Hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis C virus (HCV) are responsible for the majority of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) cases worldwide. 1-4 Multiple HBV and HDV infection has been extensively investigated in past years and found to be associated with a fulminant course of acute hepatitis, with the more severe forms of chronic liver disease, and with a rapid progression to liver cirrhosis. 5-8 An inhibitory effect exerted by HDV on HBV replication has also been shown. 9 The prevalence of patients with HCV and HBV coinfection has been described as high in geographic areas where a high endemic level of both infections is reported, such as Western Asia and the Mediterranean Basin. 10-14 The interaction between HCV and HBV has so far been poorly investigated. Little is known on the clinical presentation, the natural history, and the response to antiviral treatment of liver diseases associated with HBV and HCV coinfection. However, small pilot studies have prompted the hypothesis that HCV may have an inhibitory effect on HBV replication [15][16][17][18][19] and that multiple HBV and HCV infection may be associated with a more severe clinical presentation. 10,[20][21][22][23][24][25] The interaction between HDV and HCV in hepatitis B surface antigen (HBsAg) chronic carriers has not as yet been investigated.In this article we report the data from an Italian multicenter case-control study with incident cases, performed on a high number of patients with chronic hepatitis from a multiple hepatitis virus infection who were compared with patients with chronic hepatitis caused by a single virus. We investigated the interference between viruses, the clinical impact of a multiple virus infection compared with a single HBV or HCV infection, and tested the hypothesis that anti-HCV-positive/ anti-hepatitis B core antigen (HBc)-positive patients lacking both HBsAg and anti-hepatitis B surface antigen (HBs) might be a subgroup of patients with a multiple HBV and HCV infection. MATERIALS AND METHODSPatients. Seven liver units in different geographic areas of Italy, 1 in the north (Padua), 1 in the center (Rome), 2 in the south (Naples and Bari), 1 in Sardinia (Sassari), and 2 in Sicily (Palermo and Messina), participated in the study. These liver units had participated in numerous multicenter studies on chronic hepatitis in the past 2 decades and had been using similar criteria for the clinical approach and the histologic diagnosis. The investigation was planned as a cross-sectional case-control study with incident cases during a preliminary consensus meeting of the senior investigators from the participating centers.Chronic hepatitis was diagnosed on the basis of high serum transaminase values for at least 6 months.

We enrolled 44 patients with hepatitis B virus (HBV) acute infection, 21 anti-hepatitis C virus (HCV)-positive for at least 1 year (case BC group), 20 anti-HCV-negative (control B group), and 3 with HBV/HCV acute concurrent infection. For each case BC, a subject with chronic HCV infection alone was selected (control C group). At the first observation, 85.7% of patients in case BC group and 85% of those in control B group were HBV-DNA-positive (polymerase chain reaction [PCR]), with a similar trend towards a decrease and negativization in about 20 days; in the case BC group, seroconversion to antibody to hepatitis B e antigen (anti-HBe) was more rapid. HCV-RNA (PCR) was undetectable in all case BC patients but 1, who shortly became negative, whereas 85.7% of subjects in control C group were positive (P < .001). Severe acute hepatitis was more frequent in the case BC group than in the control B group (28.6% vs. 0%, P < .05). Of the 14 patients in the case BC group and of the 16 in the control B group followed up for more than 6 months, 1 in the first and 1 in the second group became hepatitis B surface angiten ( P atients with chronic hepatitis B virus (HBV)/hepatitis C virus (HCV) concurrent infection show a reciprocal inhibition of viral genomes, an association with a severe clinical presentation, and an infrequent response to interferon alfa treatment. 1-10 Instead, very little is known about HBV/HCV acute concurrent infection because only a few case reports are available in the literature. 11,12 Also, little is known about HBV acute infection when it develops in chronic HCV carriers, but the few case reports published on the topic suggest an association with a severe clinical presentation. [13][14][15] Acute HBV infection in chronic HCV carriers may be rather frequent in Italy and in other western countries where drug addicts are numerous, frequently anti-HCVpositive, [16][17][18][19] and infrequently vaccinated against HBV.This article reports the data from our study on the clinical presentation, course of the disease, and HBV/ HCV interaction in 21 HCV chronic carriers who developed HBV acute hepatitis (cases), compared with 20 patients with HBV-related acute hepatitis with no HCV infection (controls) observed in the same period. We also report the data on 3 cases of HBV/HCV acute concurrent infection identified in the same investigation. Patients and MethodsWe enrolled all 44 consecutive patients with HBVrelated acute hepatitis hospitalized in our ward from

The study suggests that HBV occult infection, relatively frequent in anti-HIV-positive patients, is associated with hepatic flares.

To evaluate whether HCV genotype and a "silent" HBV infection may be related to a more severe clinical presentation of liver disease, 205 anti-HCV/HCV-RNA positive, HBsAg/anti-HBs negative patients with chronic hepatitis (113 males and 92 females; median age 55 years, range 18-77), were studied on presentation at the Liver Unit from January 1993 to December 1997. Presence of serum anti-HBc, in the absence of HBsAg and anti-HBs, was considered a marker of "silent" HBV infection. Of the 205 patients, 134 had undergone percutaneous liver biopsy. Two main diagnosis groups were established: the mild liver disease group (76 patients), and the severe liver disease group (109 patients); 20 patients who had refused to undergo liver biopsy were not included in the clinical and virological evaluation because the diagnosis was uncertain. The prevalence of severe liver disease was similar in the genotype 1 and non-1 groups (61.3% of 98 patients with genotype 1 and 52.9% of 70 patients with a non-1 genotype). Instead, the 88 patients with "silent" HBV infection showed a higher percentage of severe liver disease than the 97 anti-HBc negative patients (72.7% vs. 46.4%, respectively: P < 0.0005). Of the 88 anti-HBc positive patients, the prevalence of those with severe liver disease was similar in the 32 cases with serum HBV-DNA as detected by PCR and in the 56 HBV-DNA negative (81.2% vs. 67.8%, P = 0.4). The relation between "silent" HBV infection and severe liver disease was observed both in genotype 1 and non-1 infected patients. Nevertheless, the anti-HBc negative patients infected by genotype 1 showed a severe liver disease more frequently than those infected by a non-1 genotype, with a difference that is significant to the statistical analysis (P < 0.05). The findings suggest that "silent" HBV infection in anti-HCV positive chronic hepatitis enhances the severity of the liver disease. Evidence was also found that in patients without "silent" HBV infection there is a correlation between the presence of HCV genotype 1 and the severity of liver disease.

The solid‐phase synthesis and characterization of a series of peptides (3–9), containing reverse‐turn mimetic bicyclic lactams (1a, 1b), was reported in the preceding paper. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a β‐turn. The conformational preferences of the constrained peptides have been investigated by NMR spectroscopy and IR spectroscopy. Our experimental results have been complemented by computer modelling studies and show that the constrained peptides (3–9) form an inverse γ‐turn or a type‐II′ β‐turn through intramolecular hydrogen bonding, depending on the nature of the reverse‐turn mimic. In N‐acetylated tetrapeptide mimics incorporating the two different bicyclic lactams (a series and b series), H5 is available for either a γ‐turn (7‐membered ring with the carbonyl group of the bicyclic lactam) or a β‐turn (10‐membered ring with the carbonyl group of residue 2), as shown in Figures 7 and 9. The a series incorporating the (5,7)‐bicyclic lactam predominantly induces the γ‐turn conformation, while the b series incorporating the (5,6)‐bicyclic lactam can promote either a γ‐turn or a β‐turn conformation, with the β‐turn usually being preferred and with varying degrees of β‐hairpin formation.

Knowledge of the current epidemiology of chronic liver disease in Italy is mostly obsolete and fragmentary for the lack of up-to-date consistent data. In 2001, a 6-month prevalence study was undertaken in 79 hospitals to assess the characteristics of chronic liver disease in Italy. Both prevalent and incident cases were enrolled. A total of 9,997 patients were recruited, of whom 939 (9.4%) had normal liver biochemistry, 6,210 (62.1%) had chronic hepatitis, 1,940 (19.4%) had liver cirrhosis, and 341 (3.4%) had hepatocellular carcinoma (HCC). In 567 patients (5.7%) the diagnosis was not established. Hepatitis C virus (HCV) was found in 69.9% of the patients and was the only etiological factor in 56.3% of all the patients. Hepatitis B surface antigen (HBsAg) was present in the serum of 13.4% of the cases (in 10% it was the only etiological factor). A history of alcohol abuse was found in 23% of the cases (9.4% without viral infection). The prevalence of HCV-related cases was significantly lower in incident than in prevalent cases (44.9% vs. 59.9%, P < 0.0001), while the proportion of patients with alcohol abuse was much higher in incident than in prevalent cases (18.1% vs. 6.6%, P < 0.0001). These findings indicate that nearly one quarter of patients with chronic liver diseases in Italy have a severe disease such as liver cirrhosis and HCC represents a not negligible burden for the national health system. Hepatitis B fell in importance as an etiological factor. Hepatitis C is the important pathogenic factor for chronic liver disease in Italy. However, a comparison between the prevalent and incident cases suggests that in future HCV infection will also play a progressively decreasing role, in part as a consequence of treatment.

We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν)β(3) . Because α(ν)β(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68)Ga complexation for the promising (68)Ga-PET technique; the AAZTA complex 15((68)Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity.

Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC(50)=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.