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

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

Химиотерапия в комбинации с Бевацизумабом при раке молочной железы. Результаты наблюдательного исследования в ежедневной клинической практике

In metastatic breast cancer (MBC) the combination of Bevacizumab (Avastin) and chemotherapy (CT) failed to demonstrate an increase in overall survival with a significant improvement of the objective response rate and progression-free survival (PFS) in randomized trials of the 3d phase. Nevertheless, observational studies in the daily clinical practice for the use of Bevacizumab in MBC continue in the world. We present the results of our own observational study, which goal is to assess the efficacy and tolerability of Bevacizumab in combination with CT in patients with HER/2-negative metastatic and locally advanced breast cancer. The study included 34 patients with breast cancer (6-locally advanced, 28-metastatic) at the age of 29 to 66 years (mean – 49.5). Bevacizumab was administered at a dose of 7.5 to 15 mg/kg every 3 weeks in combination with CT. In total, the patients received 294 doses of Bevacizumab (median – 10). All patients with locally advanced breast cancer were operated on after the treatment completion, a pathologic complete response was registered in 33.3%. In MBC, the objective response was registered in 46,4%, tumor growth control in 89.3%, median PFS – 10 months. Typical for Bevacizumab adverse events, such as hypertension, proteinuria, were moderate and were met respectively in 14.7% and in 5.9% cases. In 1 (2.9%) patient the treatment was complicated by deep vein thrombosis and PE due to disease progression. Conclusion. Bevacizumab in combination with CT in breast cancer treatment can achieve high rates of objective response and PFS independent of the treatment lineБевацизумаб (Авастин) в комбинации с химиотерапией (ХТ) 1–2-й линий при метастатическом раке молочной железы (мРМЖ) в рандомизированных исследованиях III фазы не продемонстрировал увеличения общей выживаемости (ОВ) при значимом повышении частоты объективного ответа и выживаемости без прогрессирования (ВБП). Тем не менее в мире продолжаются наблюдательные исследования в ежедневной клинической практике по применению Бевацизумаба при РМЖ. Приводятся результаты собственного наблюдательного исследования, целью которого является оценка переносимости и эффективности Бевацизумаба в комбинации с ХТ у больных HER/2-негативным диссеминированным и местно-распростра- ненным раком молочной железы. В исследование включено 34 больных РМЖ (6 – местно-распространенным, 28 – метаста- тическим) в возрасте от 29 до 66 лет (средний – 49,5 лет). Бевацизумаб вводили в дозе от 7,5 до 15 мг/кг 1 раз в 3 недели в комбинации с ХТ. Всего пациентки получили 294 дозы Бевацизумаба (медиана – 10). При местно-распространенном РМЖ всем больным выполнено радикальное оперативное вмешательство, полный патоморфоз отмечен в 33,3%. При мРМЖ объ- ективный ответ составил 46,4%, контроль роста опухоли – 89,3%, медиана ВБП – 10 месяцев. Характерные для Бевацизумаба нежелательные явления (гипертензия, протеинурия) были умеренно выражены и встречались соответственно в 14,7% и 5,9% случаев. У 1 (2,9%) больной лечение осложнилось тромбозом глубоких вен и ТЭЛА на фоне прогрессирования основного заболевания. Заключение. Бевацизумаб в комбинации с ХТ для лечения РМЖ позволяет достичь высоких показателей объективного эффекта и ВБП независимо от линии лечения.

Clinical and epidemiological features of acute intestinal infections in children in Arkhangelsk for 2015-2018

In recent years, there is increasing evidence of the significant role of the intestinal microbiome in the normal functioning of the whole body. The composition of the intestinal microflora affects the human immune system, and its metabolic processes, and even behavior. Therefore, maintaining an optimal balance in the structure of a normal gut microbiome is very important for human health. But the high prevalence of acute intestinal infections(AII) suggests that this balance is very fragile. The diversity of the causes of the All and the greater their specific gravity to determine the practical value of the clinical-epidemiological diagnosis, and was the basis for conducting our study. The aim of our work was to identify clinical and epidemiological features of acute intestinal infections in children of the Arkhangelsk region. We have evaluated the indicators of children's morbidity of acute intestinal infections in the Arkhangelsk region, as well as a retrospective clinical and epidemiological analysis in 143 children who underwent acute intestinal infections in 2015-2018 and hospitalized in the Center for infectious diseases of the Arkhangelsk regional clinical hospital. There is a high proportion of intestinal infections of unknown etiology (55.9%). Viral infections (mainly due to rotavirus gastroenteritis) prevail in the structure of All with established etiology. Among bacterial All met salmonellosis, shigellosis and campylobacteriosis.В последние годы появляется всё больше данных о существенной роли кишечного микробиома в нормальном функционировании всего организма. Состав кишечной микрофлоры влияет и на иммунную систему человека, и на его обменные процессы, и даже на поведение. Поэтому поддержание оптимального баланса в структуре нормального микробиома кишечника очень важно для здоровья человека. Но высокая распространённость острых кишечных инфекций (ОКИ) говорит о том, что баланс этот очень хрупок. Многообразие причин ОКИ и большой их удельный вес определяют практическое значение клинико-эпидемиологической диагностики, все это и явилось основанием для проведения нашего исследования. Целью нашей работы стало выявление клинико-эпидемиологических особенностей острых кишечных инфекций у детей Архангельской области. Нами была проведена оценка показателей детской заболеваемости острыми кишечными инфекциями в Архангельской области, а также ретроспективный клинико-эпидемиологический анализ у 143 детей, перенесших острые кишечные инфекции в 2015-2018 гг. и госпитализированных в Центр инфекционных болезней Архангельской областной клинической больницы. Отмечается высокий удельный вес кишечных инфекций неустановленной этиологии (55,9%). В структуре ОКИ с установленной этиологией превалируют вирусные инфекции (в основном, за счёт ротавирусного гастроэнтерита). Среди бактериальных ОКИ встречались сальмонеллёз, дизентерия и кампилобактериоз

The Specific Features of the Course and Efficiency of Preventive Therapy for Gestosis in Multiple Labors

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

Antibodies to cyclic citrullinated peptide and angiopoietin-like protein type 4 as markers of immune inflammation and osteoporotic processes in rheumatoid arthritis patients

Low-energy fractures in rheumatoid arthritis (RA) are more common in patients with high activity and long duration of disease and with high titers of anti-citrullinated antibodies (ACPA). Increased expression of angiopoietin-like protein type 4 (ANGPTL4) in bone tissue has also been noted in inflammatory arthritis. The purpose of the study was to analyze the effect of ACPA and ANGPTL4 on systemic bone mineral density in RA patients. Antibodies to ACPA and ANGPTL4 content were studied in the serum of 96 RA patients (women 91.7%) by enzyme immunoassay. The mineral density of the lumbar vertebrae (BMDL1-L4), femoral neck, and total femur (BMDtotal) was measured by dual-energy X-ray absorptiometry (DXA). In the study group, ACPA and ANGPTL4 were positive in 61.5% and 41.7% of patients, respectively. ACPA was negatively correlated with BMDtotal and ANGPTL4 with BMDL1-L4 (p<0.05). Dividing patients into groups with low (n=34) and high (n=62) DAS28 activity demonstrated a significant increase in ACPA with increasing RA activity (p=0.042). ACPA and ANGPTL4 scores were also significantly higher in the group of RA patients with osteoporosis (OP) (n=45) compared to the RA group without OP (n=51) (p=0.002 and p=0.028, respectively). Age, body mass index (BMI), duration and activity of the disease had no significant effect on ACPA in the general group of RA patients. But in the group of RA patients with OP, the correlation between ACPA and DAS28 became significant (beta=0.31, p=0.039). Only disease duration was significant for ANGPTL4 in the total group of RA patients (beta=0.31, p=0.039) out of all presented variables. In the regression model, BMDtotal was equally correlated with patient age (beta=-0.28), BMI (beta=0.25), and ACPA level (beta=-0.26). A search for the association of BMDL1-L4 with various RA characteristics demonstrated a strong influence of ANGPTL4 only (beta=-0.74; R2=0.57). The detected correlation between ANGPTL4 and decreased BMD specifically in the cancellous layer of bone allows us to identify a group of RA patients with high ANGPTL4 levels as a risk group specifically for spinal fractures, and to consider ANGPTL4 as a potential target for treatment of osteoporotic disorders