Implications of PNPLA3 polymorphism in chronic hepatitis C patients receiving peginterferon plus ribavirin.

BACKGROUND: Homozygosity for the PNPLA3 p.I148M polymorphism influences steatosis and fibrogenesis in chronic hepatitis C (CHC). AIM: To evaluate the effect of p.148M/M on sustained virological response (SVR) and viral kinetics in patients who underwent antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype and fibrosis severity, and secondarily, the interaction with interleukin-28B ( IL28B ) genotype on liver damage. METHODS: In this observational study, we considered 602 treatment-naïve consecutive patients from tertiary referral centres in Milan and Vienna [61% genotype 1 (G1), 30% advanced fibrosis, 33% IL28B rs12979860 CC]. RESULTS: The p.148M/M genotype, detected in 8% of patients, did not influence SVR in the overall series (P = 0.29), but it was associated with SVR (3/17, 17% vs. 56/121, 46%; P = 0.034) and complete early viral response (4/17, 23% vs. 68/121, 56%; P = 0.018) in G1/4 patients with advanced fibrosis. After adjustment for age, viral load, IL28B CC genotype, treatment dose, and steatosis, p.148M/M remained a predictor of SVR in G1/4 patients with advanced fibrosis (OR 0.23, 95% CI 0.04-0.87). The p.148M/M genotype was associated with more advanced fibrosis in the overall series (P = 0.049), whereas the rs12979860 IL28B CC genotype only in patients negative for p.148M/M (P = 0.017), independently of age, BMI and alanine transaminase levels (OR 1.51, 95% CI 1.01-2.27). CONCLUSIONS: PNPLA3 p.148M/M genotype was negatively associated with SVR and early viral kinetics independently of steatosis, albeit only in difficult-to-cure G1/4 patients with advanced fibrosis, whereas stratification for the p.148M/M PNPLA3 genotype unmasked an association between IL28B CC genotype and more severe liver fibrosis.

A tetra-primer amplification refractory mutation system polymerase chain reaction for the evaluation of rs12979860 IL28B genotype.

Recently, genome-wide association studies in patients affected by HCV infection have identified a strong association between sustained virological response to peg-interferon/ribavirin and spontaneous viral clearance and common single nucleotide polymorphisms (SNPs) near the IL28B gene, encoding for interferon-lambda-3. Thus, it is anticipated that IL28B genotype determination will be integrated in clinical practice to guide treatment decisions. Here, we describe a simple tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) for the evaluation of the rs12979860 C>T IL28B SNP, for which strong evidence of association with clinical outcomes has been collected in subjects of European descent. Valid genotypic data were obtained for over 99% of subjects analysed, and T-ARMS-PCR procedures were validated by the analysis of DNA samples of 164 patients with chronic HCV infection. In conclusion, this method allows rapid, reproducible, inexpensive and accurate detection of rs12979860 polymorphism without need of any special equipment and is also suitable for evaluation of a low number of samples on a routine basis.

Cost-benefit evaluation of influenza vaccination in the elderly in the Italian region of Liguria.

Influenza causes considerable morbidity and mortality and the damage to public health can be considerable. The most effective measures available for the prevention of influenza is vaccination. In most industrialised countries the objective of vaccination is to limit the disease among individuals at risk, especially the elderly. During the winter of 2000/2001, General Practitioners (GPs) monitored 14,818 elderly individuals. The objective was to evaluate the weekly incidence of the disease. Furthermore, we carried out a prospective study on 512 elderly individuals, arranged according to vaccination (304 vaccinated and 208 non-vaccinated), with the main objective of assessing the costs of the disease and the efficacy of vaccination. Finally, in order to assess the percentage of vaccinated elderly individuals, we carried out a telephone survey on 500 subjects. Our clinical surveillance study enabled us to establish that morbidity was particularly low in elderly individuals.The results of the prospective study allowed us to estimate the cost-benefit ratio at 8.22, with a net saving of 110.20 Euros for each vaccinated subject. We were also able to establish that the vaccine coverage among elderly individuals was 63%. Our study, though carried out during a low epidemic year, confirms the economic advantage of vaccination in the elderly.

Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles.

OBJECTIVE: To investigate the effectiveness of double IUI and to determine the optimal timing of IUI in relation to hCG administration. DESIGN: Prospective randomized study. SETTING: Infertility Center, Department of Obstetrics and Gynecology, University of Milan. PATIENT(S): Patients with male factor and unexplained infertility undergoing controlled ovarian hyperstimulation (COH) and IUI. INTERVENTION(S): After COH with clomiphene citrate and gonadotropins, patients were randomly assigned to one of the following groups: group A received a single IUI 34 hours after hCG administration, group B received a double IUI 12 hours and 34 hours after hCG administration, and group C received a double IUI 34 hours and 60 hours after hCG administration. MAIN OUTCOME MEASURE(S): Number of follicles > 15 mm in diameter on the day of hCG administration, number of motile spermatozoa inseminated, clinical pregnancy rate. RESULT(S): Two hundred seventy-three patients underwent 449 treatment cycles: 90 patients were treated for 156 cycles in group A, 92 patients for 144 cycles in group B, and 91 patients for 149 cycles in group C. The overall pregnancies rates for groups A, B, and C were 13 (14.4% per patient and 8.3% per cycle), 28 (30.4% per patient and 19.4% per cycle), and 10 (10.9% per patient and 6.7% per cycle), respectively. There was a statistically significant difference between group B and groups A and C. CONCLUSION(S): Our data indicate that two IUIs performed 12 hours and 34 hours after hCG administration is the most cost-effective regimen for women undergoing COH cycles with clomiphene citrate and gonadotropins. Although the second insemination adds up to a slightly higher cost, it significantly increases the chance of pregnancy.

Semen preparation by standard swim-up versus swim-up with test yolk buffer incubation in intrauterine insemination: a randomized study.

In order to compare the standard swim-up semen preparation with and without test yolk buffer (TYB) incubation in intrauterine insemination (IUI), we conducted a prospective multicentre randomized trial. A total of 121 infertile couples with male factor (n = 52) or unexplained infertility (n = 69) was randomly assigned to two groups following ovulation induction. Semen was prepared by standard swim-up in group A (n = 64) and by swim-up followed by TYB incubation in group B (n = 57). A maximum of two IUI cycles was performed. A total of 104 cycles was performed in the swim-up group and 90 in the TYB group. Overall, 15 pregnancies were achieved in group A and 23 in group B, with an overall pregnancy rate of 24.8 and 50.0% per patient respectively (chi2(1), P < 0.05). In the male factor group, pregnancy was achieved in six out of 24 couples (25%) following standard swim-up and in six out of 28 (21.4%) following swim-up and TYB incubation (chi2(1), not significant). In the unexplained infertility group, pregnancy was recorded in nine out of 40 couples (22.5%) following standard swim-up and in 17 out of 29 couples (58.6%) following swim-up and TYB incubation (chi2(1), P < 0.05).

Treatment of obstetric and gynecologic infections with meropenem: comparison with imipenem/cilastatin.

The aim of this study was to compare the clinical and bacteriologic efficacy of meropenem with imipenem/cilastatin in the treatment of obstetric and gynecologic infections. This was a controlled, multicenter, randomized study with two parallel groups and a follow-up period of up to 4 weeks. A total of 105 hospital in-patients requiring antibacterial parenteral therapy were enrolled, 52 in the meropenem group and 53 in the imipenem/cilastatin group. Both drugs were administered at 0.5 g every 8 hours, by slow intravenous infusion over 20-30 minutes; for meropenem the administration by intravenous bolus injection (over approximately 5 minutes) was allowed. The mean duration of therapy was 5 days for both treatments. At the end of treatment, all 46 evaluable patients in the meropenem treatment group had a satisfactory clinical response, while in the imipenem/cilastatin group 5/49 patients were clinical failures. The difference between the treatment groups in clinical response was statistically significant (100% vs 89.8%; p=.026). A similar result was seen in the intention-to-treat analysis (98% vs 84.6%; p=0.017). Both treatments were well tolerated, but fewer meropenem patients experienced treatment-related adverse events in comparison with imipenem/cilastatin (11.5% vs 15.1%).

An open randomized comparative study of an oral contraceptive containing ethinyl estradiol and cyproterone acetate with and without the GnRH analogue goserelin in the long-term treatment of hirsutism.

A multicenter randomized study was carried out to compare the efficacy of combined therapy with a GnRH analog (goserelin) + an oral contraceptive (OC) containing ethinyl estradiol and cyproterone acetate and same OC alone in the treatment of severe hirsutism. The effect of these two therapies was assessed in a subjective and an objective evaluation of hair growth. According to the subjective evaluation, judged by physician and patient. 95% of patients obtained a partial response. The objective response was assessed by measuring the mean diameter of hair from 3 different areas and 1 control area. The decrease in hair diameter compared to pretreatment was statistically significant for both treatments, mainly for the abdomen and face. The difference between the two groups did not reach statistical significance. Therefore, we assume that OC alone remains the treatment of choice for hirsutism. However, the addition of the GnRH analog to OC needs further investigation and could be justified for patients with no response to standard monotherapy.

Efficacy of placebo in the treatment of patients with amenorrhea.

Thirty-two amenorrheic patients were treated with a tablet oral placebo preparation for a period varying from 30 to 180 days. Another 24 amenorrheic patients were also treated with a placebo administered i.m. for a period varying from 30 to 120 days. As a consequence of the treatment, 27 patients (48%) had menstrual bleedings. The progestogen withdrawal test responsive patients were more responsive to placebo (73 vs. 14% in the progestogen withdrawal test nonresponsive, p < 0.001). The time lag between starting the medication and the first bleeding varied between 4 and 120 days with a mean value of 33.9 (SD 26.3). Oral placebo was more effective than the intramuscular form (56 vs. 38%, p < 0.05).

Long-term effects of time, medical treatment and pregnancy in 176 hyperprolactinemic women.

The changes in plasma prolactin (PRL) concentrations were studied in 176 hyperprolactinemic women over periods of 6-180 months, to evaluate the independent effects of time, drugs and pregnancy on the evolution of prolactinemia. CT scans showed pituitary adenoma in 87 (9 macroadenoma), the clinical presentations for 110 patients there amenorrhea, for 37 abnormal cycles and 29 had anovulatory sterility as an isolated symptom. 107 women underwent 191 cycles of dopaminergic treatment and 73 had pregnancies (86), either spontaneously or as a consequence of the treatment. Changes in prolactin induced by medical treatment and pregnancy were recorded and the spontaneous changes in prolactin in 38 patients (17 with adenoma) were followed over periods of 6-72 months. Final mean PRL concentrations were lower than basal though not significantly, in both 'functional' (54.4 vs. 79.2 ng/ml) and prolactinoma patients (87.3 vs. 116.4 ng/ml). Separate calculation of changes in prolactin after the course of medical treatment, pregnancies or 'just waiting' periods showed mean PRL concentrations to be significantly lower only for 'functional' patients after pregnancy. On the other hand, PRL variations in individual patients revealed that: (1) spontaneously, PRL rarely becomes lower over a few years; (2) dopaminergic treatment was associated with normalization of PRL in 13% of women; and (3) pregnancy normalized prolactin concentrations in 29% of the patients. Chi-square analysis of the PRL-lowering frequencies in functional patients showed a high cure rate for pregnancy (P less than 0.0001) and a lesser but still significant effect of drugs (P less than 0.025).