The present study was performed to evaluate the role of an interaction between the endothelin (ET) and the renin-angiotensin systems (RAS) in the development and maintenance of hypertension and in hypertension-associated end-organ damage in heterozygous male and female transgenic rats harboring the mouse Ren-2 renin gene (TGR). Twenty-eight days old heterozygous TGR and age-matched transgene-negative normotensive Hannover Sprague-Dawley rats (HanSD) were randomly assigned to groups with normal-salt (NS) or high-salt (HS) intake. Nonselective ETA/ETB receptor blockade was achieved with bosentan (100 mg.kg-1.day-1). All male and female HanSD as well as heterozygous TGR on NS exhibited 100 % survival rate until 180 days of age (end of experiment). HS diet in heterozygous TGR induced a transition from benign to malignant phase hypertension. The survival rates in male and in female heterozygous TGR on the HS diet were 46 % and 80 %, respectively, and were significantly improved by administration of bosentan to 76 % and 97 %, respectively. Treatment with bosentan did not influence either the course of hypertension (measured by plethysmography in conscious animals) or the final levels of blood pressure (measured by a direct method in anesthetized rats) in any of the experimental groups of HanSD or TGR. Administration of bosentan in heterozygous TGR fed the HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. Our data show that the ET receptor blockade markedly improves the survival rate and ameliorates end-organ damage in heterozygous TGR exposed to HS diet. These findings indicate that the interaction between the RAS and ET systems plays an important role in the development of hypertension-associated end-organ damage in TGR exposed to salt-loading.
Úvod: IgD typ mnohočetného myelomu (MM) představuje poměrně vzácnou formu tohoto stále nevyléčitelného onemocnění, postihuje přibližně 2 % všech nemocných s MM. Dosud platí, že se u nemocných s IgD formou MM předpokládá kratší přežití, než je obecně u MM udáváno. Cíl práce: Ověřit tuto skutečnost na souboru pacientů léčených v ČR. Typ studie: Retrospektivní analýza. Název a sídlo pracoviště: II. interní klinika – Oddělení klinické hematologie, LF UK a FN Hradec Králové; Interní hemato- -onkologická klinika, LF MU a FN Brno-Bohunice; III. interní klinika, LF UP a FN Olomouc; Oddělení klinické hematologie, FN Královské Vinohrady, Praha; Ústav klinické biochemie a diagnostiky, LF UK a FN Hradec Králové. Metody: Provedli jsme retrospektivní analýzu výsledků léčby 20 nemocných ze 4 center spolupracujících v rámci České myelomové skupiny. Šlo o 12 mužů (60 %) a 8 žen (40 %) s průměrným věkem 62 let, kteří prodělali léčbu MM v posledních 7 letech. 12 nemocných (60%) bylo léčeno režimy konvenční chemoterapie a 8 pacientů prodělalo autologní transplantaci periferních kmenových buněk po vysokodávkové léčbě. Výsledky: Velmi zajímavým zjištěním byla 100% léčebná odpověď dosažená ve skupině nemocných léčených vysokodávkovou chemoterapií oproti 58 % (CR+PR) dosaženým při použití konvenční léčby. Statisticky signifikantní rozdíl mezi oběma hodnocenými skupinami nemocných byl zjištěn v celkovém přežití (p = 0,035), kdy medián ve skupině nemocných léčených konvenční chemoterapií dosáhl 14 měsíců a u nemocných, kteří prodělali autologní transplantaci, ho zatím nebylo možné určit, protože v době hodnocení žilo 70 % takto léčených nemocných. Závěr: Z našich výsledků jednoznačně vyplývá nutnost léčit nemocné s IgD MM do 65 let věku vysokodávkovou léčbou, která umožňuje dosažení srovnatelných výsledků s ostatními typy mnohočetnému myelomu. Další zlepšení léčebných výsledků by mohlo nastat v souvislosti se stále častějším používáním nových léků v léčbě MM., Objective: To verify shorter survival of patients with the IgG form of MM in a group of patients treated in the Czech Republic. Design: Retrospective analysis. Setting: 2nd Internal Clinic – Clinical Haematology Ward, Medical Faculty, Charles University and Faculty Hospital Hradec Králové; Internal Haemato-oncological Clinic, Medical Faculty, Masaryk University and Faculty Hospital Brno- -Bohunice; 3rd Internal Clinic, Medical Faculty, University of Palacky and Faculty Hospital Olomouc; Clinical Haematology Ward, Faculty Hospital Královské Vinohrady, Prague; Institute of Clinical Biochemistry and Diagnostics, Medical Faculty, Charles University and Faculty Hospital, Hradec Králové. Methods: We carried out a retrospective analysis of 20 myeloma patients treated by 4 Czech hemato-oncological centers in last seven years. There were 12 (60%) males and 8 (40%) females, the median age was 62 years. 12 (60%) patients were treated by conventional chemotherapy regimes and 8 (40%) patients were treated by high-dose therapy with following autologous peripheral stem cells transplantation. Results: It is very interesting that we observed 100% therapy response in the group of patients treated by high-dose therapy contrary to 58% (CR+PR) in patients treated by conventional chemotherapy regimes. A statistically significant difference was found between the two groups of patients in overall survival (p=0.035), the median overall survival (OS) of group treated by conventional chemotherapy was 14 months only, whereas the median OS in group of patients after APBSCT has not yet been reached (it is still alive 70% patients). Conclusion: It is necessary to consider high-dose therapy with following APBSCT when treating patients with IgD MM under 65 years because it is possible to reach similar results compared to patients with other MM types. Further improvement of their outcome might be reached either using new drugs., Vladimír Maisnar, Roman Hájek, Vlastimil Ščudla, and Lit. 25
We studied the changes in seru m fibroblast growth factor-21 (FGF-21) concentrations, its mR NA, and protein expression in skeletal muscle and adipose tissue of 15 patients undergoing cardiac surgery. Blood samples were obtained: prior to initiation of anesthesia, prior to the start of extracorporeal circulation, upon completion of the surger y, and 6, 24, 48, and 96 hours after the end of the surgery. Tissue sampling was performed at the start and end of surgery. The mean baseline serum FGF-21 concentration was 63.1 (43.03-113. 95) pg/ml and it increased during surgery with peak 6 ho urs after its end [385.5 (274.55-761.65) pg/ml, p<0.001], and return ed to baseline value [41.4 (29.15-142.83) pg/ml] 96 hours afte r the end of the surgery. Serum glucose, insulin, CRP, IL-6, IL-8, MCP-1, and TNF-alpha concentrations significantly increased during the surgery. Baseline FGF-21 mRNA expression in skeletal muscle was higher than in both adipose tissue depots and it was not affected by the surgery. Epicardial fat FGF-21 mRNA increased after surgery. Muscle FGF-21 mRNA positively correlated with blood glucose levels at the end of the surgery. Our data suggest a possible role of FGF-21 in the regulation of glucose metabolism and insulin sensitivity in surgery-related stress., T. Kotulák ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Pulmonary hypertension (PH) unresponsive to pharmacological intervention is considered a contraindication for orthotopic heart transplantation (OHTX) due to risk of postoperative right-heart failure. In this prospective study, we describe our experience with a treatment strategy of improving severe PH in heart transplant candidates by means of ventricular assist device (VAD) implantation and subs equent OHTX. In 11 heart transplantation candidates with severe PH unresponsive to pharmacological intervention we implanted VAD with the aim of achieving PH to values acceptable for OHTX. In all patients we observed significant drop in pulmonary pr essures, PVR and TPG (p<0.001 for all) 3 months after VAD implantation to values sufficient to allow OHTX. Seven patients underwent transplantation (mean duration of support 216 days) while none of patients suffered right-side heart failure in postoperative period. Two patients died after transplantation and five patients are living in very good condition with a mean duration of 286 days after OHTX. In our opinion, severe PH is not a contraindication for orthotopic heart transplantation any more., J. Kettner ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The present study was performed to evaluate the role of neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) during the developmental phase of hypertension in transgenic rats harboring the mouse Ren-2 renin gene (TGR). The first aim of the present study was to examine nNOS mRNA expression in the renal cortex and to assess the renal functional responses to intrarenal nNOS inhibition by S-methyl-L-thiocitrulline (L-SMTC) in heterozygous TGR and in age-matched transgene-negative Hannover Sprague-Dawley rats (HanSD). The second aim was to evaluate the role of the renal sympathetic nerves in mediating the renal functional responses to intrarenal nNOS inhibition. Thus, we also evaluated the effects of intrarenal L-SMTC administration in acutely denervated TGR and HanSD. Expression of nNOS mRNA in the renal cortex was significantly increased in TGR compared with HanSD. Intrarenal administration of L-SMTC decreased the glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium excretion and increased renal vascular resistance (RVR) in HanSD. In contrast, intrarenal inhibition of nNOS by L-SMTC did not alter GFR, RPF or RVR and elicited a marked increase in sodium excretion in TGR. This effect of intrarenal L-SMTC was not observed in acutely denervated TGR. These results suggest that during the developmental phase of hypertension TGR exhibit an impaired renal vascular responsiveness to nNOS derived NO or an impaired ability to release NO by nNOS despite enhanced expression of nNOS mRNA in the renal cortex. In addition, the data indicate that nNOS-derived NO increases tubular sodium reabsorption in TGR and that the renal nerves play an important modulatory role in this process., L. Červenka, H. J. Kramer, J. Malý, I. Vaněčková, A. Bäcker, D. Bokemeyer, M. Bader, D. Ganten, K. D. Mitchell., and Obsahuje bibliografii
The role of adhesive selectin molecules in the process of atherogenesis is an open question. These molecules are known as markers of atherosclerosis activity, however, only some biological mechanisms are known up to now. In this study we examined the levels of soluble forms of E-, P-selectin and monocyte chemotactic protein (MCP-1) in the process of extracorporeal cholesterol elimination by LDL-apheresis. We measured the levels of sE-, sP-selectin and MCP-1 in the plasma before and after LDL-apheresis and in the washout solution from immunoabsorption columns Lipopak. Eighty measurements were performed repeatedly in 6 patients with severe familial hypercholesterolemia (FH) on long-term LDL-apheresis treatment. Before the procedure P-selectin levels were 204±179 ng/ml, E-selectin 32.1±33.7 ng/ml, MCP-1 323.8±121 pg/l, whereas after the procedure we found P-selectin levels 131.6±34 ng/ml, E-selectin 33.1±51 ng/ml, and MCP-1 200.4±15 pg/l. Levels of P- selectin were increased in the blood of patients with FH in spite of long-term intensive extracorporeal LDL-elimination, documenting thus the activity of atherosclerosis. The levels of
P-selectin and MCP-1 decreased significantly after the hypolidemic procedure and could be used as another marker showing the effectivity of the extracorporeal LDL-cholesterol elimination (immediately after the procedure), and, after further verification, may serve as a marker for controlling the therapy efficacy.