Endothelin-1 induces organ-specific histamine liberation and neutrophil granulocyte accumulation in the rat.

OBJECTIVE AND DESIGN: Enhanced production of endothelin-1 (ET-1) and the activation of mast cells (MCs) have been implicated in granulocyte sequestration. We compared local consequences of transient increases in circulating ET-1 in three separate circulatory beds in pentobarbital-anesthetized Wistar rats. MATERIALS AND METHODS: We determined whether pretreatment with ET-A receptor antagonist ETR-P1/fl peptide and MC stabilizer sodium cromoglycate would influence histamine- and granulocyte responses induced by 1 nmol/kg ET-1 iv. Plasma and tissue histamine contents were monitored, myeloperoxidase (MPO) level was determined from heart, lung and intestinal biopsies. RESULTS: The ET-1 infusion caused significant plasma histamine elevations, enhanced MPO activity in all organs, decreased tissue histamine content in the lung and small bowel by approx. 50% , while the histamine content of heart did not change. ETR-P1/fl significantly decreased ET-1-induced intestinal and heart MPO changes, and inhibited histamine depletion in the small intestine but not in lung and heart tissues. Sodium cromoglycate inhibited the ET-1-induced neutrophil accumulation in the heart and intestine and did not influence MPO activity in the lung. CONCLUSION: ET-1 release participates in the process of histamine liberation and subsequent secondary granulocyte accumulation through tissue-specific activation of ET-A receptors. ET-1-induced direct effects are predominating in pulmonary neutrophil activation, while MC-associated secondary changes play important roles in intestinal granulocyte recruitment.

Pathophysiology of ischemia-reperfusion injury.

Our studies characterized the intestinal microcirculatory changes in canine models of intestinal hypoperfusion (hemorrhagic shock) or ischemia-reperfusion (small bowel autotransplantation). The villus microcirculatory parameters (functional capillary density, mean red blood cell velocity) were observed by intravital microscopy using orthogonal polarization spectral imaging. The leukocyte reaction (rolling and firm adherence) in the mesentery was quantified by using conventional fluorescence videomicroscopy. The investigations were aimed at determining whether the compromised intestinal villus perfusion could be influenced by endothelin-A receptor inhibition, volume resuscitation, or ischemic preconditioning. The results demonstrated the pathophysiological significance of endothelin-A receptor activation in ischemia-reperfusion-induced microcirculatory changes. Second, it was shown that colloid fluid therapy with hydroxyethyl-starch effectively ameliorated the microcirculatory consequences of hypovolemia, which correlated with a lower endothelin release. Third, ischemic preconditioning when applied 60 minutes before ischemia, inhibited the reperfusion-induced superoxide production, improved capillary perfusion, and attenuated leukocyte activation within the intestinal graft. Among the examined therapeutic strategies aimed at improving the outcome of intestinal microcirculatory dysfunction, endothelin-A receptor antagonist pretreatment and ischemic preconditioning are promising tools to decrease the harmful consequences of ischemia/reperfusion.

Laurence-Moon-Bardet-Biedl syndrome for kidney transplantation at the age of 57 years.

Laurence-Moon-Bardet-Biedl syndrome represents a very rare indication for kidney transplantation. Previous reports mention only pediatric organ recipients with this diagnosis. We present the case of a Caucasian male patient who underwent a cadaveric renal transplantation at the age of 57 years. Our patient had an uneventful immediate postoperative course; however, 4 months after the operation he suffered pneumonia and cytomegalovirus infection. He recovered fully and had an episode of acute cholecystitis. At the time of the laparoscopic cholecystectomy we also laparoscopically removed his Tenckhoff catheter, a procedure he could not undergo for more than a year because of a chronic scabies infection. Now, 18 months after his transplantation he is fully rehabilitated with a serum creatinine of 90 micromol/L. In selected cases even in older age kidney transplantation could offer a higher quality of life for this mentally retarded, blind population.

Circulating S100B is increased after bilateral femur fracture without brain injury in the rat.

BACKGROUND: S100B is an acknowledged marker of brain damage. However, trauma without brain damage also causes an increase in S100B. S100B concentrations are highest in multiple trauma patients with long bone fractures. Clinically, extensive long bone fractures are associated with haemorrhagic shock and haemorrhagic shock per se is associated with increased S100B. The aim of our experimental study was to verify the S100B increase in long bone fracture without haemorrhagic shock. METHODS: and results. Bilateral femur fracture was carried out in 10 anaesthetized rats. Blood samples were drawn for immuno-luminometrical S100B measurement 5, 15, 30, 120, and 240 min after fracture. Mean arterial pressure (MAP), heart rate, and body temperature were monitored continuously. S100B increased after bilateral femur fracture and reached a peak 30-120 min after fracture (P<0.001). MAP remained at a level which is not associated with shock in rats. Heart rate and body temperature remained unchanged. Autopsy verified open bilateral femur fracture surrounded only by small zones of clotted blood. CONCLUSIONS: S100B is increased in bilateral femur fracture without haemorrhagic shock in rats. This finding suggests that bone marrow is a potential extracerebral source of S100B.

[Liver diseases as risk factors in surgery. View points of internal medicine]. / Májkárosodás, mint kockázati tényezó a sebészetben. Belgyógyászati vonatkozások.

Morbidity and mortality risk is higher on patients suffering from liver disorders. Data in the literature show that elective surgery is contraindicated in acute hepatic illness. In case of liver enzyme elevations, an examination is necessary to make etiological diagnosis and assess the extent of hepatic injury. Risk of surgery is primarily in conjunction with patient's age, extent of liver and surgical disease, comorbidities and type of surgery. Among clinical and laboratory data even today one can most easily use the Child's classification or the Child-Pugh score system. In Child A patients all type of operation can be made, lethality is only slightly elevated. Mortality in Child B patient is 10-30%. In Child C patients elective surgery, except transplantation, is contraindicated.

Endothelin-1 induces mucosal mast cell degranulation in the rat small intestine.

The enhanced production of endothelial cell-derived vasoactive mediators and the activation of mast cells (MCs) have been implicated in the pathogenesis of mucosal damage during ischemia and reperfusion injuries. The first objective of our study was to define the in vivo relation between endothelin-1 (ET-1) and the MC system. Secondly, we determined whether pretreatment with ET receptor antagonists would attenuate MC responses to exogenous ET-1. In the first series of experiments, increasing doses of ET-1 (0. 1, 1 and 3 nmol/kg i.v.) were administered to anesthetized rats. In the second series, the animals were pretreated with equimolar doses of the ET-A receptor antagonist BQ-610 or ETR-P1/fl peptide, and the ET-B receptor antagonist IRL-1038. Intestinal perfusion changes and macrohemodynamics were recorded, and the proportion of degranulated MCs was determined in ileal biopsies. The average mucosal thickness was recorded with an image analysis system. ET-1 induced dose-dependent alterations in the hemodynamic and morphological parameters and caused pronounced mucosal injury, with a significant reduction in villus height. The ratio of degranulated MCs was similar in all ET-treated groups (77%, 82% and 86%) to that observed in animals subjected to 15-min ischemia and 60-min reperfusion (85% degranulation). Pretreatment with BQ-610 and ETR-P1/fl peptide attenuated the ET-1 induced alterations in the hemodynamic parameters and decreased structural injury to the mucosa. ET-induced MC degranulation was significantly inhibited by the ET-A receptor antagonists, but not by IRL-1038. These results indicate that elevated levels of circulating ET-1 might induce intestinal mucosal tissue injury and MC degranulation via activation of ET-A receptors, and raise the possibility that ET-A receptor antagonist administration could exert a potentially beneficial effect through a mechanism other than the blockade of vasoconstriction in pathologies associated with an increased ET-1 release.

[Life perspectives for patients treated with chronic hemodialysis]. / Krónikus hemodialízis-kezelésben részesüló betegek életkilátása.

The authors studied life perspectives of patients in a nephrology department using up Kaplan and Meier's analysis. Data of 51 of the patients included in the chronic hemodialysis programme between 1991 and 1997 were studied. The patients were under treatment for 19 months on average, 18% received renal allograft. The three-year life expectation for dialysed patients was 55%, without the transplant patients it was only 40%. The causes of deaths were infection and cardiovascular diseases in 40-40%. The patients life perspectives were better not only in primary renal diseases, but in vascular renal failure also, than in diabetic nephropathy. The authors made comparison between theirs and the national data, and discuss the necessary works to improve their results.

Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs.

In our study the pathomechanism of sepsis-induced early myocardial depression was investigated. We determined the effects of the inducible nitric oxide synthase inhibitor and free radical scavenger mercaptoethylguanidine (MEG) on the myocardial contractility, the endothelial and inducible nitric oxide synthase (eNOS and iNOS) activities, and the activation and tissue accumulation of polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs. Group 1 served as endotoxemic control. Mean arterial pressure and cardiac output were measured, myocardial contractility was estimated from the end-systolic pressure-diameter relationship. The eNOS, iNOS and myeloperoxidase activities were determined on myocardial biopsy samples, and the free radical-producing capacity of granulocytes was measured from separated cells. The effect of MEG on the in vitro free radical production of isolated granulocytes was measured by chemiluminometry. Endotoxin induced a hyperdynamic circulatory reaction and significant myocardial depression. The myocardial eNOS activity was significantly increased 4 h after induction of endotoxemia and remained elevated, the iNOS activity was increased only 8 h after endotoxemia induction. The free radical-producing capacity and the myocardial accumulation of the granulocytes were significantly increased. In group 2, MEG treatment selectively inhibited the iNOS activity, prolonged the hyperdynamic circulatory reaction, prevented myocardial depression and decreased the activation and tissue accumulation of granulocytes. The compound dose-dependently decreased the in vitro activation of previously resting granulocytes. Our study demonstrates that iNOS do not contribute to the early cardiac failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but its beneficial effects are rather related to the decreases in leukocyte and free radical-mediated myocardial dysfunction during early endotoxemia.

[Haemodialysed, hemiparetic patient operated on for aortic aneurysm followed by successful renal transplantation]. / Vascularis encephalopathiában szenvedó krónikus hemodializált betegen végzett aortaaneurysma-mútétet követó vesetranszplantáció.

The authors present the case of a 58 years old male patient. According to his preceding record in 1991 he suffered speech disturbance and left-side hemiparesis due to multiplex vascular lesions. A fresh cerebral ictus caused a right side hemiparesis mainly in the upper limb in 1993 and sensomotororic aphasia has also been developed. In 1995 the patient was begun acute haemodialysis treatment due to his gravis uremic state, then his dialysis was continued 3 times 4 hours weekly. In 1997 the then 56 years old inveterate right-sided hemiparetic patient, treated with chronic haemodialysis requested to be put on the transplantation waiting list. The first thing that had to be done in case of this high-risk patient was the resection of the abdominal aortic aneurysm (38 mm x 67 mm x 115 mm in size) noticed at the ultrasound examination which was carried out in January 1997. The continuity of the vessel was secured by graft-interposition where the arteria mesenterica was also implanted. Following the successful operation, the patient was qualified for the transplantation list and in the February of 1998 a successful kidney-transplantation was carried out. Following the temporary, post-transplantation difficulties (post-operative 5th day acute rejection well-reacting to 3 steroid-shots; the two re-operations due to partial necrosis in the uretero-ureteralis anastomosis and successfully overcoming the Pseudomonas aeruginosa uroinfection) the patient is currently doing well and has no complaint.

Endothelin-A receptor antagonism improves small bowel graft perfusion and structure after ischemia and reperfusion.

BACKGROUND: We hypothesized that endothelin-A (ET-A) receptor activation plays a central role in intestinal ischemia-reperfusion-induced hemodynamic changes and may trigger the process of mucosal barrier destruction. Our aims were to investigate and compare the effects of systemic and intragraft ET-A receptor antagonist therapy during the early revascularization phase of small bowel transplants. METHODS: In Groups 1, 2, and 3 orthotopic small bowel autotransplants were performed in anesthetized dogs. Group 4 served as sham-operated control. Group 2 was treated i.v. with the ET-A receptor antagonist ETR-p1/fl peptide at the onset of reperfusion. In Group 3, intragraft infusion of the ETR-p1/fl peptide was applied during cold ischemia. The mucosal myeloperoxidase activity and the free radical-producing capacity of the granulocytes passing the intestinal graft were determined, and the systemic hemodynamic features were recorded. The extent of the mucosal injury was determined from tissue biopsies taken after 4 hr of reperfusion. RESULTS: Reperfusion progressively decreased the mesenteric blood flow, increased the mesenteric vascular resistance, and enhanced the accumulation and free radical production capacity of the leukocytes. These changes were significantly inhibited in Group 2 with systemic (i.v.) administration of the ET-A receptor antagonist. The local, intragraft treatment improved the mesenteric hemodynamic changes and decreased the accumulation but not the activation of the circulating leukocytes. The structural injury of the graft was prevented in both treated groups. CONCLUSIONS: Endothelins are involved in the hemodynamic events leading to structural injury of the intestinal graft after ischemia-reperfusion. The antagonism of intestinal ET-A receptors by a combination of local and systemic drug delivery offers a rational treatment modality in these conditions.

The role of endothelin-1 in circulatory changes during hypodynamic sepsis in the rat.

Our objective was to investigate the significance of endogenous endothelin-1-induced systemic circulatory reactions during hypodynamic sepsis. In the first part of this study, we observed the changes in global hemodynamic parameters in Wistar rats after exogenous endothelin-1 administration in order to test an intervention strategy aimed at preventing the development of hypodynamic cardiovascular derangement during intraabdominal sepsis. Cardiac output, mean arterial blood pressure, and peripheral vascular resistance were recorded, and the endothelin-A receptor antagonist BQ-610 and the endothelin-B receptor antagonist IRL-1038 were used to investigate the role of receptor subtypes in circulatory changes. In addition, the effects of treatment with the novel endothelin-A receptor inhibitor ETR-P1/fl peptide were examined in endothelin-1-treated anesthetized rats. The injection of 1 nmol/kg endothelin-1 induced a significant rise in peripheral vascular resistance, a transient increase in mean arterial pressure, and a decrease in cardiac output. Administration of the endothelin-A receptor antagonist BQ-610 and ETR-P1/fl peptide increased cardiac output and decreased systemic vascular resistance in the controls and in animals treated with exogenous endothelin. In the second part of the study, the animals were instrumented for hemodynamic monitoring and randomized to undergo cecal ligation and perforation for 8 h or control laparotomy. Septic animals with cecal ligation and puncture were normotensive and hypodynamic, with a significantly increased total peripheral resistance throughout the 8 h observation period. ETR-P1/fl peptide treatment started after the induction of sepsis significantly increased cardiac output and decreased systemic vascular resistance almost to control levels. We conclude that endogenous endothelin-1 contributes significantly to the systemic hemodynamic alterations during hypodynamic circulatory response, and the inhibition of endothelin-A receptors may improve global hemodynamic status in this phase of sepsis.

Endothelin-1-induced circulatory response in the rat: the role of ETA and ETB receptors.

Production of the powerful vasoconstrictor endothelin-1 (ET1) is increased in a number of pathological conditions. This study was performed 1. to assess the effects of a twofold elevation of circulating ET1 on global hemodynamics and cardiac function, and 2. to determine the ET receptor subtypes that are responsible for this action. We have used the ETA receptor-selective antagonist BQ 610, the novel ETA receptor antagonist ETR-Pl/fl peptide and the specific ETB receptor antagonist IRL 1038 to investigate the role of these receptor subtypes in mediating circulatory changes induced by ET1 in anesthetized Wistar rats. ET1 infusion produced a significant rise in mean arterial pressure (MAP), elevated total peripheral resistance (TPR), and decreased cardiac output (CO). BQ 610 and ETR-Pl/fl pretreatment significantly attenuated the ET1-induced hemodynamic changes. Pretreatment with IRL 1038 had no effect on CO, but significantly reduced MAP and TPR elevation 20 min after ET1 infusion. These results suggest that ET1 may contribute to circulatory failure in conditions with increased ET1 production via a mechanism involving ETA receptors. ETB receptors, albeit to a lesser extent than ETA receptors, are also involved in mediating ET1-induced peripheral vasoconstriction in the rat.

[Experience gained from the organization of the first group of patients who benefited from liver transplantation]. / Tapasztalatok a májátültetéssel gyógyítható betegek elsö csoportjának szervezésével.

The authors report in this ciency in the majority of the cases was alcohol abuse or article about their experiences, how could they select a small group of patients awaiting liver transplantation since September 1994. The cause of the liver insuffiHCV infection. During 37 weeks 3 liver transplantations were performed and 5 patients died on the waiting list. (15,6% of the patients on the waiting list.)

Early secondary corrections after septorhinoplasty.

We perform all secondary corrections after septorhinoplasty as early as possible. Ten or twelve days after the primary intervention, the edema has diminished to such an extent that any residual defect is clearly detectable and easy to correct. This essentially is the concept of early secondary corrections after septorhinoplasty. We are convinced that any type of secondary correction can be performed at an early time. Our experience shows with an early secondary correction, patient and surgeon alike avoid the stress of a long waiting period as well as patient dissatisfaction during this waiting time.

Social influences: effects of the social environment on the use of alcohol and other drugs.

The research aimed to measure social influences produced by the differential effects of "high use" and "low use" environments on students' vulnerability to substance misuse. Each environment was represented by 3,000 students sampled from high and low use colleges. The social influences were measured by comparing vulnerability/resistance scores derived through a cognitive mapping strategy of the Associative Group Analysis method. Using an advanced system of software, empirical measures of students' propensities to use or not to use harmful substances were obtained by comparing hundreds of spontaneous responses elicited from individual respondents to the response distributions of reference groups of frequent alcohol/drug users and nonusers. In all comparisons, students with higher levels of reported use also showed higher vulnerability. In all comparisons, students in the high use environment showed significantly higher levels of vulnerability than students in the low use environment. ANOVA results indicated the vulnerability of students was significantly related to (high vs low use) campus environment as well as to marijuana use, alcohol use, and gender. Measuring vulnerability as a function of social influences opens numerous applications in proactive prevention.

Comparative study of the circulatory effects of aminoguanidine and N-nitro-L-arginine in hyperdynamic endotoxemia.

We have studied the effects of NG-nitro-L-arginine (NNA) a nitric oxide synthase (NOS) inhibitor, and aminoguanidine (AG) a diamine oxidase inhibitor, on hemodynamic parameters and plasma histamine level using a dog model in which a hyperdynamic circulatory response was elicited with a 2-hour infusion of a low dose (13.75 micrograms/kg) of E. coli 055:B5 endotoxin (ETX). AG (50 mg/kg) or NNA (0.5 mg/kg) was administered intravenously as pretreatment. Hemodynamic variables were studied for 4 hours after the beginning of the ETX infusion. The ETX-elicited hyperdynamic response was abolished by NNA and partially inhibited by AG. AG prevented the increases in cardiac output and heart rate and delayed the early decrease in total peripheral resistance (TPR). The plasma histamine concentration elevation was higher in animals receiving AG than in those receiving only ETX. In the group treated with ETX plus NNA the cardiac output was lower and the TPR was higher than in the ETX plus AG group. In future studies, AG should be considered as one of the possible therapeutic tools in sepsis, as its adverse effect on the compensatory hyperdynamic response is less than that of NOS inhibitors of the L-arginine analog type, while it may favourably influence the deleterious excessive activity of the inducible NOS in the later stages.

Twelve years' experience of calf augmentation.

The author describes his 12 years' experience of performing calf augmentation using gel-filled implants for the correction of thin or asymmetrical legs. In essence, these implants are placed over the gastrocnemius muscle beneath the fascia cruris.