Glial fibrillary acidic protein (GFAP) immunochemical profile after Junin virus infection of rat cultured astrocytes

After five steps of purification including gel permeation, anti-angiotensin I affinity column chromatography followed by reverse-phase HPLC, a peptide immunoreactive to two different antisera (anti-angiotensin I) was purified to homogeneity from extracts of the leech Theromyzon tessulatum. The first 14 amino acid residues of the purified peptide (DRVYIHPFLLXWG) established by automated Edman degradation, reveal the existence in leeches of an angiotensin I-like molecule close to human angiotensin I. The sequence of the purified peptide presents 78.5% of homology with the N-terminal part of human angiotensin. Moreover, in its sequence, this peptide presents the cleavage sites of vertebrate angiotensin metabolic enzymes, i.e. the renin and the angiotensin-converting enzyme. This finding constitutes the first biochemical characterization of an angiotensin I in Invertebrates. It also reflects the high conservation of angiotensins in the course of evolution, suggesting a fundamental role of this family in fluid homeostasis.     

A Pilot Study Using Nominal Group Technique to Assess Residents’ Perceptions of Successful Attending Rounds

BACKGROUND  Ward attending rounds are fundamental for internal medicine residency training. An improved understanding of interns’ and residents’ perceptions of attending rounds should inform training programs and attending physicians. OBJECTIVES  The aim of this study was to assess residents’ perceptions of successful attending rounds. DESIGN  We convened two groups of interns and two groups of residents, to elicit their perceptions on attending rounds. SUBJECTS  Participants were recruited by e-mail and conference announcements from the 49 interns and 80 residents in the internal medicine and medicine-pediatrics residency programs. MEASUREMENTS  The nominal group technique (NGT) uses a structured group process to elicit and prioritize answers to a carefully articulated question. MAIN RESULTS  Seven interns (14%) identified 27 success factors and ranked attending approachability and enthusiasm and high quality teaching as most important. A second group of six (12%) interns identified 40 detractors and ranked having “mean attendings,” receiving disrespectful comments, and too long or too short rounds as the most significant detractors. Nine (11%) residents identified 32 success factors and ranked attention to length of rounds, house staff autonomy, and establishing goals/expectations as the most important success factors. A second group of six (8%) residents identified 34 detractors and ranked very long rounds, interruptions and time constraints, and poor rapport between team members as the most significant detractors). CONCLUSIONS  Although there was some overlap in interns’ and residents’ perceptions of attending rounds, interns identified interpersonal factors as the most important factors; whereas residents viewed structural factors as most important. These findings should assist attending physicians improve the way they conduct rounds targeting both interns and residents needs. Presented in part at the Southern Regional Meeting of the Society of General Internal Medicine in New Orleans, LA, in February 2005 and the Society of General Internal Medicine Annual Meeting in New Orleans, LA, in May 2005.     

A Phase Ib/II,open-label,multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

Journal of Neuro-Oncology - To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent...     

Early life stress enhances angiotensin II-mediated vasoconstriction by reduced endothelial nitric oxide buffering capacity

We reported previously that maternal separation (MS) sensitizes adult rats to angiotensin II (Ang II)-induced hypertension. The aim of this study was to investigate the vascular reactivity to Ang II and the role of renin-angiotensin system components, reactive oxygen species production, and NO synthase (NOS) buffering capacity mediating the exacerbated Ang II-induced responses. MS rats were separated from their mothers for 3 h/d from days 2 to 14 of life. Controls were nonhandled littermates. At 12 weeks of age, aortic Ang II-induced constriction was greater from MS rats compared with controls (P<0.05); moreover, endothelial denudation abolished this difference. The response to other constrictors was unchanged. Angiotensin type 2 receptor function was reduced in aortic Ang II-induced constriction from MS rats compared with controls. Angiotensin type 1 receptor function was similarly abolished in both groups. However, protein expressions of angiotensin type 1 and angiotensin type 2 receptors were similar in aortic rings from MS and control rats. Preincubation with superoxide inhibitor or scavenger attenuated the Ang II-induced vasoconstriction in control but not in MS rats. However, acute preincubation with an NOS inhibitor enhanced aortic Ang II-induced constriction in aorta from control rats, but this effect was significantly reduced in MS rats compared with control rats. Accordingly, a further increase in Ang II-induced hypertension attributed to chronic NOS inhibition (days 10 to 13) was blunted in MS rats compared with control rats. Similar NOS expression and activity were observed in control and MS rats. In conclusion, MS induces a phenotype with reduced endothelial NOS buffering capacity leading to dysfunctional endothelial Ang II-mediated signaling and sensitization to Ang II-induced vasoconstriction.     

Marked bleeding diathesis in patients with platelet dysfunction due to a novel mutation in RASGRP2, encoding CalDAG-GEFI (p.Gly305Asp)

Congenital platelet function disorders are often the result of defects in critical signal transduction pathways required for platelet adhesion and clot formation. Mutations affecting RASGRP2, the gene encoding the Rap GTPase activator, CalDAG-GEFI, give rise to a novel, and rare, group of platelet signal transduction abnormalities. We here report platelet function studies for two brothers (P1 and P2) expressing a novel variant of RASGRP2, CalDAG-GEFI(p.Gly305Asp). P1 and P2 have a lifelong history of bleeding with severe epistaxis successfully treated with platelet transfusions or rFVIIa. Other bleedings include extended hemorrhage from minor wounds. Platelet counts and plasma coagulation were normal, as was αIIbβ3 and GPIb expression on the platelet surface. Aggregation of patients’ platelets was significantly impaired in response to select agonists including ADP, epinephrine, collagen, and calcium ionophore A23187. Integrin αIIbβ3 activation and granule release were also impaired. CalDAG-GEFI protein expression was markedly reduced but not absent. Homology modeling places the Gly305Asp substitution at the GEF-Rap1 interface, suggesting that the mutant protein has very limited catalytic activity. In summary, we here describe a novel mutation in RASGRP2 that affects both expression and function of CalDAG-GEFI and that causes impaired platelet adhesive function and significant bleeding in humans.     

Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes

The influence of diabetes mellitus on brain pathology is increasingly recognized. Previous contributions of our laboratory demonstrated in models of type 1 diabetes (nonobese diabetic and streptozotocin (STZ)-treated mice), a marked astrogliosis and neurogenesis deficit in hippocampus and increased expression of hypothalamic neuropeptides. In the present investigation, we further analyzed alterations of astroglia and neurons in the hippocampus of mice 1 month after STZ-induced diabetes. Results showed that these STZ-diabetic mice presented: (a) increased number of astrocytes positive for apolipoprotein-E (Apo-E), a marker of ongoing neuronal dysfunction; (b) abnormal expression of early gene products associated with neuronal activation, including a high number of Jun + neurons in CA1 and CA3 layers and dentate gyrus, and of Fos-expressing neurons in CA3 layer; (c) augmented activity of NADPH-diaphorase, linked to oxidative stress, in CA3 region. These data support the concept that uncontrolled diabetes leads to hippocampal pathology, which adjoin to changes in other brain structures such as hypothalamus and cerebral cortex.     

Morbidity of lupus anticoagulants in children: a single institution experience

INTRODUCTION: The lupus anticoagulant (LA) and the anticardiolipin antibodies (ACA) are the antiphospholipid antibodies more relevant clinically. Their clinical manifestations are diverse with most patients being asymptomatic while others present venous or arterial thrombosis, and more rarely, bleeding. Our objectives were to evaluate clinical presentation of LA in children and to correlate it to LA behavior. PATIENTS AND METHODS: A retrospective cohort of patients (under 18 years old) who had a positive determination of LA followed by at least another determination of LA at a variable period was evaluated. Personal and family history, including infectious diseases temporally related to the event, were recorded. The screening of other coagulation disorders was performed according to symptoms, family history or laboratory results. RESULTS: Thirty-six patients were evaluated, median age was 10.8 years old, and 52.8% were female. Asymptomatic patients were 19.4% (7/36) of study population. Bleeding and thrombosis were found in 52.8% and 27.8%, respectively. Median LA determinations per patient were 3. von Willebrand disease was diagnosed in 66.7% of patients consulting for bleeding. A concomitant hemostatic defect was found in 8/10 patients with thrombosis (p = 0.003). LA behavior was not uniform and not correlated to symptoms. CONCLUSIONS: Most LA found in children is incidental and asymptomatic. In children with bleeding, LA might be a fortuitous finding associated with VWD. The persistence of LA does not imply a higher risk of thrombosis.