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Objective To study the epidemiological and clinical features of Hepatitis E Virus (HEV) infection in a migrant population. Methods We performed a retrospective chart review, identifying a cohort of 21 symptomatic patients of migrant origin with confirmed HEV infection admitted in the period between January 1995–November 2014. Results 20 (95%) patients came from South Asian countries highly endemic for HEV, all positive for HEV genotype 1. Recent travel to a highly endemic country was the most consistent risk factor identified in 90% of cases, duration from return to Italy to hospitalization ranged from 10 to 120 days. Nausea and vomiting (100%), jaundice (95.2%), and anorexia (85.7%) were the most common reported symptoms. Fever was present in 57.1% of cases. Transaminase values were elevated in all patients and serum bilirubin was raised in 86% of patients. We found no statistically significant differences between clinical symptoms, laboratory results or duration of hospitalization in patients with co-morbidities compared to those without. We also report a secondary case of HEV genotype 1 transmitted within Italy. Conclusion Our study highlights the epidemiological risk factors and clinical features of HEV infection in a migrant population in Italy and should stimulate further research regarding the prevalence and morbidity of HEV within migrant populations in Europe.

The main aim of this paper is to show the potential benefits for the Securitisation process, both in terms of the setup of operations and in the entire product life cycle, derived from the adoption of the Blockchain Technology. For this purpose, we focused on the different aspects, starting from the securitisation market in which we analysed the causes of the decrease in the number of operations occurred in the last decade, although there still is a strong need to securitise some types of assets such as NPL’s and Trade Receivables. Specifically, for these two types of assets we represent the securitisation process with the As-Is limits and improvements made possible by the blockchain technology application. Along this “path” we have deepened some key aspects of the blockchain and how the application of this technology may help Financial Institutions to experience a strong reduction in operational risks and costs, liquidity risk and credit risk on managing the underlying assets. At the same time, the new framework might give to a wider category of individuals access to a product that otherwise would have been available only to a limited number of more sophisticated investors, tapping from more structured, controlled and certified information. All this being achieved at no additional costs but rather with stronger and more organized and transparent product structures.

Background & Aims Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. Methods All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. Results A total of 179 patients were included: median age 57 (18–88) years, 74% males, median HCV-RNA 1,081,817 (482–25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). Conclusions SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. Lay summary This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Online Material: Seismic‐hazard map, figures of event location and waveforms, phase reading distribution, and background seismic noise; and tables of event parameters, 1D regional model, and earthquake catalog. The Collalto Seismic Network (Rete Sismica di Collalto, or RSC) is the infrastructure used to monitor the natural and induced seismicity of the natural gas storage concession known as Collalto Stoccaggio, which is located in northeastern Italy. This network was realized and is currently managed by the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale (OGS), a public research institute, on behalf of Edison Stoccaggio S.p.A., the storage concession holder. The storage exploits a depleted natural gas reservoir that was converted into a seasonal reservoir in the 1990s. The reservoir is a geologic trap, with porous and permeable rock layers, a few meters thick, sealed by impermeable formations. The production levels are located at 1500–1600 m depth (Picotti, 2007) and extend approximately over a 10 km×4 km wide area (Fig. 1). The gas storage activity affects four municipalities, all of which are located in the province of Treviso: Susegana, Nervesa della Battaglia, S. Pietro di Feletto, and Conegliano. Figure 1. Location of the study area, including the Collalto Seismic Network (RSC). Seismometric stations are indicated by triangles; the 10 RSC stations by white triangles (labels start with ED; all are located within area A); and the stations of the Northeastern Italy Integrated Seismic Network (NEI) by black triangles, respectively. All the stations indicated are managed by the OGS. The two rectangles bordered by thin lines indicate the two target areas, A and B. The irregular area bordered by a thick black line within area A corresponds to the surface projection of the gas storage reservoir. The fault lines indicate the active faults known for the study area according to Poli et al. (2008). Insets (a) and (b) …

Continuous GNSS networks provide unique information about the crustal dis-placements, of use for studies concerning plate motions, tectonic processes, and earthquake cycle understanding. The Istituto Nazionale di Oceanografia e di Geofisca Sperimentale—OGS, since 2002, is responsible for the installation, maintenance, and development of FReDNet (Friuli Regional Deformation Network), the system for crustal deformation monitoring in the Friuli Venezia Giulia Region. The main objective of the network is the detection of tectonic plate movements in this collision area: such movements can give some guidance to quantify the seismic hazard. The infrastructure currently consists of 16 permanent stations located in the Friuli Venezia Giulia and Veneto regions, all equipped with GNSS receiver (Global Navigation Satellite Systems) capable of tracking satellite systems GPS, GLONASS and Galileo. The system includes a central server for collecting, processing and distributing of data and results. FReDNet, furthermore, provides a service for browsing high-precision real-time positioning in the most common differential correction RTK (Real Time Kinematic) modes. The current document will briefly describe the technical implementation of FReDNet in the last years with new stations, new features (high-frequency sampling and monumentation) and upgraded services.

INTRODUCTION Short antiviral therapy has been proposed for patients with chronic hepatitis C, easy genotypes, low fibrosis score, low viral load at baseline, and rapid virological response (RVR). However, this approach is not completely accepted. OBJECTIVES The aims of this study were (a) to evaluate the sustained virological response (SVR) in noncirrhotic patients with genotype 2 or 3, achieving an RVR, randomized to receive pegylated-interferon (IFN) α-2b plus ribavirin for either 16 or 24 weeks and (b) to carry out direct cost analysis comparing patients treated for 16 versus 24 weeks. RESULTS Of the 142 initially evaluated patients, 130 were enrolled according to the selection criteria, but independent of the viral load. According to the intention-to-treat analysis, SVR was achieved in 104 patients (80%). Logistic regression analysis showed that RVR (P

International audience; Regression of hepatitis C virus (HCV)-associated lymphoma with interferon (IFN)-based antiviral treatment supports an etiological link between lymphoma and HCV infection. In addition, a favorable impact of antiviral treatment on overall survival of patients with HCV-related lymphoma has been reported. Data on IFN-free regimens combining direct-acting antivirals (DAAs) in HCV-associated lymphoproliferative disorders are scanty. We analyzed the virological and lymphoproliferative disease response (LDR) of 46 patients with indolent B-cell non-Hodgkin lymphomas (NHLs) or chronic lymphocytic leukemia (CLL) and chronic HCV infection treated with DAAs. The histological distribution was 37 marginal zone lymphomas (MZLs), 2 lymphoplasmacytic lymphomas, 2 follicular lymphomas, 4 CLL/small lymphocytic lymphomas (CLL/SLLs), and 1 low-grade NHL not otherwise specified. Thirty-nine patients received a sofosbuvir-based regimen and 7 patients received other DAAs. The median duration of DAA therapy was 12 weeks (range, 6-24 weeks). A sustained virological response at week 12 after finishing DAAs was obtained in 45 patients (98%); the overall LDR rate was 67%, including 12 patients (26%) who achieved a complete response. The LDR rate was 73% among patients with MZL, whereas no response was observed in CLL/SLL patients. Seven patients cleared cryoglobulins out of 15 who were initially positive. After a median follow-up of 8 months, 1-year progression-free and overall survival rates were 75% (95% confidence interval [CI], 51-88] and 98% [95% CI, 86-100], respectively. DAA therapy induces a high LDR rate in HCV-associated indolent lymphomas. These data provide a strong rationale for prospective trials with DAAs in this setting.

The introduction of highly active anti-retroviral therapy (HAART) for Human Immunodeficiency Virus (HIV) infection has significantly improved the life expectancy of HIV positive patients. Hepatitis C virus (HCV) co-infection is common in HIV infected patients and is now a significant cause of morbidity and mortality. Optimal management and treatment of HCV in HIV infected patients is therefore essential. Interferon-alpha (IFN-alpha) and ribavirin is the mainstay of treatment for HCV infection in HIV infected people. The sustained virological response rate (SVR) with combination therapy is lower than that commonly observed in HCV mono-infected patients. This is, at least in part, due to the very high treatment drop out rates. Ribavirin in combination with HAART is associated with particular side effects such as mitochondrial toxicity. Therefore, vigilant monitoring of patients during therapy, in specialist centers is essential. Pegylated interferon (PEG-IFN) plus ribavirin is particularly promising as it is easier to administer and will probably become the treatment of choice for co-infected patients. A SVR is associated with genotype 2 and 3, in addition to a high CD4+ cell count and a low HCV load prior to therapy. The progression of HCV related liver disease in HIV positive patients is faster than in subjects with HCV infection alone. As a result, there is an increasing incidence of cirrhosis and end-stage liver disease in co-infected patients. Liver transplantation is being evaluated in many centers. To date the experiences are very limited but encouraging in term of survival rate.

Background Pegylated interferon (PEG-IFN) and ribavirin is the most effective treatment for chronic hepatitis C virus (HCV) hepatitis, but the rate of sustained virological response (SVR) remains approximately 50%, and 15-20% of all treated patients have a virological relapse after completing the treatment. Studies on the SVR have failed to discriminate between non-responders and relapsers. Aims To identify the risk factors for relapse among patients with an end-of-treatment response (ETR). Methods We retrospectively analyzed 281 patients consecutively treated with PEG-IFN and ribavirin with a follow- up period of at least 24 weeks. The baseline details collected on each patient included demographic data, histological features, and biochemical profiles. Results Forty-six patients (16.4%) relapsed during the first 6 months of follow-up after discontinuing the therapy. Relapser patients were significantly older, had more steatosis, fibrosis, and showed significantly lower rapid virological response (RVR) rates compared with SVR patients. By logistic regression analysis, only the absence of RVR was found to be significantly associated with relapses in both subgroups of patients with genotypes 1 and 4 (p.004) and those with genotypes 2 and 3 (p.006). Severe fibrosis was also predictive of relapsing disease, but only for genotypes 2 and 3 patients (p.003). During the treatment, serum HCV-RNA decreased more rapidly in patients with SVR compared to non-responder and relapser patients (p.001). Interestingly, relapser patients exhibited an intermediate serum HCV-RNA decay during the first 4 weeks of therapy. Conclusion Among HCV patients treated with PEG-IFN and ribavirin, the absence of RVR was the most important independent predictor of relapse, independent of the HCV genotype. In the subgroup of genotypes 2 and 3 patients, the severity of fibrosis was also an important factor associated with the relapse rate.

Background / Aims The rapid decline in hepatitis C virus RNA is crucial for determining the outcome of therapy in patients with genotype 1 chronic hepatitis C. However, the variables influencing the early phase of viral decay are still largely unexplored. We aimed to assess which pre-treatment variable may predict rapid virologic response (RVR) and sustained virologic response (SVR). Methods We evaluated 90 consecutive non-diabetic patients with genotype 1 chronic hepatitis C without cirrhosis, treated with peginterferon alpha-2b plus ribavirin. Viral load (COBAS Amplicore, Roche) was measured at 1, 4 and 12 weeks after starting treatment, and then 24 weeks after the end of treatment. Results The overall SVR was 47%. The SVR in patients with RVR was 100%. Age, GGT levels, viral load, steatosis, fibrosis and HOMA-IR were significantly associated with RVR in univariate analysis. After logistic regression, HOMA-IR proved to be the strongest independent predictor of RVR (OR 0.37, 95% CI: 0.16–0.89; p =0.027), whereas fibrosis had a weaker independent association with RVR (OR 0.32, 95% CI: 0.1–1.04; p =0.057). Among the eight pre-treatment variables, both BMI and steatosis were significantly associated with HOMA-IR, either in univariate or in multivariate analyses. Conclusions Our data suggest that insulin resistance is strongly associated with RVR, thus reflecting the important role played by metabolic factors in the early phase of viral kinetics. HOMA-IR would appear to be a useful tool in predicting RVR and should be evaluated at baseline in all chronic hepatitis C patients before initiating antiviral treatment.

Prevalence and impact of occult HBV infection in HIV positive patients is controversial. The aims of this study were to determine the prevalence of occult HBV infection and its impact on histological and virological parameters. 52 HIV/HCV (but HBsAg-negative) co-infected patients, 29 HBsAg and anti-HCV negative chronic hepatitis, and 20 HBsAg positive chronic hepatitis controls were studied. DNA was extracted from frozen biopsies and amplified with primers for S, C and X regions, and for (ccc) HBV-DNA. Sera were tested for HBV-DNA with two quantitative assays (Cobas Amplicor HBV Monitor, and the real-time COBAS (r) Taqman HBV Test, Roche Diagnostics, UK). Occult HBV infection was detected in 7 (13.4%) liver biopsies of the study group, and in none case of the non viral chronic hepatitis group (p=0.04). All serum samples were HBV-DNA negative with Cobas Amplicor HBV monitor assay, while 3 cases were found positive with real time PCR. Statistical analysis didn't show any impact of occult HBV infection on liver histology, CD4+ cells count, HIV and HCV load, and ALT levels. Occult B infection is relatively frequent in HIV/HCV co-infected patients, and is underestimated by common HBV-DNA serological assays. However, it doesn't seem to exert a relevant impact.

PURPOSE An elevated frequency of the CCR5-Delta32 mutation in German patients with hepatitis C with viremia has been reported. The aim of the present study was to verify whether this mutation occurs in an Italian population with hepatitis C and whether it is an adverse host factor indicative of severity of liver disease and response to antiviral therapy. STUDY The authors amplified 189-bp (wild-type) and 157-bp (Delta32 deletion) fragments of the CCR5 gene by polymerase chain reaction in 130 patients with chronic hepatitis C. Comparisons were drawn with 110 blood donors and 135 patients with primary biliary cirrhosis. RESULTS Four (3.1%) patients with chronic hepatitis C and 1 blood donor (0.9%) were CCR5-Delta32 homozygous, whereas there was no CCR5-Delta32 homozygosity among primary biliary cirrhosis patients; the wild-type gene was present in a similar percentage in the 3 groups of patients without any significant difference (83.1% vs 90.4% vs 83.6%, respectively). Among the patients with chronic hepatitis C, no significant correlation was found between CCR5-Delta32 homozygosity and the following parameters: histologic grade/stage, hepatitis C virus genotype, viral load, serum aspartate aminotransferase, serum alanine aminotransferase, and serum gamma-glutamyltransferase. Ninety-five patients received a standard antiviral protocol with pegylated interferon (PEG Intron)+ribavirin; a sustained response was achieved in 59 patients (62.1%), and the remainder did not respond or experienced a relapse. Response to treatment was not influenced by CCR5-Delta32 deletion. CONCLUSION No greater frequency of CCR5-Delta32 homozygosity was seen in an Italian population of patients with chronic hepatitis C. This mutation does not seem to influence either the overall severity of liver disease or the response to viral therapy.

Objectives The aims of this study were to evaluate the prevalence and impact of Chlamydia pneumoniae infection in HIV-positive patients and to establish the relationship between C. pneumoniae infection and lipid profile. Methods Detection of C. pneumoniae was by polymerase chain reaction (PCR) on Peripheral Blood Mononuclear Cells (PBMCs) collected from 97 HIV-positive patients. Samples were collected after overnight fast in EDTA-treated tubes. On the same day, patients were also tested for routine chemistry, HIV viral load, CD3, CD8 and CD4 cell counts and lipid profile [cholesterol, high-density lipoproteins (HDLs), low-density lipoproteins (LDLs) and triglycerides]. Results The overall prevalence of C. pneumoniae was 39%. The prevalence of C. pneumoniae was inversely related to the CD4 lymphocyte count (P=0.03). In the naive group, C. pneumoniae-positive patients had both significantly higher HIV load (71 021±15 327 vs. 14 753±14 924 HIV-1 RNA copies/mL; P=0.03) and lower CD4 cell count (348.0±165.4 vs. 541.7±294.8; P=0.04) than C. pneumoniae-negative patients. Moreover, treatment-naive patients with C. pneumoniae infection had significantly higher mean levels of cholesterol (185.3±56.2 vs. 124.8±45.9 mg/dL; P=0.01), triglycerides (117.2±74.7 vs. 68±27.6 mg/dL; P=0.04) and LDL (122.4±60.1 vs. 55.6±58 mg/dL; P=0.05) than C. pneumoniae-negative patients. Conclusions These data indicate that, in HIV-positive subjects, C. pneumoniae infection is relatively frequent and is associated with both low CD4 cell count and high HIV load. Furthermore, C. pneumoniae appears to be associated with hyperlipidaemia and might therefore represent a further risk factor for cardiovascolar disease in HIV-positive patients.

To the Editor: Hepatitis E is an enterically transmitted infection with worldwide distribution and high prevalence in developing countries. This disease can occur as large water-borne epidemics associated with hepatitis E virus (HEV) genotypes 1 and 2. Hepatitis E is less common in industrialized countries, including Italy (1), where sporadic autochthonous cases associated with genotypes 3 and 4 have been reported. Virus strains of these genotypes are widespread in different mammalian species, including wild boar (2). We report a case of hepatitis E in a 60-year-old man born and living in Vicenza, Italy, who was admitted to the Emergency Department of Vicenza Hospital on May 9, 2012 with symptoms of acute icteric hepatitis. He had been given a diagnosis of chronic lymphocytic leukemia and hemolytic anemia in 2003 and underwent 8 treatment cycles of cyclophosphamide and steroids, which were completed 20 days before he came to the Emergency Department. His liver function test results at admission were the following: alanine aminotransferase 1,804 IU/L, total bilirubin 24.1 mg/dL, and alkaline phosphatase 137 IU/L. Test results for other causes of viral hepatitis were negative (Figure). A liver biopsy performed on June 1 showed severe acute lobular hepatitis with necrosis and cholestasis. Serum obtained at admission was positive for IgM and IgG against HEV (Dia.Pro Test, Milan, Italy). Figure Clinical and laboratory data for a 60-year-old man with hepatitis E and lymphocytic leukemia, Italy, 2012. Start of ribavirin treatment and virologic response are indicated. A differential diagnosis was obtained by using abdominal ultrasound, which showed ... HEV RNA was detected by reverse transcription PCR and open reading frame 2 (3) was detected in serum and feces samples on May 9. Phylogenetic analysis of sequences identified HEV genotype 3 subtype h in serum and fecal samples (GenBank accession nos. {"type":"entrez-nucleotide","attrs":{"text":"KC782933","term_id":"514995386","term_text":"KC782933"}}KC782933 and {"type":"entrez-nucleotide","attrs":{"text":"KC782934","term_id":"514995388","term_text":"KC782934"}}KC782934). Three months after admission, the patient had viremia, and results of liver function tests were abnormal. Recent data suggest that immunosuppressed persons who are viremic 3 months after HEV infection do not spontaneously clear HEV (4). Therefore, the patient was given antiviral therapy to achieve viral clearance. Ribavirin, 1,000 mg/day in 2 doses (400 and 600 mg), was administered during August 2–November 2, 2012. This drug was well tolerated, although the patient experienced mild anemia (hemoglobin level 10.5 mg/dL), which did not require any treatment. Liver function test results returned to reference levels on day 14 of treatment. HEV RNA was detected in blood and feces on day 18 of treatment (August 20). Viral clearance (HEV absent from feces and serum) was achieved on day 54 of treatment (September 27) and was sustained over a 6-month period after the end of therapy. The source of the HEV infection was uncertain. The patient had never traveled outside Italy. However, he had butchered a wild boar that he had hunted in Barberino del Mugello (Tuscany) in March 2012. The patient’s wife, who also butchered the animal, was positive for IgG against HEV but negative for IgM against HEV and for HEV RNA in February 2013. No boar meat was available for HEV testing, which indicated that this route of transmission was likely, but not confirmed. Autochthonous hepatitis E in industrialized countries is usually an acute, self-limiting disease, but chronic disease can occur in immunocompromised hosts (5). These hosts include transplant recipients, persons infected with HIV, and patients with hematologic malignancies. Chronic infection with HEV has only been documented with genotype 3 strains and has been observed in many countries in Europe, However, to our knowledge, no cases of chronic infection with HEV have been reported in Italy. Our results indicate that chronic infection with HEV genotype 3 occurs in Italy. Acute and chronic hepatitis E have been reported in patients with hematologic malignancies. An autochthonous case of acute hepatitis E was recently described in Germany in a patient with chronic lymphocytic leukemia that had been treated with chemotherapy, a bone marrow transplantation, and hemodialysis (6). He did not receive any specific treatment for hepatitis E and died of acute liver failure 39 days after diagnosis. Reactivation of hepatitis E in a patient with acute lymphoblastic leukemia was reported after allogeneic stem cell transplantation (7). HEV can also be transmitted directly from an infected transplanted organ. Ribavirin monotherapy is an effective treatment for most patients with chronic HEV infection (8). It has also been used successfully to treat acute severe infection by genotype 1 of HEV in developing countries and by genotype 3 in industrialized countries (9), and is used to treat hepatitis C, although its mechanism of action against HCV and HEV is uncertain. Data are limited on the use of ribavirin in patients with chronic hepatitis E and hematologic malignancies (10). The outcome for our patient suggests that ribavirin might be useful for treating hepatitis E in such patients. In conclusion, all patients with hepatitis of unknown origin should be tested for HEV, in particular, immunocompromised patients, because they are at risk of acquiring chronic hepatitis and having an adverse outcome. Ribavirin appears to be efficacious in treating hepatitis E and should be considered for any immunocompromised person who has viremia 3 months after acute infection.

Background: the frequency and the impact of occult HBV infection in patients with chronic hepatitis C infection is still a matter of some controversy. Objectives: our aim was to evaluate the prevalence of occult HBV infection and assess its impact on liver biochemistry, HCV viral titre, liver histology and on outcome of therapy in patients with chronic hepatitis C. Study design: paired liver biopsies and serum samples were collected from 51 patients (84% IVDUS) with HBsAg negative chronic hepatitis C, and tested for HBV-DNA with nested PCR. Liver biopsies were further studied histologically, with morphometric analyses and immunostaining techniques. Twenty-five were treated with alpha Interferon and ribavirin and followed for at least 18 months. Results: HBV DNA was detected in 29.4% of liver tissue specimens and in only one (1.9%) serum sample. Three liver specimens were positive for surface gene, nine for core gene, three for both and none for the X gene. No significant difference in mean transaminase values, HCV viral titre, HCV genotype, or grading and staging and morphometric analysis was observed in patients with or without HBV DNA. Moreover, all 51 liver specimens were negative for both HBsAg and HBcAg. Sustained response to combination therapy was achieved in 40% of patients with and in 53% of patients without HBV DNA in the liver specimens (P=NS). Conclusions: HBV DNA is frequently found in the liver of patients with chronic hepatitis C. However, the lack of any significant impact on HCV viral titre, liver enzymes, histological parameters and response to therapy, suggests that in most cases HBV DNA detected in the liver by PCR may be either an integrated or low level replicative form.

Type 1 diabetes mellitus is the result of an autoimmune process characterized by pancreatic beta cell destruction. It has been reported that chronic hepatitis C infection is associated with type 2 diabetes mellitus, but not with type 1. Although the prevalence of markers of pancreatic autoimmunity in hepatitis C virus-positive patients is not significantly different to that reported in the general population, it increases during alpha-interferon therapy from 3 to 7%, probably due to the immunostimulatory effects of this cytokine. To date, 31 case reports of type 1 diabetes mellitus related to interferon treatment have been published. Type 1 diabetes mellitus occurs more frequently in patients treated for chronic hepatitis C than for other conditions and is irreversible in most cases. In 50% of these patients, markers of pancreatic autoimmunity predated treatment, the majority of cases having a genetic predisposition. Thus, in predisposed individuals, alpha-interferon can either induce or accelerate a diabetogenic process already underway. We suggest that islet cell autoantibodies and glutamic acid decarboxylase autoantibodies should be investigated before and during interferon treatment in order to identify subjects at high risk of developing type 1 diabetes mellitus.

Although hepatitis C virus (HCV) is a recognized cause of circulating cryoglobulins, the role of human immunodeficiency virus (HIV) in the pathogenesis of cryoglobulinemia has not been investigated extensively. To evaluate the prevalence of circulating cryoglobulins and to assess the relationship with clinical and virological parameters, 162 HIV-positive subjects (84 anti-HCV(+)) were tested for cryoglobulins, C3, C4, RF, autoantibodies, HIV-viral titer, and CD4(+) count. Anti-HCV-positive subjects were tested for HCV-RNA, HCV-viral titer, and HCV genotype. All patients were examined for the presence of signs or symptoms of vasculitis and tested for cryoglobulins using a standard biochemical assay. Cryoglobulins were found in 30 (18.5%) cases. Of the 30 positive cases, 29 (96.7%) were anti-HCV-positive and 28 (93.3%) HCV-RNA-positive. The presence of cryoglobulins was significantly associated (P < 0.01) with HCV-RNA positivity (OR = 27), liver cirrhosis (OR = 16), decreased levels of C3 (OR = 8.6), C4 (OR = 13.6), increased levels of IgG and IgM (OR = 6.1 and 7.9, respectively), and RF positivity (OR = 6.3), but was unrelated to CD4(+) cell count, HIV viral load, diagnosis of AIDS, HCV viral load and the presence of autoantibodies. Interestingly, the presence of cryoglobulins was not significantly associated with signs and symptoms commonly associated with cryoglobulinemia. In conclusion, HIV infection does not seem to play a significant role in the production of circulating cryoglobulins, which strongly correlates with HCV co-infection and liver cirrhosis. Typical signs and symptoms of cryoglobulinemia do not correlate with the detection of circulating cryoglobulins in HIV and HCV patients.

Background: The relationship between serum parameters of gastric function and Helicobacter pylori infection in human immunodeficiency virus (HIV)-positive patients is almost unknown. Aims: To investigate in HIV-infected patients: (i) the relationship between serum gastrin and serum pepsinogens over the progressive phases of HIV-related disease; (ii) the impact of H. pylori infection on gastrin and pepsinogen serum levels and its relation to antral histology; (iii) the prevalence of parietal cell autoantibodies. Methods: Fifty-nine HIV-positive patients were studied by upper endoscopy plus gastric antral biopsy. Serum samples were tested for gastrin, pepsinogen A, pepsinogen C and parietal cell autoantibodies. Results: In patients without overt acquired immunodeficiency syndrome (AIDS), or with a CD4+ count of > 100 × 106 cells/L, mean serum levels of gastrin and pepsinogen C were higher than in subjects with AIDS or with a CD4+ count of 100 × 106 cells/L. Atrophy was more frequent in patients with overt AIDS than in those without overt AIDS (57% vs. 33%, P=N.S.), and/or in patients with a CD4+ count of 100 × 106 cells/L (62% vs. 26%, P

Objective: To assess the usefulness of human papilloma virus (HPV) typing for predicting pre-malignant and malignant cervical lesions. Study design: 314 women, who underwent colposcopy, biopsies and high and low-risk HPV typing after a confirmed abnormal routine Pap test were studied. HPV-DNAs were typed by using PCR technique. Results: We found a significant increasing rate of high-risk-HPV by the increasing severity of histology, ranging from 40% in negative cases to 86.9% in those with CIN3 lesions. The positive predictive value of high-risk-HPV ranged from 13.3% in patients with atypical squamous cells of undetermined significance (ASCUS) to 29.4% in those with HSIL. By contrast, negative predictive value was 96% in patients with ASCUS, 97.2% in low-grade squamous intraepithelial lesions (LSIL), and 71.4% in high-grade squamous intraepithelial lesions (HSIL). Sensitivity and specificity for detecting CIN2 or CIN3 was 86.0% and 41.3%, respectively. Conclusions: The high negative predictive value of high-risk HPV testing suggests that HPV negativity could be used for predicting the absence of important cervical lesions, and therefore avoiding unnecessary colposcopy in ASCUS and LSIL cases.

The role of GBV-C/HGV in the aetiology of acute non A–E hepatitis and its impact on the course of acute hepatitis of defined aetiology were investigated by detecting viral RNA by RT-PCR and antibody to the E2 protein of GB virus C (anti-E2) by EIA. Ninety-eight patients with acute nonA–E hepatitis, 35 patients with acute hepatitis A, 63 with acute hepatitis B, 29 with acute hepatitis C and 270 controls were enrolled in this study. The prevalence of GBV-C/HGV RNA was similar among patients with acute nonA–E hepatitis (3.1%), with acute hepatitis A (2.9%), and controls (3.7%), but significantly higher (P < 0.05) among those with hepatitis B or C (19.0% and 48.3%, respectively). Similar figures were obtained considering the total rate of GBV-C/HGV exposure (viral RNA or anti-E2 positivity). The majority (24/30 or 80%) of GBV-C/HGV RNA positive patients reported a parenteral source of exposure whereas the remaining 20% denied having known risk factors. The liver function test values and the rate of chronic hepatitis B and C were similar in patients co-infected and in those not co-infected with GBV-C/HGV. This study excludes a significant role of GBV-C/HGV infection in the aetiology of acute nonA–E hepatitis in Italy. Concomitant GBV-C/HGV and HBV or HCV infection does not worsen the clinical course of illness among patients with acute hepatitis. J. Med. Virol. 61:59–64, 2000. © 2000 Wiley-Liss, Inc.

Background : Non-steroidal anti-inflammatory drugs may amplify the anti-viral effect of α-interferon in vitro but in vivo data are still controversial. Aim : To test the hypothesis that ketoprofen may increase the rate of response to α-interferon of chronic hepatitis C patients. Methods : Fifty patients with chronic hepatitis C who had never received α-interferon were randomly assigned to receive 3–8 MU of α2b-interferon, three times weekly for 6 months, alone or in association with ketoprofen at a dose of 200 mg/day five times weekly. The virological response to treatment (undetectable HCV RNA in serum) was evaluated after 3 months and at the end of treatment, and 6 and 12 months after therapy withdrawal. Results : One patient under combination therapy stopped the ketoprofen for persisting epigastric pain. Complete response under treatment was observed in 15 out of 24 (62.5%) patients receiving α2b-interferon alone and in 14 out of 26 (53.8%) patients under combination therapy (P=N.S.). One year after the end of treatment, a sustained response was seen in 4 out of 24 (16.2%) patients treated with α2b-interferon and in 5 out of 26 (19.2%) patients having received the combination (P=N.S.). Conclusion : Administration of ketoprofen does not increase either the primary or the sustained response to α2b-interferon therapy of interferon-naive chronic hepatitis C patients.

Background : Ursodeoxycholic acid (UDCA) is able to improve biochemical markers of cholestasis, with a parallel decrease in transaminases, in various cholestatic liver diseases. Aim : To evaluate the effects of UDCA administration on acute viral hepatitis-related cholestasis and the course of acute viral hepatitis. Methods : Seventy-nine consecutive patients with acute viral hepatitis (HBV: 43, HCV: 11, HAV: 15, HEV: 3, Non A-E: 7) were randomized to receive either UDCA for 3 weeks or no treatment. Liver biochemistry and serum bile acid determinations were run at weekly intervals. Results : No significant differences were observed in mean percentage decreases in transaminases between treated and untreated patients. By contrast, cholestatic indexes decreased significantly more quickly in patients treated with UDCA than in controls, and this effect was more evident in patients with increasing alanine transaminase levels at admission. After a peak at the end of the first week of therapy, serum levels of conjugated ursodeoxycholic acid (CUDCA) showed a gradual decrease. Conjugated cholic acid (CCA) and chenodeoxycholic acid (CCDCA) showed a progressive decrease with the resolution of viral hepatitis, but no influence of UDCA administration was observed. Conclusions : Our study demonstrates that UDCA significantly improves cholestatic indices in patients with acute viral hepatitis, but this effect does not seem to affect the course of the illness.

Hepatitis E infection is typically associated with areas in which hepatitis E virus (HEV) is endemic. Except for a few cases in Europe and in the United States, acute hepatitis E is usually associated with travel to endemic areas. We set out to determine the etiologic role of HEV in acute non-A-C hepatitis in Italy. The presence of HEV-RNA and antibody was determined in 218 patients diagnosed with acute viral non-A-C hepatitis. Acute hepatitis E infection was defined by the presence of HEV-RNA in sera and positivity for IgM anti-HEV and seroconversion to IgG anti-HEV. Acute hepatitis E was found in 10.1% of the patients with acute non-A-C, with 95.5% exhibiting a benign course. A more severe course was observed in a patient co-infected with HAV and HEV. Most cases were travelers to endemic areas, although 18.2% reported no travel. One patient was from a household with an infected patient. Sequence analyses of the polymerase chain reaction (PCR) product derived from a patient who never visited endemic areas, identified an isolate that is divergent significantly from all reported isolates of HEV (79.5-85.8% nucleotide identity). Evidence from this study suggests that HEV accounts for approximately 10% of acute non-A-C viral hepatitis in Italy, diagnosed generally in travelers returning from endemic areas. However, the identification of a new HEV variant in an individual who never indicated travel or contact with individuals associated with endemic areas, suggests that this virus may be native to Italy.

To investigate the prevalence of hepatitis G virus (HGV/GBV-C) in patients with liver disease and to confirm its hypothesized ability to cause liver damage, we studied 130 subjects; 61 had chronic hepatitis C virus infection and 69 had acute hepatitis of either defined etiology (n = 57) or of unknown origin (n = 12). Positivity for HGV/GBV-C RNA was detected in 10 of the 61 subjects with chronic hepatitis C (16.3%) and in 11 of the 57 subjects with acute hepatitis of defined etiology (19%), whereas we failed to detect HGV/ GBV-C viremia in subjects with hepatitis of nonestablished etiology. Patients exhibiting positivity for HGV/GBV-C RNA were found to be comparable to those exhibiting negativity for HGV/GBV-C RNA in terms of both liver function tests and Knodell's score (in liver biopsies); the affect of HGV/GBV-C infection on the biohumoral and histological activity in patients with chronic hepatitis C therefore appears to be minimal or absent. Similar clinical features were observed in patients with acute hepatitis of known etiology whether they were positive or negative for HGV/GBV-C RNA. However, long-term clinical studies are still required to clarify the actual impact of HGV/GBV-C co-infection. In our geographic, i.e., a region or north-east Italy, HGV/GBV-C infection appears to be strictly related to intravenous drug use, and this agent does not seem to be responsible for acute hepatitis of unknown etiology; other etiological agents are probably involved.

Sixty-seven consecutive patients infected withthe human immunodeficiency virus (HIV-1), 72% of whichwith overt AIDS, were examinated by upper endoscopy dueto various indications and evaluated for the prevalence of H. pylori infection. Theinfection was studied by performing both histologicalexamination of gastric biopsies and serological testingfor anti-H. pylori IgG antibodies. The H. pyloriprevalence rate was 55% in histology; no significantdifferences were observed in HIV-infected subjects andthose with overt AIDS (52% vs 63%, respectively; P =NS). Positive histological testing appeared to bedirectly related to the peripheral CD4+lymphocyte count (minimum rates of 43% were detected in6 patients with CD4+ 200 ×106/liter, respectively; P < 0.05) and inversely related to the frequency ofantibiotic treatments performed over the six monthsprior to endoscopy. Low CD4+ counts were alsoapparently associated with low-grade H. pyloriinfection. Serological testing was positive for anti-H. pylori IgGantibodies in 39% of patients; compared to histology,serology displayed a sensitivity of 57% and aspecificity of 81%. The discrepancy between histologicaland serological positive results for H. pylori wasnoted to be higher in the more advanced phases of HIVinfection. Based upon our results, the serologicaltesting for anti-H. pylori IgG antibodies seems to require cautious interpretation in HIV-positivepatients.

The problem of detecting cell nuclei in fluorescence images may be faced by means of a segmentation step, to get the neighbourhood of candidate nuclei, followed by a binary classification step. Important for the latter step is the choice of the descriptors (features) to be extracted from the neighbourhood and used by the classifier. In the present paper, based on a large set of manually labelled samples, we evaluate several of such descriptors combined with some common type of support vector machines. We show that equipping the detection algorithm with the best combination of features/classifier leads to a performance comparable to human labelling by experts.

The purpose of this study was to evaluate the relationship between peripheral blood monocyte and lymphocyte subsets and response to recombinant-α2b-interferon (r-α2b-IFN) in patients with viral chronic active hepatitis (CAH). Peripheral blood mononuclear cell subsets were studied by use of flow cytometry before beginning treatment, after 24 hours, and after 15, 30, and 90 days of treatment with r-α2b-IFN (3 million U thrice weekly) in 16 patients with CAH—11 who tested anti-HCV—positive and five HBsAg-positive/anti-HBe—positive/HBV-DNA—positive (HCV = hepatitis C virus; HBsAg=hepatitis B surface antigen; HBe=hepatitis B e antigen; HBV=hepatitis B virus). r-α2b-IFN acutely decreased the number of peripheral blood B lymphocytes, natural killer (NK) cells, and T-naive cells. It also activated monocytes and T lymphocytes, as indicated by increased expression of surface human leukocyte antigen (HLA)-DR molecules and interleukin-2 receptors, respectively. These effects were no longer evident after 15 days of treatment. The number of NK cells was significantly lower in anti-HCV—positive than in HBsAg-positive patients (CD16+ cells: 277 ± 55/μL vs 450 ± 33/μL, P

In 1992, the prevalence of hepatitis B virus (HBV) markers was evaluated in 1004 subjects aged one to 76 years living in urban and rural areas in Tanzania. The overall prevalence rates of hepatitis B surface antigen (HBsAg) and of any HBV marker were 4.4% and 37.0%, respectively. No statistically significant difference by sex was found. The HBsAg prevalence among pregnant women was 4.3% (20/463). The proportion of HBeAg positive among HBsAg positive pregnant women was 10% (2/20). The HBsAg age-specific prevalence was 2.1% in the 1-5 year age-group; peak prevalence (12.1%) occurred in the 6-15 year age-group. Markers of HBV infection were 4.1% by age five years; they increased with advancing age (P < 0.01). Subjects residing in urban areas had statistically significant higher HBV exposure than those residing in rural areas (43.9% vs 27.4%, P < 0.01). Subjects belonging to the largest family size (seven or more members) showed increasing risk (OR 2.9; 95% CI = 1.96-4.28) of HBV exposure. Because maternal HBV transmission early in life appears to be of minor impact and children are mostly infected later in infancy, HBV vaccination at birth is not indicated, while vaccination of all infants at 2-3 months of age with other paediatric vaccinations is the first priority.

Objective: To investigate the behaviour of serum tumour necrosis factor-alpha (TNF-alpha) during alpha-interferon (alpha-IFN) treatment in patients with chronic viral hepatitis. Design: The study included 31 patients with chronic active hepatitis: five positive for hepatitis B surface antigen (HBsAg) and hepatitis B early antigen (HBeAg), and six positive for HBsAg, anti-HBe and hepatitis B virus (HBV) DNA; the remaining 20 were anti-hepatitis C virus (HCV) positive. All patients received 3 million units recombinant-alpha-2b-interferon three times weekly and were followed up for at least 3 months. Serum samples were collected at 0 and 24 h, and on days 1 15, 30 and 90. Responders were those patients whose transaminase levels returned to normal during alpha-IFN treatment

Aim: To evaluate the hepatitis B virus (HBV) and the hepatitis C virus (HCV) epidemiology in the general population of Northern Italy, a cohort of 965 subjects, all residents (including 47 immigrants), were anonymously tested for HBV and HCV infections. Material and Methods: Serum samples were assayed for anti-HCV and anti-HBV markers by enzyme-linked immunosorbent assay and for HCV-RNA by polymerase chain reaction, and the positive cases were genotyped. HBsAg-positive cases were assayed for HBeAg/anti-HBe, whereas HBsAg negatives were tested for both anti-HBc and anti-HBs. Results: The overall prevalence of anti-HCV was 2.6%, with a bimodal distribution characterized by the highest prevalence (12%) in subjects over 75 years old. None of the subjects under 25 years old was anti-HCV positive. Anti-HCV positivity was similar in males and females (2.4% vs. 2.7%). HCV-RNA was positive in 40% of cases and genotype 1 was the most common. The HBsAg prevalence was 1%, with a significant difference according to country of origin (0.8% in Italian subjects vs. 6.4% in immigrants, P = 0.01). HBsAg positivity increased significantly with age (R 2 = 0.57, P < 0.02). The overall percentages for the prevalence of isolated anti-HBs, anti-HBs + /anti-HBc+, and isolated anti-HBc were 23.8%, 8.4%, and 4.2%, respectively. Conclusions: Our study provides a new picture of HCV and HBV epidemiology in Northern Italy, with these features: (1) a cohort effect showing a reduction of HCV infection in the elderly, possible due to age-related mortality; (2) an unchanged overall prevalence of HBV infection, despite continuing immigration of subjects from endemic countries.

A 61-year-old man was observed to develop type 1 diabetes mellitus following a 3-month treatment with recombinant alpha-2b peginterferon combined with ribavirin for chronic hepatitis C. Serum samples, collected before the start of therapy and 2 months after the diagnosis of diabetes mellitus, revealed islet-cell antibodies at a titer of 20 and 40 JDF-U, respectively, and glutamic acid decarboxylase autoantibodies at a value of 76.5 and 196 IU/ml, respectively. Antibodies to second islet autoantigen were persistently negative. HLA class II typing revealed the presence of DRB1*04/DRB1*14, DQA1*0303-0104 and DQB1*04-0503 alleles. Eight months after the onset of type 1 diabetes mellitus, the patient is still receiving 30 IU insulin daily; the liver function tests are normal and serum hepatitis C virus RNA is negative. These data confirm that, in patients with potential diabetes mellitus, the disease may become manifest as a side-effect during therapy with peginterferon-alpha plus ribavirin. The patient as a candidate for interferon treatment should therefore be investigated, in addition to thyroid autoimmunity, also for pancreatic autoantibodies before starting therapy.

Summary Aims To assess how much patients with hepatitis C virus infection know about their condition and what impact it has on their lifestyle. Materials and methods A multiple-choice questionnaire was administered anonymously to 364 hepatitis C virus-infected subjects just before their first specialist visit. Results Even before hepatitis C virus infection was diagnosed, 257 subjects (70.6%) already knew something about this infection. Overall, 36% of patients had changed the way they behaved within the family, 25.5% had changed their sexual habits, 46.9% had changed their diet, and 69% reported having stopped or limited their alcohol intake after being told they were hepatitis C virus positive. Hepatitis C virus infection had a negative impact on the psychological status in 44.2% of patients. This effect was significantly greater among women and was independent of either the duration of their infection or any counselling received from the general practitioner. The need for specific treatment was reported by 59.8%. A demand for more detailed information about hepatitis C virus was expressed by 89.9% of patients. Conclusions Hepatitis C virus changes all aspects of lifestyle and psychological status. The patients’ strong demand for more information suggests that counselling and educational programmes must be an integral part of the activities of both the general practitioner and the specialist.

Background & Aims: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. Methods: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. Results: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. Conclusions: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Summary Background : Whether liver steatosis affects sustained virological response in patients with chronic hepatitis C is still under discussion. Aim : To evaluate the impact of liver steatosis in patients treated (for chronic hepatitis C) with combination therapy. Methods : We evaluated 97 (male/female 82/15, mean age 41.1 years) consecutive naive patients treated with pegylated interferon alpha-2b plus ribavirin. Results : Prevalence and severity of liver steatosis were significantly associated with genotype 3a [grade 3–4 in 14 of 32 patients (44%) vs. 8 of 65 patients (12%) with other genotypes; P = 0.001], while steatosis grade 1 (

Liver steatosis is frequent in chronic hepatitis C, particularly in patients infected with hepatitis C virus (HCV) genotype 3. The aim of this study was to determine the relationship between steatosis and fibrosis in chronic hepatitis C as a function of viral genotype.A multivariable logistic regression analysis was carried out in 755 chronic hepatitis C patients (mean body mass index (BMI) 24.11 kg/m(2); 178 with genotype 3), consecutively admitted to three referral hospitals. Liver histology showed steatosis in 315 and fibrosis in 605 patients, of whom 187 had cirrhosis (78 compensated and 109 decompensated).Steatosis was independently associated with fibrosis (p0.001), genotype 3 (p0.001), BMI (p0.001), ongoing alcohol abuse (p0.001), and age (p = 0.001). Fibrosis was associated with the Metavir activity score (p0.001), age (p0.001), steatosis (p = 0.001), past alcohol abuse for5 years (p = 0.015), and BMI (p = 0.034). When regression analysis was repeated on patients divided according to viral genotype (that is, 3 v non-3) to identify type specific risk factors, steatosis was associated with ongoing alcohol abuse (p0.001) and age (p = 0.01) only in non-3 genotype infected patients and with Metavir activity (p = 0.044) only in genotype 3 infected patients. Similarly, fibrosis was associated with steatosis only in genotype 3 infected individuals (p = 0.018), and with past alcohol abuse (p = 0.003) and (marginally) diabetes (p = 0.078) only in non-3 genotype infected patients.Steatosis influences chronic hepatitis C progression in a genotype specific way. Patients infected with genotype 3 and histologically confirmed steatosis should not be deferred from effective antiviral therapy.

Background/Aims Steatosis in patients with chronic hepatitis C (CHC) may be the result of both viral and host factors. To evaluate: (1) the relationship between steatosis and either host or viral factors; (2) the correlation between steatosis and fibrosis in patients with CHC. Methods A consecutive series of 349 patients were evaluated for steatosis. At liver biopsy, patients were tested for virological, and laboratory analysis and questioned for alcohol consumption. Results Logistic regression analysis demonstrated that steatosis was independently associated with genotype 3a (odds ratio, OR 3.5), alcohol intake at the time of biopsy (OR 2.6) and age >35 years (OR 2.7). In multivariate analysis the presence of fibrosis was associated with past alcohol abuse (OR 3.7), and age older than 44 years (OR 2.2). Overall, a weak correlation was found between grade of steatosis and fibrosis score ( r =0.861, P =0.05), which disappeared excluding patients without past or current alcohol intake. A direct correlation emerged between grade of steatosis and both ‘grading' and ‘staging' only in patients with genotypes other than 3a. Conclusions Genotype 3a is the main risk factor for steatosis in patients with CHC. The grade of steatosis correlated with both grading and staging only in patients with genotypes other than 3a and this relationship is strictly linked to alcohol consumption.

Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 μg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had required amputation ( P = 0.038). In conclusion, the administration of G-CSF for 3 weeks as an adjunctive therapy for limb-threatening diabetic foot infection was associated with a lower rate of amputation within 9 weeks after the commencement of standard treatment. Further clinical studies aimed at precisely defining the role of this approach to this serious complication of diabetes mellitus appear to be justified.

OBJECTIVE: The aim of the study was to investigate the prevalence of clinical and latent autoimmune diseases in Italian patients with hepatitis C virus (HCV) chronic infection before and after treatment with interferon-alpha (IFN-alpha). RESEARCH DESIGN AND METHODS: The evidence of clinical autoimmune disease and the presence of autoantibodies were assessed in 70 patients with HCV chronic infection. Autoantibodies to islet cell (ICA), glucagon-producing cells (GCA), parietal cell (PCA), adrenal cortex (ACA), adrenal medulla (AdMA), nuclei (ANA), liver-kidney microsomal (LKM-Ab), mitochondrial, and smooth muscle (SMA) were tested using the classic indirect immunofluorescence technique. Autoantibodies to GAD (GADAb), second islet cell autoantigen (IA2-Ab), and insulin (IAA) were tested by radioimmunoassay and thyroid microsomal autoantibodies (TMHA) and thyroglobulin autoantibodies (TGHA) were assessed by hemoagglutination test. RESULTS: None of the 70 patients studied showed evidence of clinical disease before treatment with IFN-alpha. However, 1 (1.4%) patient was positive for ICA, 2 (2.8%) were positive for GCA, 2 (2.8%) for GADAb, 5 (7.1%) for PCA, 2 (2.8%) for ANA, 3 (3.7%) for SMA, 4 (5.7%) for TMHA, and 2 (2.8%) for TGHA. These frequencies were not significantly different when compared with healthy control subjects. There were 29 (41%) patients who were positive for IAA at low titers compared with 2% of the control subjects (significantly different P < 0.0001). ICA titers of one patient positive for ICA/GADAb increased during the IFN-alpha therapy, and the patient developed type 1 diabetes 5 months after the beginning of treatment. IAA levels did not change during the course of treatment, and none of the IAA+ patients developed diabetes. Thyroid autoantibody titers increased in 3 of the 4 initially positive patients, with 1 patient becoming positive and 2 thyroid antibody-positive patients developing overt hypothyroidism during IFN-alpha treatment. PCA titers increased in 1 of 5 positive patients. Antibodies to other autoantigens did not change during the course of treatment. CONCLUSIONS: We have not found an increased frequency of clinical or latent autoimmune diseases in patients with chronic HCV infection. However, this study suggests that screening patients for autoantibodies (in particular, thyroid and pancreas) before and during IFN-alpha therapy may be useful in assessing the risk of patients developing autoimmune disease.

The correlation between therapeutic response and liver fibrogenesis was studied in serum and liver specimens taken from 31 patients treated with α-interferon (IFN) (14 sustained responders and 17 non-responders) for chronic hepatitis C. Serum samples, collected before therapy, and at further 6-month intervals over 2 years, were tested for markers of liver neofibrogenesis. Serum N-terminal procollagen III peptide (PIIINP) displayed a significant and persistent decrease (P < 0.05) in sustained responders but not in non-responders; significantly lowered (P < 0.05) mean levels of C-terminal procollagen I peptide (PICP) were transiently observed in both patient groups, apparently as a result of IFN administration. Serum laminin (Lam) levels remained unchanged. One year after the cessation of treatment, liver biopsy re-testing showed an improvement in necro-inflammatory scores only in sustained responders, with the histological fibrosis scores remaining unaltered in both groups. IFN treatment seemed to exert an influence on serum levels of markers of hepatic connective tissue turnover even in patients that did not respond to therapy, while no effect was observed on preexistent liver fibrosis.