Polyglutamine-expanded ataxin-7 causes cerebellar dysfunction by inducing transcriptional dysregulation.

In the present study, we prepared an animal model of adult-onset spinocerebellar ataxia type 7 (SCA7) by generating transgenic mice expressing polyglutamine-expanded ataxin-7-Q52. Mutant ataxin-7-Q52 was expressed in brain areas implicated in SCA7 neurodegeneration, including cerebellum and inferior olivary nucleus. Ataxin-7-Q52 transgenic mice exhibited symptoms of motor dysfunction with an onset age of 7 months, and neurological phenotypes deteriorated in the following months. Ten to eleven-month-old ataxin-7-Q52 mice displayed ataxic symptoms without prominent cerebellar neuronal death, suggesting that ataxin-7-Q52 causes cerebellar malfunction and ataxia. To investigate the involvement of transcriptional dysregulation in ataxin-7-Q52-induced cerebellar dysfunction, microarray analysis and real-time RT-PCR assays were performed to identify altered cerebellar mRNA expressions of 10-11-month-old ataxin-7-Q52 transgenic mice. Ataxin-7-Q52 mice exhibited downregulated mRNA expressions of proteins involved in glutamatergic transmission, signal transduction, myelin formation, deubiquitination, axon transport, neuronal differentiation or glial functions and heat shock proteins. The involvement of transcriptional abnormality in initiating SCA7 pathological process was indicated by the finding that 6-month-old ataxin-7-Q52 transgenic mice, which did not display noticeable ataxic symptoms, exhibited dysregulated mRNA expressions. Our study suggests that polyglutamine-expanded ataxin-7-induced transcriptional dysregulation causes cerebellar dysfunction and ataxia.

The ongoing variability in blood transfusion practices in cardiac surgery.

BACKGROUND: Although blood utilization has been under considerable scrutiny for the past two decades, particularly for surgery, studies comparing perioperative blood transfusion practices between countries are rare, and the evolution of international standards remains unknown. Therefore, the objective of this evaluation was to compare the perioperative transfusion of blood components in cardiac surgery in multiple centers in different countries. STUDY DESIGN AND METHODS: Transfusion practice was investigated prospectively in 70 centers among 16 countries. A total of 5065 randomly selected cardiac surgery patients of the Multicenter Study of Perioperative Ischemia Epidemiology II (EPI II) Study were evaluated. Utilization of red blood cells (RBCs), fresh-frozen plasma (FFP), and platelets (PLTs) was assessed daily, before, during, and after surgery until hospital discharge. RESULTS: Intraoperative RBC transfusion varied from 9 to 100 percent among the 16 countries, and 25 to 87 percent postoperatively (percentage of transfused patients). Similarly, frequency of transfusion of FFP varied from 0 to 98 percent intraoperatively and 3 to 95 percent postoperatively, and PLT transfusion from 0 to 51 and 0 to 39 percent, respectively. Moreover, there were not only marked differences in transfusion rates between centers in different countries but also in interinstitutional comparison of multiple centers within countries. CONCLUSION: In cardiac surgical patients, marked variability in transfusion practice exists between centers in various countries and suggests differences in perioperative practice patterns as well as possible inappropriate use. International standardization of perioperative practice patterns as well as transfusion regimes appears necessary.

Prevalence of risk factors, and not gender per se, determines short- and long-term survival after coronary artery bypass surgery.

OBJECTIVE: Much attention has been directed towards female gender as an independent risk factor for in-hospital mortality after coronary artery bypass grafting surgery; however, the effects of surgery are known to persist for 6 months or more. Studies that have compared postoperative survival in women and men beyond hospital discharge report disparate results with regard to the independent effect of gender per se on ultimate survival. DESIGN: This investigation was a prospective, observational study. SETTING: The study was a multicenter investigation involving 24 US medical centers. PARTICIPANTS: There were 2,048 patients undergoing isolated coronary artery bypass graft surgery enrolled between September 1991 and September 1993 and after discharge. INTERVENTIONS: There were no interventions with this prospective observational study. MEASUREMENTS AND MAIN RESULTS: Preoperative demographic variables, medical history, and angiographic data were collected for each patient at the time of enrollment. Patients' vital status through the National Death Index up to August 31, 1998, were added to assess postoperative long-term survival. For survivorship analysis, the Kaplan-Meier product-limit method was used with Cox regression model. Survivorship analyses were performed separately and in combination on mortality within 30 days and 6 months of coronary artery bypass graft surgery and during the entire postoperative follow-up period. Among women, preoperative disease status, as expected, was more severe than that in men. Women were older (p = 0.0001) and had more comorbidity, such as congestive heart failure (p = 0.0019), diabetes (p = 0.0001), anemia, and hypertension (p = 0.0001). After surgery, unadjusted survival of 6 months and 5 years in women was worse than that in men. However, there were no gender-related differences in short- or long-term survival after adjusting for covariates in the multivariate model. Preoperative conditions, such as congestive heart failure, anemia, diabetes, and advanced age, are indicative of greater risk in both women and men for lower survival after coronary artery bypass graft surgery. CONCLUSIONS: Disease prevalence in women, and not gender per se, affects mid- and long-term survival after cardiac surgery. Attention, therefore, should be focused on efforts to reduce or modify such disease prevalence earlier in women, which may in turn allow longer survival after surgical intervention. Differences in postoperative survival between women and men were related to the gender differences in the distribution of preoperative risk factors.