Usefulness of genetic characterization of narcolepsy and hypersomnia on phenotype definition: a study in Portuguese patients

The determination of human leukocyte antigen (HLA) class II genotype is widely used to confirm the diagnosis of narcolepsy with or without cataplexy. The HLA genotyping is reliable, easy to perform and reassures the clinician. It is also less invasive than other methodologies and is in accordance with the autoimmune hypothesis for the origin of narcolepsy. AIM. To assess the usefulness of genetic markers (HLA) in the differential diagnosis between different sleep disorders and their relevance in the context of our population

The Abundance Distribution in the Extrasolar-Planet Host Star HD19994

Abundances of 22 elements have been determined from a high-resolution, high signal-to-noise spectrum of HD19994, a star recently announced as harboring an extrasolar planet. A detailed spectroscopic analysis of this stars finds it to have a mass of 1.2+/-0.1Msun. HD19994 is found to be slightly enriched in "metals" relative to the Sun 9[Fe/H]=+0.09+/-0.05 and an average of all metals of [m/H]=+0.13), as are most stars known with extrasolar planets. In a search for possible signatures of accretion of metal-rich gas onto the parent stars (using HD19994 and published abundances for other stars), it is found that a small subset of stars with planets exhibit a trend of increasing [X/H] with increasing condensation temperature for a given element X. This trend may point to the accretion of chemically fractionated solid material into the outer (thin) convection zones of these solar-type stars. It is also found that this small group of stars exhibiting an accretion signature all have large planets orbiting much closer than is found, in general, for stars with planets not showing this peculiar abundance trend, suggesting a physical link between accretion and orbital separation. In addition, the stars showing evidence of fractionated accretion are, on average, of larger mass (1.2Msun) than stars not showing measurable evidence of accretion (1.0Msun).Comment: 19 pages, 4 tables, 13 figures, Astronomical Journal, in pres

Genetic ablation of inositol 1,4,5-Trisphosphate receptor type 2 (IP3R2) fails to modify disease progression in a mouse model of Spinocerebellar Ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020, PTDC/NEUNMC/3648/2014 and COMPETE-FEDER (POCI-01-0145-FEDER-016818); fellowships to DCG (2021.08121.BD), DMF (SFRH/BD/147947/2019), JSC (SFRH/BD/140624/2018), ANC (SFRH/BPD/118779/2016), AVF (UMINHO/BIL-CNCG/2022/11), SGG (SFRH/BD/101298/2014), and JFV (2020.05109.BD); FCT Scientific Employment Stimulus (CEEC)—Individual Call position to SDS (CEECIND/00685/2020); grants from the Bial Foundation (037/18) and “the la Caixa” Foundation (LCF/PR/HR21/52410024) to JFO; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). It was also supported by grants from the ICVS Scientific Microscopy Platform, a member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122 and national funds through the Foundation for Science and Technology (FCT)

Plasma Cytokine Profile in Tropical Endomyocardial Fibrosis: Predominance of TNF-a, IL-4 and IL-10

Background: the participation of immune/inflammatory mechanisms in the pathogenesis of tropical endomyocardial fibrosis (EMF) has been suggested by the finding of early blood and myocardial eosinophilia. However, the inflammatory activation status of late-stage EMF patients is still unknown.Methodology/Principal findings: We evaluated pro- and anti-inflammatory cytokine levels in plasma samples from late stage EMF patients. Cytokine levels of Tumor Necrosis Factor (TNF)-alpha, Interferon (IFN)-gamma, Interleukin (IL)-2, IL-4, IL-6, and IL-10 were assayed in plasma samples from 27 EMF patients and compared with those of healthy control subjects. All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-alpha, IL-6, IL-4, and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL-10, IL-4, and TNF-alpha were significantly higher than those of controls. Plasma levels of such cytokines positively correlated with each other.Conclusions/Significance: the mixed pro-and anti-inflammatory/Th2circulating cytokine profile in EMF is consistent with the presence of a persistent inflammatory stimulus. On the other hand, the detection of increased levels of TNF-alpha may be secondary to the cardiovascular involvement observed in these patients, whereas IL-4 and IL-10 may have been upregulated as a homeostatic mechanism to buffer both production and deleterious cardiovascular effects of pro-inflammatory cytokines. Further studies might establish whether these findings play a role in disease pathogenesis.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ São Paulo, Sch Med, Inst Heart InCor, Immunol Lab, São Paulo, BrazilUniv São Paulo, Sch Med, Div Clin Immunol & Allergy, São Paulo, BrazilUniv São Paulo, Sch Med, Inst Heart InCor, Cardiomyopathy Unit, São Paulo, BrazilProSangue Fdn, São Paulo, BrazilInst Investigat Immunol, INCT, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, Div Immunol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, Div Immunol, São Paulo, BrazilWeb of Scienc

description of the methodological approach

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Heart and systemic effects of statin pretreatment in a rat model of abdominal sepsis. Assessment by Tc99m-sestamibi biodistribition

PURPOSE: To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis. METHODS: Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis. RESULTS: Myocardial histologic alterations were not detected 24 hours post-sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9$\pm$0.3%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0$\pm$0.2% ID/g), control sham group+ simvastatin (1.2$\pm$0.3% ID/g) and control sham group (1.3$\pm$0.2% ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups. CONCLUSIONS: Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins

A genome survey of Moniliophthora perniciosa gives new insights into Witches' Broom Disease of cacao

<p>Abstract</p> <p>Background</p> <p>The basidiomycete fungus <it>Moniliophthora perniciosa </it>is the causal agent of Witches' Broom Disease (WBD) in cacao (<it>Theobroma cacao</it>). It is a hemibiotrophic pathogen that colonizes the apoplast of cacao's meristematic tissues as a biotrophic pathogen, switching to a saprotrophic lifestyle during later stages of infection. <it>M. perniciosa</it>, together with the related species <it>M. roreri</it>, are pathogens of aerial parts of the plant, an uncommon characteristic in the order Agaricales. A genome survey (1.9× coverage) of <it>M. perniciosa </it>was analyzed to evaluate the overall gene content of this phytopathogen.</p> <p>Results</p> <p>Genes encoding proteins involved in retrotransposition, reactive oxygen species (ROS) resistance, drug efflux transport and cell wall degradation were identified. The great number of genes encoding cytochrome P450 monooxygenases (1.15% of gene models) indicates that <it>M. perniciosa </it>has a great potential for detoxification, production of toxins and hormones; which may confer a high adaptive ability to the fungus. We have also discovered new genes encoding putative secreted polypeptides rich in cysteine, as well as genes related to methylotrophy and plant hormone biosynthesis (gibberellin and auxin). Analysis of gene families indicated that <it>M. perniciosa </it>have similar amounts of carboxylesterases and repertoires of plant cell wall degrading enzymes as other hemibiotrophic fungi. In addition, an approach for normalization of gene family data using incomplete genome data was developed and applied in <it>M. perniciosa </it>genome survey.</p> <p>Conclusion</p> <p>This genome survey gives an overview of the <it>M. perniciosa </it>genome, and reveals that a significant portion is involved in stress adaptation and plant necrosis, two necessary characteristics for a hemibiotrophic fungus to fulfill its infection cycle. Our analysis provides new evidence revealing potential adaptive traits that may play major roles in the mechanisms of pathogenicity in the <it>M. perniciosa</it>/cacao pathosystem.</p

Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease

Spinocerebellar ataxias are dominantly inherited neurodegenerative disorders with no disease-modifying treatment. We previously identified the selective serotonin reuptake inhibitor citalopram as a safe and effective drug to be repurposed for Machado-Joseph disease. Pre-symptomatic treatment of transgenic (CMVMJD135) mice strikingly ameliorated mutant ataxin-3 (ATXN3) pathogenesis. Here, we asked whether citalopram treatment initiated at a post-symptomatic age would still show efficacy. We used a cohort of CMVMJD135 mice that shows increased phenotypic severity and faster disease progression (CMVMJD135hi) compared to the mice used in the first trial. Groups of hemizygous CMVMJD135hi mice were orally treated with citalopram. Behavior, protein analysis, and pathology assessment were performed blindly to treatment. Our results show that even when initiated after symptom onset, treatment of CMVMJD135hi mice with citalopram ameliorated motor coordination and balance, attenuating disease progression, albeit to a lesser extent than that seen with pre-symptomatic treatment initiation. There was no impact on ATXN3 aggregation, which contrasts with the robust reduction in ATXN3-positive inclusions observed in CMVMJD135 mice, when treated pre-symptomatically. Post-symptomatic treatment of CMVMJD135hi mice revealed, however, a limited neuroprotective effect by showing a tendency to repair cerebellar calbindin staining, and to increase the number of motor neurons and of NeuN-positive cells in certain brain regions. While supporting that early initiation of treatment with citalopram leads to a marked increase in efficacy, these results strengthen our previous observation that modulation of serotonergic signaling by citalopram is a promising therapeutic approach for Machado-Joseph disease even after symptom onset.European Regional Development Funds (FEDER), through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER. This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to PM) and [EXPL/BIM-MEC/0239/2012] (to AT-C), by FCT through the project [POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to PM), by National Ataxia foundation (to PM and to AT-C), and by Ataxia UK (to PM). SE, SD-S, SO, and AT-C were supported by the FCT individual fellowships, SFRH/BD/78554/2011, SFRH/BD/78388/2011, PD/BD/127818/2016, and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa, and EU/FSEinfo:eu-repo/semantics/publishedVersio