Role of gamma-glutamyl transferase activity in patients with chronic hepatitis C virus infection

BACKGROUND: Increased serum gamma-glutamyl transferase (GGT) levels are frequently observed in chronic hepatitis C virus (HCV) infection. However, the significance of this finding remains unclear. The purpose of the present paper was to assess the relationship between GGT levels and clinical, biochemical and histological features in chronic HCV-infected carriers. METHODS: Patients with a liver biopsy presenting anti-HCV and HCV-RNA were evaluated. Age, gender, risk factors of transmission, serum alanine aminotransferase (ALT), GGT and alkaline phosphatase (ALP) levels and histological features were assessed in all. Data were analyzed statistically by the chi2 test and multivariate logistic regression analysis. RESULTS: Among 201 patients studied, elevated GGT levels and bile duct damage were observed in 48% and 35% of them, respectively. No association was seen between GGT level and bile duct damage or between GGT level and hepatic steatosis. Initially, age >40 years (P=0.007), elevated ALT (P=0.01), grading of inflammatory activity (P=0.004) and staging of fibrosis (P<0.001) were found to be associated with elevated GGT levels. After multivariate regression analysis, histology grading 3 and 4 inflammation activity (P=0.01) and staging 3 and 4 fibrosis (P=0.01) remained independently associated with elevated GGT level. CONCLUSIONS: A significant number of patients with chronic HCV infection had elevated serum GGT levels. Furthermore, this enzyme seemed to be useful as an indirect marker of more advanced liver disease in chronic hepatitis C.     

Safety and efficacy of therapy with botulinum toxin in obesity: a pilot study

Background Botulin toxin (BTX) has been proposed as a potential obesity treatment.Methods In a pilot study, the short-term efficacy and safety of BTX was assessed in eight subjects (four men, four women; median age, 46 years; range, 35–57 years) with severe obesity (median body mass index [BMI], 47.1 kg/m²; range 38.2–56.7 kg/m²) and multiple dietary treatment failures. In a single endoscopic session, 500 UI of BTX-A was injected in the gastric antral region.Results No clinically significant side effects were observed. In all patients, despite their not being on a specific diet, a reduction of body weight was observed at 1 month (median baseline weight, 124.4 kg vs 121.8 kg at 1 month; P < 0.05). Two treatment-unrelated dropouts were observed. At 4 months, three of the six patients had a further weight loss. The treatment effect was apparently independent of changes in hunger or satiety, or of changes in fasting and postprandial plasma ghrelin and serum leptin, thus suggesting a different pharmacological mechanism.Conclusions BTX-A treatment appears to be safe and well tolerated by obese patients, while its short-term efficacy varied widely.     

Comparison between QRS duration at standard ECG and signal-averaging ECG for arrhythmic risk stratification after surgical repair of tetralogy of fallot

INTRODUCTION: Surgical repair of tetralogy of Fallot is complicated by the occurrence of ventricular tachycardia (VT). Among different indexes proposed to assess prognosis of these patients, the study of QRS and repolarization provided useful information. Controversial results come from the analysis of signal-averaging ECG (SAECG). The aim of our study was to identify patients operated for tetralogy of Fallot at higher risk of sudden death by means of SAECG. METHODS AND RESULTS: Sixty-six consecutive patients, mean age 26 +/- 10 years, were studied 17.7 +/- 5.8 years after total correction for tetralogy of Fallot using standard ECG, 24-hour Holter recordings, SAECG, and echocardiography. The following variables were measured: standard QRS duration, filtered QRS duration (fQRS), high-frequency and low-amplitude signal duration (HFLA), root mean square of the mean voltage in the terminal portion of filtered QRS (RMS), left and right end-diastolic volumes, and ejection fractions. During a mean follow-up period of 7.3 +/- 3.1 years, 12 patients had episodes of sustained VT and two of them suddenly died. All patients had complete right bundle branch block. Patients with VT were characterized by a significantly longer fQRS duration at all filter settings. On the contrary, there was no difference in standard QRS duration in patients with or without VT. At a multivariate analysis, left ventricular ejection fraction and fQRS were independent predictors for VT. CONCLUSIONS: A longer fQRS duration is associated with an increased risk in developing malignant ventricular arrhythmias in asymptomatic patients after total correction of tetralogy of Fallot.     

Alpha-2a-interferon/melphalan/prednisone versus melphalan/prednisone in previously untreated patients with multiple myeloma

Alpha-2a-interferon (IFN) has demonstrable activity in advance and refractory multiple myeloma (MM), because of the in vitro synergism between IFNs and cytotoxic agents we report the preliminary results of a therapeutic trial of 50 patients with MM. Twenty-eight patients were randomized to receive melphalan plus prednisone (MP) and 22 were randomized to receive IFN plus MP (IFN-MP). Criteria for response, progression and relapse were those of the Southwestern Oncology Group. 95% of the patients receiving IFN-MP responded to therapy as opposed to 68% of the patients receiving MP (P less than 0.05). Response was independent of M-component immunoglobulin class but in stage III it was higher in the IFN-MP group than in the MP group (P less than 0.05). The combination IFN-MP was well tolerated without unusual or unexpected toxic effects. The response duration time was longer in the IFN-MP group than in the MP group (P less than 0.025). The median survival was 80 weeks in the MP group and in the IFN-MP group the 93% of patients were still alive after 90 weeks (P less than 0.025). Our results show that the use of the IFN as an adjuvant to MP improves the percentage of responders, the response duration time and the median survival of untreated patients with MM.     

In vivo specific uptake of labeled insulin by liver,adipose tissue,pituitary, and adrenals in the turtle Chrysemys dorbigni

Insulin labeled with ¹²⁵I was injected into turtles (Chrysemys dorbigni) to study its specific uptake by tissues. The maximum specific uptake of radioactivity by turtle tissues was obtained 1 hr after administration of [¹²⁵I]iodoinsulin. Besides liver and adipose tissue, specific uptake of labeled insulin was detected in some endocrine glands, such as pituitary and adrenals. Both glands were as active in concentrating labeled insulin as liver and adipose tissue. A significant reduction of the uptake was observed when unlabeled insulin was injected together with the labeled hormone. This reduction was dose dependent, and the concentration of unlabeled insulin that prevented 50% of the tissue uptake of [¹²⁵I]iodoinsulin was of 1 to 10 μg/kg body weight. These doses were able to induce blood glucose decrease in the turtle. Prolactin, growth hormone, or glucagon were unable to displace labeled insulin uptake. The major proportion of the radioactive material extracted from liver and pituitary 1 hr after [¹²⁵I]iodoinsulin injection into turtle coeluted with [¹²⁵I]iodoinsulin in Sephadex G-50 column. The presence of radioactive degradation products are consistent with the intracellular receptor mediated degradation hypothesis. These findings suggest the presence of specific insulin binding sites in liver, adipose tissue, pituitary, and adrenal glands from turtles.     

HIV-1 matrix protein p17 enhances the proliferative activity of natural killer cells and increases their ability to secrete proinflammatory cytokines

We investigated the effects of human immunodeficiency type-1 virus (HIV-1) matrix protein p17 on freshly isolated and purified human natural killer (NK) cells. HIV-1 p17 increased the cytokines interleukin (IL) 2, IL-12 and IL-15, and induced natural killer cell proliferation, but not cytotoxicity. This effect was specific because it was abrogated by anti-p17 monoclonal antibody. Moreover, HIV-1 p17 enhanced the cytokine-induced production of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma by NK cells. IL-4 downregulated IFN-gamma and TNF-alpha secretion in IL-2- and IL-15-treated NK cells. HIV-1 p17 restored the ability of NK cells to produce both cytokines when added to the cultures simultaneously with IL-4. The property of p17 to increase the production of TNF-alpha and IFN-gamma might be a mechanism used by HIV-1 to modulate the immune system to support its replication and spreading.     

Targeting NF-kappaB in Waldenstrom macroglobulinemia

The nuclear factor-B (NF-B) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-B pathway.      

Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians

Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.6 yr (mean +/- SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r = 0.51, P = 0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central (waist circumference) adiposity (P < 0.05 for all) and fasting glucose (r = 0.43, P = 0.02), insulin (r = 0.60, P = 0.0005), and insulin resistance by the homeostasis model (r = 0.70, P < 0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r = 0.37, P = 0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity.     

Expanding indications for the treatment of pulmonary artery stenosis in children by using cutting balloon angioplasty.

OBJECTIVES: To evaluate the role of cutting balloon angioplasty in children with pulmonary artery stenosis. BACKGROUND: Pulmonary artery stenoses can be either congenital or secondary to postoperative scar formation. Isolated multiple small-vessel pulmonary artery stenoses are very rare. No surgical procedures for their treatment are currently available. METHODS: We report on four patients in whom standard and high-pressure balloon angioplasty had failed. Three of the four (2.5-, 3-, and 3.5-years-old; two girls) had isolated multiple peripheral pulmonary artery stenosis. The fourth patient was an 11-month-old girl (8 kg) with tetralogy of Fallot and hypoplastic pulmonary artery branches treated with the implantation of two stents in the pulmonary arteries. During the follow-up this patient developed severe intrastent restenosis and showed severely hypoplasic distal left pulmonary artery. RESULTS: We treated 11 vessels. The mean vessel diameter increased by 81% (P<0.0001) and RV/LV pressure ratio decreased from 1.15 to 0.75 (P=0.05). Patient treated for intrastent restenosis underwent successful complete tetralogy of Fallot repair. None of the patients suffered procedure-related complications. At a median follow-up of 18 months, results were stable and no late complications had occurred. CONCLUSIONS: Cutting balloon angioplasty is a promising technique for the treatment of highly challenging pathologies such as small vessel pulmonary artery stenoses and intrastent restenosis.     

Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure

BACKGROUND: Heart rate (HR) reduction may be useful in treatment of patients with heart failure (HF). There are no data on the haemodynamic effects of ivabradine (a selective I(f) current inhibitor) in advanced HF patients. AIMS: To assess the haemodynamic effects of ivabradine in patients with advanced HF and markedly depressed left ventricular (LV) function. METHODS AND RESULTS: Ten NYHA class III patients (50+/-12 years, LV ejection fraction 21+/-7%) underwent 24-h haemodynamic monitoring. Ivabradine 0.1 mg/kg was infused over 90', followed by 0.05-0.075 mg/kg in the subsequent 90'. Baseline HR was 93+/-8 bpm, cardiac index (CI) 2.2+/-0.6 l/min*m2; LV stroke volume 44+/-11 ml and systolic work 39+/-13 g. Ivabradine significantly reduced HR, by a maximum of 27% (to 68+/-9 bpm) at 4 h, without decreasing CI. Ivabradine increased stroke volume and LV systolic work by a maximum of 51% (to 66+/-17 ml) and 53% (to 58+/-20 g) at 4 h. No serious adverse events occurred. CONCLUSION: In patients with advanced HF and markedly depressed LV function, the acute administration of ivabradine is well tolerated, effectively reduces HR, markedly increases stroke volume and preserves cardiac output. Ivabradine appears a promising approach for the treatment of patients with moderate and advanced heart failure.