Endoplasmic Reticulum-Targeting Self-Assembly Nanosheets Promote Autophagy and Regulate Immunosuppressive Tumor Microenvironment for Efficient Photodynamic Immunotherapy.

The poor efficiency and low immunogenicity of photodynamic therapy (PDT), and the immunosuppressive tumor microenvironment (ITM) lead to tumor recurrence and metastasis. In this work, TCPP-TER-Zn@RSV nanosheets (TZR NSs) that co-assembled from the endoplasmic reticulum (ER)-targeting photosensitizer TCPP-TER-Zn nanosheets (TZ NSs for short) and the autophagy promoting and indoleamine-(2, 3)-dioxygenase (IDO) inhibitor-like resveratrol (RSV) are fabricated to enhance antitumor PDT. TZR NSs exhibit improved therapeutic efficiency and amplified immunogenic cancer cell death (ICD) by ER targeting PDT and ER autophagy promotion. TZR NSs reversed the ITM with an increase of CD8+ T cells and reduce of immunosuppressive Foxp3 regulatory T cells, which effectively burst antitumor immunity thus clearing residual tumor cells. The ER-targeting TZR NSs developed in this paper presents a simple but valuable reference for high-efficiency tumor photodynamic immunotherapy.

Delirium in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: a multicentre randomised trial.

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).

Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial.

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.

Exosomal miR-145-5p derived from orthohantavirus-infected endothelial cells inhibits HTNV infection.

Human infection of orthohantavirus can cause potentially fatal diseases, such as hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV) in Eurasia. Exosomes are new carriers for information exchange between cells. Cumulative findings suggest that exosomes released from parental infected cells can block or promote viral infection in recipient cells, but the role of exosomes in hantavirus infection is poorly understood. In our study, we identified the exosomes derived from HTNV-infected human vascular endothelial cells (HUVECs) (Exo-HV) and found the antiviral properties of Exo-HV in the uninfected recipient cells. High-throughput sequencing revealed the distinctly expressed miRNAs transcriptomes in Exo-HV. MiR-145-5p, one of the abundant miRNAs packaged into Exo-HV, was found to be able to transferred to recipient cells and functioned by directly targeting M RNA of HTNV 76-118 and inducing type I interferon (IFN-I) response, thus, blocking the viral replication. Concluding, this study indicated that exosomes released by HTNV-infected HUVECs were able to transfer active molecules, miR-145-5p as a proving sample, to mediate novel anti-HTNV activity in the neighboring uninfected cells, which will help us to explore new strategies for the treatment of infectious disease utilizing exosomes with miRNA.

Delirium in Older Patients after Combined Epidural-General Anesthesia or General Anesthesia for Major Surgery: A Randomized Trial.

BACKGROUND: Delirium is a common and serious postoperative complication, especially in the elderly. Epidural anesthesia may reduce delirium by improving analgesia, reducing opioid consumption, and blunting stress response to surgery. This trial therefore tested the hypothesis that combined epidural-general anesthesia reduces the incidence of postoperative delirium in elderly patients recovering from major noncardiac surgery. METHODS: Patients aged 60 to 90 yr scheduled for major noncardiac thoracic or abdominal surgeries expected to last 2 h or more were enrolled. Participants were randomized 1:1 to either combined epidural-general anesthesia with postoperative epidural analgesia or general anesthesia with postoperative intravenous analgesia. The primary outcome was the incidence of delirium, which was assessed with the Confusion Assessment Method for the Intensive Care Unit twice daily during the initial 7 postoperative days. RESULTS: Between November 2011 and May 2015, 1,802 patients were randomized to combined epidural-general anesthesia (n = 901) or general anesthesia alone (n = 901). Among these, 1,720 patients (mean age, 70 yr; 35% women) completed the study and were included in the intention-to-treat analysis. Delirium was significantly less common in the combined epidural-general anesthesia group (15 [1.8%] of 857 patients) than in the general anesthesia group (43 [5.0%] of 863 patients; relative risk, 0.351; 95% CI, 0.197 to 0.627; P < 0.001; number needed to treat 31). Intraoperative hypotension (systolic blood pressure less than 80 mmHg) was more common in patients assigned to epidural anesthesia (421 [49%] vs. 288 [33%]; relative risk, 1.47, 95% CI, 1.31 to 1.65; P < 0.001), and more epidural patients were given vasopressors (495 [58%] vs. 387 [45%]; relative risk, 1.29; 95% CI, 1.17 to 1.41; P < 0.001). CONCLUSIONS: Older patients randomized to combined epidural-general anesthesia for major thoracic and abdominal surgeries had one third as much delirium but 50% more hypotension. Clinicians should consider combining epidural and general anesthesia in patients at risk of postoperative delirium, and avoiding the combination in patients at risk of hypotension.

Effects of two different anesthesia-analgesia methods on incidence of postoperative delirium in elderly patients undergoing major thoracic and abdominal surgery: study rationale and protocol for a multicenter randomized controlled trial.

BACKGROUND: Delirium is a common complication in elderly patients after surgery and associated with increased morbidity and mortality. Studies suggest that deep anesthesia and intense pain are important precipitating factors of postoperative delirium. Neuraxial block is frequently used in combination with general anesthesia for patients undergoing major thoracic and abdominal surgery. Compared with general anesthesia alone and postoperative intravenous analgesia, combined epidural-general anesthesia and postoperative epidural analgesia decreases the requirement of general anesthetics during surgery and provided better pain relief after surgery. However, whether combined epidural-general anesthesia plus epidural analgesia is superior to general anesthesia plus intravenous analgesia in decreasing the incidence of postoperative delirium remains unknown. METHODS/DESIGN: This is a multicenter, open-label, randomized, parallel-controlled clinical trial. One thousand eight hundred elderly patients (age range 60-90 years) who are scheduled to undergo major thoracic or abdominal surgery are randomized to receive either general anesthesia plus postoperative intravenous analgesia or combined epidural-general anesthesia plus postoperative epidural analgesia. The primary outcome is the 7-day incidence of postoperative delirium. Secondary outcomes include the duration of postoperative delirium, the intensity of pain during the first three days after surgery, the 30-day incidences of postoperative non-delirium complications, the length of stay in hospital after surgery and 30-day all-cause mortality. DISCUSSION: Results of the present study will provide information to guide clinical practice in choosing appropriate anesthesia-analgesia method for elderly patients undergoing major thoracic and abdominal surgery. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov NCT01661907 and Chinese Clinical Trial Registry ChiCTR-TRC-12002371 .

Role of clinical data and multidetector computed tomography findings in acute superior mesenteric artery embolism.

BACKGROUND: Superior mesenteric artery embolism (SMAE) has acute onset and fast progression, which seriously threatens the life of patients. Multidetector computed tomography (MDCT) is one of the most important diagnostic methods for SMAE, which plays an important role in the diagnosis and prognosis of SMAE. AIM: To evaluate the value of combined clinical data and MDCT findings in the diagnosis of acute SMAE and predict the risk factors for SMAE-related death. METHODS: Data from 53 SMAE patients who received abdominal MDCT multi-phase enhancement and superior mesenteric artery digital subtraction angiography examinations were collected. Univariate cox regression and multivariate cox model were used to analyze the correlation between death risk and clinical and computed tomography features in SMAE patients. RESULTS: Univariate Cox regression model showed that intestinal wall thinning, intestinal wall pneumatosis, blood lactate > 2.1 mmol/L and blood pH < 7.35 increased the risk of death in patients with SMAE. After adjusting for age, sex, embolic involvement length and embolic distribution region, multivariate Cox regression model I showed that blood lactate > 2.1 mmol/L (HR = 5.26, 95%CI: 1.04-26.69, P = 0.045) and intestinal wall thinning (HR = 9.40, 95%CI: 1.05-83.46, P = 0.044) were significantly increases the risk of death in patients with SMAE. CONCLUSION: For patients with SAME, increased blood lactate and intestinal wall thinning are the risk factors for death; hence, close monitoring may reduce the mortality rate. Clinical observation combined with MDCT signs can significantly improve SMAE diagnosis.

Fentanyl enhances HIV infection in vitro.

Acquired immunodeficiency syndrome (AIDS) caused by Human immunodeficiency virus type 1 (HIV-1) has a high tendency among illicit drug abusers. Recently, it is reported that abuse of fentanyl, a potent synthetic µ receptor-stimulating opioid, is an independent risk factor for HIV-1 infection. However, the mechanism of action in augmenting HIV-1 infection still remains elusive. In this study, we found that fentanyl enhanced infection of HIV-1 in MT2 cells, primary macrophages and Jurkat C11 cells. Fentanyl up-regulated CXCR4 and CCR5 receptor expression, which facilitated the entry of virion into host cells. In addition, it down-regulated interferon-ß (IFN-ß) and interferon-stimulated genes (APOBEC3F, APOBEC3G and MxB) expression in MT2 cells. Our findings identify an essential role of fentanyl in the positive regulation of HIV-1 infection via the upregulation of co-receptors (CXCR4/CCR5) and downregulation of IFN-ß and ISGs, and it may have an important role in HIV-1 immunopathogenesis.

Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells.

We designed to study the role of mitochondria in astaxanthin-induced apoptosis in hepatocellular carcinoma cells. Effect of astaxanthin on cell proliferation was studied by using methyl thiazolyl tetrazolium (MTT) in three tumor cell lines (CBRH-7919, SHZ-88 and Lewis) and normal human hepatocyte HL-7702 cell. Cell apoptosis rate, changes of mitochondrial morphology, mitochondrial transmembrane potential and electron transport chain were evaluated respectively. Expressions of B cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2 associated X protein (Bax) were detected by Western blot. Results as following, astaxanthin had little effect on HL-7702 cell, however its inhibition was most pronounced in CBRH-7919 cell line with an IC50 of 39 µM. This dose of astaxanthin and CBRH-7919 cell line were chosen for further studies. Astaxanthin could induce cell apoptosis and mitochondrial membrane damage. The mitochondrial transmembrane potential and function of electron transport chain were decreased. The expression of Bcl-2 protein was down-regulated but that of Bax protein was up-regulated. In conclusion, astaxanthin showed anticancer effect by inducing cell apoptosis through the regulation of mitochondrial-dependent manner.

Effect of Nephritis Rehabilitation Tablets combined with tacrolimus in treatment of idiopathic membranous nephropathy.

BACKGROUND: Idiopathic membranous nephropathy (IMN) has a high incidence in the middle-aged and elderly population, and poses a great threat to the physical and mental health and quality of life of patients. Nephritis Rehabilitation Tablets have many potential effects, such as clearing residual toxins, tumefying the kidney and spleen, replenishing qi, and nourishing yin, and have played an important role in the treatment of a variety of kidney diseases. AIM: To investigate the efficacy and safety of Nephritis Rehabilitation Tablets combined with tacrolimus in the treatment of IMN. METHODS: Eighty-four patients with IMN recruited from January 2017 to September 2020 were randomly divided into a study group (n = 42) and a control group (n = 42). On the basis of routine symptomatic treatment, both groups were treated with tacrolimus, and the study group was additionally treated with Nephritis Rehabilitation Tablets. Both groups were treated for 12 wk. The therapeutic effect, the levels of renal function indexes [serum creatinine (Scr), serum albumin, and 24-h urinary protein], urinary immunoglobulin (IgG4), membrane attack complex (C5b-9), and the incidence of adverse reactions were measured before and after 12 wk of treatment. RESULTS: The total effective rate in the study group was significantly higher than that of the control group. Before treatment, there was no significant difference in Scr, serum albumin, or 24 h urinary protein between the two groups. After 12 wk of treatment, the levels of Scr and 24-h urinary protein in both groups were significantly lower and serum albumin was significantly higher than those before treatment (P < 0.05), and the levels of Scr and 24-h urinary protein were significantly lower (P = 0.003 and 0.000, respectively), and the level of serum albumin was significantly higher (P = 0.00) in the study group than in the control group. Before treatment, there was no significant difference in urinary IgG4 and C5b-9 levels between the study group and the control group (P = 0.336 and 0.438, respectively). After 12 wk of treatment, the levels of urinary IgG4 and C5b-9 in the two groups were lower than those before treatment, and the levels of urinary IgG4 and C5b-9 in the study group were significantly lower than those in the control group (P = 0.000). There was no significant difference in the incidence of adverse reactions between the two groups (P = 0.710). CONCLUSION: Based on routine intervention, Nephritis Rehabilitation Tablets combined with tacrolimus in the treatment of IMN can effectively improve the renal function of patients and downregulate the expression of urinary IgG4 and C5b-9. In addition, they can improve the overall therapeutic effect while not increasing the risk of adverse reactions.

Association of Hypertension with Severity and Mortality in Hospitalized Patients with COVID-19 in Wuhan, China: A Single-centered, Retrospective Study. / Associação da Hipertensão com a Gravidade e a Mortalidade de Pacientes Hospitalizados com COVID-19 em Wuhan, China: Estudo Unicêntrico e Retrospectivo.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. OBJECTIVE: To investigate the association between hypertension and severity/mortality in hospitalized patients with COVID-19 in Wuhan, China. METHODS: A total of 337 patients diagnosed with COVID-19 at the Seventh Hospital of Wuhan City, from January 20 to February 25, 2020, were enrolled and analyzed in a retrospective, single-center case study. The significance level adopted in the statistical analysis was 0.05. RESULTS: Of the 337 patients with confirmed diagnosis of COVID-19, 297 (87.8%) were discharged from the hospital and 40 patients (22.9%) died. The median age was 58 years (range, 18-91 years). There were 112 (33.2%) patients diagnosed with hypertension at admission (median age, 65.0 years [range, 38-91 years]; 67 [59.8%, 95%CI: 50.6%-69.0%] men, p=0.0209). Patients with hypertension presented a significantly higher portion of severe cases (69 [61.6%, 95%CI:52.5%-70.8%] vs. 117 [52.0%, 95%CI: 45.4%-58.6%] in severe patients and 23 [19.3%, 95%CI:12.9%-28.1%] vs. 27 [12.0%, 95%CI: 7.7%-16.3%] in critical patients, p=0.0014) and higher mortality rates (20 [17.9%, 95%CI: 10.7%-25.1%] vs. 20 [8.9%, 95%CI: 5.1%-12.6%, p=0.0202). Moreover, hypertensive patients presented abnormal levels of multiple indicators, such as lymphopenia, inflammation, heart, liver, kidney, and lung function at admission. The hypertension group still displayed higher levels of TnT and creatinine at approaching discharge. CONCLUSION: Hypertension is strongly associated with severity or mortality of COVID-19. Aggressive treatment may be considered for COVID-19 patients with hypertension, especially regarding cardiac and kidney injury.

FUNDAMENTO: A doença Coronavírus 2019 (COVID-19), causada pela síndrome respiratória aguda grave Coronavírus 2 (SARS-CoV-2), espalhou-se pelo mundo. OBJETIVO: Investigar a associação entre a hipertensão e a gravidade/mortalidade de pacientes hospitalizados com COVID-19 em Wuhan, China. MÉTODOS: Um total de 337 pacientes diagnosticados com COVID-19 no Sétimo Hospital da cidade de Wuhan, de 20 de janeiro a 25 de fevereiro de 2020, foram inseridos e analisados em um estudo de caso unicêntrico e retrospectivo. O nível de significância adotado para a análise estatística foi 0,05. RESULTADOS: Dos 337 pacientes com diagnóstico confirmado de COVID-19, 297 (87.8%) tiveram alta do hospital e 40 pacientes (22,9%) morreram. A idade média foi de 58 anos (variando de 18 a 91 anos). Havia 112 (33,2%) pacientes diagnosticados com hipertensão no momento da internação (idade média, 65,0 anos [variação, 38-91 anos]; sendo 67 homens [59,8%, IC95%: 50,6%-69,0%], p=0,0209). Pacientes com hipertensão apresentaram uma porção significativamente maior de casos graves (69 [61,6%, IC95%: 52,5%-70,8%] vs. 117 [52,0%, IC95%: 45,4%-58,6%] em pacientes graves e 23 [19,3%, IC95%: 12,9%-28,1%] vs. 27 [12,0%, IC95%: 7,7%-16,3%] em pacientes críticos, p=0,0014) e maiores taxas de mortalidade (20 [17,9%, IC95%: 10,7%-25,1%] vs. 20 [8,9%, IC95%: 5,1%-12,6%, p=0,0202). Além disso, pacientes hipertensos apresentaram níveis anormais de vários indicadores, como linfopenia e inflamação, e nas funções cardíacas, hepáticas, renais e pulmonares no momento da internação. O grupo de pacientes com hipertensão também demonstrou níveis maiores de TNT e creatinina próximo da alta. CONCLUSÃO: A hipertensão está altamente associada à gravidade ou mortalidade da COVID-19. Um tratamento agressivo deve ser considerado para pacientes hipertensos com COVID-19, principalmente com relação a lesões cardíacas e dos rins.

Association of diabetes with severity and mortality in hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. The aim this study was to investigate the association of diabetes with severity and mortality among hospitalized patients with COVID-19 in Wuhan, China. METHODS: This retrospective, single-center case study enrolled a total of 564 patients diagnosed with COVID-19 at the Seventh Hospital of Wuhan City, between January 20 and March 15, 2020. RESULTS: Among the 564 patients with confirmed COVID-19, 509 (85.1%) were discharged and 55 (9.8%) died. The median age was 59 years (range, 10-93 years). A total of 85 (15.1%) patients were diagnosed with diabetes on admission (median age, 65.0 [range, 34-91] years). Patients with diabetes had significantly higher proportions of critical cases (24 [28.2%] vs. 66 [13.8%]) and in-hospital mortality (17 [20%] vs. 38 [7.9%]). Moreover, patients with diabetes presented abnormal levels of multiple indicators concerning lymphopenia, inflammation, heart, liver, kidney, and lung function on admission, while diabetic patient group still display higher troponin T (TnT) levels when approaching discharge. The Kaplan-Meier survival curve indicated a trend toward poorer survival in diabetic patients compared to non-diabetic patients, also evidenced by abnormal laboratory biomarker changes regarding multiple system impairments among COVID-19 patients with diabetes with in-hospital death. CONCLUSION: The detailed clinical investigation of 564 hospitalized patients with COVID-19 indicated a considerable association between diabetes and COVID-19 severity or mortality. Thus, more intensive treatment may be considered for COVID-19 patients with diabetes, especially regarding to cardiac injury.

Diffusion tensor imaging study of brain precentral gyrus and postcentral gyrus during normal brain aging process.

OBJECTIVE: To study the changes of white matter tracts in precentral gyrus and postcentral gyrus during normal brain aging process by analyzing fractional anisotropy (FA) values obtained from diffusion tensor imaging (DTI) technology. METHODS: Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were conducted on 120 healthy right-handed subjects. The subjects were separated into four age groups, namely Young Male/Female (<45 years old) and Senior Male/Female (>45 years old). Each subject undertakes routine MRI and DTI scans. Left/right precentral and left/right postcentral gyrus are automatically detected on the image. The area for region of interest (ROI) is set to be 18 ± 2 mm2 . RESULTS: For each age group, the FA values of white matter in precentral gyrus and postcentral gyrus are statistically different (p < .05) in both left and right sides of the brain across different age groups and genders. Additionally, the FA values are statistically different (p < .05) between two young and senior age groups across different genders, brain regions, and hemispheres. CONCLUSION: The FA values of precentral gyrus and postcentral gyrus are statistically different across genders, age groups, and hemispheres. Additionally, the FA values of both precentral gyrus and postcentral gyrus decrease over time, which is a strong indication of aging.

Methadone Inhibits Viral Restriction Factors and Facilitates HIV Infection in Macrophages.

Opioid abuse alters the functions of immune cells in both in vitro and in vivo systems, including macrophages. Here, we investigated the effects of methadone, a widely used opioid receptor agonist for treatment of opiate addiction, on the expression of intracellular viral restriction factors and HIV replication in primary human macrophages. We showed that methadone enhanced the HIV infectivity in primary human macrophages. Mechanistically, methadone treatment of macrophages reduced the expression of interferons (IFN-ß and IFN-λ2) and the IFN-stimulated anti-HIV genes (APOBEC3F/G and MxB). In addition, methadone-treated macrophages showed lower levels of several anti-HIV microRNAs (miRNA-28, miR-125b, miR-150, and miR-155) compared to untreated cells. Exogenous IFN-ß treatment restored the methadone-induced reduction in the expression of the above genes. These effects of methadone on HIV and the antiviral factors were antagonized by pretreatment of cells with naltrexone. These findings provide additional evidence to support further studies on the role of opiates, including methadone, in the immunopathogenesis of HIV disease.

HTNV Sensitizes Host Toward TRAIL-Mediated Apoptosis-A Pivotal Anti-hantaviral Role of TRAIL.

Hantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and have led to public health threat in China. The pathogenesis of HFRS is complex and involves capillary leakage due to the infection of vascular endothelial cells. Accumulating evidence has demonstrated that hantavirus can induce apoptosis in many cells, but the mechanism remains unclear. Our studies showed that Hantaan virus (HTNV) infection could induce TNF-related apoptosis-inducing ligand (TRAIL) expression in primary human umbilical vein endothelial cells (HUVECs) and sensitize host cells toward TRAIL-mediated apoptosis. Furthermore, TRAIL interference could inhibit apoptosis and enhance the production of HTNV as well as reduce IFN-ß production, while exogenous TRAIL treatment showed reverse outcome: enhanced apoptosis and IFN-ß production as well as a lower level of viral replication. We also observed that nucleocapsid protein (NP) and glycoprotein (GP) of HTNV could promote the transcriptions of TRAIL and its receptors. Thus, TRAIL was upregulated by HTNV infection and then exhibited significant antiviral activities in vitro, and it was further confirmed in the HTNV-infected suckling mice model that TRAIL treatment significantly reduced viral load, alleviated virus-induced tissue lesions, increased apoptotic cells, and decreased the mortality. In conclusion, these results demonstrate that TRAIL-dependent apoptosis and IFN-ß production could suppress HTNV replication and TRAIL treatment might be a novel therapeutic target for HTNV infection.

Lack of association between integrin αvß3 gene polymorphisms and hemorrhagic fever with renal syndrome in Han Chinese from Hubei, China.

Hantaviruses belong to the family Bunyaviridae and cause hemorrhagic fever with renal syndrome (HFRS) in humans. ß3 integrins, including αVß3 and αIIbß3 integrins, act as receptors on endothelial cells and play key roles in cellular entry during the pathogenesis of hantaviruses. Previous study demonstrated that the polymorphisms of integrin αIIbß3 are associated with susceptibility to hantavirus infection and the disease severity of HFRS in Shaanxi Province of China, rather than in Finland. However, the polymorphisms of integrin αvß3 in patients with HFRS was incompletely understood. Here, we aimed to investigate the associations between polymorphisms in human integrin αvß3 and HFRS in Han Chinese individuals. Ninety patients with HFRS and 101 healthy controls were enrolled in this study. Analysis of five single nucleotide polymorphism (SNP) sites (rs3768777 and rs3738919 on ITGAV; rs13306487, rs5921, and rs5918 on ITGB3) was performed by TaqMan SNP genotyping assays and bi-directional PCR allele-specific amplification method. No significant differences were observed between the HFRS group and controls regarding the genotype and allele frequency distributions of any of the five SNP sites, and no associations were found between ITGAV polymorphisms/genotypes and disease severity. In conclusion, our results implied that these five SNPs in the integrin αvß3 gene were not associated with HFRS susceptibility or severity in Han Chinese individuals in Hubei Province.

SS31 ameliorates age-related activation of NF-κB signaling in senile mice model, SAMP8.

Aging has been attributed to oxidative stress and inflammatory response, in which NF-κB and Nrf2-ARE signaling pathways play significant roles. Senescence accelerated mouse prone 8 (SAMP8) is generally used an animal model for aging studies. Here, we investigated the NF-κB and Nrf2-ARE signaling pathways in SAMP8 brains at different ages and their responses to SS31 peptide treatment. Thirty six SAMP8 mice were separated into aging groups and SS31-treatment groups. The hippocampus from each mouse was dissected for RNA and protein extraction. Cytokines and ROS levels were measured using ELISA and standardised method. Gene expressions of NF-κB, Nrf2 and HO-1 were measured by RT-qPCR. Total protein amount of NF-κB and HO-1, as well as the concentrations of nuclear and cytoplasmic Nrf2 were measured using Western blots. Our data showed that aging could activate both NF-κB and Nrf2-ARE signaling pathways, which could be suppressed and activated by SS31 treatment respectively. Regression analysis revealed that NF-κB gene expression was the most important parameter predicting aging process and SS31 treatment effects in SAMP8. Our findings suggested that SS31 treatment may modulate the inflammatory and oxidative stress status of the aged brains and exert protective effects during brain aging.

Association of diabetes with severity and mortality in hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective study

ABSTRACT Objective: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. The aim this study was to investigate the association of diabetes with severity and mortality among hospitalized patients with COVID-19 in Wuhan, China. Subjects and methods: This retrospective, single-center case study enrolled a total of 564 patients diagnosed with COVID-19 at the Seventh Hospital of Wuhan City, between January 20 and March 15, 2020. Results: Among the 564 patients with confirmed COVID-19, 509 (85.1%) were discharged and 55 (9.8%) died. The median age was 59 years (range, 10-93 years). A total of 85 (15.1%) patients were diagnosed with diabetes on admission (median age, 65.0 [range, 34-91] years). Patients with diabetes had significantly higher proportions of critical cases (24 [28.2%] vs. 66 [13.8%]) and in-hospital mortality (17 [20%] vs. 38 [7.9%]). Moreover, patients with diabetes presented abnormal levels of multiple indicators concerning lymphopenia, inflammation, heart, liver, kidney, and lung function on admission, while diabetic patient group still display higher troponin T (TnT) levels when approaching discharge. The Kaplan-Meier survival curve indicated a trend toward poorer survival in diabetic patients compared to non-diabetic patients, also evidenced by abnormal laboratory biomarker changes regarding multiple system impairments among COVID-19 patients with diabetes with in-hospital death. Conclusion: The detailed clinical investigation of 564 hospitalized patients with COVID-19 indicated a considerable association between diabetes and COVID-19 severity or mortality. Thus, more intensive treatment may be considered for COVID-19 patients with diabetes, especially regarding to cardiac injury.

Associação da hipertensão com a gravidade e a mortalidade de pacientes hospitalizados com COVID-19 em Wuhan, China: Estudo unicêntrico e retrospectivo / Association of hypertension with severity and mortality in hospitalized patients with COVID-19 in wuhan, China: A single-centered, retrospective study

Resumo Fundamento A doença Coronavírus 2019 (COVID-19), causada pela síndrome respiratória aguda grave Coronavírus 2 (SARS-CoV-2), espalhou-se pelo mundo. Objetivo Investigar a associação entre a hipertensão e a gravidade/mortalidade de pacientes hospitalizados com COVID-19 em Wuhan, China. Métodos Um total de 337 pacientes diagnosticados com COVID-19 no Sétimo Hospital da cidade de Wuhan, de 20 de janeiro a 25 de fevereiro de 2020, foram inseridos e analisados em um estudo de caso unicêntrico e retrospectivo. O nível de significância adotado para a análise estatística foi 0,05. Resultados Dos 337 pacientes com diagnóstico confirmado de COVID-19, 297 (87.8%) tiveram alta do hospital e 40 pacientes (22,9%) morreram. A idade média foi de 58 anos (variando de 18 a 91 anos). Havia 112 (33,2%) pacientes diagnosticados com hipertensão no momento da internação (idade média, 65,0 anos [variação, 38-91 anos]; sendo 67 homens [59,8%, IC95%: 50,6%-69,0%], p=0,0209). Pacientes com hipertensão apresentaram uma porção significativamente maior de casos graves (69 [61,6%, IC95%: 52,5%-70,8%] vs. 117 [52,0%, IC95%: 45,4%-58,6%] em pacientes graves e 23 [19,3%, IC95%: 12,9%-28,1%] vs. 27 [12,0%, IC95%: 7,7%-16,3%] em pacientes críticos, p=0,0014) e maiores taxas de mortalidade (20 [17,9%, IC95%: 10,7%-25,1%] vs. 20 [8,9%, IC95%: 5,1%-12,6%, p=0,0202). Além disso, pacientes hipertensos apresentaram níveis anormais de vários indicadores, como linfopenia e inflamação, e nas funções cardíacas, hepáticas, renais e pulmonares no momento da internação. O grupo de pacientes com hipertensão também demonstrou níveis maiores de TNT e creatinina próximo da alta. Conclusão A hipertensão está altamente associada à gravidade ou mortalidade da COVID-19. Um tratamento agressivo deve ser considerado para pacientes hipertensos com COVID-19, principalmente com relação a lesões cardíacas e dos rins.

Abstract Background Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. Objective To investigate the association between hypertension and severity/mortality in hospitalized patients with COVID-19 in Wuhan, China. Methods A total of 337 patients diagnosed with COVID-19 at the Seventh Hospital of Wuhan City, from January 20 to February 25, 2020, were enrolled and analyzed in a retrospective, single-center case study. The significance level adopted in the statistical analysis was 0.05. Results Of the 337 patients with confirmed diagnosis of COVID-19, 297 (87.8%) were discharged from the hospital and 40 patients (22.9%) died. The median age was 58 years (range, 18-91 years). There were 112 (33.2%) patients diagnosed with hypertension at admission (median age, 65.0 years [range, 38-91 years]; 67 [59.8%, 95%CI: 50.6%-69.0%] men, p=0.0209). Patients with hypertension presented a significantly higher portion of severe cases (69 [61.6%, 95%CI:52.5%-70.8%] vs. 117 [52.0%, 95%CI: 45.4%-58.6%] in severe patients and 23 [19.3%, 95%CI:12.9%-28.1%] vs. 27 [12.0%, 95%CI: 7.7%-16.3%] in critical patients, p=0.0014) and higher mortality rates (20 [17.9%, 95%CI: 10.7%-25.1%] vs. 20 [8.9%, 95%CI: 5.1%-12.6%, p=0.0202). Moreover, hypertensive patients presented abnormal levels of multiple indicators, such as lymphopenia, inflammation, heart, liver, kidney, and lung function at admission. The hypertension group still displayed higher levels of TnT and creatinine at approaching discharge. Conclusion Hypertension is strongly associated with severity or mortality of COVID-19. Aggressive treatment may be considered for COVID-19 patients with hypertension, especially regarding cardiac and kidney injury.

Outcomes for jejunal interposition reconstruction compared with Roux-en-Y anastomosis: A meta-analysis.

AIM: To compare the clinical outcomes between jejunal interposition reconstruction and Roux-en-Y anastomosis after total gastrostomy in patients with gastric cancer. METHODS: A systematic literature search was conducted by two independent researchers on PubMed, EMBASE, the Cochrane Library, Google Scholar, and other English literature databases, as well as the Chinese Academic Journal, Chinese Biomedical Literature Database, and other Chinese literature databases using "Gastrostomy", "Roux-en-Y", and "Interposition" as keywords. Data extraction and verification were performed on the literature included in this study. RevMan 5.2 software was used for data processing. A fixed-effects model was applied in the absence of heterogeneity between studies. A random effects model was applied in the presence of heterogeneity between studies. RESULTS: Ten studies with a total of 762 gastric cancer patients who underwent total gastrostomy were included in this study. Among them, 357 received jejunal interposition reconstruction after total gastrostomy, and 405 received Roux-en-Y anastomosis. Compared with Roux-en-Y anastomosis, jejunal interposition reconstruction significantly decreased the incidence of dumping syndrome (OR = 0.18, 95%CI: 0.10-0.31; P < 0.001), increased the prognostic nutritional index [weighted mean difference (WMD) = 6.02, 95%CI: 1.82-10.22; P < 0.001], and improved the degree of postoperative weight loss [WMD = 2.47, 95%CI: -3.19-(-1.75); P < 0.001]. However, there is no statistically significant difference in operative time, hospital stay, or incidence of reflux esophagitis. CONCLUSION: Compared with Roux-en-Y anastomosis, patients who underwent jejunal interposition reconstruction after total gastrostomy had a lower risk of postoperative long-term complications and improved life quality.