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Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRSs) for schizophrenia (SCZ) and a clinical diagnosis of SCZ, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures in the patient-derived neurons that implicated altered Na+ channel function, action potential interspike interval, and gamma-aminobutyric acid-ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these SCZ patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics.
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Cognición/fisiología , Fenómenos Electrofisiológicos , Células Madre Pluripotentes Inducidas/fisiología , Neuronas/fisiología , Esquizofrenia/fisiopatología , Animales , Línea Celular , Reprogramación Celular , Corteza Cerebral/patología , Humanos , Activación del Canal Iónico , Cinética , Masculino , Fenotipo , Ratas , Esquizofrenia/diagnóstico , Canales de Sodio/metabolismoRESUMEN
Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. Dysfunction of CNS glia is associated with aging-related white matter diseases and neurodegeneration, and ciliopathies are known to affect CNS white matter. To investigate age-related changes in ciliary profile, we examined ciliary length and frequency in the retinogeniculate pathway, a white matter tract commonly affected by diseases of aging but in which expression of cilia has not been characterized. We found expression of Arl13b, a marker of primary cilia, in a small group of Olig2-positive oligodendrocytes in the optic nerve, optic chiasm, and optic tract in young and aged C57BL/6 wild-type mice. While the ciliary length and ciliated oligodendrocyte cells were constant in young mice in the retinogeniculate pathway, there was a significant increase in ciliary length in the anterior optic nerve as compared to the aged animals. Morphometric analysis confirmed a specific increase in the ciliation rate of CC1+ /Olig2+ oligodendrocytes in aged mice compared with young mice. Thus, the prevalence of primary cilia in oligodendrocytes in the visual pathway and the age-related changes in ciliation suggest that they may play important roles in white matter and age-associated optic neuropathies.
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Nervio Óptico , Sustancia Blanca , Animales , Ratones , Ratones Endogámicos C57BL , Oligodendroglía , Neuroglía , MamíferosRESUMEN
BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVES: To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS: This retrospective cohort study included patients recruited between 1 December 2011 and 30 October 2020. They received ICI from 2011 to 2020 with follow-up of outcomes through October 2021. We identified 3668 recipients of ICI therapy who were seen at Massachusetts General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. RESULTS: Compared with other nonepithelial cancers (neuroendocrine, leukaemia, lymphoma, myeloma, sarcoma and central nervous system malignancies), cutaneous squamous cell carcinoma [cSCC; hazard ratio (HR) 3.57, P < 0.001], melanoma (HR 2.09, P < 0.001), head and neck adenocarcinoma (HR 2.13, P = 0.009), genitourinary transitional cell carcinoma (HR 2.15, P < 0.001) and genitourinary adenocarcinoma (HR 1.53, P = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR 0.37, P < 0.001) and cSCC (HR 0.51, P = 0.011). CONCLUSIONS: The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICI therapies. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counselling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.
Cutaneous immune-related adverse events (cirAEs) are the most common complications to occur for oncology patients treated with immune checkpoint inhibitors (ICIs). cirAEs can lead to increased use of healthcare resources and significant morbidity. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. In this study, we aimed to investigate the influence of cancer organ system and histology on the development of cirAEs and survival outcomes. To do this, we included a cohort of patients retrospectively between 1 December 2011 and 30 October 2020. We identified 3668 ICI recipients who were seen at Massachusetts General Brigham and Dana-Farber in Boston, Massachusetts. Of these, 669 people developed cirAEs. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI start, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. We found that, compared with other nonepithelial cancers, patients with cutaneous squamous cell carcinoma (cSCC) and melanoma were at significantly higher risk of cirAEs. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma and cSCC. This study improves our understanding of patients who are at highest risk of developing cirAEs those with melanoma and cSCC. Therefore, many patients could benefit from appropriate counselling and close monitoring by their oncologists and dermatologists throughout ICI therapy.
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Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/mortalidad , Neoplasias/inmunología , Neoplasias/terapia , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/epidemiología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , AdultoRESUMEN
Activity-regulated gene (ARG) expression patterns in the hippocampus (HPC) regulate synaptic plasticity, learning, and memory, and are linked to both risk and treatment responses for many neuropsychiatric disorders. The HPC contains discrete classes of neurons with specialized functions, but cell type-specific activity-regulated transcriptional programs are not well characterized. Here, we used single-nucleus RNA-sequencing (snRNA-seq) in a mouse model of acute electroconvulsive seizures (ECS) to identify cell type-specific molecular signatures associated with induced activity in HPC neurons. We used unsupervised clustering and a priori marker genes to computationally annotate 15,990 high-quality HPC neuronal nuclei from N = 4 mice across all major HPC subregions and neuron types. Activity-induced transcriptomic responses were divergent across neuron populations, with dentate granule cells being particularly responsive to activity. Differential expression analysis identified both upregulated and downregulated cell type-specific gene sets in neurons following ECS. Within these gene sets, we identified enrichment of pathways associated with varying biological processes such as synapse organization, cellular signaling, and transcriptional regulation. Finally, we used matrix factorization to reveal continuous gene expression patterns differentially associated with cell type, ECS, and biological processes. This work provides a rich resource for interrogating activity-regulated transcriptional responses in HPC neurons at single-nuclei resolution in the context of ECS, which can provide biological insight into the roles of defined neuronal subtypes in HPC function.
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Hipocampo , Neuronas , Ratones , Animales , Hipocampo/fisiología , Neuronas/fisiología , Aprendizaje/fisiología , Regulación de la Expresión Génica/genética , Convulsiones , Expresión GénicaRESUMEN
Glycolaldehyde (GAld) is a C2 water-soluble aldehyde produced during the atmospheric oxidation of isoprene and many other species and is commonly found in cloudwater. Previous work has established that glycolaldehyde evaporates more readily from drying aerosol droplets containing ammonium sulfate (AS) than does glyoxal, methylglyoxal, or hydroxyacetone, which implies that it does not oligomerize as quickly as these other species. Here, we report NMR measurements of glycolaldehyde's aqueous-phase reactions with AS, methylamine, and glycine. Reaction rate constants are smaller than those of respective glyoxal and methylglyoxal reactions in the pH range of 3-6. In follow-up cloud chamber experiments, deliquesced glycine and AS seed particles were found to take up glycolaldehyde and methylamine and form brown carbon. At very high relative humidity, these changes were more than 2 orders of magnitude faster than predicted by our bulk liquid NMR kinetics measurements, suggesting that reactions involving surface-active species at crowded air-water interfaces may play an important role. The high-resolution liquid chromatography-electrospray ionization-mass spectrometric analysis of filter extracts of unprocessed AS + GAld seed particles identified sugar-like C6 and C12 GAld oligomers, including proposed product 3-deoxyglucosone, with and without modification by reactions with ammonia to diimine and imidazole forms. Chamber exposure to methylamine gas, cloud processing, and simulated sunlight increased the incorporation of both ammonia and methylamine into oligomers. Many C4-C16 imidazole derivatives were detected in an extract of chamber-exposed aerosol along with a predominance of N-derivatized C6 and C12 glycolaldehyde oligomers, suggesting that GAld is capable of forming brown carbon SOA.
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Aminas , Carbono , Acetaldehído/análogos & derivados , Aerosoles/química , Aminas/química , Amoníaco , Sulfato de Amonio/química , Glicina/química , Glioxal/química , Imidazoles , Metilaminas/química , Piruvaldehído/química , Agua/químicaRESUMEN
BACKGROUND: Interventions to define medical jargon have been shown to improve electronic health record (EHR) note comprehension among crowdsourced participants on Amazon Mechanical Turk (AMT). However, AMT participants may not be representative of the general population or patients who are most at-risk for low health literacy. OBJECTIVE: In this work, we assessed the efficacy of an intervention (NoteAid) for EHR note comprehension among participants in a community hospital setting. METHODS: Participants were recruited from Lowell General Hospital (LGH), a community hospital in Massachusetts, to take the ComprehENotes test, a web-based test of EHR note comprehension. Participants were randomly assigned to control (n=85) or intervention (n=89) groups to take the test without or with NoteAid, respectively. For comparison, we used a sample of 200 participants recruited from AMT to take the ComprehENotes test (100 in the control group and 100 in the intervention group). RESULTS: A total of 174 participants were recruited from LGH, and 200 participants were recruited from AMT. Participants in both intervention groups (community hospital and AMT) scored significantly higher than participants in the control groups (P<.001). The average score for the community hospital participants was significantly lower than the average score for the AMT participants (P<.001), consistent with the lower education levels in the community hospital sample. Education level had a significant effect on scores for the community hospital participants (P<.001). CONCLUSIONS: Use of NoteAid was associated with significantly improved EHR note comprehension in both community hospital and AMT samples. Our results demonstrate the generalizability of ComprehENotes as a test of EHR note comprehension and the effectiveness of NoteAid for improving EHR note comprehension.
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Comprensión , Registros Electrónicos de Salud , Hospitales Comunitarios , HumanosRESUMEN
The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.
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Enfermedades Neurodegenerativas , Proteínas Quinasas , Humanos , Transducción de Señal , Inflamación , ARNRESUMEN
Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer's and Parkinson's disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible and downloadable formats.
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Locus Coeruleus , Núcleo Solitario , Humanos , Perfilación de la Expresión Génica , Sistema Nervioso Central , Norepinefrina , Expresión GénicaRESUMEN
The molecular organization of the human neocortex historically has been studied in the context of its histological layers. However, emerging spatial transcriptomic technologies have enabled unbiased identification of transcriptionally defined spatial domains that move beyond classic cytoarchitecture. We used the Visium spatial gene expression platform to generate a data-driven molecular neuroanatomical atlas across the anterior-posterior axis of the human dorsolateral prefrontal cortex. Integration with paired single-nucleus RNA-sequencing data revealed distinct cell type compositions and cell-cell interactions across spatial domains. Using PsychENCODE and publicly available data, we mapped the enrichment of cell types and genes associated with neuropsychiatric disorders to discrete spatial domains.
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Corteza Prefontal Dorsolateral , Análisis de la Célula Individual , Transcriptoma , Adulto , Humanos , Comunicación Celular , Corteza Prefontal Dorsolateral/metabolismo , Perfilación de la Expresión Génica , Neuronas/metabolismo , Neuronas/fisiología , RNA-Seq , Análisis de Secuencia de ARNRESUMEN
The rising global prevalence of myopia is a growing concern for clinicians, as it predisposes patients to severe ocular pathologies including glaucoma. High myopia can be associated with clinical features that resemble glaucomatous damage, which make an accurate glaucoma diagnosis challenging, particularly among patients with normal intraocular pressures. These patients may also present with established visual field defects which can mimic glaucoma, and standard imaging technology is less useful in disease detection and monitoring due to the lack of normative data for these anatomically unique eyes. Progression over time remains the most critical factor in facilitating the detection of early glaucomatous changes, and thus careful longitudinal follow-up of high-risk myopic patients is the most important aspect of management. Here, we review our current understanding of the complex relationship between myopia and glaucoma, and the diagnostic challenges and limitations of current testing protocols including visual field, intraocular pressure, and imaging. Furthermore, we discuss the clinical findings of two highly myopic patients with suspected glaucoma.
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Glaucoma de Ángulo Abierto , Glaucoma , Miopía , Humanos , Glaucoma de Ángulo Abierto/complicaciones , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/patología , Glaucoma/diagnóstico , Presión Intraocular , Pruebas del Campo Visual , Miopía/diagnósticoRESUMEN
Autophagy is a fundamental catabolic process whereby excessive or damaged cytoplasmic components are degraded through lysosomes to maintain cellular homeostasis. Studies of mTOR signaling have revealed that mTOR controls biomass generation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Primary cilia, the assembly of which depends on kinesin molecular motors, serve as sensory organelles and signaling platforms. Given these pathways' central role in maintaining cellular and physiological homeostasis, a connection between mTOR and primary cilia signaling is starting to emerge in a variety of diseases. In this review, we highlight recent advances in our understanding of the complex crosstalk between the mTOR pathway and cilia and discuss its function in the context of related diseases.
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Cilios , Serina-Treonina Quinasas TOR , Humanos , Cilios/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/fisiología , Autofagia/fisiología , HomeostasisRESUMEN
Objectives: Primary cilia are conserved organelles found in polarized mammalian cells that regulate neuronal growth, migration, and differentiation. Proper cilia formation is essential during eye development. Our previous reports found that both amacrine and retinal ganglion cells (RGCs) contain primary cilia in primate and rodent retinas. However, whether primary cilia are present in the inner retina of human retinal organoids remains unknown. The purpose of this study is to characterize the primary cilia distribution in human embryonic stem cell (hESC-derived retinal organoid development. Materials and Methods: Retinal organoids were differentiated from a hESC line, harvested at various developmental timepoints (day 44-day 266), and immunostained with antibodies for primary cilia, including Arl13b (for the axoneme), AC3, and Centrin3 (for the basal body). AP2α, Prox1, GAD67, Calretinin, GFAP, PKCα, and Chx10 antibodies as well as Brn3b-promoted tdTomato expression were used to visualize retinal cell types. Results: A group of ciliated cells were present in the inner aspects of retinal organoids from day 44 to day 266 in culture. Ciliated Chx10-positive retinal progenitor cells, GFAP-positive astrocytes, and PKCα-positive rod-bipolar cells were detected later during development (day 176 to day 266). Ciliation persisted during all stages of retinal developmental in AP2α-positive amacrine cells, but it was decreased in Brn3b-positive retinal ganglion cells (RGCs) at later time points. Additionally, AC3-positive astrocytes significantly decreased during the later stages of organoid formation. Conclusions: Amacrine cells in retinal organoids retain cilia throughout development, whereas RGC ciliation gradually and progressively decreases with organoid maturation.
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BACKGROUND: RPGR mutations are the most common cause of X-linked retinitis pigmentosa (XLRP). High myopia has been described as a very frequent feature among affected female carriers of XLRP. However, the clinical phenotype of female patients presenting with X-linked RPGR-related high myopia has not been well described. MATERIALS AND METHODS: Retrospective case series of four female patients with RPGR mutations and a diagnosis of high myopia, who presented to two academic eye centers. Clinical data, including age, family history, visual acuity, refractive error, dilated fundus exam, fundus photography, optical coherence tomography, electroretinography, and results of genetic testing, were collected. RESULTS: Three RPGR variants identified in the present study have not been previously associated with myopia in female carriers. One variant (c.2405_2406delAG, p.Glu802Glyfs *32) has been previously associated with a myopic phenotype in a female patient. Patients became symptomatic between the first and sixth decades of life. Myopia-associated tilted optic discs and posterior staphyloma were present in all patients. Two patients presented with intraretinal migration of the retinal pigment epithelium. CONCLUSION: RPGR-related high myopia has been associated with mutations in exons 1-14 and ORF15 in heterozygous females. There is a wide range of visual function among carriers. Although the exact mechanism of RPGR-related high myopia is still unclear, continued molecular diagnosis and description of phenotypes remain a crucial step in understanding the impact of RPGR mutations on visual function in female XLRP carriers.
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Enfermedades Genéticas Ligadas al Cromosoma X , Miopía , Retinitis Pigmentosa , Humanos , Femenino , Estudios Retrospectivos , Proteínas del Ojo/genética , Mutación , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Miopía/diagnóstico , Miopía/genética , Linaje , Análisis Mutacional de ADNRESUMEN
The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.
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Generation of a molecular neuroanatomical map of the human prefrontal cortex reveals novel spatial domains and cell-cell interactions relevant for psychiatric disease. The molecular organization of the human neocortex has been historically studied in the context of its histological layers. However, emerging spatial transcriptomic technologies have enabled unbiased identification of transcriptionally-defined spatial domains that move beyond classic cytoarchitecture. Here we used the Visium spatial gene expression platform to generate a data-driven molecular neuroanatomical atlas across the anterior-posterior axis of the human dorsolateral prefrontal cortex (DLPFC). Integration with paired single nucleus RNA-sequencing data revealed distinct cell type compositions and cell-cell interactions across spatial domains. Using PsychENCODE and publicly available data, we map the enrichment of cell types and genes associated with neuropsychiatric disorders to discrete spatial domains. Finally, we provide resources for the scientific community to explore these integrated spatial and single cell datasets at research.libd.org/spatialDLPFC/.
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Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-ß signaling. Deleting TGF-ß receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling.
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Infarto del Miocardio , Pericitos , Ratones , Animales , Pericitos/metabolismo , Infarto del Miocardio/metabolismo , Corazón , Fibrosis , Matriz Extracelular/metabolismo , Remodelación Ventricular/genética , Miocardio/metabolismoRESUMEN
Recent advances in optogenetics hold promise for vision restoration in degenerative eye diseases. Optogenetics refers to techniques that use light to control the cellular activity of targeted cells. Although optogenetics is a relatively new technology, multiple therapeutic options are already being explored in pre-clinical and phase I/II clinical trials with the aim of developing novel, safe, and effective treatments for major blinding eye diseases, such as glaucoma and retinitis pigmentosa. Optogenetic approaches to visual restoration are primarily aimed at replacing lost or dysfunctional photoreceptors by inserting light-sensitive proteins into downstream retinal neurons that have no intrinsic light sensitivity. Such approaches are attractive because they are agnostic to the genetic causes of retinal degeneration, which raises hopes that all forms of retinal dystrophic and degenerative diseases could become treatable. Optogenetic strategies can also have a far-reaching impact on translational research by serving as important tools to study the pathogenesis of retinal degeneration and to identify clinically relevant therapeutic targets. For example, the CRY-CIBN optogenetic system has been recently applied to animal models of glaucoma, suggesting a potential role of OCRL in the regulation of intraocular pressure in trabecular meshwork. As optogenetic strategies are being intensely investigated, it appears crucial to consider the opportunities and challenges such therapies may offer. Here, we review the more recent promising optogenetic molecules, vectors, and applications of optogenetics for the treatment of retinal degeneration and glaucoma. We also summarize the preliminary results of ongoing clinical trials for visual restoration.
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Degeneración Retiniana , Retinitis Pigmentosa , Animales , Optogenética/métodos , Retina/metabolismo , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/terapia , Retinitis Pigmentosa/genética , Visión Ocular/genéticaRESUMEN
OBJECTIVE: To determine whether a pharmacistled intervention would increase the number of naloxone prescriptions and naloxone administration education in a primary care family medicine setting. DESIGN: Prospective quality improvement intervention in an academic family medicine clinic. METHODS: We surveyed providers about naloxone knowledge, prescribing habits, and prescribing barriers. We identified patients on chronic opioid therapy, through electronic health records for the year 2019. Overdose risk categories based upon morphine milligram equivalent doses and concomitant benzodiazepine use were used to determine patients who met criteria for naloxone. Pharmacists phoned qualified patients to discuss overdose risk and naloxone benefits. Patients who accepted naloxone prescriptions used their local pharmacy through a department-approved standing order set. RESULTS: From the survey results, there were 47 of 54 provider responses, and the majority noted that they do not routinely prescribe naloxone in high-risk patients. The predominant barriers were lack of time during visit and naloxone administration education. The population of patients from chart review included 93 high-risk patients with a mean age of 58 years. During the time of intervention, 71 patients remained eligible for naloxone coprescribing. Of the patients contacted, 29 (40 percent) accepted the intervention prescription, and subsequently, 22 picked up their prescription from the pharmacy. Sixteen received counseling with a support person. Twelve patients had naloxone already at home, and two received counseling with a support person. CONCLUSION: The naloxone prescribing intervention is achievable. The results of this intervention support identifying patients at increased risk of opioid overdose and offer education of a support person for naloxone in a large academic family medicine clinic.
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Sobredosis de Droga , Naloxona , Analgésicos Opioides/efectos adversos , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/prevención & control , Reducción del Daño , Humanos , Persona de Mediana Edad , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Atención Primaria de Salud , Estudios ProspectivosRESUMEN
Cigarette smoking is undoubtedly the single most important risk factor and trigger for vasospastic angina, a condition also known as Prinzmetal angina secondary to coronary artery vasospasm. Even decades before vasospastic angina was first described by Dr. Myron Prinzmetal and his colleagues in 1959, there had been suspected connections between smoking and coronary artery vasospasm in what was alluded to then as "tobacco angina." The intimate relationship between smoking and vasospastic angina has since been extensively researched and validated through decades of epidemiological and clinical studies. The fact that smoking would aggravate vasospastic angina comes with very little surprise, as it has been shown to adversely impact many of the disease processes thought to underlie vasospastic angina, including autonomic dysfunction, endothelial dysfunction, smooth muscle hyperactivity, and genetic susceptibility. While avoidance of smoking is the first logical step in managing smokers with vasospastic angina, there have been reported cases of vasospastic angina paradoxically triggered by smoking cessation or relieved with smoking resumption or nicotine replacement therapy. Thus, there appears to be patient-specific factors that could significantly alter the close connection between smoking and vasospastic angina, warranting further mechanistic investigations. In this review, we will examine this complicated relationship between smoking and vasospastic angina from multiple perspectives (historical, mechanistic, and clinical) and call attention to the "smoking paradox," which, with further elucidation, may provide additional insight into the complex mechanisms of VSA and potentially new strategies to treat medically refractory VSA, at least in selected individuals.
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Neurons can carry information with both the synchrony and rate of their spikes. However, it is unknown whether distinct subtypes of neurons are more sensitive to information carried by synchrony versus rate, or vice versa. Here, we address this question using patterned optical stimulation in slices of somatosensory cortex from mouse lines labelling fast-spiking (FS) and regular-spiking (RS) interneurons. We used optical stimulation in layer 2/3 to encode a 1-bit signal using either the synchrony or rate of activity. We then examined the mutual information between this signal and the interneuron responses. We found that for a synchrony encoding, FS interneurons carried more information in the first five milliseconds, while both interneuron subtypes carried more information than excitatory neurons in later responses. For a rate encoding, we found that RS interneurons carried more information after several milliseconds. These data demonstrate that distinct interneuron subtypes in the neocortex have distinct sensitivities to synchrony versus rate codes.