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Aims. This study is aimed at assessing the efficacy of an active search and treat strategy for HBV-infected subjects in an endemic area (Campania, Italy). To do this, we created a cooperation bundle between 24 General Practitioners (GPs) and 3 Hospital Liver Units (HLU). We assessed whether this strategy improved the detection of HBV infection in patients at risk and the overall quality of care, with the aim of reducing liver disease progression. Methods. We estimated that, among about 20,000 patients cared for by the 24 GPs, approximately 280 patients unaware of or underestimating HBV infection would be found. Identified patients were to be referred to the HLU for clinical evaluation and treatment from February 2016 for 12 months. Results. Unexpectedly, screening and enrolment were poor (48 patients only). GP workloads, patient financial difficulties, and patients' refusal were the major causes of enrolment failure according to GPs. All patients referred to HLU completed the program; most of them were HBV inactive carriers. Conclusions. This program failed to scavenge chronic HBV-infected patients in an endemic area and establish a successful clinical collaboration between GPs and HLU. Underlying reasons are diverse and call for new strategies to implement cooperation between primary care providers and hospital specialists.

Purpose Endotoxin is a component of the outer membrane of gram-negative bacteria that live in the intestine. Endotoxinemia is reported in non-alcoholic fatty liver disease and in cirrhotic patients, causing various biological and clinical effects in the host. It is not known whether endotoxinemia occurs in chronic hepatitis C patients (CHC), therefore we evaluated the occurrence of endotoxinemia and its effect on inflammation, liver damage, insulin resistance (IR) and atherosclerosis. Methods Consecutive CHC patients assessed by liver biopsy were enrolled. Endotoxinemia was evaluated by LAL test. IR was estimated by HOMA-IR. Serum TNF-α, IL-8, adiponectin and MCP-1 were measured with ELISA tests. Oxidative stress was estimated by circulating IgG against malondialdehyde adducts with human serum albumin (MDA-HAS). Carotid atherosclerosis was assessed by ultrasonography. Results Endotoxinemia was found in 60% of the 126 patients enrolled. A serum level-dependent association between endotoxinemia, steatosis (p

Background & Aims: The cannabinoid receptor 2 (CB2) has been implicated in liver disease. The single-nucleotide polymorphism rs35761398 in cannabinoid receptor 2 gene (CNR2), which encodes the CB2, substitutes glutamine (Q) 63 with arginine (R), and reduces the function of the gene product. We investigated the effects of CNR2 rs35761398 in patients with hepatitis C virus (HCV) infection. Methods: We studied 169 consecutive patients with asymptomatic chronic hepatitis (tested positive for anti-HCV and HCV RNA) at 2 liver units in southern Italy. First, liver biopsy samples were collected from July 2009 through December 2011. All patients were naive to antiviral therapy; CNR2 genotype was determined by polymerase chain reaction analysis. Results: Patients with the CB2-63 QQ variant had higher serum levels of aminotransferase than those with the CB2-63 QR or RR variants; they also had higher histologic activity index (HAI) scores (8.6 ± 3.8) than patients without the CB2-63 RR variant (5.3 ± 3.6; P < .005) or those with the CB2-63 QR variant (5.8 ± 3.3; P < .001). Patients with the different variants of CNR2 did not differ in fibrosis stage or steatosis score. Moderate or severe chronic hepatitis (HAI score, >8) was identified more frequently (55.5%) in patients with the CB2-63 QQ variant than in those with the 63 QR (20%; P < .005) or RR variants (17.4%; P < .005). In logistic regression analysis, the CB2-63 QQ variant and fibrosis score were independent predictors of moderate or severe chronic hepatitis (HAI score, >8; P < .0001). Conclusions: The CB2-63 QQ variant of CNR2 is associated with more severe inflammation and hepatocellular necrosis in patients with HCV infection. © 2014 AGA Institute.

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis. © 2013 John Wiley & Sons Ltd.

Background & Aims: A common non-synonymous polymorphism, E167K, in transmembrane six superfamily member 2 (TM6SF2) gene has been recently associated with an increased hepatic triglyceride content, dyslipidemia and liver fibrosis in NAFLD patients. We investigated possible associations between the TM6SF2 variants and liver lesions in chronic hepatitis C. Patients and Methods: 148 consecutive patients with biopsy proven anti-HCV/HCV-RNA-positive chronic hepatitis, naive for antiviral therapy, were genotyped for TM6SF2 E167K and PNPLA3 I148M variants. Results: The score of liver steatosis was higher in the 18 patients with TM6SF2 E167K variant (mean 1.9 ± 1.3) than in the 130 homozygotes for TM6SF2 167E allele (1.1 ± 1.1, P = 0.02), and the prevalence of a steatosis score ≥ 3 was 33.3% vs. 12.3% respectively (P = 0.02). No difference in necroinflammatory or fibrosis scores was found between the two groups. A general linear model identified as independent predictors of steatosis TM6SF2 E167K and PNPLA3 M148M variants and waist circumference (P = 0.0376, P = 0.0069 and P = 0.0273 respectively). Conclusions: This is the first demonstration that TM6SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C. © 2015 John Wiley & Sons A/S

The inosine triphosphatase (ITPA) gene and interleukin 28B (IL28-B) gene variants have been associated to protection of anemia and sustained virological response, respectively, in patients with chronic hepatitis C (CHC) during antiviral therapy. Aim of this study was to evaluate the single and combined role of both polymorphisms in the management of peg-interferon-ribavirin treatment in CHC patients. We studied 79 Italian patients with histology proven CHC treated with pegylated interferon plus ribavirin for 6-12 months on the base of HCV genotype. Patients were carefully followed-up for anemia development which was classified as mild, moderate or severe in relation to levels of haemoglobin decreasing; ribavirin dosage reduction and/or epoietin administration were carried out, where needed. Sustained virological response (SVR) was considered for HCV-RNA clearance after 6 months of treatment stop. Decay of haemoglobin at month 1 of treatment significantly correlated with ITPA activity (p 0.0004) and at multivariate analysis ITPA activity was the only parameter associate with anemia (R - 0.4; p 0.0004). SVR was obtained in 47% of patients. IL28B CC variant was associated with SVR (p 0.01), but IL28B polymorphisms had no influence on the ITPA polymorphism. This study confirms the role of ITPA variants in the prediction of development of severe anemia during antiviral treatment for CHC and demonstrates the absence of influence of IL28B variant on ITPA polymorphisms. These two polymorphisms can be useful in the management of patients that need antiviral therapy for HCV chronic infection.

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with liver steatosis and disease progression in nonalcoholic steatohepatitis and chronic hepatitis C.The aim of the present study was to evaluate the influence of the PNPLA3 I148M polymorphisms on the clinical, histological, viral, and host parameters in Italian patients with chronic hepatitis B (CHB).Ninety-nine patients with CHB entered the study and underwent a clinical, histological, virological, and biochemical evaluation. PNPLA3 (p.I148M) variants were genotyped.PNPLA3 rare variant (148M) was significantly associated with liver steatosis (p = 0.0019) and cholesterol (p = 0.04) levels, but not with fibrosis or histological activity index. The 13 patients with severe liver steatosis (score3) (38%) were more frequently homozygous for PNPLA3 148M variant than the 86 without (6%, p = 0.003). At logistic regression analysis, severe steatosis was independently associated with the rare allele (p = 0.001) and waist circumference, but not with body mass index (BMI).In our CHB patients, the PNPLA3 polymorphisms influenced the development of liver steatosis, but not fibrosis status. The association of PNPLA3 p.I148M with liver steatosis increased with the greater amount of abdominal fat, irrespective of BMI.

Chronic hepatitis B (CHB) treatment aims at long-term suppression of HBV replication and improvement in clinical outcomes. We describe the data of a pilot, non-profit study in which patients with CHB were treated with de novo combination lamivudine-adefovir (LAM-ADV) for at least four years with a view to HBV suppression and resistance prevention, and shifted to tenofovir (TDF) when new antiviral agents were available. Fifty-one HBeAg negative patients were enrolled. Histology was available for 39 patients and data of liver stiffness (LS) for 24 patients at baseline. Serum quantification of HBsAg and HBVDNA was obtained regularly during the follow-up. In 10 and 7 patients, a paired histology and LS were available at the end of LAM-ADV treatment, respectively. The de novo LAM-ADV combination was able to obtain HBVDNA suppression and ALT normalization in one year in most of the patients and in the second year in the remaining. Histology improved in patients with paired biopsy, but tissue HBsAg was present in all but one patient after 48 months of therapy. TDF maintained biochemical and virological response throughout the follow-up. Renal impairment during LAM-ADV therapy improved on shifting to TDF; only in 4 cases was a second shift to entecavir needed. TDF was safe and effective in maintaining HBV DNA suppression achieved by a long-term course of LAM-ADV de novo combination for the treatment of HBeAg-negative CHB.

Background and aimTo evaluate in anti-HCV-positive patients the clinical impact of the rs35761398 variant of the CNR2 gene leading to the substitution of Gln (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with Arg (R).Patients and methods253 consecutive anti-HCV-/HCV-RNA-positive patients were enrolled, of whom 53 were HCV carriers with persistently normal ALT (PNALT group) and 200 had a history of steadily abnormal serum ALT values (abnormal ALT group). All patients were naive for antiviral therapy and were screened for the CNR2 rs35761398 polymorphism by a TaqMan assay.ResultsSubjects in the PNALT group, compared with those in the abnormal ALT group were older (58.5±12 vs. 50.7±12.4 years, p = 0.001), more frequently female (66% vs. 42%, p = 0.003), with lower body mass index (BMI) (24.5±3.1 vs. 26.6±4.6, p = 0.003), and more frequently with HCV genotype 2 (43.1% vs 17.7%, p = 0.0002) and CB2-63 QQ variant (34% vs. 11%, p = 0.0001). Considering all 253 patients, no difference in the demographic, biochemical, or virological data was observed between patients in the different CB2-63 variants. The logistic regression analysis identified CB2-63 QQ, HCV genotype 2, older age and lower BMI as independent predictors of PNALT (pDiscussionThe CB2-63 QQ variant in HCV patients was independently associated with the PNALT status.

Frequency-modulated (FM) signals are an integral acoustic component of ecologically natural sounds and are analyzed effectively in the auditory systems of humans and animals. Linearly frequency-modulated tone sweeps were used here to evaluate two questions. First, how rapid a sweep can listeners accurately perceive? Second, is there an effect of native language insofar as the language (phonology) is differentially associated with processing of FM signals? Speakers of English and Mandarin Chinese were tested to evaluate whether being a speaker of a tone language altered the perceptual identification of non-speech tone sweeps. In two psychophysical studies, we demonstrate that Chinese subjects perform better than English subjects in FM direction identification, but not in an FM discrimination task, in which English and Chinese speakers show similar detection thresholds of approximately 20 ms duration. We suggest that the better FM direction identification in Chinese subjects is related to their experience with FM direction analysis in the tone-language environment, even though supra-segmental tonal variation occurs over a longer time scale. Furthermore, the observed common discrimination temporal threshold across two language groups supports the conjecture that processing auditory signals at durations of approximately 20 ms constitutes a fundamental auditory perceptual threshold.

PURPOSE: Imaging of the cardiac autonomic system with (123)I-metaiodobenzylguanidine (MIBG) is useful in the evaluation of patients with a variety of cardiac conditions, including heart failure (HF), but few data are available about the reproducibility of this technique. We assessed the observer reproducibility of the results from a low-dose (123)I-MIBG cardiac imaging protocol in patients with HF. METHODS: A total of 74 patients (62 men, age 67 ± 10 years) with HF and left ventricular systolic dysfunction (ejection fraction 31 ± 7 %) underwent low-dose (111 MBq) planar and single-photon emission computed tomography (SPECT) (123)I-MIBG cardiac sympathetic imaging. The intraclass coefficient of correlation (ICC), Lin's concordance correlation coefficient, and Bland-Altman analysis were used to evaluate the intraobserver and interobserver reproducibility of early and late heart-to-mediastinum (H/M) ratios and of defect scores on SPECT images. The ? statistic was used to evaluate the concordance rates for the identification of patients with a low H/M ratio (0.90) for all measurements. For the identification of patients with a low H/M ratio, the ? values were 0.90 for intraobserver concordance and 0.83 for interobserver concordance. CONCLUSION: The present study showed a high observer reproducibility of planar H/M ratios and SPECT defect scores using a low-dose (123)I-MIBG cardiac imaging protocol in patients with HF.

Haploinsufficiency of a region located distal to 10p14 designated HDR1, is responsible for hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR syndrome). Haploinsufficiency of a more proximal region, located on 10p13-10p14, designated as DGCR2 is associated with congenital heart defects and thymus hypoplasia/aplasia or T cell defect. We describe a patient showing facial dysmorphisms, delayed psychomotor development and bilateral sensorineural hearing loss and carrying a 10p14 deletion, the smallest deletion found in the literature so far. Our patient, carrying a partial deletion of the DGCR2 region and of the HDR1 region, including the GATA3 gene, showed, unexpectedly, only few of the clinical features of DiGeorge 2 syndrome (psychomotor retardation, palpebral ptosis, epicanthic folds, anteverted nares, cryptorchidism, hand/foot abnormalities) and did not show other typical signs, such as cardiac defect, cleft palate, and abnormal T cell levels. Of the three characteristic features of the HDR syndrome, our patient had only sensorineural deafness. On the basis of the revision of the other cases reported in the literature with a deletion including the 10p14 region, we suggest that GATA3 haploinsufficiency, although not recorded for each patient, is responsible for deafness. The present case shows that even this small 10p deletion is responsible for a specific phenotype. We also underline the importance of CGH-array, in order to obtain a more precise physical mapping of the 10p deletions and an accurate genotype-phenotype correlation. (C) 2012 Wiley Periodicals, Inc.

The impact of the cannabinoid receptor 2 (CB2) rs35761398 polymorphism on chronic hepatitis B (CHB) was evaluated in 106 consecutive biopsy-proven CHB patients naive for antiviral therapy. A histological activity index (HAI) > 8 (Ishak scoring) was more frequent in patients with CB2-63 RR than in those with CB2-63 QR or QQ (37% vs. 16.7%, p 3 (p 8. The observation that the CB2-63 RR variant is an independent predictor of extensive necroinflammation opens up new prospects in the study of CHB.

OBJECTIVE Impaired parasympathetic and sympathetic nervous system activity have been demonstrated in patients with diabetes mellitus (DM) and correlated with worse prognosis. Few data are available on the effect of DM on cardiac neuropathy in heart failure (HF). The aim of the current study was to assess cardiac sympathetic activity in HF patients with and without DM. RESEARCH DESIGN AND METHODS Patients with severe HF (n = 75), with (n = 37) and without DM (n = 38), and 14 diabetic patients with normal cardiac function underwent 123I meta-iodobenzylguanidine scintigraphy from which early and late heart-to-mediastinum (H/M) ratios were calculated. Clinical, echocardiographic, and biochemical data were measured. RESULTS DM compared with non-DM patients showed significantly lower early (1.65 ± 0.21 vs. 1.75 ± 0.21; P < 0.05) and late H/M ratios (1.46 ± 0.22 vs. 1.58 ± 0.24; P < 0.03). Early and late H/M were significantly higher in DM patients without HF (2.22 ± 0.35 and 1.99 ± 0.24, respectively) than HF patients with (P < 0.0001) and without (P < 0.0001) DM. In HF patients, an inverse correlation between early or late H/M ratio and hemoglobin A1c (HbA1c) (Pearson = −0.473, P = 0.001; Pearson = −0.382, P = 0.001, respectively) was observed. In DM, in multivariate analysis, HbA1c and ejection fraction remained significant predictors of early H/M; HbA1c remained the only significant predictor of late H/M. No correlation between early or late H/M and HbA1c was found in non-DM patients. CONCLUSIONS Diabetic patients with HF show lower cardiac sympathetic activity than HF patients not having DM or than DM patients with a similar degree of autonomic dysfunction not having HF. HbA1c correlated with the degree of reduction in cardiac sympathetic activity.