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Item does not contain fulltext Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum. Over the last years, targeted and clinical exome sequencing in our center has identified 41 CACNA1A variants. Ultimately, variants were considered pathogenic or likely pathogenic in 23 cases, with most phenotypes ranging from episodic or progressive ataxia to more complex ataxia syndromes, as well as intellectual disability and epilepsy. In two cases, the causality of the variant was discarded based on non-segregation or an alternative diagnosis. In the remaining 16 cases, the variant was classified as uncertain, due to lack of opportunities for segregation analysis or uncertain association with a non-classic phenotype. Phenotypic variability and the large number of VUS make CACNA1A a challenging gene for neurogenetic diagnostics. Accessible functional read-outs are clearly needed, especially in cases with a non-classic phenotype.

Zusammenfassung. Intrakranielle atherosklerotische Stenosen sind die häufigste Ursache von ischämischen Hirnschlägen weltweit. Drei Behandlungsverfahren stehen heutzutage für Patienten mit intrakraniellen atherosklerotischen Stenosen zur Verfügung: Das beste konservative Management (bestehend aus Medikamenten, einer optimalen Einstellung vaskulärer Risikofaktoren und einem gesunden Lebensstil), die endovaskuläre Therapie und die chirurgische Therapie. Bei asymptomatischen intrakraniellen atherosklerotischen Stenosen wird aktuell ein bestes konservatives Management empfohlen, ebenso in der Regel bei Patienten mit symptomatischen intrakraniellen atherosklerotischen Stenosen. Ausgewählte Patienten können aber von einer zusätzlichen endovaskulären Therapie profitieren, bspw. wenn sie trotz bestem konservativen Management wiederholte Hirninfarkte im Gefässterritorium der Stenose zeigen. In seltenen Fällen kann auch ein chirurgisches Vorgehen in Frage kommen. Bei Patienten mit symptomatischer extrakranieller atherosklerotischer Karotisstenose konnte wiederholt gezeigt werden, dass die Behandlung mittels Karotisendarterektomie (CEA) ein tieferes Sterblichkeits- und Hirnschlagrisiko aufweist als die Behandlung mittels endovaskulärer Therapie (CAS). Insbesondere bei Patienten im Alter von über 70 Jahren sollte aktuell in der Regel eine CEA dem CAS vorgezogen werden, da das Risiko innerhalb von 30 Tagen nach Behandlung zu versterben oder einen Hirnschlag zu erleiden bei Patienten, welche mit einem CAS behandelt werden praktisch doppelt so hoch liegt, wie bei Patienten, die mittels CEA behandelt werden. Die Studienergebnisse, welche modernisierte Techniken und Devices verwenden, bleiben abzuwarten. Aktuell bleibt es unklar, ob Patienten mit asymptomatischer extrakranieller atherosklerotischer Karotisstenose unter bester konservativer Therapie überhaupt von einer invasiven Therapie im Sinne einer CEA oder eines CAS profitieren.

Iron deficiency is a frequent comorbid condition in patients with chronic heart failure. At the same time, the factors contributing to iron deficiency in these patients are poorly understood.

© 2021 American Society of Human Genetics, EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG., This work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).

[EN] This work aims to study the effect of immersion in a ethanolic food simulant in mechanically recycled poly(lactic acid) (PLAR) and its nanocomposites reinforced with halloysite nanotubes (HNT). PLAR was obtained by subjecting PLA to an accelerated ageing process, which includes photochemical, thermal and hydrothermal ageing steps, followed by a final demanding washing step. PLAR was further reinforced with 4 %wt. HNT to improve the properties of the PLAR films. The materials were melt compounded by melt extrusion and processed into films by compression molding. The resulting films were exposed to food simulant D1 (50 %vol. ethanol solution) for 10 days at 40 °C. The intrinsic viscosity, crystallization behavior, thermal stability as well as the mechanical performance were analyzed before and after the contact with the food simulant. The swelling, plasticizing and hydrolyzing effect of the food simulant led to an important decrease of the intrinsic viscosity of all the samples, along with a significant increase of the crystallinity. Thermal stability was negatively affected by the decrease of the molecular weight, while the high crystallinity values resulted in materials with higher Vickers hardness values after the immersion in the food simulant., This work was supported by European Union’s Horizon 2020 research and innovation program [grant agreement No. 860407 BIO-PLASTICS EUROPE], by MINECO-Spain [project CTM2017-88989-P] as well as Universidad Politécnica de Madrid [project UPM RP 160543006].

Over the past decade, the healthcare system of the Russian Federation has undergone progressive changes in the system of maternity care, which relate to the development of infrastructure and the introduction of new organizational models. In particular, a three-level system of providing medical care to mothers and children has been created, including a network of perinatal centers for patients at high perinatal and obstetric risk. Field events of specialists of National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation to the medical organizations of maternity care in various regions of Russia revealed hot spots that require primary attention: acute shortage of staff for the implementation of diagnostic and therapeutic measures at the modern methodological level, as well as for ensuring epidemiological safety in the medical organizations (medical microbiologists (bacteriologists), clinical pharmacologists and epidemiologists); the lack of registration of healthcare-associated infections, which is associated with the prevailing in the country mainly punitive methods of combating hospital infections. In modern conditions of nursing preterm babies, newborns with various severe somatic and surgical pathologies, it is necessary to know the real indicators of morbidity in order to reasonably and promptly carry out therapeutic and preventive measures; the need to organize modern microbiological laboratories in the perinatal centers with the availability of fast methods (proteomic and molecular-genetic) diagnostics, allowing for microbiological monitoring in specialized departments of newborns and promptly respond to the changes in the epidemiological situation in the hospital, to prevent the development of clinically pronounced cases of healthcare-associated infections.

Introduction. Among the most relevant issues in occupational health is the risk management of the contamination of working air by crystalline silicon dioxide (CSD) in enterprises dealing with its extraction and processing. Cytotoxicity of this silicon type that underlies its fibrogenic action is of particular concern. Thereby, it is an urgent goal to find drugs that increase the body’s resistance to cytotoxic effects of silicon dioxide. Materials and methods. For the study of changes in the cellular composition of the bronchoalveolar lavage (BAL) and some of its biochemical characteristics, a respirable portion of Pervouralsk quartzite (PQ) containing 98% CSD was inserted intratracheally to outbred white female rats in the form of a suspension of 10 mg of PQ in 1 ml of distilled water in the dose of 1 ml. Student’s t-test was applied for statistical analysis of the obtained data. Results. PQ sample induces the alveolar phagocytosis response typical for cytotoxic dust expressed by an increase in the total BAL cell count, the number of both alveolar macrophages (AM) and neutrophilic leukocytes (NL), and particularly the NL/AM ratio (which is a reliable comparative index of cytotoxicity). The administration of «Lymphomyosot» considerably reduced this cytotoxic effect of PQ within one month before the intratracheal injection. It showed a decrease in NL/AM ratio and some biochemical indicators of cytolysis in BAL. Conclusion. There was demonstrated the applicability of «Lymphomyosot» as a precaution against the cytotoxic effect of CSD dust.

BACKGROUND: Iron deficiency is a common comorbidity in many patients with chronic heart failure. AIM: To study the parameters of intracardiac hemodynamics in the patients with chronic heart failure in the presence of iron deficiency. MATERIALS AND METHODS: We examined 179 patients (36 men and 143 women, mean age 71.6 7.9 years) with heart failure of functional class 2-4 (NYHA). All the patients underwent a clinical examination, a 6-minute walk test, a general blood test; the level of NT-proBNP, iron, transferrin, and ferritin in blood serum were studied; the percentage of transferrin saturation with iron was calculated. The presence of iron deficiency was assessed based on a decrease in the level of serum ferritin less than 100 g/L or ferritin ranging from 100 to 299 g/L and saturation of transferrin with iron less than 20%. All the patients underwent echocardiography in one-dimensional, two-dimensional and Doppler modes (pulse-wave, constant-wave and tissue) in standard positions according to the generally accepted technique. RESULTS: It was found that in the patients with chronic heart failure and iron deficiency compared with the patients without iron deficiency; the end systolic volume of the left ventricle, the size of the right ventricle and the systolic pressure in the pulmonary artery were significantly higher, and the speed of movement of the fibrous ring of the mitral and tricuspid valves and the working capacity were lower. Significant correlations were established between the concentration of iron and ferritin and the parameters of intracardiac hemodynamics. CONCLUSIONS: Iron deficiency in the patients with chronic heart failure without anemia contributes to an early initial decrease in cardiac contractility with an intact ejection fraction.

Background: As by-products of copper smelting, lead and cadmium pollute both workplace air at metallurgical plants and adjacent territories. Their increased levels in the human body pose a higher risk of cardiovascular diseases. The objective of our study was evaluate changes in the rat myocardium contractile function following moderate subchronic exposure to soluble lead and/or cadmium salts and its attenuation by means of a complex of bioprotectors. Materials and methods: The subchronic exposure of rats was modelled by intraperitoneal injections of 3-H2O lead acetate and/or 2.5-H2O cadmium chloride in single doses, 6.01 mg of Pb and 0.377 mg of Cd per kg of body weight, respectively, 3 times a week during 6 weeks. The myosin heavy chains isoform ratio was estimated by gel electrophoresis. Biomechanical measurements were performed on isolated multicellular preparations of the myocardium (trabeculae and papillary muscles) from the right ventricle. Results: The subchronic lead exposure slowed down the contraction and relaxation cycle and increased myosin expression towards slowly cycling V3 isomyosins. Cadmium intoxication, on the contrary, shortened the contraction and relaxation cycle and shifted the ratio of isomyosin forms towards rapidly cycling V1. Following the combined exposure to lead and cadmium, some contractile characteristics changed in the direction typical of the effect of lead while others – in that of cadmium. We observed that the metal combination either neutralized or enhanced the isolated damaging effect of each heavy metal. The use of a complex of bioprotectors normalized the myocardial contractility impaired by the exposure to lead and cadmium either partially or completely. Discussion: Despite the changes in myocardial contractility following the subchronic lead and cadmium exposure, the mechanisms of heterometric regulation were maintained. The adverse cardiotoxic effect of the combination of these industrial contaminants may be weakened by administering a complex of bioprotectors.

Sergey N Avdeev,1 Alexander A Vizel,2 Vladimir N Abrosimov3 ,† Andrey A Zaicev,4 Galina L Ignatova,5 Rustem F Khamitov,2 Marina P Mikhaylusova,6 Julia S Shapovalova,7 Elena F Pavlysh,8 Basil I Trofimov,9 Alexander V Emelyanov,10 Tatiana I Martynenko,11 Vladimir A Martynenko,12 Natalia E Kostina,13 Danila A Chizhov,14 Olga Yu Chizhova,10 Natalia A Kuzubova,15 Elena V Makova,16 Ekaterina V Makarova17,18 1I.M. Sechenov First Moscow State Medical University, Moscow, Russia; 2Kazan State Medical University, Kazan, Russia; 3Ryazan State Medical University Named After Academician I.P. Pavlov, Ryazan, Russia; 4The Main Military Clinical Hospital Named After Academician N.N. Burdenko, Moscow, Russia; 5Regional Clinical Hospital No. 4, Chelyabinsk, Russia; 6Pirogov Russian National Research Medical University, Moscow, Russia; 7Chelyabinsk Road Clinical Hospital “Russian Railways”, Chelyabinsk, Russia; 8Nikiforov’s All-Russian Center for Emergency and Radiation Medicine of the Emergencies, St. Petersburg, Russia; 9I.P. Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia; 10North-Western State Medical University Named After I.I. Mechnikov, St. Petersburg, Russia; 11Regional State City Hospital No. 5, Barnaul, Russia; 12Regional State Clinical Hospital, Barnaul, Russia; 13Voronezh Regional Clinical Hospital No. 1, Voronezh, Russia; 14St. Petersburg State City Polyclinic No. 106, St. Petersburg, Russia; 15St. Petersburg State Vvedenskaya City Clinical Hospital, St. Petersburg, Russia; 16State Samara City Hospital No. 4, Samara, Russia; 17Privolzhsky Research Medical University, Nizhny Novgorod, Russia; 18State City Clinical Hospital No. 10, Nizhny Novgorod, Russia†Professor Vladimir Abrosimov passed away on January 22, 2019Correspondence: Sergey N AvdeevI.M. Sechenov First Moscow State Medical University, 8– 2, Trubetskaya St., Moscow, 119991, RussiaTel +7-495-465-74-15Fax +7-495-465-52-64Email serg_avdeev@list.ruBackground: Chronic cough declines quality of life and increases risk of complications in patients with chronic obstructive pulmonary disease (COPD). Reducing cough severity and associated negative effects is important therapeutic goal in COPD. Rengalin with anti- and protussive activity is based on technologically processed antibodies to bradykinin, histamine and morphine.Aim: To evaluate efficacy and safety of Rengalin in treatment of cough in patients with COPD.Methods: Patients (n=238, mean age 64.3± 8.2 years) with stable COPD and persistent cough despite maintenance therapy (anticholinergics, beta-2-adrenergic agonists, inhaled corticosteroids) were included and randomized in the study. The severity of cough assessment (according to the “Cough Severity Score”), COPD impact on patient’s life (COPD Assessment Test, CAT), and spirometry were performed at screening. Patients took Rengalin or Placebo 2 tablets 2 times daily for 4 weeks. The endpoints were proportion of patients who responded to treatment, dynamics of cough severity, and severity of COPD symptoms. Intention-to-treat (per protocol) analysis was performed.Results: Positive response to Rengalin was recorded in 83.6 [85.7]% (vs 72.6 [72.7]% in Placebo group, p=0.0422 [p=0.0163]). Double decrease of cough severity was reported in 42.2 [43.8]% in Rengalin group (versus 32.7 [32.7]% in Placebo; p=0.1373 [p=0.0907]). The total CAT score decreased by 3.3± 4.2 [3.6± 3.9] points (versus 2.5± 4.1 [2.5± 4.2] in Placebo group); the difference between groups was 0.79± 4.16 [1.04± 4.02] points (p=0.0870 [p=0.0416]). The number of patients with adverse events (AEs) in Rengalin (n=13) and Placebo (n=12) groups did not have significant differences (p=1.00). No AEs with certain relationship with study drug were registered.Conclusion: Rengalin is an effective and safe drug in patients with stable COPD and persistent cough, despite stable doses of maintenance therapy according to the GOLD guidelines. Four-week therapy decreases severity of cough by two times in more than 40% of patients.Trial Registration: ClinicalTrials.gov (id: NCT03159091).Keywords: cough, cough management, chronic obstructive pulmonary disease, treatment, Rengalin

Background: In 2020, the pandemic caused by novel coronavirus infection has become one of the most critical global health challenges during the past century. The lack of a vaccine, as the most effective way to control the novel infection, has prompted the development of a large number of preventive products by the scientific community. We have developed a candidate vaccine (EpiVacCorona) against novel coronavirus infection caused by SARS-CoV-2 that is based on chemically synthesized peptides conjugated to a carrier protein and adsorbed on aluminum hydroxide and studied the specific activity of the developed vaccine. Aims: Study of the immunogenicity and protectivity of the peptide candidate vaccine EpiVacCorona. Materials and methods: the work was performed using standard molecular biological, virological and histological methods. Results: It was demonstrated that EpiVacCorona, when administered twice, spaced 14 days apart, to hamsters, ferrets, and non-human primates (African green monkeys, rhesus macaques) at a dose of 260 g, which is equal to one inoculation dose for humans, induces virus-specific antibodies in 100% of the animals. Experiments in hamsters showed this vaccine to be associated with the dose-dependent immunogenicity. The vaccine was shown to accelerate the elimination of the virus from the upper respiratory tract in ferrets and prevent the development of pneumonia in hamsters and non-human primates following a respiratory challenge with novel coronavirus. Conclusions: The results of a preclinical specific activity study indicate that the use of EpiVacCorona has the potential for human vaccination.

Vaccination of the population is one of the most effective countermeasures in responding to the pandemic caused by novel coronavirus infection. Therefore, scientists all over the world have been working to develop effective and safe vaccines. We have developed a synthetic peptide vaccine, EpiVacCorona, against novel SARS-CoV-2 coronavirus, which is a suspension for intramuscular administration containing a composition of chemically synthesized peptide immunogens of the S protein of SARS-CoV-2 coronavirus conjugated to a carrier protein and adsorbed on aluminum hydroxide. Phase I–II clinical trials of the vaccine have started that consist of two stages: Stage 1 is an open study of the safety, reactogenicity, and immunological activity of the vaccine with the involvement of 14 volunteers aged 18–30 years; Stage 2 is a single blind, comparative, randomized placebo-controlled study with the involvement of 86 volunteers. The study involved volunteers aged 18–60 years; the vaccine was injected intramuscularly twice, spaced 21 days apart between injections. All local reactions in response to vaccine administration were mild, such as a short-term pain at the injection site. There were no signs of development of local or systemic adverse reactions. The two-dose vaccination scheme induced the production of antibodies, specific to the antigens that make up the vaccine, in 100% of the volunteers. Seroconversion with a neutralizing antibody titer ≥ 1:20 was reported in 100% of the volunteers 21 days following the second immunization dose. No seroconversion was reported in the groups of volunteers vaccinated with a placebo. The peptide-based EpiVacCorona Vaccine has low reactogenicity and is a safe, immunogenic product. Clinical Trials Identifier: NCT04527575.

Introduction. Non-ferrous smelters are one of the critical nanoscale cadmium particles sources in the workplace and ambient air. Materials and methods. The research was performed to evaluate the subchronic toxicity of cadmium oxide nanoparticles (CdO-NPs) in white outbred rats. Male outbred 3.5-month old rats received intraperitoneal injections of CdO-NPs 3 times a week for six weeks (18 in total) in doses of 0.25 mg/kg body mass. After the end of an exposure, there were rated more than 50 indices of universally accepted toxicity criteria (including biochemical and cytomorphometric). Student’s t-test was used for statistical analysis. Results. The hematotoxic effects of CdO-NPs were revealed by a decrease in the hemoglobin content, an increase in the number of reticulocytes, eosinophils, and monocytes. CdO NPs influenced porphyrin metabolism (an increase of δ-aminolevulinic acid in the urine). Liver toxicity resulted in an increase in organ mass and a decrease in albumin content and A/G index. Besides, there was observed a rise in γ-glutamyl transpeptidase and high-density lipoproteins in the blood serum. Oxidative stress level increased (decrease in catalase action and ceruloplasmin content). Endothelin-1 decreased. It may result from an observed decrease in blood pressure indices (statistically significant for mean B.P.). Conclusion. The intoxication of moderate severity was retrieved at the end of the subchronic exposure to cadmium oxide nanoparticles. It characterized mass, hematological, biochemical, and cytomophometric changes. There was found mild but evident cardiovascular toxicity of cadmium oxide nanoparticles.

The article presents data on the toxicological properties of the disinfectant, which includes alkyldimethylammonium propyl ketone chloride, glutaraldehyde, glyoxal. Based on the results of a series of experiments, the main parameters of the toxicity of the disinfectant were determined. For male mice, the acute toxicity LD50 was 325±14.5 mg / kg, for male rats – 350±50 mg/kg, according to the classification of GOST 12.1.007-76, the agent belongs to the 3rd hazard class. The LD50 with repeated administration of the drug was 217±13.5 mg/kg of animal weight, the cumulation coefficient was 0.67, which indicates the ability of the drug with repeated intragastric administration to accumulate in the body of animals.

Introduction. With the advent of the paradigm of heterogeneity of the bacterial population, attention has been drawn to the phenotype of dormant cells, the active generation of which occurs when adverse environmental conditions of microorganisms appear. These cells are characterized by metabolic and reproductive dormancy, as well as antibiotic resistance. However, upon the occurrence of favorable living conditions, they are able to germinate again and cause an exacerbation of infectious diseases. In recent years, a threatening decrease in the effectiveness of antimicrobial therapy and an increase in the incidence of persistent, chronic and hospital infections have been associated with these phenotypes of pathogenic bacteria. Given the key role of fatty acid (FA) in the adaptation of bacteria, the aim of this study was to identify the specific features of changes in the fatty acid composition of gram-negative bacteria from the Enterobacteriaceae family during their long-term storage under extreme conditions and the formation of dormant (uncultured) subpopulations of cell forms.Materials and methods. Static cultures of following reference strains were used in the study: Yersinia pseudotuberculosis, Salmonella enterica Typhimurium, and Escherichia coli, stored under vaseline oil at 4-8°С for 5-10 years. Dormant cell forms were obtained by removing the oil layer and collecting the microbial mass. The ultrastructural features of the dormant cell forms were confirmed by transmission electron microscopy. The viability of dormant cells was assessed by a molecular genetic method. The lack of reproductive activity of dormant forms was checked by repeated inoculations on LB broth, Endo and Serov media and incubation at 4-6°C, 22-24°C, and 37°С. Methyl esters of total FAs were obtained according to the procedure approved by the European Committee for Standardization and recommended by the Sherlock MIS protocol. Analysis of fatty acid methyl esters was carried out by gas chromatography in combination with mass spectrometry. After preliminary homogenization of the bacterial masses, lipids were extracted, and FA spectra were obtained by electron impact at 70 eVResults. It was demonstrated that phenotypic uncultured generation of dormant cells is formed under extreme conditions (low temperature, nutrient deficiency, hypoxia) in populations of E. coli, Y. pseudotuberculosis and S. Typhimurium. A comparative analysis of changes in the fatty acid spectrum in the dormant phenotype revealed certain features compared to vegetative cells associated with a decrease in the unsaturation index and the dominance of long-chain saturated FAs (C14-C18).Conclusion. The biological significance of the observed transformations is apparently associated with the special role of these FA fractions in the reversible formation of dormant (uncultivated) cell phenotype and as an alternative source of carbohydrates in a metabolically inactive state, as well as their subsequent reversal to vegetative cells upon favorable living conditions.

The aim of this study was to identify predictors of high psychosocial functioning in patients with bipolar disorder (BD). One hundred forty-five outpatients with BD and 50 healthy controls were included. Patients were categorized as having high psychosocial functioning if they concomitantly met three conditions: a) General Assessment of Functioning greater than 90, b) full-time employment, and c) full functional recovery. Clinical, demographical, and neurocognitive variables were assessed and considered as potential predictors of high functioning in regression models. We found that 22.8% (n = 33) of patients exhibited high psychosocial functioning. BD type II, higher educational level, and better performance in verbal memory, attention, and executive functions were independent predictors of high psychosocial functioning. Our results provide evidence that functional outcomes are heterogeneous in BD, including a percentage of patients who maintain good to excellent psychosocial functioning despite their illness. Neurocognitive functioning could be one of the most influential factors to explain this heterogeneity.

OBJECTIVES Caregivers are at risk of poor sleep and elevated distress during their child's cancer treatment. Russia is currently underrepresented in the international psycho-oncology field, with no identified psychosocial standards of care, and limited or inconsistent psychological service provision, particularly for caregivers. This study aimed to determine the prevalence of Russian caregivers' psychological distress and identify factors associated with caregiver sleep duration when staying on the pediatric oncology ward. METHODS We recruited 74 caregivers of children with cancer and 74 comparison caregivers in Rostov-on-Don, Russia. Participants completed a survey assessing clinical outcomes, sleep (St Mary's Hospital Sleep Questionnaire), and psychological distress (Depression Anxiety Stress Scales-21 [DASS-21]). RESULTS Caregivers of children with cancer reported significantly higher scores for all DASS-21 subscales and higher depression (48.6% vs. 24.6%), anxiety (47.3% vs. 12.3%), and stress (45.9% vs. 0%) scores from "moderate" to "extremely severe." Caregivers of children with cancer reported significantly shorter sleep duration (5.82 vs. 7.49 h, t[143] = -6.22, p = 0.002), more night-time awakenings (3.20 vs. 1.25, t[135] = 6.94, p < 0.001) and worse sleep quality (46.5% vs. 9.6%; x2 [1] = 24.4, p < 0.001) than comparison caregivers. Caregivers with a higher total DASS-21 score (B = -1.32, p = 0.032) and those who were closer to diagnosis (B = -1.53, p = 0.012) reported shorter sleep duration. CONCLUSIONS Russian caregivers of children with cancer experience high rates of psychological distress and poor sleep on the oncology ward. These findings provide an important target for future research and culturally relevant clinical interventions to improve caregivers' mental health and capacity for care.

Although melancholic depression has been associated with a more adequate premorbid personality style, the empirical evidence supporting this statement is inconclusive. We conducted a systematic review and meta-analyzed studies comparing the presence of personality disturbances in melancholic and nonmelancholic subtypes of major depressive disorder (MDD). We defined a) a continuous outcome, defining personality traits as a dimensional construct, and b) a dichotomous outcome, defined as the presence/absence of personality disorders (PD). We also evaluated the role of potential moderators. Our results showed significantly higher levels of neuroticism and interpersonal sensitivity, and a higher likelihood of presenting a PD in nonmelancholic depression. No significant differences were found for extraversion. The scarcity of studies and high heterogeneity were among our limitations. In conclusion, personality disturbances seem to be overrepresented in nonmelancholic MDD. The assessment of personality disturbances can be useful in clinical practice and in the study of MDD heterogeneity.

Lead-cadmium intoxication is an occupational risk factor for copper-smelting industry workers. People inhabiting the areas near the copper plants are also at risk. Subchronic intoxication was modeled by repeated intraperitoneal injections of lead acetate and cadmium chloride both in isolation and in combination, 3 times a week for 6 weeks. A heart rate decrease in animals with Cd intoxication and a blood flow velocity decrease in those with Pb intoxication have been found. The impact of Pb and Cd on blood pressure proved to be contra-directional. ECG analysis revealed a prolonged duration of QRS in Cd intoxication, a prolonged QT interval and a baseline lowering in Pb+Cd intoxication. A variety of changes has been found with respect to the diameter of cardiomyocytes and the thickness of aortic wall layers in Pb and/or Cd intoxication. Any toxic exposure resulted in the decrease in number of nuclei per unit area of myocardium histological preparation.

We earlier discovered a new reaction in the chemistry of organoaluminum compounds (OACs), specifically, the formation of O-isobutyl acetals on low-temperature (–70°C) treatment of seven-membered lactones with a double (or more) molar amount of diisobutylaluminum hydride (DIBAH) in methylene chloride. To assess the boundaries for the formation of isobutyl acetals depending on the ring size, we involved in the low-temperature hydride reduction six-, eight-, and thirteen-membered lactones. To determine how the scope of the new reaction depends on the nature of the organoaluminum reagent, we tested triisobutylaluminum (TIBA). To determine how the formation of isobutyl acetals on low-temperature (–70°C) reduction with excess DIBAH in CH2Cl2 depends on whether the starting ester is cyclic or acyclic and, if the former is the case, on the ring size in the ester, we used the acyclic methyl octadecanoate as the starting compound. It was found that the new reaction in the chemistry of AOC with DIBAH as the reducer is characteristic only of seven-membered lactones and atypical of acyclic methyl octadecanoate and ricinoleate (i.e. acids with the carbon chain length more than 6).

The reviewed book is a posthumously published work of the outstanding British sociologist Z. Bauman, whose title reflects the phenomenon of the state of modern society-nostalgia for the past. The author notes that behind Z. Bauman's pessimistic sentiments is his desire to develop strategies for mankind to find possible ways to move into the future, connected with the hope of change.

Recent molecular discoveries have refined vascular bone tumor classification. To investigate the clinical relevance of these refinements, we reviewed all cases of primary vascular bone tumors treated at our Institute. On the basis of morphology, cases were assessed immunohistochemically and molecularly. A total of 427 cases of primary vascular tumor of bone with available follow-up and histologic material were retrieved and reclassified according to the most recent diagnostic criteria as follows: 289 hemangiomas, 38 epithelioid hemangiomas, 21 epithelioid hemangioendotheliomas, 2 retiform hemangioendotheliomas, 1 intraosseous papillary intralymphatic angioendothelioma, 24 pseudomyogenic hemangioendotheliomas, and 52 angiosarcomas (of these, 45 were epithelioid angiosarcomas and 7 spindle cell secondary angiosarcoma). Both epithelioid and classic hemangiomas behave as benign tumors with excellent prognosis. The distinction between cellular and conventional type of epithelioid hemangioma was not associated with a different clinical course. Conversely, epithelioid hemangioendothelioma exhibited a more aggressive clinical behavior than hemangioma, with higher rates of multifocality and distant spread. Immunohistochemical positivity for CAMTA1 or TFE3 did not have a prognostic implication. In epithelioid hemangioendothelioma, the presence of morphologic malignant features was associated with reduced disease-free (P=0.064) and overall survival (P=0.055). Pseudomyogenic hemangioendothelioma featured local aggressiveness in 5/24 patients exhibiting a clinical behavior closer to epithelioid hemangioma than epithelioid hemangioendothelioma. Last, 32/45 patients with epithelioid angiosarcoma died of disease with a median survival time of 10 months from diagnosis. In conclusion, the integration of morphologic, immunohistochemical, and molecular features allows a better stratification of primary vascular tumors of bone with significant prognostic and therapeutic implications.

// Marina P. Antoch 1 , Michelle Wrobel 2 , Bryan Gillard 1 , Karen K. Kuropatwinski 1 , Ilia Toshkov 2 , Anatoli S. Gleiberman 2 , Ellen Karasik 1 , Michael T. Moser 1 , Barbara A. Foster 1 , Ekaterina L. Andrianova 2 , Olga V. Chernova 2 and Andrei V. Gudkov 3 1 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 2 Everon Biosciences, Inc., Buffalo, NY, USA 3 Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA Correspondence to: Marina P. Antoch, email: marina.antoch@roswellpark.org Keywords: prostate cancer; rapamycin; prevention; mTOR; PTEN Received: February 21, 2020 Accepted: March 14, 2020 Published: April 14, 2020 ABSTRACT The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epithelium-specific Pten -knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug’s tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention.

Introduction. There is a high chance of a link between cardiovascular conditions and occupational or environmental exposure to lead. Taking into account the peculiarities of lead intoxication and the metal common occurrence it appeared to necessarily prove further experimental research of lead cardiotoxicity. Material and methods. After repeated intraperitoneal administration of sublethal doses of lead acetate to outbred male rats 3 times a week for 5 weeks, there was obtained the moderately pronounced subchronic lead intoxication manifested by some characteristic features. Cardiotoxic effects on myocardial contractility were studied by the analysis of the mechanical activity of isolated preparations of right ventricular trabeculae and papillary muscles contracting in isotonic and physiological modes of loading. Myocardial contractile function was also studied at the molecular level by measuring the sliding velocity of reconstructed thin filaments over myosin. Results. In papillary muscles lead intoxication led to a decrease in the maximal rate of isotonic shortening for all afterloads and a decrease in the thin filament sliding velocity in the in vitro motility assay. The same type of muscle from lead-exposed rats displayed marked changes in most of the main characteristics of afterload contraction-relaxation cycles, but in trabeculae, these changes were less pronounced. The reported changes were attenuated to some extent in rats similarly exposed to lead while being treated with a Ca-containing bio protector. The amount of work produced by both muscle preparations was unchanged under lead intoxication over the entire range of afterloads, which is an evidence of adaptation to the production of adequate mechanical work despite resulting contractility disturbances. Conclusions. 1. Subchronic lead intoxication was shown to cause contractile dysfunction of rat myocardium. In papillary muscles the alterations were observed more than in trabeculae. The changes in contractile proteins corresponded with those seen in myocardium structures. 2. The reported changes were attenuated to some extent in rats being treated with a Ca-containing bio protector.

Atopic dermatitis the multifactorial disease of skin which is characterized by an itch, the recurrent course, age features of localization and morphology of the centers of defeat. Today, a significant increase in the incidence of atopic dermatitis and, at the same time, its course is worsening. Exacerbation of the disease is a stressful situation, in order to cope with which it is necessary to form protective-coping behavior. Results of a research of features protective coping behavior of patients with the diagnosis Atopic dermatitis taking into account the sex are given in article of authors. All examinees have the lichenoid form of atopic dermatitis, the beginning of a disease was at early childrens age; the symptomatology of a disease is shown seasonally, or at influence of stressful factors. Frequency of exacerbation of a disease 34 times a year, hospitalization in connection with a disease 12 times a year. All examinees are registered in Dermatovenerologic clinics; on a question whether stirs this diagnosis in everyday life, answer in the affirmative. On the basis of the analysis of the received results authors allocated targets of psychological correction: non-adaptive coping behavior, low level of adaptation opportunities (personal adaptation potential, behavioral regulation, communicative potential). The authors developed a program of psychological correction of patients with atopic dermatitis, which can later be included in the system of integrated approach to prevention, treatment and rehabilitation of this of patients.

Earlier, we discovered a novel reaction in the chemistry of organoaluminum compounds - the formation of O-isobutyl acetals during low-temperature (-70 °С) treatment of a number of seven-membered lactones with a twofold (or more) molar amount of diisobutylaluminium hydride in methylene chloride. In addition, it was shown that the acyclic derivatives of (-)-mentholactone - methyl 6-hydroxy-3,7-dimethyl-octanoate and its 6-oxo analogue - also enter into the low-temperature reduction reaction of diisobutylaluminum hydride in methylene chloride. Moreover, methyl 6-hydroxy-3,7-dimethyloctanoate in this reaction behaves similarly to (-)-mentholactone: when 4 equivalents of diisobutylaluminium hydride acts on it, the reaction proceeds with the predominant formation of isobutyl acetal as the only (2S,7S)-epimer. Methyl 6-oxo-3,7-dimethyl octanoate in a low-temperature reduction reaction with 4 equivalents of diisobutylaluminium hydride in methylene chloride acts as a mixture of (-)-mentholactone and isomentolactone, leading to a mixture of (2S,7S)-, (2S,7R)- and (2R,7R)-isobutyl acetals in a ratio of 3.2: 1.3: 1.0, respectively. In the present work, when low-temperature reduction was involved in the reaction with diisobutylaluminium hydride, methyl (3R)-6-hydroxy- or (3R)-6-oxo-3-isopropylheptanoates available from carvomentolactone reacted without the formation of isobutyl acetal: a mixture of (2: 1) 6-hydroxy-(3R)-isopropylheptanal and (4R)-isopropyl-7-methyloxepan-2-ol was obtained.

The main direction of improving the quality of medical care for pregnant women, mothers and newborns is to improve the diagnosis and prevention of inflammatory infections, including healthcare-associated infections (HAI). A huge number of types of causative agents of opportunistic infections in women and newborns significantly complicates the etiological diagnosis and timely, adequate treatment at all stages of medical care. Recently, we have seen the emergence and spread of multi-resistant strains: bacteria from the ESKAPE-pathogens group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeroginosa, Enterobacter cloacae); as well as coagulase-negative staphylococci and yeasts, which easily realize their pathogenic potential for immunocompromised patients. The changed epidemiological situation requires the creation and functioning of a local system of surveillance of opportunistic infections in obstetrics and neonatology, primarily for the HAI, which will quickly monitor changes occurring in the etiological, intraspecific, strain structure of pathogens and respond to them in a timely manner. The evolution of technologies in microbiology allows introducing new approaches to the diagnosis, prevention and treatment of infections. Active use of modern methods of etiological diagnostics, development and application of innovative antimicrobial drugs in combination with coordinated work of physicians, microbiologists, clinical pharmacologists, epidemiologists and specialists in the field of molecular biology and bioinformatics is the key to the formation of new opportunities for epidemiological surveillance and prevention of infections in childbirth.