An Oil-in-Water adjuvant significantly increased influenza A/H7N9 split virus Vaccine-Induced circulating follicular helper T (cTFH) cells and antibody responses

BackgroundUnadjuvanted A/H7N9 vaccines are poorly immunogenic. The immune response is improved with the addition of MF59, an oil-in-water adjuvant. However, the cellular immunologic responses of MF59-adjuvanted A/H7N9 vaccine are not fully understood.Methods37 participants were vaccinated with 2 doses of 2013 influenza A/H7N9 vaccine (at Days 1 and 21) with or without MF59 and enrolled in an immunology substudy. Responses were assessed at multiple timepoints (Days 0, 8, 21, 29, and 42) for hemagglutination inhibition (HAI) and neutralizing antibody (Neut) assays, memory B cell responses by enzyme-linked ImmunoSpot; circulating follicular helper T cells (cT_FH) and CD4 + T cells by intracellular cytokine staining.ResultsMF59-adjuvanted influenza A/H7N9 vaccine induced significantly higher hemagglutination inhibition (HAI) and neutralizing antibody (Neut) responses when compared to unadjuvanted vaccine. The adjuvanted vaccine elicited significantly higher levels of Inducible T-cell Co-Stimulator (ICOS) expression by CXCR3⁺CXCR5⁺CD4⁺ cT_FH cells, compared to unadjuvanted vaccine. The magnitude of increase in cT_FH cells (from baseline to Day 8) and in IL-21 expressing CD154⁺CD4⁺ T cells (from baseline to Days 8 and 21) correlated with HAI (at Day 29) and Neut antibody (at Days 8 and 29) titers. The increase in frequency of IL-21 expressing CD154⁺CD4⁺T cells (from baseline to Day 21) correlated with memory B cell frequency (at Day 42).ConclusioncT_FH activation is associated with HAI and Neut responses in recipients of MF59-adjuvanted influenza A/H7N9 vaccine relative to unadjuvanted vaccine. Future studies should focus on optimizing the cT_FH response and use cT_FH as an early biomarker of serological response to vaccination.This trial was registered at clinicaltrials.gov, trial number NCT01938742.     

Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C

Interferon can induce autoantibodies and autoimmune reactions. This study reviewed the clinical, serological, and HLA phenotypical features of patients who developed autoimmune hepatitis during interferon therapy for chronic hepatitis C, analyzing their response to immunosuppressive treatment. The diagnosis of chronic hepatitis C was based on positivity for viral RNA and a liver biopsy specimen obtained before interferon treatment. Sera were tested for autoantibodies by indirect immunofluorescence assay. HLA typing was performed by applying a standard microlymphocytotoxicity method. Of 144 patients with chronic hepatitis C treated with interferon, 7 women deteriorated during treatment; serum transaminase, γ-globulin, and immunoglobulin G levels increased; and serum autoantibodies became positive. Interferon was interrupted, a diagnosis of autoimmune hepatitis was established, and immunosuppressive therapy was initiated. All patients responded to this treatment. The 7 patients had similar HLA typing to those with autoimmune hepatitis, with DR4 in 2 patients (67%) with type 2 autoimmune hepatitis, and with DR3 and DR52 in 2 (50%) and 4 (100%) patients, respectively, with type 1 autoimmune hepatitis; additionally, 5 patients (71%) had DQ2, and 4 (57%) had both DR52 and DQ2. In female patients with chronic hepatitis C, a genetic susceptibility to autoimmune hepatitis may exist, possibly triggered by immunostimulating effects during interferon therapy. Immunosuppressive treatment has been well tolerated and seems to be effective.     

Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial

BackgroundRecent clinical evidence indicates that an intradermal (ID) delivery of vaccines confers superior immunogenicity as compared to a standard intramusclular or subcutaneous (SC) delivery.MethodsIn this exploratory study, 600 healthy adults were randomized to 6 study groups with subgroups of young adults (20–64 years old) and older adults (65 years and older). The subjects were either injected by a novel ID injection system with a single dose of 6, 9, or 15 μg HA or two doses (21 days apart) of 15 μg HA per strain or injected by an SC injection method with a single or two doses (21 days apart) of 15 μg HA per strain. Immunogenicity was assessed using hemagglutination inhibition (HAI) titer and microneutralization titer on Days 0, 10, 21, and 42. Solicited and unsolicited adverse events were recorded for 7 and 21 days post-vaccination, respectively.ResultsIn both young adults and older adults groups, the geometric titer (GMT) ratios of HAI in the ID 15 μg HA group were higher than those in the SC 15 μg HA group on both Day 10 and Day 21, while those in the ID 6 and ID 9 μg HA groups were comparable with those in the SC 15 μg HA group. The kinetics of GMTs of HAI suggested that the ID vaccine has the potential to induce the prompt immune response, which is rather hampered in older adults as seen in the SC vaccine groups. The injection-site AEs were generally mild and transient, and did not occur in a dose or dosage-dependent manner.ConclusionsThe results of this study clearly suggest that the immunologic profile of the ID vaccine is better than that of the SC vaccine, while the safety profile of the ID vaccine is similar to that of the SC vaccine. In this exploratory study with almost 100 subjects per each group, single or two-dose administration of the ID vaccine containing 15 μg HA was suggested to be an appropriate regimen in order to prevent influenza and to reduce the associated disease burden.Trial registrationJAPIC Clinical Trials Information (JapicCTI-132096).     

Calcium channel blockade as primary therapy for stable angina pectoris. A double-blind placebo-controlled comparison of verapamil and propranolol

The effectiveness and safety of the beta-adrenergic blocking agent propranolol and the calcium channel antagonist verapamil were compared in 22 patients with chronic stable angina pectoris using a double-blind randomized placebo-controlled crossover protocol. The double-blind phase was preceded by a 2 week single-blind placebo period, followed by randomization to either 4 weeks' therapy with verapamil, 360 mg/day, or propranolol, 240 mg/day, followed by crossover to the other drug. Both verapamil and propranolol increased exercise tolerance (5.5 +/- 0.4 minutes with placebo, 7.8 +/- 0.5 minutes with propranolol [p less than 0.001], and 9.1 +/- 0.5 minutes with verapamil [p less than 0.001]), but the increase with verapamil was significantly greater (p less than 0.01). Both drugs prolonged the exercise duration to 1 mm S-T depression (3.3 +/- 0.4 minutes with placebo, 5.7 +/- 0.5 minutes with propranolol [p less than 0.001] and 5.5 +/- 0.6 minutes with verapamil [p less than 0.001]); the degree of improvement was similar with both active drugs. Both drugs decreased the resting heart rate (76 +/- 3 beats/min with placebo, 56 +/- 2 beats/min with propranolol [p less than 0.001], and 71 +/- 3 beats/min with verapamil [p less than 0.01]), but the heart rate decreased more with propranolol than with verapamil (p less than 0.001). Neither drug produced significant adverse reactions. This study, along with 8 similar double-blind placebo-controlled randomized investigations which have compared verapamil with propranolol, indicate that verapamil is as effective and safe as propranolol in relieving symptoms and improving exercise tolerance in patients with chronic stable angina pectoris and may be considered a first-line therapeutic agent in patients with ischemic heart disease.     

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

Hepatocyte growth factor activator inhibitor‐1 (HAI‐1), encoded by the SPINT1 gene, is a membrane‐bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor‐1 regulates type II transmembrane serine proteases that activate protease‐activated receptor‐2 (PAR‐2). We previously reported that deletion of Spint1 in Apc^Min/+ mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor‐κB signaling. In this study, we examined the role of PAR‐2 in accelerating tumor formation in the Apc^Min/+ model in the presence or absence of Spint1. We observed that knockout of the F2rl1 gene, encoding PAR‐2, not only eliminated the enhanced formation of intestinal tumors caused by Spint1 deletion, but also reduced tumor formation in the presence of Spint1. Exacerbation of anemia and weight loss associated with HAI‐1 deficiency was also normalized by compound deficiency of PAR‐2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in Apc^Min/+‐induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR‐2, and that HAI‐1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR‐2 activating proteases.     

介入治疗治愈乳腺癌肝转移1例

目的探讨肝动脉灌注化疗对乳腺癌肝转移患者的价值。方法通过介入治疗在肝动脉注入NVB40mg＋替加氟1000mg化疗。结果四次肝动脉灌注化疗术后，患者肝上转移灶消失，无病进展期为10个月。结论肝动脉灌注化疗可使部分乳腺癌患者生活质量明显改善，生存期延长。     

消化外科老年患者发生医院感染的调查分析和护理对策

目的调查分析我院消化外科老年患者发生医院感染的情况，以提出相应的措施来降低和控制医院感染发生率。方法采用回顾性调查方法对我院消化外科2006年1-3月出院的90例老年患者发生的医院感染情况进行分析。结果90例老年患者中19例发生医院感染，医院感染发生率为21．11％；患者的年龄越大、住院时间越长，医院感染率越高。老年患者发生医院感染的高发部位为呼吸道，其次为泌尿道；胰腺疾病患者的医院感染发生率最高；引起感染的病原体中以金黄色葡萄球菌居首位（20．69％）。结论必须加强综合性医院消化外科老年住院患者院内感染的管理，尤其是控制呼吸系统感染，加强胰腺疾病的术后护理，严格无菌技术，规范抗生素使用，减少侵入性操作，以促进消化外科老年患者的身体康复。     

2002-2003年中国革兰阴性细菌耐药性监测研究

目的监测我国不同地区14家医院31个研究病房的医院获得感染(HAI)与社区获得感染(CAI)患者中分离的革兰阴性细菌耐药状况。方法按原设计方案对14家医院从2002年7月1日至2003年6月30日分离的1091株革兰阴性菌，采用国际标准平皿二倍稀释法进行体外敏感试验，测得MIC50、MIC90表示抗菌药物的抗菌活性，并按2002年美国临床实验标准委员会(NCCLS)指导原则的标准计算细菌对抗菌药物的耐药率(R)％、中介率(I)％和敏感率(S)％。结果碳青霉烯类仍是对革兰阴性杆菌(除外嗜麦芽窄食单胞菌与黄杆菌，该2种非发酵阴性杆菌对碳青霉烯类高度耐药)抗菌作用最强的一类抗生素。头孢哌酮／舒巴坦、哌拉西林／他唑巴坦、头孢吡肟和新氟喹诺酮类，如加替沙星、莫西沙星、左氧沙星对革兰阴性杆菌亦有很好的抗菌活性，但仍有50％-60％的大肠埃希菌对氟喹诺酮类耐药。从HAI患者分离的革兰阴性杆菌耐药率比从CAI患者分离的相应阴性杆菌的耐药率要高1．5倍以上。结论头孢哌酮／舒巴坦、哌拉西林／他佐巴坦和加替沙星对非发酵阴性杆菌的抗菌谱较广，抗菌作用也较好，是值得注意的抗非发酵菌抗菌药物。我们从2002-2003年度所得的监测结果与2000-2001年度的监测结果及国际监测项目报道的结果基本一致。     

Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: role of male sex hormone

Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards.