Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study

<p>Abstract</p> <p>Background</p> <p>Dehydroepinadrosterone (DHEA) supplementation improves pregnancy chances in women with diminished ovarian reserve (DOR), by possibly reducing aneuploidy. Since a large majority of spontaneous miscarriages are associated with aneuploidy, one can speculate that DHEA supplementation may also reduce miscarriage rates.</p> <p>Methods</p> <p>We retroactively compared, utilizing two independent statistical models, miscarriage rates in 73 DHEA supplemented pregnancies at two independent North American infertility centers, age-stratified, to miscarriages reported in a national U.S. in vitro fertilization (IVF) data base.</p> <p>Results</p> <p>After DHEA supplementation the miscarriage rate at both centers was 15.1% (15.0% and 15.2%, respectively). For DHEA supplementation Mantel-Hänszel common odds ratio (and 95% confidence interval), stratified by age, was significantly lower, relative to odds of miscarriage in the general IVF control population [0.49 (0.25-0.94; p = 0.04)]. Miscarriage rates after DHEA were significantly lower at all ages but most pronounced above age 35 years.</p> <p>Discussion</p> <p>Since DOR patients in the literature are reported to experience significantly higher miscarriage rates than average IVF patients, the here observed reduction in miscarriages after DHEA supplementation exceeds, however, all expectations. Miscarriage rates after DHEA not only were lower than in an average national IVF population but were comparable to rates reported in normally fertile populations. Low miscarriage rates, comparable to those of normal fertile women, are statistically impossible to achieve in DOR patients without assumption of a DHEA effect on embryo ploidy. Beyond further investigations in infertile populations, these data, therefore, also suggest the investigations of pre-conception DHEA supplementation in normal fertile populations above age 35 years.</p

Genetic Risk of Cardiovascular Disease Is Associated with Macular Ganglion Cell–Inner Plexiform Layer Thinning in an Early Glaucoma Cohort

Purpose: To evaluate the association between genetic risk for cardiovascular disease and retinal thinning in early glaucoma. Design: Prospective, observational genetic association study Participants: Multicohort study combining a cohort of patients with suspect and early manifest primary open-angle glaucoma (POAG), a cohort of patients with perimetric POAG, and an external normative control cohort. Methods: A cardiovascular disease genetic risk score was calculated for 828 participants from the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study. Participants were characterized as showing either predominantly macular ganglion cell–inner plexiform layer (GCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL) or equivalent macular GCIPL and pRNFL spectral-domain OCT thinning. The cardiovascular disease genetic risk scores for these groups were compared to an internal reference group of stable suspected glaucoma and of an external normative population. Replication was undertaken by comparing the phenotypes of participants from the Australia New Zealand Registry of Advanced Glaucoma (ANZRAG) with the normative control group. Main Outcome Measures: Spectral-domain OCT and Humphrey Visual Field (HVF) change. Results: After accounting for age, sex, and intraocular pressure (IOP), participants with predominantly macular GCIPL thinning showed a higher cardiovascular disease genetic risk score than reference participants (odds ratio [OR], 1.76/standard deviation [SD]; 95% confidence interval [CI], 1.18–2.62; P = 0.005) and than normative participants (OR, 1.32/SD; 95% CI, 1.12–1.54; P = 0.002). This finding was replicated by comparing ANZRAG participants with predominantly macular GCIPL change with the normative population (OR, 1.39/SD; 95% CI, 1.05–1.83; P = 0.022). Review of HVF data identified that participants with paracentral visual field defects also demonstrated a higher cardiovascular disease genetic risk score than reference participants (OR, 1.85/SD; 95% CI, 1.16–2.97; P = 0.010). Participants with predominantly macular GCIPL thinning exhibited a higher vertical cup-to-disc ratio genetic risk score (OR, 1.48/SD; 95% CI, 1.24–1.76; P < 0.001), but an IOP genetic risk score (OR, 1.12/SD; 95% CI, 0.95–1.33; P = 0.179) comparable with that of the normative population. Conclusions: This study highlighted the relationship between cardiovascular disease and retinal thinning in suspect and manifest glaucoma cases

Alternative splicing and differential subcellular localization of the rat FGF antisense gene product

<p>Abstract</p> <p>Background</p> <p>GFG/NUDT is a nudix hydrolase originally identified as the product of the fibroblast growth factor-2 antisense (FGF-AS) gene. While the FGF-AS RNA has been implicated as an antisense regulator of FGF-2 expression, the expression and function of the encoded GFG protein is largely unknown. Alternative splicing of the primary FGF-AS mRNA transcript predicts multiple GFG isoforms in many species including rat. In the present study we focused on elucidating the expression and subcellular distribution of alternatively spliced rat GFG isoforms.</p> <p>Results</p> <p>RT-PCR and immunohistochemistry revealed tissue-specific GFG mRNA isoform expression and subcellular distribution of GFG immunoreactivity in cytoplasm and nuclei of a wide range of normal rat tissues. FGF-2 and GFG immunoreactivity were co-localized in some, but not all, tissues examined. Computational analysis identified a mitochondrial targeting sequence (MTS) in the N-terminus of three previously described rGFG isoforms. Confocal laser scanning microscopy and subcellular fractionation analysis revealed that all rGFG isoforms bearing the MTS were specifically targeted to mitochondria whereas isoforms and deletion mutants lacking the MTS were localized in the cytoplasm and nucleus. Mutation and deletion analysis confirmed that the predicted MTS was necessary and sufficient for mitochondrial compartmentalization.</p> <p>Conclusion</p> <p>Previous findings strongly support a role for the FGF antisense RNA as a regulator of FGF2 expression. The present study demonstrates that the antisense RNA itself is translated, and that protein isoforms resulting form alternative RNA splicing are sorted to different subcellular compartments. FGF-2 and its antisense protein are co-expressed in many tissues and in some cases in the same cells. The strong conservation of sequence and genomic organization across animal species suggests important functional significance to the physical association of these transcript pairs.</p

Physical Activity Is Associated With Macular Thickness: A Multi-Cohort Observational Study

PURPOSE. To assess the association between physical activity and spectral-domain optical coherence tomography (SD-OCT)–measured rates of macular thinning in an adult population with primary open-angle glaucoma. METHODS. The correlation between accelerometer-measured physical activity and rates of macular ganglion cell–inner plexiform layer (GCIPL) thinning was measured in 735 eyes from 388 participants of the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study. The association between accelerometer-measured physical activity and cross-sectional SD-OCT macular thickness was then assessed in 8862 eyes from 6152 participants available for analysis in the UK Biobank who had SD-OCT, ophthalmic, comorbidity, and demographic data. RESULTS. Greater physical activity was associated with slower rates of macular GCIPL thinning in the PROGRESSA study (beta = 0.07 μm/y/SD; 95% confidence interval [CI], 0.03–0.13; P = 0.003) after adjustment for ophthalmic, demographic and systemic predictors of macular thinning. This association persisted in subanalyses of participants characterized as glaucoma suspects (beta = 0.09 μm/y/SD; 95% CI, 0.03–0.15; P = 0.005). Participants in the upper tertile (greater than 10,524 steps/d) exhibited a 0.22-μm/y slower rate of macular GCIPL thinning than participants in the lower tertile (fewer than 6925 steps/d): −0.40 ± 0.46 μm/y versus −0.62 ± 0.55 μm/y (P = 0.003). Both time spent doing moderate/vigorous activity and mean daily active calories were positively correlated with rate of macular GCIPL thinning (moderate/vigorous activity: beta = 0.06 μm/y/SD; 95% CI, 0.01–0.105; P = 0.018; active calories: beta = 0.06 μm/y/SD; 95% CI, 0.006–0.114; P = 0.032). Analysis among 8862 eyes from the UK Biobank revealed a positive association between physical activity and cross-sectional total macular thickness (beta = 0.8 μm/SD; 95% CI, 0.47–1.14; P < 0.001). CONCLUSIONS. These results highlight the potential neuroprotective benefits of exercise on the human retina

The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma. Design: Retrospective analysis of prospective cohort data. Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion cell–inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (β = –0.13 μm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; β = –0.20 μm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 μm vs. 71.9 μm; P = 0.011) and pRNFL (77.6 μm vs. 79.2 μm; P = 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma

Extension of Murray's law using a non-Newtonian model of blood flow

<p>Abstract</p> <p>Background</p> <p>So far, none of the existing methods on Murray's law deal with the non-Newtonian behavior of blood flow although the non-Newtonian approach for blood flow modelling looks more accurate.</p> <p>Modeling</p> <p>In the present paper, Murray's law which is applicable to an arterial bifurcation, is generalized to a non-Newtonian blood flow model (power-law model). When the vessel size reaches the capillary limitation, blood can be modeled using a non-Newtonian constitutive equation. It is assumed two different constraints in addition to the pumping power: the volume constraint or the surface constraint (related to the internal surface of the vessel). For a seek of generality, the relationships are given for an arbitrary number of daughter vessels. It is shown that for a cost function including the volume constraint, classical Murray's law remains valid (i.e. Σ<it>R</it>^{<it>c </it>}= <it>cste </it>with <it>c </it>= 3 is verified and is independent of <it>n</it>, the dimensionless index in the viscosity equation; <it>R </it>being the radius of the vessel). On the contrary, for a cost function including the surface constraint, different values of <it>c </it>may be calculated depending on the value of <it>n</it>.</p> <p>Results</p> <p>We find that <it>c </it>varies for blood from 2.42 to 3 depending on the constraint and the fluid properties. For the Newtonian model, the surface constraint leads to <it>c </it>= 2.5. The cost function (based on the surface constraint) can be related to entropy generation, by dividing it by the temperature.</p> <p>Conclusion</p> <p>It is demonstrated that the entropy generated in all the daughter vessels is greater than the entropy generated in the parent vessel. Furthermore, it is shown that the difference of entropy generation between the parent and daughter vessels is smaller for a non-Newtonian fluid than for a Newtonian fluid.</p

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mappin

Economy and Divorces: Their Impact Over Time on the Self-Employment Rates in Spain

The paper used time-series data and examined the effect of economic and social variables on the male and female self-employment rates in Spain. We also employed cointegration analysis (with and without) structural breaks. We thus find strong evidence that long run relationships exist among the variables. More precisely, we find that the unemployment rates and the ratio of self-employment to employees’ earnings have a positive effect on self-employment, whereas, economic development and divorce rates have a negative effect. Importantly, we find that the economic variables have equal or stronger long run impact on females than males, with both groups reacting to changes in family circumstances. Finally, we show that the short run family circumstances are better predictors of self-employment choices rather than economic factors, with self-employment being a means of adjustment to new personal circumstances and economic needs