Functional effects of 17alpha-hydroxyprogesterone caproate (17P) on human myometrial contractility in vitro

BACKGROUND: 17alpha-hydroxyprogesterone caproate (17P) administration reportedly improves outcome for women with a previous spontaneous preterm delivery. This study, using in vitro strips of human uterine smooth muscle, aimed to investigate the direct non-genomic effects of 17P on spontaneous and induced contractions in tissues obtained during pregnancy, and in the non-pregnant state. METHODS: Biopsies of human myometrium were obtained at elective cesarean section, and from hysterectomy specimens, and dissected strips suspended for isometric recordings. The effects of 17P (1 nmol/L -10 micro mol/L) on spontaneous and agonist-induced (oxytocin 0.5 nmol/L for pregnant, phenylephrine 10 μmol/L for non-pregnant) contractions were measured. Integrals of contractile activity, including the mean maximal inhibition values (MMI) observed at the maximal concentration, were compared with those from simultaneously run control strips. RESULTS: There was no significant direct effect exerted by 17P on pregnant or non-pregnant human myometrial contractility. The MMI ± SEM for spontaneous contractions in pregnant myometrium was 4.9% ± 7.2 (n = 6; P = 0.309) and for oxytocin-induced contractions was 2.2% ± 1.3 (n = 6; P = 0.128). For non-pregnant myometrium, the MMI ± SEM for spontaneous contractions was 8.8% ± 11.0 (n = 6; P = 0.121) and for phenylephrine induced contractions was -7.9% ± 6.5 (n = 6; P = 0.966). CONCLUSIONS: The putative benefits of 17P for preterm labor prevention are not achieved, even partially, by a direct utero-relaxant effect. These findings outline the possibility that genomic effects of 17P, achieved over long periods of administration, are required for its reported therapeutic benefits

Reduced Kidney Function is Associated with Poorer Domain‐Specific Cognitive Performance in Community‐Dwelling Older Adults

OBJECTIVES: Whilst chronic kidney disease has been associated with cognitive impairment, the association between reduced estimated Glomerular Filtration Rate (eGFR) and domain‐specific cognitive performance is less clear and may represent an important target for the promotion of optimal brain health in older adults. METHODS: Participants aged >60 years from the Trinity‐Ulster‐Department of Agriculture study underwent detailed cognitive assessment using the Mini‐Mental State Examination (Mini‐Mental State Examination (MMSE)), Frontal Assessment Battery (FAB) and Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Poisson and linear regression models assessed the relationship between eGFR strata and cognitive performance. RESULTS: In 4887 older adults (73.9 ± 8.3 years; 67.7% female), declining eGFR strata was associated with greater likelihood of error on the MMSE/FAB and poorer overall performance on the RBANS. Following robust covariate adjustment, findings were greatest for GFR 80 years. CONCLUSIONS: Reduced kidney function was associated with poorer global and domain‐specific neuropsychological performance. Associations were strongest with eGFR <45 ml/min/1.73 m(2) and in those aged 60–70 years, suggesting that this population may potentially benefit from potential multi‐domain interventions aimed at promoting optimal brain health in older adults

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

BACKGROUND: PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31. METHODS: Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin. RESULTS: Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions. CONCLUSION: These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables

Progressive improvement in short-, medium- and long-term graft survival in kidney transplantation patients in Ireland - a retrospective study

It is often quoted that while short-term graft survival in kidney transplantation has improved in recent years, it has not translated into a commensurate improvement in long-term graft survival. We considered whether this was true of the entire experience of the national kidney transplant program in Ireland. A retrospective analysis of the National Kidney Transplant Service (NKTS) database was undertaken to investigate patient and graft survival for all adult first deceased donor kidney transplant recipients in Ireland, 1971-2015. Three thousand two hundred and sixty recipients were included in this study. Kaplan-Meier methods were used to estimate survival at each time period post transplant for the various eras of transplantation. Uncensored graft survival has improved over the course of the program in Ireland at various time points despite risk factors for graft failure progressively increasing over successive eras. For example the graft survival at 15 years post transplant has increased from 10% in 1971-1975 to 45% by 1996-2000. Ireland has experienced a progressive improvement in long-term graft survival following kidney transplantation. Whether these trends are attributable to biological or nonbiological factors is unclear but likely involves a combination of both

DR-VNet: Retinal Vessel Segmentation via Dense Residual UNet

Accurate retinal vessel segmentation is an important task for many computer-aided diagnosis systems. Yet, it is still a challenging problem due to the complex vessel structures of an eye. Numerous vessel segmentation methods have been proposed recently, however more research is needed to deal with poor segmentation of thin and tiny vessels. To address this, we propose a new deep learning pipeline combining the efficiency of residual dense net blocks and, residual squeeze and excitation blocks. We validate experimentally our approach on three datasets and show that our pipeline outperforms current state of the art techniques on the sensitivity metric relevant to assess capture of small vessels

End stage kidney disease from scleroderma in the united states, 1996 to 2012

Introduction: Although the management of scleroderma continues to evolve, it is unknown whether the burden of end-stage kidney disease (ESKD) treated with maintenance renal replacement therapy from SD has changed. Methods: We examined United States Renal Data System data (n = 1,677,303) for the years 1996 to 2012 to quantify the incidence and outcomes of ESKD from scleroderma treated with renal replacement therapy (n = 2398). Outcomes assessed through demography-matched scleroderma-positive/scleroderma-negative comparisons included recovery of kidney function, mortality, listing for transplant, renal transplantations, and graft failure. Results: Overall ESKD rates from scleroderma were 0.5 per million per year. Adjusted incidence ratios fell over time, to 0.42 in 2012 (vs. 1996, 95% confidence interval [CI] = 0.32-0.54, P &amp;lt; 0.001). Adjusted incidence ratios for ESKD from scleroderma fell over time in both sexes, all age, race, and ethnicity categories except age &amp;lt; 20 years and Asian race, and in all regions of the United States. After initiating renal replacement therapy, patients with scleroderma had a greater likelihood of recovery of kidney function (hazards ratio [HR] = 2.67, 95% CI = 1.90-3.76, P &amp;lt; 0.001) and death (HR = 1.44, 95% CI = 1.34-1.54, P &amp;lt; 0.001) and a lower likelihood of transplantation (HR = 0.51, 95% CI = 0.44-0.59, P &amp;lt; 0.001) than demography-matched patients without scleroderma. Conclusion: The incidence of ESKD from scleroderma appears to have declined in the United States since 1996. ESKD from scleroderma is associated with an enhanced likelihood of recovery of kidney function and death, a reduced likelihood of transplantation, and similar outcomes after transplantation

End stage kidney disease from scleroderma in the united states, 1996 to 2012

Introduction: Although the management of scleroderma continues to evolve, it is unknown whether the burden of end-stage kidney disease (ESKD) treated with maintenance renal replacement therapy from SD has changed. Methods: We examined United States Renal Data System data (n = 1,677,303) for the years 1996 to 2012 to quantify the incidence and outcomes of ESKD from scleroderma treated with renal replacement therapy (n = 2398). Outcomes assessed through demography-matched scleroderma-positive/scleroderma-negative comparisons included recovery of kidney function, mortality, listing for transplant, renal transplantations, and graft failure. Results: Overall ESKD rates from scleroderma were 0.5 per million per year. Adjusted incidence ratios fell over time, to 0.42 in 2012 (vs. 1996, 95% confidence interval [CI] = 0.32-0.54, P &amp;lt; 0.001). Adjusted incidence ratios for ESKD from scleroderma fell over time in both sexes, all age, race, and ethnicity categories except age &amp;lt; 20 years and Asian race, and in all regions of the United States. After initiating renal replacement therapy, patients with scleroderma had a greater likelihood of recovery of kidney function (hazards ratio [HR] = 2.67, 95% CI = 1.90-3.76, P &amp;lt; 0.001) and death (HR = 1.44, 95% CI = 1.34-1.54, P &amp;lt; 0.001) and a lower likelihood of transplantation (HR = 0.51, 95% CI = 0.44-0.59, P &amp;lt; 0.001) than demography-matched patients without scleroderma. Conclusion: The incidence of ESKD from scleroderma appears to have declined in the United States since 1996. ESKD from scleroderma is associated with an enhanced likelihood of recovery of kidney function and death, a reduced likelihood of transplantation, and similar outcomes after transplantation

End stage kidney disease from scleroderma in the united states, 1996 to 2012

Introduction: Although the management of scleroderma continues to evolve, it is unknown whether the burden of end-stage kidney disease (ESKD) treated with maintenance renal replacement therapy from SD has changed. Methods: We examined United States Renal Data System data (n = 1,677,303) for the years 1996 to 2012 to quantify the incidence and outcomes of ESKD from scleroderma treated with renal replacement therapy (n = 2398). Outcomes assessed through demography-matched scleroderma-positive/scleroderma-negative comparisons included recovery of kidney function, mortality, listing for transplant, renal transplantations, and graft failure. Results: Overall ESKD rates from scleroderma were 0.5 per million per year. Adjusted incidence ratios fell over time, to 0.42 in 2012 (vs. 1996, 95% confidence interval [CI] = 0.32-0.54, P &amp;lt; 0.001). Adjusted incidence ratios for ESKD from scleroderma fell over time in both sexes, all age, race, and ethnicity categories except age &amp;lt; 20 years and Asian race, and in all regions of the United States. After initiating renal replacement therapy, patients with scleroderma had a greater likelihood of recovery of kidney function (hazards ratio [HR] = 2.67, 95% CI = 1.90-3.76, P &amp;lt; 0.001) and death (HR = 1.44, 95% CI = 1.34-1.54, P &amp;lt; 0.001) and a lower likelihood of transplantation (HR = 0.51, 95% CI = 0.44-0.59, P &amp;lt; 0.001) than demography-matched patients without scleroderma. Conclusion: The incidence of ESKD from scleroderma appears to have declined in the United States since 1996. ESKD from scleroderma is associated with an enhanced likelihood of recovery of kidney function and death, a reduced likelihood of transplantation, and similar outcomes after transplantation