Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.     

High serum tumor necrosis factor-alpha levels are associated with lack of response to infliximab in fistulizing Crohn's disease

OBJECTIVES: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor-alpha (anti-TNF-alpha), has been effective in the treatment of patients with active Crohn's disease and with fistulas. We investigated the effect of infliximab on circulating cytokines and acute phase proteins in patients with fistulas to determine the clinical response to anti-TNF-alpha. METHODS: A total of 36 patients with fistulizing Crohn's disease were selected for study. Serum from patients was drawn before the infusion on day 0 and at wk 2, 4, 6, 8, and 10 after completion of treatment. Circulating concentrations of TNF-alpha, interleukin-1beta (IL-1beta), and IL-6 were measured by ELISA. The functional activity of circulating TNF-alpha was assessed by the WEHI 164 TNF-alpha bioassay. Acute phase proteins were also determined. RESULTS: Elevated TNF-alpha, IL-1beta, IL-6, and acute phase proteins were observed in patients with Crohn's disease. Of the patients with fistulas, 22 (61.1%) responded to treatment. Before receiving infliximab, higher levels of serum TNF-alpha were found in patients who did not respond to infliximab compared with those who did (median interquartile range 26, 0-245 pg/ml; n = 14 vs 0, 0-22 pg/ml, n = 22). Patients showed no change in circulating levels of TNF-alpha during the course of the study. CONCLUSIONS: This treatment produces a clinical improvement in about two-thirds of CD patients with fistulas. The circulating levels of TNF-alpha are associated with the response to infliximab and could help to identify patients who would benefit from anti-TNF-alpha treatment.     

Anomalies of the urinary tract associated with congenital heart diseases

Due to the frequent association of congenital heart disease and urinary tract malformations we studied 434 patients undergoing angiocardiograms for diagnosis of their congenital heart disease. In every patient a plain abdominal X-ray film was made in order to observe urinary elimination of the contrast material. We found 70 patients with urinary tract malformations, the most frequent of which was pyelo-chaliceal dilatation, accounting for 47.1% of all the malformations found. A double pyelo-chaliceal system was found in 25.7%, kidney hypoplasia in 10% and in lower frequencies double urethers, kidney agenesia, pelvic kidneys, horseshoe-shaped kidney and others. Patients were usually urologically asymptomatic. In view of the frequent association of congenital heart disease and urinary tract malformations a plain abdominal X-ray film should always be performed postangiographically. In some cases a contrast urography is recommended.     

SENSE OF COMMUNITY AND SATISFACTION WITH LIFE AMONG IMMIGRANTS AND THE NATIVE POPULATION

The aim of this study was to analyze the influence of the sense of community (SOC) on satisfaction with life (SWL) in native and immigrant populations in Spain. The main hypothesis was that SOC would moderate the negative effects associated with the immigrant adaptation process. It was further hypothesized that there would be no differences in SWL between immigrants with a high SOC and the native population. The study included 1,646 participants living in Malaga (Spain), comprising 946 natives and 700 immigrants. Data were collected using random route sampling and survey methodology. The results showed that people with higher SOC had significantly greater SWL. It was also found that SWL was greater in natives than in immigrants when the level of SOC was low or medium. However, when SOC was high there were no significant differences between the groups in SWL. The data support the hypothesis that SOC acts as a moderating variable that buffers the effect of the adaptation process experienced by immigrants.     

Correction to: Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials)

Journal of Autism and Developmental Disorders - The author of the article would like to add a video abstract as a supplementary material for a published article. The supplementary file is published...     

Prevención de ictus en pacientes con diabetes mellitus tipo 2 o prediabetes. Recomendaciones del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología

ObjectiveTo update the Spanish Society of Neurology's guidelines for stroke prevention in patients with type 2 diabetes or prediabetes, analysing the available evidence on the effect of metabolic control and the potential benefit of antidiabetic drugs with known vascular benefits in addition to conventional antidiabetic treatments in stroke prevention.DevelopmentPICO-type questions (Patient, Intervention, Comparison, Outcome) were developed to identify practical issues in the management of stroke patients and to establish specific recommendations for each of them. Subsequently, we conducted systematic reviews of the PubMed database and selected those randomised clinical trials evaluating stroke as an independent variable (primary or secondary). Finally, for each of the PICO questions we developed a meta-analysis to support the final recommendations.ConclusionsWhile there is no evidence that metabolic control reduces the risk of stroke, some families of antidiabetic drugs with vascular benefits have been shown to reduce these effects when added to conventional treatments, both in the field of primary prevention in patients presenting type 2 diabetes and high vascular risk or established atherosclerosis (GLP-1 agonists) and in secondary stroke prevention in patients with type 2 diabetes or prediabetes (pioglitazone).