Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia.

Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a common phenomenon of JAK2 hyperactivation. JAK2 has the potential to activate multiple other signaling molecules, either directly through downstream effectors, or indirectly through induction of target gene expression. We have interrogated myeloproliferative signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) patient samples using mass cytometry, which allows the quantitative measurement of multiple signaling molecules simultaneously at the single-cell level, in cell populations representing a nearly complete spectrum of hematopoiesis. MF and sAML malignant cells demonstrated a high prevalence of hyperactivation of the JAK-STAT, MAP kinase, PI3 kinase and NFκB signaling pathways. Constitutive NFκB signaling was evident across MF and sAML patients. A supporting gene set enrichment analysis (GSEA) of MF showed many NFκB target genes to be expressed above normal levels in MF patient CD34+ cells. NFκB inhibition suppressed colony formation from MF CD34+ cells. This study indicates that NFκB signaling contributes to human myeloproliferative disease and is abnormally activated in MF and sAML.

[Changes in lipid and carbohydrate metabolism in patients with severe sepsis of different etiology].

UNLABELLED: Different origin (heterogeneity) of sepsis is a key stone in many discussions regarding options for the course and outcome, despite the general rules of development of the pathogenic mechanisms. PURPOSE OF THE STUDY: To compare data of systemic inflammation (CRP, PCT, IL-8, IL-6, IL-4, TNF-alpha) and markers of endothelial dysfunction (NO, lactate, D-dimers), also lipid (cholesterol, triglycerides, HDL, LDL, VLDL) and carbohydrate metabolism between the two groups of patients with severe intra-abdominal infection (n = 109) and severe sepsis of other etiologies (n = 53). RESULTS: We found out a significant difference between the groups in serum levels of the CRP, IL-4 and cholesterol at all stages of the study. During severe abdominal sepsis was accompanied by a significantly higher level of cholesterol, LDL and VLDL, as well as higher values of glycaemia. Patients with sepsis other etiology showed a lighter and more dynamic course of the disease was significantly lower 28-day mortality.

[Perinatal anaesthesia risk scale and prognosis of perinatal results during cesarean section].

UNLABELLED: The article presents analysis of informative importance of the scales estimating the somatic status and surgical and anaesthesiology risk: American Society of Anesthesiologists (ASA), Moscow Scientific Society of Anaesthesiology and Resuscitation (MSSAR) and Anaesthesiology Perinatal Risk (APR). Reliably high correlation between APR scale and blood loss, pregnancy term, Apgar score assessment, newborn body weight is shown in the article. Information importance of APR scale, its sensitivity, specificity and efficiency concerning perinatal results reliably authentically exceeded ASA and MSSAR scales. CONCLUSION: Use of the APR scale in maternity clinics and perinatal centers will allow to optimize preoperative assessment before Cesarean section, and reliably predict perinatal outcomes.

[Characteristics of septic shock in obstetrics].

Peculiarities of septic shock in obstetrics are considered in this article. Traits of pregnant woman organism concerning infectious process, etiology and risk factors, modern criteria of heavy sepsis diagnosis and septic shock are discussed. It is pointed out that septic process system manifestations considerably outstrips local manifestations of purulent process in a uterus and it is necessary to take into account modern markers and criteria when making decision on initial infection center sanitization. The modern protocol of septic shock initial intensive therapy where are defined not only modern methods of treatment, but also time of their implementation, and the basic principles of pyosepsis caused maternity mortality decrease.

[Changes in lipid metabolic parameters in patients with severe sepsis].

The vital importance of systemic inflammatory reactions in developing a critical condition of any etiology is generally accepted at the present developmental stage of reanimatology and intensive care. The metabolic component remains a less studied part of a complex of the universal pathophysiological changes that characterize a critical condition. Lipid metabolic changes in sepsis are less investigated. Some publications indicate a role of fatty acids in regulating a systemic inflammatory reaction and in maintaining the balance of pro- and anti-inflammatory reactions in the development of a systemic inflammatory reaction. Others show their role in endothelial damage. The latter are of great interest due to the fact that lipolysis occurs just on the endothelium with the involvement of lipases. The purpose of this study was to reveal lipid metabolic changes and to define an association between the lipid metabolic parameters and the severity of a systemic inflammatory reaction in patients with severe sepsis, as well as their possible impact on the outcome of the critical condition.

[Effect of various colloidal solutions on pulmonary oxygenizing function in patients with acute lung lesion].

The effects of 6% hydroxyethyl starch and 10% albumin solution on the parameters of central hemodynamics and pulmonary extravascular water were studied in acute lung lesion. The patients were divided into 2 groups that did not significantly differ by the baseline severity of a condition (APACHE II and Murray scales). Groups 1 and 2 patients were transfused 6% hydroxyethyl starch and 10% albumin solution, respectively. The "PICCO PLUS" system was used to determine the parameters of central hemodynamics, pulmonary extravascular water, and oxygenation before and after infusion of the test colloidal solutions. Unlike 10% albumin solution, 6% hydroxyethyl starch was found to significantly increase preload parameters, without deteriorating pulmonary oxygenizing function due to the accumulation of extravascular liquid.

[Nutritional support in critical conditions as intensive care technology].

The patients of intensive care units represent a group in which nutritional support methods, such as enteral and parenteral feeding, are most frequently used to correct protein and energy metabolisms. The purpose of this paper is to analyze the most significant clinical problems ensuing in nutritional support in an intensive care unit, such as the high incidence of hospital exhaustion, difficulties in metabolic monitoring and in the determination of patients' needs for nutrients, in the choice for media for intravenous and enteral feeding, in the prevention of possible complications of nutritional support; organizational aspects.

G proteins, beta-adrenoreceptors and beta-adrenergic responsiveness in immature and adult rat ventricular myocardium: influence of neonatal hypo- and hyperthyroidism.

Thyroid hormones influence a wide range of physiological responses and the heart is considered a major target organ for triiodothyronine action. In the present study we examined closely the presumed relationship between altered thyroid status in the newborn rat and maturation of the regulatory components of the myocardial hormone-sensitive adenylyl cyclase signaling system. Beta -adrenoceptors and the alpha subunits of the stimulatory (Gs) as well as inhibitory (Gi) G proteins were determined in ventricular myocardium of immature (21-day-old) hypo- or hyperthyroid rats and in adult (84-day-old) previously hypo- or hyperthyroid rats. The changes in receptor and G protein levels were correlated with basic parameters of cardiac function and inotropic responsiveness to isoproterenol. All results were compared with those obtained in age-matched controls. Hypothyroidism in immature rats was associated with markedly reduced myocardial beta-adrenoceptor density, lower content of the long isoform (Gsalpha-L) of the stimulatory G protein and increased amounts of Gialpha2 and Gialpha3. These changes were accompanied by substantially diminished sensitivity to the inotropic effect of isoproterenol. On the other hand, no change in beta-adrenoceptor number, an increased level of Gsalpha-L and decreased levels of Gialpha2 were found in hyperthyroid myocardium. Cardiac inotropic responsiveness to isoproterenol in immature hyperthyroid rats was not significantly altered. In adult hearts of previously hyper- or hypothyroid rats, beta-adrenoceptor density was decreased but G protein levels as well as functional response were comparable to those determined in control animals. It may be concluded that physiological level of thyroid hormones is an important modulator of the normal maturation of the beta-adrenergic system in the developing rat ventricular myocardium. In adult rats previously affected by altered thyroid status, the function of their myocardial beta-adrenergic signaling appears to be compensated despite a lower number of the receptors.

A theoretical study of outermost skin layer electroporation.

Two models of electrohydration of stratum corneum (SC) have been developed. In the first model, the hydration of one interbilayer region is considered on the assumption that water molecules are adsorbed on the inhomogeneous surface of a bilayer and can interact, thereby lowering their energy on the surface. The dependence of the hydration degree on the voltage across the skin had been found. At certain parameter values the degree of hydration rapidly grows at certain voltage up to the magnitudes at which continuous water pathways appear. The second model has used the macroscopic approach which presumes water to be present in the interbilayer region as microdrops. The dependence of the hydration degree on voltage has been also found. At voltages of the order of tens of volts the obtained hydrations of interbilayer regions are sufficient to generate electroinduced hydrophilic pores in the SC lipid phase. Formation of tortuous continuous pathways for the transport of small ions is little probable because it requires voltages much higher than 100 V. We suggest that small ions pass the skin by the straight way through corneocytes and lipid bilayers at voltages of the order of tens of volts and higher.

[Long-term results of the program for preventing ischemic heart disease in Moscow (10-year follow-up study)]. / Otdalennye rezultaty provedeniia programmy mnogofaktornoi profilaktiki ishemicheskoi bolezni serdtsa v Moskve (10-letnee nabliudenie).

The paper provides the results obtained from implementation of the programme on multifactorial prevention of coronary heart disease (CHD) in Moscow, which provided strong evidence for a reduction in the levels of major risk factors and mortality from cardiovascular diseases, including coronary heart disease. The efficiency of comprehensive prophylactic measures in persons with clinical signs of CHD showed up at year 3 of their implementation and retains in subsequent years. At the same time in persons without CHD signs a mortality reduction starting at years 4-5 of the follow-up virtually came to an end when a further active intervention ceased. The impact of aftereffect of active prophylactic measures after intervention cessation turned out to be different in the examinees at various baseline risk factor levels, which suggests that continuous prophylaxis should be done, on the one hand, and it requires a differential approach, on the other. The reduction in the extent and mean levels of major risk factors, which had been achieved during a 5-year prophylactic intervention, retained, though it was less pronounced and 10 years later. However, this was followed by an increase in the mortality from myocardial infarction and stroke and their incidence in the population that had undergone active prophylactic measures, though the value of these parameters was lower at the end of the tenth year than in the controls.

[Detection of ischemic heart disease in a survey of a male population 40-59 years of age (data of cooperative studies performed in Moscow, Kaunas, Kiev and Kharkov)]. / Vyiavlenie ishemicheskoi bolezni serdtsa pri obsledovanii muzhskogo naseleniia 40-59 let (dannye kooperativnogo issledovaniia v Moskve, Kaunase, Kieve, Khar'kove).

The authors analyzed the prevalence of coronary heart disease (CHD) and its various types detected by routine epidemiological methods among the examinees in four cities (Moscow, Kaunas, Kiev, and Kharkov). The results were obtained in the collaboration study, adhering to the rigid standardization of all the procedures applied. Examination of 17, 168 males aged 40-59 years revealed signs of CHD in 13.8%; 3.3% had a history of myocardial infarction; 5.3% suffered from exertional angina without prior myocardial infarction; 5.2% showed a painless course of CHD. The analysis demonstrated that simultaneous use of the standard epidemiological methods is the only way of ensuring a more complete detection of CHD. In different cities, from 36.4 to 60.8% were not aware of the presence of the disease. Secondary preventive measures should involve methods for identifying the major risk factors and eliminating the latter.

[Alcohol consumption habits in a population of 40- to 59-year-old men and its prognostic value in relation to mortality]. / Izuchenie privychki upotrebleniia alkogolia v populiatsii muzhchin 40-59 let i ee prognosticheskaia znachimost' v otnoshenii smertnosti.

Alcohol consumption practice was studied by a method of interview in an unorganized male population aged 40 to 59 investigated by a program of multifactorial CHD prevention. The frequency of spreading of this habit and its intensity were determined. The frequency of alcohol consumption was decreased with age and was associated with the examinees' educational level. Persons consuming alcohol more frequently had raised arterial hypertension and smoked. These factors increased the risk of CHD development which was confirmed by a 5-year prospective study of mortality. Alcohol abusers were characterized by higher rates of general mortality, including that from cardiovascular diseases, traumas and accidents, in particular, alcoholic intoxication.

[Chest pains detected on the basis of the WHO standard questionnaire and their prognostic significance]. / Boli v grudnoi kletke, vyiavlennye na osnovanii standartnogo oprosnika VOZ, i ikh prognosticheskoe znachenie.

A WHO standard questionnaire for the detection of angina pectoris was used in examination of 6914 males aged 40 to 59. The character of the pain syndrome was correlated with risk factor (RF) levels, the prevalence of ECG-signs of ischemic changes, the incidence of cases of myocardial infarction (MI) during a 5-year follow-up period. Examinees with angina pectoris had the highest levels of systolic and diastolic AP, cholesterol, body mass, the highest frequency of lethal and nonlethal MI. Examinees with chest pains resulting from physical exercise but atypical of angina had higher levels of the main RF and ECG-signs of ischemic changes and higher rates (2-fold) of new cases of MI and its mortality as compared to persons without chest pains or with pains unrelated with physical exercise during a 5-year prospective study. This evidence suggests a necessity of a more detailed investigation of the latter group to reach the entire group of CHD patients.