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Forests provides major ecosystem services worldwide. The Brazilian Atlantic Forest (BAF) has been dramatically devastated, with fragmentation processes jeopardizing its long-term sustainability. This study investigated the structure and successional dynamics in BAF natural regeneration along an anthroposequence characterized by increasing human disturbance histories as: secondary (SF) disturbed (DF) late forest (LF). We aimed to understand how and the degree to which BAF fragmentation and human disturbance affected plants, soils, and the whole soil-plant relationships and feedbacks. We investigated the natural regeneration conditions of plants (using plant classification and quali-quantitative analyses) and soil chemistry (including pH-CaCl

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Made available in DSpace on 2022-04-28T19:48:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 With its accumulation in upland rice, cadmium (Cd) can easily enter the human food chain, which poses a global health threat considering nearly half of the human population depends on rice as a staple food source. A study was conducted to (1) evaluate Cd accumulation by rice cultivars, grown in Cd-polluted Tropical Oxisols, with different levels of Cd tolerance; (2) quantify Cd transfer from soil to rice shoots and grain; and (3) estimate daily Cd intake by humans. Three rice cultivars, characterized by low (Cateto Seda–CS), medium (BRSMG Talento–BT), and high (BRSMG Caravera–BC) Cd uptake capacity, were investigated. Rice cultivars were exposed to increasing soil Cd concentrations (0.0, 0.7, 1.3, 3.9, 7.8, and 11.7 mg kg−1). Analysis was performed on soil, shoots, and grain. Shoot biomass and grain yield decreased with increasing Cd supply, suggesting the following Cd tolerance: CS > BT > BC. Cadmium concentrations in shoots and grain increased when exposed to Cd. Only CS did not exceed the maximum Cd limit permitted in food (0.40 mg kg−1), when rates up to 1.3 mg kg−1 of Cd were applied to soil. Considering daily rice consumption levels in Brazil, Cd intake often exceeds maximum tolerable levels. Continuous monitoring of soil Cd concentrations is a pivotal step in avoiding hazards to humans. Such monitoring is important on a global scale since outside of Asia, Brazil is the leading rice-producing and rice-consuming country. Graphical abstract: [Figure not available: see fulltext.] Department of Plant Protection Rural Engineering and Soils School of Engineering São Paulo State University School of Agricultural and Veterinarian Sciences São Paulo State University, Via de acesso Prof. Paulo Donato Castellane, s/n Centre of Nuclear Energy in Agriculture Universidade de São Paulo Federal Institute of São Paulo Indian River Research and Education Centre Institute of Food and Agricultural Sciences University of Florida Department of Biology and Chemistry California State University Dipartimento Di Architettura Design E Urbanistica Università Degli Studi Di Sassari Desertification Research Centre Università Degli Studi Di Sassari Department of Plant Protection Rural Engineering and Soils School of Engineering São Paulo State University School of Agricultural and Veterinarian Sciences São Paulo State University, Via de acesso Prof. Paulo Donato Castellane, s/n

Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65years. Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100mg) and twice-daily dasabuvir (250mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12weeks after the end of treatment (SVR12). Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5g/dL (OR 2.04: 95% CI 1.0–4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3–9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2mg/dL (OR 4.9: 95% CI 1.17–20.71, p = 0.029) as the only variable independently associated with SVR12. Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs.The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days.Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment.These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors.Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

The role of liver resection in advanced hepatocellular carcinoma (multinodular or with macroscopic vascular involvement) is still controversial. The aim of this study is to evaluate the role of surgical resection compared to other therapeutic modalities in patients with advanced hepatocellular carcinoma (HCC). Four hundred sixty four patients with HCC observed from 1991 to 2007 were included in the study. All the patients were evaluated for the treatment of HCC in relation to the severity of liver impairment and tumor stage. All the patients included in the study had no evidence of distant metastases. Median follow up time for surviving patients was 25 months (range 1–155). Two-hundred and eighty-three patients were in Child–Pugh class A, 161 in class B, and 20 in class C. Two-hundred and seventy-one patients had single HCC, 121 patients had two or three HCCs, and 72 more than three HCCs. One-hundred and thirty-six patients (29.3%) were submitted to liver resection (LR), 232 (50.0%) to local ablative therapies (LAT) (ethanol injection, radiofrequency ablation, chemoembolization), eight (1.7%) to liver transplantation (LT), and 88 (19%) to supportive therapy (ST). Median survival time for all patients was 36 months (95% CI 24–36). Median survival time was 57 months for LR, 30 months for LAT, and 8 months for ST, with a 5-year survival of 47%, 20%, and 2.5%, respectively (p = 0.001). Actuarial 5-year survival for patients submitted to LT was 75%. Overall survival was significantly shorter in patients with multiple HCCs compared to single HCC, with median survival times of 39, 16, and 11 months for patients with a single HCC, with two to three HCCs, and with more than three HCCs, respectively (p = 0.01). Survival for patients with single HCC was significantly longer in patients submitted to LR compared to LAT and ST with median survival times of 57, 37, and 14 months, respectively (p = 0.02). Also, in patients with multinodular HCCs (2–3 HCCs) LR showed the best results with a median survival time of 58 months compared to 22 and 8 months for LAT and ST (p = 0.01). In patients with more than three HCCs, LR did not show different results compared to LAT and ST. Seventy-three patients had evidence of macroscopic vascular involvement; median survival in this subgroup of patients was significantly shorter compared to patients without vascular involvement, 10 and 36 months, respectively. Survival for patients with macroscopic vascular involvement submitted to LR or LAT was significant longer compared to ST, with mean survivals of 27, 30, and 12 months, respectively (p = 0.01). The present study shows that the surgery can achieve good results in patients with single HCC and good liver function. Also, patients with multinodular HCCs (two to three nodules) could benefit from LR where survival is longer than after LAT or ST. In patients with more than three HCCs, LR have similar results of LAT. Macroscopic vascular invasion is a major prognostic factor, and the LR is justified in selected patients, where it can allow good long-term results compared to ST.

To investigate the role of oxygen free radicals in hepatocellular carcinoma we assayed tissue scavenger enzymes (superoxide dismutase and selenium-dependent glutathione peroxidase) in liver homogenate, plasma concentrations of vitamins A and E and the serum selenium level from 19 control patients, 23 cases of hepatocellular carcinoma and 18 cases of metastases to liver from different carcinomas. In hepatocellular carcinoma tissue the enzyme activities were all significantly lower than in control liver and in metastases-bearing liver; the enzyme activities of the latter tissues were not different from control liver. In contrast, normal liver adjacent to the hepatocellular carcinoma had decreased activity of superoxide dismutase. Serum selenium concentrations were significantly decreased in patients with hepatocellular carcinoma and those with liver metastases, while vitamin A was significantly decreased only in the former. These findings suggest that hepatocellular carcinoma develops in liver with severe impairment of cellular antioxidant systems, since, in patients with liver metastases from different cancers, despite low selenium concentrations, cellular scavenger enzymes have normal activities.

OBJECTIVES: Bacterial translocation seems to precede the occurrence of overt bacterial infection in patients with cirrhosis. The presence of bacterial DNA in blood and ascites correlates with bacterial translocation and is frequent in patients with advanced cirrhosis without overt infection. Our aim was to search for bacterial DNA in patients with cirrhosis both with and without ascites, and to study its correlation with abnormal intestinal motility or permeability and the presence of bacterial overgrowth. METHODS: Blood and ascites samples were obtained on day 1, and blood samples were taken twice a day for the following 3 days. Bacterial DNA was assayed by polymerase chain reaction using universal primers for rRNA 16 s. Oro-caecal transit time and bacterial overgrowth were assessed with Lactulose H(2) breath testing. Intestinal permeability was assessed by determining urinary lactulose and mannitol excretion with high performance liquid chromatography. RESULTS: We studied seven patients (six were male, age range was 42-78 years). Aetiology was alcohol in four, HCV in two, HBV in one; ascites was present in four and Child-Pugh grade was A in four and B in three. All patients had increased intestinal permeability, six had decreased transit time and one had bacterial overgrowth. In only one patient (with ascites), polymerase chain reaction was positive for bacterial DNA both in ascites and serum for all 4 days on which samples were taken. CONCLUSION: Increased intestinal permeability and abnormal motility were frequent without evidence of bacterial translocation in cirrhosis even without ascites. They are likely to be facilitators for bacterial translocation and thus precede it.

In taking an integrated ethnopedological approach, this study aims to investigate the meaning of the distribution of the toponyms used in traditional and recent cartography of Sardinia (southern Italy). It is particularly, but not only, focused on those related to soil resources. Sardinia is particularly interesting in this respect, as its unique history, geography, and linguistic position makes it one of the Italian and Mediterranean regions with the greatest number of toponyms. This research investigated the toponyms belonging to an important sub-region of Sardinia, called Ogliastra (central-eastern Sardinia). The research was conducted through the following integrated approach: i) toponymy research and collection from different sources; ii) database creation and translation of toponyms from the Sardinian language (SL); iii) categorization of toponyms; and iv) graphical, statistical, and cartographic data processing. Distribution and diversity of toponyms were assessed using the compiled database, coupled with a geographical information system (GIS). Of around 7700 toponyms collected, 79% had already been reported in SL, while just 21% were in Italian. Of the toponyms in SL, 77% are of known meaning and 54% of these toponyms were characterized by a meaning directly and/or indirectly connected to specific environmental features. On the whole, morphology would appear to be the primary environmental factor able to explain the complex, articulated presence, distribution, and typology of the investigated toponyms. A least squares regression analysis of pedodiversity vs. topodiversity shows a very closed distribution, with an impressive high correlation index (R2 = 0.824). The principal factor analysis (PFA) shows that such a connection may be morphologically based, thereby confirming that pedodiversity and topodiversity are strongly linked each other. Overall, the research shows that an integrated ethnopedological approach, combining indigenous and scientific knowledge may be of great interest in order to mitigate the impressive phenomena of the indigenous knowledge lost.

Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in hemophiliacs who received nonvirucidally treated large-pool clotting factor concentrates before 1986. In fact, although many hemophiliacs infected with HCV have a slow progression of liver disease, in a minority of them hepatitis evolves toward end-stage liver disease and hepatocarcinoma. Moreover, a significant percentage of HCV-infected hemophiliacs were also coinfected with human immunodeficiency virus (HIV), which can accelerate the progression of liver disease. Thus, the aim of anti-HCV therapy is to interrupt the chronic infection in order to prevent the progression of hepatitis to cirrhosis, liver decompensation, cancer and, ultimately, death. In this review we present the literature data on anti-HCV treatment in hemophiliacs. Combination therapy with interferon (IFN) and ribavirin has improved the poor results obtained with IFN monotherapy and has become the standard treatment of chronic hepatitis C. Given the positive results obtained with pegylated interferon plus ribavirin in nonhemophiliacs, ongoing trials are evaluating this promising therapy in HCV-chronically infected hemophilic patients; preliminary results show a sustained response rate similar to that in patients without coagulopathy. Finally, based on the encouraging results in coinfected nonhemophiliacs, anti-HCV treatment should also be considered for those HIV-positive hemophiliacs in whom anti-retroviral treatment has stabilized the HIV infection. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.

Intestinal failure impairs nutritional status and survival expectance. Though intestinal adaptation and enteral independence may be achieved, artificial nutrition is needed in about half of the patients.This study is aimed at assessing the causes of death, survival rate, enteral independence in time, and factors affecting the clinical outcome in a group of patients with intestinal insufficiency.Sixty-eight patients with intestinal insufficiency, due to major intestinal resection in 60 cases (short bowel syndrome) (remnant intestine length 101-150 cm in 31 cases, 50-100 cm in 23 cases,50 cm in 6 cases), and due to chronic idiopathic pseudo-obstruction in 8 cases, were enrolled and followed-up for (median) 36 months (25th and 75th percentile in 12 and 60 months, respectively). In 60 short bowel syndrome patients, the main conditions that led to intestinal failure were ischemic bowel (28), major surgery complications or severe adhesions (17), radiation enteritis (10), Chron's disease, intestinal tuberculosis, small bowel lymphoma and trauma (others).Seventeen variables age, underlying disorders, length of remnant bowel, type of surgery, hospital stay, type of nutrition (hospital and home) and its variations in time, causes of death, survival rate and time were considered. Statistical analysis was carried out by Mann-Whitney U-test, Pearson chi2, Spearman correlation test, Kaplan-Meyer method and Cox's proportion hazards regression model.At the time of admission to the hospital, none of the patients had nutritional independence, 54 (79.4%) were on parenteral nutrition and 14 (20.6%) were on enteral nutrition. At the time of discharge, 23 (33.8%) patients showed enteral independence, 39 were on home parenteral nutrition, 3 on enteral nutrition + i.v. feeding, 1 on enteral nutrition, and 2 needed oral supplementation with hydroelectrolyte solutions only. After a median value of 36 months, 30 and 2 patients were on home parenteral nutrition and enteral nutrition + i.v. feeding, respectively, 2 on enteral nutrition, 2 on oral supplementation with hydroelectrolyte solutions, and 26 cases reached enteral independence. A significant relationship was detected between the length of remnant bowel and types of nutrition at both admission (r = 0.38; P = 0.001) and discharge (r = 0.48; P = 0.001), parenteral nutrition being more frequent in patients with very short bowel. Twenty-two patients (32.4%) died (4 from newly occurring malignancies), 40 (58.8%) survived, and 6 (8.8%) were lost to the follow-up. Eleven of 22 patients died from conditions related to intestinal failure (8 cases) and/or home parenteral nutrition complications (3 cases). At 12, 24, 36, 48, 60 and 72 months, survival rates were 95.4, 93.3, 88.1, 78.6, 78.6 and 65.5%, respectively, but it was significantly lower for patients with50 cm of remnant bowel than those with longer residual intestine (P0.05), and in patients who started home parenteral nutrition above the age of 45 years (P0.02). Survival rate was higher in patients with enteral independence than those with enteral dependence (P0.05). Better survival rates were registered in patients with chronic obstructive intestinal pseudo-obstruction and major surgery complications, whereas ischemic bowel and even more radiation enteritis were associated with a lower survival expectance.Actuarial survival rate of patients with intestinal failure quotes 88 and 78% at 3 and 5 years, respectively. It is influenced by the length of remnant intestine, age at the start of home parenteral nutrition, enteral independence and, to some extent at least, by the primary disorder. Enteral independence can be achieved in time by about 40% of the patients with intestinal insufficiency, but for home parenteral nutrition-dependent cases, intravenous feeding can be stopped in less than one out of five patients during a median 3-year period.

At present two of the most relevant problems of the therapy of HCV-related chronic active hepatitis are the retreatment of nonresponders to interferon-alpha (IFN-alpha) and the definition of a prognostic index of response. We treated 44 patients who previously were nonresponders to IFN-alpha alone with IFN-alpha plus ribavirin for 12 months. Among the tests performed, we included the serum level of soluble intercellular adhesion molecule-1 (sICAM-1) at the beginning of the trial and at 3 months thereafter. We obtained 56.81% end of treatment responses and 47.72% sustained responses. A decrease of at least 10% of the sICAM-1 serum level during the first 3 months of treatment strongly correlated to the results of therapy while the usual important prognostic factors (HCV genotype and viral load) did not show this relation.

Since the first human liver transplantation, carried out in 1963, the procedure has become routine with an excellent outcome in terms of both quality and length of survival. One of the major challenges facing the transplant community is the shortage of donor organs. Possible approaches to overcoming this problem include changes in legislation, setting up of organizational structures, more effective use of marginal donor livers, splitting livers, and the development of living related transplants. Alternative treatments to liver transplantation have been sought, including hepatocyte transplantation, xenotransplantation, liver-directed gene therapy, extracorporeal liver support systems, tissue-engineered organs, and auxiliary partial orthotopic liver transplantation.

Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients affected by hereditary bleeding disorders and treated with non-virus inactivated clotting factor concentrates during the 1970s.In this review, we briefly report the present knowledge about HCV infection in hemophilic patients. The natural course of hepatitis C virus infection in hemophiliacs is described, by analyzing the prevalence of HCV infection, the genotype distribution and the risk factors involved in the progression of chronic hepatitis into severe liver disease such as cirrhosis, liver decompensation and hepatocellular carcinoma.We focus on the most important advances in the treatment of hepatitis C in hemophiliacs.

This study looked at 102 anti–hepatitis C virus (HCV)–positive, hepatitis B virus (HBV)–negative, and HIV-negative patients (median age, 45.1 years; range, 15-71) affected by hereditary bleeding disorders who have been infected with HCV for 15 to 34 years (median, 25.1). All these patients were infected before the mid 1980s because of non–virally inactivated pooled blood products. Fourteen patients (13.7%) were HCV-RNA negative with no signs of liver disease and were considered to have cleared the virus. Eighty-eight patients (86.3%) were HCV-RNA positive. The HCV genotype distribution was 1a in 20.5%, 1b in 36.4%, 2 in 17.0%, 3 in 15.9%, 4 in 3.4%, and mixed in 6.8% of cases. Twenty-four patients (23.5%) had serum cryoglobulins, symptomatic in 4 cases, and associated with liver disease and with genotype 1. Among the 88 HCV-RNA–positive patients, 15 (17.0%) had normal alanine aminotransferase levels and abdominal ultrasound, 61 (69.3%) had nonprogressive chronic hepatitis, and 12 (13.7%) had severe liver disease (6 [6.9%] liver cirrhosis, 4 [4.5%] hepatic decompensation, and 2 [2.3%] hepatocellular carcinoma) after a follow-up period of 25 years. There were 3 (3.4%) liver-related deaths. HCV genotype 1, patient's age at evaluation, duration of infection, and severity of congenital bleeding disorder were associated with more advanced liver disease. The results confirm the slow progression of HCV infection in HIV-negative hemophiliacs.

Intercellular adhesion molecule 1 (ICAM-1) is a marker of inflammation and tissue damage. Levels of soluble ICAM-1 (sICAM-1) were measured in 71 patients with chronic C hepatitis treated with interferon (IFN)-alpha-2a, at baseline and at every 3 months of therapy, and in 42 normal control subjects. The levels of sICAM-1 were significantly higher in the patient than in the control subject group, particularly among cirrhotics. Baseline sICAM-1 levels were similar in responders and nonresponders. By contrast, the concentration of sICAM-1 decreased significantly only in responders during the first 3 months of therapy. The probability of response to treatment, analyzed by Kaplan-Meier analysis, was much higher in the group showing a decrease of sICAM-1 than in the patients who did not show such a decrease. In conclusion, a "longitudinal" evaluation of serum levels of sICAM-1 in the first period of treatment is particularly useful in the identification of patients with high significant probability of response to treatment.

Laminin P1 (pepsin-resistant fragment of laminin) and aminoterminal peptide of type III procollagen are measurable in serum and are now considered useful serum markers of fibrogenesis and inflammation in chronic liver diseases. However, very few studies thus far have focused on assessing the diagnostic value of these markers in detecting fibrosis and necro-inflammatory activity in chronically diseased liver. The aim of the present study was therefore to investigate the correlations of laminin and type III procollagen with liver histology and to compare their diagnostic value in detecting the degree of liver fibrosis and necro-inflammatory activity in a homogeneous group of 99 patients suffering from chronic hepatitis C, and lacking other factors which can directly affect the serum levels of the two markers. Both these serum markers were measured by radioimmunoassay, employing commercially available kits. The three main aspects of liver pathology, i.e. portal-periportal activity, lobular activity and fibrosis, were histologically evaluated and semiquantitatively expressed by numerical scores. The results of this study show that laminin and type III procollagen were both positively correlated with the histological scores for portal-periportal activity and with those for fibrosis, whereas no significant correlation was observed between each of the two serum markers and the histological scores for lobular activity. The sensitivity and specificity of laminin and type III procollagen in detecting histological aspects of fibrosis and disease activity in liver, computed at various cut-off levels, showed overlapping trends for the two markers; however, the diagnostic value was in general rather low, whatever the cut-off considered. We therefore conclude that the ‘static’ measurement of both serum laminin and type III procollagen is of limited value for individual diagnosis of liver damage.

We investigated the prevalence of mixed cryoglobulinemia (MC) in 100 cases of chronic hepatitis C virus (HCV) infection and the effect of a 6-month treatment with interferon-alpha (IFN-alpha). Cryoglobulins were detected on admission in 36 of 100 patients and appeared during observation in a further 18 cases. Cryocrit ranged from 0.5% to 20%. Patients with MC were older and had a higher incidence of cirrhosis than those without MC. Immunologic characterization of the cryoprecipitate showed the presence of type II in 84% of cases and type III in 16%. The patients received IFN-alpha (6 MU three times per week) for 6 months. Fifty-seven were responders (i.e., reached normal aminotransferase levels), 26 of these relapsed within 2 months after IFN withdrawal, and 30 did not relapse. After IFN-alpha treatment, cryoglobulinemia disappeared in 11 of the 21 evaluable responders, but in none of the 15 nonresponder patients (p0.003). The clearance of MC was associated in all cases with clearance of HCV RNA. The delayed appearance of cryoglobulinemia in responders seems to be associated with a higher probability of relapse.

Laminin is a major basement membrane-associated, non-collagenous glycoprotein of the extracellular matrix and is deposited in the space of Disse during sinusoidal capillarisation. Laminin P1, a pepsin-resistant fragment originating from the central portion of the cross-shaped laminin molecule, is detectable in serum and has been related to liver fibrosis and portal hypertension. In this study we investigated the behaviour of serum laminin P1, measured by radioimmunoassay, in a homogeneous group of 95 patients suffering from chronic viral hepatitis, types C or B, in order to determine the relationships between serum laminin P1 and each of the main histological aspects of the disease process (i.e. portal-periportal activity, lobular activity and fibrosis), which were assigned numerical scores. Moreover, we computed, at several cut-off levels, the sensitivity, specificity and positive and negative predictive values of laminin P1 in detecting both necroinflammatory activity and fibrosis in the liver. The results show that serum laminin P1 levels parallel the severity of liver disease, the highest laminin concentrations being observed in cirrhotic patients. They suggest also that serum laminin P1 should be considered a marker of the liver disease process as a whole, rather than a marker exclusively linked to fibrosis. Nevertheless, the usefulness of serum laminin P1 measurement, as investigated in this study, seems too limited to be recommended for routine clinical practice.

Forty patients with chronic viral hepatitis or active cirrhosis (33 anti-HCV positive) entered a recombinant human alpha 2A interferon randomized trial. Twenty-one subjects were treated with 6 million units (MU) three times per week for 6 months. Nineteen were not treated. Six months later in 12 patients of the treated group (60% of the evaluable 20) with normalized serum aminotransferases levels (responders), fibrogenesis serum markers (NPIIIP and laminin) were significantly lower than baseline. In the untreated patients and in non-responders NPIIIP and laminin were unchanged. Semi quantitative histological evaluation (allotting scores for inflammation, necrosis and fibrosis) confirmed a significant improvement of necro-inflammation in the responders. These data suggest that alpha-IFN treatment may decrease stimuli for fibrogenesis by reducing liver inflammation and necrosis, thus preventing evolution to cirrhosis.

The frequency and histological pattern of multiple hepatitis virus infection was studied in 161 Italian patients who had consecutively undergone liver biopsy from 1989 to 1991. The histological features were compared with that of infection with a single virus. Thirty-nine per cent of patients had evidence of past or present multiple infection, the commonest of which was hepatitis C virus (HCV) in patients with evidence of previous infection with hepatitis B virus (HBV). In general, the severity of the histological pattern of each viral infection was maintained even when more than one virus was involved; there was neither exacerbation nor diminution of the histological changes. The delta-virus (HDV) was not associated with severe necro-inflammatory lesions, but HDV-positive patients were few in this cohort. Lymphoid follicle formation (a putative histological marker of HCV infection) was also found in a high proportion of HCV-negative patients but expressing much HBcAg or HDAg in liver tissue. Possible explanations for this finding are that follicles are relatively non-specific for HCV infection, or that these cases represent HCV infection with false-negative serology. The results of this study suggest that multiple hepatitis virus infection is common in the population investigated and that HBV and HCV co-infection cannot be reliably diagnosed histologically. Whether double infection with these viruses influences the cirrhotic evolution of the liver lesion remains unclear.

In 55 patients with alcoholic cirrhosis and in 47 healthy individuals we assayed the concentration of selenium in serum (S-Se) by proton induced X-ray emission, the aminoterminal peptide of type III procollagen (NPIIIP) by RIA and the plasma fibronectin (FN) by immuno-nephelometry, together with routine biochemical tests. S-Se was lower in cirrhosis than in controls (0.57, SD 0.20 vs 0.92, SD 0.16 mumol/l; p less than 0.001) and was more reduced in ascitic than in compensated patients (0.50, SD 0.19 vs 0.66, SD 0.17 mumol/l; p less than 0.001). Regression analysis showed a positive correlation of S-Se with serum albumin and FN, whereas necrotic or inflammatory activity seems unrelated to S-Se; a negative correlation was found between S-Se and NPIIIP, suggesting a protective role of selenium against fibrosis.

An involvement of calcitonin in the mechanism of pain perception has recently been hypothesized. In order to collect information about the relationship between this hormone and well known analgesic substances such as opioids, we have studied the serum levels of calcitonin in a group of heroin addicts, finding higher average concentrations than in normal subjects of matched age and sex. In these addicts there were no severe signs of impaired renal or hepatic function, or alterations of the serum levels of calcium and phosphate. So we think that opioids, in a direct or indirect way, can stimulate the secretion of calcitonin.

To evaluate the prognostic value of serum copper (S-Cu) and ceruloplasmin and their pathophysiologic significance in human hepatocellular carcinoma (HCC), we studied 49 patients with HCC (20 of which were submitted to partial hepatectomy) compared with 110 patients with liver cirrhosis. In HCC both S-Cu and ceruloplasmin were higher than in cirrhosis; moreover, S-Cu was correlated with the extension of HCC, evaluated by instrumental data and by surgical inspection. In cirrhotic patients, mean S-Cu was 122.9 micrograms/dl (SD, 29.3), in early HCC, 153.0 micrograms/dl (SD, 34.5), and in advanced HCC, 193.1 micrograms/dl (SD, 37.7). Variance analysis gave F = 59.4. In HCC patients S-Cu was positively correlated with ceruloplasmin and with fibrinogen. Survival, evaluated by Mantel's test stratified for surgical therapy, was longer in patients with S-Cu levels lower than 175 micrograms/dl and in those at an earlier stage. We therefore conclude that S-Cu has a relevant diagnostic value in detecting HCC also in early stage and allows prognostic evaluation as regards survival.

In order to clarify the significance of procollagen III peptide (PIIIP) and fibronectin (FN) blood concentration in alcohol related chronic liver disease (ALD), we have investigated their relationships with histological liver features and biochemical liver tests in 44 ALD patients. PIIIP was measured in serum by radioimmunoassay whereas FN was determined in plasma using an immunonephelometric method. In each liver biopsy, steatosis, portal infiltrate, lobular necro-inflammation, portal fibrosis and lobular fibrosis were semiquantitatively assessed by scoring from 0 to 3. A close correlation of PIIIP was found with morphological features of fibrosis (both of lobular and portal type), but not with necro-inflammation or steatosis. PIIIP was also positively correlated with ALP and GGT and exhibited a good diagnostic value in liver fibrosis. On the contrary, FN did not distinguish between normals and patients and was not correlated with any morphological liver feature or biochemical liver test. We also conclude that serum NP3P effectively reflects liver fibrosis, whereas plasma FN seems not related to any of the main histological aspects of liver damage in ALD.

2-Mercaptopropionylglycine (2-MPG) transformed normal red blood cells (RBCs) into paroxysmal nocturnal haemoglobinuria (PNH)-like RBCs in vitro, depending on the concentration, pH and time of incubation. The incorporation of radioactive choline in the presence of acetylcholine was reduced, as in RBCs treated with aminoethylisothiouronium salt (AET). In contrast, the uptake in the presence of choline differed when the RBCs were incubated with the two compounds, being reduced in AET-treated RBCs and increased in 2-MPG-treated ones. As true PNH RBCs incorporated to a higher extent the radioactivity in the presence of both acetylcholine and choline, 2-MPG-treated RBCs seemed to resemble the PNH RBCs better than the AET-treated ones. Present results suggest the possibility of modifying selectively the activity of acetylcholinesterase and the transport of choline through the cell membrane.

In a group of 23 patients with advanced liver cirrhosis we have found a statistically significant positive correlation (r = 0.746; p less than 0.0001) between fibronectin and prealbumin levels measured in plasma by immunonephelometric methods and found significantly lower than in healthy controls (p less than 0.001). On the contrary, no correlation of fibronectin neither to albumin nor to the presence of an enlarged spleen was observed. Since the sensitivity of prealbumin as an index of liver function is believed to be higher than that of albumin, our results support the view that the decreased fibronectin in advanced cirrhotics is mainly due to their liver failure, an enlarged spleen playing only a minor role.

Since 1981 high doses of human intravenous immunoglobulin (IVIG) were used for the treatment of different haematologic diseases. We describe the case of a patient suffering from a severe hereditary spherocytosis (HS) treated with IVIG before splenectomy