从《世说新语》看魏晋南北朝志人小说的特点

《世说新语》继承史传文学讲究“实录”的传统 ,崇尚真实。表达方式多为直陈其事 ,较少描写 ,缺乏完整的故事情节。善于即事见人 ,通过典型的细节刻划及对比手法等突现人物性格。人物语言简洁生动 ,较少用典。比喻手法的运用更增添了作品的形象性和艺术感染力。以《世说新语》为代表的魏晋南北朝志人小说的艺术成就对后世小说的影响是深远的。     

Urinary mutagenicity as a biomarker in workers exposed to benzidine: correlation with urinary metabolites and urothelial DNA adducts

Urinary mutagenicity has been used in occupational and epidemiological studies for over two decades as a cost-effective, general biomarker of exposure to genotoxic agents. However, few studies have compared urinary mutagenicity to additional biomarkers determined among low- and high-exposed groups. To address this issue, we evaluated the relationship between urinary mutagenicity and other types of biomarkers in a cross-sectional study involving 15 workers exposed to the urinary bladder carcinogen benzidine (BZ, high exposure), 15 workers exposed to BZ-dyes (low exposure), and 13 unexposed controls in Ahmedabad, India. Urinary organics were extracted by C18/methanol and evaluated for mutagenicity in the presence of S9 in the Salmonella strain YG1024, which is a frameshift strain that overproduces acetyltransferase. The results were compared to biomarker data reported recently from the same urine samples (Rothman et al., Proc. Natl Acad. Sci. USA, 93, 5084- 5089, 1996) that included a metabolite biomarker (the sum of the urinary levels of BZ + N-acetylbenzidine + N,N'-diacetylbenzidine) and a DNA adduct biomarker [a presumptive N-(3'-phosphodeoxyguanosin-8-yl)- N'-acetylbenzidine (C8dG-ABZ) DNA adduct in exfoliated urothelial cells]. The mean +/- SE urinary mutagenicity (revertants/micromol of creatinine) of the low-exposure (BZ-dye) workers was 8.2 +/- 2.4, which was significantly different from the mean of the controls (2.8 +/- 0.7, P = 0.04) as was that of the mean of the high-exposure (BZ) workers (123.2 +/- 26.1, P < 0.0001). Urinary mutagenicity showed strong, positive correlations with urinary metabolites (r = 0.88, P < 0.0001) and the level of the presumptive C8dG-ABZ urothelial DNA adduct (r = 0.59, P = 0.0006). A strong association was found between tobacco use (bidi smoking) and urinary mutagenicity among the controls (r = 0.68, P = 0.01) but not among the exposed workers (r = 0.18, P = 0.11). This study confirms the ability of a biomarker such as urinary mutagenicity to detect low-dose exposures, identify additional genotoxic exposures among the controls, and correlate strongly with urinary metabolites and DNA adducts in the target tissue (urinary bladder epithelia) in humans.      

Effects of enkephalins on bile-secreting function

Various doses of leu- and met-enkephalins injected into the portal vein of rats inhibited predominantly the secretory function of the liver. In most instances, the changes in bile secretion were observed to coincide in direction, time of occurrence, and magnitude with those in the secretion of bile acids. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 10, pp. 354–356, October, 1995 Presented by B. I. Tkachenko, Member of the Russian Academy of Medical Sciences     

Biliary dysgenesis in the PCK rat, an orthologous model of autosomal recessive polycystic kidney disease

Hepatic polycystic disease occurs alone or in combination with polycystic kidney disease (PKD). In autosomal recessive PKD (ARPKD), liver lesions are the major cause of morbidity and mortality in older patients. ARPKD is caused by a mutation to PKHD1 and the PCK rat is an orthologous model of disease. Recently, we showed that fibrocystin, Pkhd1 protein, is localized to primary cilia in rat cholangiocytes and that disruption of its ciliary expression results in biliary cystogenesis. This study describes biliary phenotype in the PCK rat using micro-computed tomography scanning and three-dimensional reconstruction, and light, scanning, and transmission microscopy. Our results show that the biliary tree undergoes extensive remodeling resulting in bile duct dilatation, focal budding, and formation of cysts that are initially connected to bile ducts, but throughout time separate from them. Progressive liver enlargement results from massive cyst formation while liver parenchymal volume remains unchanged. Cilia in cystic cells are abnormal consistent with the notion that the primary defect in ARPKD resulting in cystogenesis may be linked to ciliary dysfunction. Our results suggest that the PCK rat is a useful model for studies of biliary cystogenesis and treatment options of inherited cystic liver disease.     

Extraluminal colonic arteriovenous haemangioma: an unusual cause of chronic lower gastrointestinal bleeding

Lower gastrointestinal bleeding is a common general surgical presentation in acute and chronic settings. Vascular anomalies account for 2% of such cases and can therefore be missed. We discuss a rare vascular anomaly in one of our patients where the diagnosis was not established for a ten-year period. We describe the subsequent management and a brief review of the literature of this uncommon condition.     

Experimental models to study cholangiocyte biology

Cholangiocytes-the epithelial cells which line the bile ducts-are increasingly recognized as important transporting epithelia actively involved in the absorption and secretion of water, ions, and solutes. This recognition is due in part to the recent development of new experimental models. New biologic concepts have emerged including the identification and topography of receptors and flux proteins on the apical and/or basolateral membrane which are involved in the molecular mechanisms of ductal bile secretion. Individually isolated and/or perfused bile duct units from livers of rats and mice serve as new,physiologically relevant in vitro models to study cholangiocyte transport. Biliary tree dimensions and novel insights into anatomic remodeling of proliferating bile ducts have emerged from three-dimensional reconstruction using CT scanning and sophisticated software. Moreover, new pathologic concepts have arisen regarding the interaction of cholangiocytes with pathogens such as Cryptosporidium parvum. These concepts and associated methodologies may provide the framework to develop new therapies for the cholangiopathies, a group of important hepatobiliary diseases in which cholangiocytes are the target cell.     

A case of kernicterus in New Zealand: A predictable tragedy?

Abstract: A case of neonatal kernicterus due to glucose-6-phosphate dehydrogenase deficiency (G6PD) is described. Diagnosis was delayed as the primary healthcare attendant had no knowledge of this condition and its potential to cause rapidly escalating levels of bilirubin and as she was reassured by the lack of signs of systemic illness or anaemia. The baby has been left deaf, blind, intellectually handicapped, epileptic and paralysed due to athetoid cerebral palsy. The re-organization of perinatal care in New Zealand, which has ted to neonates sometimes being managed solely by primary healthcare attendants with minimal training in paediatrics may have increased the risk of a late diagnosis of potentially devastating diseases such as this.     

Centrosomal Abnormalities Characterize Human and Rodent Cystic Cholangiocytes and Are Associated with Cdc25A Overexpression

Hepatic cystogenesis in polycystic liver diseases is associated with abnormalities of cholangiocyte cilia. Given the crucial association between cilia and centrosomes, we tested the hypothesis that centrosomal defects occur in cystic cholangiocytes of rodents (Pkd2^WS25/− mice and PCK rats) and of patients with polycystic liver diseases, contributing to disturbed ciliogenesis and cyst formation. We examined centrosomal cytoarchitecture in control and cystic cholangiocytes, the effects of centrosomal abnormalities on ciliogenesis, and the role of the cell-cycle regulator Cdc25A in centrosomal defects by depleting cholangiocytes of Cdc25A in vitro and in vivo and evaluating centrosome morphology, cell-cycle progression, proliferation, ciliogenesis, and cystogenesis. The cystic cholangiocytes had atypical centrosome positioning, supernumerary centrosomes, multipolar spindles, and extra cilia. Structurally aberrant cilia were present in cystic cholangiocytes during ciliogenesis. Depletion of Cdc25A resulted in i) a decreased number of centrosomes and multiciliated cholangiocytes, ii) an increased fraction of ciliated cholangiocytes with longer cilia, iii) a decreased proportion of cholangiocytes in G1/G0 and S phases of the cell cycle, iv) decreased cell proliferation, and v) reduced cyst growth in vitro and in vivo. Our data support the hypothesis that centrosomal abnormalities in cholangiocytes are associated with aberrant ciliogenesis and that accelerated cystogenesis is likely due to overexpression of Cdc25A, providing additional evidence that pharmacological targeting of Cdc25A has therapeutic potential in polycystic liver diseases.Polycystic liver diseases (PLDs) are inherited genetic disorders that include but are not limited to i) autosomal dominant polycystic kidney disease (ADPKD), the most common of these disorders; ii) autosomal recessive PKD (ARPKD), less common but generally more severe; and iii) autosomal dominant polycystic liver disease (ADPLD), a rare condition in which cyst formation is limited to the liver (unlike the other two conditions, in which cysts occur in both liver and kidneys).^1–4 Defects in ciliary morphology and impaired ciliary-mediated intracellular signaling trigger atypical cell cycle and benign cell hyperproliferation, which are the major contributors to cyst formation and expansion. Indeed, we and others have shown that abnormalities in ciliary length (both elongation and shortening) and disturbed expression of ciliary-associated proteins are sufficient to generate the pathological cystic phenotype.^5–11Primary cilia have an intimate relationship with another cell organelle, the centrosome. Centrosomes play an important role in microtubule nucleation and organization, in cell-cycle progression, migration, ubiquitin-proteasome degradation, cell polarity and, importantly, in cilia formation.^12,13 Centrosomes are composed of two centrioles linked by interconnecting fibers and surrounded by pericentriolar material. The older centriole (the mother centriole) is structurally distinguished from the daughter centriole by the presence of fibrous appendages. In the G1/G0 phase of the cell cycle, after centriole duplication, the mother centriole is recruited to the apical cell membrane to become the basal body, providing a template for nucleation of the ciliary axoneme.^13–17Both ciliary and centrosomal defects have been detected in nearly all human cancers. Many molecules have been implicated in centrosomal abnormalities, but most experimental evidence defines the tumor suppressor p53 (levels of which are abnormal in most tumors) as a major regulator of centrosome number, size, and appearance in cancer.^{13,14,18–23} Dysfunctional links between centrosomes and primary cilia have also been observed in polycystic kidney. Indeed, in several animal models of PKD and in patients with ADPKD, renal epithelial and endothelial cells have supernumerary centrosomes, defects in mitotic spindle formation, abnormal cell division, and malformed primary cilia.^24–29Our research group previously showed that primary cilia in cholangiocytes lining liver cysts of animal models of PLD (PCK rat and Pkd2^WS25/− and Pkhd1^del2/del2 mice) are morphologically abnormal.^7,30,31 However, the structural and functional relationships between the centrosome and primary cilia in cystic cholangiocytes have not been addressed previously. Thus, to test the hypothesis that centrosomal defects contribute to ciliogenesis and cyst formation, we analyzed i) the centrosome cytoarchitecture (ie, their number, size, and cellular position), ii) the ability of supernumerary centrosomes to nucleate extra cilia, iii) the effects of centrosomal abnormalities on temporal ciliary growth (ie, ciliogenesis), and iv) the potential mechanisms responsible for centrosomal aberrations in PLD. Our results show that i) cystic cholangiocytes of animal models and human patients with PLD have improper centrosome positioning, overduplicated centrosomes, multipolar spindles, and extra cilia; ii) these defects are associated with impaired ciliogenesis in cystic cholangiocytes; iii) Cdc25A, a cell-cycle phosphatase overexpressed in PLD,⁸ is involved in regulation of the observed centrosomal abnormalities; and iv) genetic and pharmacological suppression of Cdc25A reduces the abnormal number of centrosomes per cell, reduces the proportion of cholangiocytes with multiple centrosomes and extra cilia, and alters the cell cycle, leading to decreased cholangiocyte proliferation and attenuated cyst growth. Taken together, our data confirm the importance of centrosomal abnormalities in hepatic cystogenesis and provide further support for Cdc25A as a potential therapeutic target in PLD.