published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Paediatrics / Master / Master of Philosophy

Ο ιός της ηπατίτιδας C (HCV) είναι η κύρια αιτία της χρόνιας ηπατίτιδας. Το γενετικό υλικό του ιού είναι ένα μονόκλωνο RNA θετικής πολικότητας μήκους 9600 νουκλεοτιδίων, που κωδικοποιεί ένα ανοιχτό πλαίσιο ανάγνωσης. Στα 5’ και 3’ άκρα της κωδικής περιοχής υπάρχουν ιδιαίτερα συντηρημένες και με έντονη δευτεροταγή δομή μη μεταφραζόμενες περιοχές. Αντίθετα με το γενικό κανόνα, η έναρξη της μετάφρασης του γονιδιώματος πραγματοποιείται με το μηχανισμό της εσωτερικής πρόσδεσης του ριβοσώματος (IRES). Η αλληλουχία RNA που απαιτείται για τη λειτουργία IRES, περιλαμβάνει όλη την 5’ μη- μεταφραζόμενη περιοχή, εκτός της περιοχής I, και τα πρώτα 75 νουκλεοτίδια της κωδική περιοχής. Μέχρι τώρα είναι γνωστό ότι μέσω της HCV IRES εξαρτώμενης μετάφρασης εκφράζονται όλες οι δομικές και μη δομικές πρωτεΐνες του ιού. Με την βοήθεια δισιστρoνικών συστημάτων μελέτης έχει δειχθεί ότι η HCV IRES εξαρτώμενη μετάφραση του γονιδιώματος του ιού καταστέλλεται από την μη-δομική πρωτεΐνη NS5Α του ιού. Σκοπός της παρούσας διπλωματικής εργασίας είναι α) να διερευνηθεί εάν η καταστολή αυτή της HCV IRES εξαρτώμενης μετάφρασης του ιού επηρεάζεται από την παρουσία των υπολοίπων μη δομικών πρωτεϊνών και β) να διερευνηθεί εάν το φαινόμενο αυτό παρατηρείται και στα υπόλοιπα μέλη της οικογένειας Flaviviridae και συγκεκριμένα στον GBV-B ιό. Τα αποτελέσματα έδειξαν ότι η HCV IRES εξαρτώμενη μετάφραση του ιού που καταστέλλεται από την HCV NS5A δε μεταβάλλεται παρουσία των υπολοίπων μη δομικών πρωτεϊνών. Σε αντίθεση η GBV-B NS5A δε φαίνεται να έχει την ικανότητα καταστολής της μετάφρασης μέσω του ομόλογου GBV-B IRES / -

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Objective. To describe the factors predictive of hepatitis A disease severity. / Design and setting. Cross-sectional study of hepatitis A cases during the recent HAV outbreak in the Montreal gay community. / Subjects. All 631 hepatitis A cases documented in the Montreal-Centre region between November 1994 and December 1996. / Outcome measures. Hepatitis A severity was operationalized as (1) the need for hospitalization and (2) a symptom severity index (vomiting, dark urine and abdominal pain). / Results. Subjects were predominantly male (84%). Homosexual behaviour was reported in 68% of cases. Prevalence of a high severity index was 8%, and 12% of cases required hospitalization. Non parenteral drug use was the only factor predictive of both hospitalization status and severity index. Our data could not establish homosexual behaviour as a determinant of disease severity. / Conclusion. Non parenteral drug users are at increased risk of suffering from a severe disease when infected with the hepatitis A virus. In addition to the current recommendation for routine vaccination of travelers and of homosexual men, drug users could benefit from immunization against this virus.

No description available.

This research explores the lived experiences of what it means to women when they receive a diagnosis of Hepatitis C (HCV). The approach to guide the conversations is hermeneutic phenomenology. Phenomenological text can have the effect of making one suddenly “see” something in a way that enriches one’s everyday understanding of women’s lived experiences (van Manen, 1997a). The intent is to share the lived experience knowledge, embedded in stories women have shared, with nurses and health care professionals. The hope is that, through these stories, health-care providers will develop insights and understanding which informs compassionate and sensitive care for women who have HCV. This study involved in-depth tape recorded conversations with nine women who have been diagnosed with HCV. The transcribed conversations were analyzed following the steps of a nursing Gadamerian based research method (Fleming, Gaidys & Robb, 2003). Analysis of the conversations occurred with the hermeneutic rule of movement from the whole to the part and back to the whole (Gadamer cited in Fleming et. al). Each of the participant’s stories are described followed by identification of shared experiences giving insight into the phenomena of receiving a diagnosis and living with HCV. Women described: shock and disbelief, a need for information on how to take care of themselves, feeling they were treated like garbage, wondering how they could tell anyone they have this illness, receiving this diagnosis during a hugely fragile time, fears of infecting others, and concerns about being a mom with HCV. They relived past traumas of how they became infected by the virus. / Graduate

Up to 170 million people are infected with Hepatitis C Virus worldwide. Chronic HCV infection is the leading cause of fibrosis, cirrhosis and liver cancer. Treatment options are currently limited to interferon based therapies alone or in conjunction with direct acting antivirals (DAA) such as viral protease inhibitors. While the implementation of DAAs has increased the effective cure rate of HCV infected individuals, treatment is far from being complete or ideal. New DAAs with unique modes of action will be necessary to compliment our current repertoire of anti-HCV therapies. Previously our lab identified three dihydropyridines (DHP) as potent HCV replication inhibitors. We investigated and characterized the anti-HCV properties of nine additional DHP compounds. We also show that DHP compounds inhibit IRES dependent translation in full-length HCV. This inhibition of two separate steps of the viral life cycle may be a unique feature of DHPs making them superior DAAs. Among these DHPs, efonidipine emerged as the most effective HCV replication and translation inhibitor with the least toxicity. Using a real-time evolution strategy, we developed and characterized a mutant virus which was resistant to DHPs and several other drugs which modify intracellular calcium stores. Our results further the understanding of DHP inhibition of HCV providing a solid basis for investigation of more structurally related compounds as potent inhibitors of HCV.