93 research outputs found
Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial
In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA
High prevalence of the MYD88 L265P mutation in IgM anti-MAG paraprotein-associated peripheral neuropathy
Immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) paraprotein-associated peripheral neuropathy (anti-MAG PN) is the most frequent type of paraprotein-associated neuropathy. It typically presents as a chronic demyelinating disorder with progressive ataxia, tremor and sensory disturbance.1 By definition, IgM paraproteinaemia and high-titre anti-MAG antibodies are present. Up to 50% of patients develop significant disability. Progressive disease-related disability is considered an indication to start treatment. However, there is no consensus on the optimal treatment approach and a high clinical need for effective therapies
Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease: a case-control study
<p>Abstract</p> <p>Background</p> <p>Autoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménière's disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC.</p> <p>Methods</p> <p>The functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ<sup>2 </sup>with Fisher's exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC.</p> <p>Results</p> <p>Elevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fisher's test, corrected p = 6.9 × 10<sup>-4 </sup>for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fisher's test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11).</p> <p>Conclusions</p> <p>Elevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.</p
Is there an association between depressive and urinary symptoms during and after pregnancy?
Depressive symptoms and urinary symptoms are both highly prevalent in pregnancy. In the general population, an association is reported between urinary symptoms and depressive symptoms. The association of depressive and urinary symptoms has not yet been assessed in pregnancy. In this study, we assessed (1) the prevalence of depressive symptoms, over-active bladder (OAB) syndrome, urge urinary incontinence (UUI) and stress urinary incontinence (SUI) during and after pregnancy using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Urogenital Distress Inventory (UDI) and (2) the association of depressive symptoms with urinary incontinence and over-active bladder syndrome during and after pregnancy, controlling for confounding socioeconomic, psychosocial, behavioural and biomedical factors in a cohort of healthy nulliparous women. Our data show a significant increase in prevalence of depressive symptoms, UUI, SUI and OAB during pregnancy and a significant reduction in prevalence of depressive symptoms, SUI and OAB after childbirth. UUI prevalence did not significantly decrease after childbirth. In univariate analysis, urinary incontinence and the OAB syndrome were significantly associated with a CES-D score indicative of a possible clinical depression at 36 weeks gestation. However, after adjusting for possible confounding factors, only the OAB syndrome remained significantly associated (OR 4.4 [1.8–10.5]). No association was found between depressive and urinary symptoms at 1 year post-partum. Only OAB was independently associated with depressive symptoms during pregnancy. Possible explanations for this association are discussed
Galectin-9 and CXCL10 as biomarkers for disease activity in juvenile dermatomyositis: a longitudinal cohort study and multi-cohort validation
OBJECTIVE: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (JDM) due to lack of biomarkers, but crucial to avoid both under- and overtreatment. Recently, we identified two proteins that highly correlate with JDM disease activity: galectin-9 and CXCL10. Here, we validate galectin-9 and CXCL10 as biomarkers for disease activity, assess disease-specificity and investigate their potency to predict flares. METHODS: Galectin-9 and CXCL10 were measured in serum samples of 125 unique JDM patients in three international cross-sectional cohorts and a local longitudinal cohort, by multiplex immunoassay. Disease-specificity was examined in 50 adults with (dermato)myositis and 61 patients with other systemic autoimmune diseases. RESULTS: Galectin-9 and CXCL10 outperformed the currently used marker creatine kinase (CK) to distinguish between JDM patients with active disease and remission, both cross-sectionally and longitudinally (area ROC curve: 0.86-0.90 for galectin-9 and CXCL10, 0.66-0.68 for CK). The sensitivity and specificity were 0.84 and 0.92 for galectin-9, and 0.87 and 1.00 for CXCL10. In 10 prospectively followed patients with a flare, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before symptoms, even in absence of elevated CK. Galectin-9 and CXCL10 distinguished between active disease and remission in adults with (dermato)myositis and were suited for measurement in minimally-invasive dried blood spots. CONCLUSIONS: Galectin-9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in (J)DM. Implementation of these biomarkers into clinical practice, as tools to monitor disease activity and guide treatment, might facilitate personalized treatment strategies
Selection for Genetic Variation Inducing Pro-Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population
BACKGROUND:Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions. METHODOLOGY/PRINCIPAL FINDINGS:In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-alpha levels (p = 1.39 x 10(-3)), was enriched among Ghanaian elders (p = 2.46 x 10(-6)). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09-1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (p(interaction) = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped. CONCLUSIONS/SIGNIFICANCE:Altogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments
Improved Characterization of EV Preparations Based on Protein to Lipid Ratio and Lipid Properties.
In recent years the study of extracellular vesicles has gathered much scientific and clinical interest. As the field is expanding, it is becoming clear that better methods for characterization and quantification of extracellular vesicles as well as better standards to compare studies are warranted. The goal of the present work was to find improved parameters to characterize extracellular vesicle preparations. Here we introduce a simple 96 well plate-based total lipid assay for determination of lipid content and protein to lipid ratios of extracellular vesicle preparations from various myeloid and lymphoid cell lines as well as blood plasma. These preparations included apoptotic bodies, microvesicles/microparticles, and exosomes isolated by size-based fractionation. We also investigated lipid bilayer order of extracellular vesicle subpopulations using Di-4-ANEPPDHQ lipid probe, and lipid composition using affinity reagents to clustered cholesterol (monoclonal anti-cholesterol antibody) and ganglioside GM1 (cholera toxin subunit B). We have consistently found different protein to lipid ratios characteristic for the investigated extracellular vesicle subpopulations which were substantially altered in the case of vesicular damage or protein contamination. Spectral ratiometric imaging and flow cytometric analysis also revealed marked differences between the various vesicle populations in their lipid order and their clustered membrane cholesterol and GM1 content. Our study introduces for the first time a simple and readily available lipid assay to complement the widely used protein assays in order to better characterize extracellular vesicle preparations. Besides differentiating extracellular vesicle subpopulations, the novel parameters introduced in this work (protein to lipid ratio, lipid bilayer order, and lipid composition), may prove useful for quality control of extracellular vesicle related basic and clinical studies
Control of sulphide during anaerobic treatment of S-containing wastewaters by adding limited amounts of oxygen or nitrate
Sulphide generated during anaerobic treatment of S-containing wastewaters represents an environmental problem. Adding limited amounts of oxygen or nitrate (or nitrite) to biologically (or chemically) oxidise sulphide forms a simple process level strategy to control this problem. This short review evaluates the feasibility and limitations of this strategy on the basis of the results of bioreactor studies.Sulphide generated during anaerobic treatment of S-containing wastewaters represents an environmental problem. Adding limited amounts of oxygen or nitrate (or nitrite) to biologically (or chemically) oxidise sulphide forms a simple process level strategy to control this problem. This short review evaluates the feasibility and limitations of this strategy on the basis of the results of bioreactor studies.Spanish Ministry
of Education and Science; AEA Technology
Environment; Nova Energie; The
Swedish Gas Centre; University of Southern
Denmark
Association of FcγRIIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression
<p>Abstract</p> <p>Background</p> <p>A significant genetic component has been described for idiopathic pulmonary fibrosis (IPF). The R131H (rs1801274) polymorphism of the IgG receptor FcγRIIa determines receptor affinity for IgG subclasses and is associated with several chronic inflammatory diseases. We investigated whether this polymorphism is associated with IPF susceptibility or progression.</p> <p>Methods</p> <p>In a case-control study, we compared the distribution of FcγRIIa R131H genotypes in 142 patients with IPF and in 218 controls using allele-specific PCR amplification.</p> <p>Results</p> <p>No differences in the frequency of FcγRIIa genotypes were evident between IPF patients and control subjects. However, significantly impaired pulmonary function at diagnosis was observed in HH compared to RR homozygotes, with evidence of more severe restriction (reduced forced vital capacity (FVC)) and lower diffusing capacity for carbon monoxide (D<smcaps>L</smcaps><sub>CO</sub>). Similarly, increased frequency of the H131 allele was observed in patients with severe disease (D<smcaps>L</smcaps><sub>CO </sub>< 40% predicted) (0.53 vs. 0.38; p = 0.03). Furthermore, the H131 allele was associated with progressive pulmonary fibrosis as determined by > 10% drop in FVC and/or > 15% fall in D<smcaps>L</smcaps><sub>CO </sub>at 12 months after baseline (0.48 vs. 0.33; p = 0.023).</p> <p>Conclusions</p> <p>These findings support an association between the FcγRIIa R131H polymorphism and IPF severity and progression, supporting the involvement of immunological mechanisms in IPF pathogenesis.</p
Time to clearance of Chlamydia trachomatis RNA and DNA after treatment in patients coinfected with Neisseria gonorrhoeae – a prospective cohort study
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