The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumilast in chronic obstructive pulmonary disease (COPD). Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. However, real-time polymerase chain reaction analysis revealed that GSK 256066 was a weak stimulus, and the negative microarray results reflected low statistical power due to small sample sizes. Furthermore, GSK 256066, roflumilast, and its biologically active metabolite roflumilast N-oxide generally potentiated gene expression changes produced by the long-acting β2-adrenoceptor agonists (LABAs) salmeterol, indacaterol, and formoterol. Many of these genes encode proteins with antiviral, anti-inflammatory, and antibacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-sequencing experiments established that the sensitivity of genes to salmeterol varied by ∼7.5-fold. Consequently, the degree to which a PDE4 inhibitor potentiated the effect of a given concentration of LABA was gene-dependent. Operational model fitting of concentration-response curve data from cells subjected to fractional, β2-adrenoceptor inactivation determined that PDE4 inhibition increased the potency and doubled the efficacy of LABAs. Thus, adding roflumilast to standard triple therapy, as COPD guidelines recommend, may have clinical relevance, especially in target tissues where LABAs behave as partial agonists. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD.
Chronic Kidney Disease is a longterm complication due to obstructive nephropathy secondary to the neurogenic bladder. There are many case reports of Neurogenic bladder caused by Pelvic/Gynecological surgeries. We present two such cases who had a history of pelvic surgery and developed neurogenic bladder which eventually lead to ESRD due to delay in diagnosis, evaluation, and management. First, is the case of a 48-year-old female, who underwent abdominal tubal ligation 15 years ago developed neurogenic bladder and then later chronic kidney disease. The second case is that of a 49-year-old female who underwent abdominal hysterectomy 10 years ago, developed neurogenic bladder, and eventually chronic kidney disease.
Data on performance records of 1249 Frieswal daughters of 71 sires over a period of 13 years from 2000-2012 were analyzed to determine the effects of farm, parity, type of calving, period of birth and season of birth on lactation length (LL), 305-day milk yield (305-DY) and calving interval (CI). The age at first calving (AFC) was considered as covariable. The overall least-squares means for AFC, LL, 305-DY and CI were 31.45±0.89 months, 303.31 ± 7.02 days, 2997.01 ± 123.24 kg and 431.19 ± 16.53 days respectively. Period of birth had significant effect on age at first calving. Farm, type of calving and period of birth had significant effect on lactation length. Farm, parity and season of birth had significant effect on 305-day milk yield. Parity, type of calving, period of birth and season of birth had significant effect on calving interval. Heritability estimates for LL and CI were low (0.17 ± 0.10 and 0.11 ± 0.09), while it was high (0.51±0.14) for 305-DY. The phenotypic and genetic correlation between lactation length, 305-day milk yield and calving interval were observed high and positive.
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