Hepatitis C viraemia in adults with type 2 autoimmune hepatitis.

Sera from 14 patients with type 2 autoimmune hepatitis (anti-LKM1 positive) were investigated for evidence of hepatitis C virus (HCV) infection. Antibodies to HCV were detected in 13 patients by both commercial and "in-house" ELISAs and also by a second generation recombinant immunoblot assay. Nine of the 13 (69%) anti-HCV positive patients were shown to be viraemic by a polymerase chain reaction-based assay for serum HCV RNA. Neither anti-HCV nor serum HCV RNA were detected in any of 6 controls with primary biliary cirrhosis or in 39 healthy blood donors. These findings strongly suggest a role for HCV in the pathogenesis of type 2 autoimmune hepatitis.     

Mesh repair for lateral inguinal hernias: a non-evidence-based practice

Introduction

The EHS clinical guidelines recommend the use of mesh to repair symptomatic primary inguinal hernias (PIH) in adult males but, in spite of this, it begs the question as to why there is still place for tissue techniques. Lack of stratification of patients according to risk of recurrence in RCTs might be a cause of results disparity, since medial and mixed are hernias with higher risk of recurrence (HRRH), whereas lateral hernias present a lower risk (LRRH).

Objective

To determine whether the lack of stratification may lead to questionable conclusions regarding the protective effect of mesh techniques and to identify other methodological flaws.

Methods

In the RCTs included in the clinical guidelines that addressed recurrences of PIH after mesh and non-mesh techniques, we assessed the type of hernias classification used, the number needed to treat in LRRH and HRRH and the statistical power.

Results

Most of trials were underpowered; five studies classified the hernia types; in the three studies that compared the recurrence rates of LRRH and HRRH the effect of mesh techniques was small; only two trials record data needed to calculate the NNT in LRRH (46 y 84 patients, respectively).

Conclusion

The idea that mesh techniques reduce the recurrence rate in all PIHs is not supported by high level of evidence. The NNT for pure lateral hernias was very high and should be interpreted taking into account chronic pain rates and costs.

     

Bcl-6 gene mutations in primary cutaneous B-cell lymphomas

We analyzed mutations in the 5' non-coding region of the BCL-6 gene in 46 cases of primary cutaneous B-cell lymphomas (PCBCL), using a polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) method. The results indicate that PCBCL display a low frequency of mutations and support a marginal zone B-cell origin for most of these neoplasms.     

Antibodies to dietary antigens in coeliac disease

Antibodies to gliadin (AGA) were found in 77 (94%) of 82 sera from patients with active coeliac disease (untreated and after gluten challenge). Although IgG AGA had a higher nosological sensitivity than IgA AGA (88% versus 67%), their nosological specificity was lower than that of IgA antibodies (87% versus 100%). The sensitivity of antibodies to casein, beta-lactoglobulin, and ovalbumin in active coeliac disease varied from 36% to 48% without significant difference between IgG and IgA antibodies. IgG and IgA antibodies to milk and egg proteins showed a specificity similar to that of AGA, although some IgA antibodies other than AGA were found in disease controls (Crohn's disease, ulcerative colitis, post-enteritis syndrome).     

Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction

Aims

To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies.

Methods

Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT–RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation.

Results

Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p < 0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p < 0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia).

Conclusion

The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.     

Reproductive factors and clinical features of Parkinson's disease

BackgroundLiterature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients.MethodsAll IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy.ResultsIn total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant.ConclusionsOur observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified.     

The role of fulvestrant in endometrial cancer

Introduction: Endometrial cancer is the most common malignancy of the female genital tract in industrialized countries. The traditional treatment of endometrial cancer is based on a surgical approach. In recent years, systemic endocrine therapy has demonstrated good efficacy in recurrent or metastatic setting, delaying progression, ameliorating quality of life and palliating symptoms.

Areas covered: Phase I and II studies on selective estrogen receptor down-regulators used for the treatment of endometrial cancer treatment have been reviewed. The pharmacokinetic and pharmacodynamic features of selective receptor down-regulators have been also investigated.

Expert opinion: Selective estrogen receptor down-regulators may exhibit clinical efficacy in the treatment of gynecological malignancies due to their pure estrogen receptor antagonist properties. However, up to now data are still limited and some unsolved questions remain. Fulvestrant has poor oral bioavailability and low pharmacodynamic characteristics. Further trials are required to examine new selective estrogen receptor down-regulator agents with better pharmacodynamic and pharmacokinetic profiles.