Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells

In mucopolysaccharidosis-I (MPS-I), alpha-L-iduronidase deficiency leads to progressive heparan sulfate (HS) and dermatan sulfate (DS) glycosaminoglycan (GAG) accumulation. The functional consequences of these accumulated molecules are unknown. HS critically influences tissue morphogenesis by binding to and modulating the activity of several cytokines (eg, fibroblast growth factors [FGFs]) involved in developmental patterning. We recently isolated a multipotent progenitor cell from postnatal human bone marrow, which differentiates into cells of all 3 embryonic lineages. The availability of multipotent progenitor cells from healthy volunteers and patients with MPS-I (Hurler syndrome) provides a unique opportunity to directly examine the functional effects of abnormal HS on cytokine-mediated stem-cell proliferation and survival. We demonstrate here that abnormally sulfated HS in Hurler multipotent progenitor cells perturb critical FGF-2-FGFR1-HS interactions, resulting in defective FGF-2-induced proliferation and survival of Hurler multipotent progenitor cells. Both the mitogenic and survival-promoting activities of FGF-2 were restored by substitution of Hurler HS by normal HS. This perturbation of critical HS-cytokine receptor interactions may represent a mechanism by which accumulated HS contributes to the developmental pathophysiology of Hurler syndrome. Similar mechanisms may operate in the pathogenesis of other diseases where structurally abnormal GAGs accumulate.     

儿童房室结折返性心动过速患者经冷冻消融和射频消融的结果比较

目的 比较经导管冷冻消融和射频消融治疗儿童房室结折返性心动过速（AVNRT）的临床效果。方法 73例年龄在18岁以下，诊断为AVNRT的患者入选本研究，根据治疗方法分为冷冻消融组（冷冻组）和射频消融组（射频组），记录并分析比较两组的临床特点、冷冻标测次数、消融次数、X线曝光时间、消融术总时间、成功率、并发症发生率以及复发率。结果 共73例患者入选，冷冻组33例，男性16例，女性17例，平均年龄（12．4±2．8）岁；射频组40例，男性18例，女性22例，平均年龄（13．6±2．2）岁。冷冻组和射频组的消融次数分别为（2．7±1．7）次和（11±6．3）次（P〈0．001），X线曝光时间分别为（20±7）min和（25±9）min（P〈0．05），消融术总时间分别为（214±33）min和（164±36）min（P〈0．05），消融成功率88％（29／33）对100％（40／40）（P〈0．01），一过性房室阻滞的并发症发生率为12％对2．5％（P〈0．01）。冷冻组所有术中发生的传导阻滞均在5min内恢复。两组的复发率差异无统计学意义（6％与2．5％，P=NS）。结论 经导管冷冻消融治疗儿童AVNRT安全有效，但成功率低于射频消融，目前可作为后者的一种补充。     

The occurrence of terminal ileal histological abnormalities in patients with coeliac disease

INTRODUCTION: Coeliac disease causes histological changes throughout the small bowel, but is often a proximal lesion. We wanted to assess whether terminal ileal histological abnormalities occurred more commonly in patients with coeliac disease and if specific assessment of intraepithelial lymphocytes increases the recognition of undiagnosed coeliac disease. METHODS: Terminal ileal biopsies were prospectively examined over a 3-year period (April 2001-May 2004). Patients were included if they were found to have a synchronous duodenal biopsy that gave a new diagnosis of coeliac disease (n=20). Terminal ileal biopsies taken at colonoscopy during the same period were also examined from four groups of patients: coeliac disease established on a gluten-free diet but with persisting symptoms (n=25), inflammatory bowel disease (n=47), chronic diarrhoea (n=44) and polyp surveillance (n=47). All biopsies were graded according to the Marsh criteria and an intraepithelial lymphocytes count per 100 enterocytes was obtained. RESULTS: There was only one patient from all five groups who had villous atrophy of the terminal ileal. This patient had a new diagnosis of coeliac disease. The mean intraepithelial lymphocytes count in the coeliac disease group was 23.7 intraepithelial lymphocytes/100 enterocytes. This was significantly higher than the control groups: coeliac disease on a gluten-free diet=17.5 (p<0.012), inflammatory bowel disease=12.3 (p<0.0001), diarrhoea=12.6 (p<0.0001) and polyp=13.7 (p<0.0002). Validating terminal ileal villous intraepithelial lymphocytes counts as a test for coeliac disease using an intraepithelial lymphocytes/100 enterocytes of >25 gives a sensitivity of 45% and a specificity of 97.8%. CONCLUSION: Routinely quantifying terminal ileal intraepithelial lymphocytes may be of limited clinical value. However, subjective recognition of raised intraepithelial lymphocytes on a terminal ileal biopsy should alert the clinician to the possibility of coeliac disease.     

An in vitro model for the study of phagocytosis of damaged hepatocytes by rat Kupffer cells

Abstract: Aims/Background: One function of Kupffer cells is the phagocytosis of nonviable hepatocytes. Our aims were to develop a model for phagocytosis of damaged hepatocytes by rat Kupffer cells in vitro, and to characterise prostaglandin E₂ (PGE₂), prostacyclin (PGI), and tumour necrosis factor-α (TNF) production in this model. Methods: Kupffer cells were incubated alone or with damaged hepatocytes for up to 18 h, then washed and cultured for up to 66 h. To compare mediator responses produced during inert particle phagocytosis, Kupffer cells were also incubated with latex beads. Results: Phagocytic uptake of hepatocyte debris was confirmed in at least 50% of Kupffer cells. A dissociation between TNF and PGI responses was found for both latex beads and damaged hepatocytes, such that a TNF secretory response was not triggered by either stimulus whereas PGI production was increased for both. Although phagocytosis of beads increased PGE₂ production, phagocytosis of hepatocytes did not. Conclusions: Phagocytosis of damaged hepatocytes by Kupffer cells results in the production of PGI but not PGE₂ or TNF.