Full-right-full-left split liver transplantation: the retrospective analysis of an early multicenter experience including graft sharing.

Full-right-full-left split liver transplantation divides a donor liver into two grafts to be transplanted in adult-size patients. Major technical and organizational difficulties have limited its application to few single center series. We retrospectively analyzed the long-term results of the first multicenter series of this procedure with graft sharing. Between November 1998 and January 2005, 43 transplants were performed by five centers from 23 full-right-full-left in situ split liver procedures; 65% of the grafts were shared. A total of 31 (72%) patients had complications above grade II; 3 (6.9%) were retransplanted. Hospital mortality was 23% with sepsis as the main cause. Six patients died in the long term, two of them for a road accident. A total of 27 patients are alive after a median follow-up of 3200 days (2035-4256). Actuarial survival at 1 and 10 years were 72.1%, 62.6% and 65.1%, 57.9%, respectively for patients and grafts. These figures are similar to those reported for adult living donor liver transplantation by the European Registry over a similar period. Multicenter collaboration in sharing of these grafts is feasible and can help facing the organizational limits, thus increasing diffusion of full-right-full-left split liver transplantation.

Stem cells therapy in acute myocardial infarction: a new era?

Stem cells transplantation after acute myocardial infarction (AMI) has been claimed to restore cardiac function. However, this therapy is still restricted to experimental studies and clinical trials. Early un-blinded studies suggested a benefit from stem cell therapy following AMI. More recent blinded randomized trials have produced mixed results and, notably, the last largest pan-European clinical trial showed the inconclusive results. Furthermore, mechanisms of potential benefit remain uncertain. This review analytically evaluates 34 blinded and un-blinded clinical trials comprising 3142 patients and is aimed to: (1) identify the pros and cons of stem cell therapy up to a 6-month follow-up after AMI comparing benefit or no effectiveness reported in clinical trials; (2) provide useful information for planning future clinical programs of cardiac stem cell therapy.

Predictors of survival in idiopathic interstitial pneumonia.

AIM: To evaluate the ability of newly identified clinical factors to predict prognosis and survival in idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). METHODS: Seventy-eight patients referred to the University of Genoa and the Regional Hospital of Aosta between January 1995 and December 2006 were evaluated prospectively. Fifty-nine patients were diagnosed with IPF and 19 with NSIP on the basis of surgical lung biopsy specimens. Gender, age at diagnosis, smoking, New York Heart Association class (NYHA), systolic pulmonary artery pressure (sPAP), Octreoscan uptake index (UI), and therapy were the chosen variables. Primary end-point was survival. RESULTS: With the exception of gender and smoking history, all baseline patient characteristics correlated significantly with the diagnosis (IPF vs. NSIP). Median survival for the entire study group was 52.7 months. Univariate analysis showed poorer survival for the IPF group versus the NSIP group, and survival was significantly lower for older patients (p < 0.001). Multivariate analysis confirmed the negative prognostic effect of age (p < 0.001) on survival with a risk of death for older patients ( > OR =66 years old) being more than 4 times higher than that for younger patients (<58 yr.). NYHA class and pulmonary artery pressure were also significant predictors of survival, and all patients with a sPAP < OR = 35-mm Hg were alive at the end of the follow-up period. There was a good correlation between Octreoscan uptake index and the diagnosis. CONCLUSION: Diagnosis (IPF vs. NSIP), NYHA class, sPAP, and especially age appear to represent important prognostic indicators in the two most prevalent forms of idiopathic pulmonary fibrosis (IPF and NSIP). Lower Octreoscan uptake values were found in all patients with IPF, suggesting that this test may have a role as a new predictor of survival for differentiating IPF from NSIP.

New York Heart Association class associated with imaging is a prognostic mortality risk predictor in interstitial lung diseases.

OBJECTIVE: Mortality risk factors as forced vital capacity, diffuse lung capacity for carbon monoxide, and 6-minutes' walk test were studied in clinical trials monitoring patients affected by interstitial lung diseases (ILD). However, these parameters showed scarce accuracy. Our aim was to identify New York Heart Association (NHYA) class, in association with high resolution computed tomography (HRCT) and somatostatin receptor scintigraphy (Octreoscan), as a prognostic mortality risk factor in ILD patients. PATIENTS AND METHODS: Study population comprised 128 ILD patients (78 Males and 50 Females). Histological diagnosis was usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP) and granulomatous lung disease in 59, 19 and 50 patients, respectively. Patients were monitored by NYHA class, HRCT and Octreoscan at baseline and every 3 years up to a 10-year follow up. Overall survival was calculated from the date of diagnosis until death or last follow-up update. Statistical analysis was performed using Kaplan-Meier, log-rank test (LRT), multivariate analysis with Cox proportional hazard regression model, and log-likelihood ratio test. RESULTS: Overall median survival was 89.3 months (7.4 years) with the poorer survival rate observed in UIP patients. NYHA class came out as a reliable prognostic mortality risk factor in each group of patients and prognosis was progressively worse with NYHA class increase (LRT p<0.001). A strong correlation was found between NYHA class and age, CT-score, and Octreoscan in UIP patients (p<0.001). CONCLUSIONS: The determination of NYHA class can therefore be recommended as an additional prognostic mortality risk factor in ILD patients.

Predictors of mortality of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a disease with histological features corresponding to usual interstitial pneumonia (UIP), is a disorder of unknown cause. Not only it is the most common subtype of idiopathic interstitial pneumonias but it is also associated with the highest mortality rate. Despite a good number of studies investigating the mortality of patients with UIP the prognostic factors that have been studied have several limitations. To date it is unclear when in the course of the disease and with what modality these patients should be treated. According to the literature we subcategorized predictors of mortality into (a) baseline predictors; (b) dynamic predictors. IPF perspectives in therapy have been also analyzed. Moreover, the principal aims of this review were: (1) to analyze and to clarify the clinical utility of different prognostic factors for IPF; (2) to enable clinicians to better evaluate the eligibility criteria for lung transplantation in the clinical practice.

Model for End-Stage Liver Disease (MELD) score and organ allocation from cadaveric donors for 198 liver transplantation procedures performed in a single center.

Since February 2002, the United Network for Organ Sharing (UNOS) proposed to adopt a modified version of the Model for End-Stage Liver Disease (MELD) to assign priority on the waiting list for orthotopic liver transplantation (OLT). In this study, we evaluated the impact of MELD score on liver allocation in a single center series of 198 liver recipients (mean age of patients, 52.21+/-8.92 years), considering the relationship between clinical urgency derived from MELD score (overall MELD, 18.7+/-6.83; MELD <15 in 69 patients, MELD >or=15 in 129 patients) and geographical distribution of cadaveric donors (inside/outside Liguria Region, 125/73). The waiting time for OLT was 230+/-248 days, whereas the 3-month and 1-year patient survivals were 87.37% and 79.79%, respectively. No difference was observed for MELD score retrospectively calculated for patients who underwent OLT before February 2002 (n=71) compared with MELD score calculated for patients who received a liver thereafter (18.26+/-6.68 vs 18.94+/-6.92; P= .504). No significant difference was found in waiting time before and after adoption of MELD score (213+/-183 vs 238+/-278 days; P= .500), or by stratifying patients for MELD <15/>or=15 (225+/-234 vs 232+/-256 days; P= .851). Using the geographical distribution of donors as a grouping variable (outside vs inside Liguria Region), no significance occurred for MELD score (19.68+/-7.42 vs 18.17+/-6.42; P= .135) or waiting time (211+/-226 vs 242+/-261 days; P= .394). In our series, more OLTs were performed among sicker patients and no differences were found in the management of livers procured from cadaveric donors outside or inside Liguria Region. However, further efforts are needed to reduce the waiting time among patients with higher MELD scores.

Sirolimus therapy in liver transplant patients: an initial experience at a single center.

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.

Preliminary results of liver transplantation for hepatocellular carcinoma among allocation organ policy strategies, neoadjuvant treatments, and intention-to-treat analysis.

We retrospectively evaluated the impact of our strategy for patients with hepatocellular carcinoma (HCC) according to an intention-to-treat analysis and drop-out probability. We evaluated only patients within the Milan criteria. We analyzed the outcomes of neoadjuvant strategies for HCC, organ allocation policy, and systematic application of strategies to increase the deceased donor pool as the current tendency to expand transplantability criteria for those patients. Kaplan-Meier survival probability rates at 1, 3, and 5 years according to an intention-to-treat analysis were 87.02%, 74.53%, and 65.93% for transplanted patients (n=108), and 50%, 14.29%, and 14.29% for the excluded or waiting list group (n=13), respectively (P< .0001). Drop-out risk at 3, 6, and 12 months was 2.40%, 8.59%, and 16.54%, respectively. During the same period, the mortality probability rates at 3, 6, and 12 months among patients without HCC awaiting orthotopic liver transplantation (OLT) were 3.60%, 9.50%, and 18.34%, respectively. Drop-out rate was lower among patients treated before OLT (P< .0001). On the basis of the neoadjuvant treatment results to reduce drop-out risk, we suggest avoiding the high priority for the HCC cohort, particularly within the first 6 months from entrance on the waiting list, because this approach can reduce the chances of patients with end-stage liver disease (ESLD) alone.

Medical report type in liver transplantation as a quality system document: new prospects for computerization.

The usage of a computerized system to organize data and ease the activity procedures of liver transplantation is useful in clinical transplantation. Preliminary cognitive research on systems of clinical transplantation database concerning medical reports was performed to verify their development level. The survey highlighted that, so far, there has been no experimentation that can be applied to a medical report type devoted to liver transplantation. Regulations in force substantially point out that the medical report ought to contain all items that have to be taken into account in handling the patient from pretransplantation to follow-up. The Department of Transplantation of Genoa chose its medical report model for liver transplantation. The medical report model included the following items: personal data; case history; diagnosis; initial examination for prelisting; fitness for transplantation; assistance context; clinical data including subjective, objective, and instrumental parameters; pharmacological therapies; informed consent, evaluation of fitness; nursing data; counseling and clinical evaluations according to protocols and guidelines of the national transplantation centers. If the computing is well trained, it is supposed to help maintain a whole data view provided it is supplied information in an adequate way. Immediate clinical procedural advantages and useful scientific observations may be obtained from a high-quality database. In fact, all functions have to be applied to specific clinical, administrative needs to be remotely shared and conveniently integrated with each other to make the liver transplantation medical report an easy and handy instrument for inputting and handling data. It must be a precise, complete instrument that may be accessible in real time from any site connected with the intranet network, be unchangeable, and be protected to ensure certification and forensic medicine value.

Split liver transplantation for acute Wilson's disease: new option for urgent recipient?

Wilson's disease is a rare metabolic disorder that may lead to fulminant hepatitis and subsequent liver failure. Herein, we present a case of split liver transplantation performed on a patient with acute Wilson's disease. A 27-year-old female with acute presentation of Wilson's disease and advanced neurological impairment, received a Right Split liver Graft (Segments: IV, V, VI, VII and VIII) transplant. The graft was obtained by an in situ splitting technique. The graft implantation was performed in a standard fashion. No acute rejection episodes of the organ occurred. The postoperative course was uneventful. The graft function, ceruloplasmine level and copper levels progressively normalized. The patient totally recovered from neurological symptoms and the Kayser-Fleischer rings disappeared within one month. At 13 months of follow-up, the patient presented with no symptoms and in good condition. The current literature reports high preoperative mortality rate in patients that underwent partial liver graft for acute hepatic failure. However, our experience indicates that in situ split technique of liver may be a feasible and effective alternative to whole graft transplantation in urgent cases. Moreover, to our knowledge, this is the first successfully case of in situ split liver transplantation for acute Wilson's disease described in literature.

Role of Liver Transplantation in Bilio-Vascular Liver Injury After Cholecystectomy.

BACKGROUND: The aim of this study was to report 2 cases of liver transplantation (LT) for iatrogenic bile-vascular injury (BVI) sustained during cholecystectomy and to review the literature for LT after cholecystectomy. METHODS: Between March 2001 and July 2013, within our institution, 12 patients were treated after cholecystectomy, 3 of 12 received LT, 1 for acute de-compensation in a cirrhotic patient and 2 after iatrogenic lesions. RESULTS: The majority of iatrogenic injury occurred during video-laparocholecystectomy (63,6%; 7/11). Three patients of 12 (25%) received LT: the first patient developed acute de-compensation in chronic and after liver failure. The second patient developed recurrent cholangitis and secondary biliary cirrhosis. The third patient had undergone emergency hepatectomy because of bleeding and subsequent total hepatectomy with porto-caval shunt. Five of 12 (42%) patients were treated with bilio-digestive anastomosis: 1 patient with direct repair on T-tube; 2 patients (17%) with arterial vascular lesion requiring surgical treatment; and 1 patient treated with medical therapy. No deaths occurred. The post-operative morbidity included 1 re-intervention, 3 recurrent cholangitis, 1 anastomotic biliary stricture, 1 anastomotic bile leak, and cholestasis in 3 patients. The overall hospital stays were higher after LT. Median follow-up was 8.25 years (range, 2-14). CONCLUSIONS: The management of iatrogenic injury during cholecystectomy depends on the time of recognition, extent of injury, experience of the surgeon, and the patient's general condition. If safe repair is possible, BVI should be treated promptly, otherwise all patients should be treated in an experienced center.

Bronchial hyperresponsiveness in asthmatic adults--a long-term correlation study.

BACKGROUND: Bronchial hyper responsiveness (BHR), is a risk factor for asthma. It is a state in which excessive narrowing of the airways occurs in response to varying stimuli. BHR seems to be due to the interaction of multiple factors and its relation to asthma is complex. Asthma without BHR is unusual. Indeed, patients who show a higher degree of symptoms have higher levels of BHR. To date no study has investigated the correlation between BHR in mild persistent asthmatic adults and a long-term therapy of five years. The aim of this study is to evaluate (i) the role of BHR in the clinical evaluation of asthma, (ii) the correlation between BHR and therapy in asthma. METHODS: Seventy patients (were recruited 34 men, age 21-55 years) suffering from: (a) mild seasonal allergic asthma (17/70), (b) mild perennial allergic asthma (34/70) and (c) mild non-allergic [corrected] asthma (19/70). 14 patients from group (a) and 28 patients from group (b) were treated with inhaled beta2-agonists, beclomethasone, disodiumcromoglycate and immunotherapy. 14 patients from group (c) underwent the same treatment regimen without immunotherapy. All patients were evaluated with a metacholine challenge test. The BHR (PD20 FEV1) was calculated at baseline and after a two-year symptom free period. Fifteen pts were followed-up for five years with an evaluation every year. All other patients did not receive any treatment. The results (expressed as mean +/- SE) were evaluated. RESULTS: Fourteen pts and three pts from group (a) showed a mean BHR value of 984 +/- 3.66 and 674 +/- 2.06; 343 +/- 7.60 and 208 +/- 7.70 respectively. The results were not statistically significant Twenty-eight and six pts from group (b) showed mean values of 685 +/- 1.45 and 1405 +/- 5.65; 856 +/- 7.09 and 435 +/- 2.20 with apparent improvement for the former. Five pts and fourteen pts from group (c) showed mean value of 2682 +/- 7.85 and 2099 +/- 6.82; 816 +/- 2.53 and 877 +/- 4.78 respectively. As for the 5-yr follow up ten pts and five pts from group (b) showed mean values of 705 +/- 1.6 and 861 +/- 7.15; 911 +/- 7.3 and 457 +/- 2.3 respectively. CONCLUSIONS: Although the clinical picture improved with therapy, BHR was not significantly affected in any patient group, at two and five years of follow-up. Furthermore, no correlation was found between the clinical picture and PD20 FEV1 values. BHR seems to result from the interaction of multiple factors that are worth further investigating. BHR cannot be considered a marker of disease activity in asthma and therefore is not a useful tool for guiding asthma therapy.

Secondary pulmonary hypertension--diagnosis and management.

Secondary pulmonary hypertension (SPHtn) is generally attributable to abnormalities in structure or function of the heart or lung parenchyma. While often defined as a physiologic parameter, pulmonary hypertension (PHtn) can be a major contributor to death and disability in cardiopulmonary diseases. Both detection and management are a challenge. We will review the pathophysiology, diagnostic tools, and treatment strategies in SPHtn with an emphasis on cor pulmonale associated with chronic obstructive pulmonary disease (COPD), pulmonary vasculopathies, and pulmonary embolus. The pathophysiology and common etiologies of SPHtn can be divided into three major categories: (1) elevated pulmonary venous pressure (LV failure and mitral valve disease), (2) pulmonary vascular occlusive disease with or without pulmonary parenchymal disease (pulmonary emboli, COPD, connective tissue diseases), and (3) hypoxemia (sleep apnea). The echo-Doppler is a simple cost-effective tool for detecting PHtn, evaluating right ventricular function, and distinguishing common etiologies such as abnormal systolic and diastolic left ventricular function and mitral valve disease. The ventilation-perfusion radionuclide scan can be used to exclude thromboembolic PHtn, but a helical computer tomography with contrast or pulmonary angiography are necessary to distinguish patients that may benefit from a pulmonary thromboendarterectomy. The six minute walk oxygen saturation test is useful as a quantitative measure of functional capacity, prognosis, response to therapy, and oxygen requirement. Treatment strategies in cor pulmonale are tailored to the specific diagnosis, but generally include proper nutrition, exercise, oxygen supplementation, medications such as digoxin, diuretics, anti-coagulation, and pulmonary vasodilator therapy in selected patients.

Impact of different cadaveric donor age cut-offs on adult recipient survival after liver transplantation: a single-center analysis.

The increase in the number of patients awaiting liver transplantation (OLT) has forced the use of cadaveric donors (CD) with suboptimal characteristics. Of these, donor age is perhaps the most investigated parameter. Although excellent outcomes were observed for OLT using CD aged over 60 years, the European Liver Transplant Registry (ELTR) Group found an increased risk by using CD of more than 55 years. The Italian National Transplant Center has recently assumed that CD age more than 60 years is a potential risk factor for OLT. In this study, a single-center analysis was performed by stratifying CD by three age cut-offs (< or =55 or >55, < or =60 or >60, and < or =65 or >65 years) to evaluate effects on OLT outcome. Although no significant difference in 6-month and 1-year patient or graft survival occurred after stratification for each donor age cut-off, a better survival was observed with OLT performed using livers procured from CD >55 years. A significant increase in cold ischemia time (CIT) was observed among OLT performed with grafts procured from CD < or =55 and < or =65 years (P = .007), and there was an inverse correlation between overall CIT and donor age (R = -0.300; P = .0022). However, no impact on 1-year patient survival was observed by introducing CIT in univariate logistic regression models as well as donor age, recipient age, donor/recipient age ratio, donor/recipient sex mismatch, ELTR diagnostic categories, and UNOS status. The results of this study suggest the suitability of CD of more than 55 years for OLT and the need to further investigate the cut-off value for CIT-related risk.

Regional pharmacokinetic selectivity of intrapleural cisplatin.

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Atypical tumor lysis syndrome in a patient with T cell lymphoma treated with recombinant leukocyte interferon.

Biochemical and clinical signs of tumor lysis syndrome developed in a 57-year-old man with recurrent T cell lymphoma during therapy with recombinant leukocyte A interferon. When therapy was interrupted due to thrombocytopenia and later resumed, biochemical changes compatible with tumor lysis recurred. This is the first case of tumor lysis syndrome observed during therapy with a biologic response modifier, a new class of agents entering cancer clinical trials. The atypical features of the clinical presentation and possible implications of these observations are discussed.

Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia.

Recombinant leukocyte A interferon is a highly purified single molecular species of alpha-interferon prepared by recombinant DNA methods. In 1982, a phase II trial to evaluate the efficacy of recombinant leukocyte A interferon for patients with previously treated chronic lymphocytic leukemia was begun, and 19 patients were entered in this study. Patients received one of two dose schedules depending on their pretreatment platelet counts. Those with platelet counts greater than 100,000/mm3 received 50 X 10(6) units/m2 intramuscularly three times weekly, with dose reductions to 25 X 10(6) units/m2 and 5 X 10(6) units/m2 for unacceptable toxicity. Those with platelet counts less than 100,000/mm3 received 5 X 10(6) units/m2 intramuscularly three times weekly. Toxicity was dose-dependent and included fever, chills, fatigue, anorexia, myalgias, headache, leukopenia, and thrombocytopenia. Response was evaluable in all but one of the patients entered in this study. Two of the 12 patients treated with 50 X 10(6) units/m2 had a partial response, three had no response, and seven had progressive disease. Of the six patients starting at 5 X 10(6) units/m2 in whom response was evaluable, two had no response and four had progressive disease. Five patients with progressive disease (three at 50 X 10(6) units/m2 and two at 5 X 10(6) units/m2) had an acceleration of disease while receiving recombinant leukocyte A interferon. It is concluded that the dose and schedule of recombinant leukocyte A interferon therapy tested in this study are not effective in previously treated patients with advanced chronic lymphocytic leukemia.

Some effects of prolonged treatment with nicardipine in chronic bronchial asthma.

A study was carried out in 10 patients with chronic non-severe asthma to investigate the effects of prolonged treatment with the calcium blocker, nicardipine. Patients received 60 mg nicardipine daily for 3 months. Measurements were taken before and after treatment of FEV1, PaO2 and PD20 his. The results showed no statistically significant effect on FEV1. Although there was a statistically significant decrease in PaO2 this was not important clinically. There was a statistically significant increase in PD20 his, demonstrating the protective effect of nicardipine on histamine-induced bronchoconstriction. Breathlessness was reduced in 70% of the patients and the drug was well tolerated throughout the study.

Hyperresponsiveness of airway muscle to acetylcholine in asthmatic and non-asthmatic subjects.

BACKGROUND: Despite a long-standing recognition, the bronchial hyperresponsiveness (BHR) of airway smooth muscle, in asthmatic and non-asthmatic subjects is still under investigation. OBJECTIVE: In order to better understand the mechanism regulating the airway function, some results obtained with cellular physiology techniques are compared, for some non-asthmatic without BHR subjects and other subjects suffering from real bronchial asthma. SUBJECTS: Eighteen subjects without chronic or acute bronchopathy and seven patients with a typical history of bronchial asthma were considered. All of them were non-smokers, with a wide range of in vivo hyperresponsiveness to Acetylcholine (ACh). Owing to neoplastic lesions, all patients underwent a thoracic surgery. MEASUREMENTS AND RESULTS: In vitro hyperresponsiveness of airway-smooth-muscle chains was assessed with isotonic contractions to incremental doses of ACh, in accordance with a non-cumulative dose-response technique. Regression between muscle contractions and ACh doses was studied for both groups, and it turned out to be linear in both cases. The slopes and elevations of the regression lines of the two groups were statically identical. There was no correlation between in vivo hyperresponsiveness (as PD20-ACh-FEV1) and in vitro responses (as EC50), for both asthmatic and non-asthmatic group. CONCLUSIONS: (i) in vitro, the same BHR of smooth-muscle resulted, for both asthmatic and non-asthmatic subjects, (ii) in vivo, a different BHR of the former group resulted. This can be explained with the peculiarity of the micro-environmental surrounding the bronchial tissue, not with an intrinsic defect of the isolated bronchial tissue.

Neurotensin pulmonary metabolism in normal and asthmatic subjects.

BACKGROUND: The role of pulmonary metabolism of endogenous neurotensin (NT) in asthma is still unclear. Information on this subject in humans is scarce. OBJECTIVES: Evaluation of the pulmonary metabolism of the endogenous NT in asthmatic subjects during symptom-free periods and after a methacoline challenge test and in healthy individuals. METHODS: Ten asthmatic subjects (aged 34 to 70 years), diagnosed with extrinsic (n = 5), atopic (n = 3), and mixed asthma (n = 2), were compared to a group of 10 healthy individuals (aged 45 to 69 years). The asthmatic group of patients was evaluated with a PD20-FEV1 methacoline challenge test 3 days after a washout period from cessation of their regular medications. Two catheters were inserted in order to draw blood samples for the evaluation of NT concentration: one was inserted into the pulmonary artery and the other into the radial artery. The mean concentration of NT in pulmonary and systemic arterial blood, as well as the arteriovenous difference of NT and the absolute value of production rate [PR/m'], PR/m'/kg and PR/m'/m2 were calculated for each participant. RESULTS: The mean neurotensin concentration in normal subjects was higher in mixed venous blood (pulmonary artery) than in systemic arterial blood (p < 0001). Similarly, mean NT mixed venous levels in asthmatic subjects was shown to be higher than mean NT levels in systemic arterial blood, before and after the bronchoconstriction with methacoline (p = 0.05 and p = 0.02, respectively). In contrast, the arterovenous difference and the mean values of PR of NT were similar in both groups. CONCLUSIONS: Our findings suggest that (1) NT concentration in mixed venous blood changes in transit through the pulmonary parenchyma, indicating that the pulmonary parenchyma is an important site of NT metabolism; (2) Pulmonary clearance of NT is unaffected by cholinergic bronchoconstriction. Further clinical studies are needed in order to improve both the understanding and the therapeutic approach of the neurogenic process in asthmatic subjects.