[The awareness of primary health care physicians about methods of evaluation of risks of stroke].

The assessment of prevalence of acute cerebral circulation disorders in persons with arterial hypertension, together with study of awareness of primary health care physicians about methods of assessing risk of stroke, allows to judge effectiveness of measures preventing acute cerebral circulation disorders and to outline further ways preventing cerebrovascular complications of hypertension.The purpose of study was to investigate morbidity of acute cerebral circulation disorders and awareness of primary care physicians about clinical and instrumental methods assessing risk of stroke in persons with arterial hypertension.Materials and methods included official statistical materials on morbidity of intracerebral bleeding and cerebral infarction in population of Russia, the Chelyabinsk Oblast in 2008-2020, totals of survey of internists and emergency physicians in six regions of Russia.It was established that morbidity of intracerebral bleeding and cerebral infarction in 2008-2020 in the Chelyabinsk Oblast has not changed, while morbidity of intracerebral bleeding and brain infarction in Russia significantly (p.

Validation and development of MTH1 inhibitors for treatment of cancer.

BACKGROUND: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. MATERIAL AND METHODS: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. RESULTS: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. CONCLUSION: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.

[Diagnosis, Prognosis, Monitoring of Cardiac Complications of Arterial Hypertension. Hypertensive Heart Disease].

AIM: of the study was further investigation of diagnostics and management of cardiac complications of essential hypertension (EH). METHODS: Retrospective analysis of annual reports of cardiological departments for 10 year period was carried out. Internists (n=330) from 6 regions of Russia participated in the study. Anonymous questioning was used for the study of physicians views on diagnosis, prognostication of outcomes, and monitoring of hypertensive heart disease (HHD). Responses were compared with information from practical clinical recommendations. RESULTS AND CONCLUSIONS: Clinicians were poorly informed about nosology, echocardiographic criteria of diagnosis of HHD. They did not use prognostication of development of cardiac arrhythmias caused by hypertension. Large portion of participants (39.09%) was not aware of possibilities of drug therapy of HHD. About 1/3 of physicians could not select appropriate indications for echocardiographic examination of patients with EH. One third of participating physicians did not know EH induced echocardiographic changes. These results stress the importance of creation of a complex method of ambulatory monitoring of EH complications. Such method is suggested in this paper.

[Ways to improve diagnosis and surgical treatment for pathology of brachiocephalic arteries].

UNLABELLED: Over 2010-2013 we anonymously interrogated a total of 397 therapeutists of municipal polyclinics of six regions of Russia (Chelyabinsk, Kurgan, Sverdlovsk, Orenburg, and Saratov Regions and the Republic of Bashkortostan), studying their awareness of the indications and AIM: of ultrasound examination of brachiocephalic arteries (US BCA) in patients presenting with arterial hypertension (AH) and revealing the physicians' attitude to carrying out surgical prevention of stroke in hypertensive patients. As the indications for USS BCA 35 (8.82%) of physicians reported symptoms of local cerebrovascular lesions, mentioning: "complaints of unilateral weakness in the extremities" (n=18), "complaints of speech impairments disorders" (n=2), "complaints of loss of fields of vision" (n=4), "endured TIA" (n=11). A total of 261 (65.74%) respondents considered the grounds for US BCA to be as non-specific cerebrovascular symptoms (isolated dizziness, headache, disequilibrium, syncope). 242 (60.96%) physicians with the purpose of examining asymptomatic hypertensive patients mentioned the type and character of a vascular lesion: 16 (4.03%) - "determining the intima media thickness"; (22 (5.4%) - "an atherosclerotic plaque"; 100 (25.18%) - "arterial stenoses/occlusions". 155 (39.04%) interrogated physicians failed to determine the AIM: of ultrasonic duplex scanning of major arteries of the head. 256 (64.65%) physicians answered that they do not recommend their hypertensive patients with AH to undergo surgical prevention of ischaemic stroke. The obtained findings reflect poor awareness of physicians of the primary medical care (PMC) on diagnostic criteria for cerebrovascular diseases (CVDs). The revealed problems concerning follow up of CVDs would help decide upon publication and active distribution of All-Russian guidelines for primary care physicians (therapeutists, cardiologists, neurologists, functionalinsts) on selection patients for BCA USS and angiosurgical interventions. A draft of the informational letter "Indications for BCA ultrasound examination" is attached to the article.

[Awareness of physicians about the causes of heart failure in hypertensive patients].

We studied awareness of physicians of the city health clinics (polyclinics) about the causes of heart failure in hypertensive patients and their attitude to the prevention of complications of hypertension. The study involved 194 general practitioners from five regions of Russia. The questionnaire method in the form of single-blind questionnaire survey was used. It was found that 36.6% (95% confidence interval [DI] from 29.81 to 43.80) of respondents were aware of the cause-effect relation between hypertension and heart failure. Only 31.44% (95% DI from 24.98 to 38.48) medical professionals perceived left ventricular hypertrophy as risk factor for heart failure in people with high blood pressure. The percentage of internists-respondents who were aware of the major mechanisms of heart failure in hypertension was 28.37% (95% DI from 21.18 to 4.16]. Outdated or incorrect professional notions can become a barrier to early diagnosis, treatment and prevention of heart failure in patients with hypertension.

[Direct incorporation of 18O isotopes into peptides and proteins for quantative analysis by mass spectrometry method].

The method of direct introduction 18O isotopes in peptides and proteins carboxylic groups through the exchange with H218O in the presence of TFA is shown. The isotope label is steady enough in awide range of pH. Because the labeled compounds retain their physical and chemical characteristics, they can be used as an internal standard in quantitative determination of authentic compounds in the analyzed sites by mass spectrometry methods. The technique may be applicable for quantitative analysis of peptides and proteins in biological environments, for quantitative study of the kinetics of metabolism and enzymatic activity. For polypeptides and proteins the quantitative analysis is combined with trypsinolysis. If necessary, the isotope label may be introduced simultaneously in all peptides and proteins control bioassays, making it suitable for use as a standard for the comparative analysis of experimental bioassays.

[Analysing causes of low efficacy of ultrasonographic diagnosis of stenosing major arteries of the head in hypertensive patients].

The authors analyse herein the reasonable use of ultrasonographic methods of examination of carotid arteries for diagnosis of stenosing pathology in hypertensive patients. At the stage of primary medical care of the city of Chelyabinsk, a non-selective referral of patients presenting with elevated arterial pressure to duplex ultrasonography of the carotid artery is not uncommon. Doubtful criteria of selecting the hypertensive patients who really require undergoing ultrasonography of the carotid artery result in low efficacy of the examination.

[Barriers to prevention of cerebrovascular complications of hypertension].

An analysis of well-established aspects of stroke prevention is presented. The authors present results of the questionnaire survey of 286 primary care physicians of six regions of Russia (Chelyabinsk, Kurgan, Orenburg, Saratov, Sverdlovsk Oblasts and the Republic of Bashkortostan). Most of respondents (71.68%, 95% CI: 66.08-76.83) have reported that ischemic stroke often develops due to vasospasm and / or reduction of the cerebral blood flow during systemic hypotension; 91.26% (95% CI: 87.37-94.26) of surveyed physicians use vasodilators and metabolic agents for prevention of stroke and 67.48% (95% CI: 61.72-72.88) administer treatment similar to that used after a transient ischemic attack. Approximately half of the physicians prefers maintaining the normal blood pressure in elderly as a preventive measure of the first and second stroke events.