WWP-1 Is a Novel Modulator of the DAF-2 Insulin-Like Signaling Network Involved in Pore-Forming Toxin Cellular Defenses in Caenorhabditis elegans

Pore-forming toxins (PFTs) are the single largest class of bacterial virulence factors. The DAF-2 insulin/insulin-like growth factor-1 signaling pathway, which regulates lifespan and stress resistance in Caenorhabditis elegans, is known to mutate to resistance to pathogenic bacteria. However, its role in responses against bacterial toxins and PFTs is as yet unexplored. Here we reveal that reduction of the DAF-2 insulin-like pathway confers the resistance of Caenorhabditis elegans to cytolitic crystal (Cry) PFTs produced by Bacillus thuringiensis. In contrast to the canonical DAF-2 insulin-like signaling pathway previously defined for aging and pathogenesis, the PFT response pathway diverges at 3-phosphoinositide-dependent kinase 1 (PDK-1) and appears to feed into a novel insulin-like pathway signal arm defined by the WW domain Protein 1 (WWP-1). In addition, we also find that WWP-1 not only plays an important role in the intrinsic cellular defense (INCED) against PFTs but also is involved in innate immunity against pathogenic bacteria Pseudomonas aeruginosa and in lifespan regulation. Taken together, our data suggest that WWP-1 and DAF-16 function in parallel within the fundamental DAF-2 insulin/IGF-1 signaling network to regulate fundamental cellular responses in C. elegans

Maternal depressive symptoms, and not anxiety symptoms, are associated with positive mother–child reporting discrepancies of internalizing problems in children: a report on the TRAILS Study

Maternal internalizing problems affect reporting of child’s problem behavior. This study addresses the relative effects of maternal depressive symptoms versus anxiety symptoms and the association with differential reporting of mother and child on child’s internalizing problems. The study sample comprised a cohort of 1,986 10- to 12-year-old children and their mothers from the Dutch general population in a cross sectional setup. Children’s internalizing problems were assessed with the DSM-IV anxiety and affective problem scales of the Child Behavior Checklist (CBCL) and the Youth Self-Report (YSR). Current maternal internalizing problems were assessed with the depressive and anxiety symptom scales of the Depression Anxiety Stress Scale (DASS), while the TRAILS Family History Interview (FHI) measured lifetime maternal depression and anxiety. Results show that current and lifetime maternal depressive symptoms were associated with positive mother–child reporting discrepancies (i.e. mothers reporting more problems than their child). Considering the small amount of variance explained, we conclude that maternal depressive symptoms do not bias maternal reporting on child’s internalizing problems to a serious degree. Studies concerning long term consequences of mother–child reporting discrepancies on child’s internalizing problems are few, but show a risk for adverse outcome. More prognostic research is needed

Informant discrepancies in assessing child dysfunction relate to dysfunction within mother-child interactions.

We examined whether mother-child discrepancies in perceived child behavior problems relate to dysfunctional interactions between mother and child and stress in the mother. Participants included 239 children (6–16 years old; 58 girls, 181 boys) referred for oppositional, aggressive, and antisocial behavior, and their mothers. Mother-child discrepancies in perceived child behavior problems were related to mother-child conflict. Moreover, maternal stress mediated this relationship. The findings suggest that discrepancies among mother and child evaluations of child functioning are not merely reflections of different perspectives or artifacts of the assessment process, but can form components of conceptual models that can be developed and tested to examine the interrelations among critical domains of child, parent, and family functioning.This work was supported, in part, by a grant from the National Institute of Mental Health (MH67540) awarded to the first author and by grants from the Leon Lowenstein Foundation, the William T. Grant Foundation (98-1872-98), and the National Institute of Mental Health (MH59029) awarded to the second author

Global Functional Analyses of Cellular Responses to Pore-Forming Toxins

Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we performed the first genome-wide RNA interference (RNAi) screen for genes that, when knocked down, result in hypersensitivity to a PFT. This screen identifies 106 genes (∼0.5% of genome) in seven functional groups that protect Caenorhabditis elegans from PFT attack. Interactome analyses of these 106 genes suggest that two previously identified mitogen-activated protein kinase (MAPK) pathways, one (p38) studied in detail and the other (JNK) not, form a core PFT defense network. Additional microarray, real-time PCR, and functional studies reveal that the JNK MAPK pathway, but not the p38 MAPK pathway, is a key central regulator of PFT-induced transcriptional and functional responses. We find C. elegans activator protein 1 (AP-1; c-jun, c-fos) is a downstream target of the JNK-mediated PFT protection pathway, protects C. elegans against both small-pore and large-pore PFTs and protects human cells against a large-pore PFT. This in vivo RNAi genomic study of PFT responses proves that cellular commitment to PFT defenses is enormous, demonstrates the JNK MAPK pathway as a key regulator of transcriptionally-induced PFT defenses, and identifies AP-1 as the first cellular component broadly important for defense against large- and small-pore PFTs

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

LA U INVESTIGA: Revista Científica. Facultad Ciencias de la Salud. Volumen 3. Número 2

En el presente volumen se distinguen varios ámbitos de la investigación en salud desde artículos asociados a la promoción de salud, prevención de enfermedades, así como investigaciones de casos clínicos que evidencia la experiencia del equipo de salud en patologías específicas. Hay que resaltar que muchos de los artículos presentados en el volumen actual corresponden a los resultados de investigaciones ejecutadas en la academia, propias de la Universidad Técnica del Norte y de otras.1._ Melanoma antebraquial derecho metastásico a pa¬red abdominal y pelvis presentación de un caso clínico. 2._ Carcinoma papilar de localizacion extratiroidea. 3._ Tumores del golfo de la yugular 4._ Estudio comparativo del desarrollo psicomotor en niños/as de 1 a 3 años del Centro Infantil del Buen Vivir “CENTRO PUCARA” y “GOTITAS DE AMOR” del cantón Antonio Ante de la provincia de Imbabura. 5._ Adaptaciones de las técnicas comunicacionales al proceso terapéutico de salud mental infantil. 6._ La dinámica de la investigación científica en la formación de los profesionales de enfermería: una aproximación al problema de investigación. 7._ Las agresiones en las parejas de enamorados en la adolescencia y el equilibrio emocional. 8._ Rasgos de personalidad y su influencia en la calidad de vida en los estudiantes de la Unidad Educativa” Las Américas” 9._ Estudio de la postura corporal y su relación con la obesidad y sobrepeso en niños de 6 a 12 años del cantón Antonio Ante de la provincia de Imbabura. 10._ Caracterización de cuidadores informales de personas con discapacidad de la provincia de Im¬babura. 11._ Intervención educativa sobre embarazo en la adolescencia en estudiantes del tercer año de bachillerato de la unidad educativa “Madre Tere¬sa Bacq” Imbabura-Ecuador. 12._ Acceso a la atención de consulta externa de los usuarios del centro de llamadas, que asisten al subcentro de salud San Antonio, Tanguarin Iba¬rra, ecuador 2016. 13._ Prevalencia de disfunción familiar en la parro¬quia urbana de Urcuquí

Isolation and biochemical characterization of the LH1-RC pigment-protein complex from the aerobic photosynthetic bacteria

Department of BiochemistryKatedra biochemieFaculty of SciencePřírodovědecká fakult