Interaction between LIS1 and doublecortin, two lissencephaly gene products

Mutations in either LIS1 or DCX are the most common cause for type I lissencephaly. Here we report that LIS1 and DCX interact physically both in vitro and in vivo. Epitope-tagged DCX transiently expressed in COS cells can be co-immunoprecipitated with endogenous LIS1. Furthermore, endogenous DCX could be co-immunoprecipitated with endogenous LIS1 in embryonic brain extracts, demonstrating an in vivo association. The two protein products also co-localize in transfected cells and in primary neuronal cells. In addition, we demonstrate homodimerization of DCX in vitro. Using fragments of both LIS1 and DCX, the domains of interaction were mapped. LIS1 and DCX interact with tubulin and microtubules. Our results suggest that addition of DCX and LIS1 to tubulin enhances polymerization in an additive fashion. In in vitro competition assays, when LIS1 is added first, DCX competes with LIS1 in its binding to microtubules, but when DCX is added prior to the addition of LIS1 it enhances the binding of LIS1 to microtubules. We conclude that LIS1 and DCX cross-talk is important to microtubule function in the developing cerebral cortex.     

Risk factors for delayed healing of neuropathic diabetic foot ulcers: a pooled analysis

OBJECTIVE: To estimate the effect of various risk factors on the probability that neuropathic diabetic foot ulcers will heal within 20 weeks of care. DESIGN AND SETTING: A pooled or meta-analysis of individual patient data from the standard care arms of 5 randomized clinical trials was conducted. We analyzed 586 subjects with diabetes mellitus who had a neuropathic diabetic foot ulcer. All patients received good wound care, debridement, and "off-loading" of the wound. MAIN OUTCOME MEASURE: Multivariable logistic regression was used to calculate the magnitude of the association of each risk factor with patients having healed wounds. RESULTS: Logistic regression odds ratios (ORs; 95% confidence intervals [95% CIs]) revealed that those patients with a diabetic neuropathic foot ulcer that healed within 20 weeks using standard care were more likely to have a smaller wound (OR = 0.67; 95% CI, 0.55-0.81), a wound that existed for a shorter period (OR = 0.73; 95% CI, 0.61-0.87), and be nonwhite (OR = 0.64; 95% CI, 0.43-0.96) compared with patients whose wounds did not heal within 20 weeks. The patient's age (OR = 0.99; 95% CI, 0.89-1.01), serum level of glycosylated hemoglobin at the start of the study (OR = 1.03; 95% CI, 0.97-1.10), and sex (OR = 1. 02; 95% CI, 0.69-1.50) were unassociated with the probability of wound healing. Substantial heterogeneity was not found among the studies. CONCLUSIONS: A standard care regimen for diabetic neuropathic foot ulcers is most likely to be effective for patients who have wounds that are small and of brief duration. This information should help dermatologists decide initially whether to use standard care, to try a new treatment, or to refer the patient to a specialty center.     

Prognostic models: evidence-based approach to predicting disease outcome

BACKGROUND: A thorough understanding of the techniques underlying prognostic modelling, the potential shortcomings of prognostic models, and their applicability to dermatology are important for both clinicians and researchers. OBJECTIVE: This article distinguishes between prognostic and explanatory (causal) models, discusses some of the techniques used in developing a prognostic model, and addresses the importance of model generalizability. CONCLUSION: Prognostic models may be useful to the clinician, but must be used with care. It is important to critically appraise prognostic models and to assure that they are relevant to the population of interest. The ability to critically appraise prognostic models is predicated on a thorough understanding of the techniques used in their development and evaluation.     

Strategies in the development of recombinant vaccines for colon cancer

A new era involving the evaluation of recombinant vaccines for colon cancer has begun with the concurrent emergence of insights and technologies in the fields of molecular biology and immunology. These advances include (I) the identification and cloning of an array of genes associated with the neoplastic process, such as oncogenes, suppressor genes, genes encoding oncofetal antigens, and tissue lineage determinants; (2) the development of a variety of viral and bacterial vectors to deliver and present gene products; (3) the identification of numerous T-cell costimulatory molecules and the knowledge of their mode of action; (4) the cloning and analysis of the modes of action of an array of cytokines and other immunomodulatory molecules; and (5) a more sophisticated knowledge of the mode(s) of antigen presentation and T-cell activation.     

Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes

We have reported that inhibition of protein kinase C blocks the Ca(2+)-independent reverse transport of dopamine mediated by amphetamine. In this study we investigated whether activation of protein kinase C by 12-O-tetradecanoyl phorbol-13-acetate (TPA) would mediate dopamine release through the plasmalemmal dopamine transporter. TPA, at 250 nM, increased the release of dopamine from rat striatal slices and synaptosomes while the inactive phorbol ester, 4alpha-phorbol, was ineffective. The TPA-mediated dopamine release was independent of extracellular calcium and was blocked by a selective protein kinase C inhibitor, Ro31-8220. The dopamine transporter antagonists, cocaine and GBR 12935 blocked the TPA-mediated dopamine release. In addition, cocaine blocked TPA-mediated phosphorylation of the plasmalemmal dopamine transporter. These results suggest that activation of protein kinase C results in reverse transport of dopamine through the plasmalemmal dopamine transporter and the phosphorylated substrate could be the dopamine transporter.     

Radiothérapie d''un hémangiome massif du foie chez une enfant d''un mois et demi

We report the case of a six-week-old baby who underwent irradiation for a giant hepatic hemangioma. After medical treatment including corticosteroids and interferon, no response was observed. She progressed to respiratory failure, requiring the use of mechanical ventilation. An emergency radiation therapy of the liver was decided. We observed a rapid improvement of the child, with the recovery of autonomous breathing without mechanical ventilation and a normalization of cardiac functions. Two months later, a partial left hepatic embolization was needed due to a progression of a localized blood flow. Six months later, she finally came back home. Cardiac output was normal and hepatomegaly began to regress. One year later, ponderal status is satisfactory, and it remains a localized hepatic right lobe hypertrophy without functional consequence.     

The relationship between premature rupture of the membranes and the respiratory distress syndrome. An update and plan of management

The records of 340 infants of 36 weeks' gestational age or less were reviewed to study the relationship between premature rupture of the membranes (PRM) and the development of the respiratory distress syndrome (RDS). Twins and infants of diabetic mothers were excluded from the data analysis. PRM of 16 hours or more was associated with statistically significant reduction in the incidence of RDS in infants of 31 weeks' gestational age and older. The association between PRM in excess of 16 hours and survival, however, was only statistically significant for infants of 33 weeks' gestational age and older. The implications of these results and a proposed plan of management for premature infants with PRM are discussed.     

Prolonged breastfeeding in Bangladesh: indicators of inadequate feeding practices or mothers'' response to children''s poor health?

The association between breastfeeding and diarrhoeal morbidity was examined in a prevalence study of 5502 children aged 6-71 months from rural and urban Bangladesh. Breastfeeding was found to be associated with reduced prevalence of diarrhoea. This association was most pronounced at the age of six months and declined linearly to zero at approximately 30 months of age; thereafter, breastfeeding was increasingly associated with diarrhoeal illness. The linear association was found only among those children who have no access to modern health services and information, when controlling for urban and rural differences. The literature provides two opposing explanations for the positive association of prolonged breastfeeding with diarrhoeal illness. The first explanation suggests that breastfeeding can be seen as mothers' response to children's poor health. The second explanation incriminates sub-optimal child feeding practices, characterised by prolonged breastfeeding and inadequate quality and quantity of complementary foods, as the cause of malnutrition and diarrhoea. Further studies are needed to identify which explanation is correct, given the public health implications in terms of children's survival, growth and development.