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1.  Polyfunctional Type-1, -2, and -17 CD8+ T Cell Responses to Apoptotic Self-Antigens Correlate with the Chronic Evolution of Hepatitis C Virus Infection 
PLoS Pathogens  2012;8(6):e1002759.
Caspase-dependent cleavage of antigens associated with apoptotic cells plays a prominent role in the generation of CD8+ T cell responses in various infectious diseases. We found that the emergence of a large population of autoreactive CD8+ T effector cells specific for apoptotic T cell-associated self-epitopes exceeds the antiviral responses in patients with acute hepatitis C virus infection. Importantly, they endow mixed polyfunctional type-1, type-2 and type-17 responses and correlate with the chronic progression of infection. This evolution is related to the selection of autoreactive CD8+ T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients who clear infection. These findings demonstrate a previously undescribed strict link between the emergence of high frequencies of mixed autoreactive CD8+ T cells producing a broad array of cytokines (IFN-γ, IL-17, IL-4, IL-2…) and the progression toward chronic disease in a human model of acute infection.
Author Summary
The emergence of a large population of mixed polyfunctional (type-1, -2, -17) CD8+ T cell effector responses specific for apoptotic T cell-associated self-epitopes rather than the dysfunction or altered quality of virus-specific CD8+ T cells is associated with the progression toward chronic disease in the human model of acute HCV infection. The chronic evolution is associated with the selection of autoreactive CD8+ T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction, as seen in patients undergoing infection resolution. We suggest that these autoreactive responses are secondary to the viral persistence and can participate to the HCV-related immunopathology. This data has implications for the prognosis and therapy of infections undergoing chronic evolution.
doi:10.1371/journal.ppat.1002759
PMCID: PMC3380931  PMID: 22737070
2.  Impact of comorbidities on the severity of chronic hepatitis B at presentation 
AIM: To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B.
METHODS: Out of 1366 hepatitis B surface antigen (HBsAg) positive subjects consecutively observed in 79 Italian hospitals, 53 (4.3%) showed as the only cofactor hepatitis D virus (HDV) infection [hepatitis B virus (HBV)/HDV group], 130 (9.5%) hepatitis C virus (HCV) (group HBV/HCV), 6 (0.4%) human immunodeficiency virus (HIV) (group HBV/HIV), 138 (10.2%) alcohol abuse (group HBV/alcohol); 109 (8.0%) subjects had at least two cofactors and 924 were in the cofactor-free (CF) group.
RESULTS: Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis (P < 0.001), those in group HBV/HDV were younger (P < 0.001), more frequently resided in the south of the country and had cirrhosis (P <0.001), those in group HBV/HCV were older (P < 0.001) and more frequently had cirrhosis (P < 0.001). These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients. Multivariate analysis showed that an older age [odds ratio (OR) 1.06, 95% CI: 1.05-1.08], alcohol abuse with more than 8 drinks daily (OR 2.89, 95% CI: 1.81-4.62) and anti-HDV positivity (OR 3.48, 95% CI: 2.16-5.58) are all independently associated with liver cirrhosis. This association was found also for anti-HCV positivity in univariate analysis, but it was no longer associated (OR 1.23, 95% CI: 0.84-1.80) at multivariate analysis.
CONCLUSION: Older age, HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection, while HCV replication plays a lesser role in the severity of hepatic damage.
doi:10.3748/wjg.v18.i14.1616
PMCID: PMC3325527  PMID: 22529690
Chronic hepatitis B; Hepatitis B virus/hepatitis D virus dual infection; Hepatitis B virus/hepatitis C virus dual infection; Alcohol abuse
3.  The association of hepatitis B virus infection with B-cell non-Hodgkin lymphoma – a review 
Epidemiological studies performed over the last decade have demonstrated a positive association between persistent, hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), with HBV-infected patients having a 2-3-fold higher risk to develop NHL than non-infected patients. Moreover, there is evidence that also occult HBV infection (HBsAg-negative, HBV DNA-positive) associates with NHL. An association with HBV infection may exist also for other hematological malignancies, but available evidence is much less persuasive than for NHL. In this review article we will discuss available results on the association between HBsAg-positive HBV infection and NHL, as well as the significance of other serological markers of HBV infection in these subjects. We will also discuss the possible etiopathogenic role of HBV, and propose a multifactorial model for lymphomagenesis. Experimental evidence for multifactorial etiopathogenesis has been obtained in recent years for HBV-associated hepatocellular carcinoma (HCC), and we suggest that a similar model may apply to HBV-associated lymphoma as well. Eventually, we will also address some unresolved questions. Two of these are of particular relevance. First, do HBV-positive NHL patients show regression of their hematologic malignancy upon antiviral therapy? A positive answer would represent a direct demonstration of the necessary etiological role of the virus in the development of NHL, as has been shown previously for HCV-associated lymphomas. Second, if HBV plays a necessary role in lymphomagenesis, then expansion of HBV vaccination is expected to reduce the number of incident NHL cases, even though this effect might become evident only after a long time interval. Studies in those countries which have introduced universal HBV vaccination about two decades ago, like Italy, may soon provide results on this important point.
PMCID: PMC3301438  PMID: 22432084
Hepatitis B virus; occult infection; anti-HBs antibodies; anti-HBe antibodies; anti-HBc antibodies; non-Hodgkin lymphoma; hematologic malignancies; antiviral therapy; multicausal etiology; vaccination
4.  Graft selection in arthroscopic anterior cruciate ligament reconstruction 
Background
Anterior cruciate ligament (ACL) surgical reconstruction is performed with the use of an autogenic, allogenic or synthetic graft. The document issued by the Italian National Guidelines System (SNLG, Sistema Nazionale Linee Guida) at the National Institute of Health aims to guide orthopaedic surgeons in selecting the optimal graft for ACL reconstruction using an evidence-based approach.
Materials and methods
A monodisciplinary panel was formed to define a restricted number of clinical questions, develop specific search strategies and critically appraise the literature using the grading of recommendations assessment, development, and evaluation (GRADE) method. The final draft was shared by the panel and then sent to four external referees to assess its readability and clarity, its clinical relevance and the feasibility of recommendations.
Results
Autograft shows moderate superiority compared with allograft, in relation to the relevant outcomes and the quality of selected evidence, after an appropriate risk–benefit assessment. Allograft shows higher failure rate and higher risk of infection. The panel recommends use of autografts; patellar tendon should be the first choice, due to its higher stability, while use of hamstring is indicated for subjects for whom knee pain can represent a particular problem (e.g., some categories of workers).
Conclusions
Autograft shows better performance compared with allograft and no significant heterogeneity in relation to relevant outcomes. The GRADE method allowed collation of all the information needed to draw up the recommendations, and to highlight the core points for discussion.
doi:10.1007/s10195-010-0124-9
PMCID: PMC3014473  PMID: 21181226
Anterior cruciate ligament (ACL); Evidence-based guideline; Systematic review; Knee
5.  Graft selection in arthroscopic anterior cruciate ligament reconstruction 
Background
Anterior cruciate ligament (ACL) surgical reconstruction is performed with the use of an autogenic, allogenic or synthetic graft. The document issued by the Italian National Guidelines System (SNLG, Sistema Nazionale Linee Guida) at the National Institute of Health aims to guide orthopaedic surgeons in selecting the optimal graft for ACL reconstruction using an evidence-based approach.
Materials and methods
A monodisciplinary panel was formed to define a restricted number of clinical questions, develop specific search strategies and critically appraise the literature using the grading of recommendations assessment, development, and evaluation (GRADE) method. The final draft was shared by the panel and then sent to four external referees to assess its readability and clarity, its clinical relevance and the feasibility of recommendations.
Results
Autograft shows moderate superiority compared with allograft, in relation to the relevant outcomes and the quality of selected evidence, after an appropriate risk–benefit assessment. Allograft shows higher failure rate and higher risk of infection. The panel recommends use of autografts; patellar tendon should be the first choice, due to its higher stability, while use of hamstring is indicated for subjects for whom knee pain can represent a particular problem (e.g., some categories of workers).
Conclusions
Autograft shows better performance compared with allograft and no significant heterogeneity in relation to relevant outcomes. The GRADE method allowed collation of all the information needed to draw up the recommendations, and to highlight the core points for discussion.
doi:10.1007/s10195-010-0124-9
PMCID: PMC3014473  PMID: 21181226
Anterior cruciate ligament (ACL); Evidence-based guideline; Systematic review; Knee
6.  Informing women about hormone replacement therapy: the consensus conference statement 
BMC Women's Health  2009;9:14.
Background
The risks/benefits balance of hormone replacement therapy is controversial. Information can influence consumers' knowledge and behavior; research findings about hormone replacement therapy are uncertain and the messages provided by the media are of poor quality and incomplete, preventing a fully informed decision making process.
We therefore felt that an explicit, rigorous and structured assessment of the information needs on this issue was urgent and we opted for the organisation of a national consensus conference (CC) to assess the current status of the quality of information on hormone replacement therapy (HRT) and re-visit recent research findings on its risks/benefits.
Methods
We chose a structured approach based on the traditional CC method combined with a structured preparatory work supervised by an organising committee (OC) and a scientific board (SB). The OC and SB chose the members of the CC's jury and appointed three multidisciplinary working groups (MWG) which were asked to review clinical issues and different aspects of the quality of information. Before the CC, the three MWGs carried out: a literature review on the risk/benefit profile of HRT and two surveys on the quality of information on lay press and booklets targeted to women. A population survey on women's knowledge, attitude and practice was also carried out. The jury received the documents in advance, listened the presentations during the two-day meeting of the CCs, met immediately after in a closed-door meeting and prepared the final document. Participants were researchers, clinicians, journalists as well as consumers' representatives.
Results
Key messages in the CC's deliberation were: a) women need to be fully informed about the transient nature of menopausal symptoms, about HRT risks and benefits and about the availability of non-pharmacological interventions; b) HRT is not recommended to prevent menopausal symptoms; c) the term "HRT" is misleading and "post menopausal hormone therapy" should be the preferred definition.
Conclusion
This CC led to the identification of specific information drawbacks. Women are exposed to messages that are often partial, non evidence-based nor transparently developed. The structured and participative methodology of this CC allowed a multidisciplinary perspective and a substantial lay people input.
doi:10.1186/1472-6874-9-14
PMCID: PMC2698849  PMID: 19480688
7.  Hepatitis A, Italy 
Emerging Infectious Diseases  2005;11(7):1155-1156.
doi:10.3201/eid1107.041157
PMCID: PMC3371791  PMID: 16032799
HAV; Italy; Seroprevalence; Epidemiology
8.  Use of the Minimum Spanning Tree Model for Molecular Epidemiological Investigation of a Nosocomial Outbreak of Hepatitis C Virus Infection 
Journal of Clinical Microbiology  2004;42(9):4230-4236.
The minimum spanning tree (MST) model was applied to identify the history of transmission of hepatitis C virus (HCV) infection in an outbreak involving five children attending a pediatric oncology-hematology outpatient ward between 1992 and 2000. We collected blood samples from all children attending since 1992, all household contacts, and one health care worker positive for antibody to HCV (anti-HCV). HCV RNA detection was performed with these samples and with smears of routinely collected bone marrow samples. For all isolates, we performed sequence analysis and phylogenetic tree analysis of hypervariable region 1 of the E2 gene. The MST model was applied to clinical-epidemiological and molecular data. No additional cases were detected. All children, but not the health care worker, showed genotype 3a. On six occasions, all but one child had shared the medication room with another patient who later seroconverted. HCV RNA detection in bone marrow smears revealed, in some cases, a delay of several months in anti-HCV responses. Sequence analysis and phylogenetic tree analysis revealed a high identity among the isolates. The MST model applied to molecular data, together with the clinical-epidemiological data, allowed us to identify the source of the outbreak and the most probable patient-to-patient chain of transmission. The management of central venous catheters was suspected to be the probable route of transmission. In conclusion, the MST model, supported by an exhaustive clinical-epidemiological investigation, appears to be a useful tool in tracing the history of transmission in outbreaks of HCV infection.
doi:10.1128/JCM.42.9.4230-4236.2004
PMCID: PMC516344  PMID: 15365016

Results 1-8 (8)