Synthesis, biological activity and molecular modelling studies of tricyclic alkylimidazo-, pyrimido- and diazepinopurinediones

Syntheses and biological activities of imidazo-, pyrimido- and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3-chloropropyl)- or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f]purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A1 and A2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i = 0.28 μM) with fivefold A2A selectivity and the non-selective A1/A2A AR ligand pyrimidopurinedione 35 (K i A1 = 0.28 μM and K i A2A = 0.30 μM). The compounds were also evaluated for their affinity at human A1, A2A, A2B and A3 ARs. All of the obtained compounds were docked to the A2A AR X-ray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido- and diazepino[2,1-f]purinediones with the residues forming the A2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds

Lung transplantation in patients with pulmonary arterial hypertension: The opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation

Pulmonary arterial hypertension is a rare but progressive disease that leads to death. Modern drug treatment slows the progression of the disease and prolongs patients’ lives, but often, even maximal treatment with parenteral prostacyclin does not prevent deterioration. In the case of inadequate clinical response to drug treatment, lung transplantation (LTx) should be considered. This article aims to analyze thoroughly indications to refer a patient for consultation with a transplant center, the optimal timing of listing for LTx, contraindications for the procedure, bridging techniques, as well as tests needed before and after transplantation. We outline the technique of the procedurę and evaluate psychological aspects of LTx

One-step immunopurification and lectinochemical characterization of the Duffy atypical chemokine receptor from human erythrocytes

Duffy antigen/receptor for chemokines (DARC) is a glycosylated seven-transmembrane protein acting as a blood group antigen, a chemokine binding protein and a receptor for Plasmodium vivax malaria parasite. It is present on erythrocytes and endothelial cells of postcapillary venules. The N-terminal extracellular domain of the Duffy glycoprotein carries Fya/Fyb blood group antigens and Fy6 linear epitope recognized by monoclonal antibodies. Previously, we have shown that recombinant Duffy protein expressed in K562 cells has three N-linked oligosaccharide chains, which are mainly of complex-type. Here we report a one-step purification method of Duffy protein from human erythrocytes. DARC was extracted from erythrocyte membranes in the presence of 1% n-dodecyl-β-D-maltoside (DDM) and 0.05% cholesteryl hemisuccinate (CHS) and purified by affinity chromatography using immobilized anti-Fy6 2C3 mouse monoclonal antibody. Duffy glycoprotein was eluted from the column with synthetic DFEDVWN peptide containing epitope for 2C3 monoclonal antibody. In this single-step immunoaffinity purification method we obtained highly purified DARC, which migrates in SDS-polyacrylamide gel as a major diffuse band corresponding to a molecular mass of 40–47 kDa. In ELISA purified Duffy glycoprotein binds anti-Duffy antibodies recognizing epitopes located on distinct regions of the molecule. Results of circular dichroism measurement indicate that purified DARC has a high content of α-helical secondary structure typical for chemokine receptors. Analysis of DARC glycans performed by means of lectin blotting and glycosidase digestion suggests that native Duffy N-glycans are mostly triantennary complex-type, terminated with α2-3- and α2-6-linked sialic acid residues with bisecting GlcNAc and α1-6-linked fucose at the core

Safety and ergonomics in the work of long-term care nurses

Celem badań było poznanie warunków pracy, a w szczególności zagrożeń podczas prac wykonywanych przez personel pielęgniarski w stacjonarnych zakładach opieki długoterminowej. W badaniach wykorzystano anonimowe kwestionariusze, które zostały wypełnione przez 95 (84%) pielęgniarek pracujących w siedmiu placówkach opieki długoterminowej. Kwestionariusz zawierał pytania, które dotyczyły procesu pracy, warunków pracy, wyposażenia, obciążenia pracą, zagrożeń, ciężkości wykonywanej pracy oraz dolegliwości odczuwanych w trakcie realizacji świadczeń. W opinii pielęgniarek praca w opiece długoterminowej jest bardzo ciężka. Największymi zagrożeniami i uciążliwościami w ich pracy są: duże obciążenie fizyczne (prace związane z ręcznym podnoszeniem i przemieszczaniem pacjentów) i duże obciążenie psychiczne (związane ze stanem zdrowia pacjentów, agresją pacjentów, trudnością w porozumiewaniu się z nimi). Zebrane dane wskazują, że ponad 90% pielęgniarek w zakładach opieki długoterminowej zgłasza dolegliwości związane z wykonywaną pracą (ból kręgosłupa 97%, ból pleców 78%, ból kończyn górnych 77%, ból kończyn dolnych 66%, ból głowy 45%, ból mięśni 28%, pieczenie powiek 18%, swędzące zmiany skórne 17%, zawroty głowy 15%, ból brzucha 13%).The aim of the study was to identify working conditions, of nursing staff in the stationary long-term care facilities with special reference to occupational hazards. An anonymous questionnaire was used as a major tool of this study, which was filled out by 95 (84%) of nurses working in 7 long-term care facilities. The questionnaire contained questions concerning the work process, working conditions, equipment, workload, hazards, work arduousness and work-related complaints. Long-term care nurses generally assessed their work as very hard. In the nurses’ opinion the greatest hazards and arduousness at their work are: demanding physical load (tasks related to manual lifting and moving around of patients); demanding mental load (related to patients’ health status, patients’ aggression, difficulty in communications with patients). The collected data indicate that more than 90% of the nurses in long-term care facilities report the work-related complaints (spine pain—97%, back pain—78%, arm pains—77%, leg pains—66%, headache—45%, muscular pain—28%, eye-lids burning—18%, itching dermal lesions—17%, dizziness—15%, abdominal pain—13%)

A Retrospective Cross-Sectional Study on the Risk of Getting Sick with COVID-19, the Course of the Disease, and the Impact of the National Vaccination Program against SARS-CoV-2 on Vaccination among Health Professionals in Poland

Six months after starting the National Vaccination Program against COVID-19, a cross-sectional retrospective study was conducted among 1200 salaried and non-salaried healthcare workers (HCWs) in Poland. Its aim was to assess factors including the risk of exposure to COVID-19, experiences with COVID-19, the trust in different sources of knowledge about the pandemic and SARS-CoV-2 vaccines, and the government campaign on vaccination as predictors of vaccination acceptance. The strongest awareness of a high risk of work-associated infection was demonstrated by doctors (D) (72.6%) and nurses and midwives (N) (64.8%); however, almost half of the medical students (MS) and nursing and midwifery students (NS) did not identify as a risk group. Out of several dozen variables related to sociodemographic characteristics and personal experience of COVID-19, only occupation, previous COVID-19 infection, and high stress seemed to significantly influence vaccination acceptance. Interestingly, only 6.7% of respondents admitted that the government campaign impacted their decision to vaccinate. This result is not surprising considering that the vast majority of respondents (87.8%) learned about vaccinations from sources such as academic lectures (29.9%), health professionals (29.0%), or the internet (28.9%). Those who gained information about vaccination from traditional media (radio, television, and daily press), a popular platform of the government campaign, had a lower propensity to vaccinate (OR = 0.16, p < 0.001). Additionally, almost twice as many considered the information provided in the campaign to be unreliable. Our findings, from this retrospective study, do not confirm that the government campaign was effective for healthcare professionals. Therefore, in this group, other forms of vaccination incentives should be sought. However, the vaccinated respondents were significantly more likely to support compulsory vaccination against COVID-19 among health professionals

Pre-Vaccination Stress, Post-Vaccination Adverse Reactions, and Attitudes towards Vaccination after Receiving the COVID-19 Vaccine among Health Care Workers

The vaccines against COVID-19 are the best treatment for limiting the spread of the epidemic, and from an individual point of view, for avoiding getting sick. A cross-sectional retrospective survey was conducted from 15 May to 15 July 2021 among healthcare workers, including doctors, nurses, midwives, and students at the Medical University of Lodz (nursing, midwifery and medical students) in Poland. Data were obtained from 1080 participants. The aim of the study was to evaluate vaccination coverage against COVID-19 among healthcare workers (HCWs) in Poland, and to analyze their attitude towards the available vaccines, stress before taking, and side effects after administrating them, and motivation towards continuing vaccination in the future (if necessary). The survey also estimated the frequency and quality of adverse post-vaccination reactions after two doses of BioNTech/Pfizer and two doses of AstraZeneca vaccines. The present study revealed that the vaccination ratio after 6 months from the start of vaccination against COVID-19 in Poland among HCWs was very high at 91.2%. However, doctors and medical students were more likely to be vaccinated than nurses and midwives, and nursing and midwifery students (94.8%, 98.3% vs. 78.9% and 86.3%, respectively). The main reasons that HCWs reported receiving a vaccination were to protect the health of themselves and their families, while the main reasons for avoiding a vaccination were fear of side effects, doubts about effectiveness, and an expedited clinical trial process of vaccines. Furthermore, more than two-thirds of those vaccinated reported side effects after receiving at least one dose of the vaccine. Most of the side effects were short-term symptoms with only slight and moderate intensification. The univariate and multivariate logistic regressions showed that the type of vaccine used had a significant impact on the occurrence of adverse post-vaccination effects and the severity and duration of vaccination symptoms. In addition, chronic disease and fear of vaccination also had some influence. Despite this, most participants (more often older than younger participants; p < 0.001) were in favor of compulsory vaccination against COVID-19 for HCWs