Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and ...whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.
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•iPSC-derived motor neurons harboring SOD1 mutations exhibit cell survival deficits•Genetic correction rescues ALS-related phenotypes•RNA-seq reveals expression changes and mitochondrial and ER stress disturbances•Motor neurons exhibit inherent ER stress linked to electrical activity
Motor neurons differentiated from human-ALS-patient-derived iPSCs were used to define transcriptional and functional changes arising from SOD1 mutations, which could be reversed by genome engineering of the SOD1 locus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human induced pluripotent stem cells (iPSCs) present exciting opportunities for studying development and for in vitro disease modeling. However, reported variability in the behavior of iPSCs has ...called their utility into question. We established a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, and extensively characterized the lines with respect to pluripotency and the ability to terminally differentiate. Under standardized procedures in two independent laboratories, 13 of the iPSC lines gave rise to functional motor neurons with a range of efficiencies similar to that of human embryonic stem cells (ESCs). Although three iPSC lines were resistant to neural differentiation, early neuralization rescued their performance. Therefore, all 16 iPSC lines passed a stringent test of differentiation capacity despite variations in karyotype and in the expression of early pluripotency markers and transgenes. This iPSC and ESC test set is a robust resource for those interested in the basic biology of stem cells and their applications.
To report a unique presentation of ciliochoroidal effusion syndrome with central serous-like chorioretinopathy and secondary angle closure following exogenous testosterone use.
A 37 year-old man ...presented with a two week history of blurred vision, elevated intraocular pressure, and myopic shift in his right eye. Gonioscopy showed angle closure. After YAG iridotomy, ultrasound biomicroscopy (UBM) showed ciliochoroidal effusion and anterior rotation of the ciliary processes. Subsequent color fundus photography, enhanced depth imaging optical coherence tomography (EDI-OCT) and near-infrared reduced-illuminance autofluorescence imaging (NIR-RAFI) showed macular striae, choroidal folds, and increased choroidal thickness without presence of subretinal fluid (SRF) or pigment epithelial detachment (PED). Further questioning revealed the patient was using dermal testosterone gel for six months for treatment of hypogonadism. The patient stopped using the testosterone gel, and his visual acuity and intraocular pressure significantly improved six weeks later. Follow-up UBM showed significant improvement of the ciliochoroidal effusion, and repeat multimodal images demonstrated resolution of the macular striae and choroidal folds, and slightly improved choroidal thickness.
Our patient demonstrates a rare case of ciliochoroidal effusion, central serous-like chorioretinopathy, and secondary angle closure that dramatically improved with cessation of testosterone. We believe that this unique clinical constellation is the first to be reported associated with exogenous testosterone use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:A robust predictor of visual outcome in idiopathic intracranial hypertension (IIH) would be useful in management, but there is limited information on this point. The purpose of this study ...was to ascertain whether visual field mean deviation on standard static perimetry performed at diagnosis in a large patient cohort is a reliable predictor of visual outcome.
METHODS:We retrospectively reviewed the automated visual field mean deviations at diagnosis and at final encounter in 79 patients with IIH examined in the neuro-ophthalmology clinics at a single academic medical center from 1999 to 2015.
RESULTS:Of the 79 study patients, 66 (84%) entered with visual field mean deviations of −7 dB or better. Of those 66 patients, 59 (89%) had final mean deviations of −4 dB or better and 33 (56%) had final mean deviations of −2 dB or better. The single patient who had an initial mean deviation of −7 dB or better and a poor final mean deviation (−32 dB) was nonadherent to prescribed medication. Of the 13 (21%) patients who entered with mean deviations worse than −7 dB, 11 (85%) ended up with poor visual outcomes, their final mean deviations ranging from −5 dB to −32 dB. Over half of those 13 patients had required surgery for IIH, often within 3 weeks of diagnosis, owing to severe papilledema and visual dysfunction at the time of diagnosis.
CONCLUSIONS:Based on this retrospective study, patients with IIH who have relatively mild visual dysfunction at diagnosis are likely to have a favorable visual outcome, provided they are adherent to recommended treatment. Many of those with poor visual function at diagnosis will have unfavorable visual outcomes despite aggressive treatment.
To examine demographic and geographic variation in the use of ranibizumab and bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) among Medicare beneficiaries.
...Retrospective cohort study.
Using a 100% sample of Medicare claims data, we evaluated Medicare beneficiaries (N = 195 812) with an index claim for neovascular AMD between July 1, 2006, and June 30, 2009, to determine whether beneficiaries first received ranibizumab or bevacizumab following initial diagnosis.
The overall proportion of beneficiaries that first received ranibizumab for neovascular AMD was 35%, and varied significantly (0.9%–84.6%) across the 306 US hospital referral regions (median = 33%, interquartile range = 17%–49%). Based on hierarchical logistic regression models, the likelihood of receiving ranibizumab declined over time (adjusted odds ratio (aOR) comparing treatment in 2009 vs 2006 = 0.39, P < .001). After we controlled for year of treatment, black beneficiaries were 45% less likely to receive ranibizumab compared to non-blacks (P < .0001). Beneficiaries residing in urban areas (aOR vs isolated rural towns = 1.12, P < .001), in zip codes with higher median incomes, and in the New England and East South Central census regions (aOR vs Pacific census region = 5.57, P < .001; aOR = 3.58, P < .001, respectively) had increased odds of receiving ranibizumab.
The odds of receiving bevacizumab vs ranibizumab as initial therapy for neovascular AMD among US Medicare beneficiaries varied substantially across geographic and demographic groups. Relatively fewer patients received ranibizumab for initial neovascular AMD treatment in 2009 vs 2006. Future research should study the drivers of variation in utilization of these interventions, the extent this variation indicates differential access to these agents, and whether treatment choice impacts patient outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Facial lipoatrophy refers to the loss of adipose tissue and is manifested by flattening or indentation of the convex contours of the face while lipodystrophy is a wider term associated with ...abnormalities of fat tissue distribution and its metabolism, leading to excessive loss and/or accumulation of adipocytes. Although the management of facial lipoatrophy is very important for a patient’s social life and mental health, no treatment framework has been developed due to the unknown nature of the disease manifestation. Early recognition and treatment of the active stage of connective tissue diseases is of essential significance in prevention of subsequent scarring and atrophic lesions. Diagnostic techniques such as computed tomography (CT), magnetic resonance imaging (MRI) and ultrasonography (USG), are used to measure the severity of the lipoatrophy. The present study was designed to provide sequential imaging to visualize the disease progression.
Human induced pluripotent stem cells (iPSCs) present exciting opportunities for studying development and for in vitro disease modeling. However, reported variability in the behavior of iPSCs has ...called their utility into question. We established a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, and extensively characterized the lines with respect to pluripotency and the ability to terminally differentiate. Under standardized procedures in two independent laboratories, 13 of the iPSC lines gave rise to functional motor neurons with a range of efficiencies similar to that of human embryonic stem cells (ESCs). Although three iPSC lines were resistant to neural differentiation, early neuralization rescued their performance. Therefore, all 16 iPSC lines passed a stringent test of differentiation capacity despite variations in karyotype and in the expression of early pluripotency markers and transgenes. This iPSC and ESC test set is a robust resource for those interested in the basic biology of stem cells and their applications.
PURPOSETo report a unique presentation of ciliochoroidal effusion syndrome with central serous-like chorioretinopathy and secondary angle closure following exogenous testosterone use. OBSERVATIONSA ...37 year-old man presented with a two week history of blurred vision, elevated intraocular pressure, and myopic shift in his right eye. Gonioscopy showed angle closure. After YAG iridotomy, ultrasound biomicroscopy (UBM) showed ciliochoroidal effusion and anterior rotation of the ciliary processes. Subsequent color fundus photography, enhanced depth imaging optical coherence tomography (EDI-OCT) and near-infrared reduced-illuminance autofluorescence imaging (NIR-RAFI) showed macular striae, choroidal folds, and increased choroidal thickness without presence of subretinal fluid (SRF) or pigment epithelial detachment (PED). Further questioning revealed the patient was using dermal testosterone gel for six months for treatment of hypogonadism. The patient stopped using the testosterone gel, and his visual acuity and intraocular pressure significantly improved six weeks later. Follow-up UBM showed significant improvement of the ciliochoroidal effusion, and repeat multimodal images demonstrated resolution of the macular striae and choroidal folds, and slightly improved choroidal thickness. CONCLUSIONS AND IMPORTANCEOur patient demonstrates a rare case of ciliochoroidal effusion, central serous-like chorioretinopathy, and secondary angle closure that dramatically improved with cessation of testosterone. We believe that this unique clinical constellation is the first to be reported associated with exogenous testosterone use.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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