第一部分 中枢神经系统肿瘤（central nerous system tumors）
一、流行病学特征（epidemiological features）
中枢神经系统原发肿瘤，从高度恶性胶质瘤和原始神经外胚层肿瘤到良性脑膜瘤、神经瘤及垂体腺瘤，可表现出不同的生物学...第一部分 中枢神经系统肿瘤（central nerous system tumors）
一、流行病学特征（epidemiological features）
中枢神经系统原发肿瘤，从高度恶性胶质瘤和原始神经外胚层肿瘤到良性脑膜瘤、神经瘤及垂体腺瘤，可表现出不同的生物学行为。根据来自美国脑肿瘤注册中心（Central Brain Tumor Registry of the United States，CBTRUS）的最新报告，每年新诊断的原发脑恶性肿瘤的人数为7．30／10万人。美国脑肿瘤注册中心2005年报告新诊断的中枢神经系统原发肿瘤患者为21690例，死亡12760例。胶质瘤占神经系统原发肿瘤的42％，占恶性肿瘤的77％。胶质瘤起源于不同的组织类型，包括少突胶质细胞瘤、星形细胞瘤、混合型少突星形细胞瘤，表现为不同的恶性程度，而且均具有向高度恶性转化的趋势，其中多形性胶质母细胞瘤（glioblasto mamultiforme，GBM）为成人中最常见的并具有浸润性的原发脑肿瘤。展开更多
治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代...治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代动力学药物-药物相互作用等情况下,测定药物浓度是很有用的。在精神科,有可能明显获益于TDM的主要患者群体包括儿童、孕妇、老年患者、智力障碍患者、涉及司法的患者、已知或怀疑携带药代动力学相关基因变异的患者,以及合并躯体疾病影响药代动力学的患者。然而,只有将TDM充分整合到临床治疗过程中去,才能发挥其优化药物治疗的潜在优势。为了促进TDM的合理应用,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了精神药物治疗药物监测指南。之后,随着知识不断更新,又有许多可能需要进行TDM的新药上市。因此,本次更新将神经精神药物的种类扩展到了128种,并将其TDM必要性划分为从"强烈推荐"到"可能有用"的四个等级。经过大量细致且全面的文献检索与分门别类的汇总整理,将基于循证医学理念的"治疗参考浓度范围"和"剂量相关参考浓度范围"呈现给大家。本共识指南引入了"实验室警戒浓度"的新概念,即实验室需要马上告知治疗医生的药物浓度上限。本共识指南还给出了诸如药物作为细胞色素P450酶的底物和抑制剂的性质,代谢物与母药浓度比值的常见范围,以及与结果解释相关的内容,还提供了何时将TDM与遗传药理学检测相结合的建议。遵循本指南,有助于改善许多患者精神药物治疗的效果,特别是那些存在药代动力学异常的患者。TDM是一门交叉学科,有时针对看起来不一致的数据,需要多学科坦诚地讨论,只有这样,患者才能从这种合作中获益。展开更多
Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the...Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the rapid rise of the metabolic syndrome, the prevalence of NAFLD has recently dramatically increased and will continue to increase. NAFLD has also the potential to progress to hepatocellular carcinoma (HCC) or liver failure. NAFLD is strongly linked to caloric overconsumption, physical inactivity, insulin resistance and genetic factors. Although significant progress in understanding the pathogenesis of NAFLD has been achieved in years, the primary metabolic abnormalities leading to lipid accumulation within hepatocytes has remained poorly understood. Mitochondria are critical metabolic organelles serving as "cellular power plants". Accumulating evidence indicate that hepatic mitochondrial dysfunction is crucial to the pathogenesis of NAFLD. This review is focused on the significant role of mitochondria in the development of NAFLD.展开更多
AIM: To investigate the relationship between Helicobacter pylori(H. pylori) and mucin expression in gastric mucosa.METHODS: English Medical literature searches were conducted for gastric mucin expression in H. pylori ...AIM: To investigate the relationship between Helicobacter pylori(H. pylori) and mucin expression in gastric mucosa.METHODS: English Medical literature searches were conducted for gastric mucin expression in H. pylori infected people vs uninfected people. Searches wereperformed up to December 31 th 2014,using MEDLINE,Pub Med,EMBASE,Scopus,and CENTRAL. Studies comparing mucin expression in the gastric mucosa in patients positive and negative for H. pylori infection,were included. Meta-analysis was performed by using Comprehensive meta-analysis software(Version 3,Biostat Inc.,Englewood,NJ,United States). Pooled odds ratios(ORs) and 95% confidence intervals(CIs) were calculated compared mucin expression in individual studies by using the random effects model. Heterogeneity between studies was evaluated using the Cochran Q-test,and it was considered to be present if the Q-test P value was less than 0.10. I2 statistic was used to measure the proportion of inconsistency in individual studies,with I2 > 50% representing substantial heterogeneity. We also calculated a potential publication bias.RESULTS: Eleven studies,which represent 53 substudies of 15 different kinds of mucin expression,were selected according to the inclusion criteria. Every kind of mucin has been considered as one study. When a specific mucin has been studied in more than one paper,we combined the results in a nested metaanalysis of this particular mucin: MUC2,MUC6,STn,Paradoxical con A,Tn,T,Type 1 chain mucin,Le A,SLe A,Le B,AB-PAS,MUC1,and MUC5 AC. The odds ratio of mucin expression in random analysis was 2.33,95%CI: 1.230-4.411,P = 0.009,higher expression in H. pylori infected patients. Odds ratio for mucin expression in H. pylori positive patients was higher for MUC6(9.244,95%CI: 1.567-54.515,P = 0.014),and significantly lower for MUC5AC(0.447,95%CI: 0.211-0.949,P = 0.036). Thus,H. pylori infection may increase MUC6 expression and decrease MUC5 AC expression by 924% and 52%,respectively.CONCLUSION: H. pylori inhibits MUC5 AC expression in the gastric epithelium,and facilitates colonization. In contrast,increased MUC6 expression may help inhibiting colonization,using MUC6 antibiotics properties.展开更多
AIM： To study the factors that may affect survival of cholangiocarcinoma in Lebanon. METHODS： A retrospective review of the medical records of 55 patients diagnosed with cholangio- carcinoma at the American Universi...AIM： To study the factors that may affect survival of cholangiocarcinoma in Lebanon. METHODS： A retrospective review of the medical records of 55 patients diagnosed with cholangio- carcinoma at the American University of Beirut between 1990 and 2005 was conducted. Univariate and multivariate analyses were performed to determine the impact of surgery, chemotherapy, body mass index, bilirubin level and other factors on survival. RJ^SULTS： The median survival of all patients was 8.57 mo （0.03-105.2）. Univariate analysis showed that low bilirubin level （〈 10 mg/dL）, radical surgery and chemotherapy administration were significantly associated with better survival （P = 0.012, 0.038 and 0.038, respectively）, in subgroup analysis on patients who had no surgery, chemotherapy administration prolonged median survival significantly （17.0 mo vs 3.5 mo, P = 0.001）. Multivariate analysis identified only low bilirubin level 〈 10 mg/dL and chemotherapy administration as independent predictors associated with better survival （P 〈 0.05）. CONCLUSION： Our data show that palliative and postoperative chemotherapy as well as a bilirubin level 〈 10 mg/dL are independent predictors of a significant increase in survival in patients with cholangiocarcinoma.展开更多
AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy’s rule...AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy’s rule and the most important predictors for outcome. METHODS: The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed. RESULTS: From January 1997 to December 2004, 265 patients were diagnosed with DILD,and 140 (52.8%) of them were female. hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminanthepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012). CONCLUSION: Death occurs in 9.8% of patients with DILD. Chinese herbal medicine stands out as the most common drug for DILD. While antitubercular drugs are found to be the primary etiological factor for fetal DILD, hepatic encephalopathy, ascites, jaundice, alcohol abuse and direct bilirubin levels are associated with the death of DILD patients.展开更多
The cDNA fragment of human TRAIL (TNF-related apoptosis inducing ligand) was cloned into RevTet-On, a Tetregulated and high-level gene expression system. The gene expression system was constructed in a human leukemic ...The cDNA fragment of human TRAIL (TNF-related apoptosis inducing ligand) was cloned into RevTet-On, a Tetregulated and high-level gene expression system. The gene expression system was constructed in a human leukemic cell line: Jurkat. By using RevTet-On TRAIL gene expression system in Jurkat as a cell model, we studied the influence of TRAIL gene on the changes of cellular apoptosis before and after the TRAIL gene expression, which was induced by adding tetracycline derivative doxycycline (Dox). The results indicated that the cellular apoptosis ratio was largely dependent on the TRAIL gene expression level. Moreover, it was found that the apoptosis-inducing TRAIL could cause significant changes in the biophysical properties of Jurkat cells. The cell surface charge density decreased, the membrane fluidity declined, the elastic coefficients K_I increased, and the proportion of α-helix in membrane protein secondary structure decreased. Thus, the apoptosis-inducing TRAIL gene caused significant changes on the biomechanic properties of Jurkat cells.展开更多
AIM: To investigate the effects of adrenomedullin (AM) gene overexpression on the biological characteristics of human hepatic stellate cells (hHSCs) by stable transfection.METHODS: hHSCs which express low basal levels...AIM: To investigate the effects of adrenomedullin (AM) gene overexpression on the biological characteristics of human hepatic stellate cells (hHSCs) by stable transfection.METHODS: hHSCs which express low basal levels of AM were stably transfected with an expression construct containing rat AM gene or with an empty expression vector. Expression of AM in hHSCs was determined by reverse transcription (RT)-polymerase chain reaction (PCR) and radioimmunoassay (RIA). Cell proliferation was evaluated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and immunocytochemistry. RT-PCR and Western blot were used to test the expression of procollagen types Ⅰ and Ⅲ. Protein expressions of interstitial collagenase (MMP-1), gelatinase (MMP-2) and tissue inhibitors of matrix metalloproteinases-2 (TIMP-2) were assessed by Western blot.RESULTS: Two cell clones (A-2, A-8) transfected withthe AM gene expressed higher levels of AM mRNA (nontransfected group: 0.86±0.11, empty vector group: 1.01±0.11, A-2 clone group: 1.44±0.08 and A-8 clone group: 1.36±0.05) and protein (12.31±0.17, 12.35±0.12,12.56±0.06 and 12.62±0.07) (P＜0.05). AM geneoverexpression had inhibitory effects on cell proliferation of hHSCs (29.6%, 30.9%, 18.9% and 21.8%, respectively. P＜0.05) and expression of procollagen type Ⅰ (0.58±0.1,0.48±0.11, 0.3±0.06 and 0.31±0.07 at mRNA level)(0.27±0.07, 0.3±0.06, 0.14±0.05 and 0.13±0.05 at protein level) (P＜0.05) and procollagen type Ⅲ (0.17±0.04, 0.15±0.03, 0.1±0.02 and 0.09±0.02 at mRNA level) (0.22±0.04, 0.2±0.03, 0.11±0.04 and 0.13±0.03 at protein level) (P＜0.05). Compared with cells non-transfected (TIMp2: 2.77±0.03, MMP-2: 0.5±0.04, MMP-1: 0.49±0.07) and transfected with empty vector (TIMP2: 2.79±0.04,MMP-2: 0.48±0.03, MMP-1: 0.45±0.09), these two clones had lower expression levels of TIMP2(A-2 clone group: 2.7±0.02 and A-8 clone group: 2.71±0.02) (P＜0.05) and MMP-2(A-2 clone group: 0.15±0.05 and A-8 clone group: 0.13±0.04) (P＜0.05) but displayed a higher expression level of MMP-1(A-2 clone group: 0.68±0.06 and A-8 clone group: 0.81±0.09) (P＜0.05).CONCLUSION: AM gene exerts negative influence to some extent on hHSCs by inhibiting proliferation and production of extracellular matrix (ECM) in addition to inducing MMP-1 expression.展开更多
AIM： To describe the characteristics of Dutch patients with chronic.inflammatory bowel disease （IBD） first diagnosed above 60 years of age-a disease also known as old-age colitis （OAC） and to highlight a conditio...AIM： To describe the characteristics of Dutch patients with chronic.inflammatory bowel disease （IBD） first diagnosed above 60 years of age-a disease also known as old-age colitis （OAC） and to highlight a condition that has a similar appearance to IBD, namely segmen- tal colitis associated with diverticular disease （SCAD）. METHODS： A retrospective longitudinal survey of patient demographic and clinical characteristics, disease characteristics, diagnostic methods, management and course of disease was performed. The median follow-up period was 10 years. RESULTS： Of a total of 1100 IBD patients attending the Department of Gastroenterology, 59 （50） [median age 82 years （range 64-101）; 25 male （42%）] were identified. These patients were diagnosed with ulcerative colitis （n = 37, 61%）, Crohn＇s disease （n = 14, 24%）, and indeterminate colitis （n = 8, 15%）. Remission was induced in 40 （68%） patients within a median interval of 6 mo （range 1-21） and immunosuppressive therapy was well tolerated. Histological evaluation based on many biopsy samples and the course of the disease led to other diagnosis, namely SCAD instead of IBD in five （8%） patients. CONCLUSION： OAC is not an infrequent problem for the gastroenterologist, and should be considered in the evaluation of older patients with clinical features suggestive of IBD. Extra awareness and extensive biopsy sampling are required in order to avoid an erroneous diagnosis purely based on histological mimicry of changes seen in SCAD, when diagnosing IBD in the presence of diverticulosis coli.展开更多
Pathologic hyperplasia of various pancreatic endocrine cells is rare but has been long known.β cell hyperplasia contributes to persistent hyperinsulinemic hypoglycemia of infancy,which is commonly caused by mutations...Pathologic hyperplasia of various pancreatic endocrine cells is rare but has been long known.β cell hyperplasia contributes to persistent hyperinsulinemic hypoglycemia of infancy,which is commonly caused by mutations in the islet ATP-sensitive potassium channel,and to noninsulinoma pancreatogenous hypoglycemia in adults,which may or may not be associated with bariatric surgery.α cell hyperplasia may cause glucagonoma syndrome or induce pancreatic neuroendocrine tumors.An inactivating mutation of the glucagon receptor causes α cell hyperplasia and asymptomatic hyperglucagonemia.Pancreatic polypeptide cell hyperplasia has been described without a clearly-characterized clinical syndrome and hyperplasia of other endocrine cells inside the pancreas has not been reported to our knowledge. Based on morphological evidence,the main pathogenetic mechanism for pancreatic endocrine cell hyperplasia is increased endocrine cell neogenesis from exocrine ductal epithelium.Pancreatic endocrine cell hyperplasia should be considered in the diagnosis and management of hypoglycemia,elevated islet hormone levels,and pancreatic neuroendocrine tumors.Further studies of pathologic pancreatic endocrine cell hyperplasia will likely yield insights into the pathogenesis and treatment of diabetes and pancreatic neuroendocrine tumors.展开更多
AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by d...AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 F-fluorothymidine.RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MSI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAS^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAS^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAS^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.展开更多
Background- Postpacing precordial T- wave inversion(TWI), known as cardiac memory(CM), mimics ischemic precordial TWI, and there are no established ECG criteria that adequately distinguish between the two. On the basi...Background- Postpacing precordial T- wave inversion(TWI), known as cardiac memory(CM), mimics ischemic precordial TWI, and there are no established ECG criteria that adequately distinguish between the two. On the basis of CM properties(postpacing sinus rhythm T vector approaching the direction of the paced QRS vector), we hypothesized that CM induced by right ventricular pacing would manifest a TWI pattern different from that of precordial ischemic TWI, thereby discriminating between the two. Methods and Results- T- wave axis, polarity, and amplitude on a 12- lead ECG during sinus rhythm were compared between CM and ischemic patients. The CM group incorporated 13 patients who were paced in DDD mode with short atrioventricular delay for 1 week after elective pacemaker implantation. The ischemic group consisted of 47 patients with precordial TWI identified among 228 consecutive patients undergoing percutaneous coronary intervention for an acute coronary syndrome. The combination of(1) positive TaVL,(2) positive or isoelectric T1, and(3) maximal precordial TWI >TWIIII was 92% sensitive and 100% specific for CM, discriminating it from ischemic precordial TWI. Conclusions- CM induced by right ventricular pacing results in a distinctive T- vector pattern that allows discrimination from ischemic precordial T- wave inversions regardless of the coronary artery involved.展开更多
Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have be...Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.展开更多
文摘第一部分 中枢神经系统肿瘤（central nerous system tumors）
一、流行病学特征（epidemiological features）
中枢神经系统原发肿瘤，从高度恶性胶质瘤和原始神经外胚层肿瘤到良性脑膜瘤、神经瘤及垂体腺瘤，可表现出不同的生物学行为。根据来自美国脑肿瘤注册中心（Central Brain Tumor Registry of the United States，CBTRUS）的最新报告，每年新诊断的原发脑恶性肿瘤的人数为7．30／10万人。美国脑肿瘤注册中心2005年报告新诊断的中枢神经系统原发肿瘤患者为21690例，死亡12760例。胶质瘤占神经系统原发肿瘤的42％，占恶性肿瘤的77％。胶质瘤起源于不同的组织类型，包括少突胶质细胞瘤、星形细胞瘤、混合型少突星形细胞瘤，表现为不同的恶性程度，而且均具有向高度恶性转化的趋势，其中多形性胶质母细胞瘤（glioblasto mamultiforme，GBM）为成人中最常见的并具有浸润性的原发脑肿瘤。
文摘治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代动力学药物-药物相互作用等情况下,测定药物浓度是很有用的。在精神科,有可能明显获益于TDM的主要患者群体包括儿童、孕妇、老年患者、智力障碍患者、涉及司法的患者、已知或怀疑携带药代动力学相关基因变异的患者,以及合并躯体疾病影响药代动力学的患者。然而,只有将TDM充分整合到临床治疗过程中去,才能发挥其优化药物治疗的潜在优势。为了促进TDM的合理应用,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了精神药物治疗药物监测指南。之后,随着知识不断更新,又有许多可能需要进行TDM的新药上市。因此,本次更新将神经精神药物的种类扩展到了128种,并将其TDM必要性划分为从"强烈推荐"到"可能有用"的四个等级。经过大量细致且全面的文献检索与分门别类的汇总整理,将基于循证医学理念的"治疗参考浓度范围"和"剂量相关参考浓度范围"呈现给大家。本共识指南引入了"实验室警戒浓度"的新概念,即实验室需要马上告知治疗医生的药物浓度上限。本共识指南还给出了诸如药物作为细胞色素P450酶的底物和抑制剂的性质,代谢物与母药浓度比值的常见范围,以及与结果解释相关的内容,还提供了何时将TDM与遗传药理学检测相结合的建议。遵循本指南,有助于改善许多患者精神药物治疗的效果,特别是那些存在药代动力学异常的患者。TDM是一门交叉学科,有时针对看起来不一致的数据,需要多学科坦诚地讨论,只有这样,患者才能从这种合作中获益。
文摘Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the rapid rise of the metabolic syndrome, the prevalence of NAFLD has recently dramatically increased and will continue to increase. NAFLD has also the potential to progress to hepatocellular carcinoma (HCC) or liver failure. NAFLD is strongly linked to caloric overconsumption, physical inactivity, insulin resistance and genetic factors. Although significant progress in understanding the pathogenesis of NAFLD has been achieved in years, the primary metabolic abnormalities leading to lipid accumulation within hepatocytes has remained poorly understood. Mitochondria are critical metabolic organelles serving as "cellular power plants". Accumulating evidence indicate that hepatic mitochondrial dysfunction is crucial to the pathogenesis of NAFLD. This review is focused on the significant role of mitochondria in the development of NAFLD.
文摘AIM: To investigate the relationship between Helicobacter pylori(H. pylori) and mucin expression in gastric mucosa.METHODS: English Medical literature searches were conducted for gastric mucin expression in H. pylori infected people vs uninfected people. Searches wereperformed up to December 31 th 2014,using MEDLINE,Pub Med,EMBASE,Scopus,and CENTRAL. Studies comparing mucin expression in the gastric mucosa in patients positive and negative for H. pylori infection,were included. Meta-analysis was performed by using Comprehensive meta-analysis software(Version 3,Biostat Inc.,Englewood,NJ,United States). Pooled odds ratios(ORs) and 95% confidence intervals(CIs) were calculated compared mucin expression in individual studies by using the random effects model. Heterogeneity between studies was evaluated using the Cochran Q-test,and it was considered to be present if the Q-test P value was less than 0.10. I2 statistic was used to measure the proportion of inconsistency in individual studies,with I2 > 50% representing substantial heterogeneity. We also calculated a potential publication bias.RESULTS: Eleven studies,which represent 53 substudies of 15 different kinds of mucin expression,were selected according to the inclusion criteria. Every kind of mucin has been considered as one study. When a specific mucin has been studied in more than one paper,we combined the results in a nested metaanalysis of this particular mucin: MUC2,MUC6,STn,Paradoxical con A,Tn,T,Type 1 chain mucin,Le A,SLe A,Le B,AB-PAS,MUC1,and MUC5 AC. The odds ratio of mucin expression in random analysis was 2.33,95%CI: 1.230-4.411,P = 0.009,higher expression in H. pylori infected patients. Odds ratio for mucin expression in H. pylori positive patients was higher for MUC6(9.244,95%CI: 1.567-54.515,P = 0.014),and significantly lower for MUC5AC(0.447,95%CI: 0.211-0.949,P = 0.036). Thus,H. pylori infection may increase MUC6 expression and decrease MUC5 AC expression by 924% and 52%,respectively.CONCLUSION: H. pylori inhibits MUC5 AC expression in the gastric epithelium,and facilitates colonization. In contrast,increased MUC6 expression may help inhibiting colonization,using MUC6 antibiotics properties.
文摘AIM： To study the factors that may affect survival of cholangiocarcinoma in Lebanon. METHODS： A retrospective review of the medical records of 55 patients diagnosed with cholangio- carcinoma at the American University of Beirut between 1990 and 2005 was conducted. Univariate and multivariate analyses were performed to determine the impact of surgery, chemotherapy, body mass index, bilirubin level and other factors on survival. RJ^SULTS： The median survival of all patients was 8.57 mo （0.03-105.2）. Univariate analysis showed that low bilirubin level （〈 10 mg/dL）, radical surgery and chemotherapy administration were significantly associated with better survival （P = 0.012, 0.038 and 0.038, respectively）, in subgroup analysis on patients who had no surgery, chemotherapy administration prolonged median survival significantly （17.0 mo vs 3.5 mo, P = 0.001）. Multivariate analysis identified only low bilirubin level 〈 10 mg/dL and chemotherapy administration as independent predictors associated with better survival （P 〈 0.05）. CONCLUSION： Our data show that palliative and postoperative chemotherapy as well as a bilirubin level 〈 10 mg/dL are independent predictors of a significant increase in survival in patients with cholangiocarcinoma.
文摘AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy’s rule and the most important predictors for outcome. METHODS: The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed. RESULTS: From January 1997 to December 2004, 265 patients were diagnosed with DILD,and 140 (52.8%) of them were female. hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminanthepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012). CONCLUSION: Death occurs in 9.8% of patients with DILD. Chinese herbal medicine stands out as the most common drug for DILD. While antitubercular drugs are found to be the primary etiological factor for fetal DILD, hepatic encephalopathy, ascites, jaundice, alcohol abuse and direct bilirubin levels are associated with the death of DILD patients.
基金This work was supported by The National Natural Science Foundation of China(No.30270355,No.39930110)a Doctoral Funding(No.20010001082).
文摘The cDNA fragment of human TRAIL (TNF-related apoptosis inducing ligand) was cloned into RevTet-On, a Tetregulated and high-level gene expression system. The gene expression system was constructed in a human leukemic cell line: Jurkat. By using RevTet-On TRAIL gene expression system in Jurkat as a cell model, we studied the influence of TRAIL gene on the changes of cellular apoptosis before and after the TRAIL gene expression, which was induced by adding tetracycline derivative doxycycline (Dox). The results indicated that the cellular apoptosis ratio was largely dependent on the TRAIL gene expression level. Moreover, it was found that the apoptosis-inducing TRAIL could cause significant changes in the biophysical properties of Jurkat cells. The cell surface charge density decreased, the membrane fluidity declined, the elastic coefficients K_I increased, and the proportion of α-helix in membrane protein secondary structure decreased. Thus, the apoptosis-inducing TRAIL gene caused significant changes on the biomechanic properties of Jurkat cells.
基金Supported by the National Natural Scientific Foundation of China,No.30170417
文摘AIM: To investigate the effects of adrenomedullin (AM) gene overexpression on the biological characteristics of human hepatic stellate cells (hHSCs) by stable transfection.METHODS: hHSCs which express low basal levels of AM were stably transfected with an expression construct containing rat AM gene or with an empty expression vector. Expression of AM in hHSCs was determined by reverse transcription (RT)-polymerase chain reaction (PCR) and radioimmunoassay (RIA). Cell proliferation was evaluated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and immunocytochemistry. RT-PCR and Western blot were used to test the expression of procollagen types Ⅰ and Ⅲ. Protein expressions of interstitial collagenase (MMP-1), gelatinase (MMP-2) and tissue inhibitors of matrix metalloproteinases-2 (TIMP-2) were assessed by Western blot.RESULTS: Two cell clones (A-2, A-8) transfected withthe AM gene expressed higher levels of AM mRNA (nontransfected group: 0.86±0.11, empty vector group: 1.01±0.11, A-2 clone group: 1.44±0.08 and A-8 clone group: 1.36±0.05) and protein (12.31±0.17, 12.35±0.12,12.56±0.06 and 12.62±0.07) (P＜0.05). AM geneoverexpression had inhibitory effects on cell proliferation of hHSCs (29.6%, 30.9%, 18.9% and 21.8%, respectively. P＜0.05) and expression of procollagen type Ⅰ (0.58±0.1,0.48±0.11, 0.3±0.06 and 0.31±0.07 at mRNA level)(0.27±0.07, 0.3±0.06, 0.14±0.05 and 0.13±0.05 at protein level) (P＜0.05) and procollagen type Ⅲ (0.17±0.04, 0.15±0.03, 0.1±0.02 and 0.09±0.02 at mRNA level) (0.22±0.04, 0.2±0.03, 0.11±0.04 and 0.13±0.03 at protein level) (P＜0.05). Compared with cells non-transfected (TIMp2: 2.77±0.03, MMP-2: 0.5±0.04, MMP-1: 0.49±0.07) and transfected with empty vector (TIMP2: 2.79±0.04,MMP-2: 0.48±0.03, MMP-1: 0.45±0.09), these two clones had lower expression levels of TIMP2(A-2 clone group: 2.7±0.02 and A-8 clone group: 2.71±0.02) (P＜0.05) and MMP-2(A-2 clone group: 0.15±0.05 and A-8 clone group: 0.13±0.04) (P＜0.05) but displayed a higher expression level of MMP-1(A-2 clone group: 0.68±0.06 and A-8 clone group: 0.81±0.09) (P＜0.05).CONCLUSION: AM gene exerts negative influence to some extent on hHSCs by inhibiting proliferation and production of extracellular matrix (ECM) in addition to inducing MMP-1 expression.
文摘AIM： To describe the characteristics of Dutch patients with chronic.inflammatory bowel disease （IBD） first diagnosed above 60 years of age-a disease also known as old-age colitis （OAC） and to highlight a condition that has a similar appearance to IBD, namely segmen- tal colitis associated with diverticular disease （SCAD）. METHODS： A retrospective longitudinal survey of patient demographic and clinical characteristics, disease characteristics, diagnostic methods, management and course of disease was performed. The median follow-up period was 10 years. RESULTS： Of a total of 1100 IBD patients attending the Department of Gastroenterology, 59 （50） [median age 82 years （range 64-101）; 25 male （42%）] were identified. These patients were diagnosed with ulcerative colitis （n = 37, 61%）, Crohn＇s disease （n = 14, 24%）, and indeterminate colitis （n = 8, 15%）. Remission was induced in 40 （68%） patients within a median interval of 6 mo （range 1-21） and immunosuppressive therapy was well tolerated. Histological evaluation based on many biopsy samples and the course of the disease led to other diagnosis, namely SCAD instead of IBD in five （8%） patients. CONCLUSION： OAC is not an infrequent problem for the gastroenterologist, and should be considered in the evaluation of older patients with clinical features suggestive of IBD. Extra awareness and extensive biopsy sampling are required in order to avoid an erroneous diagnosis purely based on histological mimicry of changes seen in SCAD, when diagnosing IBD in the presence of diverticulosis coli.
文摘Pathologic hyperplasia of various pancreatic endocrine cells is rare but has been long known.β cell hyperplasia contributes to persistent hyperinsulinemic hypoglycemia of infancy,which is commonly caused by mutations in the islet ATP-sensitive potassium channel,and to noninsulinoma pancreatogenous hypoglycemia in adults,which may or may not be associated with bariatric surgery.α cell hyperplasia may cause glucagonoma syndrome or induce pancreatic neuroendocrine tumors.An inactivating mutation of the glucagon receptor causes α cell hyperplasia and asymptomatic hyperglucagonemia.Pancreatic polypeptide cell hyperplasia has been described without a clearly-characterized clinical syndrome and hyperplasia of other endocrine cells inside the pancreas has not been reported to our knowledge. Based on morphological evidence,the main pathogenetic mechanism for pancreatic endocrine cell hyperplasia is increased endocrine cell neogenesis from exocrine ductal epithelium.Pancreatic endocrine cell hyperplasia should be considered in the diagnosis and management of hypoglycemia,elevated islet hormone levels,and pancreatic neuroendocrine tumors.Further studies of pathologic pancreatic endocrine cell hyperplasia will likely yield insights into the pathogenesis and treatment of diabetes and pancreatic neuroendocrine tumors.
基金the German Cancer Foundation to Oliver H Kr?mer,No.KR 2291/7-1
文摘AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 F-fluorothymidine.RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MSI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAS^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAS^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAS^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.
文摘Background- Postpacing precordial T- wave inversion(TWI), known as cardiac memory(CM), mimics ischemic precordial TWI, and there are no established ECG criteria that adequately distinguish between the two. On the basis of CM properties(postpacing sinus rhythm T vector approaching the direction of the paced QRS vector), we hypothesized that CM induced by right ventricular pacing would manifest a TWI pattern different from that of precordial ischemic TWI, thereby discriminating between the two. Methods and Results- T- wave axis, polarity, and amplitude on a 12- lead ECG during sinus rhythm were compared between CM and ischemic patients. The CM group incorporated 13 patients who were paced in DDD mode with short atrioventricular delay for 1 week after elective pacemaker implantation. The ischemic group consisted of 47 patients with precordial TWI identified among 228 consecutive patients undergoing percutaneous coronary intervention for an acute coronary syndrome. The combination of(1) positive TaVL,(2) positive or isoelectric T1, and(3) maximal precordial TWI >TWIIII was 92% sensitive and 100% specific for CM, discriminating it from ischemic precordial TWI. Conclusions- CM induced by right ventricular pacing results in a distinctive T- vector pattern that allows discrimination from ischemic precordial T- wave inversions regardless of the coronary artery involved.
文摘Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.
