Система дистанційної освіти та її захист

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given

Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis

BACKGROUND: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. METHODS: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. “No evidence of disease activity-3” (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI®) were recorded during 4 years of follow-up. RESULTS: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p < 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. CONCLUSIONS: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively

Ispitivanje antidepresivnog, sedativnog i analgetskog djelovanja novih fuzioniranih derivata tiofena

This study was aimed at the synthesis of fused benzothiophene derivatives containing heterocyclic moiety. The reaction of the tetrahydrobenzo[b]thiophene derivatives 1a,b with ethoxycarbonylisothiocyanate afforded the thiourea derivatives 2a,b. Cyclization of the latter products gave the annulated benzo[b]thienopyrimidine derivatives 3a,b. Compounds 2a,b and 3a underwent a series of heterocyclization reactions through the reaction with some chemical reagents to give the new benzo[b]thienopyrimidine derivatives 5a,b to 8a-c. Also, this work was extended to study the potential role of the novel synthesized thiourea derivative 2a and benzo[b]thienopyrimidine derivatives 3a, 5b, 6a and 8b as antidepressant, sedative or analgesic agents at two doses (15 or 30 mg kg1 body mass). Some compounds (2a, 3a and 5b) showed mild antidepressant activity in the forced-swimming test. No compound showed sedative effect. Visceral pain evoked by i.p. injection of acetic acid in mice was significantly inhibited by all compounds at a high doses.U radu je opisana sinteza fuzioniranih derivata benzotiofena koji sadrže heterociklički ostatak bitan za farmakološko djelovanje. Tiourea derivati 2a,b dobiveni su reakcijom derivata tetrahidrobenzo[b]tiofena 1a,b s etoksikarbonilizotiocijanatom. Iz njih su dalje priređeni anulirani derivati benzo[b]tienopirimidina 3a,b. Spojevi 2a,b i 3a prevedeni su reakcijama heterociklizacije u benzo[b]tienopirimidine 5a,b-8a-c. Ispitivano je antidepresivno, sedativno i analgetsko djelovanje novosintetiziranih derivata tiouree 2a i benzo[b]tienopirimidina 3a, 5b, 6a i 8b u dvije doze (15 ili 30 mg kg1 tjelesne mase). Spojevi 2a, 3a i 5b pokazali su blago antidepresivno djelovanje u testu forsiranog plivanja, dok sedativni učinak nije pokazao niti jedan ispitivani spoj. Visceralna bol inducirana i.p. injekcijom octene kiseline u miševa značajno je inhibirana sa svim spojevima, ali u visokim dozama

Mapping of hormones and cortisol responses in patients after Lyme neuroborreliosis

<p>Abstract</p> <p>Background</p> <p>Persistent symptoms after treatment for neuroborreliosis are common for reasons mainly unknown. These symptoms are often unspecific and could be caused by dysfunctions in endocrine systems, an issue that has not been previously addressed systematically. We therefore mapped hormone levels in patients with previous confirmed Lyme neuroborreliosis of different outcomes and compared them with a healthy control group.</p> <p>Methods</p> <p>Twenty patients of a retrospective cohort of patients treated for definite Lyme neuroborreliosis were recruited 2.3 to 3.7 years (median 2.7) after diagnosis, together with 23 healthy controls. Lyme neuroborreliosis patients were stratified into two groups according to a symptom/sign score. All participants underwent anthropometric and physiological investigation as well as an extensive biochemical endocrine investigation including a short high-dose adrenocorticotropic hormone stimulation (Synacthen^®) test. In addition to hormonal status, we also examined electrolytes, 25-hydroxy-vitamin D and interleukin-6.</p> <p>Results</p> <p>Eight patients (40%) had pronounced symptoms 2-3 years after treatment. This group had a higher cortisol response to synacthen as compared with both controls and the Lyme neuroborreliosis patients without remaining symptoms (p < 0.001 for both comparisons). No other significant differences in the various baseline biochemical parameters, anthropometric or physiological data could be detected across groups.</p> <p>Conclusions</p> <p>Apart from a positive association between the occurrence of long-lasting complaints after Lyme neuroborreliosis and cortisol response to synacthen, no corticotropic insufficiency or other serious hormonal dysfunction was found to be associated with remaining symptoms after treatment for Lyme neuroborreliosis.</p

Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans

Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.Original Publication: Johanna Sjöwall, Linda Fryland, Marika Nordberg, Florence Sjögren, Ulf Garpmo, Christian Jansson, Sten-Anders Carlsson, Sven Bergstrom, Jan Ernerudh, Dag Nyman, Pia Forsberg and Christina Ekerfelt, Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans, 2011, PLOS ONE, (6), 3, 0018220. http://dx.doi.org/10.1371/journal.pone.0018220 Copyright: Public Library of Science (PLoS) http://www.plos.org

Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis

<p>Abstract</p> <p>Background</p> <p>Central nervous system is a common site of metastasis in NSCLC and confers worse prognosis and quality of life. The aim of this prospective study was to evaluate the prognostic significance of clinical-pathological factors (CPF), serum CEA levels, and EGFR and HER2 tissue-expression in brain metastasis (BM) and overall survival (OS) in patients with advanced NSCLC.</p> <p>Methods</p> <p>In a prospective manner, we studied 293 patients with NSCLC in IIIB-IV clinical stage. They received standard chemotherapy. CEA was measured prior to treatment; EGFR and HER2 were evaluated by immunohistochemistry. BM development was confirmed by MRI in symptomatic patients.</p> <p>Results</p> <p>BM developed in 27, and 32% of patients at 1 and 2 years of diagnosis with adenocarcinoma (RR 5.2; 95% CI, 1.002–29; p = 0.05) and CEA ≥ 40 ng/mL (RR 11.4; 95% CI, 1.7–74; <it>p </it>< 0.01) as independent associated factors. EGFR and HER2 were not statistically significant. Masculine gender (RR 1.4; 95% CI, 1.002–1.9; <it>p </it>= 0.048), poor performance status (RR 1.8; 95% CI, 1.5–2.3; <it>p </it>= 0.002), advanced clinical stage (RR 1.44; 95% CI, 1.02–2; <it>p </it>= 0.04), CEA ≥ 40 ng/mL (RR 1.5; 95% CI, 1.09–2.2; <it>p </it>= 0.014) and EGFR expression (RR 1.6; 95% CI, 1.4–1.9; <it>p </it>= 0.012) were independent associated factors to worse OS.</p> <p>Conclusion</p> <p>High CEA serum level is a risk factor for BM development and is associated with poor prognosis in patients with advanced NSCLC. Surface expression of CEA in tumor cells could be the physiopathological mechanism for invasion to CNS.</p

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Longitudinal interferon-β effects in multiple sclerosis: differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL