The roles of cyclic adenosine monophosphate- and cyclic guanosine monophosphate-dependent protein kinase pathways in hydrogen peroxide-induced contractility of microvascular lung pericytes

BACKGROUND: Sepsis and posttraumatic inflammatory processes are accompanied by definite changes in microvascular permeability, particularly in the lung. These permeability changes may occur because of damaged regulatory mechanisms at the level of the capillary wall. Pericytes are adventitial cells located within the basement membrane of capillaries. These cells contain multiple cytoplasmic processes that envelope endothelial cells, and are consequently thought to stabilize capillary walls and participate in microcirculation and endothelial cell permeability. Data from this laboratory and other laboratories have confirmed that pericytes are contractile cells, adding to the evidence that pericytes may influence or help regulate capillary permeability. We have already determined that hydrogen peroxide (H2O2) causes dose-dependent relaxation in microvascular lung pericytes (MLPs) at 10 minutes and, conversely, dose-dependent contraction at 30 minutes. It is the aim of this study to determine the mechanism of this biphasic contractile response. Specifically, we will determine whether cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP)-dependent protein kinase intracellular pathways are responsible for the hydrogen peroxide-induced contractility of MLPs. METHODS: Rat MLPs were isolated by previously published protocol and cultured on collagen gel matrices. MLPs were pretreated with either ODQ, a soluble guanylate cyclase inhibitor (100 mumol/L), for 15 minutes; GKIP, a protein kinase G inhibitor (100 mumol/L), for 1 hour; SQ22536, an adenylate cyclase inhibitor (100 mumol/L), for 15 minutes; or H89, a protein kinase A inhibitor (10 mumol/L), for 1 hour. Hydrogen peroxide was then introduced to each MLP culture at 10 mumol/L, 100 mumol/L, and 1 mmol/L. After each of these treatments, the surface area of the collagen gels was digitally quantified at 10 and 30 minutes. RESULTS: SQ22536 attenuated both relaxation at 10 minutes and the contraction seen at 30 minutes for all concentrations of H2O2. H89 caused a marked basal relaxation and prevented the cells from contracting at 30-minute exposures to all concentrations of H2O2. Both ODQ and GKIP attenuated the relaxation at 10 minutes but had no affect on the later contraction. CONCLUSION: The cGMP-dependent protein kinase pathway is a mechanism for H2O2-induced relaxation of MLPs. Up-regulation of cAMP and cGMP is responsible for early H2O2-induced relaxation and late contraction. Protein kinase A (cAMP-dependent protein kinase pathway) may be an important intracellular signaling protein in the H2O2-induced contraction of MLPs or may be unable to down-regulate cAMP once inhibited. This evidence further supports the concept that there are separate intracellular pathways that regulate divergent cellular responses. This idea parallels the clinical concept of reversible and irreversible dysfunction of cellular processes in shock, and that the cellular dysfunction is initiated by separate intracellular pathways.     

Intracavernous papaverine in the management of psychogenic impotence

Intracavernous papaverine has found an important place in the management of male erectile failure. The effect of this mode of therapy was studied in 48 patients with psychogenic impotence. The average follow-up for this group of patients ranged from 7 months to 37 months (mean 16.3 months). All the patients in this group were advised sex therapy as an initial mode of therapy. On refusal to undergo sex therapy, they were offered an option of intracavernous papaverine injection. Papaverine appears to break the performance anxiety erectile failure cycle and was noted to have good results. Overall 57.9% patients expressed complete satisfaction with this mode of therapy. One patient (2.1%) developed priapism, which was adequately treated with intracavernous epinephrine. Use of low dosage of papaverine is suggested as an additional mode of therapy in the management of psychogenic impotence.     

Hepatitis C in children: a quaternary referral center perspective

INTRODUCTION: Chronic hepatitis C virus (HCV) infection affects 0.3% of children in the United States, and the general impression is that it has a benign course in childhood. We analyzed a pediatric population with chronic HCV in a quaternary referral center. MATERIAL AND METHODS: This is a retrospective clinical review comprising all patients with chronic HCV referred to the Pediatric Liver/Liver Transplant Program between January 1999 and December 2004. RESULTS: Ninety-one patients (52% female; mean age, 9 years) were assessed. Eight-three percent of the patients were genotype 1. Twenty-one patients received/are receiving interferon and ribavirin for chronic HCV (treatment indications--advanced disease, 9; clinical trial, 6; genotype 2, 2; social, 2; prerenal transplant, 1). Eight (53%) of 15 patients, who have completed therapy and follow-up, achieved sustained viral response. Seven of 91 patients had cirrhosis at presentation (mean age, 11.7 years). Four underwent liver transplantation, all experienced HCV recurrence, 2 died, 1 was retransplanted, and 1 has compensated cirrhosis. CONCLUSION: Although, in general, HCV in children has a slow progression, there are cases with an accelerated course and early development of cirrhosis requiring liver transplant. Hepatitis C virus recurs universally after transplant, and its prognosis is usually poor; therefore, the most promising long-term approach is to clear this infection before transplantation.     

Isolated single coronary artery (RII-B type) presenting as an inferior wall myocardial infarction: A rare clinical entity

Isolated single coronary artery without other congenital cardiac anomalies is very rare among the different variations of anomalous coronary patterns. The prognosis in patients with single coronary varies according to the anatomic distribution and associated coronary atherosclerosis. If the left main coronary artery travels between the aorta and pulmonary arteries, it may be a cause of sudden cardiac death. We present multimodality images of a single coronary artery, in which the whole coronary system originated by a single trunk from the right sinus of Valsalva with inter-arterial course of left main coronary artery. This rare type of single coronary artery was classified as RII-B type according to Lipton's scheme of classification. A significant flow-limiting lesions were found in the right coronary artery that was successfully treated with percutaneous coronary intervention.     

Orthotopic liver transplantation for adults with Alagille syndrome

Arnon R, Annunziato R, Schiano T, Miloh T, Baisley M, Sogawa H, Contreras AG, Lee S, Kerkar N. Orthotopic liver transplantation for adults with Alagille syndrome.
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01574.x.
© 2011 John Wiley & Sons A/S. Abstract: Introduction: Alagille syndrome (AGS) is an inherited multisystem disorder, and liver transplantation (LT) may be required in pediatric patients with AGS (P‐AGS). There are limited data regarding the outcomes of LT in adults with AGS (A‐AGS). Aim: To determine and compare the outcomes of LT in A‐AGS vs. P‐AGS as well as A‐AGS vs. adults with biliary atresia (A‐BA). Methods: Adults (>18 yr), with AGS and BA, and children (≤18 yr), with AGS who underwent isolated first LT between 10/1987 and 5/2008, were identified from the UNOS database. Results: Forty‐four of 79 400 adults transplanted for AGS were compared with 407 P‐AGS and 56 A‐BA, respectively. A‐AGS patients had a significantly higher rate of encephalopathy, lower serum albumin, and higher serum creatinine in comparison with P‐AGS. One‐ and five‐yr patient and graft survival in A‐AGS who underwent LT were not significantly different in comparison with either P‐AGS or A‐BA (A‐AGS patient survival: 95.5%, 90.9%, P‐AGS: 88. 7%, 86.2%, A‐BA: 89.3%, 87.5%; A‐AGS graft survival: 84.1%, 79. 5%, P‐AGS: 80.3%, 76%. 1%, A‐BA: 82.1%, 78.6%, respectively). Conclusion: The outcome of first LT in A‐AGS is excellent compared with the overall reported adult patient and graft survival. Although A‐AGS were sicker than P‐AGS at transplant, their outcomes were comparable with that of P‐AGS.