Long-term hypertension causes excessive vascular remodeling and leads to adverse cardiovascular events. Balance of ubiquitination and deubiquitination has been linked to several chronic conditions, including pathological vascular remodeling. In this study, we discovered that the expression of ubiquitin-specific protease 25 (USP25) is significantly up-regulated in angiotensin II (Ang II)-challenged mouse aorta. Knockout of Usp25 augments Ang II-induced vascular injury such as fibrosis and endothelial to mesenchymal transition (EndMT). Mechanistically, we found that USP25 interacts directly with Forkhead box O3 (FOXO3) and removes the K63-linked ubiquitin chain on the K258 site of FOXO3. We also showed that this USP25-mediated deubiquitination of FOXO3 increases its binding to light chain 3 beta isoform and autophagosomic-lysosomal degradation of FOXO3. In addition, we further validated the biological function of USP25 by overexpressing USP25 in the mouse aorta with AAV9 vectors. Our studies identified FOXO3 as a new substrate of USP25 and showed that USP25 may be a potential therapeutic target for excessive vascular remodeling-associated diseases.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

Objective: To investigate the surgical indications and perioperative clinical outcomes of pelvic exenteration (PE) for locally advanced, recurrent pelvic malignancies and complex pelvic fistulas. Methods: This was a descriptive study.The indications for performing PE were: (1) locally advanced, recurrent pelvic malignancy or complex pelvic fistula diagnosed preoperatively by imaging and pathological examination of a biopsy; (2)preoperative agreement by a multi-disciplinary team that non-surgical and conventional surgical treatment had failed and PE was required; and (3) findings on intraoperative exploration confirming this conclusion.Contraindications to this surgical procedure comprised cardiac and respiratory dysfunction, poor nutritional status,and mental state too poor to tolerate the procedure.Clinical data of 141 patients who met the above criteria, had undergone PE in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2018 to September 2022, had complete perioperative clinical data, and had given written informed consent to the procedure were collected,and the operation,relevant perioperative variables, postoperative pathological findings (curative resection), and early postoperative complications were analyzed. Results: Of the 141 included patients, 43 (30.5%) had primary malignancies, 61 (43.3%) recurrent malignancies, 28 (19.9%) complex fistulas after radical resection of malignancies,and nine (6.4%)complex fistulas caused by benign disease. There were 79 cases (56.0%) of gastrointestinal tumors, 30 cases (21.3%) of reproductive tumors, 16 cases (11.3%) of urinary tumors, and 7 cases (5.0%) of other tumors such mesenchymal tissue tumors. Among the 104 patients with primary and recurrent malignancies, 15 patients with severe complications of pelvic perineum of advanced tumors were planned to undergo palliative PE surgery for symptom relief after preoperative assessment of multidisciplinary team; the other 89 patients were evaluated for radical PE surgery. All surgeries were successfully completed. Total PE was performed on 73 patients (51.8%),anterior PE on 22 (15.6%),and posterior PE in 46 (32.6%). The median operative time was 576 (453,679) minutes, median intraoperative blood loss 500 (200, 1 200) ml, and median hospital stay 17 (13.0,30.5)days.There were no intraoperative deaths. Of the 89 patients evaluated for radical PE surgery, the radical R0 resection was achieved in 64 (71.9%) of them, R1 resection in 23 (25.8%), and R2 resection in two (2.2%). One or more postoperative complications occurred in 85 cases (60.3%), 32 (22.7%)of which were Clavien-Dindo grade III and above.One patient (0.7%)died during the perioperative period. Conclusion: PE is a valid option for treating locally advanced or recurrent pelvic malignancies and complex pelvic fistulas.
Humans ; Pelvic Exenteration/methods* ; Pelvic Neoplasms/surgery* ; Retrospective Studies ; Neoplasm Recurrence, Local/surgery* ; Postoperative Complications

Objective: To compare the effects of 3 treatment strategies (emergent surgery, self-expanding metallic stents, self-expanding metallic stents plus neoadjuvant chemotherapy) on postoperative anal function and quality of life in patients with complete obstructive left hemicolon cancer. Methods: A retrospective cohort study was conducted. Clinical data of patients with complete obstructive left hemicolon cancer admitted to General Surgery Department of Beijing Chaoyang Hospital between January 2017 and October 2019 were retrospectively collected. Patient inclusion criteria: (1) complete obstructive left hemicolon cancer was confirmed through clinical manifestation and abdominal computed tomography; (2) adenocarcinoma was confirmed by postoperative pathology; (3) emergent radical resection of primary tumor was performed with temporary stoma, or radical resection of primary tumor and primary anastomosis was performed without stoma, 7 to 14 days after completion of insertion of self-expanding metallic stents. Patients who did not receive stoma reversion after emergent operation were excluded. According to different therapies, patients were divided into three groups: emergent surgery (ES) group, self-expanding metallic stents (SEMS) group and self-expanding metallic stents plus neoadjuvant chemotherapy (SEMS+NAC) group. Wexner score for incotinence (higher score indicates the worse anal function), Vaizey score (>10 indicates fecal incontinence) and low anterior resection syndrome (LARS) scale (higher score indicates the worse anal function) were applied to evaluate anal function of patients among groups at postoperative 1-, 6- and 12-month. EORTC QLQ-C30 questionnaire was used to assess the quality of life. Risk factors of decreased anal function were identified by logistic regression analysis. Results: A total of 72 patients were enrolled, including 27 (37.5%) patients in ES group, 23 (31.9%) in SEMS group and 22 (30.6%) in SEME+NAC group. The baseline characteristics including age, gender, tumor location, comorbidities, total blood loss, operation time and postoperative complications, were comparable among groups, except that the proportion of laparoscopic surgery was significantly lower in ES group (4/27, 14.9%) than that in SEMS (15/23, 65.2%) and SEMS+NAC group (16/22, 72.7%) with significant difference (P<0.001). The follow-up ended up to October 2020, and the overall follow-up rate was 79.2% (57/72). No significant differences existed in the Wexner score of patients among groups at postoperative 1-, 6- and 12-month (all P>0.05). The Vaizey scores at postoperative 1-month in ES, SEMS and SEMS+NAC group were 7 (0-17), 3 (0-7) and 4 (0-8) respectively with significant difference (H=18.415, P=0.001), and the scores in SEMS and SEMS+NAC groups were significantly lower than that in ES group (both P<0.05), while no significant difference existed between SEMS and SEMS+NAC group (P>0.05). Vaizey scores at postoperative 6- and 12-month among 3 groups were not significantly different (both P>0.05). The LARS scores at postoperative 1-month in ES, SEMS and SEMS+NAC groups were 20 (0-37), 15 (0-24) and 16 (0-28) respectively with significant difference (H=3.660, P=0.036), and the scores in SEMS and SEMS+NAC groups were significantly lower than that in ES group (both P<0.05), while no significant difference existed between SEMS and SEMS+NAC groups (P>0.05). LARS scores at postoperative 6- and 12-month among 3 groups were not significantly different (both P>0.05). The QLQ-C30 score revealed that the social function of patients in SEMS group and SEMS+NAC group was significantly better than that in ES group (both P<0.05), while no significant difference existed between SEMS and SEMS+NAC group (P>0.05). The logistic regression analysis revealed that only ES was an independent risk factor of decreased anal function (OR=2.264, 95% CI: 1.098-4.667, P=0.027). Conclusion: Compared to ES, SEMS may improve quality of life and short-term anal function of patients with complete obstructive left hemicolon cancer.
Humans ; Intestinal Obstruction ; Postoperative Complications ; Quality of Life ; Rectal Neoplasms ; Retrospective Studies ; Syndrome ; Treatment Outcome

Shaoyao Gancaotang, first seen in Treatise on Febrile and Miscellaneous Diseases, is composed of Paeoniae Radix Alba and Glycyrrhizae Radix et Rhizoma Praeparata cum Melle in equal proportion.It has the functions of preserving Yin to nourish blood, harmonizing liver and spleen, relieving spasm and pain.This formula is applied in leg and foot spasm and abdominal pain caused by blood deficiency, body fluid consuming and the unmoistened muscles and veins.It has been highly praised and used by medical experts throughout the ages and has extended its application scope.Modern pharmacological studies have shown that Shaoyao Gancaotang has significant effects in antispasmodic, analgesic, antitussive and other areas, and is used to treat spastic diseases, painful diseases, inflammatory diseases and so on.This paper will systematically elaborate the historical evolution, compatibility analysis, pharmacological and pharmacodynamic studies, modern clinical application of Shaoyao Gancaotang, in order to provide theoretical basis and reference for the development of this famous classical formula.

Background:: Portosystemic shunts, including surgical portosystemic shunts and transjugular intra-hepatic portosystemic shunt (TIPS), may have benefit over endoscopic therapy (ET) for treatment of variceal bleeding in patients with cirrhotic portal hypertension; however, whether there being a survival benefit among them remains unclear. This study was to compare the effect of three above-mentioned therapies on the short-term and long-term survival in patient with cirrhosis. Methods:: Using the terms "variceal hemorrhage or variceal bleeding or variceal re-bleeding" OR "esophageal and gastric varices" OR "portal hypertension" and "liver cirrhosis," the Cochrane Central Register of Controlled Trials, PubMed, Embase, and the references of identified trials were searched for human randomized controlled trials (RCTs) published in any language with full texts or abstracts (last search June 2017). Risk ratio (RR) estimates with 95% confidence interval (CI) were calculated using random effects model by Review Manager. The quality of the included studies was evaluated using the Cochrane Collaboration’s tool for the assessment of the risk of bias. Results:: Twenty-six publications comprising 28 RCTs were included in this analysis. These studies included a total of 2845 patients: 496 (4 RCTs) underwent either surgical portosystemic shunts or TIPS, 1244 (9 RCTs) underwent either surgical portosystemic shunts or ET, and 1105 (15 RCTs) underwent either TIPS or ET. There was no significant difference in overall mortality and 30-day or 6-week survival among three interventions. Compared with TIPS and ET, separately, surgical portosystemic shunts were both associated with a lower bleeding-related mortality (RR = 0.07, 95% CI = 0.01–0.32; P < 0.001; RR = 0.17, 95% CI = 0.06–0.51, P < 0.005) and rate of variceal re-bleeding (RR = 0.23, 95% CI = 0.10–0.51, P < 0.001; RR = 0.10, 95% CI = 0.04–0.24, P < 0.001), without a significant difference in the rate of postoperative hepatic encephalopathy (RR = 0.52, 95% CI = 0.25–1.00, P = 0.14; RR = 1.09, 95% CI = 0.59–2.01, P = 0.78). TIPS showed a trend toward lower variceal re-bleeding (RR = 0.46, 95% CI = 0.36–0.58, P < 0.001), but a higher incidence of hepatic encephalopathy than ET (RR = 1.78, 95% CI = 1.34–2.36, P < 0.001). Conclusions: The overall analysis revealed that there seem to be no short-term and long-term survival advantage, but surgical portosystemic shunts are with the lowest bleeding-related mortality among the three therapies. Surgical portosystemic shunts may be the most effective without an increased risk of hepatic encephalopathy and TIPS is superior to ET but at the cost of a higher incidence of hepatic encephalopathy. However, some of findings should be interpreted with caution due to the lower level of evidence and the existence of significant heterogeneity.

BACKGROUND: Portosystemic shunts, including surgical portosystemic shunts and transjugular intra-hepatic portosystemic shunt (TIPS), may have benefit over endoscopic therapy (ET) for treatment of variceal bleeding in patients with cirrhotic portal hypertension; however, whether there being a survival benefit among them remains unclear. This study was to compare the effect of three above-mentioned therapies on the short-term and long-term survival in patient with cirrhosis. METHODS: Using the terms "variceal hemorrhage or variceal bleeding or variceal re-bleeding" OR "esophageal and gastric varices" OR "portal hypertension" and "liver cirrhosis," the Cochrane Central Register of Controlled Trials, PubMed, Embase, and the references of identified trials were searched for human randomized controlled trials (RCTs) published in any language with full texts or abstracts (last search June 2017). Risk ratio (RR) estimates with 95% confidence interval (CI) were calculated using random effects model by Review Manager. The quality of the included studies was evaluated using the Cochrane Collaboration's tool for the assessment of the risk of bias. RESULTS: Twenty-six publications comprising 28 RCTs were included in this analysis. These studies included a total of 2845 patients: 496 (4 RCTs) underwent either surgical portosystemic shunts or TIPS, 1244 (9 RCTs) underwent either surgical portosystemic shunts or ET, and 1105 (15 RCTs) underwent either TIPS or ET. There was no significant difference in overall mortality and 30-day or 6-week survival among three interventions. Compared with TIPS and ET, separately, surgical portosystemic shunts were both associated with a lower bleeding-related mortality (RR = 0.07, 95% CI = 0.01-0.32; P < 0.001; RR = 0.17, 95% CI = 0.06-0.51, P < 0.005) and rate of variceal re-bleeding (RR = 0.23, 95% CI = 0.10-0.51, P < 0.001; RR = 0.10, 95% CI = 0.04-0.24, P < 0.001), without a significant difference in the rate of postoperative hepatic encephalopathy (RR = 0.52, 95% CI = 0.25-1.00, P = 0.14; RR = 1.09, 95% CI = 0.59-2.01, P = 0.78). TIPS showed a trend toward lower variceal re-bleeding (RR = 0.46, 95% CI = 0.36-0.58, P < 0.001), but a higher incidence of hepatic encephalopathy than ET (RR = 1.78, 95% CI = 1.34-2.36, P < 0.001). CONCLUSIONS The overall analysis revealed that there seem to be no short-term and long-term survival advantage, but surgical portosystemic shunts are with the lowest bleeding-related mortality among the three therapies. Surgical portosystemic shunts may be the most effective without an increased risk of hepatic encephalopathy and TIPS is superior to ET but at the cost of a higher incidence of hepatic encephalopathy. However, some of findings should be interpreted with caution due to the lower level of evidence and the existence of significant heterogeneity.
Confidence Intervals ; Esophageal and Gastric Varices ; pathology ; Gastrointestinal Hemorrhage ; prevention & control ; Humans ; Portasystemic Shunt, Transjugular Intrahepatic ; Randomized Controlled Trials as Topic

RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.

China ; Cross-Cultural Comparison ; Environmental Exposure ; standards ; Hearing ; Humans ; Noise ; adverse effects ; United States

China ; Health Facilities ; Humans ; Infection Control ; Tuberculosis ; prevention & control