GlObal Secondary Prevention strategiEs to Limit event recurrence after myocardial infarction: the GOSPEL study. A trial from the Italian Cardiac Rehabilitation Network: rationale and design.

BACKGROUND: Cardiac rehabilitation programmes are a proven treatment for individuals with recent myocardial infarction, resulting in reduced morbidity and mortality compared to usual care. Unfortunately, following completion of a cardiac rehabilitation programme, risk factors and lifestyle behaviours may deteriorate. The GlObal Secondary Prevention strategiEs to Limit event recurrence after myocardial infarction (GOSPEL) study investigates the benefits of a programme of continued educational and behavioural interventions to achieve optimal long-term secondary prevention goals. DESIGN: This will be a multicentre, randomized, controlled study carried out in 78 Italian cardiac rehabilitation centres. METHODS: After completion of an initial cardiac rehabilitation programme, patients with recent (<3 months) myocardial infarction were randomized to either a long-lasting (over 3 years) multifactorial continued educational and behavioural programme (intensive approach) or usual care (control) group. Intensive approach patients participated in extensive cardiac rehabilitation sessions, monthly from months 1 to 6, then every 6 months for 3 years. Each session consisted of aerobic exercise, comprehensive lifestyle and risk factor counselling, and clinical assessment. Usual care patients returned to their family physicians' care, and attended the reference centre only for the 6-month and then annual scheduled assessment. The efficacy of the two different strategies will be evaluated in terms of morbidity and mortality as primary endpoint. RESULTS: From January 2001 through December 2002, 3241 patients were enrolled. Results will be available in mid 2006. CONCLUSIONS: The GOSPEL trial, the rationale and design of which we present here, was designed to test a new strategy of secondary prevention delivery and to raise standards of long-term secondary prevention in Italy. With a cohort of over 3200 patients, GOSPEL is the largest randomized, multifactorial lifestyle and risk factor intervention trial after myocardial infarction conducted so far.     

Clinical relevance of soluble HLA class I molecules in Waldenstrom Macroglobulinemia

Objectives: Waldenstrom Macroglobulinemia (WM) is a B‐cell neoplasm characterised by secretion of IgM by lymphoplasmacytic bone marrow cells and by cytopenias and hypogammaglobulinemia in a subset of patients. Beta‐2 microglobulin (b2m) is a major prognostic factor in WM and the heavy chain of HLA class I molecules, which are known to have immunosuppressive properties and have been implicated in the pathogeny of several malignancies. Methods: We assessed the serum levels of the total soluble HLA‐I molecules and the HLA‐Gs molecules in 105 patients with IgM‐related disorders [WM (n = 42) and IgM MGUS (n = 63)], and compared the results to 41 healthy subjects. Results: We found higher levels of HLA‐Is in WM, compared to IgM MGUS and healthy donors. HLA‐Gs levels were similar in WM and in IgM MGUS, but higher than in healthy donors. The association between HLA‐Is at the cut‐off of 1.8 μg/mL and known markers of poor prognosis was then evaluated among WM patients using univariate and multivariate methods. Based on this, high HLA‐Is level was strongly associated with high serum β2M level >3 mg/L [OR = 2, (CI 95% 1.1–5.7); P = 0.04], age > 65 yrs [OR = 1.5, (CI 95% 0.5–4.1), P = 0.06] and haemoglobin ≤11.5 g/dL [OR = 3.3, (CI 95% 1.2–9.7); P = 0.03]. High levels of serum HLA‐Is were also found in patients with cryoglobulinemia, however irrespectively of WM or IgM‐MGUS status. Conclusion: Together our results suggest a possible role for soluble MHC class I molecules in WM disease. Further investigations are necessary to further demonstrate the prognostic impact of soluble MHC class I molecules in Waldenstrom Macroglobulinemia.     

Radionuclide angiocardiography in evaluation of patients after repair of transposition of the great arteries

The ability of first pass radionuclide angiocardiography to detect and quantitate residual intracardiac shunts and systemic venous obstruction after repair of transposition of the great arteries was evaluated in 29 children. Information from radionuclide scans was compared with data obtained during cardiac catheterization. Three children had a residual right to left shunt detected with both methods. There was good agreement between radionuclide and catheterization quantitation of left to right shunt in the nine patients with a residual defect, five of whom had significant shunting. Nineteen patients with signs suggesting superior vena caval obstruction were evaluated with both radionuclide and catheterization methods. In eight, complete obstruction was detected with both techniques; in one additional patient, partial obstruction was found on catheterization only. One of six patients evaluated for possible inferior vena caval obstruction was identified with both techniques. In the group as a whole, information obtained with radionuclide angiography correlated well with cardiac catheterization data in evaluation of residual shunts and obstruction to systemic venous return.     

A reappraisal of the Rb1 gene abnormalities in the diagnosis of parathyroid cancer

OBJECTIVES: Some histological features may suggest the malignant nature of a parathyroid tumour. However, the diagnosis of parathyroid cancer can only be definitively established in the presence of local invasion or metastases. DESIGN: We further investigated the role of the retinoblastoma gene (Rb1) and the breast cancer susceptibility gene (BRCA2) in the differential diagnosis between benign and malignant parathyroid tumours by evaluating loss of heterozygosity (LOH) at these loci and Rb protein (pRb) immunohistochemistry. PATIENTS AND MEASUREMENTS: Fifty-three parathyroid adenomas from patients with sporadic primary hyperparathyroidism (PHPT) and 10 parathyroid cancer specimens were studied. Microsatellite polymorphisms at the Rb1 and BRCA2 loci were polymerase chain reaction (PCR) amplified from each patient's paired tumour and leucocyte DNA samples, using oligonucleotide primers flanking the repeat sequence. Immunohistochemical staining of pRb was carried out using a monoclonal antibody. RESULTS: All but one of the 53 tumour-leucocyte pairs was informative for at least one of the three polymorphic markers of the Rb1 gene. Fifteen adenomas (28.8%) showed LOH. Regarding the BRCA2 gene, 46 tumour-leucocyte pairs were informative and LOH was present in eight (17.4%). All six carcinomas had LOH for at least one marker at the Rb1 locus. LOH for the BRCA2 microsatellite was found in three of the five informative primary tumour samples. Immunohistochemical analysis revealed that all adenomas were positive and the number of pRb-positive cells varied significantly among different samples. The mean percentage of stained cells was 15.7%. Eleven of the 30 (36.7%) adenomas showed sparse positive staining, 13 (43.3%) intermediate staining and six (20%) extensive staining. All parathyroid cancers were entirely negative for pRb immunostaining. CONCLUSIONS: Inactivation of the Rb1 gene is a common event in parathyroid tumorigenesis. Retention of heterozygosity seems to exclude parathyroid malignancy, which is suggested by the combined finding of LOH and lack of protein expression.     

Simian virus 40-like sequences from early and late regions in human thyroid tumors of different histotypes

Simian virus 40 (SV40) sequences were investigated in human thyroid tumors of different histotypes, Graves' disease thyroid specimens, normal thyroid tissues, and peripheral blood mononuclear cells (PBMC) of healthy donors. Specific SV40 large T antigen (Tag) sequences were detected, by PCR and filter hybridization, in human thyroid tumors with a frequency ranging from 66% in papillary thyroid carcinomas (PTC) to 100% in anaplastic thyroid carcinomas (ATC). SV40 was revealed in 60% and 100% of normal thyroid tissues adjacent to PTC and ATC, respectively, but in only 10% of control normal thyroid tissues (NTT) from patients affected by multinodular goiter. Thyroid tissues from patients affected by the Graves' disease were found to be SV40 positive with a frequency of 20%. In agreement with previous investigations, the presence of SV40 sequences was detected in 25% of PBMC of healthy individuals. SV40 Tag mRNA was detected by RT-PCR, whereas the viral oncoprotein was revealed by immunohistochemistry with a specific monoclonal antibody. The high prevalence of SV40 footprints in human thyroid tumors indicates that the oncogenic virus may participate as a cofactor in the onset/progression of specific human thyroid cancers. Detection of SV40 sequences in NTT adjacent to thyroid cancers suggests that the viral infection may spread from transformed cells to normal cells surrounding the tumor. The presence of the SV40 footprint in PBMC implies that blood cells are vectors of the virus in other tissues of the host.     

Percutaneous mitral valve repair: a feasibility study in an ovine model of acute ischemic mitral regurgitation.

Annuloplasty is the cornerstone of surgical mitral valve repair. A percutaneous transvenous catheter-based approach for mitral valve repair was tested by placing a novel annuloplasty device in the coronary sinus of sheep with acute ischemic mitral regurgitation. Mitral regurgitation was reduced from 3-4+ to 0-1+ in all animals (P < 0.03). The annuloplasty functioned by reducing septal-lateral mitral annular diameter (30 +/- 2.1 mm preinsertion vs. 24 +/- 1.7 mm postinsertion; P < 0.03). These preliminary experiments demonstrate that percutaneous mitral annuloplasty is feasible. Further study is necessary to demonstrate long-term safety and efficacy of this novel approach.     

Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis

Ursodeoxycholic acid has been proposed for the treatment of primary biliary cirrhosis. The aim of this study was to evaluate the effect of ursodeoxycholic acid administration on bile acid metabolism in patients with early-stage primary biliary cirrhosis. Biliary bile acid composition, primary bile acid pool sizes, synthesis, and fractional turnover rate were measured before and after four weeks of ursodeoxycholic acid administration (600 mg/day) in nine patients with biopsy-proven primary biliary cirrhosis (stages I-III). Molar percentages of chenodeoxycholic, cholic, and deoxycholic acids in bile were significantly decreased by ursodeoxycholic acid administration, while its biliary concentration increased to 34.2% at the end of the same four-week period. The cholic and chenodeoxycholic acid pools decreased, although not significantly, while the deoxycholic acid pool was reduced by 60% (from 0.7±0.12 to 0.29±0.07 mmol,P<0.002). Primary bile acid synthesis was slightly increased, and fractional turnover rate was significantly increased. The conversion rate of cholic to deoxycholic acid was measured and found to be significantly increased (P<0.05) after ursodeoxycholic acid administration; however, serum levels of both free and conjugated deoxycholic acid were significantly decreased (from 23.2±9.7 to 3.8±1.9 μmol/liter,P<0.001). We conclude that in patients with primary biliary cirrhosis, ursodeoxycholic acid administration replaces endogenous bile acids in the enterophepatic circulation by increasing bile acid fractional turnover rate without significant increments of their hepatic synthesis.     

Influence of human body composition on serum peak thyrotropin (TSH) after recombinant human TSH administration in patients with differentiated thyroid carcinoma

OBJECTIVES: In this study, we evaluated the influence of height, weight, body mass index (BMI), body surface area, and body composition [total lean body mass (LBM) and fat body mass] on serum peak TSH levels obtained after recombinant human (rh)TSH. Furthermore, to verify whether the serum peak TSH influenced the efficacy of radioiodine ((131)I), we compared the rate of thyroid remnant ablation according to the patients' BMI. PATIENTS: We studied 105 patients with differentiated thyroid carcinoma who underwent rhTSH stimulation test. Serum TSH measurements were performed before and 24, 48, and 72 h after rhTSH administration. We also compared the rate of thyroid remnant ablation among 70 differentiated thyroid carcinoma patients with different BMI. RESULTS: The serum peak TSH after rhTSH was significantly lower in overweight and obese subjects compared with normal-weight subjects (92.1 +/- 41.8, 82.4 +/- 24.2, and 112.7 +/- 46.3 microU/ml, respectively; P = 0.01) and in males compared with females (74.6 +/- 22.3 and 105.0 +/- 43.0 microU/ml, respectively; P = 0.0002). By univariate analysis, serum peak TSH was negatively related to weight, height, body surface area, BMI, LBM, and fat body mass, but only LBM was independently associated with serum peak TSH levels. Although it was confirmed that overweight and obese patients had a lower serum peak TSH, the rate of ablation did not differ among normal-weight, overweight, and obese patients. CONCLUSIONS: With this study we demonstrated that LBM is the only parameter independently associated with serum peak TSH after rhTSH administration. However, the serum peak TSH does not influence the rate of (131)I remnant ablation.     

Influence of antiviral therapy on the liver stiffness in chronic HBV hepatitis

Purpose

The aim of this study was to evaluate the effects of antiviral therapy on liver stiffness measurement (LSM).

Methods

Two hundred HBV patients were enrolled from four hospital centers in southern Italy; median age was 50.7 (25–75) males were 68%; 171 patients underwent to liver biopsy and 200 patients had LSM at baseline and 189 at the end of follow-up. One hundred and forty-nine patients were treated with nucleos(t)ide analogs, while 51 patients were untreated. The cutoffs of the LSM, related to the fibrosis stages, were as follows: non-advanced fibrosis ≤ 8.1 kPa and advanced fibrosis ≥ 8.2 Kpa.

Results

At baseline, the median value of LSM was 14.1 kPa for advanced fibrosis/cirrhosis and 6.9 kPa for non-advanced fibrosis. LSM was performed at 24 months from the start of therapy. The treated patients (68% received Entecavir and 32% Tenofovir) showed a decrease in liver stiffness measurement of 1.5 kPa (p < 0.001) in non-advanced fibrosis and of 6 kPa (p < 0.001) in advanced fibrosis/cirrhosis. In the patients not undergoing antiviral treatment, no statistically significant change of the LSM was observed (p = 0.26). A logistic binary regression model showed that the only independent factor associated with a significant change in the LSM was the liver stiffness value at baseline (odd ratio 2.855; 95% CI 1.456–5.788; (p = 0.007).

Conclusion

Long-term antiviral therapy induced a significant reduction of liver stiffness measurement and this result may be related to the reduction of liver fibrosis.

     

Serum and Bile Lipids in Young Women with Radiolucent Gallstones

To investigate the relationship between blood and bile lipids, serum cholesterol, high density lipoprotein cholesterol, and triglycerides were correlated with cholesterol saturation index of bile in 21 women-10 with radiolucent gallstones and 11 without stones. All of the women had regular menstrual cycles, were normolipidemic, and on a hospital diet. On the same morning, blood and the darkest duodenal bile were taken after cholecystokinin (CCK) stimulation. Standard laboratory procedures were used to analyze serum and bile lipids. We found: 1) statistically significant (t test, p less than 0.05) but only slight hypercholesterolemia (+ 12%) in patients with gallstones; 2) a negative correlation of serum cholesterol with cholesterol saturation index of bile, both in the control group (r = -0.654, p less than 0.05) and in gallstone patients (r = -0.665, p less than 0.05); 3) a correlation of high density lipoprotein cholesterol with cholesterol saturation index only in normal women (r = -0.619, p less than 0.05); 4) conversely, a correlation of triglycerides with the same index in only gallstone patients (r = 0.641, p less than 0.05). With the stepwise multiple regression analysis (independent variables: diagnosis of gallstones, serum cholesterol, HDL cholesterol, triglycerides; dependent variable: biliary cholesterol saturation index), only gallstone diagnosis and serum cholesterol influenced significantly (F test, p less than 0.05) the biliary cholesterol saturation index. These findings suggest that young women with radiolucent gallstones are slightly hypercholesterolemic, that in women both with and without gallstones there is a negative correlation between serum cholesterol and biliary cholesterol saturation, but women with gallstones have a higher cholesterol saturation index of the bile than women without gallstones with the same level of cholesterol in the blood.