Interaction of Disabled-1 and the GTPase activating protein Dab2IP in mouse brain

The Reelin signaling pathway controls neuronal positioning during mammalian brain development by binding to the very low density lipoprotein receptor and apolipoprotein E receptor-2, and signaling through the intracellular adapter protein Disabled-1 (Dab1). To identify new components in the Reelin signaling pathway, we used a yeast two-hybrid screen to select Dab1-interacting proteins. Here, we report the characterization of a new mouse Dab1-interacting protein that is orthologous to rat Dab2IP, a Ras-GTPase activating protein previously shown to bind to Dab2/DOC. The interaction of Dab1 and Dab2IP was confirmed in biochemical assays and by co-immunoprecipitation from brain lysates. The site of interaction between Dab1 and Dab2IP was narrowed to the Dab1-PTB domain and the NPxY motif in Dab2IP. The deduced amino acid sequence of mouse Dab2IP encompasses 1,208 residues containing several protein interaction motifs as well as a Ras-like GAP-related domain. Northern blot analysis revealed at least two isoforms of Dab2IP mRNA in the brain, both of which exhibited increased expression during development. In situ hybridization analyses indicated that Dab2IP mRNA is diffusely expressed throughout the developing and the adult brain. Using a polyclonal antiserum specific for Dab2IP, we observed protein expression in the soma and processes of neurons in a variety of brain structures, including the developing cerebral cortex. Our findings suggest that Dab2IP may function as a downstream effector in the Reelin signaling pathway that influences Ras signaling during brain development.     

Atypical antipsychotics in first admission schizophrenia: medication continuation and outcomes

This study compares the effects of atypical and conventional antipsychotic medications on treatment continuation and outcomes in a first admission sample of patients with schizophrenia treated in usual practice settings. In a sample of 189 participants with a research diagnosis of DSM-IV schizophrenia drawn from the Suffolk County Mental Health Project, we compared the effects of atypical and conventional agents on change of medication, medication gaps, and rehospitalization. For these analyses we used the method of survival analysis for recurrent events, in which the episodes of treatment rather than individual subjects are the units of analysis. In addition, we compared improvement in positive and negative symptoms from intake to 24- or 48-month followups for subjects who stayed on one type of medication or changed to atypicals from conventional antipsychotics. Atypical agents were associated with lower risk of medication change, medication gaps, and rehospitalization. Both conventional and atypical agents were associated with improvement of positive symptoms at followup, but only subjects on atypical agents at followup experienced a significant improvement in negative symptoms. We conclude that in usual practice settings, as in randomized clinical trials, atypical agents are associated with improved treatment continuation and outcomes.     

Ventricular fibrillation resulting from acute right ventricular infarction from isolated occlusion of a right ventricular branch artery

Malignant ventricular arrhythmias can result from isolated right ventricular infarction, and reports of this phenomenon in the literature are rare. We present a case of a 46-year-old man with acute onset of chest pain angiographically confirmed to be a result of isolated occlusion of a right ventricular branch artery. He developed ventricular fibrillation within 5 hours of symptom onset. This case highlights the point that despite its benign clinical appearance and preserved left ventricular function, necrosis of right ventricular tissue can have life-threatening consequences.     

Dissociated optic nerve fiber layer appearance of the fundus after idiopathic epiretinal membrane removala

Purpose

To report the appearance of the fundus, that is seen frequently after removal of an idiopathic epiretinal membrane and which we refer to as the dissociated optic nerve fiber layer appearance.

An appraisal of treatment guidelines for antepartum community-acquired pneumonia

OBJECTIVE: The optimal strategy for the initial evaluation and management, including criteria for hospitalization, of pregnant women with pneumonia has not been defined. Our purpose was to evaluate a treatment protocol for antepartum pneumonia and to identify criteria for selection of women for potential outpatient treatment. STUDY DESIGN: A protocol based on British and American Thoracic Society guidelines was introduced and included prompt hospitalization and empiric initiation of erythromycin therapy. Maternal and neonatal outcomes were analyzed to assess the efficacy of the protocol. A second analysis involved the retrospective application of published guidelines to ascertain for which women outpatient management might have been appropriate. RESULTS: There were no maternal deaths among the 133 women studied, and in 14 (10%) women there was a misdiagnosis at admission. Erythromycin monotherapy was judged adequate in all but one of the 99 women so treated. Using a modified version of the American Thoracic Society guidelines, we project that only 25% of the women hospitalized with pneumonia could have been managed safely as outpatients. CONCLUSION: Most pregnant women with pneumonia respond well to monotherapy with erythromycin. Outpatient management may be a reasonable option for selected women.     

Other factors/conditions associated with cerebral palsy

The cause for most cases of cerebral palsy is unknown. There are however, risk factors that have been associated with this chronic neuromuscular disease. The objective of this article is to review the maternal and fetal conditions (other than asphyxia and infection) strongly associated with increased rate of cerebral palsy. What remains to be elucidated is whether or not these associations are causative.     

Metabolic syndrome and leptin concentrations in obese children

Objective Obesity and its complications including metabolic syndrome has been increased in children and adolescents recently. Leptin is known to play an important role in the pathogenesis of obesity. Methods The objective of this study was to evaluate the relationship of leptin and metabolic syndrome in obese Iranian children. A cross sectional study was carried out in 65 primary schools in Tehran. The children with waist circumferences equal or above 90^th percentile for their height and age were chosen for further evaluations. 505 children aged 7–12 years participated in the study. Anthropometric variables measurements, blood pressure, fasting plasma glucose, triglyceride, high-density lipoprotein cholesterol and serum leptin were obtained from the study sample. Results Serum leptin levels were significantly higher in girls in comparison to the boys (with median 11.0 Vs 8.25 ng/dl; P value =0.007). Serum level of leptin were higher in children with metabolic syndrome (median 11.3 Vs 8.9 ng/dl; P value=0.045). However, after adjustment for sex, this association was removed. Conclusion Leptin did not appear to have a major role in metabolic syndrome, even though it was strongly associated with obesity parameters. More studies evaluating the relationship between leptin and metabolic syndrome in various ethnic groups are recommended.     

Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist

Histamine H3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H3 receptor ligand, displaying high affinity for recombinant rat and human H3 receptors, with pKi values of 9.4 and 8.8, respectively, and high selectivity for the H3 receptor versus H1, H2, and H4 histamine receptors. A-349821 is a potent H3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (pKb= 8.2 and pKb= 8.1, respectively), [35S]-GTPgammaS binding (pKb= 9.3 and pKb= 8.6, respectively) and calcium levels (human pKb= 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (pA2= 9.5) and histamine-mediated inhibition of [3H]-histamine release from rat brain cortical synaptosomes (pKb= 9.2). Additionally, A-349821 inhibited constitutive GTPgammaS binding at both rat and human H3 receptors with respective pEC50 values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4 mg/kg-4 mg/kg) potently blocked (R)-alpha-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1-10mg/kg, with the 1mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3mg/kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats.