The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.

Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV1) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10-6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10-6, replication p=5.9×10-5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele β 56.36 mL·year-1, 95% CI 29.96-82.76 mL·year-1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β -27.57 mL·year-1, 95% CI -53.27- -1.87 mL·year-1).The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD

Genetic Influences on Pulmonary Function: A Large Sample Twin Study

Heritability of forced expiratory volume in one second (FE

Irrigação intranasal: avaliação dos efeitos do uso de soluções hidroeletrolíticas na mucosa de ratos Nasal irrigation: effects of hydroelectrolytic solutions on rats mucosa

A irrrigação intranasal tem grande importância como terapia adjuvante de doenças nasossinusais. Entretanto, faltam estudos que avaliem as alterações histológicas que as diferentes soluções utilizadas podem causar na mucosa do nariz. OBJETIVO: Analisar os aspectos histológicos da mucosa nasal de ratos após irrigação local com diferentes soluções hidroeletrolíticas. FORMA DE ESTUDO: Experimental. MATERIAL E MÉTODO: 120 ratos Wistar foram divididos igualmente em 4 grupos. O grupo número 1 recebeu solução salina a 0,9%. Os grupos 2 e 3 receberam soluções contendo Cloreto de Sódio associado a Cloreto de Potássio e Glicose, em diferentes concentrações. O grupo 4 foi o grupo controle. Duas vezes ao dia, 0,1ml (2 gotas) das soluções foram aplicados na narina esquerda dos ratos, através de uma seringa. Metade dos animais de cada grupo foi sacrificado após a primeira semana e a metade restante após a quarta semana de tratamento. Os fragmentos de mucosa obtidos foram processados e estudados em microscopia óptica, utilizando a hematoxilina e eosina. RESULTADOS: Pôde-se observar que a infiltração de células inflamatórias foi estatisticamente mais intensa no grupo 2, em 1 e 4 semanas de administração das soluções (p<0,05), quando comparada ao grupo controle. A formação de glândulas intraepiteliais foi estatisticamente mais evidente no grupo 1, quando comparada aos grupos 3 e 4 (p<0,05). CONCLUSÃO: A solução salina hipertônica testada causou a menor reação tecidual na mucosa nasal de ratos quando comparada ao grupo controle. Não foram encontradas vantagens na utilização da solução salina a 0,9% em comparação com o uso das demais soluções em estudo.<br>Nasal irrigation is an important adjuvant therapy for nasosinusis diseases. Many hydroelectrolytic solutions have been used for it, but studies are lacking to analyze the histological reactions they may cause to the nasal mucosa. PURPOSE: to examine the histological patterns in nasal mucosa after application of three different hydroelectrolytic solutions. STUDY DESIGN: Experimental. MATERIAL AND METHOD: 120 Wistar rats were equally divided into four groups. Group number 1 received a 0.9% saline solution. Group's number 2 and 3 received solutions composed by Sodium Chloride, associated to Potassium Chloride and Glucose in different concentrations. Group 4 was the control group. Twice a day, 0.1ml (2 drops) of the solutions were applied to the rats left nostril, using a bulb syringe. Half of the rats of each group were sacrificed after 1 week and the rest after 4 weeks of nasal irrigation. The collected nasal septal mucosa was studied on H&E stain, under optic microscopy. RESULTS: Inflammatory cell infiltration was statistically more intense for the group 2, in both 1 and 4 weeks of drug administration (p<0,05), when compared to the control group. Intraepithelial glandular formation was statistically more evident in the group 1, when compared to the groups 3 and 4 (p<0,05). CONCLUSION: The hypertonic hydroelectrolytic solution tested caused the lowest tissue reaction on rats' nasal mucosa when compared with the control group. No advantages were found in using 0,9% saline solution in comparison with the others solutions tested

Plasma Fibronectin Concentration in Obese/Overweight Pregnant Women: A Possible Risk Factor for Preeclampsia

Plasma fibronectin (FN) levels in obese/overweight and non-obese pregnant women were evaluated as a possible risk factor for preeclampsia. A total of one hundred and sixty three pregnant women attending antenatal clinic at University of Calabar Teaching Hospital participated in the study and sixty non-pregnant women served as control. About 77 (47.24%) of the pregnant women were followed up for any subsequent development of preeclampsia during the pregnancy. Fibronectin levels in plasma were measured by ELISA assay and serum total protein, urea and creatinine were determined spectrophotometrically. The mean plasma FN concentration of non-obese pregnant women in first trimester was lower than those of the non-pregnant women by 24%, but however, increased to the non-pregnant level in second and third trimesters. Obese/overweight pregnant women had significantly (P < 0.05) higher values than non-obese pregnant women in second and third trimesters. FN in obese/overweight pregnant women correlated positively with mean arterial blood pressure (MAP: r = 0.414, P = 0.04). About 28.57% of the pregnant women with FN above cut off point of 330 μg/ml at 18–24 weeks of gestation developed preeclampsia. This value increased to 40.0% when only the obese/overweight women were considered. On analysis of both fibronectin >330 μg/ml and MAP > 90, the predictive value increased to 66.7%. We therefore conclude that elevated FN may be regarded as a risk factor of preeclampsia especially among the obese women