Synthesis of N-heterocyclic amides based on (+)-camphoric acid and study of their antiviral activity and pharmacokinetics.

Efficient conditions for the synthesis of nitrogen-containing heterocyclic derivatives of (1R,3S)(+)-camphoric acid were selected. A series of heterocyclic compounds based on (+)-camphoric acid bearing pharmacophoric fragments was synthesized using the developed methodology. The compounds were tested for their antiviral activity against SARS-CoV-2 and H1N1 influenza viruses, and efficient inhibitors were identified that are of significant interest for further studies. The stability of the compounds and pharmaco-kinetics of the leader compound were studied when administered intragastrically and intramuscularly to mice at a dose of 200 mg kg-1 using the HPLC-MS/MS method.

Hereditary breast cancer: syndromes, tumour pathology and molecular testing.

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes - TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz-Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low-penetrance breast cancer susceptibility alleles, is also a well-recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype-phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.

[Long-term treatment for multiple sclerosis with interferon beta-1b. Outcomes of an open, retrospective, observational study]. / Dolgosrochnaya terapiya rasseyannogo skleroza interferonom beta-1b. Rezul'taty retrospektivnogo otkrytogo nablyudatel'nogo issledovaniya.

OBJECTIVE: To assess the outcomes of long-term treatment in multiple sclerosis (MS) patients with Infibeta (interferon beta-1b). MATERIAL AND METHODS: The article presents the results a real-world, multicenter, retrospective, observational study of treatment with interferon beta-1b. We enrolled 332 patients with MS who had been receiving Infibeta for at least 8 years. 60.2% of them had a relapsing-remitting MS (RRMS). 73.2% patients received only interferon beta-1b that was initial DMT. RESULTS: During the first year of the treatment, 66% of the patients reported no relapses regardless of the MS type. No relapses in the 8th year of treatment were observed in 86.9% of patients with RRMS and 77.7% with secondary progressive MS (SPMS). The median number of relapses during the whole follow-up period in RRMS patients was 1. The time to first relapse in the subgroup of patients who received interferon beta as the first treatment was longer compared to other treatment (median 4 and 2, respectively, p=0.0017). 42% of patients with RRMS remained progression-free during 8 years of follow-up. The flu-like syndrome was observed in 61.7% for the first year of treatment; in 36.3% it was periodically and was mild in 71.3%. CONCLUSION: The study outcomes confirm a high clinical response to the long-term treatment with Infibeta in patients with RRMS and SPMS and demonstrate that interferon beta-1b is one an optimal option for the initial treatment of patients with moderate disease activity.

Molecular Profile of Sensitization to Dermatophagoides pteronyssinus Dust Mite in Portugal

Objective: To analyze component-resolved diagnosis of sensitization to Dermatophagoides pteronyssinus (Der p) in patients with respiratory allergy and the association between diagnostic findings and clinical severity in different geographical areas.Methods: The study population comprised 217 patients (mean age, 25.85 [12.7] years; 51.16% female) selected from 13 centers in Portugal (5 from the North, n=65). All had allergic rhinitis with or without asthma and positive skin prick test results to at least 1 dust mite. Specific IgE (sIgE) to Der p, Dermatophagoides farinae, Lepidoglyphus destructor, Der p 1, Der p 2, Der p 10, and Der p 23 was determined using ImmunoCAP. The Mann-Whitney test was applied for the following comparisons: rhinitis vs rhinitis and asthma; mild vs moderate-to-severe rhinitis; North vs South.Results: The prevalence of sensitization was 98.2% for Der p, and 72.4%, 89.4%, 9.7%, and 77% for Der p 1, Der p 2, Der p 10, and Der p 23, respectively. The corresponding median sIgE levels were 8.56, 17.7, 0.01, and 3.95 kUA/L. sIgE to all allergens was higher in patients with moderate-to-severe rhinitis and rhinitis with asthma (nonsignficant). Concentrations of sIgE to Der p 2 were significantly higher in the South than in the North (P=.0496).Conclusions: The most common sensitization in Portugal was to Der p. The highest prevalence and median sIgE level were observed for Der p 2. All sIgE values for molecular components were higher in more symptomatic patients (nonsignificant). Concentrations of sIgE to Der p 2 were higher in the South, probably because of the warmer temperature and/or the larger sample size (AU)

Objetivo: Analizar el diagnóstico por componentes para Dermatophagoides pteronyssinus (Der p) en pacientes con alergia respiratoria ysu relación con la gravedad clínica en diferentes áreas geográficas.Métodos: Se incluyeron 217 pacientes (edad media 25,85±12,7 años; 51,16% mujeres), seleccionados de 13 centros en Portugal (5 delNorte, n = 65). Todos tenían rinitis alérgica, con o sin asma, y tenían pruebas positivas en prick a al menos un ácaro del polvo. La IgEespecífica (sIgE) para Der p, Dermatophagoides farinae, Lepidoglyphus destructor, Der p 1, Der p 2, Der p 10 y Der p 23 se determinaronpor ImmunoCAP. El análisis estadístico (prueba U de Mann Whitney) comparó pacientes con rinitis frente a rinitis y asma; rinitis leve frentea moderada-grave; Norte frente a Sur.Resultados: La prevalencia de sensibilización fue del 98,2% para Der p, y del 72,4%, 89,4%, 9,7% y 77% para Der p 1, Der p 2, Der p 10y Der p 23, respectivamente. Las medianas de sIgE fueron de 8,56, 17,7, 0,01 y 3,95 kUA/ L. Las medianas de sIgE de todos los alérgenosfue mayor en pacientes con rinitis de moderada a grave y rinitis con asma, pero no estadísticamente significativo (NSS). El valor de Der p2 fue significativamente mayor en el Sur en comparación con el Norte (p = 0,0496).Conclusiones: La sensibilización a Der p es la más común en Portugal. Der p 2 tuvo la prevalencia más alta y los niveles medios más altos.Todos los componentes moleculares fueron mayores en pacientes más sintomáticos (NSS). El valor de Der p 2 fue mayor en el Sur, lo quepuede estar relacionado con la temperatura más cálida y/o el tamaño de muestra más grande (AU)

The first observation of osmotically neutral sodium accumulation in the myocardial interstitium.

The aim of this study was the detection and quantification of the Na+ depositions in the extracellular matrix of myocardial tissue, which are suggested to be bound by negatively charged glycosaminoglycan (GAG) structures. The presented experimental results are based on high resolution X-ray fluorescence (XRF) spectromicroscopy technique used to perform a comparative analysis of sodium containment in intracellular and interstitial spaces of cardiac tissues taken from animals selected by low and high sodium intake rates. The experimental results obtained show that high sodium daily intake can result in a remarkable increase of sodium content in the myocardial interstitium.

Molecular Profile of Sensitization to Dermatophagoides pteronyssinus Dust Mite in Portugal.

BACKGROUND AND OBJECTIVES: To analyze component-resolved diagnosis of sensitization to Dermatophagoides pteronyssinus (Der p) in patients with respiratory allergy and the association between diagnostic findings and clinical severity in different geographical areas. METHODS: The study population comprised 217 patients (mean age, 25.85 [12.7] years; 51.16% female) selected from 13 centers in Portugal (5 from the North, n=65). All had allergic rhinitis with or without asthma and positive skin prick test results to at least 1 dust mite. Specific IgE (sIgE) to Der p, Dermatophagoides farinae, Lepidoglyphus destructor, Der p 1, Der p 2, Der p 10, and Der p 23 was determined using ImmunoCAP. The Mann-Whitney test was applied for the following comparisons: rhinitis vs rhinitis and asthma; mild vs moderate-to-severe rhinitis; North vs South. RESULTS: The prevalence of sensitization was 98.2% for Der p, and 72.4%, 89.4%, 9.7%, and 77% for Der p 1, Der p 2, Der p 10, and Der p 23, respectively. The corresponding median sIgE levels were 8.56, 17.7, 0.01, and 3.95 kUA/L. sIgE to all allergens was higher in patients with moderate-to-severe rhinitis and rhinitis with asthma (nonsignficant). Concentrations of sIgE to Der p 2 were significantly higher in the South than in the North (P=.0496). CONCLUSION: The most common sensitization in Portugal was to Der p. The highest prevalence and median sIgE level were observed for Der p 2. All sIgE values for molecular components were higher in more symptomatic patients (nonsignificant). Concentrations of sIgE to Der p 2 were higher in the South, probably because of the warmer temperature and/or the larger sample size.

[Risk Assessment of Development of the Major Adverse Cardiac Events in Patients with Chronic Heart Failure with a Preserved and Intermediate Ejection Fraction in the Presence of a Bendopnea Symptom].

Aim To evaluate the risk of major cardiovascular complications (CVC) in patients with chronic heart failure (CHF) with intermediate and preserved ejection fraction (EF) depending on the presence of bendopnea symptom.Material and methods The study included 104 patients with stage II CHF and left ventricular EF ≥40 %. Mean age of the patients was 72.8±10.6 years. A test for detection of bendopnea symptom was performed for all patients. Two groups were formed: group 1, 69 patients with the bendopnea symptom and group 2, 35 patients with a negative test. Follow-up duration was 24 months. The composite endpoint (CEP) was death and hospitalization for any CVC.Results Mean time to the bendopnea symptom was 17.3±6.61 s. At two years of follow-up, the CEP was observed in 36 (34.6 %) patients, including 30 (43.5 %) patients in group 1 and 6 (17.1 %) patients in group 2. 12 patients died, and 9 of them had the bendopnea symptom. 21 patients of group 1 were hospitalized for CVC. Risk of CEP was significantly 1.7 times higher for men (relative risk, RR 1.7 [1.1; 2.6]) than for women. The presence of bendopnea symptom increased the risk of CEP 1.4 times (ОР 1.4 [1.1;1.9]) for women and 2.3 times (RR 2.3 [1.4; 3.6]) for men.Conclusion Results of the study demonstrated an unfavorable effect of bendopnea symptom on risk of CEP during the two-year follow-up of CHF patients with preserved and intermediate EF.

Atopic Dermatitis Host and Environment Model: Revisiting Therapeutic Options.

Summary: Atopic Dermatitis affects both children and adults and is a serious health concern in many countries. AD is a complex disease with host and environmental factors underlying its pathology. Its treatment is multidimensional reflecting the diverse nature of its triggers and includes emollients, topical steroids and calcineurin inhibitors among others. Immunological dysfunction can be addressed broadly with systemic immunosupressors and specifically with monoclonal antibodies. Dupilumab, which targets IL-4 and IL-13 was granted approval for treatment of moderate-to-severe AD. Biologics targeting IgE/Th2 pathways may have its role in patients with overlapping AD and asthma. Psychological distress can exacerbate symptoms and is associated with increased severity of AD. Environmental triggers, such as, allergens can be addressed in selected cases with allergic immunotherapy. In this paper, we discuss AD treatment and propose a new step-by-step approach aiming at maintaining disease control and improving quality of life.

[Prevention of thromboembolic and hemorrhagic events in patients with atrial fibrillation undergoing elective surgery]. / Profilaktika tromboémbolicheskikh i gemorragicheskikh oslozhnenii u patsientov s fibrilliatsiei predserdii pri provedenii planovogo khirurgicheskogo lecheniia.

OBJECTIVE: To compare incidence of thromboembolic and hemorrhagic complications in patients with atrial fibrillation (AF) undergoing elective surgery on different schemes of perioperative anticoagulant therapy (ACT). MATERIAL AND METHODS: There were 86 patients (56 (65.1%) men and 30 (34.9%) women, mean age was 69 (64; 78) years) with non-valvular AF who underwent elective interventions. Forty (46.5%) patients underwent abdominal surgery, 34 (39.5%) - cardiovascular procedures, 12 (14.0%) patients underwent surgery for malignant diseases. We have analyzed incidence of thromboembolic and hemorrhagic events and compliance of perioperative ACT modes with current international guidelines. RESULTS: Thromboembolic and hemorrhagic events developed in 14 (16.3%) patients. Thromboembolic complications were noted in 6 (7.0%) patients, hemorrhagic events - in 8 (9.3%) cases. Maximum complication rate was observed in case of bridge-therapy (n=12, 20.0%). Cancellation of ACT was followed by 2 (9.5%) complications, bridge-therapy - by 4 (6.7%) thromboembolic complications. Hemorrhagic events were 2 times more common in case of this therapy (n=8, 13.3%). It was found that ESC guidelines for perioperative ACT were applied in less than half of patients (41, 47.7% patients with AF undergoing elective surgery). Half of complications (8 out of 16) occurred if unapproved modes of ACT were used (including 7 cases of bridge-therapy was not necessary). The causes of these complications were inadequate assessment of perioperative risk of thromboembolic and hemorrhagic events; unreasonable administration of bridge therapy. CONCLUSION: An unambiguous clinical effect of bridge therapy has not been confirmed in patients with high risk of thromboembolic complications. Cancer patients have higher risk of complications compared with others. These events occur mainly due to non-compliance with clinical guidelines and insufficient prevention of thromboembolic events.

[Quality of life in patients with heart failure with preserved ejection fraction and the bendopnea symptom].

PURPOSE: The study of quality of life (QOL) in patients with CHF with preserved LVEF (left ventricular ejection fraction) and a symptom of bendopnea with different levels of salt intake. Materials and methods. The study included 66 patients. The main symptoms of CHF were edema in 54.5% of cases, dyspnea in 77% of cases, ascites was detected in only 2 patients, an enlarged liver in 7 patients. Abdominal obesity was detected in 53 patients. Quality of life was assessed by the SF­36 questionnaire, the level of salt intake was assessed by the Charlton: SaltScreener questionnaire. Results. On average, the time of occurrence of the bendopnea was 22.5±9.3 seconds, the minimum was 5 seconds. The absence of the effect of abdominal obesity on the risk of bendopnea (relative risk 1.18 [0.76; 1.83]) was revealed. According to the SF­36 questionnaire, a decrease in physical health indicators (median 31.3 points [20.7; 42.3]) and psychological health (average score 43.2±21.7) was found. In patients with bendopnea, QOL was reduced due to both physical and mental health, unlike patients without bendopnea: physical functioning (Physical Functioning - PF) 24.8±16.1 against 47±28.9 points, p=0.001 ; role­based functioning due to physical condition (Role­Physical Functioning - RP), 0 [0; 25] vs. 37.5 [0; 100] points, p=0.008; general health (General Health - GH) 29.9±15.8 against 50±14.2 points, p=0.0005, social functioning (Social Functioning - SF) 56 ± 38 against 78.9 ± 17.8 points ; p = 0.004. Multidimensional regression analysis revealed the relationship between the time of occurrence of the symptom bendopnea and the level of salt intake, physical and psychological activity (r2=0.25; p<0.009). The time of onset of the symptom of bendopnea in patients with CHF decompensation was significantly longer (18.9±8.7 vs. 26.2±8.5 seconds, p=0.003). The presence of diseases such as hypertension, COPD, IHD, atrial fibrillation, cerebrovascular disease did not significantly affect QOL (p> 0.05), while the presence of bronchial asthma or chronic kidney disease significantly reduced QOL of patients (p<0.05). Conclusion. The presence of the symptom bendopnea significantly reduces the quality of life of patients with CHF with preserved LVEF (left ventricular ejection fraction).

Energy-resolved neutron imaging options at a small angle neutron scattering instrument at the Australian Center for Neutron Scattering.

Energy-resolved neutron imaging experiments conducted on the Small Angle Neutron Scattering (SANS) instrument, Bilby, demonstrate how the capabilities of this instrument can be enhanced by a relatively simple addition of a compact neutron counting detector. Together with possible SANS sample surveying and location of the region of interest, this instrument is attractive for many imaging applications. In particular, the combination of the cold spectrum of the neutron beam and its pulsed nature enables unique non-destructive studies of the internal structure for samples that are opaque to other more traditional techniques. In addition to conventional white beam neutron radiography, we conducted energy-resolved imaging experiments capable of resolving features related to microstructure in crystalline materials with a spatial resolution down to ∼0.1 mm. The optimized settings for the beamline configuration were determined for the imaging modality, where the compromise between the beam intensity and the achievable spatial resolution is of key concern.

[Personalized approach for direct oral anticoagulant prescription: from theory to practice].

Data on possibilities of personalized approach for direct oral anticoagulants (DOAC) choice in patients with atrial fibrillation are presented in the article. We also review clinical and fundamental studies and future perspectives on pharmacogenetic and pharmacokinetic tests to predict the efficacy and safety of DOAC.

[Correlations of IL-18 and IL-6 with sodium consumption in patients with arterial hypertension and diabetes mellitus].

AIM: To determine correlations of AH-associated interleukins (IL-18, IL-6) with sodium consumption in AH patients with and without DM. MATERIALS AND METHODS: The study included AH patients with and without DM (n=63) who were managed at the Municipal Clinic #64, Moscow Department of Health Care, Branch 1. Plasma levels of IL-6 and IL-18 were measured using ELISA kits (Bender Med-Systems). Salt consumption was determined using a Charlton: SaltScreener questionnaire. Statistical analyses were performed using the Statistica 10.0 software. RESULTS: Four groups were formed: Group 1, grade 2 AH and DM (n=19); Group 2, grade 2 AH and no DM (n=4); Group 3, grade 3 AH and no DM (n=28); and Group 4, grade 3 AH and DM (n=12). Group 2 was small and was excluded from further analysis due to impossibility of statistical treatment. All patients consumed more than 6 g of salt per day (approximately 10 g). Analysis of intergroup differences in selected parameters showed differences between groups in levels of cholesterol, triglycerides, LDL, and GFR. The following correlations were identified in the groups: Group 1, positive correlation of IL-18 with sodium consumption (r=0.65) and CRP level (r=0.52) and of IL-6 with LDL level (r=0.48); Group 3, positive correlation of IL-18 with IL-6 (r=0.66) and of IL-6 with CRP (r=0.52); Group 4, positive correlation of IL-18 with GFR (r=0.82) and of IL-6 with waist circumference (WC) (r=0.84) and IL-6 (r=0.73). CONCLUSION: Patients consuming more than 6 g of salt daily (approximately 10 g) with AH and DM had more pronounced inflammation, which promoted progression of kidney disease.

[Direct oral anticoagulants in atrial fibrillation patients aged 75 years or older: Efficacy and safety balance]. / Priamye peroral'nye antikoagulianty u patsientov s fibrilliatsiei predserdii v vozraste 75 let i starshe: balans éffektivnosti i bezopasnosti.

Atrial fibrillation (AF) is one of the most common heart rhythm disorders in the population. Researchers revealed a direct relationship between their incidence and a patient's age long ago. One of the most challenging issues of clinical practice in patients with AF is anticoagulant therapy used in the so-called very elderly patients aged 75 years and older when age itself is a risk factor for developing both thromboembolic and hemorrhagic events due to anticoagulants, regardless of the mechanism of action of the latter. However, scientific data regarding the treatment and prevention of thromboembolic events in elderly and senile patients with AF are very scarce and often uninformative. The data from the EURObservational Research Programme-Atrial Fibrillation Registry Pilot Phase (EORP-AF Pilot) and the randomized clinical studies RELY, ROCKET AF, ARISTOTLE, and AVERROES were analyzed to identify the most safe and most effective anticoagulant for elderly patients (over 75 years). Relying on the analyses of literature data, the authors propose an algorithm based on clinical characteristics for choosing the anticoagulant for patients older than 75 years.

[The effect of the level of total sodium deposited in the myocardium on its stiffness]. / Vliianie urovnia obshchego natriia, deponirovannogo v miokarde, na ego zhestkost'.

AIM: To determine a relationship between the level of total sodium in the myocardium to its stiffness. SUBJECTS AND METHODS: The investigation enrolled 18 hypertensive patients who had suddenly died; their mean age was 40±10 years; mean waist circumference, 102±12.5 cm; height, 170±7.7 cm; myocardial mass, 319±53 g. RESULTS: The variation in the myocardial level of total sodium averaged 211.7±37.5 (min, 71.5; max, 226.17) mmol/l. The sodium level was ascertained to be affected to the greatest extent by myocardial mass (SS=3615.56; p=0.00029) and age at death (SS=1965.568; p=0.0029), whereas gender and smoking had a considerably lower impact (SS=778.584; p=0.03). A univariate regression analysis showed that there was a relationship between myocardial sodium levels and the thickness of the anterior wall of the left ventricle (ß=0.94; p=0.000001; r2=0.88), that of the anterior wall of the right ventricle (ß=0.82; p=0.000021; r2=0.66), and that of the interventricular septum (ß=0.94; p=0.000001; r2=0.89). The wall thickness of the myocardium was established to depend on its sodium level (SS=21813.89; p=0.000001; r2=0.88): the higher sodium amount in the myocardium, the thicker its walls. The average velocity of acoustic wave propagation was 6.24±0.51 m/sec. A significant correlation was observed between sodium concentrations in the myocardium and its stiffness (ß=0.72; p=0.00062; r2=0.49). CONCLUSION: The level of sodium deposited in the myocardium, which is directly related to dietary sodium intake, is significantly correlated with myocardial stiffness. It can be assumed that the elevated level of sodium deposited in the myocardium is an independent factor that changes the stiffness of the myocardium and appears to influence the development of its diastolic dysfunction.

The Mayak Worker Dosimetry System-2013: Treatment of Organ Masses in the Calculation of Organ Doses.

Previous Mayak worker epidemiological studies designed to quantify the risk of cancer following exposure to airborne plutonium have calculated organ doses by dividing the organ-absorbed energy by the individual's estimated organ mass. For living workers, this was done by using a relationship between organ mass and total mass and height. For autopsy cases, this was measured directly. In the Mayak Worker Dosimetry System-2013 study, organ doses are calculated by dividing this energy by a population average organ mass. The reasons for departing from previous methodologies are described in this note. The average organ masses that were used in the final analysis are tabulated for males and females.

[Factors associated with levels of interleukins -18, -8, and -6 in hypertensive patients at high and very high cardiovascular risk].

AIM: To identify the most significant factor influencing blood levels of cytokines in patients at high and very high cardiovascular risk. MATERIALS AND METHODS: A patient base from the "Management of chronic patients with multiple diseases" project was analyzed. 523 patients (mean age, 87±17.8) were included. Plasma samples were analyzed for concentrations of sodium, creatinine, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, and NT-proBNP. GFR was calculated using the CKD-EPI formula. Time-related CHF progression was assessed in one year; the time-related progression was considered an increase in CHF stage. Salt consumption was determined using the Charlton: SaltScreener questionnaire at the baseline visit and at one year. Low-salt diet containing 5 g of salt per day was recommended to all patients; 3.5 g of salt per day was recommended to patients with a documented diagnosis of CHF. Statistical analysis was performed using the Statistica 10.0 software. RESULTS: 52.2 % of included patients consumed 6-10 g of salt per day; 43.4 % of patients consumed 10 g of salt or more per day; and only 4.4 % of patients consumed 5 g of salt or less per day. 21 % of included patients were at high risk of cardiovascular complications whereas for the vast majority of patients (79 %), the risk was stratified as very high. Two clusters of patients were formed based on the grade of hypertension, one-year CHF progression, and plasma levels of IL-6, -8, and -18. The one-year progression of CHF most significantly influenced the levels of IL-18, -8, and -6. The IL-6 level was correlated with the NT-proBNP level; an approximately similar degree of correlation was found for NT-proBNP and BP. CONCLUSION: Therefore, the performed statistical analysis determined correlations between the following factors: IL-6 level, NTproBNP level, and one-year CHF progression.