WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.

Aim: Henoch‐Schönlein purpura is an IgA‐mediated autoimmune vasculitis of children. It often presents with symptoms including purpuric rash, abdominal pain, renal involvement or arthritis. Abdominal pain is a frequent symptom in children with HSP and raises the suspicion of intussusception or perforation. We sought to evaluate abdominal pain via stool occult blood and image studies. Methods: A retrospective study of 261 patients diagnosed with Henoch‐Schönlein purpura from December 1991 to December 2001 was conducted. Image studies, including abdominal echo, abdominal CT and panendoscopy, were performed for patients who suffered from abdominal pain. Results: Of the 261 patients, 151 (58%) had abdominal pain, and 46 (17.6%) suffered either overt gastrointestinal bleeding or had positive stool occult blood. Seven patients had gross bloody stools. One acute intussusception and one bowel perforation were noted. One patient suffered from hypovolemic shock due to massive gastrointestinal bleeding. When stool occult blood was 3+ or 4+, the incidence of a positive image finding was high. Conclusion: We found that stool occult blood and image studies may be necessary regarding severe gastrointestinal involvement. Ultrasonography is an important tool when intussusception or bowel perforation is suspected. Monitoring the vital signs is important, especially in patients with massive gastrointestinal bleeding.

SummaryRecently, sera from children with active Henoch-Schönlein purpura (HSP) have been found to enhance interleukin (IL)-8 production by human umbilical venous endothelial cells (HUVEC). To further determine the possible factor with the ability to enhance endothelial IL-8 production in sera from acute stage of HSP, 10 children with HSP at the acute stage and 10 healthy controls were enrolled. IgA antiendothelial cell antibodies (AECA) were detected by cell-based ELISA. Active sera with or without pretreatment with anti-human IgA antibody, sera of controls, and immunoglobulin A (IgA) derived from sera were used to stimulate the HUVEC. The ability of these factors to enhance endothelial IL-8 production was evaluated. Furthermore, signalling pathways were also assayed by different inhibitors, and confirmed by immunoblotting. Serum levels of IgA AECA in HPS patients at the acute stage were significantly higher than in controls ( P < < < < 0·001). The active sera could enhance endothelial IL-8 production ( P = = = = 0·004, compared with control sera), and the ability of these sera was mostly abolished when pretreated with fixed anti-human IgA antibody. The supernatant IL-8 levels of endothelial cells stimulated by IgA derived from acute stage of HSP were statistically higher than controls ( P < < < < 0·001). PD98059, an inhibitor of ERK phosphorylation, significantly reduced IgA AECA-stimulated endothelial IL-8. IgA AECA also enhanced the phosphorylation of ERK1 with a time-dependent manner. Together with these findings, it is concluded that IgA AECA derived from acute stage of HSP may bind to endothelial and enhance endothelial cells to produce IL-8 via MEK/ REK signalling pathway.

Background and purpose: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been identified as a prominent agent that prevents the fructose-induced arterial stiffening in male Wistar rats. Our aims were to examine whether AG produced benefits on the left ventricular (LV)-arterial coupling in fructose-fed (FF) animals in terms of the ventricular and arterial chamber properties. Experimental approach: Rats given 10% fructose in drinking water (FF) were daily treated with AG (50 mg Á kg À1 , i.p.) for 2 weeks and compared with the untreated FF group. In anaesthetised rats, LV pressure and ascending aortic flow signals were recorded to calculate LV end-systolic elastance (E es , an indicator of myocardial contractility) and effective arterial volume elastance (E a ). The optimal afterload (Q load ) determined by the ratio of E a to E es was used to measure the coupling efficiency between the left ventricle and its vasculature. Key results: There was a significant interaction between fructose and AG in their effects on E a . Fructose loading significantly elevated E a and AG prevented the fructose-derived deterioration in arterial chamber elastance. Both fructose and AG affected E es and Q load , and there was an interaction between fructose and AG for these two variables. Both E es and Q load exhibited a decline with fructose feeding but showed a significant rise after AG treatment in the FF rats. Conclusions and Implications: AG prevented not only the contractile dysfunction of the heart caused by fructose loading, but also the fructose-induced deterioration in matching left ventricular function to the arterial system. Keywords: aminoguanidine; effective arterial volume elastance; fructose loading; end-systolic elastance; ventricular-arterial coupling Abbreviations: AG, aminoguanidine; AGEs, advanced glycation endproducts; BW, body weight; CO, cardiac output; E a , effective arterial volume elastance; E es , left ventricular end-systolic elastance; HR, basal heart rate; LVW, left ventricular weight; P es , end-systolic pressure of the left ventricle; P isomax , peak isovolumic pressure of the left ventricle; Q load , optimal afterload; SV, stroke volume; V ed , end-diastolic volume of the left ventricle; V eed , effective end-diastolic volume of the left ventricle; V 0 , the zero-pressure volume

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