Identification of a genetic marker associated with the resistance to Schistosoma mansoni infection using random amplified polymorphic DNA analysis

In schistosomiasis, the host/parasite interaction remains not completely understood. Many questions related to the susceptibility of snails to infection by respective trematode still remain unanswered. The control of schistosomiasis requires a good understanding of the host/parasite association. In this work, the susceptibility/resistance to Schistosoma mansoni infection within Biomphalaria alexandrina snails were studied starting one month post infection and continuing thereafter weekly up to 10 weeks after miracidia exposure. Genetic variations between susceptible and resistant strains to Schistosoma infection within B. alexandrina snails using random amplified polymorphic DNA analysis technique were also carried out. The results showed that 39.8% of the examined field snails were resistant, while 60.2% of these snails showed high infection rates.In the resistant genotype snails, OPA-02 primer produced a major low molecular weight marker 430 bp. Among the two snail strains there were interpopulational variations, while the individual specimens from the same snail strain, either susceptible or resistant, record semi-identical genetic bands. Also, the resistant character was ascendant in contrast to a decline in the susceptibility of snails from one generation to the next.

Gestió d'incidències post venda de productes electrodomèstics

Base de dades per gestionar incidències post venda de productes electrodomèstics. Inclou anàlisi, disseny i creació de la base de dades i del magatzem de Dades.

In Vivo Modulation of Mitochondrial Activity Determines HSC Engraftment and Post-Transplant Survival in Mice

Cellular metabolism is emerging as a potential fate determinant in cancer and stem cell biology, constituting a crucial regulator of the hematopoietic stem cell (HSC) pool [1-4]. The extremely low oxygen tension in the HSC microenvironment of the adult bone marrow forces HSCs into a low metabolic profile that is thought to enable their maintenance by protecting them from reactive oxygen species (ROS). Although HSC quiescence has for long been associated with low mitochondrial activity, as testified by the low rhodamine stain that marks primitive HSCs, we hypothesized that mitochondrial activation could be an HSC fate determinant in its own right. We thus set to investigate the implications of pharmacologically modulating mitochondrial activity during bone marrow transplantation, and have found that forcing mitochondrial activation in the post-transplant period dramatically increases survival. Specifically, we examined the mitochondrial content and activation profile of each murine hematopoietic stem and progenitor compartment. Long-term-HSCs (LT-HSC, Lin-cKit+Sca1+ (LKS) CD150+CD34-), short-term-HSCs (ST-HSC, LKS+150+34+), multipotent progenitors (MPPs, LKS+150-) and committed progenitors (PROG, Lin-cKit+Sca1-) display distinct mitochondrial profiles, with both mitochondrial content and activity increasing with differentiation. Indeed, we found that overall function of the hematopoietic progenitor and stem cell compartment can be resolved by mitochondrial activity alone, as illustrated by the fact that low mitochondrial activity LKS cells (TMRM low) can provide efficient long-term engraftment, while high mitochondrial activity LKS cells (TMRM high) cannot engraft in lethally irradiated mice. Moreover, low mitochondrial activity can equally predict efficiency of engraftment within the LT-HSC and ST-HSC compartments, opening the field to a novel method of discriminating a population of transitioning ST-HSCs that retain long-term engraftment capacity. Based on previous experience that a high-fat bone marrow microenvironment depletes short-term hematopoietic progenitors while conserving their long-term counterparts [5], we set to measure HSC mitochondrial activation in high-fat diet fed mice, known to decrease metabolic rate on a per cell basis through excess insulin/IGF-1 production. Congruently, we found lower mitochondrial activation as assessed by flow cytometry and RT-PCR analysis as well as a depletion of the short-term progenitor compartment in high fat versus control chow diet fed mice. We then tested the effects of a mitochondrial activator known to counteract the negative effects of high fat diet. We first analyzed the in vitro effect on HSC cell cycle kinetics, where no significant change in proliferation or division time was found. However, HSCs responded to the mitochondrial activator by increasing asynchrony, a behavior that is thought to directly correlate with asymmetric division [6]. As opposed to high-fat diet fed mice, mice fed with the mitochondrial activator showed an increase in ST-HSCs, while all the other hematopoietic compartments were comparable to mice fed on control diet. Given the dependency on short-term progenitors to rapidly reconstitute hematopoiesis following bone marrow transplantation, we tested the effect of pharmacological mitochondrial activation on the recovery of mice transplanted with a limiting HSC dose. Survival 3 weeks post-transplant was 80% in the treated group compared to 0% in the control group, as predicted by faster recovery of platelet and neutrophil counts. In conclusion, we have found that mitochondrial activation regulates the long-term to short-term HSC transition, unraveling mitochondrial modulation as a valuable drug target for post-transplant therapy. Identification of molecular pathways accountable for the metabolically mediated fate switch is currently ongoing.

A preliminary analysis of the population genetics and molecular phylogenetics of Onchocerca volvulus (Nematoda: Filarioidea) using nuclear ribosomal second internal transcribed spacer sequences

Nuclear internal transcribed spacer 2 (ITS2) rDNA sequences were used for a molecular phylogenetics analysis of five Onchocerca species. The sister species of the human parasite O. volvulus was found to be the cattle parasite O. ochengi and not O. gibsoni, contrary to chromosomal evidence. The genetic differentiation of two African populations (representing the two African strains) and a Brazilian population of O. volvulus was also studied. Phylogenetic and network reconstruction did not show any clustering of ITS2 alleles on geographic or strain grounds. Furthermore, population genetics tests showed no indication of population differentiation but suggested gene flow among the three populations.

Ambulatory gait analysis results after total knee arthroplasty : arguments for mobile or fixed bearing?

Background: Mobile-bearing knee replacements have some theoretical advantages over fixed-bearing devices. However, very few randomized controlled clinical trials have been published to date, and studies showed little clinical and subjective advantages for the mobile-bearing using traditional systems of scoring. The choice of the ideal outcome measure to assess total joint replacement remains a complex issue. However, gait analysis provides objective and quantifying evidences of treatment evaluation. Significant methodological advances are currently made in gait analysis laboratories and ambulatory gait devices are now available. The goal of this study was to provide gait parameters as a new objective method to assess total knee arthroplasty outcome between patients with fixed- and mobile-bearing, using an ambulatory device with minimal sensor configuration. Methods: This randomized controlled double-blind study included to date 31 patients: the gait signatures of 12 patients with mobile-bearing were compared to the gait signatures of 19 patients with fixed-bearing pre-operatively and post-operatively at 6 weeks, 3 months and 6 months. Each participant was asked to perform two walking trials of 30m long at his/her preferred speed and to complete a EQ-5D questionnaire, a WOMAC and Knee Society Score (KSS). Lower limbs rotations were measured by four miniature angular rate sensors mounted respectively, on each shank and thigh. Results: Better relative differences between pre-operative and post-operative 3 months and 6 months KSS (122% vs 34% at 3 months, 138% vs 36% at 6 months) and KSS function (154% vs 8% at 3 months, 183% vs 42% at 6 months) scores were observed for the fixed-bearing compared to the mobile-bearing. The same better improvements for fixed-bearing were also found with the range of knee angles (Affected side: 31% vs -5% at 3 months, 47% vs 5% at 6 months), (Unaffected side: 16% vs 5% at 3 months, 15% vs 6% at 6 months) and peak swing speeds of shank (Affected side: 18% vs -2% at 3 months, 30% vs 4% at 6 months), (Unaffected side: 8% vs -3% at 3 months, 7% vs 4% at 6 months). Conclusions: A new method for a portable system for gait analysis has been developed with very encouraging results regarding the objective outcome of total knee arthroplasty using mobile- and fixed-bearings.

Cluster analysis of behavioural and event-related potentials during a contingent negative variation paradigm in remitting-relapsing and benign forms of multiple sclerosis

Background: Event-related potentials (ERPs) may be used as a highly sensitive way of detecting subtle degrees of cognitive dysfunction. On the other hand, impairment of cognitive skills is increasingly recognised as a hallmark of patients suffering from multiple sclerosis (MS). We sought to determine the psychophysiological pattern of information processing among MS patients with the relapsing-remitting form of the disease and low physical disability considered as two subtypes: 'typical relapsing-remitting' (RRMS) and 'benign MS' (BMS). Furthermore, we subjected our data to a cluster analysis to determine whether MS patients and healthy controls could be differentiated in terms of their psychophysiological profile.Methods: We investigated MS patients with RRMS and BMS subtypes using event-related potentials (ERPs) acquired in the context of a Posner visual-spatial cueing paradigm. Specifically, our study aimed to assess ERP brain activity in response preparation (contingent negative variation -CNV) and stimuli processing in MS patients. Latency and amplitude of different ERP components (P1, eN1, N1, P2, N2, P3 and late negativity -LN) as well as behavioural responses (reaction time -RT; correct responses -CRs; and number of errors) were analyzed and then subjected to cluster analysis. Results: Both MS groups showed delayed behavioural responses and enhanced latency for long-latency ERP components (P2, N2, P3) as well as relatively preserved ERP amplitude, but BMS patients obtained more important performance deficits (lower CRs and higher RTs) and abnormalities related to the latency (N1, P3) and amplitude of ERPs (eCNV, eN1, LN). However, RRMS patients also demonstrated abnormally high amplitudes related to the preparation performance period of CNV (cCNV) and post-processing phase (LN). Cluster analyses revealed that RRMS patients appear to make up a relatively homogeneous group with moderate deficits mainly related to ERP latencies, whereas BMS patients appear to make up a rather more heterogeneous group with more severe information processing and attentional deficits. Conclusions: Our findings are suggestive of a slowing of information processing for MS patients that may be a consequence of demyelination and axonal degeneration, which also seems to occur in MS patients that show little or no progression in the physical severity of the disease over time.

Options for clinical trials of pre and post-natal treatments for congenital toxoplasmosis

Clinical trials comparing different drug regimens and strategies for the treatment of congenital toxoplasmosis and its clinical manifestations in the liveborn child in different clinical settings should aim at formally evaluating the net benefit of existing treatments and at developing new therapeutic options. Currently, there is no ideal drug for congenital toxoplasmosis; future research should focus on the screening of new active drugs and on their pre-clinical and early clinical development, with a focus on pharmacokinetic/dynamic studies and teratogenicity. For the prenatal treatment of congenital toxoplasmosis, a trial comparing spiramycine to pyrimethamine-sulphadiazine and placebo would allow a formal estimation of the effect of both drugs in infected pregnant women. In newborn children, the net benefit of pyrimethamine-sulphadiazine should also be formally assessed. These trials will be implemented in settings where prenatal screening for Toxoplasma gondii is currently implemented. Trials should be carefully designed to allow for translation to other settings and modelling tools like cost-effectiveness analysis should be used to provide clinicians and founders with the best available evidence to establish recommendations.

The effect of post-discharge educational intervention on patients in achieving objectives in modifiable risk factors six months after discharge following an episode of acute coronary syndrome, (CAM-2 Project): a randomized controlled trial

We investigated whether an intervention mainly consisting of a signed agreement between patient and physician on the objectives to be reached, improves reaching these secondary prevention objectives in modifiable cardiovascular risk factors six-months after discharge following an acute coronary syndrome. BACKGROUND: There is room to improve mid-term adherence to clinical guidelines' recommendations in coronary heart disease secondary prevention, specially non-pharmacological ones, often neglected. METHODS: In CAM-2, patients discharged after an acute coronary syndrome were randomly assigned to the intervention or the usual care group. The primary outcome was reaching therapeutic objectives in various secondary prevention variables: smoking, obesity, blood lipids, blood pressure control, exercise and taking of medication. RESULTS: 1757 patients were recruited in 64 hospitals and 1510 (762 in the intervention and 748 in the control group) attended the six-months follow-up visit. After adjustment for potentially important variables, there were, between the intervention and control group, differences in the mean reduction of body mass index (0.5 vs. 0.2; p < 0.001) and waist circumference (1.6 cm vs. 0.6 cm; p = 0.05), proportion of patients who exercise regularly and those with total cholesterol below 175 mg/dl (64.7% vs. 56.5%; p = 0.001). The reported intake of medications was high in both groups for all the drugs considered with no differences except for statins (98.1% vs. 95.9%; p = 0.029). CONCLUSIONS: At least in the short term, lifestyle changes among coronary heart disease patients are achievable by intensifying the responsibility of the patient himself by means of a simple and feasible intervention.

Population pharmacokinetic study of gentamicin: A retrospective analysis in a large cohort of neonate patients

Objectives: Gentamicin is one of the most commonly prescribed antibiotics for suspected or proven infection in newborns. Because of age-associated (pre- and post- natal) changes in body composition and organ function, large interindividual variability in gentamicin drug levels exists, thus requiring a close monitoring of this drug due to its narrow therapeutic index. We aimed to investigate clinical and demographic factors influencing gentamicin pharmacokinetics (PK) in a large cohort of unselected newborns and to explore optimal regimen based on simulation. Methods: All gentamicin concentration data from newborns treated at the University Hospital Center of Lausanne between December 2006 and October 2011 were retrieved. Gentamicin concentrations were measured within the frame of a routine therapeutic drug monitoring program, in which 2 concentrations (at 1h and 12h) are systematically collected after the first administered dose, and a few additional concentrations are sampled along the treatment course. A population PK analysis was performed by comparing various structural models, and the effect of clinical and demographic factors on gentamicin disposition was explored using NONMEM®. Results: A total of 3039 concentrations collected in 994 preterm (median gestational age 32.3 weeks, range 24.2-36.5 weeks) and 455 term newborns were used in the analysis. Most of the data (86%) were sampled after the first dose (C1 h and C12 h). A two-compartment model best characterized gentamicin PK. Average clearance (CL) was 0.044 L/h/kg (CV 25%), central volume of distribution (Vc) 0.442 L/kg (CV 18%), intercompartmental clearance (Q) 0.040 L/h/kg and peripheral volume of distribution (Vp) 0.122 L/kg. Body weight, gestational age and postnatal age positively influenced CL. The use of both gestational age and postnatal age better predicted CL than postmenstrual age alone. CL was affected by dopamine and furosemide administration and non-significantly by indometacin. Body weight, gestational age and dopamine coadminstration significantly influenced Vc. Model based simulation confirms that preterm infants need higher dose, superior to 4 mg/kg, and extended interval dosage regimen to achieve adequate concentration. Conclusions: This study, performed on a very large cohort of neonates, identified important factors influencing gentamicin PK. The model will serve to elaborate a Bayesian tool for dosage individualization based on a single measurement.

The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response.

OBJECTIVE: To assess the post-ischemic skin blood flow response after withdrawal of antihypertensive therapy in hypertensive patients with normal blood pressure during treatment. DESIGN AND METHODS: Twenty hypertensive patients (group A) with a normal clinic blood pressure (<140/ 90 mmHg) receiving antihypertensive treatment (any monotherapy; one pill per day for at least 6 months) had their treatment discontinued. Before medication withdrawal and 2, 4, 12 and 24 weeks thereafter, the following measurements were made: clinic blood pressure, home blood pressure (three times per week, morning and evening) and skin blood flow response to a 5 min forearm arterial occlusion (using laser Doppler flowmetry). The patients were asked to perform an ambulatory blood pressure recording at any time if home blood pressure was > or =160/95 mmHg on two consecutive days, and treatment was initiated again, after determination of the skin hyperemic response, if daytime ambulatory blood pressure was > or =140/90 mmHg. The same studies were performed in 20 additional hypertensive individuals in whom antihypertensive treatment was not withdrawn (group B). The allocation of patients to groups A and B was random. RESULTS: The data fom 18 patients in group A who adhered strictly to the procedure were available for analysis. Seven of them had to start treatment again within the first 4 weeks of follow-up; four additional patients started treatment again during the next 8 weeks (group A1). The seven other patients remained untreated (group A2). The skin hyperemic response decreased significantly in patients in group A1 and returned to baseline values at the end of the study, when there were again receiving antihypertensive treatment. In patients in group A2 a significant attenuation of the hyperemic response was also observed. This impaired response was present even at the end of the 6 month follow-up, at which time the patients were still untreated but exhibited a significantly greater blood pressure than before drug discontinuation. The hyperemic response of patients who did not stop treatment (group B) did not change during the course of the study. CONCLUSIONS: Our findings show a decrease in the postischemic skin blood flow response after withdrawal of antihypertensive treatment in hypertensive patients. This impaired response may be due to the development of endothelial dysfunction, vascular remodeling, or both, and might contribute to the return of blood pressure to hypertensive values after withdrawal of antihypertensive therapy.

Effectiveness of holistic neuropsychological rehabilitation for Spanish population with acquired brain injury measured using Rasch analysis.

INTRODUCTION The Rasch model is increasingly used in the field of rehabilitation because it improves the accuracy of measurements of patient status and their changes after therapy. OBJECTIVE To determine the long-term effectiveness of a holistic neuropsychological rehabilitation program for Spanish outpatients with acquired brain injury (ABI) using Rasch analysis. METHODS Eighteen patients (ten with long evolution - patients who started the program > 6 months after ABI- and eight with short evolution) and their relatives attended the program for 6 months. Patients' and relatives' answers to the European Brain Injury Questionnaire and the Frontal Systems Behavior Scale at 3 time points (pre-intervention. post-intervention and 12 month follow-up) were transformed into linear measures called logits. RESULTS The linear measures revealed significant improvements with large effects at the follow-up assessment on cognitive and executive functioning, social and emotional self-regulation, apathy and mood. At follow-up, the short evolution group achieved greater improvements in mood and cognitive functioning than the long evolution patients. CONCLUSIONS The program showed long-term effectiveness for most of the variables, and it was more effective for mood and cognitive functioning when patients were treated early. Relatives played a key role in the effectiveness of the rehabilitation program.

Increased audiovisual integration in cochlear-implanted deaf patients: independent components analysis of longitudinal positron emission tomography data.

It has been demonstrated in earlier studies that patients with a cochlear implant have increased abilities for audio-visual integration because the crude information transmitted by the cochlear implant requires the persistent use of the complementary speech information from the visual channel. The brain network for these abilities needs to be clarified. We used an independent components analysis (ICA) of the activation (H2 (15) O) positron emission tomography data to explore occipito-temporal brain activity in post-lingually deaf patients with unilaterally implanted cochlear implants at several months post-implantation (T1), shortly after implantation (T0) and in normal hearing controls. In between-group analysis, patients at T1 had greater blood flow in the left middle temporal cortex as compared with T0 and normal hearing controls. In within-group analysis, patients at T0 had a task-related ICA component in the visual cortex, and patients at T1 had one task-related ICA component in the left middle temporal cortex and the other in the visual cortex. The time courses of temporal and visual activities during the positron emission tomography examination at T1 were highly correlated, meaning that synchronized integrative activity occurred. The greater involvement of the visual cortex and its close coupling with the temporal cortex at T1 confirm the importance of audio-visual integration in more experienced cochlear implant subjects at the cortical level.

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia.

Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (P<0.01) and less likely to receive aggressive treatment (P=0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P=0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

Globalization and the Symphony of the New (Post-modern) World: From Westphalia to Maastricht…passing by Washington DC

Taking on the challenge of understanding and explaining the Symphony of (today’s) New World in realistic terms (not realist), this essay aims to analyse the Post-Cold war era by devising a multi-conceptual framework that combines different theoretical contributions not yet linked in a fully explanatory way. This paper suggests two inter-related analytical contexts (or background melodies) to understand Dvorak´s "New World”. First, the socio-economic structural context that falls under the controversial category of Globalization and, second, the post-modern political structural context that is built on Robert Cooper’s threefold analysis (Pre-modern, Modern and Post-modern) of today’s world [Cooper, R: 1997, 1999]. Lastly, the closing movement (allegro con fuoco) enters the normative arena to assess American foreign policy options in the light of the theoretical framework devised in the first part of the essay.

Performance in post-compulsory education: evidence from vocational and academic tracks

This paper investigates the factors in_uencing grade performance in two different high school tracks (academic and vocational), including the effect of the amount of work achieved while studying. The empirical strategy analyzes grade progression through the outcomes, passing, repeating and dropping out, conditioning on previous outcomes, and dealing with the endogeneity introduced by the working variable. The analysis is based on a unique Spanish data with information on schooling and labor histories. Findings show that working reduces performance in both tracks, mainly during the first year, although the ffects are less detri- mental in the vocational path. Additionally, good performance in compulsory education, at- tending a private high school, or having high-educated parents improve outcomes, particularly in academic high school.