RESUMO
Chimeric antigen receptor (CAR) T-cell therapy has become a novel approach in the treatment of many hematologic malignancies. However, ocular adverse effects have not been well described. This report presents a case of a pediatric patient with relapsed B-cell acute lymphoblastic leukemia with ocular involvement treated with CAR T-cell therapy who developed an exudative retinal detachment likely secondary to an inflammatory response to CAR T-cell therapy. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:113-115.].
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Descolamento Retiniano , Terapia Baseada em Transplante de Células e Tecidos , Criança , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/etiologiaRESUMO
Purpose: The purpose of this paper was to develop a deep learning algorithm to detect retinal vascular leakage (leakage) in fluorescein angiography (FA) of patients with uveitis and use the trained algorithm to determine clinically notable leakage changes. Methods: An algorithm was trained and tested to detect leakage on a set of 200 FA images (61 patients) and evaluated on a separate 50-image test set (21 patients). The ground truth was leakage segmentation by two clinicians. The Dice Similarity Coefficient (DSC) was used to measure concordance. Results: During training, the algorithm achieved a best average DSC of 0.572 (95% confidence interval [CI] = 0.548-0.596). The trained algorithm achieved a DSC of 0.563 (95% CI = 0.543-0.582) when tested on an additional set of 50 images. The trained algorithm was then used to detect leakage on pairs of FA images from longitudinal patient visits. Longitudinal leakage follow-up showed a >2.21% change in the visible retina area covered by leakage (as detected by the algorithm) had a sensitivity and specificity of 90% (area under the curve [AUC] = 0.95) of detecting a clinically notable change compared to the gold standard, an expert clinician's assessment. Conclusions: This deep learning algorithm showed modest concordance in identifying vascular leakage compared to ground truth but was able to aid in identifying vascular FA leakage changes over time. Translational Relevance: This is a proof-of-concept study that vascular leakage can be detected in a more standardized way and that tools can be developed to help clinicians more objectively compare vascular leakage between FAs.
Assuntos
Vasos Retinianos , Uveíte , Algoritmos , Angiofluoresceinografia/métodos , Humanos , Retina , Vasos Retinianos/diagnóstico por imagemRESUMO
One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse-Diagnostic and Statistical Manual (DSM) defined-neuropsychiatric diseases. While involved in numerous cellular functions, Ca(v)1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Ca(v)1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Ca(v)1.2 that are most relevant to psychiatric illness.
Assuntos
Canais de Cálcio Tipo L/genética , Variação Genética/genética , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , HumanosRESUMO
The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental manipulations that are aimed at rendering or preventing depressive-like states. Mice are placed in an inescapable transparent tank that is filled with water and their escape related mobility behavior is measured. The forced swim test is straightforward to conduct reliably and it requires minimal specialized equipment. Successful implementation of the forced swim test requires adherence to certain procedural details and minimization of unwarranted stress to the mice. In the protocol description and the accompanying video, we explain how to conduct the mouse version of this test with emphasis on potential pitfalls that may be detrimental to interpretation of results and how to avoid them. Additionally, we explain how the behaviors manifested in the test are assessed.
Assuntos
Comportamento Animal , Avaliação Pré-Clínica de Medicamentos/métodos , Natação , Animais , Camundongos , Estresse PsicológicoRESUMO
The tail-suspension test is a mouse behavioral test useful in the screening of potential antidepressant drugs, and assessing of other manipulations that are expected to affect depression related behaviors. Mice are suspended by their tails with tape, in such a position that it cannot escape or hold on to nearby surfaces. During this test, typically six minutes in duration, the resulting escape oriented behaviors are quantified. The tail-suspension test is a valuable tool in drug discovery for high-throughput screening of prospective antidepressant compounds. Here, we describe the details required for implementation of this test with additional emphasis on potential problems that may occur and how to avoid them. We also offer a solution to the tail climbing behavior, a common problem that renders this test useless in some mouse strains, such as the widely used C57BL/6. Specifically, we prevent tail climbing behaviors by passing mouse tails through a small plastic cylinder prior to suspension. Finally, we detail how to manually score the behaviors that are manifested in this test.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Elevação dos Membros Posteriores/métodos , Animais , Comportamento Animal , Camundongos , Camundongos Endogâmicos C57BL , Estresse PsicológicoRESUMO
BACKGROUND: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis. METHODS: The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). RESULTS: In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10â»4, 2.1 × 10â»4; p(corrected) = .03, .04) and were consistent across two large datasets. CONCLUSIONS: Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.