Experimental candidiasis in liver injury

In an attempt to evaluate effects of liver injury and roles of iron metabolism on systemic fungal infection, experimental systemicCandida infection was produced in mice with galactosamine-induced liver injury. Survival rate and extent of fungal lesion are compared between mice with liver injury (Group 1) and ones without liver injury (Group 2). Median survival was 7 and 18 days in Group 1 and 2 respectively after 21 days observation. Mortality rate of Group 1 was significantly higher (P=0.05) than that of Group 2. This difference was reflected to the extent of fungal lesions in that they were extensive and disseminated, involving the multiple organs in Group 1 but predominantly localized to the kidneys in Group 2. UIBC (unbound iron binding capacity) and TIBC (total iron binding capacity), i.e., serum transferrin as well as serum iron levels were significantly lower in Group 1 as compared with those in Group 2. These results indicate that hepatic injury promotesCandida infectionin vivo and suggest that increased susceptibility toCandida in the presence of liver injury is, at least partially, attributable to low UIBC and/or TIBC.     

束缚应激对D-氨基半乳糖联合脂多糖诱导小鼠肝损伤的保护作用

目的探讨束缚应激对D-氨基半乳糖联合脂多糖（D–galactosamine and lipopolysaccharide combination,D＋L）诱导的小鼠肝损伤的保护作用。方法正常BALB/c小鼠随机分为正常对照组（con）、应激对照组（str）、模型组（D＋L）、束缚应激组（D＋L＋str）。con组小鼠常规饲养;str组小鼠给予定时定量的束缚应激;D＋L组小鼠腹腔注射D-氨基半乳糖和脂多糖的混合溶液,1次/2天;D＋L＋str组小鼠腹腔注射等量D＋L混合液后,给予与str组相同的束缚应激。第8周,各组小鼠取血检测血清AST、ALT,肝脏固定后HE及Masson染色观察小鼠肝脏结构、细胞形态及纤维化程度。结果第8周D＋L＋str组与D＋L组小鼠相比,血清ALT和AST显著降低（P〈0.01）,AST/ALT显著增高（P〈0.01）;HE及Masson染色显示,D＋L组小鼠肝小叶结构紊乱,出现结节性增生及大量上皮细胞核浓缩、溶解、坏死,枯否氏细胞浸润,而D＋L＋str组未见明显病理变化;纤维化程度评分显示,D＋L＋str组与D＋L组小鼠相比,病理评分与纤维显色吸光度值均显著降低（P〈0.05）。结论束缚应激对D＋L诱导的小鼠肝损伤具有一定保护作用。     

四君子汤对急性肝损伤伴发菌群失调及内毒素血症的保护作用

目的　观察急性肝损伤时肠道微生态学、血内毒素含量变化及四君子汤的保护作用。方法　小白鼠腹腔注射D-氨基半乳糖( D- Ga L N) ,制备肝损伤模型,观察中药对肠道正常细菌,组织二胺氧化酶( DAO)活性,血内毒素( L PS)含量的影响及肝脏病理学影响。结果　急性肝损伤时肠杆菌、肠球菌数量明显上升,乳酸杆菌、双歧杆菌数量显著下降,DAO活性下降,L PS含量明显上升,病理学显示,肝细胞大片状、多灶性坏死,大量炎细胞浸润。而中药治疗组上述指标得到明显改善,差异有非常显著性( P<0 .0 0 1)。结论　中药四君子汤对肠道微生态失衡有调整作用,能够减少内毒素的产生和吸收,对肝脏具有保护作用     

先天性皮肤念珠菌病

先天性皮肤念珠菌病是新生儿于子宫内获得的较为少见的感染性疾病.临床表现主要为皮肤受累,可以伴发或仅有甲改变,其病程良性,部分患者可以自愈.伴有系统感染时需系统给予抗真菌药物治疗,病情严重也可引起患儿死亡.现对该病的易感因素、发病机制、临床表现、诊断及治疗等做一简要综述.     

Autophagy and apoptosis in liver injury

Apoptosis is a primary characteristic in the pathogenesis of liver disease. Hepatic apoptosis is regulated by autophagic activity. However, mechanisms mediating their interaction remain to be determined. Basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy also is an adaptive response under stressful conditions. Autophagy can control cell fate through different cross-talk signals. A complex interplay between hepatic autophagy and apoptosis determines the degree of hepatic apoptosis and the progression of liver disease as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances on roles of autophagy that plays in pathophysiology of liver. The autophagic pathway can be a novel therapeutic target for liver disease.     

Autophagy inhibition‐enhanced assembly of the NLRP3 inflammasome is associated with cisplatin‐induced acute injury to the liver and kidneys in rats

The nucleotide‐binding oligomerization domain‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has a key role in the inflammatory response. We found that cisplatin (7.5, 15 mg/kg, IV) could induce acute injury to the liver and kidneys of rats. Western blot and immunohistochemical analyses showed that expression of NLRP3, caspase‐1 and interleukin‐1β was upregulated significantly in a dose‐dependent manner after cisplatin exposure. Autophagy could inhibit NLRP3 expression and assembly of the NLRP3 inflammasome. Expression of light chain 3 II/I and p62 suggested that autophagy was inhibited during injury to the liver and kidneys. These data suggested that cisplatin might activate NLRP3 by inhibiting autophagy in the liver and kidneys of rats.     

达肝清对小鼠免疫性肝损伤的保护作用

采用卡介苗(BCG)+脂多糖(LPS)造成免疫性肝损伤动物模型,观察达肝清对小鼠血清ALT、AST活性及肝组织匀浆SOD、MDA、GSH-PX水平的影响,并观察肝组织病理学改变。结果表明:达肝清可明显降低小鼠血清中ALT、AST活性,同时能减少肝匀浆MDA含量,并能使降低的肝匀浆SOD、GSH-PX活性升高。该实验属首次报道。     

Congenital cutaneous candidiasis associated with maternal peripartum candidemia

BackgroundCutaneous congenital candidiasis (CCC) is a rare condition consisting of invasive fungal infection of the epidermis and dermis that mostly affects preterm infants. Maternal vaginal candidiasis is present in half of the cases, although the occurrence of invasive candidiasis during pregnancy or peripartum period is exceptional.Case reportWe present the case of a full-term infant that was born by vacuum-assisted vaginal delivery to an apparently healthy 33 year-old woman with no history of intravenous drug use or vaginal candidiasis during pregnancy. The newborn showed a diffuse maculopapular rash with respiratory distress and bilateral interstitial lung infiltrates, requiring nasal continuous positive airway pressure support. Blood cultures obtained from the mother due to intrapartum fever yielded Candida albicans. Cultures of vaginal discharge and neonate skin also yielded C. albicans with the same in vitro susceptibly pattern. No alternative source for candidemia was identified. The clinical course after starting a systemic antifungal therapy was favorable in both the mother and the neonate, with clearance of candidemia and resolution of the skin lesions.ConclusionsCCC must be considered in full-term newborns with maculopapular rash at birth or during the first days of life. The absence of alternative sources for bloodstream infection in the present case suggests a potential etiopathogenic relationship between CCC and maternal candidemia. It is reasonable to rule out postpartum candidemia when CCC is suspected.     

Transfer factor in chronic mucocutaneous candidiasis

Fifteen patients suffering from chronic mucocutaneous candidiasis were treated with an in vitro produced TF specific for Candida albicans antigens and/or with TF extracted from pooled buffy coats of blood donors. CMI of the patients was assessed using the LMT and the LST in presence of candidine. The aim of the study was the clinical evaluation of TF treatment and the incidence of positive tests before, during, and after therapy. Immunological data were matched using the Chi square test. 87 LMT were performed for each antigen dose and at the dilution of 1/50, 58.9% (33/56) tests were positive during non-treatment or non-specific TF treatment. On the contrary 83.9% (26/31) were positive during specific TF treatment (P<0.05). In the LST, a significant decrease of thymidine uptake in the control cultures in presence of autologous or AB serum was observed when patients were matched according to non-treatment, and both non specific (P<0.05) and specific TF treatment (P<0.01). Only during specific TF treatment was a significant increase of reactivity against the Candida antigen at the highest concentration noticed, when compared with the period of non specific treatment (P<0.01). Clinical observations were encouraging: all but one patient experienced significant improvement during treatment with specific TF. These data confirm that orally administered specific TF, extracted from induced lymphoblastoid cell-lines, increases the incidence of reactivity against Candida antigens in the LMT. LST reactivity appeared not significantly increased with respect to the periods of non treatment, but was significantly increased when it was compared to the non-specific TF treatment periods. At the same time, a clinical improvement was noticed.     

One-shot delayed-type hypersensitivity reaction in the mouse liver causes a sustained liver injury to picryl chloride

The developmental characteristics of liver injury induced by a delayed-type hypersensitivity (DTH) mechanism against picryl chloride were examined for 9 consecutive weeks in 3 mouse strains, BALB/c, Kunming and ICR mice. The changes of most biochemical parameters were similar in these three strains, namely, the activities of serum transaminases, lactic dehydrogenase, and prolidase were elevated significantly on day 1, during the first several weeks, and almost throughout the duration, respectively, of liver injury. The content of liver hydroxyproline was also increased after 1–9 weeks of liver injury. In addition, a significant decrease of liver weight, serum alkaline phosphatase and albumin level was observed in BALB/c and Kunming mice. Similar changes in liver histology were also found in the three strains. The hepatocellular necrosis and inflammatory infiltration into the portal area were the predominant features on day 1 and were still distinct during the subsequent several weeks. The mild or moderate hepatocellular degeneration, regeneration and connective tissue hyperplasia were observed after 1 or 3 weeks. A bridging necrosis between portal and portal was observed in several BALB/c and ICR mice, reflecting the possibility of exacerbation of liver injury. These results suggest that the liver injury could be caused and sustained by a one-shot DTH reaction to picryl chloride. The chronicity of the biochemical and histopathological characteristics may be helpful in elucidating the mechanisms of chronic development of liver injury.     

Necrotic cell death and suppression of T-cell immunity characterized acute liver failure due to drug-induced liver injury

Background & aims: The aim of this study was to investigate the clinical characteristics and pathophysiology of drug-induced liver injury (DILI) – acute liver failure (ALF). Methods: The patients with acute liver injury (ALI) including ALF from 2009 to 2014 were analyzed. The hepatic encephalopathy (HE) development rate was compared with the findings from a national survey in Japan. The serum cytokines levels and the findings of a liver function test were evaluated in the DILI patients. Results: The HE development rate substantially decreased for autoimmune hepatitis (AIH) – and undetermined cause-induced ALI owing to the early prediction system, but not in DILI-ALI. Among the DILI-ALF and AIH-ALF cases, the CK-18 fragment (1480.1 U/L, 3945.4 U/L), IL-8 (82.9 pg/mL, 207.5 pg/mL), IP-10 (1379.6 pg/mL, 3731.2 pg/mL) and MIP-1β (1017.7 pg/mL, 2273.3 pg/mL) levels were lower in the DILI-ALF cases. Among the DILI-ALI and DILI-ALF cases, IL-4 (19.8 pg/mL, 25.4 pg/mL) and RANTES (14028.0 pg/mL, 17804.7 pg/mL) were higher in DILI-ALI, and HMGB-1 (397.1 pg/μL, 326.2 pg/μL) and HGF (2.41 ng/mL, 0.55 ng/mL) were higher in DILI-ALF. We observed that HGF independently associated with DLI-ALF development. Conclusions: Despite the low grade apoptosis and inflammation, DILI patients progressed to ALF comparable with that of the AIH patients.     

Diagnostic potential of IgA coated Candida cells in mucous membrane candidiasis

The significance of in vivo IgA coated yeast cells for the diagnosis of candidiasis of the oral and vaginal mucosal membranes was evaluated by direct immunofluorescence in 70 patients with or without clinical symptoms, shown to be positive for yeast growth in the cultural test. Most of the patients with clinically suspected candidiasis of the mucosal membranes gave positive results by serologic assays in contrast to the majority of symptomless patients. The diagnostic approach proved to be essentially consistent with the clinical signs, persistance of infection, response to antifungal therapy and quantitative cultural data.     

念珠菌性外阴阴道炎发病机制研究进展

念珠菌性外阴阴道炎是一种常见的妇女感染性疾病,该病发病机制尚未完全明确,其发病与多种因素有关,但主要归因于致病菌与宿主两方面因素。近20a的动物及临床研究显示适应性免疫涉及的几种免疫调节机制可能不是主要的保护性机制,天然免疫被认为是黏膜念珠菌感染的主要宿主防御机制;而念珠菌毒力因子的变化对于该病的发生也有重要作用。     

Albumin and apolipoprotein H mRNAs in human plasma as potential clinical biomarkers of liver injury: analyses of plasma liver-specific mRNAs in patients with liver injury

Context: Plasma liver-specific mRNAs are useful biomarkers of hepatotoxicity in rats.

Objective: To investigate the potential application of liver-specific mRNAs as biomarkers for liver injury in humans.

Methods: We determined the plasma levels of liver-specific mRNAs by real-time qRT-PCR in healthy donors and patients with liver injury.

Results: Plasma levels of albumin (ALB) and apolipoprotein H (APOH) mRNAs increased in patients with elevated serum alanine aminotransferase. These mRNAs also increased in plasma after transcatheter arterial chemoembolization, which induces specific injury to liver.

Conclusions: We demonstrated the potential application of plasma ALB and APOH mRNAs as clinical biomarkers for liver injury.     

The spatiotemporal program of zonal liver regeneration following acute injury

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Liver injury due to iron overload in thalassemia: histopathologic and ultrastructural studies

The livers of 30 cases of thalassemia (19/-thal/HbE, seven thal/HbH and four -thal major) were studied histopathologically and electron microscopically, in an effort to define the morphologic alterations due to iron overload. The results of light and electron microscopy were similar in most cases. Iron accumulation and fibrosis were the common features found in these patients, except that thal/HbH exhibited lesser hepatic damage. The degrees of iron deposition and fibrosis were found to be higher in splenectomized and cirrhotic than non-splenectomized and non-cirrhotic patients. The subcellular changes were swollen mitochondria, with the presence of an electron dense matrix and ruptured mitochondrial membrane. Proliferation of smooth endoplasmic reticulum (ER) and dilated rough ER was observed. Increases in lysosomal hemosiderin in hepatocytes and in Kupffer cells were demonstrated. The possible ways by which the iron compounds or free radicals mediated membrane damage are mentioned. The pattern of liver cell damage is similar to that of viral hepatitis.     

肝硬化合并严重肝损伤并发感染的临床特点及危险因素分析

目的 了解肝硬化合并严重肝损伤患者的继发感染发生率、感染特征、危险因素以及病死率。方法 从浙江大学附属第一医院感染科2014年5月—2015年4月住院治疗的1 264例肝硬化病例中筛选出150例合并严重肝损伤的病例进行回顾性分析。分析上述人群发生感染的情况,包括感染率、感染发生部位、细菌培养结果及预后。同时行多因素Logistic回归分析及Cox比例风险模型分析,探讨肝硬化合并严重肝损伤患者合并感染及90天病死的危险因素。结果 （1）本研究150例患者中,52例患者发生58次感染,感染率34.67%,6例患者发生二次感染。其中社区获得性感染36次,院内感染22次;感染常见部位依次为肺、腹腔（自发性腹膜炎）、泌尿道、血流、皮肤软组织;感染伴肝外器官衰竭23人,占44.23%;病原菌培养阳性感染发生17次,占总感染次数的29.31%,大肠埃希菌、肺炎克雷伯杆菌感染7次,排在前两位,其中产ESBLs菌株占57.14%（4/7）。（2）感染和未感染组比较,谷丙转氨酶、国际标准化比值、白细胞总数、MELD评分、28天病死率、90天病死率差异具有统计学意义（Ps<0.05）。（3）入院90天内病死人群与存活人群比较,年龄、血清总胆红素、国际标准化比值、白细胞数、肌酐、肝性脑病、MELD评分等指标差异具有统计学意义（Ps<0.05）。（4）采用多因素Logistic回归分析发现,血钠水平下降是肝硬化合并严重肝损伤患者并发院内感染独立危险因素（OR＝1.112,P＝0.047）;Cox比例风险模型分析发现年龄（HR＝1.039,P＝0.001）、性别（HR＝2.010,P＝0.043）、白蛋白（HR＝1.073,P＝0.030）、白细胞（HR＝1.081,P＝0.010）、MELD评分（HR＝1.308,P＜0.001）及院内感染（HR＝2.136,P＝0.021）是90天病死率的高危因素。结论 肝硬化患者在发生严重肝损伤后易继发感染最常见的部位为肺及腹腔,病原体以革兰阴性菌为主;血钠水平下降与院内感染相关。感染增加了肝硬化合并严重肝损伤患者的病死率。     

A murine model of esophageal candidiasis with local characteristic symptoms

A simple method to establish a murine esophageal candidiasis model that displayed characteristic symptoms of the condition was developed using the sedative agent, chlorpromazine. Mice were immunosuppressed with prednisolone and were given tetracycline hydrochloride. One day later, the mice received chlorpromazine to keep them in a sedated state for about 3 hr. Under the sedated condition, they were infected with 4 x 10(7) viable cells of Candida albicans by intra-esophageal injection with a round-head needle on syringe. From day 3 to day 6 post inoculation, 10(5)-10(6) colony forming units of C. albicans were recovered from the esophageal tube of each mouse and whitish, curd-like patches were observed on most of the inner surface of the tube. Histological examination showed that C. albicans in esophageal lesions grew mainly in mycelial form. In this experimental model, intragastric administration of an itraconazole oral solution (20 mg/kg/day) was clearly effective. This model would provide a useful tool to investigate the pathogenesis of C. albicans esophageal infection and the efficacy of various antifungal agents microbiologically and symptomatically.     

基于超高效液相色谱质谱的药物性肝损害患者血清代谢组学研究

目的 应用代谢组学结合多变量统计学方法研究药物性肝损害患者血清当中的小分子代谢物质,寻找可用于药物性肝损害早期诊断的潜在生物标志物.方法 选择药物性肝损害患者26例和正常对照23例,应用非靶向的线性梯度超高效液相色谱质谱系统检测血清中的小分子代谢物质.结果 药物性肝损害组和对照组相比,血清中溶血卵磷脂C16∶0、溶血卵磷脂C18∶0、溶血卵磷脂C18∶3、溶血卵磷脂C18∶2的浓度明显降低,硬脂酰胺、油酰胺、十四酰胺、卵磷脂、甘氨鹅去氧胆酸、甘氨胆酸、胆红素、次黄嘌呤显著升高.结论 药物性肝损害患者代谢发生了显著的变化,根据代谢物质的变化有助于临床诊断,研究表明代谢组学是临床研究的一个强有力工具.     

乳杆菌活菌制剂用于外阴阴道假丝酵母菌病疗效分析

目的探讨乳杆菌活菌制剂联合克霉唑治疗外阴阴道假丝酵母菌病的效果。方法将169例外阴阴道假丝酵母菌病的妇女随机分为2组,分别给予2种治疗方法。A组(85例),乳杆菌活菌胶囊(定君生)与克霉唑联合用药:每日晨1粒定君生胶囊塞入阴道,且每日晚1片克霉唑栓塞入阴道,连续用药10 d;B组(84例),单用克霉唑,每晚1片克霉唑栓塞入阴道,连续用药10 d。2组患者经治疗的5 d、10 d、停药后7 d及月经来潮后复检,临床进行综合评价并行比较。结果A组治疗第5天的痊愈率和显效率比B组明显增高,差异有显著性(P<0.01);A组治疗第5天的无效率比B组明显降低,差异有显著性(P<0.01)。治疗第10天2组间的痊愈率、显效率、有效率差异无显著性。而停药后7 d、月经来潮后的总有效率A组比B组明显增高,复发率A组比B组明显下降,差异有显著性(P<0.05)。结论治疗外阴阴道假丝酵母菌病时,乳杆菌活菌制剂联合克霉唑较单用克霉唑能更快起效,并且有效减少停药后7 d及月经来潮后的复发率。