Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL

Here, we provide evidence for a detrimental role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in neural death in T cell-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Clinical severity and neuronal apoptosis in brainstem motor areas were substantially reduced upon brain-specific blockade of TRAIL after induction of EAE through adoptive transfer of encephalitogenic T cells. Furthermore, TRAIL-deficient myelin-specific lymphocytes showed reduced encephalitogenicity when transferred to wild-type mice. Conversely, intracerebral delivery of TRAIL to animals with EAE increased clinical deficits, while naive mice were not susceptible to TRAIL. Using organotypic slice cultures as a model for living brain tissue, we found that neurons were susceptible to TRAIL-mediated injury induced by encephalitogenic T cells. Thus, in addition to its known immunoregulatory effects, the death ligand TRAIL contributes to neural damage in the inflamed brain

Особенности течения и эффективности превентивной терапии гестоза при многократных родах

Objective: to study the course of gestosis in multiple labors and the impact of preventive therapy (a prospective study).Subjects. A hundred and fifty-eight females in the third trimester, including 108 multiparas with gestosis were examined (a study group). The study group was also divided in 2 subgroups: 1) 58 multipara pregnant females having a complete prenatal preparation in accordance with the current reasons for the treatment of gestosis and for the prevention of its complications; 2) 50 multipara pregnant females having a partial antenatal preparation due to late admission or to the onset of labor activity, which required accelerated delivery. A control group comprised 50 multiparas without gestosis.Methods. Clinical, statistical, and calorimetric studies using sets of commercial reagents (Boenringer Mannheim (Germany)); plasma hematocrit (determination of OTsK) and calculation (determination of OPTs and OTsE) methods.Results. Complex preventive therapy used in multiparas with gestosis promoted the occurrence of clinical remission in 82.7% of subgroup 1 pregnant females. After therapy, the critical forms of gestosis, diagnosed in 16% of subgroup 2 pregnant females, were observed in only 5.2% of subgroup 1 females. However, in patients with baseline severe nephropathy, the effect was temporary, which testified to a severe impairment of protective and adaptive mechanisms and to significant catabolism in multiparas with gestosis. The values of OTsK, OPTs, and OTsE in multiparas tended to decrease particularly in subgroup 2 of the study group. In multipara, progressive gestosis was accompanied by a pronounced decrease in the blood levels of proteins with a relatively compensatory rise in their concentration and, to a lesser extent, in that of globulins, suggesting the tension of metabolic processes in the body. Gestosis in multipara was attended by impairments in all hemostatic links, as compared to the control group. There was a significant decrease in the venous blood count of platelets, an increase in the level of hematocrit, and a reduction in the times of clotting and recalcification; there were also rises in the prothrombin index and fibrinogen levels.Conclusion. The findings lead to the conclusion that hemodynamic and hemostatic disorders are reversible when the treatment for mild and moderate gestosis is correct and is initiated in due time. At the same time, no benefit from the performed therapy testifies to the stability and refractoriness of metabolic shifts in severe gestosis during multiple labors. Цель исследования — изучить течение гестоза при многократных родах и влияние предлагаемой превентивной терапии (проспективное исследование).Материалы исследования. Обследовано 158 женщин в III триместре беременности, из них 108 многорожавших женщин с гестозом — основная группа. Основная группа также была разделена на 2 подгруппы: 1-я подгруппа — 58 многорожавших беременных, получивших полную пренатальную подготовку соответственно современным подходам к лечению гестоза и профилактики его осложнений; 2-я подгруппа — 50 многорожавших беременных, получивших частичную дородовую подготовку в связи с поздней госпитализацией или началом родовой деятельности, что требовало ускорения родоразрешения. В группу сравнения вошли 50 многорожавших женщин без гестоза. Методы исследования. Клинико-статистический, калориметрический с помощью наборов коммерческих реактивов фирмы Boenringer Mannheim (ФРГ); плазменно-гематокритный (определение ОЦК), расчётный (определение ОЦП и ОЦЭ). Результаты исследования. Применение комплексной превентивной терапии у многорожавших женщин с гестозом способствовало наступлению клинической ремиссии у 82,7% беременных 1-й подгруппы. После проведённого лечения критические формы гестоза, диагностированные у 16% беременных 2-й подгруппы, отмечались лишь у 5,2% женщин из 1-й подгруппы. Однако, у пациенток с исходно тяжёлой нефропатией эффект имел временный характер, что свидетельствовало о глубоком нарушении защитно-приспособительных механизмов и выраженном катаболизме в организме многорожавших женщин с гестозом. Показатели ОЦК, ОЦП и ОЦЭ у многорожавших имеют тенденцию к снижению, особенно во 2-й подгруппе основной группы. Прогрессирование течения гестоза у многорожавших женщин сопровождается выраженным снижением уровня белков крови с относительным компенсаторным повышением концентраций — и, в меньшей степени, — глобулинов, свидетельствующие о напряжении метаболических процессов в организме. Гестоз у многорожавших женщин сопровождается нарушениями всех звеньев гемостаза по сравнению с группой многорожавших без гестоза. Наблюдается достоверное снижение числа тромбоцитов в венозной крови, повышение уровня гематокрита, укорочение времени свертывания и рекальцификации, отмечается возрастание ПТИ и уровня фибриногена. Заключение. На основании вышеизложенного можно сделать вывод об обратимости гемодинамических и гемостазиологических нарушений при правильном и своевременно начатом лечении гестоза лёгкой и средней степени тяжести. В то же время отсутствие эффекта от проводимой терапии указывает на стойкость и рефрактерность метаболических сдвигов при тяжёлых формах гестоза при многократных родах.

Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients:A prospective inception cohort study in treatment-free patients

Background: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. Objectives: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. Methods: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (Delta HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and Delta HAM-D. Results: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in postmenopausal women found a similar comparison between alleles. Limitations: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. Conclusions: Patients taking tricylic antidepressants were noted to have a significant improvement in Delta HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia D. Osmanova(1), A.S. Boiko(1), O.Y. Fedorenko(1), I.V. Pozhidaev(1), M.B. Freidin(2), E.G. Kornetova(3), S.A. Ivanova(1), B. Wilffert(4), A.J.M. Loonen(5) (1)Mental Health Research Institute- Tomsk NRMC, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Research Institute of Medical Genetics, Tomsk NRMC, Laboratory of Population Genetics, Tomsk, Russia (3)Mental Health Research Institute- Tomsk NRMC, Department of Clinical and Social Psychiatry and Addiction, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1,2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorphisms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36–0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accordingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed. References [1] Ivanova, S.A., Osmanova, D.Z., Boiko, A.S., Pozhidaev, I.V., Freidin, M.B., Fedorenko, O.Y., Semke, A.V., Bokhan, N.A., Kornetova, E.G., Rakhmazova, L.D., Wilffert, B., Loonen, A.J., 2016. Prolactin gene polymorphism (-1149G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics. Schizophrenia Research Oct 21, pii: S0920-9964 (16)30473-X. doi: 10.1016/j.schres.2016.10.029. [2] Ivanova, S.A., Osmanova, D.Z., Freidin, M.B., Fedorenko, O.Y., Boiko, A.S., Pozhidaev, I.V., Semke, A.V., Bokhan, N.A., Agarkov, A.A., Wilffert, B., Loonen, A.J., 2017. Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia. World J Biol Psychiatry 18 (3), 239–246. [3] Miura, I., Zhang, J.P., Hagi, K., Lencz, T., Kane, J.M., Yabe, H., Malhotra, A.K., Correll, C.U., 2016. Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis. Psychoneuroendocrinology 72, 1–10. [4] Al Hadithy, A.F.Y., Ivanova, S.A., Pechlivanoglou, P., Semke, A., Fedorenko, O., Kornetova, E., Ryadovaya, L., Brouwers, J.R.B.J., Wilffert, B., Bruggeman, R., Loonen, A.J.M., 2009. Tardive dyskinesia and DRD3, HTR2A and HTR2C gene polymorphisms in Russian psychiatric inpatients from Siberia. Progress in NeuroPsychopharmacology and Biological Psychiatry 33, 475–481. Keywords: Dopamine Genetics / Molecular genetics Schizophrenia: basi

Association of COMT gene polymorphisms with Parkinson's disease

Parkinson’s disease (PD) is one of the most serious and widespread neurodegenerative disorders. Genetic susceptibility plays a significant role in the development of PD.The aim of our study was to investigate associations between single nucleotide polymorphisms (SNPs) of the COMT gene coding dopamine catabolism enzyme and Parkinson’s disease.Materials and methods. In this study seven SNPs (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696) of COMT were genotyped. 232 patients with PD and 127 healthy individuals in the Siberian region of Russia were examined. Venous blood samples were drawn as a marker of PD. Statistical differences in the prevalence of alleles and genotypes between groups of patients were assessed using IBM SPSS Statistics 23.1 software.Results. A significant association between the rs165774 polymorphism and PD was observed. Our study demonstrates that polymorphisms in the COMT gene may play an important role in the pathophysiology of Parkinson’s disease

Talaromyces atroroseus, a new species efficiently producing industrially relevant red pigments

Some species of Talaromyces secrete large amounts of red pigments. Literature has linked this character to species such as Talaromyces purpurogenus, T. albobiverticillius, T. marneffei, and T. minioluteus often under earlier Penicillium names. Isolates identified as T. purpurogenus have been reported to be interesting industrially and they can produce extracellular enzymes and red pigments, but they can also produce mycotoxins such as rubratoxin A and B and luteoskyrin. Production of mycotoxins limits the use of isolates of a particular species in biotechnology. Talaromyces atroroseus sp. nov., described in this study, produces the azaphilone biosynthetic families mitorubrins and Monascus pigments without any production of mycotoxins. Within the red pigment producing clade, T. atroroseus resolved in a distinct clade separate from all the other species in multigene phylogenies (ITS, β-tubulin and RPB1), which confirm its unique nature. Talaromyces atroroseus resembles T. purpurogenus and T. albobiverticillius in producing red diffusible pigments, but differs from the latter two species by the production of glauconic acid, purpuride and ZG-1494α and by the dull to dark green, thick walled ellipsoidal conidia produced. The type strain of Talaromyces atroroseus is CBS 133442