mm × 2.0 mm, 3 µm) at 40 °C using isocratic mobile phase consisting of 0.2% formic acid-methanol (13 : 87, v/v) at a flow rate of 0.2 mL/min. The tandem mass detection was constructed on a triple-quadrupole tandem mass spectrometer with an electrospray ionization (ESI) source operating in positive-ion mode. The selected reaction monitoring of transitions was m/z 456.2 → 354.2 for lacidipine and m/z 389.2 → 315.0 for IS, respectively. Then, the established method was applied in a bioequivalence study comparing lacidipine dispersible tablet with commercial tablet in 20 healthy Chinese subjects. RESULTS: The calibration curve exhibited great linearity in the range of 0.10 - 10.00 ng/mL (r2 = 0.999). The intraday and interday precision and accuracy met the acceptance criteria, and no matrix effect was found. In addition, the 90% confidence intervals for the test/reference ratio of Cmax, AUC0-24, and AUC0-∞ fell within the bioequivalence acceptance criteria (80 - 125%). CONCLUSION: The method is suitable for quantification of lacidipine in human plasma. Moreover, the two preparations are bioequivalent.
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Effects of surgical trauma and intraoperative blood loss on tumour progression.

Surgery is the primary treatment of choice for tumours, and improves prognosis, prolongs survival and is potentially curative. Previous studies have described the effects of anaesthesia and changes in the neuroendocrine, circulatory and sympathetic nervous systems on postoperative cancer progression. There is growing evidence that intraoperative blood loss is an independent prognostic factor for tumour recurrence, postoperative inflammation is a predictor of cancer prognosis, and immunosuppressive status correlates with the degree of surgical damage. This paper outlines the potential mechanisms by which blood loss, surgical trauma and postoperative immunosuppressive status contribute to tumour growth and recurrence by reducing intraoperative haemorrhage and perioperative immunotherapy, thereby reducing tumour growth and recurrence, and improving long-term prognosis.

Highest order moderation of extraversion and neuroticism into the relationship between job stress and flourishing: Mediated by readiness to change among Chinese medical teachers.

This study investigates the mediating role of Readiness to Change in the relationship between job stress and flourishing among Chinese medical teachers, as well as the highest order moderation of Extraversion and Neuroticism into this relationship. The research utilized a quantitative approach, surveying a sample of Chinese Medical Education teachers (N = 500) consisted of 342 males and 158 females with an age range between 30 and 65 (M = 43.69; SD = 9.31). The average tenure in the education landscape was 12.39 years (SD = 10.91) through an online platform. The primary aim was to explore how readiness attitudes influence the well-being and work capacity of Teachers in high-stress medical teaching environments. The survey incorporated self-assessment instruments to measure job stress, Readiness to Change attitudes, levels of flourishing, and personality traits (Extraversion and Neuroticism). Statistical analyses, including mediation models, were employed to test the relationships between these variables. Preliminary findings suggest a significant mediating role of Readiness to Change into the effects of job stress on flourishing and a moderation of extraversion into this relationship. The findings also failed to support the moderation of Neuroticism into the relationships, while the Higher order moderation showed a statistical marginal value. This indicates that effective readiness attitudes may not only mitigate the negative impacts of job stress but also enhance personal well-being and professional capacity. These results hold critical implications for the development of support systems and interventions aimed at fostering resilience and adaptive skills among medical teachers. Such initiatives could potentially improve job satisfaction, mental health, and teaching effectiveness in medical education settings. The study contributes to the growing body of literature on occupational stress and coping mechanisms in the educational sector, particularly within the field of medical education.

Development and validation of a nomogram for predicting heterotopic ossification following spinal cord injury.

OBJECTIVE: Heterotopic ossification (HO) following spinal cord injury (SCI) can severely compromise patient mobility and quality of life. Precise identification of SCI patients at an elevated risk for HO is crucial for implementing early clinical interventions. While the literature presents diverse correlations between HO onset and purported risk factors, the development of a predictive model to quantify these risks is likely to bolster preventive approaches. This study is designed to develop and validate a nomogram-based predictive model that estimates the likelihood of HO in SCI patients, utilizing recognized risk factors to expedite clinical decision-making processes. METHODS: We recruited a total of 145 patients with SCI and presenting with HO who were hospitalized at the China Rehabilitation Research Center, Beijing Boai Hospital, from June 2016 to December 2022. Additionally, 337 patients with SCI without HO were included as controls. Comprehensive data were collected for all study participants, and subsequently, the dataset was randomly partitioned into training and validation groups. Using Least Absolute Shrinkage and Selection Operator regression, variables were meticulously screened during the pretreatment phase to formulate the predictive model. The efficacy of the model was then assessed using metrics including receiver-operating characteristic (ROC) analysis, calibration assessment, and decision curve analysis. RESULTS: The final prediction model incorporated age, sex, complete spinal cord injury status, spasm occurrence, and presence of deep vein thrombosis (DVT). Notably, the model exhibited commendable performance in both the training and validation groups, as evidenced by areas under the ROC curve (AUCs) of 0.756 and 0.738, respectively. These values surpassed the AUCs obtained for single variables, namely age (0.636), sex (0.589), complete spinal cord injury (0.681), spasm occurrence (0.563), and DVT presence (0.590). Furthermore, the calibration curve illustrated a congruence between the predicted and actual outcomes, indicating the high accuracy of the model. The decision curve analysis indicated substantial net benefits associated with the application of the model, thereby underscoring its practical utility. CONCLUSIONS: HO following SCI correlates with several identifiable risk factors, including male gender, youthful age, complete SCI, spasm occurrence and DVT. Our predictive model effectively estimates the likelihood of HO development by leveraging these factors, assisting physicians in identifying patients at high risk. Subsequently, correct positioning to prevent spasm-related deformities and educating healthcare providers on safe lower limb mobilization techniques are crucial to minimize muscle injury risks from rapid iliopsoas muscle extension. Additionally, the importance of early DVT prevention through routine screening and anticoagulation is emphasized to further reduce the incidence of HO.

[Effects of acupuncture on fecal short-chain fatty acids and TLR4/MyD88/NF-κB signaling pathway in spontaneously hypertensive rats].

OBJECTIVE: To observe the effects of acupuncture on blood pressure, fecal short-chain fatty acids (SCFAs) and toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway in spontaneously hypertensive rats (SHR), and to explore the mechanism of acupuncture for anti-hypertension. METHODS: Twenty-four male SHR of SPF grade were randomly divided into a model group, a western medication group, an acupuncture group and a sham acupuncture group, with 6 rats in each group, and 6 male Wistar-Kyoto rats were selected as the blank group additionally. Hydrochlorothiazide solution was given by gavage in the western medication group; acupuncture was applied at bilateral "Renying" (ST 9) and "Zusanli" (ST 36) in the acupuncture group, 20 min a time; acupuncture was applied at the non-meridian and non-acupoint points close to bilateral "Renying" (ST 9) and "Zusanli" (ST 36) in the sham acupuncture group, 20 min a time. The intervention was adopted once a day for 4 weeks continuously in each group. The systolic blood pressure (SBP) of the caudal artery was measured before intervention and after 1, 2, 3 and 4 weeks of intervention. After intervention, the morphology of colonic tissue was observed by HE staining; the fecal level of SCFAs was detected by gas chromatography; the serum levels of interleukin (IL)-6, IL-1ßand tumor necrosis factor-α (TNF-α) were detected by ELISA; the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was detected by Western blot. RESULTS: Compared with the blank group, in the model group, the SBP was increased (P<0.05), significant pathological changes could be found in the colonic tissue, the fecal SCFAs level was decreased (P<0.05), the serum levels of IL-6, IL-1ß and TNF-α were increased (P<0.05), the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was increased (P<0.05). Compared with the model group, the SBP after 2, 3 and 4 weeks of intervention was decreased (P<0.05), the serum levels of IL-6, IL-1ß and TNF-α were decreased (P<0.05) in the acupuncture group and the western medication group; the mucosal epithelium of colonic tissue was intact, the number of intestinal glands was abundant, the fecal SCFAs level was increased (P<0.05), and the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was decreased (P<0.05) in the acupuncture group. Compared with the sham acupuncture group, the SBP after 2, 3 and 4 weeks of intervention was decreased (P<0.05), the fecal SCFAs level was increased (P<0.05), the serum levels of IL-6, IL-1ß and TNF-α were decreased (P<0.05), the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was decreased (P<0.05) in the acupuncture group. CONCLUSION: Acupuncture at bilateral "Renying" (ST 9) and "Zusanli" (ST 36) can effectively play an anti-hypertensive role in SHR. Its mechanism may be related to regulating fecal SCFAs level and inhibiting the TLR4/MyD88/NF-κB signaling pathway.

Association of overweight, obesity and risk of urinary incontinence in middle-aged and older women: a meta epidemiology study.

Aims: The aim of this meta-analysis is to evaluate the potential correlation between obesity and overweight, and the vulnerability to urinary incontinence (UI) in women aged middle-aged and above. Methods: We searched PubMed, Cochrane Library, and Embase for observational studies published between the inception of the databases and April 25, 2023. A fixed-effects model was used when the P>0.1 and the I2 ≤ 50%. In cases where I2 ≥ 50% (indicating significant heterogeneity), a random-effects model was applied. For the purpose of evaluating publication bias, a funnel plot and Egger's test were used. Stata 14.0 was used for all statistical analyses. Findings: This meta-analysis includes 16 observational studies, covering29,618 individuals. The pooled analysis shows that being overweight(25 kg/m2≤BMI<30kg/m2) in middle-aged and elderly women is more likely to develop UI (OR=1.27; 95% CI: 1.17-1.37; I2 = 51.8%, P=0.013). Middle-aged and elderly women with obesity(30 kg/m2≤BMI<35 kg/m2) are significantly more likely to develop UI (OR=1.60; 95% CI: 1.42-1.81; I2 = 71.8%, P=0.000). In addition, the results indicated a higher probability of UI in middle-aged and older women with obesity class II (BMI≥35 kg/m2) (OR=1.85; 95% CI: 1.59-2.16; I2 = 48.1%, P=0.103). In subgroup analysis, there is no direct relationship between the obesity in middle-aged and elderly women and an increased risk of stress urinary incontinence (SUI) (OR=1.31; 95% CI: 0.99-1.74; I2 = 63.7%, P=0.011). In middle-aged and elderly women with obesity are more likely to develop urgent urinary incontinence (UUI) (OR=2.11; 95% CI: 1.54-2.89; I2 = 80.2%, P=0.000). Conclusion: In this meta-analysis, overweight and obesity are associated with an increased risk of UI in middle-aged and elderly women. Obesity and overweight are independent risk factors for UI, as demonstrated by this study. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023421986.

Acteoside improves adipocyte browning by CDK6-mediated mTORC1-TFEB pathway.

Adipocyte browning increases energy expenditure by thermogenesis, which has been considered a potential strategy against obesity and its related metabolic diseases. Phytochemicals derived from natural products with the ability to improve adipocyte thermogenesis have aroused extensive attention. Acteoside (Act), a phenylethanoid glycoside, exists in various medicinal or edible plants and has been shown to regulate metabolic disorders. Here, the browning effect of Act was evaluated by stimulating beige cell differentiation from the stromal vascular fraction (SVF) in the inguinal white adipose tissue (iWAT) and 3T3-L1 preadipocytes, and by converting the iWAT-SVF derived mature white adipocytes. Act improves adipocyte browning by differentiation of the stem/progenitors into beige cells and by direct conversion of mature white adipocytes into beige cells. Mechanistically, Act inhibited CDK6 and mTOR, and consequently relieved phosphorylation of the transcription factor EB (TFEB) and increased its nuclear retention, leading to induction of PGC-1α, a driver of mitochondrial biogenesis, and UCP1-dependent browning. These data thus unveil a CDK6-mTORC1-TFEB pathway that regulates Act-induced adipocyte browning.

Efficacy and safety of daratumumab in the treatment of relapsed/refractory multiple myeloma: A meta-analysis of randomized controlled trials.

BACKGROUND: Daratumumab as a monoclonal antibody has shown promising results in the treatment of relapsed/refractory multiple myeloma (RRMM). However, the efficacy and safety of daratumumab-based regimens compared to control regimens have not been fully established. METHODS: The search was conducted using electronic databases (PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases) up to December 2022. We conducted a meta-analysis of randomized controlled trials that evaluated the efficacy and safety of daratumumab in the treatment of RRMM. Data were extracted from eligible studies and were presented as hazard ratio or risk ratio (RR) with 95% confidence interval (CI). RESULTS: A total of 5 randomized controlled trials comprising 2003 patients were included in this meta-analysis. The results showed that daratumumab-based regimens significantly improved progression-free survival compared to control regimens (hazard ratio = 0.44, 95% CI 0.32-0.60, P < .00001). Additionally, daratumumab-based regimens significantly improved overall response rate compared to control regimens (RR = 1.25, 95% CI 1.16-1.36, P < .00001). the rate of minimal residual disease was also significantly higher in the daratumumab-based regimens (RR = 6.10, 95% CI 4.09-9.11, P < .00001). However, there was an increased risk of pneumonia, upper respiratory tract infections, and diarrhea in the daratumumab-based regimens. CONCLUSION: Our results suggest that daratumumab-based regimens are effective in the treatment of RRMM, improving progression-free survival, minimal residual disease, and overall response rate. However, there is an increased risk of pneumonia, upper respiratory tract infections, and diarrhea. Further studies are needed to determine the long-term safety and efficacy of daratumumab in the treatment of multiple myeloma.

Kernel-based gene-environment interaction tests for rare variants with multiple quantitative phenotypes.

Previous studies have suggested that gene-environment interactions (GEIs) between a common variant and an environmental factor can influence multiple correlated phenotypes simultaneously, that is, GEI pleiotropy, and that analyzing multiple phenotypes jointly is more powerful than analyzing phenotypes separately by using single-phenotype GEI tests. Methods to test the GEI for rare variants with multiple phenotypes are, however, lacking. In our work, we model the correlation among the GEI effects of a variant on multiple quantitative phenotypes through four kernels and propose four multiphenotype GEI tests for rare variants, which are a test with a homogeneous kernel (Hom-GEI), a test with a heterogeneous kernel (Het-GEI), a test with a projection phenotype kernel (PPK-GEI) and a test with a linear phenotype kernel (LPK-GEI). Through numerical simulations, we show that correlation among phenotypes can enhance the statistical power except for LPK-GEI, which simply combines statistics from single-phenotype GEI tests and ignores the phenotypic correlations. Among almost all considered scenarios, Het-GEI and PPK-GEI are more powerful than Hom-GEI and LPK-GEI. We apply Het-GEI and PPK-GEI in the genome-wide GEI analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the UK Biobank. We analyze 18,101 genes and find that LEUTX is associated with SBP and DBP (p = 2.20×10-6) through its interaction with hemoglobin. The single-phenotype GEI test and our multiphenotype GEI tests Het-GEI and PPK-GEI are also used to evaluate the gene-hemoglobin interactions for 22 genes that were previously reported to be associated with SBP or DBP in a meta-analysis of genetic main effects. MYO1C shows nominal significance (p < 0.05) by the Het-GEI test. NOS3 shows nominal significance in DBP and MYO1C in both SBP and DBP by the single-phenotype GEI test.