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Genética e Fisiopatologia

de Freitas MB, Moreira EAM, Tomio C, Moreno YMF, Daltoe FP, Barbosa E, Ludwig Neto N, Buccigrossi V, Guarino A. 

PLoS One. 2018 Jun 22;13(6):e0198457. doi: 10.1371/journal.pone.0198457. PMID: 29933382; PMCID: PMC6014676.


Abstract
The aim of the present study was to evaluate the effect of cystic fibrosis and antibiotic therapy on intestinal microbiota composition and intestinal inflammation in children and adolescents. A cross-sectional controlled study was conducted with 36 children and adolescents: 19 in the cystic fibrosis group (CFG) and 17 in the control group (CG) matched for age and sex. The CFG was subdivided based on the use of antibiotic therapy (CFAB group) and non-use of antibiotic therapy (CFnAB group). The following data were evaluated: colonization, antibiotic therapy, mutation, breastfeeding, use of infant formula, type of delivery, introduction of solid foods, body mass index, fecal calprotectin and intestinal microbiota composition (fluorescence in situ hybridization). Intestinal inflammation evaluated by fecal calprotectin was significantly higher in the CFG (median: 40.80 µg/g, IQR: 19.80-87.10, p = 0.040) and CFAB group (median: 62.95 µg/g, IQR: 21.80-136.62, p = 0.045) compared to the CG (median: 20.15 µg/g, IQR: 16.20-31.00), and the Bacteroides, Firmicutes, Eubacterium rectale and Faecalibacterium prausnitzii were significantly decreased (p < 0.05) in the CFG compared to the CG, whereas the bacteria Clostridium difficile, Escherichia coli and Pseudomonas aeruginosa were significantly increased in the CFG (p < 0.05). The main differences were found between the CG and CFAB group for Eubacterium rectale (p = 0.006), Bifidobacterium (p = 0.017), Escherichia coli (p = 0.030), Firmicutes (p = 0.002), Pseudomonas aeruginosa (p < 0.001) and Clostridium difficile (p = 0.006). The results of this study confirm intestinal inflammation in patients with CF, which may be related to changes in the composition of the intestinal microbiota.

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Ventura JC, Hauschild DB, Moreira EAM, Pereira LCR, Rosa AF, Barbosa E, Ludwig-Neto N, Rosa JSD, Fröde TS, Moreno YMF.


Sao Paulo Med J. 2018 Jan-Feb;136(1):29-36. doi: 10.1590/1516-3180.2017.0109100917. Epub 2017 Dec 18. PMID: 29267535.

 

Abstract

BACKGROUND
Chronic lung infections, inflammation and depletion of nutritional status are considered to be prognostic indicators of morbidity in patients with cystic fibrosis. The aim of this study was to investigate the association between inflammatory markers and lung function, nutritional status and morbidity among children/adolescents with cystic fibrosis. 
DESIGN AND SETTINGS
Prospective three-year longitudinal study conducted in an outpatient clinic in southern Brazil. 
METHODS
Children/adolescents aged 1-15 years with cystic fibrosis were enrolled. Nutritional status was determined from weight-to-length and body mass index-to-age z-scores and was classified as acceptable, at risk or nutritional failure. Tumor necrosis factor-a, interleukin-1ß, myeloperoxidase, C-reactive protein and C-reactive protein/albumin ratio were analyzed. Lung function was evaluated based on the forced expiratory volume in the first second and morbidity according to the number of hospitalizations for pulmonary exacerbation and infections by Pseudomonas aeruginosa. Lung function, nutritional status and morbidity were the outcomes. Odds ratios and 95% confidence intervals were to evaluate the effect of baseline inflammatory markers on the clinical outcomes after three years of follow-up and p-values < 0.05 were considered significant. 
RESULTS
We evaluated 38 children/adolescents with cystic fibrosis: 55% female; median age (with interquartile range), 3.75 years (2.71-7.00). Children/adolescents with high C-reactive protein/albumin ratio at baseline had odds of 18 (P = 0.018) of presenting forced expiratory volume in the first second <= 70% after three years. The other inflammatory markers were not associated with the outcomes. 
CONCLUSION
C-reactive protein/albumin ratio was associated with forced expiratory volume in the first second <= 70% after three years.

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Cutting GR1.

Nat Rev Genet. 2015 Jan;16(1):45-56. doi: 10.1038/nrg3849. Epub 2014 Nov 18.
 

Abstract

The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to applygenetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate howgenetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.

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Coutinho CA1, Marson FA, Ribeiro AF, Ribeiro JD, Bertuzzo CS.

J Bras Pneumol. 2013 Sep-Oct;39(5):555-61. doi: 10.1590/S1806-37132013000500005.

 

Abstract

OBJECTIVE
To determine the frequency of six mutations (F508del, G542X, G551D, R553X, R1162X, and N1303K) in patients with cystic fibrosis (CF) diagnosed, at a referral center, on the basis of abnormal results in two determinations of sweat sodium and chloride concentrations.

METHODS
This was a cross-sectional study involving 70 patients with CF. The mean age of the patients was 12.38 ± 9.00 years, 51.43% were female, and 94.29% were White. Mutation screening was performed with polymerase chain reaction (for F508del), followed by enzymatic digestion (for other mutations). Clinical analysis was performed on the basis of gender, age, ethnicity, pulmonary/gastrointestinal symptoms, and Shwachman-Kulczycki (SK) score.

RESULTS
All of the patients showed pulmonary symptoms, and 8 had no gastrointestinal symptoms. On the basis of the SK scores, CF was determined to be mild, moderate, and severe in 22 (42.3%), 17 (32.7%), and 13 (25.0%) of the patients, respectively. There was no association between F508del mutation and disease severity by SK score. Of the 140 alleles analyzed, F508del mutation was identified in 70 (50%). Other mutations (G542X, G551D, R553X, R1162X, and N1303K) were identified in 12 (7.93%) of the alleles studied. In F508del homozygous patients with severe disease, the OR was 0.124 (95% CI: 0.005-0.826).

CONCLUSIONS
In 50% of the alleles studied, the molecular diagnosis of CF was confirmed by identifying a single mutation (F508del). If we consider the analysis of the six most common mutations in the Brazilian population (including F508del), the molecular diagnosis was confirmed in 58.57% of the alleles studied.

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Saraiva-Pereira ML, Fitarelli-Kiehl M, Sanseverino MTV.
Rev HCPA 2011;31(2):160-7.

 

Resumo

A fibrose cística (FC) é a doença autossômica recessiva mais comum em euro-descendentes, com uma incidência estimada de 1 caso a cada 2.500 nascimentos. A FC é uma doença multissistêmica, caracterizada principalmente por doença pulmonar progressiva, disfunção pancreática exócrina e concentração elevada de eletrólitos no suor. O gene associado a essa doença é denominado CFTR e se localiza no cromossomo 7, sendo dividido em 27 éxons. Até o momento, mais de 1.800 variações de sequência foram identificadas no gene CFTR, sendo que a mutação p.Phe508del é a mais frequente entre os pacientes de FC. No Brasil, a frequência dessa mutação não é tão elevada, devido provavelmente à miscigenação e, consequentemente, o locus CFTR apresenta maior heterogeneidade alélica. A probabilidade de um filho afetado com FC é de 1 em 4, ou 25%, para filhos de um casal em que ambos são portadores de uma mutação. O risco de um indivíduo com FC ter filhos afetados depende de seu parceiro – se o parceiro for portador da doença o risco se á de 50%. Para casais em risco de terem filhos com FC e com mutação ou mutações identificadas, é possível oferecer diagnóstico pré-natal (DPN) e diagnóstico genético pré-implantacional (DPI). Considerando a complexidade da informação genética relacionada à FC e das alternativas reprodutivas que estão surgindo, é muito importante a disponibilização do aconselhamento genético para o paciente e sua família.
Palavras-chave: Fibrose cística; gene CFTR; aconselhamento genético; análise molecular; diagnóstico pré-natal; diagnóstico pré-implantacional .

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Faucz FR, Souza DA, Olandoski M, Raskin S.

J Hum Genet. 2010 Feb;55(2):71-6. doi: 10.1038/jhg.2009.123. Epub 2009 Nov 27.

Abstract

The goal of the present study was to provide a complete and updated spectrum of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutations in the Brazilian population combining all available in silico data for patients with CF in Brazil, including founder background and migration flow that consisted of the actual genetic pool of the Brazilian population. Information sources in international databases (PUBMED and SCIELO) were searched. The Brazilian population shows a wide variation in the frequency of CFTR mutations in states Rio Grande do Sul (RS), Santa Catarina (SC), Paraná (PR), São Paulo (SP), Rio de Janeiro (RJ), Minas Gerais (MG), Pará (PA) and Bahia (BA); this variation includes the most common mutation p.F508del. Apparently, this frequency variation is because of the different ethnic compositions. States such as SC and PR have a greater European admixture with almost 90% of CF alleles identified. In other states, such as BA, higher frequency of alleles that are common among African populations is seen. Overall, the CFTR mutational spectrum indicates the presence of European, African and Amerindian ethnic groups in the contemporary Brazilian CF patients. Here, we present an analysis of the CFTR allelic heterogeneity and discuss the origin of its genetic composition, in an attempt to provide improved perspective for the CF population screening in Brazil and genetic counseling.

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