Clinical study on CXCL13, CCL17, CCL20 and IL-17 as immune cell migration navigators in relapsing-remitting multiple sclerosis patients

BackgroundThere has been a growing evidence for the role of chemokines in the pathology of multiple sclerosis. Recently, there has been great emphasis placed on humoral immunity and the T(H)-17 response, which has not yet been thoroughly described in MS. The aim of this study was to investigate the role of specific chemokines involved in B-cell migration (CXCL13) and in the T(H)-17 immune response (IL-17, CCL17, CCL20).MethodsUsing ELISA, the chosen chemokine concentrations were measured in the serum and cerebrospinal fluid of relapsing?remitting MS patients with both active and stable disease, and the relapse prediction rate was calculated.ResultsWe found that the CSF concentrations of CXCL13 in patients with RRMS both, during relapse and remission, were significantly higher than in controls. CCL17 and CCL20 were not detected in CSF in either of the groups, whereas serum CCL20 level was significantly higher in remission than during relapse. Intravenous methylprednisolone treatment of patients with relapse did not influence serum CXCL13 and CCL20 levels. However, it did lower CCL17 and IL-17 concentrations.ConclusionsCXCL13 is an important mediator in MS that is strongly linked to the neuroinflammatory activity of the disease. However, more studies are needed for elucidating the roles of CCL17, CCL20 and IL-17 in MS pathology.     

Effect of combined spironolactone-β-blocker ± enalapril treatment on occurrence of symptomatic atrial fibrillation episodes in patients with a history of paroxysmal atrial fibrillation (SPIR-AF study)

Angiotensin II and aldosterone are key factors responsible for the structural and neurohormonal remodeling of the atria and ventricles in patients with atrial fibrillation (AF). The aim of the present study was to evaluate the antiarrhythmic effects of spironolactone compared to angiotensin-converting enzyme inhibitors in patients with recurrent AF. A cohort of 164 consecutive patients (mean age 66 years, 87 men), with an average 4-year history of recurrent AF episodes, was enrolled in a prospective, randomized, 12-month trial with 4 treatment arms: group A, spironolactone, enalapril, and a β blocker; group B, spironolactone and a β blocker; group C, enalapril plus a β blocker; and group D, a β blocker alone. The primary end point of the trial was the presence of symptomatic AF episodes documented on the electrocardiogram. At 3-, 6-, 9-, and 12 months, a significant (p < 0.001) reduction had occurred in the incidence of AF episodes in both spironolactone-treated groups (group A, spironolactone, enalapril, and a β blocker; and group B, spironolactone plus a β blocker) compared to the incidence in patients treated with enalapril and a β blocker (group C) or a β blocker alone (group D). No significant difference was seen in AF recurrences between patients taking spironolactone and a β blocker with (group A) and without (group B) enalapril. No significant differences were found in the systolic or diastolic blood pressure or heart rate among the groups before and after 1 year of follow-up. In conclusion, combined spironolactone plus β-blocker treatment might be a simple and valuable option in preventing AF episodes in patients with normal left ventricular function and a history of refractory paroxysmal AF.     

Eating patterns and portion size associated with obesity in a Swedish population

The objective of this study was to describe the association between meal pattern and obesity. The study is based on data from the INTERGENE research programme, and the study population consists of randomly selected women and men, aged 25-74, living in the V?stra G?taland Region in Sweden. A total of 3610 were examined. Participants with measured BMI> or =30 were compared with others (BMI<30) with respect to questionnaire data on habitual meal patterns and intake of energy estimated from food frequencies and standard portions. Odds ratios (OR) with 95% confidence intervals were adjusted for age, sex, smoking and physical activity in logistic regression models. Being obese was significantly associated with omitting breakfast, OR 1.41 (1.05-1.90), omitting lunch OR 1.31 (1.04-1.66) and eating at night OR 1.62 (1.10-2.39). Obesity was also related to significantly larger self-reported portion sizes of main meals. No statistically significant relationship with intake of total energy was revealed. Thus, the results indicate that examination of meal patterns and portion sizes might tell us more about obesogenic food patterns than traditional nutrient analyses of food frequencies. Being obese was associated with a meal pattern shifted to later in the day and significantly larger self-reported portions of main meals.     

Design, synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy-propyl]-3,3-diphenylpyrrolidin-2-one derivatives with antiarrhythmic, antihypertensive, and α-adrenolytic activity

A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for α₁- and α₂-adrenoceptors (ARs), as well as their antiarrhythmic, and antihypertensive activities. The highest affinity for the α₁-AR was displayed by 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pK_i = 7.28. The highest affinity for the α₂-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pK_i = 6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for α_1B- and α_1D-AR, which gave pA₂ α_1B = 6.55 and pA₂ α_1D = 7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED₅₀ value was 1.1 mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5–5.0 mg/kg (i.v.) and their hypotensive effects lasted for longer than 1 h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both α₁- and α₂-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure–activity relationship, a preliminary molecular modeling study was undertaken.     

Remission of chronic urticaria in the course of house dust mite immunotherapy—Mere coincidence or something more to it?

It has been hypothesised that house dust mite is as a causative and/or deteriorating factor in some cases of chronic urticaria. In this report we describe two patients with the history of respiratory house dust mite allergy and chronic urticaria, which resolved in the course of house dust mite immunotherapy. Basing on literature and our own experiences, we can only speculate that some patients suffering from mite-induced respiratory allergy and concomitant chronic urticaria may benefit additionally from allergen immunotherapy, manifesting as the withdrawal or alleviation of urticaria symptoms.     

Long-term Dietary Acrylamide Intake and Breast Cancer Risk in a Prospective Cohort of Swedish Women

The association between dietary acrylamide intake and the incidenceof invasive breast cancer was examined among 61,433 Swedishwomen who were cancer free and completed a food frequency questionnairein 1987–1990 and again in 1997. During a mean follow-upof 17.4 years, a total of 2,952 incident cases of breast cancerwere diagnosed in the cohort. In multivariate analyses controllingfor breast cancer risk factors, no statistically significantassociation was observed between long-term acrylamide intake(assessed at baseline and in 1997) and the risk of breast cancer,overall or by estrogen receptor (ER) and progesterone receptor(PR) status. The multivariate rate ratios comparing extremequartiles of acrylamide intake were 0.91 (95% confidence interval(CI): 0.80, 1.02) for overall breast cancer, 0.89 (95% CI: 0.74,1.08) for ER+PR+ tumors, 1.17 (95% CI: 0.84, 1.64) for ER+PR–tumors, and 0.91 (95% CI: 0.61, 1.38) for ER–PR–tumors. The association between acrylamide intake and breastcancer risk did not differ by smoking status. These findingsfor Swedish women do not support the hypothesis that dietaryacrylamide is positively associated with risk of breast cancer,at least not within the ranges of acrylamide consumed by thispopulation. acrylamide; breast neoplasms; cohort studies; diet; prospective studies     

Statins enhance toll-like receptor 4-mediated cytokine gene expression in astrocytes: implication of Rho proteins in negative feedback regulation

Toll-like receptors (TLRs) are sentinels of innate immunity that recognize pathogenic molecules and trigger inflammatory response. Because inflammatory mediators are detrimental to the host, the TLR response is regulated by feedback inhibition. Statins, the inhibitors of isoprenoid biosynthesis, have been shown to be potent modulators of TLR activity, and this modulation may provide insight regarding mechanisms of the feedback inhibition. In the present study, we examined feedback mechanisms that regulate TLR4 activity in astrocytes using statins to perturb postligational signaling. Astrocytic cultures established from newborn rat brains were exposed to lipopolysaccharide (LPS), the ligand for TLR4. The up-regulation of expression of genes encoding interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNFalpha) was determined by real-time RT-PCR. Pretreatment of the cells with either atorvastatin or simvastatin enhanced the LPS-induced up-regulation of cytokine gene expression. The most profound enhancement of approximately 17-fold was observed for the Il-6 gene. The enhancements for the Tnfa and Il-1b genes were approximately 5- and 3.5-fold, respectively. Mevalonate fully reversed the effects of statins, indicating that these drugs act through the inhibition of isoprenoid synthesis. The inhibition of protein geranylgeranylation, but not protein farnesylation, mimicked the effects of statins, strongly indicating that the enhancement is mediated by the Rho proteins. In support of this notion, pretreatment of cells with toxin B, a specific inhibitor of the Rho proteins, also enhanced LPS-triggered up-regulation of the cytokine genes. These results indicate that the Rho proteins are involved in the activation of negative feedback inhibition of TLR4 signaling in astrocytes.     

Long-term cognitive outcome in teenage survivors of arrhythmic cardiac arrest

BACKGROUND: Sudden cardiac arrest (SCA) can be the first sign of ventricular arrhythmia in teenagers. Neurocognitive problems are common after successful resuscitation. We studied cognitive function in teenage survivors of SCA, including emotional status and coping ability. METHOD: Ten SCA survivors, aged 11-19 years, had neuropsychological tests within a few weeks of resuscitation. Awareness status, orientation, episodic and semantic memory, basic auditory-visual functions, praxis and speech, short-term memory, ability to learn new verbal and visual material were assessed. These tests were repeated at about 6 months. RESULTS: Eight patients had an initial assessment; one boy remained in a coma and one was making simple emotional contact, revealing intensified mixed aphasia and dyskinesia. Six patients had severe disturbances of memory, motor functions and praxis. After 6 months, four patients had no neurocognitive disturbance. Four patients had memory impairment making school education difficult. Two patients were totally dependent on caregivers. Because of the absence of symptoms before SCA, and amnesia relating to the SCA episodes, patients had problems accepting their heart problems and limitations resulting from it. CONCLUSION: Teenagers surviving SCA have significant neurcognitive and psychological problems. They need psychological care and guidance in understanding their condition.