O curso da infecção pelo HCV é determinado pela competência da resposta imune inata e adaptativa do hospedeiro. A IL-18 é uma citocina pró-inflamatória importante em ambas as respostas imunes e atua sinergicamente com IL-12 induzindo a expressão de IFN-y pelas células T e natural killer. O IFN-? por sua vez possui um papel chave no combate de infecções intracelulares, induzindo um estado antiviral nas células infectadas. O balanço de IL-18 é controlado pela IL18BP, uma citocina importante que atua como um antagonista natural. Estudos mostram que indivíduos cronicamente infectados pelo HCV possuem elevados níveis séricos de IL-18 e IL18BP. Sendo assim, o presente estudo teve como objetivos: 1) determinar o genótipo de polimorfismos de base única (SNPs) localizados nos genes da IL-18 (-607 C > A e -137 G > C), IL18BP (rs2298455 e rs1541304) e IFN-y +874 T > A; 2) quantificar a expressão de seus respectivos mRNAs; e por fim, 3) dosagem dos níveis séricos das respectivas citocinas. Para isto, foram selecionados 51 indivíduos com resolução espontânea e 50 com infecção crônica pelo HCV genótipo 1 que submetidos a técnica de PCR em tempo real para a genotipagem dos polimorfismosIL-18 (-607 C > A e -137 G > C), IL18BP (rs2298455 e rs1541304) e IFN-? +874 T > A; posteriormente foi feita a análise da expressão gênica destes mRNA utilizando como controle endógeno o GAPDH e a dosagem das citocinas foi determinada peta técnica de ELISA. A distribuição dos genótipos nos polimorfismos nos genes IL-18 e IL18BP foram semelhantes nos dois grupos de estudo. No entanto, para o polimorfismo no gene do IFN-?, observamos frequência maior do genótipo TA no grupo de infecção crônica, enquanto que no grupo de resolução espontânea foi mais frequente o genótipo AA (p=0.006). Em contrapartida a expressão gênica nos permitiu observar que nos indivíduos com infecção crônica o mRNA de IL-18 (p < 0.001) e IL18BP (p < 0.001) estavam com uma maior expressão quando comparados com os indivíduos com resolução espontânea, e que isto refletia nas dosagens séricas, onde os indivíduos cronicamente infectados pelo HCV apresentavam altos níveis séricos de IL-18 (p < 0.001) e IL18BP (p=0.012) do que os indivíduos com resolução espontânea. O alelo G foi associado com uma maior produção de IL-18(p=0.02) nos indivíduos com resolução espontânea. Em relação à expressão gênica do mRNA do IFN-y não foi possível observar nenhuma diferença entre os grupos estudados (p=0.322) e a dosagem sérica não foi detectada em ambos os grupos. Os resultados sugerem que apesar do sistema imune ser estimulado durante a infecção pelo HCV, a persistência viral leva a um estado de anergia onde a produção de IFN- y parece ser escassa para uma resposta imune eficaz, sendo que os meios nos quais modulam a expressão gênica do IFN- y ainda parecem obscuros, no entanto já foram descritos mecanismos pós-transcricionais que tem como alvo a região 3\'UTR do mRNA do IFN- y podendo interferir na sua expressão / The course of HCV infection is determined by the competence of the innate and adaptive immune response of the host. IL-18 is an important proinflammatory cytokine in both immune responses and acts synergistically with IL-12 induces the expression of IFN-y by T and natural killer cells. The IFN-yturn plays a key role in fighting intracellular infections, inducing an antiviral state in infected cells. The balance of IL-18 is controlled by IL18BP, an important cytokine that acts as a natural antagonist. Studies show that individuals chronically infected with HCV have elevated serum levels of IL-18 and IL18BP. Therefore, this study aimed to: 1) determine the genotype of single nucleotide polymorphisms (SNPs) located in genes of IL-18 (-607 C > A and -137 G > C), IL18BP (rs2298455 and rs1541304) and IFN-y +874 T > A; 2) to quantify the expression of their respective mRNAs; and finally 3) the determination of serum levels of the respective cytokines. Fifty-one individuals with spontaneous clearance and 50 were selected with chronic HCV genotype 1 infection who underwent the technique of real-time PCR for genotyping polymorphisms of IL-18 (-607 C > A and -137 G > C), IL18BP (rs2298455 and rs1541304) and IFN-y +874 T > A; later analysis of gene expression of these mRNA was performed using GAPDH as endogenous control and used the ELISA method for the serum of these cytokines. The distribution of genotypes in the IL-18 polymorphisms and IL18BP genes were similar in both study groups. However, for the polymorphism in the IFN-y gene, the genotype most frequently observed in the group of TA chronic infection, whereas in the group of spontaneous clearance AA was more frequent (p = 0.006) genotype. In contrast to gene expression allowed us to observe that in individuals with chronic infection the mRNA of IL-18 (p < 0.001) and IL18BP (p < 0.001) had a higher expression when compared with individuals with spontaneous resolution, and that this reflected in serum using the ELISA technique, where individuals chronically infected with HCV had higher serum levels of IL-18 (p < 0.001) and IL18BP (p = 0.012) than subjects with spontaneous clearance. The G allele was associated with increased production of IL-18 (P = 0.02)in spontaneous clearance group. Regarding the gene expression of IFN-y mRNA was not observed any difference between the groups (p = 0.322) and the serum was not detected in both groups. The results suggest that although the immune system is stimulated during HCV infection leads to viral persistence of anergy a state where the production of IFN-? appears to be scarce for an effective immune response, and the means in which modulate the expression the IFN-y gene still seem unclear, however have been described post-transcriptional mechanisms which target the 3\'UTR of the mRNA of IFN-y may interfere with its expression

Σκοπός: Η θυμεκτομή αποτελεί κοινώς αποδεκτή θεραπεία της μυασθένειας με τις διάφορες προσπελάσεις να αναφέρονται ως ανάλογης αξίας για την επίτευξη ύφεσης της νόσου. Έχοντας πλέον την μόνιμη σταθερή ύφεση ως καθαρή και μετρήσιμη νευρολογική έκβαση των μυασθενικών ασθενών μετά θυμεκτομή και γνωρίζοντας ότι η ύφεση της νόσου αποτελεί χρόνο-εξαρτώμενο γεγονός, πραγματοποιήσαμε μια αναδρομική μελέτη των ασθενών με μυασθένεια που αντιμετωπίστηκαν χειρουργικά με σκοπό τον πιο αξιόπιστο καθορισμό του ρόλου των μεγίστων θυμικών εκτομών και την ταυτοποίηση προγνωστικών παραγόντων για ύφεση της νόσου μετά θυμεκτομή. Υλικό και μέθοδος. Η μελέτη περιλαμβάνει 78 ασθενείς που υποβλήθηκαν σε τροποποιημένη μέγιστη θυμεκτομή από το 1990 έως το 2007. Οι ενδείξεις θυμεκτομής περιελάμβαναν: οφθαλμική μυασθένεια ανθιστάμενη στη φαρμακευτική αγωγή, γενικευμένη μυασθένεια και μυασθένεια με θύμωμα. Τα στοιχεία που συλλέχθηκαν αφορούσαν τη βαρύτητα της νόσου (τροποποιημένη Osserman ταξινόμηση), την προεγχειρητική φαρμακευτική αγωγή, την ηλικία έναρξης της νόσου (≤ 40/ > 40 έτη), το χρονικό διάστημα που μεσολάβησε από τη διάγνωση στη θυμεκτομή (≤ 12/ > 12 μήνες), το φύλο, την ιστολογία του θύμου αδένα, τη θνητότητα και τις επιπλοκές. Στους ασθενείς με θύμωμα περαιτέρω στοιχεία που ελήφθησαν υπόψη αφορούσαν τον ιστολογικό τύπο του θυμώματος κατά την Παγκόσμια Οργάνωση Υγείας και το στάδιο του όγκου κατά Masaoka. Η εκτίμηση της νευρολογικής έκβασης στο τέλος του μετεγχειρητικού follow up έγινε βάση της νέας ταξινόμησης του Αμερικανικού Ιδρύματος για τη Βαρεία Μυασθένεια με την πλήρη σταθερή ύφεση να λαμβάνεται υπόψη για τον καθορισμό της επάρκειας της διενεργηθείσας εκτομής και για τη σύγκριση των αποτελεσμάτων μας με αυτά προηγουμένων μελετών. Η στατιστική ανάλυση των αποτελεσμάτων έγινε με το SPSS 17 και αφορούσε δύο ομάδες ασθενών ανάλογα με την παρουσία ή μη θυμώματος. Η μέθοδος Kaplan-Meier χρησιμοποιήθηκε για την εκτίμηση της επίπτωσης των υπό εκτίμηση προγνωστικών παραγόντων στην επίτευξη της πλήρους ύφεσης ενώ η Cox Regression ανάλυση αποτέλεσε το μοντέλο για την ανάλυση της ταυτόχρονης επίδρασης των υπό μελέτη παραμέτρων στην επίτευξη πλήρους σταθερής ύφεσης. Τιμές του p < 0.05 θεωρήθηκαν στατιστικά σημαντικές. Αποτελέσματα: 51 ασθενείς είχαν μυασθένεια χωρίς θύμωμα και 27 ασθενείς παρανεοπλασματική μυασθένεια. Δεν υπήρχαν στατιστικά σημαντικές διαφορές στα προεγχειρητικά κλινικά χαρακτηριστικά των ασθενών πλην της αναμενομένης εμφάνισης της νόσου σε απώτερη ηλικία στους ασθενείς με θύμωμα. Η θνητότητα ήταν μηδενική ενώ η χειρουργική νοσηρότητα, ανάλογη προηγουμένων μελετών θυμεκτομής με διαφορετικού τύπου προσπέλασεις, ανήλθε στο 7,7% και ήταν ως επί το πλείστον ήσσονος σημασίας. Το ποσοστό μετεγχειρητικής μυασθενικής κρίσης ήταν μόλις 3,8%. Οι ασθενείς με μυασθένεια και θύμωμα βίωσαν όψιμη νευρολογική έκβαση ανάλογη αυτής των ασθενών χωρίς θύμωμα (πιθανότητα ύφεσης 74,5% vs 85,7%, p= 0.632). Η μη χρήση στεροειδών στην προεγχειρητική φαρμακευτική αγωγή, ως έμμεσος δείκτης της βαρύτητας της νόσου, σχετίστηκε με στατιστικά καλύτερη πιθανότητα για πλήρη ύφεση των συμπτωμάτων τόσο στους ασθενείς με θύμωμα (95% CI 2.687-339.182, p= 0.006) όσο και σε αυτούς χωρίς θύμωμα (CI 95% 1.607-19.183, P= 0.007) στην πολυπαραγοντική ανάλυση. Αξιόλογη διαφορά, αν και στατιστικά μη σημαντική, για τη έκβαση της νόσου είχε η πρώιμη σε σχέση με την απώτερη χειρουργική αντιμετώπιση των ασθενών. Στη σύγκριση των 27 ασθενών με μυασθένεια και θύμωμα με 12 επιπλέον ασθενείς που υποβλήθηκαν στην ίδια επέμβαση για θύμωμα άνευ μυασθένειας η παρουσία των συμπτωμάτων μυϊκής αδυναμίας συνδυάστηκε με στατιστικά σημαντική βελτίωση της επιβίωσης των ασθενών (100% vs 38,8% στη 10ετία, p< 0.001). Στους ασθενείς με μυασθένεια χωρίς θύμωμα και απώτερης ηλικιακά έναρξης της νόσου το ποσοστό σημαντικής βελτίωσης των μυασθενικών συμπτωμάτων, εξαιρουμένης της πλήρους ύφεσης, ήταν 70%. Στους ασθενείς με μυασθένεια και θύμωμα η ιστολογική ταυτοποίηση των θυμωμάτων κατά την Παγκόσμια Οργάνωση Υγείας προέκυψε στατιστικά σημαντική τόσο στην μονοπαραγοντική όσο και στην πολυπαραγοντική ανάλυση με τα θυμώματα τύπου Β2, Α και Β3 να επιτυγχάνουν από πολύ καλή έως άριστη πιθανότητα πλήρους ύφεσης και τα θυμώματα τύπου ΑΒ, Β1 και C να έχουν απογοητευτική έκβαση όσον αφορά την ίαση. Συμπεράσματα: Η παρούσα μελέτη δείχνει ότι η τροποποιημένη μεγίστη θυμεκτομή είναι ασφαλής και σχετίζεται με υψηλή πιθανότητα για ίαση των μυασθενικών ασθενών με και χωρίς θύμωμα. Οι ασθενείς πρέπει να αντιμετωπίζονται χειρουργικά πρώιμα μετά τη διάγνωση με κυριότερο προγνωστικό παράγοντα για το απώτερο νευρολογικό αποτέλεσμα την προεγχειρητική βαρύτητα της νόσου. Η ασφαλής και πιο αξιόπιστη εκτίμηση της τελευταίας απαιτεί πιο αντικειμενικά κριτήρια όπως αυτά που θεσπίστηκαν από το Αμερικανικό Ίδρυμα για τη Βαρεία Μυασθένεια. Η ενσωμάτωση σε αυτά τα κριτήρια μοριακών παραμέτρων που φαίνεται να επηρεάζουν την πρόγνωση της νόσου, ενδεχόμενα να βελτιώσουν την αξιοπιστία της κλινικής σταδιοποίησης του MGFA και να αναδείξουν υποομάδες ασθενών με διαφορετική νευρολογική πρόγνωση μετά από θυμεκτομή. Επίσης η πρώιμη διάγνωση των θυμωμάτων εξαιτίας των συνυπαρχόντων μυασθενικών συμπτωμάτων μπορεί να οδηγήσει σε καλύτερη επιβίωση τους συγκεκριμένους ασθενείς. Τέλος η νευρολογική έκβαση των ασθενών με θυμωματώδη μυασθένεια σχετίζεται με τον ιστολογικό τύπο των θυμωμάτων, αλλά όχι αναγκαία και με την κακοήθη συμπεριφορά τους. / Objective: Thymectomy represents a widely accepted treatment for myasthenia gravis with different surgical approaches reported as comparably efficient in achieving disease’s remission. With the complete stable remission being currently accepted as a clear measurable outcome of patients with myasthenia undergoing surgical treatment and the knowledge that disease’s remission should be evaluated as a time dependent event we proceeded to a retrospective analysis of our experience on the surgical management of myasthenic patients. The objective was to access the effect of maximal resection on the neurological outcome and identify predictors of disease remission. Materials and methods: The study group consisted of 78 patients who underwent modified maximal thymectomy for myasthenia from 1990 to 2007. Indications for thymectomy included: ocular myasthenia refractory to medical treatment, generalized myasthenia and thymomatous myasthenia. The data collected included preoperative disease’s severity (modified Osserman classification), preoperative medical treatment, age at onset of the disease (≤ 40/ > 40 years), time elapsed between diagnosis and thymectomy (≤ 12/ > 12 months), gender, thymus gland histology, mortality and morbidity. In thymoma patients further analysis was carried out according the World Health Organization histological classification and the Masaoka stage of the tumors. The evaluation of the neurological outcome at the end of follow up was performed according the Myasthenia Gravis Foundation of America classification. Both the effectiveness of the resection performed and the comparison of our results with those of previous studies were done using the complete stable remission as the end point of the study. The statistical analysis of the results was carried out using the SPSS 17. Kaplan-Meier life table analysis was performed and the log rank test was used to evaluate the effect of the variables examined on the distribution of disease’s remission over time. The Cox proportional hazard model was also applied to verify the concurrent effect of the evaluated factors on the achievement of complete stable remission. P values < 0.05 were considered statistically significant. Results: 51 patients suffered of non thymomatous myasthenia while 27 patients had myasthenia with thymoma. The two groups were comparable in refer to the clinical features of the patients apart the more advanced age at the time of the diagnosis for thymoma patients. There was no perioperative mortality, while the surgical morbidity was comparable to the one reported in other series of patients with different surgical approaches and was 7.7%. The rate of postoperative myasthenic crisis was only 3.8%. Thymoma and non thymoma patients experienced comparable complete stable remission prediction (74.5% vs 85.7% at 15 years, p= 0.632). The absence of steroids in the preoperative medical regimen was statistically associated with the achievement of complete stable remission in both thymoma (95% CI 2.687-339.182, p= 0.006) and non thymoma patients (CI 95% 1.607-19.183, P= 0.007) in multivariate analysis. There was an important difference, although not statistically significant, for the neurological outcome between early and late surgical treatment. When the 27 patients with myasthenia and thymoma were compared with other 12 patients similarly operated for thymoma without symptoms and signs of muscular weakness we found that the presence of myasthenia was statistically associated with improved survival (100% vs 38.8% at 10 years, p< 0.001). Non thymoma patients presenting with late onset myasthenia, experienced high improvement (complete stable remission excluded) rate reaching up to 70% at the end of follow up. Among patients with thymomatous myasthenia gravis the World Health Organization histological classification was statistically associated with the late neurological outcome. Thymoma types A, B3 and B2 reached a high to excellent prediction of disease’s remission while types AB, B2 and C had a disappointing neurological outcome. Conclusons: The present study demonstrated that the modified maximal thymectomy is a safe procedure, associated with an excellent neurological outcome in both thymomatous and non thymomatous myasthenia. The patients should be operated early after the diagnosis is made with the disease’s severity being the prime determinant of the possibility to achieve complete remission of myasthenic symptoms. The evaluation of disease’s severity requires objective criteria like the ones proposed by the Myasthenia Gravis Foundation of America. The inclusion in these criteria of molecular markers related to myasthenia’s prognosis and its neurological outcome after thymectomy may further enhance its validity and may allow the identification of subgroups of patients with different disease prognosis after thymectomy. The presence of muscular weakness may lead to early diagnosis and surgical treatment of thymomas with improved survival. Finally the neurologic outcome in thymoma patients after thymectomy may be statistically associated with the World Health Organization classification subtypes but not necessarily with the aggressiveness of these tumors.

The additional tax ("penalties") imposable in terms of section 76(1) of the Income Tax Act (No 58 of 1962) when a taxpayer is in default, can be very harsh (up to 200% of the tax properly chargeable). The Commissioner may, in terms of section 76(2)(a), remit any penalty imposed, as he sees fit. However, when there was intent on the part of the taxpayer to evade the payment of tax, the Commissioner may not remit any portion of the 200% penalty imposable, unless he is of the opinion that "extenuating circumstances" exist. This dissertation examines the meaning of "extenuating circumstances", as interpreted by the judiciary, and lists the factors and defences that a taxpayer may plead to justify a remission of penalties, both in the case of an intention by the taxpayer to evade tax and in cases where the taxpayer is merely in default of section 76(1). / Accounting / MCOM (Accounting)

Myasthenia Gravis (MG) is an autoimmune disease affecting neuromuscular transmission, in which the thymus is considered pathogenic organ. Earlier ideas suggesting that MG is only the receptors disease have been proven wrong. There are immunopathological changes in both target structures [specific receptors for acetylcholine (AChR] muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein 4 (Lrp4)], the thymus, as well as in peripheral lymphoid organs. Initial findings of the humoral immunity defect with the decisive role of the pathologic autoantibodies, were corrected with findings of the immune dysregulation at the level of T lymphocytes. According to today's knowledge, the development and maintenance of MG involves almost all cell types of immune function in the autoimmune inflammation: helper CD4+ T lymphocytes, cytotoxic CD8+ T lymphocytes, regulatory CD4+CD25+ T lymphocytes, Th17 lymphocytes, B lymphocytes and plasma cells. Thymus plays a dominant immunopathogenetic role in younger patients with MG, while extrathymic mechanisms are applied in older patients. As a result of that, the thymectomy (TE) is generally accepted as part of treatment for MG. However, there is still no data verified by a prospective controlled study, which would demonstrate a useful result of this treatment...

O curso da infecção pelo HCV é determinado pela competência da resposta imune inata e adaptativa do hospedeiro. A IL-18 é uma citocina pró-inflamatória importante em ambas as respostas imunes e atua sinergicamente com IL-12 induzindo a expressão de IFN-y pelas células T e natural killer. O IFN-? por sua vez possui um papel chave no combate de infecções intracelulares, induzindo um estado antiviral nas células infectadas. O balanço de IL-18 é controlado pela IL18BP, uma citocina importante que atua como um antagonista natural. Estudos mostram que indivíduos cronicamente infectados pelo HCV possuem elevados níveis séricos de IL-18 e IL18BP. Sendo assim, o presente estudo teve como objetivos: 1) determinar o genótipo de polimorfismos de base única (SNPs) localizados nos genes da IL-18 (-607 C > A e -137 G > C), IL18BP (rs2298455 e rs1541304) e IFN-y +874 T > A; 2) quantificar a expressão de seus respectivos mRNAs; e por fim, 3) dosagem dos níveis séricos das respectivas citocinas. Para isto, foram selecionados 51 indivíduos com resolução espontânea e 50 com infecção crônica pelo HCV genótipo 1 que submetidos a técnica de PCR em tempo real para a genotipagem dos polimorfismosIL-18 (-607 C > A e -137 G > C), IL18BP (rs2298455 e rs1541304) e IFN-? +874 T > A; posteriormente foi feita a análise da expressão gênica destes mRNA utilizando como controle endógeno o GAPDH e a dosagem das citocinas foi determinada peta técnica de ELISA. A distribuição dos genótipos nos polimorfismos nos genes IL-18 e IL18BP foram semelhantes nos dois grupos de estudo. No entanto, para o polimorfismo no gene do IFN-?, observamos frequência maior do genótipo TA no grupo de infecção crônica, enquanto que no grupo de resolução espontânea foi mais frequente o genótipo AA (p=0.006). Em contrapartida a expressão gênica nos permitiu observar que nos indivíduos com infecção crônica o mRNA de IL-18 (p < 0.001) e IL18BP (p < 0.001) estavam com uma maior expressão quando comparados com os indivíduos com resolução espontânea, e que isto refletia nas dosagens séricas, onde os indivíduos cronicamente infectados pelo HCV apresentavam altos níveis séricos de IL-18 (p < 0.001) e IL18BP (p=0.012) do que os indivíduos com resolução espontânea. O alelo G foi associado com uma maior produção de IL-18(p=0.02) nos indivíduos com resolução espontânea. Em relação à expressão gênica do mRNA do IFN-y não foi possível observar nenhuma diferença entre os grupos estudados (p=0.322) e a dosagem sérica não foi detectada em ambos os grupos. Os resultados sugerem que apesar do sistema imune ser estimulado durante a infecção pelo HCV, a persistência viral leva a um estado de anergia onde a produção de IFN- y parece ser escassa para uma resposta imune eficaz, sendo que os meios nos quais modulam a expressão gênica do IFN- y ainda parecem obscuros, no entanto já foram descritos mecanismos pós-transcricionais que tem como alvo a região 3\'UTR do mRNA do IFN- y podendo interferir na sua expressão / The course of HCV infection is determined by the competence of the innate and adaptive immune response of the host. IL-18 is an important proinflammatory cytokine in both immune responses and acts synergistically with IL-12 induces the expression of IFN-y by T and natural killer cells. The IFN-yturn plays a key role in fighting intracellular infections, inducing an antiviral state in infected cells. The balance of IL-18 is controlled by IL18BP, an important cytokine that acts as a natural antagonist. Studies show that individuals chronically infected with HCV have elevated serum levels of IL-18 and IL18BP. Therefore, this study aimed to: 1) determine the genotype of single nucleotide polymorphisms (SNPs) located in genes of IL-18 (-607 C > A and -137 G > C), IL18BP (rs2298455 and rs1541304) and IFN-y +874 T > A; 2) to quantify the expression of their respective mRNAs; and finally 3) the determination of serum levels of the respective cytokines. Fifty-one individuals with spontaneous clearance and 50 were selected with chronic HCV genotype 1 infection who underwent the technique of real-time PCR for genotyping polymorphisms of IL-18 (-607 C > A and -137 G > C), IL18BP (rs2298455 and rs1541304) and IFN-y +874 T > A; later analysis of gene expression of these mRNA was performed using GAPDH as endogenous control and used the ELISA method for the serum of these cytokines. The distribution of genotypes in the IL-18 polymorphisms and IL18BP genes were similar in both study groups. However, for the polymorphism in the IFN-y gene, the genotype most frequently observed in the group of TA chronic infection, whereas in the group of spontaneous clearance AA was more frequent (p = 0.006) genotype. In contrast to gene expression allowed us to observe that in individuals with chronic infection the mRNA of IL-18 (p < 0.001) and IL18BP (p < 0.001) had a higher expression when compared with individuals with spontaneous resolution, and that this reflected in serum using the ELISA technique, where individuals chronically infected with HCV had higher serum levels of IL-18 (p < 0.001) and IL18BP (p = 0.012) than subjects with spontaneous clearance. The G allele was associated with increased production of IL-18 (P = 0.02)in spontaneous clearance group. Regarding the gene expression of IFN-y mRNA was not observed any difference between the groups (p = 0.322) and the serum was not detected in both groups. The results suggest that although the immune system is stimulated during HCV infection leads to viral persistence of anergy a state where the production of IFN-? appears to be scarce for an effective immune response, and the means in which modulate the expression the IFN-y gene still seem unclear, however have been described post-transcriptional mechanisms which target the 3\'UTR of the mRNA of IFN-y may interfere with its expression

A leucemia linfóide aguda nos adultos apresenta prognóstico reservado. Os objetivos deste estudo são descrição e análise de parâmetros clínicos, laboratoriais e fatores prognósticos em 102 pacientes tratados com diferentes protocolos de quimioterapia no período de 1990 a 2005, no Serviço de Hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Em estudo de coorte retrospectivo, com exclusão de LLA subtipo L3 (FAB) ou B-IV (EGIL), foram analisadas a taxa de remissão completa (RC), sobrevida global (SG) e sobrevida livre de doença (SLD) para a população geral e para os dois principais protocolos de tratamento. A análise estatística foi feita pelo programa SPSS 10.0. Associação entre variáveis, fatores prognósticos e resposta foram observados através do teste ?2 de Person. Curvas de SG e SLD foram construídas pelo método de Kaplan-Meier e as diferenças analisadas pelo teste de log-rank. A idade média foi de 30,6 anos (12 a 82 anos) e predominou o sexo masculino (55,9%). Ao diagnóstico, os achados clínicos foram: fadiga (58,2%), esplenomegalia (59,7%), hepatomegalia (54,6%), linfadenopatia (52,6), febre (38,8%), dor óssea(28,6%), sangramento (27,5%) e cefaléia (15,3%). Envolvimento do sistema nervoso central (SNC) foi detectado em 11 (11,8%) pacientes, enquanto envolvimento testicular acometeu um paciente. O valor médio de hemoglobina, leucócitos e plaquetas foram 8,5g/dl, 84.341/mm3 e 76.275/mm3, respectivamente. 98,7% dos pacientes apresentaram linfoblastos no sangue periférico. A classificação FAB foi igualmente observada entre os tipos L1 e L2. As LLA B e T foram observadas em 69,7% e 30,2%, respectivamente. O cariótipo foi realizado em 40 pacientes, e t (9;22) foi identificada em 20% (8/40) dos casos. Os pacientes foram tratados com quatro diferentes protocolos: BFM 86 modificado (BFM 86M) em 47,15% (48/102), Linker et al em 39,2% (40/102), Lister et al em 5,9% (6/102) e CHOP em 7,8% (8/102). Na análise para a população geral, na fase de indução, 70,6% (65/92) dos pacientes entraram em RC. Idade inferior a 18 anos e ausência de infiltração de SNC foram fatores preditores positivos de resposta em análise multivariada (p=0,03). Com mediana de seguimento de 49 meses, observamos taxa de 30,5% e 27% para SG e SLD em 4 anos. Ausência de sangramento e hepatomegalia, ao diagnóstico, e idade < 35 anos estiveram associados à maior SG através de análise multivariada (p=0,01). Os dois protocolos com maior número de pacientes, apresentaram distribuição semelhante de parâmetros clínicos e laboratoriais, a exceção da variável FAB. RC foi obtida em 76,7% e 63,9% dos pacientes tratados respectivamente com os protocolos BFM 86M e Linker (p=0,21). A SG foi de 49,5% com o BFM 86M em 4 anos Vs 16% com o protocolo Linker (p=0,004). Observou-se que o protocolo BFM86M teve melhor SG para pacientes com idade <35 anos (p=0,01), sem sangramento e hepatomegalia ao diagnóstico (p=0,03 e p=0,01) e sem leucocitose (B <30.000mm3 e T <100.000mm) (p=0,04); enquanto que pacientes com LLA T tratados com o protocolo Linker apresentaram SG inferior (p=0,05). A diferença de SLD entre os dois protocolos não foi significativa (p=0,58), entretanto na faixa etária entre 21-35 anos, o protocolo BFM se mostrou superior (p=0,03). Verificamos que o BFM 86M é superior ao Linker et al, sendo um bom protocolo para tratamento de LLA em pacientes adolescentes e adultos jovens sem fatores de risco. / Acute lymphoblastic leukemia in adults has a poor outcome. The aim of this study is to describe and evaluate clinical, laboratory and prognostic factors in 102 patients reated with different protocols of chemotherapy from 1990 to 2005. Adult ALLsubtype L3 (FAB) or B-IV (EGIL) was excluded. We evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS) rates for the whole population and for the two principal treatment protocols. This retrospective cohort was done in hematology department of the FMUSP. Statistical analysis was done by SPSS 10.0. The association of features and prognosis was assessed by Person\'s chi-square. OS and DFS curves were constructed by Kaplan-Meier method and the differences were calculated by the log-rank test. Mean age was 30,6 (12 to 82) years and 55,9% was male. Clinical findings, at diagnosis, were fatigue (58,2%), splenomegaly (59,7%), hepatomegaly (54,6%), ymphadenopathy (52,6%), fever (38,8%), bone pain (28,6%), bleeding (27,5%) and headache (15,3%). Involvement of central nervous system (CNS) was detected in 11 (11,8%) patients and testicular involvement was observed in one patient. Mean blood values were 8,5g/dl, 84.341/mm3 and 76.275/mm3 for hemoglobin, leucocytes and platelets respectively. 98,7% of the patients presented with lymphoblasts in peripheral blood. FAB classification was equally observed between L1 and L2. B and T ALL was noted in 69,7% and 30,2% respectively. Karyotype analysis was performed in 40 cases, where Philadelphia chromosome (ph) was identified in 20% (8/40) of them. Patients were treated with four different protocols: BFM 86 modified (BFM 86M) in 47,1% (48/102), Linker et al in 39,2% (40/102), Lister et al in 5,9% (6/102) and CHOP in 7,8% (8/102) of the patients. In the judgment for the entire population, in induction treatment, 70,6% (65/92) of the patients had CR. Age below 18 years and no infiltration in CNS were positive factors for CR in multivariate analyses (p=0,03). In a median follow up of 49 months, we have observed a 4 years OS and DFS of 30,5% and 27% respectively. No bleeding and hepatomegaly, at diagnosis, and age less than 35 years were factors associated a better OS in multivariate analyses (p=0, 01). Protocols with highest number of patients (BFM and Linker) showed the same distribution of clinical and laboratory factors; exception FAB classification. CR were seen in 76,7% and 63,9% of the patients treated with BFM 86M and Linker respectively. (p=0,21). OS was 49,5% with BFM protocol in 4 years Vs 16% with Linker (p=0,004). We observed a better OS for patients with age below 35 years (p=0,01), no bleeding and no hepatomegaly at diagnosis (p=0,03 ; p=0,01) and no leucocytosis ( B < 30000/mm3 and T < 100000/mm3) treated with BFM 86M; however ALL - T treated with Linker protocols had inferior OS (p=0,05). DFS between protocols wasn\'t significant (p=0,58), but with age between 21 and 35 years BFM was better (p=0,03). We conclude that BFM 86M is superior than Linker et al and it is a good treatment for childhood / young adults without risk factors

Submitted by Fernanda Terra de Castro Collicchio (fernanda@terraevecci.com.br) on 2018-11-16T12:59:04Z No. of bitstreams: 1 Dissertação Depósito.pdf: 817890 bytes, checksum: 2733b8cc35486ed3aaf9472cb77c6d3a (MD5) / Approved for entry into archive by Thais Oliveira (thais.oliveira@fgv.br) on 2018-11-21T18:05:36Z (GMT) No. of bitstreams: 1 Dissertação Depósito.pdf: 817890 bytes, checksum: 2733b8cc35486ed3aaf9472cb77c6d3a (MD5) / Approved for entry into archive by Isabele Garcia (isabele.garcia@fgv.br) on 2018-11-22T12:13:34Z (GMT) No. of bitstreams: 1 Dissertação Depósito.pdf: 817890 bytes, checksum: 2733b8cc35486ed3aaf9472cb77c6d3a (MD5) / Made available in DSpace on 2018-11-22T12:13:34Z (GMT). No. of bitstreams: 1 Dissertação Depósito.pdf: 817890 bytes, checksum: 2733b8cc35486ed3aaf9472cb77c6d3a (MD5) Previous issue date: 2018-10-05 / Analisa a remissão proposta na Lei Complementar nº 160 de 07 de agosto de 2017, como solução para extinção dos créditos tributários decorrentes da concessão de incentivos e benefícios fiscais de ICMS sem a aprovação do CONFAZ, concedidos no âmbito da Guerra Fiscal existente entre os Estados, até a publicação da referida Lei Complementar. Tendo como objetivo confirmar o alcance da remissão, proposição, considerando a natureza da remissão, subdividindo os benefícios e incentivos fiscais em três categorias: a) benefícios e incentivos fiscais que não são devidos, porque não foram declarados inconstitucionais, seja por não serem objeto de discussão judicial ou porque não são conhecidos (aqueles concedidos por atos infra-legais); b) benefícios e incentivos fiscais que estão sub judice, mas ainda não foram declarados inconstitucionais e c) benefícios e incentivos fiscais que já foram declarados inconstitucionais pelo STF. Responde quanto a eficácia de seu alcance ainda que sob condição e conclui que a remissão disposta na Lei Complementar nº160/2017 não é de eficácia plena imediata, mas está posta e pode ser alcançada por todos que usufruíram os benefícios e incentivos fiscais concedidos em desacordo com o disposto na alínea “g” do inciso XII do § 2o do art. 155 da Constituição Federal e por esta razão traz segurança jurídica. / This paper analyses the revision of Complementary Law no. 160 of August 7, 2017, as a solution to the issue originated with the granting of the tax credits originated from the concession of incentives and tax benefits of ICMS (state VAT) without the approval of CONFAZ, until the publication of the Complementary Law itself. Aiming at confirming the reaching of the remission, proposition, considering the nature of the remission, subdividing the benefits and incentives into three categories: a) tax benefits and incentives which are not due, because they have not been declared unconstitutional, either because they are not subject to legal proceedings or because they are not known yet (those granted by infra-legal acts); b) tax benefits and incentives which are under examination (sub judice), but have not yet been declared unconstitutional and c) benefits and tax incentives that have already been declared unconstitutional by the STF (Superior Federal Court). Responding to the efficiency of its scope even though under condition and, it concludes that the remission set forth in the Supplementary Law no. 160/2017, is not immediately effective, but it is posted and can be reached by all who have benefited from the benefits and tax incentives granted in disagreement with the provisions of item "g" of item XII of paragraph 2 of art. 155 of the Federal Constitution and for that reason brings legal certainty.

Antenatal depression (depression under graviditeten) drabbar 10–20% av gravida och innebär risker för både den gravida och barnet. Forskning visar att internetbaserad kognitiv beteendeterapi (IKBT) tycks vara effektivt jämfört med sedvanlig mödravård. Uppsatsen var en sambands- och prediktionsstudie som genomfördes inom den randomiserade DANA-studien för IKBT vid antenatal depression. En inomgruppsdesign med upprepade mätningar tillämpades där 40 kvinnor med antenatal depression deltog. Syftet var att undersöka (a) patientnöjdhet med bedömningssamtalet i relation till behandlingsföljsamhet, avhopp och minskning av depressionssymtom under IKBTbehandlingen, samt (b) jämföra förändring i depressionssymtom mot två tidigare studier. Resultatet visade att en högre patientnöjdhet med bedömningssamtalet signifikant predicerade en mindre minskning av depressionssymtom mellan screening och förmätning. Inga signifikanta samband hittades mellan patientnöjdhet med bedömningssamtalet och behandlingsföljsamhet eller avhopp. Slutsatser bör dras med stor försiktighet utifrån metodologiska begränsningar. Resultatet visade även att depressionssymtom jämfört med förmätningen signifikant minskade från andra veckomätningen i behandlingen till och med eftermätningen vecka tio. Detta bekräftade tidigare studiers resultat. Framtida randomiserade prövningar kan ge underlag till utvecklingen av bedömningssamtal och IKBT mot antenatal depression. / Antenatal depression (depression during pregnancy) affects 10–20% of pregnant women and involves risks for both the pregnant woman and the child. Research shows that internet-based cognitive behavioral therapy (ICBT) seems to be effective compared to conventional maternity care. The thesis was a correlational predictive study that was conducted within the randomized DANAstudy for ICBT during antenatal depression. An in-group design with repeated measurements was applied in which 40 women with antenatal depression participated. The purpose was to examine (a) patient-satisfaction with the assessment interview in relation to adherence, dropouts and remissionof depressive symptoms during ICBT treatment, and (b) compare changes in depressive symptoms against two previous studies. The result showed that a higher patient-satisfaction with the assessment interview significantly predicted a lesser reduction of depressive symptoms between screening and pre-measurement. No significant correlations were found between patient-satisfaction with the assessment interview and treatment adherence or dropouts. Conclusions should be drawn with great caution based on methodological limitations. The result also showed that depressive symptoms compared with the pre-measurement decreased significantly from the second weekly measurement in the treatment until the post-measurement week ten. This confirmed the results of previous studies. Future randomized trials may provide a basis for the development of assessment interviews and ICBT for antenatal depression.

Myasthenia Gravis (MG) is an autoimmune disease affecting neuromuscular transmission, in which the thymus is considered pathogenic organ. Earlier ideas suggesting that MG is only the receptors disease have been proven wrong. There are immunopathological changes in both target structures [specific receptors for acetylcholine (AChR] muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein 4 (Lrp4)], the thymus, as well as in peripheral lymphoid organs. Initial findings of the humoral immunity defect with the decisive role of the pathologic autoantibodies, were corrected with findings of the immune dysregulation at the level of T lymphocytes. According to today's knowledge, the development and maintenance of MG involves almost all cell types of immune function in the autoimmune inflammation: helper CD4+ T lymphocytes, cytotoxic CD8+ T lymphocytes, regulatory CD4+CD25+ T lymphocytes, Th17 lymphocytes, B lymphocytes and plasma cells. Thymus plays a dominant immunopathogenetic role in younger patients with MG, while extrathymic mechanisms are applied in older patients. As a result of that, the thymectomy (TE) is generally accepted as part of treatment for MG. However, there is still no data verified by a prospective controlled study, which would demonstrate a useful result of this treatment...

La maladie de Crohn (MC) a une incidence élevée dans la population pédiatrique en Amérique du Nord et cette incidence est en augmentation. L’évolution naturelle de la MC est mal comprise. L'évolution du délai à la rémission au fil des ans et les causes influençant le délai à la rémission sont très limitées dans la littérature. Peu de facteurs de risque sont identifiés dans la littérature pour prédire les rechutes de la maladie chez les enfants. Le premier objectif de cette étude était de décrire les variations du phénotype clinique, des caractéristiques endoscopiques, histologiques et de laboratoire de la MC pédiatrique au cours de la dernière décennie et de décrire les variations saisonnières de la présentation de la maladie au moment du diagnostic. Le deuxième objectif était de décrire le délai à la rémission chez les enfants atteints de MC ainsi que son évolution au cours de la dernière décennie et de déterminer les facteurs associés au délai à la rémission. Le troisième objectif de l’étude était de décrire le taux de rechutes chez les enfants atteints de la MC, son évolution au cours de la dernière décennie et de déterminer les facteurs de risque associés à la rechute de la maladie. Les patients éligibles étaient âgés de 4 à 18 ans et diagnostiqués entre 2009 et 2019. Toutes les caractéristiques cliniques, endoscopiques, histologiques et de laboratoire des patients, ainsi que leurs traitements, ont été recueillis à partir de leurs dossiers médicaux. Des analyses de survie et des modèles de régression linéaire ont été utilisés pour évaluer l'impact de ces facteurs sur le délai à la rémission et des analyses de survie et des modèles de régression de Cox ont été utilisés pour évaluer l'impact de ces facteurs sur le risque de rechute. 654 patients ont été inclus dans cette étude de cohorte rétrospective. Le nombre de nouveaux diagnostics annuels de MC a augmenté au fil des ans et les patients diagnostiqués entre 2015 et 2019 avaient un âge au diagnostic plus bas (OR 2.53, IC à 95% [1.29; 4.98]), plus de maladies périanales (OR: 2.30, IC à 95% [ 1.52; 3.48]), plus de granulomes (OR: 1.61, IC à 95% [1.17; 2.22]), mais moins d’éosinophiles (OR: 0.35, IC à 95% [0.25; 0.48]) et moins d’infiltrat lympho-plasmocytaire chronique (OR: 0.56, IC à 95% [0.36; 0.86]) comparé aux patients diagnostiqués entre 2009 et 2014. Il y avait moins de diagnostics de MC chez les enfants en hiver. Les patients diagnostiqués à l'automne avaient une activité de la maladie plus faible (score PCDAI), moins de retard de croissance et des maladies digestives moins diffuses. Les MC diagnostiquées au printemps et à l’été avaient des taux d'hémoglobine plus faibles et des taux de vitesse de sédimentation plus élevés associées à plus d’atteintes articulaires et plus d'érythème noueux. La localisation colique était significativement plus fréquente l’été et l’automne. Il n'y a pas eu de changement dans le délai à la rémission au cours de la dernière décennie. Le sexe féminin chez les adolescents (coefficient de regression bêta ajusté (aβ) = 31.8 jours, p=0.02), l'atteinte du tube digestif supérieur (aβ= 46.4 jours, p=0.04), la maladie périanale (aβ= 32.2 jours, p=0.04), les signes d'inflammation active sur les biopsies (aβ= 46.7 jours, p=0.01) et l’exposition aux 5-ASA oraux lors de la phase d'induction (aβ= 56.6 jours, p=0.002) étaient associés à un délai à la rémission plus long. À l’inverse, l'utilisation d'antibiotiques (aβ= -29.3 jours, p=0.04), l’augmentation des éosinophiles sur les biopsies (aβ= -29.6 jours, p=0.008) et l'utilisation de la nutrition entérale exclusive comme traitement d'induction avec les anti TNF-alpha (aβ= -36.8 jours, p=0.04) étaient associés à un délai à la rémission plus court. Il y a eu une diminution du taux de rechute au cours de la dernière décennie : 69.59% chez les patients diagnostiqués entre 2009 et 2014 et 47.76% chez les patients diagnostiqués entre 2015 et 2019 (p<0.0001). Le sexe féminin (hazard ratio ajusté (aHR) = 1.51, p=0.0009), les scores PCDAI (aHR= 1.02, p=0.04) et SES-CD élevés (aHR= 1.03, p=0.03) au diagnostic, l'atteinte du tube digestif supérieur (aHR= 1.59, p=0.0003), l’utilisation des 5-ASA oraux (aHR= 1.91, p=0.0003), l’usage d'agents immunomodulateurs par rapport aux biologiques (methotrexate aHR= 1.91, p=0.0006; thiopurines aHR= 2.06, p<0.0001), la présence de granulomes (aHR= 1.27, p=0.04) et l’augmentation des éosinophiles sur les biopsies (aHR= 1.34, p=0.02), des niveaux élevés de protéine C-réactive (aHR= 1.01, p<0.0001) et de calprotectine fécale (aHR=1.09, p<0.0001) pendant la rémission clinique et de faibles taux sériques d'infliximab en post-induction (aHR pour les niveau moyen d’infliximab inférieur à 7ug/mL = 2.48, p=0.005) étaient indépendamment associés à la rechute. Le phénotype de la maladie a changé au fil des ans et des tendances saisonnières dans la fréquence et la gravité des diagnostics existent, suggérant des hypothèses étiologiques telles que la carence en vitamine D en hiver, les colites bactériennes saisonnières, les processus de réactivation virale et les changements dans la composition du microbiote. Plusieurs résultats de l'étude sont originaux et ceux-ci ont apporté de nouvelles connaissances et certains pourraient être intégrés dans les lignes directrices de prise en charge de la MC pédiatrique afin d’améliorer la qualité de vie des patients, soit obtenir une rémission rapide et durable. / Crohn's disease (CD) has a high incidence in the pediatric population in North America. The etiology of CD remains unknown and the disease incidence has been increasing. The natural evolution of CD is misunderstood, especially in the pediatric population. The trends of time-to-remission over the years and the influencing factors are very limited in the literature. Few risk factors are identified in the literature to predict relapses of the disease in children. The first part of this study was to describe the trends in the clinical phenotype, endoscopic, histological, and laboratory characteristics of pediatric CD during the last decade and to describe the seasonal variation of disease presentation at diagnosis. The secondary part of this study was to describe the time to remission in children with CD as well as its evolution over the past decade and to determine factors associated with time to remission. The third part of the study was to describe the rate of relapses in children with CD, its evolution over the past decade and to determine risk factors associated with relapse of the disease. Eligible patients were aged from 4 to 18 years and diagnosed between 2009 and 2019. All clinical, endoscopic, histological, laboratory and treatment data were collected from their medical records. Survival analyses and linear regression models were used to assess the impact of those factors on time to remission. Likewise, survival analyses and Cox regression models were applied to assess the impact of those risk factors on relapse. A total of 654 patients were included in this retrospective cohort study. The number of new diagnoses per year increased over the decade. Patients diagnosed between 2015 and 2019 had a lower age at diagnosis (OR 2.53, 95% CI [1.29; 4.98]), more perianal diseases (OR: 2.30, 95% CI [1.52; 3.48]), more granulomas (OR: 1.61, 95% CI [1.17; 2.22]), but less eosinophils (OR: 0.35, 95% CI [0.25; 0.48]) and less chronic lympho-plasma cells infiltrate (OR: 0.56, 95% CI [0.36; 0.86]) on ileo-colonic biopsies compared to patients diagnosed in 2015-2019. There were fewer diagnoses of CD in children in winter. Patients diagnosed in fall had lower PCDAIs and less failure to thrive. CD diagnosed in spring and summer had lower hemoglobin levels and higher erythrocyte sedimentation rate levels. In addition, arthritis and erythema nodosum were more frequent in spring and summer. Colonic location was significantly more frequent in summer and fall. There was no change in the time to clinical remission over the past decade. Female sex in adolescents (adjusted bêta regression coefficient (aβ)= 31.8 days, p=0.02), upper digestive tract involvement (aβ= 46.4 days, p=0.04) perianal disease (aβ= 32.2 days, p=0.04), presence of active inflammation on biopsies (aβ= 46.7 days, p=0.01) and oral 5-ASA exposure (aβ= 56.6 days, p=0.002) were all associated with longer time to clinical remission. However, antibiotic exposure (aβ= -29.3 days, p=0.04), increased eosinophils on biopsies (aβ= -29.6 days, p=0.008) and combination of exclusive enteral nutrition and TNF-alpha inhibitors as induction therapy (aβ= -36.8 days, p=0.04) were associated with shorter time to clinical remission. There has been a decrease in the relapse rate over the past decade : 69.6% in patients diagnosed between 2009 and 2014 and 47.8% in patients diagnosed between 2015 and 2019 (p<0.0001). Female sex (adjusted hazard ratio (aHR) = 1.51, p=0.0009), high PCDAI (aHR= 1.02, p=0.04) and SES-CD (aHR= 1.03, p=0.03) scores at diagnosis, upper digestive tract involvement (aHR= 1.59, p=0.0003), exposure to oral 5-ASA (aHR= 1.91, p=0.0003), use of immunomodulatory agents compared to TNF-alpha inhibitors (methotrexate aHR= 1.91, p=0.0006; thiopurines aHR= 2.06, p<0.0001), presence of granulomas (aHR= 1.27, p=0.04) and increased eosinophils on biopsies (aHR= 1.34, p=0.02), high levels of C-reactive protein (aHR= 1.01, p<0.0001) and fecal calprotectin (aHR=1.09, p<0.0001) during clinical remission and low serum infliximab levels during maintenance (aHR for mean serum infliximab level under 7ug/mL = 2.48, p=0.005) were all significantly associated with relapse in patients. The disease phenotype has changed over the years and important trends in the frequency and severity of diagnoses exist according to the diagnosis period within a year, suggesting etiological hypotheses such as vitamin D deficiency in winter, seasonal bacterial and viral colitis and academic stress. Many of the results of the study are original and brought new knowledge while confirming certain statements which had not obtained consensus in recent studies of expert opinions and some could be incorporated into management guidelines of pediatric CD to short time to remission and avoid relapse in patients.