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Made available in DSpace on 2021-06-25T11:01:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Background: Hepatitis C virus infection is a significant global health burden, which causes acute or chronic hepatitis. Acute hepatitis C is generally asymptomatic and progresses to cure, while persistent infection can progress to chronic liver disease and extrahepatic manifestations. Standard treatment is expensive, poorly tolerated, and has variable sustained virologic responses amongst the different viral genotypes. New therapies involve direct acting antivirals; however, it is also very expensive and may not be accessible for all patients worldwide. In order to provide a complementary approach to the already existing therapies, natural bioactive compounds are investigated as to their several biologic activities, such as direct antiviral properties against hepatitis C, and effects on mitigating chronic progression of the disease, which include hepatoprotective, antioxidant, anticarcinogenic and anti-inflammatory activities; additionally, these compounds present advantages, as chemical diversity, low cost of production and milder or inexistent side effects. Objective: To present a broad perspective on hepatitis C infection, the chronic disease, and natural compounds with promising anti-HCV activity. Methods: This review consists of a systematic review study about the natural bioactive compounds as a potential therapy for hepatitis C infection. Results: The quest for natural products has yielded compounds with biologic activity, including viral replication inhibition in vitro, demonstrating antiviral activity against hepatitis C. Conclusion: One of the greatest advantages of using natural molecules from plant extracts is the low cost of production, not requiring chemical synthesis, which can lead to less expensive therapies available to low and middle-income countries. Food and Nutrition Department School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Biotechnology Institute of Chemistry São Paulo State University (UNESP) Food and Nutrition Department School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Biotechnology Institute of Chemistry São Paulo State University (UNESP)

Systemic lupus erythematosus and ANCA-associated vasculitis overlap syndrome is rare and complex. Moreover, the mechanisms that explain the interaction between these two conditions are still unclear. The authors describe the case of a patient who had myeloperoxidase ANCA-associated vasculitis as the initial diagnosis, with biopsy-proven pauci immune crescentic glomerulonephritis, attaining complete remission after immunosuppression. Five years later, Systemic Lupus Erythematosus was diagnosed and a second kidney biopsy showed a pattern of lupus nephritis class III. While on immunosuppression treatment, the patient developed a progressive elevation of liver enzymes and was later diagnosed with primary biliary cholangitis. It seems that in this case, the overlap of Systemic Lupus Erythematosus and ANCA-associated vasculitis may be part of a poliautoimmune syndrome suggested by association with a third autoimmune disease.

Objective. To describe the development of the bacterial cellulose coating with anti-inflammatory Ibuprofen (BC/ Ibu) and to evaluate the cicatrization process with its use in patients with chronic wounds of venous and diabetic etiology. Methods. Longitudinal descriptive study. The cellulose membrane, cultivated with bacteria Gluconacetobacter xylinus and with incorporation of Ibuprofen, was used in the treatment of patients with chronic wounds in public health services in a Brazilian municipality. The ideal coverage characteristics were evaluated through physical, chemical and cell proliferation tests. Results. The sample consisted of 14 patients (10 women and 4 men), 8 with venous ulcer, 5with diabetic foot and one with mixed wound. There was reduction of area and pain in lesions; total healing of 3 wounds; and debridement of the devitalized tissue in 5 wounds with increased area. The use of the membrane was important in the reduction of pain, exudation and ease in the accomplishment of the curative. Conclusion. BC/Ibu favored the cicatrization process of patients with chronic vasculogenic wounds. How to cite this article : Zanoti MDU, Sonobe HM, Ribeiro SJL, Gaspar AMM. Development of coverage and its evaluation in the treatment of chronic wounds. Invest. Educ. Enferm. 2017; 35(3):330-339.

Fatty acid β-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient. Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well. What is Known: Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders; Neonatal screening intends to reduce the incidence of severe metabolic crisis and death. What is New: Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening; Sudden deaths were not avoided by starting treatment precociously. info:eu-repo/semantics/publishedVersion

Background: Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a congenital rare metabolic disease with broad clinical phenotypes and variable evolution. This inborn error of metabolism is caused by mutations in the ETFA, ETFB or ETFDH genes, which encode for the mitochondrial ETF and ETF:QO proteins. A considerable group of patients has been described to respond positively to riboflavin oral supplementation, which constitutes the prototypic treatment for the pathology. Objectives: To report mutations in ETFA, ETFB and ETFDH genes identified in Portuguese patients, correlating, whenever possible, biochemical and clinical outcomes with the effects of mutations on the structure and stability of the affected proteins, to better understand MADD pathogenesis at the molecular level. Methods: MADD patients were identified based on the characteristic urinary profile of organic acids and/or acylcarnitine profiles in blood spots during newborn screening. Genotypic, clinical and biochemical data were collected for all patients. In silico structural analysis was employed using bioinformatic tools carried out in an ETF:QO molecular model for the identified missense mutations. Results: A survey describing clinical and biochemical features of eight Portuguese MADD patients was made. Genotype analysis identified five ETFDH mutations, including one extension (p.X618QextX*14), two splice mutations (c.34+5G>C and c.405+3A>T) and two missense mutations (ETF:QO-p.Arg155Gly and ETF:QO-p.Pro534Leu), and one ETFB mutation (ETFβ- p.Arg191Cys). Homozygous patients containing the ETFDH mutations p.X618QextX*14, c.34+5G>C and ETF:QO-p.Arg155Gly, all presented severe (lethal) MADD phenotypes. However, when any of these mutations are in heterozygosity with the known ETF:QO-p.Pro534Leu mild variant, the severe clinical effects are partly and temporarily attenuated. Indeed, the latter destabilizes an ETF-interacting loop, with no major functional consequences. However, the position 155 in ETF:QO is localized at the ubiquinone binding and membrane interacting domain, and is thus expected to perturb protein structure and membrane insertion, with severe functional effects. Structural analysis of molecular models is therefore demonstrated to be a valuable tool to rationalize the effects of mutations in the context of the clinical phenotype severity. Conclusion: Advanced molecular diagnosis, structural analysis and clinical correlations reveal that MADD patients harboring a severe prognosis mutation in one allele can actually revert to a milder phenotype by complementation with a milder mutation in the other allele. However, such patients are nevertheless in a precarious metabolic balance which can revert to severe fatal outcomes during catabolic stress or secondary pathology, thus requiring strict clinical follow-up. This work was supported by the Fundação para a Ciência e Tecnologia (FCT/MCTES, Portugal) through fellowships to B.J.H. (SFRH/BPD/74475/2010) and T.G.L. (SFRH/BD/89690/2012) and a grant PTDC/ BBB-BQB/5366/2014 (to B.J.H.) and PTDC/NEUNMC/2138/2014 (to C.M.G.). The Gomes laboratory is partly supported by grant UID/MULTI/04046/2013 from FCT/MCTES/PIDDAC (to BioISI). info:eu-repo/semantics/publishedVersion

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the commonest genetic defect of mitochondrial fatty acid β-oxidation. About 60% of MCADD patients are homozygous for the c.985A>G (p.Lys329Glu) mutation in the ACADM gene (G985 allele). Herein, we present the first report on the molecular and biochemical spectrum of Portuguese MCADD population. From the 109 patients studied, 83 were diagnosed after inclusion of MCADD in the national newborn screening, 8 following the onset of symptoms and 18 through segregation studies. Gypsy ancestry was identified in 85/109 patients. The G985 allele was found in homozygosity in 102/109 patients, in compound heterozygosity in 6/109 and was absent in one patient. Segregation studies in the Gypsy families showed that 93/123 relatives were carriers of the G985 allele, suggesting its high prevalence in this ethnic group. Additionally, three new substitutions-c.218A>G (p.Tyr73Cys), c.503A>T (p.Asp168Val) and c.1205G>T (p.Gly402Val)-were identified. Despite the particularity of the MCADD population investigated, the G985 allele was found in linkage disequilibrium with H1(112) haplotype. Furthermore, two novel haplotypes, H5(212) and H6(122) were revealed.

Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity. Patients develop symptoms in the neonatal period, which can be ameliorated by dietary restriction of galactose. Many patients develop long-term complications, with a broad range of clinical symptoms whose pathophysiology is poorly understood. The high allelic heterogeneity of GALT gene that characterizes this disorder is thought to play a determinant role in biochemical and clinical phenotypes. We aimed to characterize the mutational spectrum of GALT deficiency in Portugal and to assess potential genotype-phenotype correlations. Direct sequencing of the GALT gene and in silico analyses were employed to evaluate the impact of uncharacterized mutations upon GALT functionality. Molecular characterization of 42 galactosemic Portuguese patients revealed a mutational spectrum comprising 14 nucleotide substitutions: ten missense, two nonsense and two putative splicing mutations. Sixteen different genotypic combinations were detected, half of the patients being p.Q188R homozygotes. Notably, the second most frequent variation is a splicing mutation. In silico predictions complemented by a close-up on the mutations in the protein structure suggest that uncharacterized missense mutations have cumulative point effects on protein stability, oligomeric state, or substrate binding. One splicing mutation is predicted to cause an alternative splicing event. This study reinforces the difficulty in establishing a genotype-phenotype correlation in classic galactosemia, a monogenic disease whose complex pathogenesis and clinical features emphasize the need to expand the knowledge on this "cloudy" disorder.

Hyperphenylalaninemia (HPA, OMIM #261600), which includes phenylketonuria (PKU), is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH), being already described more than 600 different mutations. Genotype-phenotype correlation is a useful tool to predict the metabolic phenotype, to establish the better tailored diet and, more recently, to assess the potential responsiveness to BH(4) therapy, a current theme on PKU field. The aim of this study was the molecular analysis of the PAH gene, evaluation of genotype-phenotype relationships and prediction of BH(4)-responsiveness in the HPA population living in South Portugal. We performed the molecular characterization of 83 HPA patients using genomic DNA extracted from peripheral blood samples or Guthrie cards. PAH mutations were scanned by PCR amplification of exons and related intronic boundaries, followed by direct sequence analysis. Intragenic polymorphisms were determined by PCR-RFLP analysis. The results allowed the full characterization of 67 patients. The mutational spectrum encompasses 34 distinct mutations, being the most frequent IVS10nt-11G>A (14.6%), V388M (10.8%), R261Q (8.2%) and R270K (7.6%), which account for 46% of all mutant alleles. Moreover, 12 different haplotypes were identified and most mutations were associated with a single one. Notably, more than half of the 34 mutations belong to the group of more than 70 mutations already identified in BH(4)-responsive patients, according to BIOPKU database. Fifty one different genotypic combinations were found, most of them in single patients and involving a BH(4)-responsive mutation. In conclusion, a significant number (30-35%) of South Portugal PKU patients may potentially benefit from BH(4) therapy which, combined with a less strict diet, or eventually in special cases as monotherapy, may contribute to reduce nutritional deficiencies and minimize neurological and psychological dysfunctions.