Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons.

Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.

Metabolic Reprogramming of Host Cells by Virulent Francisella tularensis for Optimal Replication and Modulation of Inflammation.

A shift in macrophage metabolism from oxidative phosphorylation to aerobic glycolysis is a requirement for activation to effectively combat invading pathogens. Francisella tularensis is a facultative intracellular bacterium that causes an acute, fatal disease called tularemia. Its primary mechanism of virulence is its ability to evade and suppress inflammatory responses while replicating in the cytosol of macrophages. The means by which F. tularensis modulates macrophage activation are not fully elucidated. In this study, we demonstrate that virulent F. tularensis impairs production of inflammatory cytokines in primary macrophages by preventing their shift to aerobic glycolysis, as evidenced by the downregulation of hypoxia inducible factor 1α and failure to upregulate pfkfb3 We also show that Francisella capsule is required for this process. In addition to modulating inflammatory responses, inhibition of glycolysis in host cells is also required for early replication of virulent Francisella Taken together, our data demonstrate that metabolic reprogramming of host cells by F. tularensis is a key component of both inhibition of host defense mechanisms and replication of the bacterium.

Evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer.

Circulating intercellular adhesion molecule-1 (ICAM-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been widely proposed as potential diagnostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). We report on serum protein levels prior to clinical presentation of pancreatic cancer. Serum ICAM-1 and TIMP-1 were measured by ELISA in two case­control sets: 1) samples from patients diagnosed with pancreatic cancer (n = 40), chronic pancreatitis (n = 20), benign jaundice due to gall stones (n = 20) and healthy subjects (n = 20); 2) a preclinical set from the UK Collaborative Trial of Ovarian Cancer Screening biobank of samples collected from 27 post-menopausal women 0­12 months prior to diagnosis of pancreatic cancer and controls matched for date of donation and centre. Levels of ICAM-1 and TIMP-1 were significantly elevated in set 1 in PDAC patients with jaundice compared to PDAC patients without jaundice and both proteins were elevated in patients with jaundice due to gall stones. Neither protein was elevated in samples taken 0­12 months prior to PDAC diagnosis compared to non-cancer control samples. In conclusion, evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. Failure to account for obstructive jaundice may have contributed to the previous promise of these candidate biomarkers. BIOLOGICAL SIGNIFICANCE: Pancreatic cancer is usually diagnosed when at an advanced stage which greatly limits therapeutic options. Biomarkers that could facilitate earlier diagnosis are urgently sought.

iTRAQ reveals candidate pancreatic cancer serum biomarkers: influence of obstructive jaundice on their performance.

BACKGROUND: The aims of our study were to identify serum biomarkers that distinguish pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) patients from benign pancreatic disease patients and healthy subjects, and to assess the effects of jaundice on biomarker performance. METHODS: Isobaric tags for relative and absolute quantification were used to compare pooled serum and pancreatic juice samples from a test set of 59 and 25 subjects, respectively. Validation was undertaken in 113 independent subjects. RESULTS: Candidate proteins Complement C5, inter-α-trypsin inhibitor heavy chain H3, α1-ß glycoprotein and polymeric immunoglobulin receptor were elevated in cancer, as were the reference markers CA19-9 and Reg3A. Biliary obstruction had a significant effect on the performance of the markers, in particular within the PDAC group where the presence of jaundice was associated with a significant increase in the levels of all six proteins (P<0.01). Consequently, in the absence of jaundice, proteins showed reduced sensitivity for PDAC patients over benign subjects and healthy controls (HCs). Similarly, in the presence of jaundice, markers showed reduced specificity for PDAC patients over benign subjects with jaundice. Combining markers enabled improved sensitivity for non-jaundiced PDAC patients over HCs and improved specificity for jaundiced PDAC patients over jaundiced benign disease subjects. CONCLUSIONS: The presence-absence of jaundice in the clinical scenario severely impacts the performance of biomarkers for PDAC diagnosis and has implications for their clinical translation.

Disseminated histoplasmosis and AIDS at the University Hospital of the West Indies. A case report.

Disseminated histoplasmosis is rare in Jamaica. However, with the increase in the number of immunocompromised patients in the population, the prevalence of this infection is likely to increase. We present a case of disseminated histoplasmosis in a 16-year-old girl with the acquired immune deficiency syndrome who presented to the Paediatric Infectious Diseases Service of the University Hospital of the West Indies, with cervical lymphadenitis progressing to ulcers and abscesses showing granulomatous inflammation likely to be of fungal aetiology. She later presented to the Emergency Room, with respiratory and gastrointestinal symptoms and was admitted to hospital, disoriented and with a persistent fever. She developed nuchal rigidity while in hospital and was anaemic, leukopaenic and thrombocytopaenic. She died of gastrointestinal bleed ten days post admission. She was the oldest known survivor of mother-to-child-transmission of human immunodeficiency virus in Jamaica. The slow growing fungus, Histoplasma capsulatum, was isolated from the patient's blood three weeks after the specimen was sent to the laboratory.

Disseminated histoplasmosis and AIDS at the University Hospital of the West Indies. A case report

Disseminated histoplasmosis is rare in Jamaica. However, with the increase in the number of immunocompromised patients in the population, the prevalence of this infection is likely to increase. We present a case of disseminated histoplasmosis in a 16-year-old girl with the acquired immune deficiency syndrome who presented to the Paediatric Infectious Diseases Service of the University Hospital of the West Indies, with cervical lymphadenitis progressing to ulcers and abscesses showing granulomatous inflammation likely to be of fungal aetiology. She later presented to the Emergency Room, with respiratory and gastrointestinal symptoms and was admitted to hospital, disoriented and with a persistent fever. She developed nuchal rigidity while in hospital and was anaemic, leukopaenic and thrombocytopaenic. She died of gastrointestinal bleed ten days post admission. She was the oldest known survivor of mother-to-child-transmission of human immunodeficiency virus in Jamaica. The slow growing fungus, Histoplasma capsulatum, was isolated from the patient's blood three weeks after the specimen was sent to the laboratory

Parental health beliefs and compliance with prophylactic penicillin administration in children with sickle cell disease.

PURPOSE: Prophylactic penicillin is effective in preventing severe invasive pneumococcal infection in children with sickle cell disease. In some families, compliance has been problematic. The aims of this study were to monitor compliance and to assess the efficacy of the Health Belief Model (HBM) in predicting compliance. METHODS: Fifty mothers of children with sickle cell disease, ages 6 to 60 months, participated in the study. On enrollment, mothers completed surveys assessing their health beliefs regarding sickle cell disease and infections. Compliance was assessed through self-reporting by the mothers and through review of local pharmacy records of penicillin refills. RESULTS: Sixty percent of the mothers reported that they were highly compliant with obtaining the prescribed 14-day refills. Pharmacy records indicated that only 12% actually adhered to this schedule. The self-reports were significantly related to compliance ratings; mothers who admitted less than optimal compliance averaged 42 days between refills, compared with 19 days for mothers who reported good compliance. Varying perceptions identified through the HBM accounted for approximately 30% of the variance in compliance rates. The perceived burdens of picking up the refills and remembering to administer the medication were the most significant factors. CONCLUSIONS: Educational efforts alone are not sufficient to ensure compliance with penicillin prophylaxis. Routinely monitoring compliance through pharmacy records, reviewing parental beliefs about sickle cell disease and infections, and exploring barriers to treatment will promote dialogue about the importance of strict compliance with this relatively simple yet life-saving prophylaxis.

Chronic dieting and the belief that smoking controls body weight in a biracial, population-based adolescent sample.

OBJECTIVE: To evaluate the prevalence of weight concerns and smoking for body weight reasons as a function of race and gender. DESIGN: A questionnaire measuring a number of factors thought to be predictive of smoking was administered. SETTING: The Memphis (Tennessee) school system. PARTICIPANTS: Participants were 6961 seventh-grade students (mean age 13 years). This population consisted of 80.8% black children, 16.5% white children, and 2.7% of other ethnic origins. MAIN OUTCOME MEASURES: Weight concerns were assessed using items from a restraint scale. Students were questioned regarding their smoking status, beliefs that smoking controls body weight, and their own weight-control smoking behaviour. RESULTS: Dietary restraint interacted with race in that, whereas white girls scored the highest on dietary restraint, black boys scored higher on dietary restraint than white boys. Almost 40% of subjects at this school level believed that smoking controls their body weight. Of the regular smokers, 12% indicated they have smoked to control their weight, with white girls endorsing this belief significantly more than other respondents. CONCLUSIONS: The propensity to smoke for weight control reasons, previously described by other researchers among white females of college and high-school age, was also found among this sample of students of junior high school age.

Tobacco use among pediatric cancer patients: recommendations for developing clinical smoking interventions.

PURPOSE AND METHODS: The current status of tobacco use among young cancer patients and the acute and chronic complications associated with tobacco use in these patients is reviewed. RESULTS AND CONCLUSION: Studies report that adolescent cancer survivors use tobacco as much as their peers who have never been treated for cancer, despite the adverse consequences of engaging in this unhealthy habit. Health care professionals have the opportunity and responsibility to incorporate tobacco counseling as a routine component of medical care delivery. Nurse/physician-delivered smoking interventions have been found to promote smoking cessation in adults, although little effort has been devoted to the development of similarly effective smoking interventions for pediatric cancer patients who smoke. Components of existing smoking prevention/cessation curricula from successful school-based interventions and physician-delivered smoking interventions can be adapted and tailored to pediatric cancer patients in medical settings. Smoking interventions that educate patients about their increased vulnerability to tobacco-related consequences, relative to their healthy peers, may have an enhanced impact. Guidelines for conducting a comprehensive assessment of tobacco use and implementing smoking interventions with pediatric cancer patients is provided. Strategies for modifying the cancer patient's perceived vulnerability to tobacco-related consequences is also discussed.

Estrategias de ensenanza-aprendizaje en la atención primaria de salud

Esta publicación presenta esquemas prácticos de capacitacion de grupos interdisciplinarios de salud para el trabajo directo en y con la comunidad, asi como en la formacion y supervision del forma esquematica, se combina la teoria y la practica a fin de facilitar la comprension simplicacion y aplicacion de los conocimientos en los varios componentes de la atención primaria. La publicación esta dividida en tres partes: Parte I: La habilidad social y el trabajador de atención primaria. Parte II: Salud de la comunidad. Parte III: Salud del individuo (Madre, Nino, Adulto)