Endothelial Dysfunction in the Context of Blood-Brain Barrier Modeling.

Here, we discuss pathophysiological approaches to the defining of endothelial dysfunction criteria (i.e., endothelial activation, impaired endothelial mechanotransduction, endothelial-to-mesenchymal transition, reduced nitric oxide release, compromised endothelial integrity, and loss of anti-thrombogenic properties) in different in vitro and in vivo models. The canonical definition of endothelial dysfunction includes insufficient production of vasodilators, pro-thrombotic and pro-inflammatory activation of endothelial cells, and pathologically increased endothelial permeability. Among the clinical consequences of endothelial dysfunction are arterial hypertension, macro- and microangiopathy, and microalbuminuria. We propose to extend the definition of endothelial dysfunction by adding altered endothelial mechanotransduction and endothelial-to-mesenchymal transition to its criteria. Albeit interleukin-6, interleukin-8, and MCP-1/CCL2 dictate the pathogenic paracrine effects of dysfunctional endothelial cells and are therefore reliable endothelial dysfunction biomarkers in vitro, they are non-specific for endothelial cells and cannot be used for the diagnostics of endothelial dysfunction in vivo. Conceptual improvements in the existing methods to model endothelial dysfunction, specifically, in relation to the blood-brain barrier, include endothelial cell culturing under pulsatile flow, collagen IV coating of flow chambers, and endothelial lysate collection from the blood vessels of laboratory animals in situ for the subsequent gene and protein expression profiling. Combined with the simulation of paracrine effects by using conditioned medium from dysfunctional endothelial cells, these flow-sensitive models have a high physiological relevance, bringing the experimental conditions to the physiological scenario.

[Screening analysis of proteolytic enzymes and their inhibitors in the leaflets of epoxy-treated bioprosthetic heart valves explanted due to dysfunction]. / Skriningovyi analiz proteoliticheskikh fermentov i ikh ingibitorov v stvorkakh époksiobrabotannykh bioproteznykh klapanov serdtsa, éksplantirovannykh po prichine disfunktsii.

Bioprosthetic heart valves (BHVs) are known for their lower thrombogenicity rates and excellent hemodynamic parameters similar to native valves. However, the lifespan of these medical devices is limited to 15 years due to the structural valve degeneration. One of the mechanisms underlying functional impairment and calcification of BHVs includes proteolytic degradation of biomaterials. However, proteases found in xenogeneic BHVs tissue remain poorly studied. In this study using the dot blot assay, we have performed a screening analysis of proteolytic enzymes and their inhibitors in the leaflets of five BHVs explanted due to their dysfunction. Five aortic valves (AVs) explanted due to calcific aortic valve disease were studied as a comparison group. The results of the study have demonstrated that at least 17 proteases and 19 of their inhibitors can be found in BHVs. In the AVs 20 proteases and 21 their inhibitors were identified. Small quantitative differences were noted between proteomic profiles of the BHVs and AVs. Matrix metalloproteinases (MMPs) were expressed in BHVs and AVs at comparable levels, but the level of tissue inhibitors of metalloproteinases-1/-2 and RECK protein in implant tissues was lower than in natural valves. Probably, excessive activity of MMPs cannot be counterbalanced by their inhibitors in BHVs and therefore MMPs can degrade prosthetic biomaterial. Moreover, the detection of a wide range of proteolytic enzymes and their inhibitors in the degenerated BHVs suggests the existence of several pathophysiological pathways that can lead to structural valve degeneration.

Analysis and Forecast of the Poverty Rate in the Arctic Zone of the Republic of Sakha (Yakutia).

The article analyzes the indicators of the poverty level in the regions of the Arctic zone of the Russian Federation, and assesses the level of poverty and quality of life in the Arctic zone of Yakutia. The results of sociological studies on the level of poverty in the Arctic regions are presented as well as the measures for its reduction associated with addressing the problems of employment, increasing incomes of the population, and the development of traditional crafts.

Explanatory models and help-seeking for symptoms of PTSD and depression among Syrian refugees.

OBJECTIVE: This study investigates how Syrian refugees explain and prefer to seek help for symptoms of post-traumatic stress disorder (PTSD) and depression. METHODS: We conducted five semi-structured focus group interviews based on a vignette-technique with Syrian refugees (n = 21 men, n = 10 women). The vignettes describe a fictional person suffering from symptoms of PTSD or depression in line with DSM-5 and ICD-10 criteria. RESULTS: Despite never mentioning PTSD, participants in the PTSD-interviews recognized the symptoms. They perceived them as a common reaction to extreme situations, mainly the war, the flight, and post-migratory stressors. Depression was labeled as either depression or feelings caused by social problems, and the participants were more hesitant to identify with these symptoms. Despite some differences, both the PTSD and depression vignettes were explained in terms of situational explanatory models and externally caused stress. The main finding is how participants described changing stressors resulting from migration and resettlement leading to a difference in how they would seek help in Syria and in Norway. Specifically, we found that preferred help-seeking and coping strategies are contextual. CONCLUSIONS: These findings point to the need to consider transformations following forced migration when studying aspects of explanatory models, preferred help-seeking, and coping strategies in refugee groups.

[A rare variant in the sortilin-related receptor 1 gene is associated with declined cognitive functions in the elderly]. / Redkii variant v gene sortilinpodobnogo retseptora 1: sviaz' s pokazateliami kognitivnykh funktsii u pozhilykh.

AIM: To estimate the association of rs11218343 in the sortilin-related receptor 1 (SORL1) gene with cognitive performance in the elderly and with Alzheimer's disease (AD) in the Russian population. MATERIAL AND METHODS: A sample included 586 elderly people (mean age 70.9±5.7 years) without AD diagnosis and 100 patients with late-onset AD (mean age 72.1±7.8 years) from the Tomsk population. SORL1 rs11218343 was genotyped using PCR and MALDI-TOF mass spectrometry. Cognitive performance in the sample of elderly without AD was assessed by Montreal Cognitive Assessment (MoCA) test. RESULTS: Allele frequencies of the SORL1 polymorphism were not significantly different between the elderly without AD and AD patients. However mean MoCA score in the carriers of the rare allele (19.00±6.61) was significantly lower than in homozygotes for the common variant (22.25±3.89) (F=4.97; p=0.026). CONCLUSION: The rare variant in SORL1 gene previously associated with AD in genome-wide association studies and meta-analyses was associated with lower total МоСА scores in the random sample of elderly people that suggests declined cognitive functions in the carriers of this variant in elderly.

[Abdominal pain in migraine patients]. / Abdominal'naia bol' u bol'nykh c migren'iu.

AIM: To study the frequency of comorbid abdominal pain in migraine patients and the influence of that symptom on the formation of disease phenotype. MATERIAL AND METHODS: Clinical features of migraine were studied in 66 patients with episodic migraine and 40 patients with chronic migraine. Presence of pain, intensity, duration of seizure-associated abdominal pain and interictal abdominal pain were assessed. RESULTS AND CONCLUSION: The frequency of abdominal pain in the painful phase of migraine was >11% and did not depend on the type of migraine. Pain in the abdomen were reported by 88% of patients, with the increase in the frequency in patients with chronic migraine. The intensity and frequency of abdominal pain did not depend on organic pathology of the digestive system. Correlations between the intensity and duration of abdominal pain during the migraine attack phase (k=0.59), between the intensity of associated pain and maladjustment severity (k=0.59), and also between the abdominal pain intensity during the painful phase and in the interictal period were identified. Allodynia developed more frequently in patients with abdominal pain between migraine attacks (РF=0.005). Also relationships between the level of intensity of interictal abdominal pain and the rates of alexithymia (k=0.24), anxiety (k=0.29) and depression (k=0.25) were revealed. The association of abdominal pain with disease severity and allodynia suggests similar development of these symptoms.

[Clinical significance of nausea in migraine]. / Klinicheskoe znachenie toshnoty pri migreni.

AIM: To study the prevalence and intensity of nausea in pain, prodromal and postdromal phases of migraine paroxysm, and in between the paroxysms in migraine patients, depending on the type of migraine paroxysm and frequency of pain days, and to evaluate an effect of nausea on the course of migraine. MATERIAL AND METHODS: One hundred and four patients with migraine, aged from 18 to 60 years, were examined. The intensity of nausea was evaluated by a 5-point verbal analogue scale, and its intensity in between the paroxysms by the Gastrointestinal Symptom Rating Scale. All of the patients underwent a complex examination of the gastrointestinal tract. RESULTS AND CONCLUSION: Paroxysms with accompanying nausea were found in 90% patients. Acute nausea was associated with older age, earlier onset and longer experience of migraine. In a group of patients with acute nausea, the frequency and intensity of migraine paroxysms, probability of reoccuring pain in the first day and the severity of social disability were higher. Development of nausea in between the paroxysms and its intensity was significantly higher in patients with high intensity of nausea in migraine paroxysms. Nausea in the prodrome was significantly associated with migraine without aura and chronicity of the disorder. Patients with nausea in the prodrome also had a longer painful phase and more severe social disability. No relationship between organic diseases of the digestive tract and nausea was found. Nausea can have its own pathological mechanisms not related to concomitant diseases of the digestive tract that should be taken into account in therapeutic interventions aimed at improving quality of life of the patients.

[Gestational surrogacy - sin, whim or necessity].

The authors propose the gestational surrogacy to be permitted but only for medical indications and under exact requirements. The surrogate mother if married, her husband, too, sign with the commissioning adopting couple a legal agreement at the beginning of the procedures.

Oxygen-dependent metabolism of intact and activated neutrophil granulocytes of the saliva.

The effects of phorbol-12-myristate-13-acetate on functional activity and viability of neutrophil granulocytes in the saliva of women at various phases of menstrual cycle were studied using NBT-test and method for detection of neutrophil traps in mucosa secretions. The activator increased the number of neutrophil traps and parameters of neutrophil NBT-test.

Electrophoretic finding of bisalbuminemia.

BACKGROUND: Bisalbuminemia or alloalbuminemia is a rare inherited or acquired condition characterized by the presence of two albumin fractions during electrophoretical separation of serum proteins. METHODS: Bisalbuminemia was incidentally detected by agarose gel electrophoresis (AGE) during standard laboratory investigation of a 36-year old female patient, referred to our laboratory with the diagnosis of immune thrombocytopenia. RESULTS: The electrophoregram showed dysproteinemia with the presence of two distinct albumin bands. This initiated testing of other family members - mother, father, and son of the patient. CONCLUSIONS: We report a case of inherited bisalbuminemia in a Bulgarian family with two affected members of four investigated. This is the first report of inherited bisalbuminemia in the Plovdiv region and could be of great interest to laboratory practitioners and clinicians providing some new data on the protein evolution and the clinical approach.

[Prevalence of alleles of polymorphic variants Leu33Pro and Leu66Arg gene ITGB3 among inhabitants of Siberia].

The frequency of the polymorphic variant T196C (Leu33Pro, rs5918) of ITGB3 gene was studied in several groups of inhabitants of Siberia, including pregnant women with reproductive disorders (n = 186), patients with acute coronary syndrome (n = 330), and population control (n = 858). The frequency of the rare PLA2 allele among residents of Tomsk and Kemerovo was 14.7 and 15.0% respectively. There were no differences in the allele and genotype frequencies of polymorphic variant between patients with acute coronary syndrome and the control group (p = 0.925, p = 0.622). The highest frequency of abnormal PLA2 allele (22.1%) and the PLA2/PLA2 genotype (8.8%) was observed among women, who had miscarried, which was significantly different from the frequency of this allele and genotype in the control group (14.7%, p = 0.017; 2.1%, p = 0.0009). Sequencing showed that all samples with the nonspecific band had the polymorphic rs5918 variant and rs36080296 mutations (T216G, Leu66Arg). The frequency of the rs36080296 mutation among the residents of Siberia was 0.51%. Among the women with reproductive disorders, the frequency of rs36080296 was 2.7%, while in the group who suffered from miscarriages, it was 4.4%; this was different from the frequency in the control group (0.08%, p = 0.2 x 10(-6)). The accumulation of mutations was also observed among men with acute coronary syndrome (0.6%), but the differences from the control group (0%) had no statistical significance.

Expression of the skeletal calsequestrin isoform in normal and regenerated skeletal muscles and in the hearts of rats with altered thyroid status.

We have investigated expression of skeletal calsequestrin (CSQ1) and fiber type composition in normal and regenerated fast and slow skeletal muscles and in the left heart ventricles of euthyroid (EU), hypothyroid (HY) and hyperthyroid (TH) adult inbred Lewis strain rats. The CSQ1 level was determined by SDS-PAGE followed by Western blot analysis. CSQ1 gene expression was assessed using reverse transcription and subsequent real time polymerase chain reaction. Muscle regeneration was achieved by intramuscular grafting of either soleus or extensor digitorum longus (EDL) from 3- to 4-week-old rats to either EDL or soleus muscle of 2-month-old rats. The fiber type composition was assessed by a stereological method applied to stained muscle cross sections. We found that the protein and mRNA levels for CSQ1 were highest in the EDL muscle, the relative CSQ1 protein levels in the soleus muscle were two times lower and the transcript levels more than 5 times lower compared to the EDL. In the left heart ventricle, protein isoform and CSQ1 transcript were also present, although at protein level, CSQ1 was hardly detectable. TH status increased and HY status decreased the expression of CSQ1 in the EDL, but its relative levels in the soleus and in the heart did not change. The regenerated soleus transplanted into EDL, as well as EDL transplanted into soleus exhibited protein and mRNA levels of CSQ1 corresponding to the host muscle and not to the graft source. TH status increased the percentages of the fastest 2X/D and 2B fibers at the expense of slow type 1 and fast 2A fibers in the EDL and that of fast 2A fibers in the soleus at the expense of slow type 1 fibers. HY status led to converse fiber type changes. We suggest that the observed changes in CSQ1 levels in TH and HY compared to EU rats can be related to fiber type changes caused by alteration of the thyroid status rather than to the direct effect of thyroid hormones on CSQ1 gene expression.

["Flare up" and modified natural cycle IVF for patients with expected poor response].

UNLABELLED: The aim of this study is to compare the efficiency of the "flare up" protocol (mini-dose GnRH-ag, macro-dose FSH, GnRH-ant, HCG)-gr. A, with a modified natural cycle IVF (GnRH-ant, HCG)-gr. B. RESULTS: In gr. A 140 and in gr. B 17 patients were assessed. The average age is 35.5 in gr. A and 35 years in gr. B. The embryo transfer is realized 48-72 hours after ovarian puncture in 98 cases (70%) in gr. A and 11 cases (64.7%) in gr. B. Clinical pregnancy is registered in 32 cases (22.8% per cycle, 32.6% per transfer) in gr. A and 4 cases (23.5% per cycle, 36.3% per transfer) in gr. B. In gr. A the cancellation rate is 30%-42 cases and in gr. B--35.3%--6 cases. CONCLUSION: The preliminary results indicate that the 2 methods are equal as regards cancellation and success rate. The natural and modified natural cycle IVF have the following advantages: minimization of severe early and late complications and multifetal pregnancies as well as cost-effectiveness and better chance for pregnancy cumulation rate. There is no doubt that the "mild" and natural, resp. modified natural protocols will displace the conventional hyperstimulation regimens.

[Spread and features of chronic and recurrent infectious diseases in patients with primary headache].

AIM: Study of spread and clinical-immunologic features of chronic and recurrent infectious diseases in patients with primary headache. MATERIALS AND METHODS: 158 patients with migraine and 79 patients with tension headache were examined. Diagnostics of chronic and recurrent infectious diseases were carried out by the appropriate specialists according to the current standards. Immunologic studies included evaluation of cellular, humoral, innate immunity, cytokine status parameters. RESULTS: Spread of chronic and recurrent infectious diseases, that were considered as clinical manifestations of secondary immunodeficiency, in patients with primary headache exceeded the spread in the population of the region. In the patients with a combination of cephalgia and infectious pathology a tendency of leucopenia, lymphocyte subpopulation composition disorders, neutrophil functional activity, IgG level decrease, cytokine system imbalance were characteristic. In chronic primary headache course rate of occurrence of infectious diseases and intensity of immune status disorders were higher than in episodic course of these cephalgias. CONCLUSION: Results of these studies suggest a connection between chronic and recurrent infectious diseases within secondary immunodeficiency with primary headache.

[Oocyte and embryo donation and surrogacy. Religious, medico-social, ethical, financial and legal problems].

The authors quote and discuss the postulates of the Orthodox, Jewish, Catholic and Islamic religions towards ART as well as worldwide legislations and standards and the attitude of female students of medicine in Varna. Indications of oocyte and embryo donation and surrogacy are proposed but all kinds or surrogacy should be permitted. The ART legislation and standards in Bulgaria should be thoroughly revised.

Monitoring of the effect of low-intensity laser radiation with constant pulse generation on neutrophil granulocytes in vitro.

We studied the effect of low-intensity laser radiation with constant pulse generation on bactericidal activity of neutrophilic granulocytes, in particular, on their capacity to form extracellular structures, so-called extracellular neutrophil traps. It was found that exposure to low-intensity laser radiation with constant pulse generation enhanced bactericidal activity of neutrophilic granulocytes, which manifested in the increase of the percent of neutrophils forming extracellular neutrophil traps.

[Ovulation induction in high risk IVF patients: GnRH-agonist, diminished dose of urinary or recombinant chorion gonadotropin].

In high risk IVF patients the ovulation triggering was done with agonist (0.2 mg), 1.gr., Pregnyl 5000 IE, 2. and 4.gr., Ovitrelle 0.250 mg, 3.gr., and Pregnyl 10000 IE in the fifth--non-risk group. The protocol of the first and fourth group included antagonist, the second and third group was with short and the fifth group with long agonist protocol. There was no grave OHSS in the first group, one case in each second, third and fourth group and 4 cases in the fifth group, as a whole 7 patients (3.3%). In all of them an abdominal drainage lasting 4 to 30 days was performed and all pregnancies were preserved. The average success rate was 50%, 71.4% in the fourth and 43.1% in the fifth group. A protocol with antagonist and ovulation triggering with agonist or reduced dose ChG in order to diminish OHSS in high risk IVF patients is recommended.

[Role of intercellular adhesion molecule-1 and E-selectin in the pathogenesis of ovarian hyperstimulation syndrome].

OBJECTIVE: To explore the ICAM-1 and E-selectin in patients with OHSS and clarifying its role in pathogenesis of the syndrome. MATERIALS AND METHODS: 20 patients were included in the research and 20 control patients with stimulating ovarian cycle for the purposes of ART, during the period from 01.01.2004 till 01.01.2005 years in the center of ART-MU-Varna and Department of Obstetrics and Gynecology-IVF-ward-MU-Ben-Gurion, Israel. The patients were divided into 3 subgroups according to the degree of OHSS by the classification of Golan- mild, moderate, severe. The method of ELISA was used to record the values of the factors under research. RESULTS: Six patients with severe OHSS, showed increase in the value of the ICAM-1 and somebody of them, showed low level of E-selectin testing in serum and ascitic fluid in comparison with the control group and the rest of the patient with OHSS. CONCLUSION: OHSS is a life-threatening complication in which the main pathophysiology factor is the increased of capillary permeability. ICAM-1 are expressed on human granulosa cells and by the vascular endothelium after the stimulation by inflammatory cytokines and acts as a mediator of the cohesion with the lymphoid cells. E-selectin is produced by the endothelium after cytokine activation. The soluble forms of these molecules are found in serum, follicular fluid during the COH, as well as in ascitic fluid in severe OHSS. In our research adhesion molecules- ICAM-1 are correlated to the OHSS, especially in the severe forms of the syndrome.

[The importance of the sonographic control for a successful embryotransfer after in vitro fertilization]. / Znachenie na ekhografskiia kontrol za uspeshen embriotransfer sled in-vitro fertilizatsiia.

Two groups of patients have been assessed for a period from January 2000 till Mai 2004. In the first group of 222 patients the Embryotransfer was performed without sonographic control. In the second group of 253 patients the transfer was sonographically controlled. The results of the second group - 54,1% pregnancy rate per transfer are statistically better than of the first group - 29,3% pregnancy rate. ET performed under sonographic control improves significantly the results.

[Is there a correlation between the vaginal colonization with group B streptococci and premature deliveries?]. / Ima li zavisimost mezhdu vaginalnata kolonizatsiia sus streptokoki ot grupa B i prezhdevremennite razhdaniia?

The study covered 110 pregnant females during the period from January 1, 2002 till April 30, 2003. Nine females (8.18%) delivered premature newborns. Samples were taken from the posterior vaginal fornix and canalis cervicalis in the 18th and 24th gestational week. The preparations stained after Gram were examined under light microscope. Microbial cultures on blood agar were examined, too. It was established that 18 or 16.36% of all the cases presented with cultures positive for group B streptococci (Str. agalactiae) and Ureaplasma urealythicum. Some other microbial flora representatives such as Chlamydia trachomatis, Neisseria gonorrhoea and Trichomonas vaginalis were additionally identified. The independent colonization with Str. agalactiae prior to the 18th gestational week does not relate to the spontaneous abortions and premature deliveries at all. On the other hand, the colonization with Group B streptococci or their symbiosis with other microorganisms after the 23rd-24th gestational week displays a certain correlation with the premature births.