Environmental mimic of receptor interaction: conformational analysis of CCK-15 in solution

CCK-15, a peptide derived from the 115-membered CCK preprohormone, was the object of a comparative conformational analysis by NMR spectroscopy and molecular modeling methods. NMR data in several solvents demonstrate that the propensity of the peptide to fold into a helical conformation is intrinsic, not merely a consequence of the interaction with phosphatidylcholine micelles or with a putative receptor, as suggested by a previous study on CCK-8 (Pellegrini, M.; Mierke, D. Biochemistry 1999, 38, 14775-14783.). The prevailing CCK-15 conformer in a mixture 1,1,1,3,3,3-hexafluoroacetone/water reveals that the residues common to CCK-15 and CCK-8 assume very similar conformations. Our CCK-15 structure is consistent with the model of receptor interaction proposed by Pellegrini and Mierke and discloses possible novel interactions that involve a larger area of the putative receptor. The consensus structure between CCK-15 and CCK-8 shows a good superposition of the side chains of residues 12-14 with crucial moieties of two non-peptidic CCK-A antagonists.     

Mortality after kidney transplant failure: the impact of non-immunologic factors

BACKGROUND: One third of cadaveric kidney transplant recipients suffer graft loss within five years of transplantation. Non-immunologic factors that predict mortality among non-transplant patients also may be potentially modifiable risk factors for mortality among patients with transplant failure. METHODS: Applying multivariate survival analysis to data from the United States Renal Data System, we determined the effect of immunologic or transplant related factors and non-immunologic factors on mortality in patients who initiated dialysis after kidney transplant failure in the United States between April 1995 and September 1998. RESULTS: A total of 4741 patients were followed for a median +/- standard deviation of 15 +/- 11 months after initiation of dialysis after transplant failure. The majority of the 1016 (21%) deaths were due to cardiac (36%) or infectious (17%) causes. Patients in the following groups had an increased risk for all-cause mortality: older patients [hazard ratio (HR) = 1.04 per year, 95% confidence interval (95% CI) 1.03-1.04], women (HR = 1.31, 95% CI 1.10-1.56), patients of white race (HR = 1.94, 95% CI 1.32-2.84), patients with diabetes (HR = 1.76, 95% CI 1.43-2.16), peripheral vascular disease (HR = 1.94, 95% CI 1.54-2.43), congestive heart failure (HR = 1.26, 95% CI 1.05-1.53), drug use (HR = 2.23; 95% CI 1.08-4.60), smokers (HR = 1.35, 95% CI 1.01-1.81), first transplant recipients (HR = 1.32, 95% CI 1.02-1.69), and patients with a higher glomerular filtration rate (GFR) at dialysis initiation (HR = 1.04 per mL/min higher, 95% CI 1.02-1.06). Those with private insurance (HR = 0.67, 95% CI 0.49-0.93) and higher serum albumin (HR = 0.73 per g/dL higher, 95% CI 0.64-0.83) had a decreased risk for all-cause mortality. Acute rejection, antibody induction, donor source, duration of graft survival and the maximum attained GFR during transplantation did not predict all-cause mortality. CONCLUSIONS: Non-immunologic factors predicted mortality among patients with transplant failure but immunologic and transplant related factors did not. Prevention, early diagnosis and treatment of co-morbid conditions and the complications of chronic kidney disease may improve the survival of patients with transplant failure.     

Pulmonary blastoma after liver transplant: a case report

There is an increased risk of cancer after organ transplantation mainly due to the immunosuppressive therapy required in these patients. We report a case of biphasic pulmonary blastoma in an adult male who underwent liver transplant for hepatocellular carcinoma in March 1999, followed by immunosuppressive treatment and adjuvant chemotherapy with epirubicin. Disease-free survival lasted 18 months, then a diagnosis of biphasic pulmonary blastoma was made and the patient underwent a lung lobectomy. Five months after surgical resection a recurrence of this rare tumor was recorded and two cycles of cisplatin + etoposide and ifosfamide + etoposide and one cycle of second-line chemotherapy with vinorelbine were administered. The tolerability and the efficacy of this treatment were poor. The patient died less than one year after diagnosis. To our knowledge this is the first reported case of pulmonary blastoma in a transplant patient. Our findings confirm that organ transplant recipients deserve long-term medical surveillance also in the absence of graft complications, and that pulmonary blastoma is an aggressive tumor with a poor prognosis.     

Billroth I versus Billroth II versus Roux-en-Y after subtotal gastrectomy. Prospective [correction of prespective] randomized study

BACKGROUND/AIMS: The aim of this study was to evaluate functional results after Billroth I, Billroth II and Roux-en-Y reconstruction in subtotal gastrectomy. METHODOLOGY: Forty-five patients were randomized between 1990 and 1995 and stratified in 3 different groups: 15 BI, 15 BII and 15 Roux. They were investigated by esophagogastroduodenoscopy with multiple biopsies and upper gastrointestinal scintiscanning, to evaluate gastroesophageal reflux and dynamics of gastric emptying. They also answered a questionnaire: Gastrointestinal Quality of Life. Index. RESULTS: A reflux esophagitis was found in 5 BI, in 7 BII and in 2 Roux (p < 0.001). No gastric lesions were found in 6 BI, in 5 BII and in 12 Roux, (BI vs. Y, p < 0.05; BII vs. Y, p < 0.001). Chronic superficial gastritis was present in 9 BI, in 4 BII and in 3 Roux (BI vs. Y, p < 0.05). Dynamic scintiscan demonstrated the presence of gastroesophageal reflux in 5 BI and gastric emptying was fast (37' < T 1/2 < 86'), but incomplete (60' residual activity: 49-62%). Gastroesophageal reflux was evident in 7 BII with slow (28' < T 1/2 < 143') and incomplete (60' residual activity: 48-72%) gastric emptying. Gastroesophageal reflux was detected in 2 Roux and radioactive bolus progression in the Roux limb was fast (24' < T 1/2 < 53') and complete (60' residual activity: 42-52%) (BI vs. Y; BII vs. Y, p < 0.001). There was no statistical significance between Gastrointestinal Quality of Life Index score in the 3 groups. CONCLUSIONS: The Authors affirm that Roux-en-Y is the technique of choice in subtotal gastrectomy, if compared with BI and BII.     

Topographic analysis of esophageal double-peaked waves

BACKGROUND & AIMS: Esophageal double-peaked waves occur with increased frequency in patients with functional esophageal symptoms. This study was undertaken to further understand the mechanisms responsible for their production. METHODS: Topographic methods that consider temporal and spatial relationships of pressure data were used to examine 74 double-peaked waves detected in 18 subjects referred for manometric evaluation of unexplained symptoms. The studies were performed with a computerized data acquisition and analysis system designed for topographic plotting. RESULTS: The second peak appeared to represent muscle contraction that merged with an unusually strong pressure site in the third topographic segment and covered 6.3 +/- 1.6 cm (33.5% +/- 8.5% esophageal length) proximal to this site. In 50 swallows (67.6%), the peak itself progressed in a retrograde direction at 13.2 +/- 10.8 cm/s, suggesting cephalad extension of a strong distal motor event. Analysis of wave onsets and movement of the peristaltic trailing edge detected retrograde propagation in up to 33.8% of waves, antegrade propagation in 2.7%, and simultaneous contraction in the remainder. CONCLUSIONS: In symptomatic patients, the second peak in a double-peaked wave is typically a short, simultaneous, or retrograde pressure event in the region of and merging with the third topographic segment in the distal esophageal body. Topographic methods help explain the common association of these waveforms with other features of exaggerated contraction in the distal esophagus and suggest their relationship to inadequate inhibitory nerve function.     

The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury

BACKGROUND: Oxidative stress contributes to the pathogenesis of hepatic ischemia-reperfusion injury. This study aimed to determine whether fatty degeneration affects the oxidative damage during warm ischemia reperfusion and whether mitochondria, the major intracellular site of energy synthesis, represent a preferential target of this injury. MATERIALS AND METHODS: Fed rats with control or fatty liver induced by choline deficiency underwent 60' lobar ischemia and reperfusion. Oxidative damage was assessed by measuring in whole liver tissue and in isolated mitochondria the thiobarbituric acid-reactive substances (TBARs), protein carbonyls (PC), and total and oxidized glutathione (GSH and GSSG) concentrations. The mitochondrial F0-F1-ATPase content and the oxidative phosphorylation activity were also determined. Rat survival and ALT release were assessed as parameters of liver injury. RESULTS: In the whole liver tissue, with the exception of TBARs, no differences were observed for GSH, GSSG, and PC between the two groups throughout all of the experiment. In contrast, in isolated mitochondria, fatty infiltration was associated with a mild oxidative imbalance already under basal conditions. The preischemic differences in the mitochondrial TBARs, PC, and GSSG levels were significantly amplified by reperfusion in the presence of steatosis. The enhanced oxidative damage was associated to a reduced F0-F1-ATPase content and oxidative phosphorylation activity in fatty liver mitochondria. Finally, serum ALT levels were significantly greater and survival significantly lower in rats with steatotic liver. CONCLUSIONS: Fatty infiltration exacerbates mitochondrial oxidative injury during warm ischemia reperfusion. The increased oxidative stress can alter mitochondrial functions, including key processes for ATP synthesis, thus, contributing to the reduced tolerance to reperfusion injury.     

The complementary role of sonography and arteriography in the evaluation of the atheromatous abdominal aorta

Sonography was performed on 41 patients, 24 of whom were suspected of having abdominal aortic aneurysms and 17 of whom had symptomatic peripheral vascular disease. The accuracy of sonography in the diagnosis of aneurysms of the abdominal aorta was evaluated, and the instances in which angioggraphy contributed to the management of these patients was defined. Sonography is adequate for the diagnosis and management of many aneurysms of the abdominal aorta. Aortography is necessary when: (1) an inadequate study has been obtained, (2) the iliac arteries are not visualized, (3) renal or mesenteric artery involvement is suspected, (4) multiple or lobulated aneurysms are found, or (5) the aorta is very tortuous.     

Multiple lines of chemotherapy are the main risk factor for severe infections in patients with chronic lymphocytic leukemia with febrile episodes

We report on febrile episodes occurring among 379 patients affected by chronic lymphocytic leukemia, observed from 1984 to 2002. One hundred and twenty eight patients (33.7%) developed 341 febrile episodes, of which 251 were documented infections (82 severe and 169 moderate). Among various risk factors, only previous treatment with multiple regimens of chemotherapy was associated with severity of infection (p=0.0005).