Varenicline and evaluated outcomes in smoking cessation programmes.

The morbidity and mortality rates attributed to smoking are substantial and cigarette smoke remains the first preventable cause of premature death worldwide. Despite the knowledge of the adverse consequences of smoking, many smokers struggle to quit. Cigarette smoking is the primary cause of chronic obstructive pulmonary disease, and smoking cessation represents the most effective way of stopping its progression. Varenicline is one of the first-line smoking cessation aids recommended in many Clinical Practice Guidelines and its efficacy and safety have been demonstrated in several clinical trials. Varenicline has a unique mechanism of action and clinical trials support its use as an effective and generally well-tolerated therapy. This article reviews the clinical pharmacological trials on smoking cessation published in recent years on varenicline, with particular attention to the outcomes used in the studies. MedLine, the Cochrane database and Embase were evaluated. Almost all the trials have, as a primary endpoint, the abstinence from cigarettes at 9-12 weeks of treatment. Only one study considers lung function spirometric changes as a secondary endpoint. No study has evaluated lung function. This marker could be very important as a way of evaluating, objectively, an improvement in lung function, which correlates also with subjective parameters, as dyspnea and fatigue.

Structure-function relationships of iodinated contrast media and risk of nephrotoxicity.

Characteristics of CM have greatly changed over time. First-generation ionic CM have many-fold (5-7) greater osmolalities than plasma. Subsequently non ionic CM generations were looked for to reduce osmolality, and encompass nonionic monomers and nonionic dimers reaching osmolality as low as that of plasma (iso-osmolar CM) but paying however dear, as viscosity is considerably increased. Intrarenal microcirculation has its "Achilles" heel in the outer medulla, where the smallness of capillary lumen and the slackness of the capillary mesh render regular blood flow at high risk, mainly because it is the same area in which the only renal work needing oxygen is made and? Iodinated CM may exert their nephrotoxic effects in three different ways: by interfering with vascular hemodynamics, by interfering with intratubular fluid volume and composition, and by producing direct cytotoxic effects to glomerular and tubular cells due to iodine by-itself. Furthermore, effects of oxygen free radical can damage glomerular cells by increasing the permeability and tubular cells impairing specific function and leading to apoptosis. Although clinical nephrotoxicity has considerably improved over time, there is no evidence for an a priori superiority of a specific CM. In general, low-osmolar (2-3 times blood) and iso-osmolar (the same as blood) CM are recommended, keeping in mind that within last generation CM dimeric iso-somolar compounds reach viscosity values higher than monomeric low-osmolar compounds and hyperviscosity is a neglected mechanisms of nephrotoxicity. We suggest that CM should be classified not only by osmolality, but also by viscosity.

Prevalence and clinical relevance of occult hepatitis B virus infection in patients on the waiting list for kidney transplantation.

BACKGROUND: Occult hepatitis B virus (HBV) infection can be defined as the long-lasting persistence of viral genomes in the liver tissue, and sometimes also in the serum at low levels of viremia in individuals with undetectable HBV surface antigen (HBsAg). Viral replication can be reactivated by immunosuppressive therapies or immunologic diseases, leading to the development of typical hepatitis B. METHODS: All patients on the waiting list for renal transplantation at the only 2 transplant centers in our region (Piemonte, Italy) were checked for the presence of occult HBV infection by an highly sensitive quantitative HBV-DNA polymerase chain reaction (PCR) assay (nested PCR); the only exclusion criterion was HBsAg-positivity. The enrollment lasted from October 1, 2006, to May 31, 2007. The prospective follow-up will continue for 5 years. RESULTS: HBV-DNA sequences were detected in blood samples from 10 of 300 cases examined (3.3%), being more frequent among Asian (1/3; 33.3%) and African (1/16; 6.25%) subjects as compared with the Caucasians (8/281; 2.8%; P = .011), among anti-hepatitis C virus (HCV) positive versus HCV negative patients (3/32 [9.3%] vs 7/268 [2.6%]; P = .004) and mainly among patients with a previous history of overt liver diseases (3/22 [14%] vs 7/278 [2.5%]; P = .019). HBV-DNA sequences became undetectable at 1 month after renal transplantation in 3 patients; the follow-up is in progress for these and the other patients. CONCLUSION: Occult HBV infection occurs in patients undergoing renal transplantation. Longer observation and prospective studies will clarify the clinical impact of this occult infection on transplant outcomes and the possibility of viral reactivation related to immunosuppressive therapy.

Lack of a strong association between HLA class II, tumour necrosis factor and transporter associated with antigen processing gene polymorphisms and virological response to alpha-interferon treatment in patients with chronic hepatitis C.

The aim of the study was to investigate whether polymorphisms of the HLA class II, tumour necrosis factor (TNF) and transporter associated with antigen processing (TAP) genes influence the response to alpha-interferon in patients with chronic hepatitis C. Twenty-seven sustained responders and 55 non-responders to alpha-interferon monotherapy were investigated. HLA-DRB1, DQA1, DQB1, TNFA, TNFB, TAP1 and TAP2 alleles were determined by PCR-based molecular techniques. Sustained virological response was defined as undetectable serum hepatitis C virus (HCV) RNA for at least 3 years after the end of treatment. Probability (P) values were corrected for the number of alleles tested (Pc). Viral genotype 1b was more frequent in responders than in non-responders (56% vs. 26%, P = 0.009). HLA-DQB1*02 occurred less frequently in responders than in non-responders (14.8% vs. 29%, Pc not significant). HLA-DRB1*11 and DQB1*0602 were found in 22.2% and 9.3% of responders and in 10.9% and 1.8% of non-responders, respectively (Pc not significant). There was no difference in the distribution of TNF alleles in the two groups. Twenty-four (88.8%) responder patients as compared with 34 (61.8%) non-responders were TAP1*0101 homozygous (Pc not significant). Thus, in European Caucasoids with chronic hepatitis C, we could not demonstrate a strong association between HLA class II, TNF, and TAP gene polymorphisms and response to interferon treatment.

Combined therapy with interferon and low-dose ribavirin in posttransplantation recurrent hepatitis C: a pragmatic study.

Recurrent hepatitis C is a common problem after liver transplantation that can progress to liver cirrhosis of the graft. Preliminary reports of combination treatment with interferon (IFN) and ribavirin have been promising, but long-term follow-up data are not yet available. We report our experience with 1 year of combination therapy with IFN (3 million units thrice weekly) and low-dose ribavirin (600 mg/d), followed by long-term ribavirin monotherapy in 18 patients with moderate to severe recurrent hepatitis C and a median follow-up of 32 months after the completion of combined therapy. All patients were followed up clinically and histologically at regular intervals. Overall, in an intention-to-treat analysis, 15 patients had normal alanine aminotransferase levels (biochemical end-treatment response [ETR], 83%), and 8 patients were also hepatitis C virus RNA negative in serum (virological ETR, 44%) at the end of combined treatment. At last follow-up after the completion of combined therapy (median, 32 months; range, 18 to 73 months), 13 patients were biochemical responders (biochemical long term-sustained response [LT-SR], 72%), and 5 patients also maintained viral clearance (virological LT-SR, 27%). Comparison of liver biopsy specimens before and after 12 months of combined therapy showed improvement in grading scores of at least two points in the majority of the patients (73%). Notably, a trend toward fibrotic progression was only noted in nonresponders. Regarding side effects, despite the low dose of ribavirn, almost half the patients developed hemolytic anemia requiring dose reductions. In addition, long-term ribavirin monotherapy was not associated with iron accumulation. We conclude that combined therapy with low-dose ribavirin followed by long-term ribavirin monotherapy can be recommended because it favorably modifies the natural history of recurrent hepatitis C in most patients and possibly halts histological disease progression without causing iron accumulation.

Dynamics of tearing modes during strong electron cyclotron heating on the FTU tokamak.

The localized electron cyclotron resonance heating power that can suppress sawteeth reconnection often drives m = 2 tearing modes in a tokamak operating at constant current. The dynamics of mode onset and coupled mode evolution is described in detail and compared with a nonlinear theoretical model that identifies the effects of mode coupling, finite inertia of the rotating islands, and wall braking.

Antiviral therapy of HBV- and HCV-induced liver cirrhosis.

Antiviral therapy is generally indicated in patients who have histologic evidence of chronic hepatitis and ongoing viral replication. The aim of treatment is to normalize alanine aminotransferase levels and to eliminate virus replication. Interferon-alfa (IFN-alpha) is the most used agent. The standard treatment regimen for hepatitis B e antigen (HBeAg)-positive cirrhosis is based on IFN-alpha given alone, but the efficacy of new antivirals (famciclovir, lamivudine) with or without IFN-alpha is currently under investigation. Conversely, the therapy of antiHBe-positive cirrhosis is far from being satisfactory. The results of treatment of patients affected by type C cirrhosis with IFN-alpha alone have been disappointing, as 10-15% of treated patients shows a sustained virologic response. Although current evidence suggests that the combination of ribavirin and IFN-alpha might be more efficacious than IFN alone in increasing the response rate in patients in the advanced fibrotic stage, the efficacy of this regimen for patients with well-compensated HCV-related cirrhosis is still unknown and prospective well-designed studies are urgently needed. Patients with decompensated cirrhosis are not generally treated unless they are included in liver transplantation programs. Prospective long-term trials with large sample sizes are needed to determine if responders to IFN-alpha have a low incidence of liver-related complications and hepatocellular carcinoma.

A randomized, controlled study of thymosin-alpha1 therapy in patients with anti-HBe, HBV-DNA-positive chronic hepatitis B.

No consistently effective therapy is yet available for the treatment of chronic HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that the response rates are not significantly different when patients with anti-HBe-positive hepatitis are treated with six-month course of thymosin-alpha1 or of interferon-alpha. However, since among these patients, interferon's real efficacy is still debated, with sustained biochemical response achieved in only a few of the treated patients, we conducted this controlled study to investigate the safety and efficacy of thymosin-alpha1 as compared with no treatment. Forty-four chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA-positive, were randomized, with stratification for the presence of cirrhosis at baseline liver biopsy, to receive either thymosin-alpha1 at a dose of 900 microg/m2 twice a week for six months or no treatment. At entry, both groups of patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range 12-32 months) after completion of therapy: one dropped out, and one developed hepatocellular carcinoma at six months. Thymosin-alpha1 treatment had no side effects. Six months after the end of the therapy, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group, while IgM anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the controls. Among the treated patients, the median ALT levels stayed significantly lower compared to the pretreatment values during the treatment period and six months of follow-up. During the first year, there were six flares of hepatitis in the control group and five among the treated patients (P = NS), yielding a per year average of 0.3 and 0.23 flares per patient, respectively. Among the treated patients, median IgM anti-HBc levels were low with respect to baseline values 4-10 months after treatment started. None became HBsAg negative. In conclusion, these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B, thymosin-alpha1 therapy alone does not increase the response rate, but may contribute to reduce the immune-mediated liver cell necrosis as indirectly assessed by ALT and IgM anti-HBc levels.

Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study.

OBJECTIVE: After non-response to the initial course of therapy, retreatment with alpha-interferon is not effective. The aim of this study was to ascertain whether the administration of N-acetyl cysteine and vitamin E could increase the response rate to retreatment with alpha-interferon. DESIGN: Prospective, multicentre clinical trial. SETTING: Twelve hospitals in Lombardy, Italy. PARTICIPANTS: 120 consecutive patients affected by biopsy-proven chronic hepatitis C who had been non-responders to a previous course of alpha-interferon, administered at the dosage of 3-6 million units (MU) three times a week (tiw) for 6 months. INTERVENTIONS: The patients were randomly assigned to one of two groups of treatment: group A, natural interferon-alphaN3, 6 or 9 MU tiw, when the body weight was < 60 kg or > or = 60 kg, respectively; group B, the same dosage of natural interferon-alphaN3 in association with oral administration of N-acetyl cysteine 1200 mg/day and vitamin E 600 mg/day. The period of treatment was 6 months in both groups. RESULTS: Neither end-therapy biochemical response nor sustained biochemical response rates were improved by the combination treatment, and in no case was clearance of the virus from serum observed. CONCLUSIONS: In this randomized study carried out on 120 patients with chronic hepatitis C not responsive to alpha-interferon, oral supplementation with N-acetyl cysteine and vitamin E did not improve the poor efficacy of retreatment with alpha-interferon alone.

Intramuscular beta interferon for chronic hepatitis C: is it worth trying?

BACKGROUND AND AIMS: The intramuscular use of beta interferon has been tested in the treatment of chronic hepatitis C, but it did not prove effective when the schedule was 3 million units three times a week for six months. Since the lack of effectiveness of this treatment might be due to the low bioavailability of beta interferon when administered intramuscularly, we tested a higher dosage of the drug: 6 million units three times a week for twelve months. PATIENTS AND METHODS: Ninety-two patients were randomized to receive, intramuscularly, either 3 or 6 million units of natural human fibroblast beta interferon three times a week for 12 months. RESULTS: The short-term biochemical response was significantly more frequent in the group of patients who received the higher dosage of beta interferon: 21% vs 4.5% (p < 0.05). Nevertheless, a sustained biochemical response was obtained in only one patient (2%), who received the higher dosage of beta interferon. CONCLUSIONS: Since the better short-term response rate was obtained with the higher dosage of beta interferon, a further increase in the dosage might improve the short-term and, possibly, the long-term response to treatment. However, due to the high cost of beta interferon, this high-dose schedule would probably not be cost-effective in the treatment of chronic hepatitis C.

Association between HLA class II alleles and protection from or susceptibility to chronic hepatitis C.

BACKGROUND/AIMS: Recent studies have suggested that the course of chronic hepatitis C may be influenced by the immunogenetic background of the host. Specifically, HLA-DR11 (5) has been associated with less advanced hepatitis C virus (HCV)-related liver disease. The aim of the present study was to investigate whether HLA-DRB1*11 subtypes or HLA-DQA1 and DQB1 genes might be associated with protection from or susceptibility to chronic HCV infection, histological severity of HCV-induced liver disease and infecting HCV genotype. METHODS: Ninety-nine unrelated outpatients with histologically documented chronic hepatitis C were studied and their allele frequencies were compared with those of 179 ethnically matched controls and with those of 41 HCV RNA-positive patients with persistently normal aminotransferase levels (HCV carriers). HLA-DQ types and HLA-DRB1*11 subtypes were determined by polymerase chain reaction gene amplification with sequence specific primers. RESULTS: None of 10 DQA1 or 12 DQB1 alleles was significantly associated with susceptibility to or protection from chronic HCV infection or with histological staging or with HCV genotype. However, analysis of DQA1-DQB1 combinations showed that DQA1*0201-DQB1*0201 combination was significantly more frequent in patients compared to controls, both in cis (26.3% vs 16.2%, p = 0.04, odds ratio = 1.8, 95% confidence interval, 0.96-3.5) and in trans (12.1% vs. 1.1%, p = 0.0001, OR = 12.2, 95% CI, 2.6-113.7). HCV carriers did not differ from controls or from patients in the frequency of DQA1-DQB1 combinations. The extended haplotype DRB1*1104, DQA1*0501, DQB1*0301 was seen significantly less frequently in patients than in controls (8% vs 22.3%, p = 0.0025, OR = 0.31, 95% CI, 0.12-0.7) or HCV-RNA carriers (8% vs 26.8%, p = 0.003, OR = 0.24, 95% CI, 0.08-0.73). CONCLUSIONS: Immunogenetic factors may play a role in determining both protection from and susceptibility to chronic hepatitis C, the trans-dimer DQA1*0201-DQB1*0201 predisposing to and the DRB1*1104, DQA1*0501, DQB1*0301 haplotype protecting from chronic hepatitis C.

[Urolithiasis in pregnancy]. / Urolitiasi in gravidanza.

Urolithiasis is a cause of abdominal pain occurring during pregnancy requiring hospitalization. Of 3793 deliveries in a 5-year period 11 were complicated by urinary calculi during pregnancy. The incidence was 0.29% and in 45% the calculi passed spontaneously. Conservative therapy was resolute in 100% of cases and didn't have any consequence on pregnancy and neonatal outcome. Pathogenesis, diagnostic and therapeutic approach are considered.

The Survival of Salmonella typhimurium in Propylene Glycol/Water Mixtures.

The effect of propylene glycol, a coolant used in dairy processing plants, on the growth and survival of Salmonella typhimurium was studied. Cultures were inoculated into 0.1% reconstituted nonfat dry milk with glycol concentrations ranging from 0 to 50% (Aw 0.99-0.83) and were incubated at 37°C or -1°C. Serial dilutions were plated on tryptic soy agar (Difco), incubated at 37°C for 24 h and enumerated. At 37°C, 5% or more glycol inhibited the growth of S. typhimurium . At concentrations >20% glycol, Aw<0.96, no recovery was possible after 4 h at 37°C. At -1°C, a slow decline in population was seen regardless of glycol concentration. The higher the concentration, the faster the rate of decline in population. Aeration of the system resulted in a more rapid decrease in the number of S. typhimurium than the static system.