Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: modulation by betamethasone

OBJECTIVES: To study the expression of preproendothelin-1 messenger RNA (mRNA) in tissue after Escherichia coli lipopolysaccharide challenge and to evaluate the possible effects of betamethasone both regarding endothelin-1 production as well as hemodynamic and vascular effects during E. coli lipopolysaccharide infusion in pigs in vivo. DESIGN: Prospective trial. SETTING: Laboratory at a university medical center. SUBJECTS: Ten domestic pigs, weighing 18 to 25 kg. INTERVENTIONS: Anesthetized pigs were given continuous infusions of E. coli lipopolysaccharide (15 micrograms/kg/hr for 3 hrs), with or without prior treatment with betamethasone (0.5 mg/kg im 12 hrs before the start of the surgical preparation and 0.5/kg iv at the start of the preparation). MEASUREMENTS AND MAIN RESULTS: The E. coli lipopolysaccharide infusion evoked the characteristic cardiovascular changes observed in septic shock: decreased mean arterial pressure and cardiac output; increased heart rate and increased pulmonary vascular resistance. Large increases in both arterial plasma concentrations of endothelin-1-like immunoreactivity, as well as preproendothelin-1 mRNA concentrations in tissues, were also observed during the E. coli lipopolysaccharide infusion. Treatment with betamethasone significantly attenuated the E. coli lipopolysaccharide-induced increase in endothelin-1 plasma concentrations, whereas the increased mRNA concentrations were only slightly affected. Furthermore, betamethasone treatment also affected cardiovascular parameters, with significant attenuation of the E. coli lipopolysaccharide-induced increase in heart rate and a higher cardiac output after 60 mins of the E. coli lipopolysaccharide infusion. The urine production, which was markedly decreased during the E. coli lipopolysaccharide infusion, was significantly higher in the betamethasone-treated group compared with the control group. CONCLUSIONS: The present results indicate that the increased concentrations of endothelin-1-like immunoreactivity that are observed in septic shock may have negative effects on both cardiovascular parameters as well as renal function, which is in agreement with a possible role for endothelin-1 in the pathogenesis of septic shock.     

Longer treatment with vasoactive drugs to prevent early variceal rebleeding in cirrhosis

Bleeding oesophageal varices (BOV), resulting from portal hypertension, can prove fatal. Not only is it important to stop the initial bleeding, which may lead to hypovolaemic shock, but also to treat this condition in the longer term, and, consequently, the prevention of rebleeding needs to be addressed. This review highlights the current findings on the haemostatic drug, terlipressin, focusing particular attention on the potential for longer-term treatment strategies in the prevention of rebleeding. The efficacy of terlipressin in treating acute BOV, its low incidence of severe side-effects (comparable to those of somatostatin) and its favourable comparison with sclerotherapy in the prevention of early rebleeds, all indicate the potential for terlipressin administration to be extended to 5 days in the longer-term treatment of BOV. In addition, terlipressin administration, in conjunction with sclerotherapy, can significantly reduce the likelihood of rebleeding compared with sclerotherapy alone and further supports its potential use in the longer-term treatment of BOV.     

Pharmacological distribution diagrams: a tool for de novo drug design

BACKGROUND: There is no empirical data available on attitudes concerning AIDS and habits towards HIV infected patients of physicians in general or private practice. In this study results of a self-evaluation are presented. METHODS: 178 physicians working with out-patients in different medical fields were randomly selected for a cross sectional study and interviewed using a standardised questionnaire. RESULTS: 89% think that they are sufficiently informed about AIDS (in the USA 20%). They regarded the risk of infection to be lower than the Anglo-American physicians. They believed there is a lack of interchange of information between colleagues regarding the degree of infectiousness of referred patients. A third of the physicians fear that other patients will go elsewhere if they find out that their physician is treating AIDS patients. 54% would hold special clinic sessions for HIV-patients outside the normal schedule for practice times. 89% believed that HIV patients were partly to blame for their illness. CONCLUSIONS: Although the physicians recognise the problem of HIV-infection, they partly deny the real necessities and facts. A reason for this could be the emotions underlying the general attitude to everything pertaining to HIV-disease. Attitudes to HIV-disease and the dealing with it in daily practice must be considered on the basis of individual emotional motives.     

HLA-DR mismatching correlates with early cardiac allograft rejection, incidence, and graft survival when high-confidence-level serological DR typing is used

To determine if cardiac allograft outcome is improved among patients with fewer HLA-DR mismatches with their donors, we studied 132 recipients of a primary cardiac allograft who were transplanted between December 1985 and December 1991. These recipients and their donors all had high-confidence-level serological HLA-DR typing, previously shown to correlate highly with DNA DR typing. Patients were divided in two groups based on the HLA-DR mismatch with their donors. Group I consisted of 78 patients with 1 or zero DR mismatch and group II of 54 patients with 2 DR mismatches. Allograft outcome measurements included incidence of moderate rejection, incidence of allograft vasculopathy at 12 months, cardiac function measured as left ventricular ejection fraction (LVEF) and cardiac index (CI), and actuarial graft survival up to 7 years. Groups I and group II were not different with regard to recipient age, donor age, ischemia time, pulmonary vascular resistance, sex, or PRA greater than 0%. Group II had a higher incidence of moderate rejection on the first-week biopsy (47% vs. 25%, P = 0.019), and during the first month (84% vs. 58%, P = 0.006), but no difference was found in frequency of rejection from months 2 to 12. LVEF was not different in the groups at any point. CI was better in group I at 12 months (2.76 vs. 2.5, P = 0.03). No statistically significant difference was found in incidence of allograft vasculopathy (17% vs. 26%, P = 0.204). Actual graft survival at 1 year was better for group I (91% vs. 74%, P = 0.008), and actuarial graft survival at 6 years also favored group I (76% vs. 56%, P = 0.04). Using high-confidence-level serological HLA-DR typing assignments we demonstrated that HLA-DR mismatching correlates highly with cardiac allograft outcome. Implications are that heart transplant survival could be improved if prospective matching were feasible and prioritized or if immunosuppression were tailored to the HLA-DR match.     

Study of adenovirus production in serum-free 293SF suspension culture by GFP-expression monitoring

BACKGROUND: Recently, investigators have reported the use of endoscopic myotomy in the treatment of esophageal achalasia. As with the open operation, considerable disagreement exists regarding the appropriate length of the myotomy and the need for a concomitant antireflux procedure. METHODS: Patients presenting with symptomatic achalasia between 1993 and 1997 were included in this prospective study. Preoperative studies included barium upper gastrointestinal study, endoscopy, and esophageal manometry. Laparoscopic myotomy was completed in all 20 patients; 18 had concomitant Toupet fundoplication. RESULTS: Operative times ranged from 95 to 345 minutes (mean 216). Blood loss ranged from 50 to 300 cc (mean 100 cc). There were 7 minor complications (5 mucosal injuries repaired laparoscopically, 1 bile leak and 1 splenic capsular tear). Nine patients began a liquid diet on the first day postoperatively; 19 were tolerating liquids by postoperative day 3. Hospital stay ranged from 2 to 20 days (mean 5). Eighteen patients had complete relief of dysphagia, with less than one reflux episode per month. One individual continues to have mild persistent solid food dysphagia. Another patient initially did well but subsequently developed mild recurrent dysphagia and reflux. One patient required laparoscopic take-down of the wrap because of recurrent dysphagia and now has no problems swallowing, but does complain of mild reflux. Two other patients also have mild reflux, 1 of whom did not undergo fundoplication. CONCLUSIONS: Laparoscopic Heller myotomy can be performed safely with excellent results in patients with achalasia. Adding a partial fundoplication appears to help control postoperative symptoms of reflux. This procedure should be considered the procedure of choice in patients with symptomatic esophageal achalasia.