Does SARS‐Cov‐2 invade the brain? Translational lessons from animal models

The current coronavirus disease (COVID‐19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS‐CoV‐2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS‐CoV‐2. One key finding that may unify these pathogens is that all require angiotensin‐converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS‐CoV‐2 binds to cell membranes, binds angiotensin‐converting enzyme 2 with a higher affinity compared with SARS‐CoV. The expression of this receptor in neurons and endothelial cells hints that SARS‐CoV‐2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune‐mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune‐mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID‐19.     

Refractory Ascites After Liver Transplantation: An Analysis of 1058 Liver Transplant Patients at a Single Center

A retrospective study of 1058 liver transplant recipients was performed to determine: (i) the incidence, etiology, timing, clinical features and treatment of refractory ascites (RA), (ii) risk factors for RA development, (iii) predictors of RA disappearance, (iv) predictors of survival following RA and (v) the impact of RA on patient survival. Sixty-two patients (5.9%) developed RA and its disappearance occurred in 27/62 cases. Patients having hepatitis C virus (HCV) had a significantly higher hazard rate of developing RA (p < 0.00001). No other baseline characteristic was associated with RA. Cox stepwise regression analysis of the hazard rate of RA disappearance found two significant factors: HCV recurrence as the reason for developing RA implied a poorer outcome (p = 0.006), whereas an unknown reason implied a favorable outcome (p = 0.02). In addition, survival following RA was significantly poorer among patients having bacterial peritonitis or HCV recurrence. Finally, the mortality rate was significantly (nearly 8.6 times) higher in patients following RA development while it was ongoing (p < 0.00001); however, if the RA disappeared, then the additional risk of death also disappeared. This study illustrates the importance of developing an optimal treatment strategy to (i) effectively treat RA if it develops and (ii) prevent hepatitis C recurrence.     

Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment.

BACKGROUND: Major depression has been associated cross-sectionally with increased cell-mediated immune activation but causality has been difficult to establish. This study prospectively investigated the hypothesis that baseline level of immune activation predicts the development of depression during interferon-alpha (IFN-alpha) treatment. METHODS: Sixteen hepatitis C patients without psychiatric disorder underwent IFN-alpha treatment. Proinflammatory and anti-inflammatory cytokines were determined before starting treatment. Presence of a major depressive disorder (MDD) was assessed at baseline and several times during treatment. RESULTS: Baseline soluble interleukin-2 receptor (sIL-2r), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations were significantly increased in the five subjects that developed MDD during treatment compared with those that did not, with standardized effect sizes of 1.08, 1.16, and 1.25, respectively, controlling for marijuana use, cigarette smoking, and baseline level of depressive symptoms. CONCLUSIONS: Results suggest that increased immune activation, rather than an epiphenomenon, is a causal risk factor for the development of MDD.     

Use of anti-HBc positive allografts in adult liver transplantation: toward a safer way to expand the donor pool

The use of livers from anti-hepatitis B core (HBc) positive donors can alleviate donor shortage. Nineteen of 367 (6%) adults receiving anti-HBc positive allografts [three were hepatitis B antigen (HBsAg) negative, hepatitis B antibody (HBsAb) positive; four were HBsAg positive and 12 were not exposed to hepatitis B viral (HBV) infection] were retrospectively reviewed. In HBsAg negative recipients, immunoprophylaxis (IP) was guided by viral serology and immunohistochemistry (IH) of day 0 and day 7 liver biopsies. If IH was negative, IP was stopped. None of three HBsAg negative, HBsAb positive recipients infected; one (replicating) of four HBsAg positive recipients reinfected and seven of eight (87.5%) HBsAg, HBsAb negative recipients, who did not receive long-term IP, infected after a median time of 2 years (range 1-5); one patient died of liver failure. Four HBsAg, HBsAb negative recipients, receiving life-long IP, remained infection free. Anti-HBc positive donor livers must be directed selectively first to HBsAg positive recipients, next to recipients having HBV antibodies and finally to HBV-naive recipients. Identification of both donor and recipient risk factors for HBV infection before transplantation allows indiscriminate use of antiviral prophylaxis. The necessity for IP therapy should be guided by HBV-DNA testing of donor liver tissue and serum. IH of early liver biopsies is an unreliable marker for predicting antiviral treatment requirements.     

凯时治疗慢性重型肝炎患者疗效观察

目的探讨凯时即前列地尔脂微球载体制剂（Lipo-PGE1）治疗慢性重型肝炎的疗效。方法将84例慢性重型肝炎患者随机分成两组，对照组予综合治疗及对症治疗，治疗组在该基础上加用凯时10μg溶于5％葡萄糖注射液250ml中静脉缓慢滴注，1次/d，疗程为4周。结果治疗组对慢性重型肝炎的疗效优于对照组（P〈0．01），肝功能改善优于对照组（P〈0．01）。结论Lipo-PCEI是一种治疗慢性重型肝炎安全、有效的药物。     

Development of autoimmune hepatitis in primary biliary cirrhosis.

AIM/BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown aetiology. Up to 10% of patients with typical features of PBC will have additional features of autoimmune hepatitis (AIH). A subset, however, have no such features but go on to develop a 'sequential' AIH overlap syndrome. Objectives: Describe our experience with eight patients who developed AIH after the diagnosis of PBC was made. METHODS: We reviewed the charts of all PBC patients over a 9-year period (from 1996 to 2005). Only PBC patients with no features of AIH were included. RESULTS: There were 1476 patients with PBC. Of these, eight patients developed features of AIH overlap syndrome based on biochemical and histological parameters. Treatment included prednisone and azathioprine for 24 or more months. The majority of patients remained on ursodeoxycholic acid (UDCA) throughout treatment. Response to therapy was defined by improvement in enzymes, and was rapid for all patients. One patient was able to discontinue treatment with prednisone and azathioprine, while seven have continued on therapy to date. CONCLUSIONS: A 'sequential' overlap syndrome of AIH with PBC can occur. Treatment with prednisone and azathioprine may lead to a rapid improvement in aminotransferase levels.     

增强子Ⅰ对乙型肝炎病毒DNA疫苗免疫应答的影响

目的 研究乙型肝炎病毒（HBV）自身增强子I（enhancerI，ENHI）对HBV DNA疫苗免疫应答的影响。方法 采用PCR法以HBVadr亚型全基因DNA序列为模板分别扩增表面抗原（HBsAg）和HBsA-ENHI基因片段，重组到载体VR1012中，构建两种HBV DNA疫苗，转染CADS-7细胞及HepG2细胞并免疫BALB／c小鼠。采用蛋白印迹、ELISA、ELISPOT等方法检测其在COS-7和HepG2细胞内的表达及小鼠的体液及细胞免疫应答效果。结果 转染的HepG2和COS-7细胞均表达HBsAg;连接ENHI的HBV DNA疫苗转染HepG2细胞后HBsAg表达量明显升高，两种疫苗转染COS-7细胞表达HBsAg无明显差异；免疫小鼠后第2周产生HBsAb及HBsAg特异性细胞毒T淋巴细胞（CTL），两种疫苗免疫产生的HBsAb及HBsAg特异性CTL无明显差异。结论ENHI可使HBV DNA疫苗转染HepG2细胞表达HBsAg明显增加，对转染COS-7细胞表达HBsAg及接种BALB／C小鼠引起的免疫应答无明显影响。     

4110例肝炎分型分析

[目的]探讨各型肝炎的感染率。[方法]研究对象为我院住院及门诊患者，共计4110例。采用微粒子酶免分析法（MEIA）及酶联免疫吸附法（ELISA）进行肝炎分型（甲、乙、丙、丁、戊、庚肝）检测。[结果]4110例受检者中，单纯乙肝感染者133例，占3．24％；单纯丙肝感染者134例，占3．26％；单纯戊肝感染者2例，占0．05％；乙肝合并丙肝感染者3例，占0．07％；丙肝合并戊肝感染者1例，占0．02％；HAV、HDV、HGV无一例感染，感染率为0。另外，男性受检者2088人，乙肝感染者88人，占4．21％；丙肝感染者48人，占2．30％；女性受检者2022人，乙肝感染45人，占2．23％；丙肝感染86人，占4．25％。[结论]除丙肝外，各型感染率均低于全国平均感染率，与相关资料报道相差甚远。乙肝及丙肝仍以单纯感染多见。另，本组资料还显示，男性较女性更易感染乙肝病毒，而女性感染丙肝者远远高于男性，对于丙肝感染的性别差异，尚无报道，需进一步探讨。     

Emerging Issues in Hepatitis C Virus-Positive Liver and Kidney Transplant Recipients

Hepatitis C virus (HCV) infection is a major health care issue in liver and kidney transplantation. Besides negatively affecting both patient and graft survival, HCV is associated with a heightened risk for new onset diabetes mellitus (NODM). The mechanisms underlying the diabetogenicity of HCV are complex but are likely to involve insulin resistance caused by inhibitory actions of the virus on insulin regulatory pathways in the liver. The resultant glucose dysregulation is an important determinant of increased morbidity and mortality in liver and kidney recipients. This review highlights the concerns for outcomes in HCV-positive liver and kidney transplant patients with particular focus on the interrelationship between hepatitis C and diabetes. Data about the potential role of calcineurin inhibitors, corticosteroids and mycophenolate mofetil in HCV infection and HCV-associated NODM will also be discussed.     

92例重型肝炎并发自发性细菌性腹膜炎的诊断与治疗

目的探讨重型肝炎并发自发性细菌性腹膜炎(SBP)的诊断和抗生素使用。方法回顾性分析2002年7月~2005年6月间收治的92例并发SBP的重型肝炎患者的临床资料。结果92例患者中,发热72例(78.26%),腹胀85例(92.39%),腹痛38例(41.30%),反跳痛35例(38.04%),83例(90.21%)外周血中性粒细胞(PMN)分类≥0.75,40例(45.98%)腹水PMN计数≥250个/mm3,79例(90.80%)腹水PMN比值≥0.50,11例(12.00%)腹水细菌培养阳性,共分离出细菌17株,G-杆菌占52.9%(9/17),其对头孢曲松、头孢哌酮、头孢他啶、左旋氧氟沙星及泰能敏感,对丁胺卡那、氧哌嗪青霉素敏感性较低。临床治疗显示,联合使用头孢他啶和甲硝唑效果较好,并较少出现继发真菌感染。结论重型肝炎并发SBP患者的临床表现不典型,腹水培养阳性率低,外周血和腹水PMN比值是诊断SBP比较可靠的参数。治疗SBP,可首选二联使用头孢他啶与甲硝唑,疗程约10~14日。