Sector Retinitis Pigmentosa: Extending the Molecular Genetics Basis and Elucidating the Natural History

PURPOSE: To determine the genetic background of sector retinitis pigmentosa (RP), natural history, in order to better inform patient counselling. DESIGN: Retrospective case series. METHODS: Review of clinical notes, retinal imaging including color fundus photography (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT), electrophysiological assessment (ERG), and molecular genetic testing was performed in patients with sector RP from a single tertiary referral center. MAIN OUTCOME: Measures: Reporting demographic data, signs and symptoms, visual acuity, molecular genetics, ERG, FAF and OCT findings. RESULTS: Twenty-six molecularly confirmed patients from 23 different families were identified, harboring likely disease-causing variants in nine genes. The mode of inheritance was autosomal recessive (AR, n=6: USH1C, n=2; MYO7A, n=2; CDH3, n=1; EYS, n=1), X-linked (XL, n=4: PRPS1, n=1; RPGR, n=3), and autosomal dominant (AD, n=16: IMPDH1, n=3; RP1, n=3; RHO, n=10), with a mean age of disease onset of 38.5, 30.5 and 39.0 years respectively. Five of these genes have not previously been reported to cause sector RP (PRPS1, MYO7A, EYS, IMPDH1, and RP1). Inferior and nasal predilection was common across the different genotypes and patients tended to maintain good central vision. Progression on serial FAF was observed in RPGR, MYO7A, CDH23, EYS, IMPDH1, RP1 and RHO-associated sector RP. CONCLUSIONS: The genotypic spectrum of the disease is broader than previously reported. The provided longitudinal data will help to provide more accurate patient prognosis and counselling, as well as inform patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments

Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy

PURPOSE: To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. METHODS: Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). RESULTS: The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. CONCLUSIONS: The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy

How participatory is parental consent in low literacy rural settings in low income countries? Lessons learned from a community based study of infants in South India

<p>Abstract</p> <p>Background</p> <p>A requisite for ethical human subjects research is that participation should be informed and voluntary. Participation during the informed consent process by way of asking questions is an indicator of the extent to which consent is informed.</p> <p>Aims</p> <p>The aims of this study were to assess the extent to which parents providing consent for children's participation in an observational tuberculosis (TB) research study in India actively participated during the informed consent discussion, and to identify correlates of that participation.</p> <p>Methods</p> <p>In an observational cohort study of tuberculosis in infants in South India, field supervisors who were responsible for obtaining informed consent noted down questions asked during the informed consent discussions for 4,382 infants who were enrolled in the study. These questions were post-coded by topic. Bivariate and multivariate analysis was conducted to examine factors associated with asking at least one question during the informed consent process.</p> <p>Results</p> <p>In total, 590 out of 4,382 (13.4%) parents/guardians asked any question during the informed consent process. We found that the likelihood of parents asking questions during the informed consent process was significantly associated with education level of either parent both parents being present, and location.</p> <p>Conclusions</p> <p>The findings have implications for planning the informed consent process in a largely rural setting with low levels of literacy. Greater effort needs to be directed towards developing simple participatory communication materials for the informed consent process. Furthermore, including both parents in a discussion about a child's participation in a research study may increase the extent to which consent is truly informed. Finally, continuing efforts need to be made to improve the communication skills of research workers with regard to explaining research processes and putting potential research participants at ease.</p

Relationship between B-type natriuretic peptide levels and echocardiographic indices of left ventricular filling pressures in post-cardiac surgery patients

<p>Abstract</p> <p>Background</p> <p>B-type natriuretic peptide (BNP) is increased in post-cardiac surgery patients, however the mechanisms underlying BNP release are still unclear. In the current study, we aimed to assess the relationship between postoperative BNP levels and left ventricular filling pressures in post-cardiac surgery patients.</p> <p>Methods</p> <p>We prospectively enrolled 134 consecutive patients referred to our Center 8 ± 5 days after cardiac surgery. BNP was sampled at hospital admission and related to the following echocardiographic parameters: left ventricular (LV) diastolic volume (DV), LV systolic volume (SV), LV ejection fraction (EF), LV mass, relative wall thickness (RWT), indexed left atrial volume (_iLAV), mitral inflow E/A ratio, mitral E wave deceleration time (DT), ratio of the transmitral E wave to the Doppler tissue early mitral annulus velocity (E/E').</p> <p>Results</p> <p>A total of 124 patients had both BNP and echocardiographic data. The BNP values were significantly elevated (mean 353 ± 356 pg/ml), with normal value in only 17 patients (13.7%). Mean LVEF was 59 ± 10% (LVEF ≥50% in 108 pts). There was no relationship between BNP and LVEF (p = 0.11), LVDV (p = 0.88), LVSV (p = 0.50), E/A (p = 0.77), DT (p = 0.33) or RWT (p = 0.50). In contrast, BNP was directly related to E/E' (p < 0.001), LV mass (p = 0.006) and _iLAV (p = 0.026). At multivariable regression analysis, age and E/E' were the only independent predictors of BNP levels.</p> <p>Conclusion</p> <p>In post-cardiac surgery patients with overall preserved LV systolic function, the significant increase in BNP levels is related to E/E', an echocardiographic parameter of elevated LV filling pressures which indicates left atrial pressure as a major determinant in BNP release in this clinical setting.</p

Evidence for 'critical slowing down' in seagrass:a stress gradient experiment at the southern limit of its range

The theory of critical slowing down, i.e. the increasing recovery times of complex systems close to tipping points, has been proposed as an early warning signal for collapse. Empirical evidence for the reality of such warning signals is still rare in ecology. We studied this on Zostera noltii intertidal seagrass meadows at their southern range limit, the Banc d'Arguin, Mauritania. We analyse the environmental covariates of recovery rates using structural equation modelling (SEM), based on an experiment in which we assessed whether recovery after disturbances (i.e. seagrass & infauna removal) depends on stress intensity (increasing with elevation) and disturbance patch size (1 m(2) vs. 9 m(2)). The SEM analyses revealed that higher biofilm density and sediment accretion best explained seagrass recovery rates. Experimental disturbances were followed by slow rates of recovery, regrowth occurring mainly in the coolest months of the year. Macrofauna recolonisation lagged behind seagrass recovery. Overall, the recovery rate was six times slower in the high intertidal zone than in the low zone. The large disturbances in the low zone recovered faster than the small ones in the high zone. This provides empirical evidence for critical slowing down with increasing desiccation stress in an intertidal seagrass system

Repeated evolution of self-compatibility for reproductive assurance

Sexual reproduction in eukaryotes requires the fusion of two compatible gametes of opposite sexes or mating types. To meet the challenge of finding a mating partner with compatible gametes evolutionary mechanisms such as hermaphroditism and self-fertilisation have repeatedly evolved. Combining insight from comparative genomics, computer simulations and experimental evolution in fission yeast, we shed light on the conditions promoting separate mating types or self-compatibility by mating-type switching. Analogous to multiple independent transitions between switchers and non-switchers in natural populations mediated by structural genomic changes, novel switching genotypes were readily evolving under selection in experimental populations. Detailed fitness measurements accompanied by computer simulations show the benefits and costs of switching during sexual and asexual reproduction governing the occurrence of both strategies in nature. Our findings illuminate the trade-off between the benefits of reproductive assurance and its fitness costs under benign conditions governing the evolution of self-compatibility