Analysis of the Association between the Tgfb1 Gene Haplotype and Liver Diseases in Children.

Transforming growth factor-ß1 (TGF-ß1), a cytokine with immunosuppressive and pro-fibrogenic activity, is a potential marker of infection, liver transplant rejection, and fibrosis. Its levels in the blood and tissues depend on many factors; however, the role of gene polymorphism is still unclear. In this work, the distribution frequency of three single nucleotide polymorphism (SNP) variants of the Tgfb1 gene, namely rs1800469, rs1800470, and rs1800471, was studied in children with end-stage liver disease (ESLD). The study included 225 pediatric liver recipients aged 1 month to 16 years (median, 8 months), including 100 boys and 125 girls, and 198 healthy individuals aged 32.7 ± 9.6 years, including 78 men and 120 women. The indication for liver transplantation in children was ESLD, which was mostly caused by congenital and inherited liver diseases. SNPs were detected by real-time polymerase chain reaction using TaqMan probes and DNA isolated from peripheral blood. SNP frequency distribution was in Hardy-Weinberg equilibrium and did not differ between children with liver diseases and the healthy ones. Analysis of the SNPs frequency based on allelic interaction models did not reveal any differences between patients and the healthy individuals. Evaluation of linkage disequilibrium for Tgfb1 polymorphic variant pairs revealed a statistically significant linkage between all studied variants. Seven haplotypes, which are variants of SNP combinations, were observed in the studied groups of patients and healthy individuals. A total of 80% of the group had three haplotypes, whose frequencies did not differ between patients and the healthy individuals. Significant differences were found in the frequency of the haplotypes A-A-C, G-G-C, and G-A-G (at rs1800469, rs1800470, and rs1800471, respectively), which were observed up to 11 times more often in recipients compared to the healthy individuals. It is possible that these haplotypes are ESLD-predisposing variants, which may also contribute to the development of complications after liver transplantation in children.

[Features of the neurocognitive profile of patients with protracted and chronic endogenous manic and manic-delusional states]. / Osobennosti neirokognitivnogo profilya bol'nykh s zatyazhnymi i khronicheskimi endogennymi maniakal'nymi i maniakal'no-bredovymi sostoyaniyami.

OBJECTIVE: To study the neurocognitive profile of patients with protracted and chronic endogenous manic and manic-delusional states (EMDS). MATERIAL AND METHODS: Thirty-two female patients, aged 18 to 55 years (mean age 36.2±10.2 years), with protracted and chronic EMDS were studied. Based on the clinical typology of EMDS, patients were divided into 4 groups of 8 patients each: group 1 - «acute¼ subtype, group 2 - «chronified¼ subtype, group 3 - «developing¼ subtype and group 4 - subtype «double mania¼. Neuropsychological, clinical-psychopathological and statistical methods were used. RESULTS: Disturbances of regulatory and executive functions and a decrease in neurodynamic indicators of mental activity in patients with EMDS are significantly more pronounced compared with the control group (p<0.05). The values of the index of severity of disturbances of regulatory and executive functions in patients with EMDS range from 0.95 points (group 1) to 1.14 points (group 4), without statistically significant differences between the groups. The highest severity of neurodynamic disorders is observed in group 1 (1.88 points), while in other groups the index values range from 0.88 points in group 2 to 1.09 in group 4 (p<0.05). Patients of group 1 have greater severity and wider spectrum of neurodynamic symptoms compared with group 2 (U=45.00; p<0.0021), group 3 (U=30.00; p<0.04), and group 4 (U=45.00; p<0.001). It should be noted that the cognitive impairments identified in patients with EMDS did not reach the level of dementia. CONCLUSION: The most characteristic of EMBS are cognitive impairments associated with a decrease in the parameters of the neurodynamics of mental activity related to the first functional block, as well as with deficiency of executive functions, impaired planning and organization of cognitive activity, due to the weakness of the structures of the third functional block.

The rs1800470 Polymorphism of the TGFB1 Gene Is Associated with Myocardial Fibrosis in Heart Transplant Recipients.

The transforming growth factor ß1 (TGFß1), whose level may depend on the polymorphism of the TGFB1 gene, is involved in the formation of myocardial fibrosis. Myocardial fibrosis in a cardiac allograft may lead to a heart's structural and functional remodeling and subsequent dysfunction. The frequency of occurrence of alleles and genotypes of the TGFB1 gene polymorphic regions rs1800469, rs1800470, and rs1800471 in heart transplant recipients and their association with graft myocardial fibrosis were analyzed. Carriers of the CC genotype (p = 0.023, OR = 0.12, 95% CI: 0.017-1.0), and more often the G allele of rs1800471 (p = 0.023, OR = 7.76, 95% CI: 1.0-60.20), were found among heart transplant recipients less frequently than among healthy individuals. In patients with ischemic heart disease (IHD), the GG genotype was less common (p = 0.035, OR = 2.68, 95% CI: 1.061-6.793), while the A allele of rs1800469 was found more frequently (p = 0.035, OR = 0.37 95% CI: 0.148-0.942) than in patients with dilated cardiomyopathy (DCM). In heart transplant recipients with the AA genotype of rs1800470, myocardial fibrosis, verified by endomyocardial biopsy, was detected more often than in carriers of the G allele (OR = 10.4, 95% CI: 1.152-94.538, p = 0.013). The revealed differences suggest a relationship between TGFB1 gene polymorphism and graft myocardial fibrosis. Studies on a larger group of patients would make it possible to characterize the influence of genetic factors on the formation of myocardial fibrosis in heart transplant recipients.

[The relationship of level of transforming growth factor beta 1 with liver fibrosis in children with congenital diseases of hepatobilliary system.]

The article considers results of studying level of transforming growth factor beta 1 (TGF-ß1) in blood plasma of children with terminal stage of hepatic failure before and after transplantation of liver. The relationship of level of cytokine with degree of of liver fibrosis is analyzed. It is demonstrated that level of TGF-ß1 in blood plasma of children with hepatic failure is lower in comparison with healthy children and depends on degree of severity of liver fibrosis. Thus, level of cytokine in blood of patients is higher under fibrosis severity stage II and III, than under fibrosis of severity stage I and IV. After kindred transplantation of hepatic lobe, level of TGF-ß1in blood plasma of patients increases independently of initial degree of severity of fibrosis.

[THE ROLE OF TRANSFORMING GROWTH FACTOR BETA 1 UNDER DISEASES OF LIVER].

The review present analysis of publications considering role of transforming growth factor beta 1 (TGF-ß1) under various diseases of liver. The analysis was applied to 46 published articles more than a half of which were published in last five years. Under diseases of liver, TGF-ß1 plays a key role both in development of fibrosis and in maintenance of immune homeostasis. The chronic damage of liver results in activation of liver stellated cells and intensification of their production of various cytokines, including TGF-ß1 that stimulates stellated cells and hepatocytes acquiring characteristics of miofibroblasts and producing proteins of extracellular matrix that results in development of fibrosis. TGF-ß1 also has anti-inflammatory and immune suppressive characteristics manifested in suppression of differentiation of Th cells type I and II thereby controlling inflammatory processes. The clinical data of role of TGF-ß1 under various diseases of liver in many ways are contradictory that probably related to its dosage-dependent pleiotropic effect. The value of level of TGF-ß1шт blood can reflect complicated balance between fibrinogen and immune suppressive effects of cytokine. The detection of content of cytokine in blood can have diagnostic and prognostic significance in evaluation of condition of liver.

CLINICAL SIGNIFICANCE LEVELS OF C-REACTIVE PROTEIN AND CERULOPLASMIN IN PATIENTS WITH ISCHEMIC HEART DISEASE.

INTRODUCTION: The study examined the relationship of levels of ceruloplasmin and CRP in patients with coronary heart disease and assessed the possibility of their use for diagnosis and prediction of developing complications. AIM: The study investigated the relationship of levels of ceruloplasmin and CRP in patients with coronary heart disease and their potential use in the diagnosis and prediction of complications. MATERIALS AND METHODS: Examined 117 patients with ischemic heart disease at the age of 39 to 80 years (median age + 13.9 61.7 years), among them 56 were women and 61 men. Assessment of prognosis in patients with ischemic heart disease was conducted based on the two-year observation. RESULTS: The reverse relationship between the levels of ceruloplasmin and CRP was identified. When comparing the survival curves without adverse events using the log-rank analysis in patients with levels of CPU of more than 0.2 grams per liter and CRP of less than 6.0 mg/l, the prognosis was significantly better than in patients with simultaneously detected low levels of the CPU (less than 0.2 g/l) and high levels of CRP (more than 6.0 mg/l) in the blood (p < 0.05), CONCLUSIONS: Highly sensitive measurement method of levels of c-reactive protein in patients with coronary heart disease combined with measurement of levels of ceruloplasmin, gives an opportunity to assess the activity of vascular inflammation that can be used to predict the development of acute coronary events.

[Evolution of ideas on the assessment of cardiovascular risks in the perioperative period].

Substantial advance has been made in operative surgery and anesthesiology; on the one hand, population ageing and, on the other, increasing surgical care needs make the prediction of perioperative complications an important component of the entire current model of surgical care. In the last decades, the concept of risk in perioperative medicine has been formulated; the theoretical base for a statistical description of the risk concept has been created, and different integral risk prediction models based on the risk index obtained by regression analysis have been elaborated and promoted. At the same time, none of the created models can reliably assess the risk of cardiovascular events associated with surgical intervention and predict the probability of poor clinical outcomes with a high degree of accuracy.

[The analysis of relationship between numbers of hemopoietic hematoblasts and laboratory indicators of state of hepatobiliary system in children with congenital and hereditary diseases of liver].

The content of CD34/CD45dim-positive cells in peripheral blood of children with congenital and hereditary diseases of hepatobiliary system is studied. The analysis of relationship between numbers of studied cells and level of C-reactive protein, sCD40L, sCD30 and laboratory parameters specific to liver functions is applied The number of CD34-positive hemopoietic hematoblasts in children with hepatocirrhosis correlated with the level of C-reactive protein, albumin, hemoglobin concentration and quantity of blood erythrocytes. No relationship was established with the levels of sDC40L and sDC30. The number ofstudied cells in children with liver diseases was higher than in healthy adult donors.

[Laboratory diagnosis of atherosclerotic plaque damage in patients with coronary heart disease: PAPP-A (a review of literature)].

Vascular inflammation is a major pathogenetic factor for the progression of an atherosclerotic process and for the development of destructive plaque changes. Now an active search is under way for markers to diagnose acute coronary syndrome at the early stage of development. The paper discusses the role of markers of inflammation and endogenous destruction in the development of atherosclerotic plaque instability. Pregnancy-associated plasma protein A (PAPP-A) is its most promising marker. It may be used to stratify the risk of cardiovascular complications in coronary heart disease and to assess their prognosis.

[Lisinopril: antihypertensive activity, effects on heart rhythm variability and carbohydrate metabolism in patients with metabolic syndrome].

AIM: To examine antihypertensive activity, heart rate variability (HRV) and carbohydrate metabolism of ACE inhibitor lisinopril in patients with metabolic syndrome (MS). MATERIAL AND METHODS: Twenty MS patients (13 females and 7 males) received lisinopril monotherapy for 12 weeks. Before the treatment and after 12 weeks of lisinopril treatment the following tests were made: office measurement of blood pressure (BP), 24-hour BP monitoring, exercise test, investigation of HRV and carbohydrate profile. RESULTS: A 12-week treatment with lisinopril had high antihypertensive efficacy, its positive action on HRV and carbohydrate metabolism manifested in reduction of postprandial glycemia and insulinemia.

[Efficacy of combined antihypertensive treatment with amlodipine and lisinopril in metabolic syndrome].

AIM: To assess efficacy of monotherapy with ACE inhibitor lisinopril (diroton) or calcium antagonist amlodipine (normodipine) and their combination in patients with metabolic syndrome (MS). MATERIAL AND METHODS: The study enrolled 42 patients (30 females, 12 males) with MS. The examination at baseline and after 12 weeks of treatment included office blood pressure (BP) measurement, 24-hour BP monitoring, heart rate variability (HRV) and carbohydrate profiles estimation. RESULTS: In moderate hypertension BP normalized in 40 and 44% on monotherapy with lisinopril or amlodipine, respectively, and in 78% patients given lisinopril+amlodipine. The latter combination and lisinopril monotherapy had a positive effect on HRV parameters. Lisinopril monotherapy improved carbohydrate metabolism as shown by reduction of postprandial hyperglycemia and hyperinsulinemia in MS patients. CONCLUSION: Combined treatment with amlodipin and lisinopril is more effective than monotherapy with each of the above drugs.

[Effects of amlodipine on blood pressure. Results of cardiovascular tests and heart rate variability in patients with metabolic syndrome].

AIM: To study effects of calcium antagonist amlodipine (normodipine) on blood pressure, heart rate variability (HRV) and carbohydrate metabolism in patients with metabolic syndrome (MS). MATERIAL AND METHODS: The trial included 52 patients (37 females, 15 males) with MS. The examination at baseline and after 12 weeks of amlodipine treatment included: office blood pressure (BP) measurement, 24-h BP monitoring, exercise tolerance test, estimation of HRV and carbohydrate profile. Amlodipine was administered as monotherapy for 12 weeks. RESULTS: A 12-week treatment with amlodipine demonstrated high antihypertensive effect (BP normalized in 72.7% patients) without negative effects on HRV and carbohydrate profile. CONCLUSION: Monotherapy with calcium antagonist amlodipine (normodipine) has high antihypertensive efficacy and is metabolically neutral in MS patients.

[Neoangiogenesis and coronary atherosclerosis: diagnostic value of a novel biochemical marker placenta growth factor in patients with ischemic heart disease].

BACKGROUND: Placenta growth factor (PlGF), a member of the vascular endothelial growth factor family, promotes neoarteriogenesis and triggers intraplaque inflammation thereby stimulating atherosclerotic plaque progression and plaque rupture. OBJECTIVE: To investigate prognostic significance of circulating placenta growth factor (PlGF) in coronary artery disease (CAD) patients. METHODS: 78 patients, aged 44-81 years (mean age 61.6+/-13.1 years) with acute myocardial infarction (AMI) (n=19), unstable angina (UA) (n=23), stable effort angina (n=23), and with no evidence of CAD (n=13) were followed-up for at least 48 months. Death, AMI, any revascularization, and hospitalization for UA or progressive effort angina were considered as end points. Plasma levels of PlGF, C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, tumor necrosis factor alpha (TNF-a), haptoglobin and homocysteine were measured at primary admission. RESULTS: During follow up (617+/-263 days) 3 deaths, 1 nonfatal AMI, 4 UA, and 7 angina progression related hospitalizations occurred. Mean event-free survival periods differed significantly between subgroups of patients with low (<7.5 pg/ml), medium (7.5-20.5 pg/ml), and high (>20.5 pg/ml) PlGF levels (1038+/-56, 729+/-55, and 578+/-63 days, respectively). Logrank survival in patients with low PlGF was significantly better than in high PlGF subgroup (p=0.038). PlGF levels did not correlate with age, lipid levels, blood pressure and smoking. A significant positive correlation was found between PlGF and haptoglobin (r=0.34, p=0.028), homocysteine (r=0.455, p=0.044), neopterin (r=0.31, p=0.048), and carotid intima-media thickness. CONCLUSION: Elevated PlGF plasma levels predict worse prognosis in CAD patients; PlGF levels correlate with haptoglobin, neopterin, and homocysteine blood levels and with the carotid artery intima-media thickness.

[Vasculopathy of the grafted heart: the synergism of proinflammatory and proatherogenous factors and viral infection].

The authors analyze the pathogenetic significance of hyperhomocysteinemia, antiphospholipid syndrome, the hyperexpression of cell adhesion molecules, inflammation, and oxidative disorders for, as well as the role of viral infections in the development of coronary artery disease of the grafted heart. The paper shows that viral infections in recipients lead to the development of proinflammatory, proatherogenous, and prothrombogenous status, expressing themselves in an increase in the corresponding laboratory markers in recipients' blood plasma, and points out the role of viral infection in the pathogenesis of coronary artery disease of the transplanted heart. Control and treatment of viral infections, as well as pharmacocorrection of proinflammatory, proatherogenous, and prothrombogenous status would made it possible to influence the development of coronary artery disease of the grafted heart.