Coronary calcified nodules versus nonnodular coronary calcifications: a systematic review and meta-analysis.

BACKGROUND: Percutaneous coronary intervention (PCI) on severely calcified coronary lesions is challenging. Coronary calcified nodule (CN) refers to an eccentric and protruding coronary calcification associated with plaque vulnerability and adverse clinical events. This study aims to conduct an extensive review of CNs, focusing on its prognostic impact in comparison with nonnodular coronary calcification (N-CN). METHOD: A systematic literature review on PubMed, MEDLINE, and EMBASE databases was conducted for relevant articles. Observational studies or randomized controlled trials comparing CNs and N-CNs were included. RESULTS: Five studies comparing CNs and N-CNs were pertinent for inclusion. The total number of individuals across these studies was 1456. There were no significant differences in the baseline demographic, clinical, and angiographic data between the CN and N-CN groups. Intracoronary imaging was always utilized. At follow-up, CNs were associated with significantly increased, target vessel revascularization [odds ratio (OR) 2.16; 95% confidence interval (CI): 1.39-3.36, P-value < 0.01, I2 = 0%] and stent thrombosis (OR 9.29; 95% CI: 1.67-51.79, P-value = 0.01, I2 = 0%) compared with N-CN. A trend for greater cardiac death was also assessed in the CN group (OR 1.75; 95% CI: 0.98-3.13, P-value = 0.06, I2 = 0%). CONCLUSION: CN has a significantly negative impact on outcomes when compared with N-CN.

Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection.

The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross-sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti-HIV-negative patients (71 males; median age 49.8 [21.7-66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV-DNA, HBcrAg, total anti-HBc, HDV-RNA, IgM and total anti-HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti-HBc/IgM anti-HDV ratio (OR 0.990, 95% CI 0.981-0.999, P = .038), whereas disease activity was associated with higher total anti-HDV (OR 10.105, 95% CI 1.671-61.107, P = .012) and HDV-RNA levels (OR 2.366, 95% CI 1.456-3.844, P = .001). HDV-RNA serum levels showed a positive correlation with HBV-DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV-RNA, IgM anti-HDV, total anti-HDV, total anti-HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.

Early and accurate prediction of Peg-IFNs/ribavirin therapy outcome in the individual patient with chronic hepatitis C by modeling the dynamics of the infected cells.

A novel biomathematical model that analyzes the combined alanine transaminase (ALT) and viral-load kinetics during the first month of pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy was successfully applied in 90 of 97 (93%) chronic hepatitis C patients in order to compute the number of infected cells at the end of therapy (I(eot)). The I(eot) indices were lower in sustained virological responders than in relapsers (RELs) and nonresponders (NRs) (median values: 31 vs. 2,190 vs. 1,090,000; P < 0.001), and were independently associated with treatment outcomes (P = 0.003). A threshold of 250 I(eot) was shown to identify sustained virological response (SVR) with high positive predictive value (93%) and good diagnostic accuracy (81%). The time taken to attain 250 I(eot) ranged from 3 to 11 months in patients with hepatitis C virus (HCV) genotypes 2 or 3 and from 3 to 18 months in those with HCV genotypes 1 or 4. Overall, the duration of therapy would have been 49 months less than that suggested by the most recent algorithms based on a rapid virological response (RVR) at week 4.

Isolation and characterization of unusual Mycoplasma spp. from captive Eurasian Griffon (Gyps fulvus) in Sicily.

Mycoplasmas have been isolated from birds of prey during clinical examinations, but their significance to the health of raptors is unclear. We report the isolation and characterization of four mycoplasmas found in the upper respiratory tract of four sick Eurasian Griffon (Gyps fulvus) that were housed in a Sicilian rehabilitation center at Ficuzza, near Palermo in Sicily, before reintroduction into the wild. These included Mycoplasma gallinarum, an unidentified mycoplasma highly similar to Mycoplasma glycophilum, and two unidentified mycoplasmas with similarities to Mycoplasma falconis and Mycoplasma gateae.

Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment.

OBJECTIVES: We studied the impact of hepatitis B virus (HBV) polymerase/reverse transcriptase (Pol/Rt) heterogeneity on adefovir rescue therapy in 34 consecutive chronic hepatitis B patients with viral breakthrough during lamivudine monotherapy. METHODS: The Pol/Rt A-F domains were directly sequenced in all patients at baseline, and 12 and 24 months. Response to therapy was evaluated at 3, 6, 12 and 24 months by quantitative HBV-DNA. RESULTS: Primary treatment failures did not occur. At 6 months 24/34 (70.6%) patients had viraemia<10(4) copies/mL [initial viral response (IVR)]; at 12 and 24 months 23 (71.9%) and 26 (81.3%) of 32 had HBV-DNA<200 copies/mL [complete viral response (CVR)]. IVR or CVR patients did not show viral breakthroughs, which occurred in one of the six remaining patients. All but three patients had baseline rtM204I/V substitutions associated with rtL180M in 23, rtL80I/V in 14, rtV173L in 4, rtT184S in 3, rtQ215S in 2 and rtA181S in 2 cases. rtA181S without rtM204I/V was found in one patient. Four of the six patients (67%) without 24 month CVR showed rtA181S or rtT184S substitutions either alone or with typical lamivudine resistance profiles. Baseline HBV-DNA levels were negatively associated with IVR (univariate analysis, P=0.023). At least one of rtA181S and rtT184S substitutions correlated negatively with IVR and CVR (univariate analysis, P=0.001) and was independently associated with absence of CVR (P = 0.016). CONCLUSIONS: Lamivudine monotherapy favours the emergence of viral quasispecies that influence the response rate to adefovir rescue therapy independently from baseline viraemia and lower the susceptibility to other nucleos(t)ide analogues.

Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.

Liver stiffness was measured by transient elastography (FibroScan) in 228 consecutive patients with chronic viral hepatitis, with (115) or without cirrhosis (113), to study its correlations with serum transaminases [alanine aminotransferase (ALT)], fibrosis stage and surrogate noninvasive markers of fibrosis (APRI, FORNS, FibroTest and hyaluronic acid). The dynamic profiles of serum transaminases and liver stiffness were compared by multiple testing in 31 patients during a 6-month follow-up. We identified 8.3 and 14 kPa as the fibrosis >/=F2 and cirrhosis cut-offs, respectively: their sensitivities were 85.2%/78.3%; specificities 90.7%/98.2%; positive predictive values 93.9%/97.8%; negative predictive values 78.8%/81.6%; diagnostic accuracies 87.3%/88.2%. FibroScan performed better than the other surrogate markers of fibrosis (P < 0.001). Other than fibrosis, other factors independently associated with liver stiffness were ALT for all patients and chronic hepatitis patients (P < 0.001), and 12-month persistently normal ALT (biochemical remission, P < 0.001) in cirrhotics. In patients with biochemical remission either spontaneous or after antiviral therapy (48 of 228, 21%), liver stiffness was lower than in patients with identical fibrosis stage, but elevated ALT (P < 0.001). The liver stiffness dynamic profiles paralleled those of ALT, increasing 1.3- to 3-fold during ALT flares in 10 patients with hepatitis exacerbations. Liver stiffness remained unchanged in 21 with stable biochemical activity (P = 0.001). In conclusion, transient elastography is a new liver parameter that behaves as a reliable surrogate marker of fibrosis in chronic viral hepatitis patients, provided that its relationship with major changes of biochemical activity is taken into account.

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves.

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves' ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Horse antilymphocytic globulin in hepatitis B exacerbation after bone marrow transplantation adoptive immunity transfer.

We describe the case of a HBsAg+, HBeAg+ carrier, treated with lamivudine, who experienced exacerbation of hepatitis after BMT from an anti-HBs+, anti-HBc+, anti-HBe+ donor. The serological profile of the donor and the timing of exacerbation suggested that the adoptive immunity transfer played a major pathogenetic role. Antilymphocyte globulin administration resulted in resolution of hepatitis and seroconversion to anti-HBs+. Therapy aimed at blocking the effector arm of liver damage could represent a novel approach to avoid the risk of progression to fulminant hepatitis without hampering the chances of recovery from hepatitis B.

Increasing serum levels of IgM anti-HCV are diagnostic of recurrent hepatitis C in liver transplant patients with ALT flares.

Recurrent hepatitis and acute rejection share common features which make difficult for diagnosis in liver transplant hepatitis C virus (HCV) positive patients. We studied the usefulness of quantitative monitoring of HCV RNA and immunoglobulin (Ig)M anti-HCV in the differential diagnosis between recurrent hepatitis and acute rejection in 98 consecutive anti-HCV positive liver transplant patients. Aminotransferase levels, serum HCV RNA and IgM anti-HCV were measured at the time of transplantation and monthly thereafter. A liver biopsy (LB) was obtained when serum aminotransferase levels increased to twice or more than normal. During a mean follow-up of 16 months 86 aminotransferase flares were observed. Histology was compatible with recurrent hepatitis C in 44 cases and with acute rejection in 28, doubtful in 14. The fluctuations of HCV RNA serum levels were not significantly different in the three groups. Serum IgM anti-HCV levels increased (from negative to positive or with value variations > or = 0.18) in 36 of 44 cases with recurrent hepatitis C at the time of alanine aminotransferase (ALT) flare. IgM anti-HCV remained unchanged in all rejection cases (P < 0.001), but increased in 10 of 11 histologically doubtful cases that were diagnosed as hepatitis at the second LB. Increasing serum levels of IgM anti-HCV at the time of ALT flares are significantly associated with recurrent hepatitis C in liver transplant patients. The quantitative monitoring of IgM anti-HCV appears to be an additional diagnostic tool for distinguishing recurrent hepatitis C from acute graft rejection with a 100% specificity; 100% positive predictive value and 88.9% diagnostic accuracy.

Hepatitis C virus infection: early diagnosis and identification of response to antiviral therapy.

Early diagnosis of hepatitis C infection and early identification of virologic response to antiviral therapy represent major hallmarks of the quality of a case. They contribute to reducing the risk of hepatitis C infection from blood product and improve disease management in patients treated with antivirals. Some of the current issues and perspectives involved in detection and quantification of viral load during the incubation phase of infection and monitoring the early phase of antiviral therapy are discussed.

Tailoring interferon dose and monitoring viral load in hepatitis C virus genotype 1b infected patients: a pilot study.

BACKGROUND AND AIMS: Complete [biochemical and virological) primary response remains the first goal of any antiviral therapy and its early assessment could be particularly useful in the management of the high viral load, genotype 1b infected patients, who have the worst chance of response. We evaluated whether tailoring interferon dose according to pre-treatment viral load and early monitoring of quantitative HCV-RNA could either improve or predict the results of recombinant alpha-2a interferon treatment in these patients. PATIENTS: Fifty-three consecutive genotype 1b HCV-infected patients, stratified in two groups by viral load (cut off 6 MEq/ml), received randomly 6 or 9 MU of recombinant alpha-2a interferon thrice weekly for 6 months, followed by 6 MU for another 6 months. METHODS: HCV-RNA was measured [b-DNA] assay) two months apart prior to therapy, at baseline, after 2 weeks of therapy and monthly thereafter. RESULTS: In the high viraemic group, complete primary response was observed in 80% of patients treated with high dose recombinant alpha 2a interferon and only in 14.3% of low dose treated patients [p<0.03]. In low viraemic patients, complete primary response was 53. 8% in low dose patients and 80% (8 out of 10) in the high dose group. Sustained response was 60% in high viraemic patients treated with high dose and absent in those treated with low dose [p<0.05]. One log viral load decrease at 2 or 4 weeks showed 0.87 and 0.80 positive predictive values, 0.95 and 1.0 negative predictive values with 96% and 100% sensitivities and 83% and 70% specificities. CONCLUSIONS: 6 MU recombinant alpha-2a interferon thrice weekly schedules were completely ineffective in the large majority (85.7%) of patients with viral load above 6 million HCV-RNA copies/ml and the treatment failure could be predicted by lack of one log viral load decrease after 2-4 weeks of treatment.

Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand.

Human ICOS (huICOS) is a T cell-specific molecule structurally related to CD28 and CTLA-4 with potent co-stimulatory activities on T cell proliferation, cytokine induction and T cell help for B cells. We have now cloned and characterized murine ICOS (muICOS). muICOS mRNA of 1.5 kb and 3.3 kb encodes a protein with a deduced molecular mass of 20.3 kDa, which is 71.7 % identical to huICOS. On the cell surface, muICOS is expressed as a disulfide-linked, glycosylated homodimer of 47-57 kDa, with subunits of approximately 26 kDa. With a panel of monoclonal antibodies we have determined the expression of muICOS in vitro and in vivo. Following activation of splenic T cells via CD3, muICOS became detectable at 12 h and reached a maximum of expression at around 48 h, thus exhibiting expression kinetics similar to huICOS. In vivo, muICOS was found to be substantially expressed in the thymic medulla and in the germinal centers and T cell zones of lymph nodes and Peyer's patches. Non-lymphoid tissue was ICOS negative. The muICOS gene was mapped to a region of chromosome 1 also harboring the CD28 and CTLA-4 genes. Using recombinant chimeric muICOS-Ig we determined that B7h, a recently cloned B7-like molecule, is a ligand for muICOS.

The impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) : from research to clinical practice.

Hepatic carcinogenesis is a complex process that involves profound alterations of the hepatocyte genome (1,2) and has been graded in three stages: induction, promotion, and progression in the animal models (3-5). In recent years, the use of molecular biology techniques have improved significantly the understanding of the mechanisms (alteration of gene and gene expression) that occur during the different steps of carcinogenesis.

High prevalence of G1 and G2 TT-virus infection in subjects with high and low blood exposure risk: identification of G4 isolates in Italy.

BACKGROUND/AIMS: A non-enveloped single-stranded DNA virus (TTV) was detected in Japanese patients with fulminant hepatitis (47%) and chronic liver disease of unknown etiology (46%) more frequently than in blood donors (12%). Subsequent studies, however, questioned the association of TTV with liver disease. We further investigated the role of this novel virus in liver diseases. METHODS: We tested 106 patients and 102 blood donors for TTV by polymerase chain reaction using conserved region primers. RESULTS: TTV DNA was found in 19 of 102 volunteer blood donors (18.6%) and in 27 of 106 patients with liver disease (25.5%): 10 of 28 chronic hepatitis B (35.7%), 9 of 28 chronic hepatitis C (32.1%) and 8 of 50 (16%) cryptogenic liver disease patients. Previous interferon treatment was not associated with a significantly lower prevalence of TTV infection. TTV prevalence was higher in patients with blood exposure (42.8%, 6/14) than in patients without risk factors (21.4%, 18/84). Four of five patients (80%) with HBV familial infection and without blood exposure were also TTV positive. Partial nucleotide sequences from 3 Italian isolates diverged more than 30% from the 2 prototype genotypes G1 and G2 and were 88% homologous to the recently described genotype G4. CONCLUSIONS: G1 and G2 TTV are common in Italy and in the USA in liver disease patients and in blood donors. The prevalence is high in patients with blood exposure but also in subjects without risk factors; other routes of transmission should therefore be considered.