Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a: a Phase II, multicenter, double-blind, randomized, placebo-controlled trial.

Recent studies have demonstrated the immunomodulatory properties of vitamin D, and vitamin D deficiency may be a risk factor for the development of MS. The risk of developing MS has, in fact, been associated with rising latitudes, past exposure to sun and serum vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels have also been associated with relapses and disability progression. The identification of risk factors, such as vitamin D deficiency, in MS may provide an opportunity to improve current treatment strategies, through combination therapy with established MS treatments. Accordingly, vitamin D may play a role in MS therapy. Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions. However, large randomized clinical trials of vitamin D supplementation in patients with MS are lacking. SOLAR (Supplementation of VigantOL(®) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif(®) treatment) is a 96-week, three-arm, multicenter, double-blind, randomized, placebo-controlled, Phase II trial (NCT01285401). SOLAR will evaluate the efficacy of vitamin D(3) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS. Recruitment began in February 2011 and is aimed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels.

Experimental chagas' disease in rhesus monkeys. I. Clinical parasitological, hematological and anatomo-pathological studies in the acute and indeterminate phase of the disease

Rhesus monkeys (macaca mulatta) were infected subcutaneously with 1.0 x 10**4 to 1.5 x 10**4 metacyclic trypomastigotes of Trypanosoma cruzi (Colombian strain). Parasitological and immunological parameters were evaluated in these animals for periods of 1 month to over 3 years. a chagona was observed between the 3 rd and the 13th day after infection (a.i) and patent parasitaemia between the 13th and 59th day a.i.. Thereafter, parasites were demonstrated only by haemoculture and/or xenodiagnosis. Circulating specifc IgM and IgC antibodies were observed as early as in the 2nd week a. i. IgG levels persisted until the end of the expriment, but IgM antibodies were detectable nine months a. i. Haematological alterations comprised leucocytosis and lymphocytosis. Eletrocardiographic alterations were minor and transient, similar to those observe in non-lethal human acute Chagas' myocarditis. Myocarditis and myositis, characterized by multiple foci of lympho-histiocyte inflammatory infiltrate, were present in monkeys sacrificed on the 41 th, 70th and 76 th day but not in the animal sacrificed 3 years and 3 months a. i.. The results suggest that Chagas' disease in rhesus monkeys reproduces the acute and indeterminate phases of human Chagas' disease.

A computational and geometric approach to phase resetting curves and surfaces

"Vegeu el resum a l'inici del document del fitxer adjunt."

Automatic front-crawl temporal phase detection using adaptive filtering of inertial signals

This study introduces a novel approach for automatic temporal phase detection and inter-arm coordination estimation in front-crawl swimming using inertial measurement units (IMUs). We examined the validity of our method by comparison against a video-based system. Three waterproofed IMUs (composed of 3D accelerometer, 3D gyroscope) were placed on both forearms and the sacrum of the swimmer. We used two underwater video cameras in side and frontal views as our reference system. Two independent operators performed the video analysis. To test our methodology, seven well-trained swimmers performed three 300 m trials in a 50 m indoor pool. Each trial was in a different coordination mode quantified by the index of coordination. We detected different phases of the arm stroke by employing orientation estimation techniques and a new adaptive change detection algorithm on inertial signals. The difference of 0.2 +/- 3.9% between our estimation and video-based system in assessment of the index of coordination was comparable to experienced operators' difference (1.1 +/- 3.6%). The 95% limits of agreement of the difference between the two systems in estimation of the temporal phases were always less than 7.9% of the cycle duration. The inertial system offers an automatic easy-to-use system with timely feedback for the study of swimming.

On a size-structured two-phase population model with infinite states-at-birth

In this work we introduce and analyze a linear size-structured population model with infinite states-at-birth. We model the dynamics of a population in which individuals have two distinct life-stages: an “active” phase when individuals grow, reproduce and die and a second “resting” phase when individuals only grow. Transition between these two phases depends on individuals’ size. First we show that the problem is governed by a positive quasicontractive semigroup on the biologically relevant state space. Then we investigate, in the framework of the spectral theory of linear operators, the asymptotic behavior of solutions of the model. We prove that the associated semigroup has, under biologically plausible assumptions, the property of asynchronous exponential growth.

Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation.

Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent.

Mean platelet volume in the early phase of acute ischemic stroke is not associated with severity or functional outcome.

Background: Previous studies reported an increase of mean platelet volume (MPV) in patients with acute ischemic stroke. However, its correlation with stroke severity has not been investigated. Moreover, studies on the association of MPV with functional outcome yielded inconsistent results. Methods: We included all consecutive ischemic stroke patients admitted to CHUV (Centre Hospitalier Universitaire Vaudois) Neurology Service within 24 h after stroke onset who had MPV measured on admission. The association of MPV with stroke severity (NIHSS score at admission and at 24 h) and outcome (Rankin Scale score at 3 and 12 months) was analyzed in univariate analysis. The chi(2) test was performed to compare the frequency of minor strokes (NIHSS score </=4) and good functional outcome (Rankin Scale score </=2) across MPV quartiles. The ANOVA test was used to compare MPV between stroke subtypes according to the TOAST classification. Student's two-tailed unpaired t test was performed to compare MPV between lacunar and nonlacunar strokes. MPV was generated at admission by the Sysmex XE-2100 automated cell counter (Sysmex Corporation, Kobe, Japan) from EDTA blood samples. Results: There was no significant difference in the frequency of minor strokes (p = 0.46) and good functional outcome (p = 0.06) across MPV quartiles. MPV was not associated with stroke severity or outcome in univariate analysis. There was no significant difference in MPV between stroke subtypes according to the TOAST classification (p = 0.173) or between lacunar and nonlacunar strokes (10.50 +/- 0.91 vs. 10.40 +/- 0.81 fl, p = 0.322). Conclusions: MPV, assessed within 24 h after ischemic stroke onset, is not associated with stroke severity or functional outcome.

The p53 gene expression and its developmental regulation in schistosomes

We have studied the gene expression, especially of the oncoproteins, and its regulation in schistosomes. Schistosomes have a complex life cycle with defined dimorphic lifestyle. The parasite are so far unique in biology in expressing oncogene products in their adult stage. In order to characterize the expression and developmental regulation, a lambda gt 11 cDNA library and lambda EMBL4 genomic DNA library of each growth stage of Schistosoma mansoni and S. japonicum was constructed, and was screened with various monoclonal antibodies against ongogene products. One positive plaque reacted to anti-p53 antibody (Ab-2, Oncogene Science, Inc.) was further analyzed. This fusion protein was about 120 KDa in molecular weights, and expressed as 1.4 Kb RNA in the adult stage. P53 gene is well-known as the negative regulator of the cell cicle, and the mutations in the gene are turning out to be the most common genetic alterations in human cancers. The comparison of the gene structure among species and stages were being conducted. Chromosome structures, C-band formation, and the results of in situ hybridization using the phage probe would be discussed.

T cell derived cytokines in lung-phase immunity to Schistosoma mansoni

In C57Bl/6 strain mice vaccinated with radiation-attenuated cercariae of Schistosoma mansoni immune elimination of challenge parasites occurs in the lungs. Leococytes were recovered from the lungs of such mice by bronchoalveolar lavage and cultured in vitro with larval antigen; the profile of cytokines released was then analyzed. From 14 days after vaccination, BAL cultures contained infiltrating lymphocytes wich produced abundant quantitties of IFN-g and IL-3. Challenge of vaccinated mice resulted in a second influx of IFN-g nd IL-3- producing cells, earlier than after vaccination or in the appropriate contropls. Ablation studies revealed that CD4+ T cells were the source of IFN-g. The timing of cytokine production after vaccination, and challenge was coincident with the phases of macrophage activation previously reported. At no time could lymphocytes in BAL cultures to stimulated to proliferate with either larval Ag or mitogen, in contrast to splenocytes from the same mice. Furthermore, T cell growth factor activity was not detected in BAL cultures stimulated with Ag. We suggest that the lymphocytes recruited to the lungs are memory/effector cells, When Ag. released challenge schistosomula is presented to these cells, they respond by secreting cytokines wich mediate the formation of cellular aggregates around the parasites, blocking their onward migration.

Experimental murine schistosomiasis mansoni: estabilishment of the chronic phase of the disease

After the acute hyperergic phase of schistosomal infection, the chronic phase of the disease corresponds to the estabilishment of a relative equilibrium between the host and the parasite. This involves: (1) A shift from the predominance of the TH2 response observed in the acute phase, to the predominance of the TH1 response in the chronic phase of the disease, with modification of lymphokine and immunoglobulin secretions patterns. (2) Redistribution of hosts responses to parasite, with predominance of systemic controls in the acute phase, and a shift towards local tissue responses in the chronic phase. This redistribution relieves the hyperergic responses involving the whole body of the host, and delimits cellular and molecular reactions to parasites to only those tissues that are directly involved by the adult parasites and their eggs. Mobilization of eosinophil granulocytes in schistosomal periovular granulomas is one of examples of this redistribution.

Developmental critical period in gentic redox dysregulation: animal and human studies in schizophrenia

Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the major cellular antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Importantly, abnormal GSH synthesis of genetic origin was observed: Two case-control studies showed an association with a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease associated genotypes (35% of patients) correlated with decreased GCLC protein, GCL activity and GSH content. Similar GSH system anomalies were observed in early psychosis patients. Such redox dysregulation combined with environmental stressors at specific developmental stages could underlie structural and functional connectivity anomalies. In pharmacological and knock-out (KO) models, GSH deficit induces anomalies analogous to those reported in patients. (a) morphology: spine density and GABA-parvalbumine immunoreactivity (PV-I) were decreased in anterior cingulate cortex. KO mice showed delayed cortical PV-I at PD10. This effect is exacerbated in mice with increased DA from PD5-10. KO mice exhibit cortical impairment in myelin and perineuronal net known to modulate PV connectivity. (b) physiology: In cultured neurons, NMDA response are depressed by D2 activation. In hippocampus, NMDA-dependent synaptic plasticity is impaired and kainate induced g-oscillations are reduced in parallel to PV-I. (c) cognition: low GSH models show increased sensitivity to stress, hyperactivity, abnormal object recognition, olfactory integration and social behavior. In a clinical study, GSH precursor N-acetyl cysteine (NAC) as add on therapy, improves the negative symptoms and decreases the side effects of antipsychotics. In an auditory oddball paradigm, NAC improves the mismatched negativity, an evoked potential related to pre-attention and to NMDA receptors function. In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysregulation of GSH synthesis combined with environmental insults in early development represent a major risk factor contributing to the development of schizophrenia Conclusion Based on these data, we proposed a model for PSIP1 promoter activity involving a complex interplay between yet undefined regulatory elements to modulate gene expression.

Development of Eosinophilia in dogs intradermically inoculated with sand fly saliva and Leishmania (Leishmania) chagasi stationary-phase promastigotes

Salivary glad lysates of the sand fly Lutzomia longipalpis have been shown to enhance the infectivity of Leishmania in mice. As shown herein, the simultaneous inoculation of Leishmania chagasi stationary-phase promastigotes and L. longipalpis salivary gland by the intradermal route in a group of mongrel dogs induced a statistically significant eosinophilia, in relation to dogs inoculated with Leishmania or with salivary gland lysate only. These dogs had no evidence of infection, in spite of the infectivity of the promastigotes when inoculated by the intravenous route.

Induction of synthesis of the rat cystatin S protein by the submandibular gland during the acute phase of experimental Chagas disease

Rats experimentally infected with Trypanosoma cruzi Y strain exhibited hypertrophy of the submandibular gland at 18 days after infection.SDS-PAGE of infected rats saliva revealed the presence of an additional band with an apparent molecular weight of about 13KDa. Electrophoresis of protein salivaand immunochemical analysis with antibody against rat cystatin S confirmed that the protein was identical to that induced by beta adrenergic stimulation.

MMP-9 as predictive factor for response and progression free survival in breast cancer patients treated with bevacizumab and pegylated liposomal doxorubicin. A multicenter, single-arm phase II trial (SAKK24/06). On behalf of the Swiss Group for Clinical Cancer Research (SAKK).

The benefit of bevacizumab (Bv) has been shown in different tumors including colorectal cancer, renal cancer, pulmonary non-small cell cancer and also breast cancer. However to date, there is no established test evaluating the angiogenic status of a patient and monitoring the effects of anti-angiogenic treatments. Tumor angiogenesis is the result of a balance between multiple pro- and anti¬angiogenic molecules. There is very little published clinical data exploring the impact of the anti-angiogenic therapy on the different angiogenesis-related molecules and the potential role of these molecules as prognostic or predictive factors.