Clinical and Genetic Features of Choroideremia in Childhood.

PURPOSE: To review the functional and anatomic characteristics of choroideremia in the pediatric population, aiming to describe the earliest features of the disease and to identify biomarkers useful for monitoring disease progression. DESIGN: Retrospective case series. PARTICIPANTS: Children diagnosed with choroideremia at a single institution. METHODS: Patients were identified using an electronic patient record system. Case notes and retinal imaging (color fundus photography [CFP], spectral-domain [SD] optical coherence tomography [OCT], and fundus autofluorescence [FAF]) then were reviewed. The results of genetic testing also were recorded. MAIN OUTCOME MEASURES: Presenting symptoms, visual acuity, fundus changes (CFP, SD OCT, FAF), and CHM sequencing results. RESULTS: Twenty-nine patients were identified with a mean age at referral of 9 years (range, 3-16 years). CHM mutations were identified in 15 of 19 patients tested. Nyctalopia was the predominant symptom (66%). Five of 29 patients were asymptomatic at presentation. At the final follow-up visit (mean age, 16 years; range, 7-26 years), most maintained excellent visual acuity (mean, 0.98±0.13 decimalized Snellen acuity). The first sign of retinopathy was widespread pigment clumping at the level of the retinal pigment epithelium (RPE). This later evolved to chorioretinal atrophy, most marked in the mid-peripheral retina. Peripapillary atrophy also was an early feature and was progressive in nature. Three different zones of FAF change were visible. Persistence of the inner retinal layers, detected by SD OCT, was visible at presentation in 15 of 27 patients. Subfoveal choroidal thickness decreased with age, whereas central retinal thickness increased over a similar interval. Four patients in whom visual acuity decreased over the follow-up period recorded a reduction in central retinal thickness. CONCLUSIONS: Progressive structural changes occur at a time when central visual function is maintained. Pigmentary changes at the level of the RPE occur early in the disease course. Peripapillary chorioretinal atrophy, central retinal thickness, and subfoveal choroidal thickness are likely to be valuable in monitoring disease progression and should be considered as potential biomarkers in future therapeutic trials

The Fundus Phenotype Associated With The p.Ala243Val BEST1 Mutation

PURPOSE: To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. METHODS: Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. RESULTS: Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P 0.05). CONCLUSION: The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes

Functional and Anatomical Outcomes of Choroidal Neovascularization Complicating Best1-related Retinopathy

PURPOSE: To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). METHODS: Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. RESULTS: Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8-6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6-72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1-10). The median gain in visual acuity was greater in the treated versus the observed group-0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P 0.05 Mann-Whitney U test). CONCLUSION: There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone

Detailed Retinal Imaging In Carriers Of Ocular Albinism

BACKGROUND: Albinism refers to a group of disorders primarily characterized by hypopigmentation. Affected individuals usually manifest both ocular and cutaneous features of the disease, but occasionally hair and skin pigmentation may appear normal. This is the case in ocular albinism, an X chromosome linked disorder resulting from mutation of GPR143. Female carriers may be recognized by a "mud-splatter" appearance in the peripheral retina. The macula is thought to be normal, however. METHODS: Obligate female carriers of pathogenic GPR143 alleles were recruited. Molecular confirmation of disease was performed only for atypical cases. Detailed retinal imaging was performed (colour fundus photography, optical coherence tomography, fundus autofluorescence. RESULTS: Eight individuals were ascertained. A novel GPR143 mutation was identified in one family (p.Gln328Ter). Foveal fundus autofluorescence was subjectively reduced in 6/6 patients imaged. A "tapetal-like" pattern of autofluorescence was visible at the macula in 3/6. Persistence of the inner retinal layers at the fovea was observed in 6/8 females. CONCLUSION: Female carriers of ocular albinism may manifest signs of retinal pigment epithelium mosaicism at the macula and the peripheral fundus. A tapetal-like reflex on fundus autofluorescence may be considered the macular correlate of "mud-splatter.

Depression, sleeping pattern, and suicidal ideation among medical students in Bangladesh: a cross-sectional pilot study

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Background: Depression is a major morbidity and the most common mental disorder among the medical students in medical schools globally. Undergraduate students suffer stress more due to their academic curriculum than the students of other faculties. In low-resource settings like Bangladesh, there is a dearth in research on the mental health of undergraduate medical students. This pilot study was conducted to add to the existing limited evidence by reporting the prevalence of depression and describing sleeping pattern and suicidal tendencies among medical students. Relevantly, we have investigated the overall mental health status among the medical students in Bangladesh. Methods: This cross-sectional study was conducted in two medical colleges of Dhaka between July 2013 and December 2013, among 221 Bangladeshi medical students from first to fifth year. By the convenience sampling technique, data were collected by a pretested, structured, self-administered questionnaire and analysis was done by SPSS version 18.0. Depression was assessed by the validated Patient Health Questionnaire-9 (PHQ-9) tool among the respondents. Goldberg’s General Health Questionnaire (GHQ-28) was used for assessing overall mental health status. Results: Depression was found in 38.9% of participants, with 3.6%, 14.5%, and 20.8% being severe, moderate, and mild depression, respectively. 17.6% of medical students had suicidal tendency or attempted suicide at least once after attending medical school. The sleeping hours were inadequate and altered after starting this stressful academic course. 33.5% of medical students had poor mental health status. There was a statistically significant association between poor mental health status in the age group less than 22 years old and initial academic study year (1st to 3rd of MBBS). Conclusion: The findings are suggestive of a higher prevalence of depression among early-year medical students and marginal predominance in males. Suicidal tendency is also higher. This calls for further investigation with situation analysis, qualitative explorations, and surveys to explore the burden of such disorders in Bangladesh

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

PURPOSE: To evaluate the electrooculogram (EOG) in a large series of patients with Best disease and autosomal recessive bestrophinopathy. METHODS: A retrospective review of consecutive cases at Moorfields Eye Hospital, London, United Kingdom. Patients with Best disease or autosomal recessive bestrophinopathy who, after electrophysiologic testing, had a normal or atypical EOG light rise were identified. Main outcome measure was EOG amplitude, clinical phenotype and genotype. RESULTS: One hundred thirteen patients were identified with likely disease-causing sequence variants in BEST1 (99 Best disease and 14 autosomal recessive bestrophinopathy). Electrooculograms had been performed in 75 patients. Twenty patients (27%) had no detectable light rise (Arden ratio of 100%) and 49 (65%) had Arden ratios of between 100% to 165%. Six patients (8%) were found to have an EOG light rise of >165%. No cases demonstrated significant interocular asymmetry in EOG amplitude. CONCLUSION: The current work provides significant clinical evidence that the EOG phenotype in Best disease and autosomal recessive bestrophinopathy is more variable than currently appreciated. As a normal EOG may occur in the presence of a classical fundus appearance, the consequences of BEST1 mutation may be independently expressed, possibly mediated through differential effects on intracellular calcium homeostasis

Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability.

Background: Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. Methods and results: Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. Conclusions: Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling

Vitamin A deficiency due to bi-allelic mutation of RBP4: There's more to it than meets the eye

Vitamin A deficiency is the leading cause of preventable blindness in children worldwide and results in a well-recognized ocular phenotype. Herein we describe a patient presenting to the eye clinic with a retinal dystrophy and ocular colobomata. This combination of clinical signs and consanguineous pedigree structure suggested a genetic basis for the disease, a hypothesis that was tested using whole genome sequencing. Bi-allelic mutations in RBP4 were identified (c.248+1G>A), consistent with a diagnosis of inherited vitamin A deficiency. We describe a constellation of signs that appear to be characteristic for this disease, increasing clinical awareness of this rare condition

Bioformulation of microbial biocontrol agents for a sustainable agriculture

The application of microbial based biopesticides has become a sustainable alternative to the use of chemicals to prevent yield losses due to plant pathogens. However, microbial based biopesticides are often unsuccessfully formulated and do not meet the demanding regulatory standards required by the agencies, which hinders their commercialization. Hence, an outline on the approaches to attain more effective formulations might be useful for the development of future more effective products. With this aim, this chapter reports the current state of biocontrol strategies and describes the principles of microbial biocontrol formulations. Emphasis is placed on techniques and tools available for the development and characterisation of microbial products. To provide glimpses on the possible formulations, the different existing additives, carriers, inoculation techniques and formulation types are exhaustively reviewed. Finally, requirements and principles for efficacy evaluation of plant protection products in the European Union are include

AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs)