The kynurenic acid analog SZR104 induces cytomorphological changes associated with the anti-inflammatory phenotype in cultured microglia.

We previously showed the anti-inflammatory effects of kynurenic acid (KYNA) and its brain-penetrable analog N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide (SZR104) both in vivo and in vitro. Here, we identified the cytomorphological effects of KYNA and SZR104 in secondary microglial cultures established from newborn rat forebrains. We quantitatively analyzed selected morphological aspects of microglia in control (unchallenged), lipopolysaccharide (LPS)-treated (challenged), KYNA- or SZR104-treated, and LPS + KYNA or LPS + SZR104-treated cultures.

A conserved MTMR lipid phosphatase increasingly suppresses autophagy in brain neurons during aging.

Ageing is driven by the progressive, lifelong accumulation of cellular damage. Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. Despite its physiological and medical significance, it remains largely unknown why autophagy becomes incapable of effectively eliminating harmful cellular materials in many cells at advanced ages.

High risk of depression, anxiety, and an unfavorable complex comorbidity profile is associated with SLE: a nationwide patient-level study.

Objectives: The aim of this national population-based, retrospective database study is to compare the comorbidity profiles of systemic lupus erythematosus (SLE) patients and general population controls matched for age, gender, and region and assess the risk of depression or anxiety when controlled for age, gender and adjusted for the Charlson Comorbidity Index (CCI).

Methods: Claims data of 1051 patients diagnosed with SLE (full population between January 01, 2011, and December 31, 2014) from the Hungarian National Health Insurance Fund have been analyzed against matched controls (1:5 ratio) with a follow-up of 30 months. The first record of SLE diagnosis was considered the diagnosis date.

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains.

Kynurenic acid (KYNA) is implicated in antiinflammatory processes in the brain through several cellular and molecular targets, among which microglia-related mechanisms are of paramount importance. In this study, we describe the effects of KYNA and one of its analogs, the brain-penetrable SZR104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide), on the intracellular distribution and methylation patterns of histone H3 in immunochallenged microglia cultures. Microglia-enriched secondary cultures made from newborn rat forebrains were immunochallenged with lipopolysaccharide (LPS).

Epigenetic Consequences of in Utero Exposure to Rosuvastatin: Alteration of Histone Methylation Patterns in Newborn Rat Brains.

Rosuvastatin (RST) is primarily used to treat high cholesterol levels. As it has potentially harmful but not well-documented effects on embryos, RST is contraindicated during pregnancy. To demonstrate whether RST could induce molecular epigenetic events in the brains of newborn rats, pregnant mothers were treated daily with oral RST from the 11th day of pregnancy for 10 days (or until delivery).

Sensitivity of Rodent Microglia to Kynurenines in Models of Epilepsy and Inflammation In Vivo and In Vitro: Microglia Activation is Inhibited by Kynurenic Acid and the Synthetic Analogue SZR104.

Kynurenic acid is an endogenous modulator of ionotropic glutamate receptors and a suppressor of the immune system. Since glutamate and microglia are important in the pathogenesis of epilepsy, we investigated the possible action of the synthetic kynurenic acid analogue, SZR104, in epileptic mice and the action of kynurenic acid and SZR104 on the phagocytotic activity of cultured microglia cells. Pilocarpine epilepsy was used to test the effects of SZR104 on morphological microglia transformation, as evaluated through ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry.

Large-scale mortality gap between SLE and control population is associated with increased infection-related mortality in lupus.

Objective: The aim of the present study was to analyse the incidence, prevalence, mortality and cause of death data of adult SLE patients and matched controls in a full-populational, nationwide, retrospective study.

Methods: This non-interventional study was based on database research of the National Health Insurance Fund of Hungary. A total of 7888 patients were included in the analyses, within which two subgroups of incident patients were created: the 'All incident SLE patients' group consisted of all incident SLE patients (4503 patients), while the 'Treated SLE patients' group contained those who received relevant therapy in the first 6 months after diagnosis (2582 patients).

Genetic Polymorphism of GSTP-1 Affects Cyclophosphamide Treatment of Autoimmune Diseases.

Cyclophosphamide is one of the most potent and reliable anti-cancer and immunosuppressive drugs. In our study, 33 individuals with different autoimmune diseases were treated with cyclophosphamide according to standard protocols. The responses to the treatments were determined by measuring the alteration of several typical parameters characterizing the given autoimmune diseases over time.

Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents.

The five TNF inhibitors currently approved for the treatment of RA are characterised by differences in their molecular structures, half-lives, administration routes, dosing intervals, immunogenicity, and use in women who wish to become pregnant. TNF inhibitors still represent the first biologic after conventional synthetic DMARD (csDMARD) in the majority of patients according to registry data. This was possibly because they were historically the first biological agents available (biological DMARDS with a different mechanism of action or targeted synthetic DMARDs did not become available until 2006s), and so switching from one to another was frequent in the case of an inadequate response and/or side effects.

[Rheumatological manifestations in primary immunodeficiency diseases].

Primary immune deficiencies (PIDs) are characterized by quantitative and/or functional abnormalities of the immune system elements. Bone and joint abnormalities are not rare in patients with immunodeficiencies. Joint manifestations, of which arthritis is the most common, occur mainly in humoral PIDs (X-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency) and occasionally in defects of the phagocyte system (chronic granulomatous disease, glicogen storage diseases).

Dyslipidemia in systemic lupus erythematosus.

Cardiovascular disease is one of the major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Accelerated atherosclerosis is related to traditional (age, hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and positive family history) and non-traditional, disease-related factors. Traditional risk factors are still more prominent in patients with lupus, as both hypertension and hypercholesterinemia were independently associated with premature atherosclerosis in several SLE cohorts.

[Recent advances in the treatment of large vessel vasculitides].

Giant cell arteritis and Takayasu arteritis classified to large vessel vasculitides have similar histopathology in the vascular wall proposing that these entities can be different phenotypes on a spectrum of a single disorder. Glucocorticoids are the mainstay of therapy combined with cyclophosphamide, azatioprine and mycofenolate mofetil, when it is required. However, a significant proportion of patients are glucocorticoid-dependent despite of the conventional disease-modifying antirheumatic drugs and suffer from serious side effects of the steroids, therefore alternate options for more effective disease management are needed.

[Clinical guideline for the treatment of lupus nephritis and single-centre results of mycofenolate mofetil among patients with lupus nephritis in the National Institute of Rheumatology and Physiotherapy, Budapest].

The authors present the latest guideline for the treatment of lupus nephritis and their own single-centre results with mycofenolate mofetil treated lupus nephritis. Lupus nephritis and mainly its proliferative form is a frequent and potentially life-threatening manifestation of systemic lupus erythematosus that can lead to end-stage renal disease. The treatment of lupus nephritis greatly improved in the last decades; mycofenolate mofetil has become an alternative of cyclophosphamide both in remission induction and as a maintenance regimen as well in the treatment of Class III and IV glomerulonephritis.

[Recent advances in the treatment of antineutrophil cytoplasm antibody associated vasculitides].

The authors review the nomenclature of vasculitides and the classification of antineutrophil cytoplasm antibody associated vasculitides and present the method of measuring disease activity (Five-factor Score, Birmingham Vasculitis Activity Score) and its role in defining therapeutical needs. They discuss the treatment algorithm of antineutrophil cytoplasm antibody associated vasculitides, present the sometimes equipotential medications used during the induction therapy followed by a maintenance regimen, and outline their usage and possible side-effects that may require medical attention. They point out the importance of plasmapheresis as an adjunctive treatment in some cases, as well as indications and possible outcome of kidney transplantation in therapy-resistant cases.

Calmodulin inhibition regulates morphological and functional changes related to the actin cytoskeleton in pure microglial cells.

The roles of calmodulin (CaM), a multifunctional intracellular calcium receptor protein, as concerns selected morphological and functional characteristics of pure microglial cells derived from mixed primary cultures from embryonal forebrains of rats, were investigated through use of the CaM antagonists calmidazolium (CALMID) and trifluoperazine (TFP). The intracellular localization of the CaM protein relative to phalloidin, a bicyclic heptapeptide that binds only to filamentous actin, and the ionized calcium-binding adaptor molecule 1 (Iba1), a microglia-specific actin-binding protein, was determined by immunocytochemistry, with quantitative analysis by immunoblotting. In unchallenged and untreated (control) microglia, high concentrations of CaM protein were found mainly perinuclearly in ameboid microglia, while the cell cortex had a smaller CaM content that diminished progressively deeper into the branches in the ramified microglia.

High prevalence of CYP2C19*2 allele in Roma samples: study on Roma and Hungarian population samples with review of the literature.

The purpose of our study was to characterise the CYP2C19*2 and CYP2C19*3 alleles in healthy Roma and Hungarian populations. DNA of 500 Roma and 370 Hungarian subjects were genotyped for CYP2C19*2 (G681A, rs4244285) and CYP2C19*3 (G636A, rs4986893) by PCR-RFLP assay and direct sequencing. Significant differences were found comparing the Roma and Hungarian populations in CYP2C19 681 GG (63.

Difference of interleukin-23 receptor gene haplotype variants in ulcerative colitis compared to Crohn's disease and psoriasis.

Objective: Polymorphisms of the interleukin-23 receptor (IL23R) gene have been found to play a role in the development of several autoimmune diseases. Our aim was to examine the possible effect of not only simple individual variants, but of haplotypes composed of them.

Subjects: We analysed 263 patients with psoriasis, 199 patients with Crohn's disease (CD), 282 patients with ulcerative colitis (UC), and 253 controls for rs1884444, rs11805303, rs7517847, rs2201841, rs10889677 and rs11209032 variants.

Marked diversity of IL23R gene haplotype variants in rheumatoid arthritis comparing with Crohn's disease and ankylosing spondylitis.

Haplotype tagging SNPs of interleukin-23 receptor gene rs1004819, rs7517847, rs7530511, rs2201841, rs1343151 and rs10889677 were determined in 396 patients with rheumatoid arthritis, 190 patients with Crohn's disease, 206 patients with ankylosing spondylitis and 182 controls. Using regression analysis models the rs1004819, rs2201841, and rs10889677 SNPs were found to confer risk for Crohn's disease and ankylosing spondylitis, while rs1343151 had a protective effect in both of these diseases, and the rs2201841 and rs10889677 SNPs showed susceptibility nature for rheumatoid arthritis. Using these SNPs we could study the susceptibility haplotype profiles in these diseases with special attention to the rheumatoid arthritis, first in the literature.

[Postgastrectomy symptoms following total gastrectomy with or without preservation of the duodenal passage].

Introduction: Total gastrectomy leads to decreased quality of life, which is characterized by different symptoms of the postgastrectomy syndrome. Aim of this study was to investigate the correlation of different alimentary symptoms and habits in correlation with the reconstruction type after total gastrectomy.

Patients And Methods: Between 2005-2009 34 patients after total gastrectomy for gastric cancer were evaluated with questionnaires.

Interaction between CTLA4 gene and IBD5 locus in Hungarian Crohn's disease patients.

Backgrounds And Aims: The IGR2198a_1 and IGR2096a_1 variants of the IBD5 region were found to be associated with Crohn's disease (CD) in the Hungarian population, while IGR2230a_1 does not seem to confer risk for the disease. In the present study, our aim was to investigate the statistical interaction of these three IBD5 polymorphisms with the +49 A/G substitution within the cytotoxic T lymphocyte antigen-4 (CTLA4) gene, detected previously as neutral gene variant in Hungarian IBD patients.

Methods: A total of 305 unrelated subjects with CD and 310 healthy controls were genotyped with PCR-RFLP methods.

Genetic variability and haplotype profile of MDR1 (ABCB1) in Roma and Hungarian population samples with a review of the literature.

The genetic variability, haplotype profile and ethnic differences of MDR1 polymorphisms in healthy Roma and Hungarian populations were analyzed and the results were compared with those of other populations available from the literature. Healthy subjects (465 Roma and 503 Hungarian) were genotyped for C1236T, G2677T/A and C3435T variants of MDR1 by PCR-RFLP assay. Differences were found between the Roma and Hungarian populations in the frequencies of MDR1 1236 CC (20.

Stepwise positive association between APOA5 minor allele frequencies and increasing plasma triglyceride quartiles in random patients with hypertriglyceridemia of unclarified origin.

Apolipoprotein A5 (ApoA5) gene and its protein product play a central role in the complex regulation of circulating triglyceride levels in humans. Naturally occurring variants of the apolipoprotein A5 gene have been associated with increased triglyceride levels and have been found to confer risk for cardiovascular diseases. In our study, four polymorphisms, the T-1131C, IVS3+G476A, T1259C, and C56G alleles of APOA5 were analyzed in a total of 436 patients by polymerase chain reaction-restriction fragment length polymorphism methods.

[Acute pancreatitis caused by an intraluminal duodenal diverticulum].

Intraluminal duodenal diverticula are a rare congenital disorders, which usually become symptomatic in adults. In our case, recurrent pancreatitis was caused by an intraluminal duodenal diverticulum in a 26 year old woman. The diagnosis was established by CT scan and upper gastroduodenal endoscopy.

Interethnic differences of CYP2C9 alleles in healthy Hungarian and Roma population samples: relationship to worldwide allelic frequencies.

CYP2C9 gene polymorphisms are widely studied in several ethnic groups, however they are less known in the Roma population. The aim of this work was to study the ethnic differences of the CYP2C9 allele distribution in a healthy Roma population in order to compare them with a healthy Hungarian population. A total of 535 Hungarian and 465 Roma volunteers were genotyped for the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) allelic variants by PCR-RFLP assay.

Vitamin K epoxide reductase complex 1 (VKORC1) haplotypes in healthy Hungarian and Roma population samples.

The aim of this work was to determine the VKORC1 haplotype profile in healthy Hungarian and Roma population samples, and to compare our data with other selected populations. Using haplotype tagging SNPs (G-1639A, G9041A and C6009T), we characterized Hungarian (n = 510) and Roma (n = 451) population samples with regard to VKORC1*1, *2, *3 and *4 haplotypes. In the Hungarian samples, the VKORC1*1, *2, *3 and *4 haplotypes accounted for 3, 39, 37 and 21%, respectively and by contrast, in the Roma population samples the VKORC1 variants were 5, 30, 46 and 19%, respectively.