Angelo Balestrieri

Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children

We investigated the course of distinct episodes of acute non-A, non-B (NANB) hepatitis in three polytransfused thalassaemic children. In each case, the first episode was associated with the appearance of serum hepatitis C virus (HCV) RNA and anti-HCV seroconversion. The second episode was accompanied by the reappearance of HCV viraemia, which in two patients was due to reinfection with a different HCV strain and in the third could be the result of either reactivation of primary infection or reinfection with a new but closely related strain. Thus HCV infection may not induce protective immunity, which has implications for vaccine development.

Treatment of Chronic Hepatitis D with Interferon Alfa-2a

BACKGROUND AND METHODS Chronic hepatitis D is a severe and rapidly progressive liver disease for which no therapy has been proved effective. To evaluate the efficacy of treatment with interferon, we studied 42 patients with chronic hepatitis D who were randomly assigned to receive either 9 million or 3 million units of recombinant interferon alfa-2a (three times a week for 48 weeks) or no treatment. RESULTS By the end of the treatment period, serum alanine aminotransferase values had become normal in 10 of 14 patients receiving 9 million units (71 percent), as compared with 4 of 14 treated with 3 million units (29 percent, P = 0.029) and 1 of 13 untreated controls (8 percent, P = 0.001). Seven patients treated with the higher dose of interferon (50 percent) had a complete response (normal levels of alanine aminotransferase and no detectable serum hepatitis delta virus [HDV] RNA), as compared with three of those who received the lower dose (21 percent, P = 0.118), and none of the controls (P = 0.004). Treatment with 9 million units of interferon was associated with a marked improvement in the histologic findings (reduced periportal necrosis and portal and lobular inflammation), whereas in the untreated controls there was considerable histologic deterioration. In 5 of the 10 patients treated with 9 million units of interferon whose alanine aminotransferase values became normal, the biochemical responses persisted for up to 4 years (mean, 39 months), but the effects of treatment on viral replication were not sustained. In contrast, none of those who received 3 million units and none of the untreated controls had a sustained biochemical or virologic response. CONCLUSIONS In about half the patients with chronic hepatitis D treated with high doses of interferon alfa-2a (9 million units three times a week for 48 weeks), the serum alanine aminotransferase level becomes normal, HDV RNA becomes undetectable in serum, and there is histologic improvement. However, a relapse is common after treatment has been stopped.

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.

Independent expression of serological markers of thyroid autoimmunity and hepatitis virus C infection in the general population: Results of a community-based study in northwestern Sardinia

To assess the relationship between serological markers of thyroid autoimmunity and chronic hepatitis C, we surveyed the general population of two villages in the region of Sardinia, Italy, where infection with hepatitis viruses is endemic and the prevalence of autoimmune diseases is elevated. A total of 1310 subjects aged 6–88 years (65% of the total resident population) participated in the survey, and 1233 (94%; 444 males and 789 females) agreed to provide a blood sample. Autoantibodies to thyroid peroxidase (anti-TPO) were measured by radioimmunoassay; antibodies to HCV (anti-HCV) by a third generation enzyme immunoassay and borderline positive results confirmed by recombinant immunoblot assay. For both anti-HCV and anti-TPO the ageand gender-standardized prevalence rates (SPR) were calculated and the significance of the association between the two antibodies tested by Yates corrected χ2 test. The overall SPR for anti-HCV was 50.7×10−3 (86/1,233), similar between men [49.1×10−3 (22/444)] and women [52.3×10−3 (64/789)]. The overall SPR for anti-TPO was 136.9×10−3 (204/1,233), and that among women [201×10−3 (174/789)] was almost 3-fold that among men [71.6×10−3 (30/444)]. A concurrent anti-HCV and anti-TPO positivity was found in a small minority of subjects [8/1,233 (0.65%)], all women aged 57–81 years. The SPR for the two concurrent events was 3.3×10−3, which was not significantly different (Yates corrected χ2 test = 0.65) from that expected under the assumption of unrelated events. To explore whether HCV infection is a risk factor for anti-TPO positivity, we designed a casecontrol study with anti-TPO positive subjects as the cases, and anti-TPO negative subjects as the controls. The age- and gender-adjusted odd ratio (OR) was 0.4 (95% CI 0.2,0.7), indicating a negative association. In conclusion, no evidence for epidemiological association of circulating thyroid autoantibodies and antibodies to HCV was found. Our findings do not therefore support a pathogenetic link between HCV infection and thyroid autoimmunity.

Failure of ketamine to interact with opiate receptors.

Ketamine, an anesthetic agent endowed with several morphine-like effects, failed to displace 3H-dihydromorphine or 3H-methionine-enkephalin from opiate receptors in the rat brain synaptosomal-mitochondrial membrane preparations. Furthermore, ketamine-induced analgesia in rats was not antagonized by naloxone, suggesting that this effect is not mediated by opiate receptors.

The role of pre-core hepatitis B virus mutants on the long-term outcome of chronic hepatitis B virus hepatitis. A longitudinal study.

To define the relationship between pre-core hepatitis B virus mutants and the long-term outcome of chronic hepatitis B virus infection, we monitored the type of circulating pre-core hepatitis B virus-DNA by polymerase chain reaction and sequencing in 41 selected chronic HBsAg carriers with extensive follow up. They included 12 HBeAg-positive patients with chronic hepatitis, who seroconverted to anti-HBe during follow up and 29 anti-HBe positive patients, 23 of whom had chronic hepatitis and six acute severe exacerbation occurring spontaneously (three cases) or during antitumor chemotherapy (three cases). In the presence of HBeAg, all showed prevalence of the pre-core wild type along with high levels of viral replication and elevated alanine aminotransferase. Anti-HBe seroconversion was accompanied by a dramatic reduction of hepatitis B virus replication and normalization of alanine aminotransferase in all, except one, and by the emergence of mutated strains with a pre-core stop codon (point mutation G to A at nt 1896) that replaced the wild type in seven of the 12. Of the seven who harboured the pre-core mutant, three continued to show normal alanine aminotransferase during subsequent follow up, three had mild alanine aminotransferase elevation and one had an acute short-lived reactivation after 4.4 years of normal alanine aminotransferase. The five cases who continued to show prevalence of wild type in spite of anti-HBe seroconversion all revealed persistently normal alanine aminotransferase.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamus-pituitary-adrenal axis of heroin addicts

The hypothalamus-pituitary-adrenal axis of heroin addicts was investigated by evaluating plasma cortisol levels throughout the day in 37 heroin abusers (HA), 17 of whom showed detectable morphine levels, indicating heroin administration in the previous hours and in 12 controls. All HA showed lower cortisol levels in basal condition (100.7 +/- 61.7 ng/ml, M +/- S.D.) compared to the control group (159.7 +/- 40.6, P less than 0.05). Moreover all HA (65.1 +/- 28.9%), and in particular those taking heroin during the study (39.1 +/- 41.4%), show a reduced cortisol decrease in the evening, which was significantly lower than in controls (85.3 +/- 10.1%; P less than 0.01). As far as the acute effects of opiates are concerned morphine (0.1 mg/kg) significantly reduced plasma cortisol levels within 60 min in a group of 8 healthy subjects. The same pattern was displayed by only 3/8 HA whose morphine levels were higher than 1 ng/ml, i.e. in those reaching the highest plasma morphine concentrations. These data indicate that chronic opiate abuse leads to a hypoadrenalism which could be the result of morphine-induced changes at the hypothalamic level.

Abnormalities of Blood Coagulation and Fibrinolysis in Psoriasis

Contrasting data have been reported about cardiovascular diseases in psoriatic patients. The aim of this study was therefore to evaluate blood coagulation and fibrinolysis in psoriatic patients. For this purpose, in a first group of 48 patients, we measured blood coagulation and fibrinolysis inhibitors [antithrombin III (AT), protein C (PC) and alpha 2-antiplasmin (AP)], the products of thrombin and plasmin activity [fibrinopeptide A (FpA) and B beta(15-42) (B beta)], plasminogen (PLG) and fibrinogen (FBG). When all patients were considered we found a significant increase in B beta and FpA levels, while PC, PLG and AP values were significantly decreased when compared to controls. FBG and AT were not different from the controls. In order to understand whether the observed abnormalities of blood coagulation and fibrinolysis were related only to psoriasis we divided all the patients into two groups: (1) patients with cardiovascular disease or other risk factors (n = 28) and (2) patients affected only by psoriasis (n = 20). Since no difference was observed between groups 1 and 2, we conclude that these findings are related to psoriasis. Subsequently we considered a different group of psoriatic patients. In these patients we measured FpA and two new thrombin activation indicators, such as prothrombin fragment 1 + 2 and thrombin-antithrombin complex (TAT). In addition we evaluated the levels of D-dimer, the product of the dissolution of cross-linking fibrin by plasmin. In this second group FpA, prothrombin fragment 1 + 2 and D-dimer were significantly higher than controls. Only TAT was not statistically different from those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult celiac disease is frequently associated with sacroiliitis

No data are available on the presence and frequency of peripheral or central joint disease, routinely determined by bone scintigraphy with 740 MBq of [99mTc]MDP, in adult celiac disease. Bone scintigraphy was carried out to detect early acute inflammatory lesions in 22 adult celiac patients (15 females and seven males; mean age 36.72 years, range 17–63). Bone scintigraphy was positive for sacroiliitis in 14 cases (63.6%). Except in the case of one patient suffering from rheumatoid arthritis, laboratory data were normal. Our data suggest that as in other chronic intestinal diseases, celiac disease in adults, is frequently associated with central joint disease. This high incidence of sacroiliitis, the joint disease most frequently found in our patients, has not been previously reported in other series. We believe, therefore, this difference could be explained by the different methodology used for the screening of joint difference could be explained by the different methodology used for the screening of joint disease.

Is the imbalance between thrombin and plasmin activity in diabetes related to the behaviour of antiplasmin activity

The aim of this study was to evaluate the balance between thrombin and plasmin activity in a group of 79 diabetic patients (IDDM and NIDDM). For this purpose we determined fibrinopeptide A (FPA) and B beta 15-42, specific products of thrombin and plasmin activity. Moreover we investigated the behaviour of antithrombin III and alpha 2 antiplasmin, important inhibitors of blood coagulation and fibrinolysis. Results show an increase both in FPA and B beta 15-42 in IDDM and NIDDM patients when compared to healthy controls. However the ratio between B beta 15-42 and FPA was lower than in controls indicating an imbalance between thrombin and plasmin activity. Antithrombin III levels were not different from the controls and no correlation was found with Hb A1c. alpha 2 antiplasmin was found to be higher in IDDM when compared both with NIDDM and controls. A non linear correlation was found between Hb A1c and alpha 2 AP in both diabetic groups. We conclude that the imbalance between thrombin and plasmin activity may have a role in determining fibrin deposition. These subclinical abnormalities, unrelated to vascular complications and duration of the disease, may progressively contribute to the development of the vascular complications in diabetes.