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2.
JAMA Ophthalmol ; 140(9): 889-893, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35951321

RESUMO

Importance: Familial exudative vitreoretinopathy (FEVR) is a nonsyndromic autosomal dominant retinal disorder commonly caused by variants in the FZD4 gene. This study investigates the potential role beyond ocular abnormalities for FZD4 gene variants in patients with FEVR. Objective: To evaluate the role of FZD4 in symptoms beyond those associated with FEVR through a patient with biallelic variants in FZD4. Design, Setting, and Participants: This case series included the DNA testing and phenotyping of 1 patient proband and her parents, combined with signaling assays, to determine the association of patient-derived compound heterozygous variants on FZD4 signaling and biologic function. Main Outcomes and Measures: FZD4 genes were tested using next-generation sequencing and Sanger sequencing. Cell-based assays measured the effect of the variants on FZD4 signaling. Results: The proband presented with absent red reflexes from complete tractional retinal detachments diagnosed at 3 days of age and failed the newborn screening hearing test. Auditory brainstem response at 6 months of age showed bilateral mild to moderate high-frequency sensorineural hearing loss. The patient manifested developmental delays in speech and walking. Intravenous fluorescein angiography (IVFA) of the patient's parents detected stage 1 FEVR. Genetic testing revealed 2 FZD4 variants in the patient, each variant found in 1 parent. Signaling assays confirmed that the presence of both variants was associated with significantly worse signaling activity compared with the heterozygous state. Conclusions and Relevance: Results of this case series suggest that extraocular syndromic FEVR was associated with FZD4 variants. The decrease in FZD4 signaling owing to the biallelic nature of the disease resulted in hearing deficits, developmental delays, and a more severe retinal phenotype.


Assuntos
Produtos Biológicos , Oftalmopatias Hereditárias , Perda Auditiva Neurossensorial , Doenças Retinianas , DNA/genética , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Vitreorretinopatias Exsudativas Familiares , Feminino , Receptores Frizzled/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Mutação , Linhagem , Doenças Retinianas/diagnóstico
4.
J Am Coll Radiol ; 19(1 Pt B): 122-130, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35033299

RESUMO

PURPOSE: The purpose of this study was to understand how social determinants of health might influence lung cancer screening (LCS) adherence. METHODS: All LCS low-dose CT appointments scheduled at an urban, tertiary care academic medical center in the New England region between January 1, 2015, and December 31, 2018, were included. Demographics, insurance type, information on social determinants of health, and appointment status were obtained from the electronic medical records. Multivariate logistic regression was performed to evaluate the associations between the appointment status and the explanatory variables. RESULTS: During the study period, 2,797 patients had 4,747 scheduled LCS appointments. Forty-one percent of patients had at least one missed appointment, and 32.7% of all scheduled appointments were missed. The retention rate of patients after the baseline examination was approximately 50%. Self-reported Black race was independently associated with 1.5 times the odds of missing appointments compared with White race (P = .012). Patients with Medicaid had 6.1 times the odds of missing appointments compared with patients with private insurance and 4.6 times the odds of missing appointments compared with patients with Medicare (P < .0001). Housing insecurity was a risk factor for failing to follow up after the baseline examination, with an odds ratio of 5.3 (P = .0013). CONCLUSIONS: The high rate of missed LCS appointments underscores the need to improve screening compliance. The identification of specific social determinants of health that contribute to disparities in access to LCS could empower policymakers, hospital systems, and providers to use targeted interventions to promote more equitable access.


Assuntos
Detecção Precoce de Câncer , Neoplasias Pulmonares , Idoso , Agendamento de Consultas , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Medicare , Determinantes Sociais da Saúde , Estados Unidos
5.
J Alzheimers Dis ; 68(1): 159-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814357

RESUMO

Structural neuroimaging is a useful non-invasive biomarker commonly employed to evaluate the integrity of mesial temporal lobe structures that are typically compromised in Alzheimer's disease. Advances in quantitative neuroimaging have permitted the development of automated segmentation protocols (e.g., FreeSurfer) with significantly increased efficiency compared to earlier manual techniques. While these protocols have been found to be suitable for large-scale, multi-site research studies, we were interested in assessing the practical utility and reliability of automated FreeSurfer protocols compared to manual volumetry on routinely acquired clinical scans. Independent validation studies with newer automated segmentation protocols are scarce. Two FreeSurfer protocols for each of two regions of interest-the hippocampus and entorhinal cortex-were compared against manual volumetry. High reliability and agreement was found between FreeSurfer and manual hippocampal protocols, however, there was lower reliability and agreement between FreeSurfer and manual entorhinal protocols. Although based on a the relatively small sample of subjects drawn from a memory clinic (n = 27), our study findings suggest further refinements to improve measurement error and most accurately depict true regional brain volumes using automated segmentation protocols are required, especially for non-hippocampal mesial temporal structures, to achieve maximal utility for routine clinical evaluations.


Assuntos
Córtex Entorrinal/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/normas , Imageamento por Ressonância Magnética/normas , Transtornos da Memória/diagnóstico por imagem , Ambulatório Hospitalar , Idoso , Feminino , Hospitais Privados , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Interpretação de Imagem Assistida por Computador/normas , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
PLoS One ; 11(8): e0158320, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27489958

RESUMO

Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.


Assuntos
Receptores Frizzled/genética , Oxigênio/toxicidade , Retinopatia da Prematuridade/etiologia , Animais , Modelos Animais de Doenças , Feminino , Receptores Frizzled/metabolismo , Genótipo , Haploinsuficiência , Masculino , Camundongos , Microscopia de Fluorescência , Nervo Óptico/irrigação sanguínea , Retina/metabolismo , Retina/patologia , Neovascularização Retiniana , Vasos Retinianos/crescimento & desenvolvimento , Vasos Retinianos/metabolismo , Retinopatia da Prematuridade/genética
7.
Cell Rep ; 16(6): 1701-1716, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27477289

RESUMO

The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma.


Assuntos
Adapaleno/imunologia , Antígeno CD47/imunologia , Melanoma/imunologia , Melanoma/metabolismo , Adapaleno/metabolismo , Antígeno CD47/metabolismo , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Macrófagos/imunologia , Melanoma/patologia , Melanoma/terapia , Metástase Neoplásica , Fagocitose/fisiologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
PLoS One ; 11(5): e0156123, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27213683

RESUMO

Automated segmentation is a useful method for studying large brain structures such as the cerebellum and brainstem. However, automated segmentation may lead to inaccuracy and/or undesirable boundary. The goal of the present study was to investigate whether SegAdapter, a machine learning-based method, is useful for automatically correcting large segmentation errors and disagreement in anatomical definition. We further assessed the robustness of the method in handling size of training set, differences in head coil usage, and amount of brain atrophy. High resolution T1-weighted images were acquired from 30 healthy controls scanned with either an 8-channel or 32-channel head coil. Ten patients, who suffered from brain atrophy because of fragile X-associated tremor/ataxia syndrome, were scanned using the 32-channel head coil. The initial segmentations of the cerebellum and brainstem were generated automatically using Freesurfer. Subsequently, Freesurfer's segmentations were both manually corrected to serve as the gold standard and automatically corrected by SegAdapter. Using only 5 scans in the training set, spatial overlap with manual segmentation in Dice coefficient improved significantly from 0.956 (for Freesurfer segmentation) to 0.978 (for SegAdapter-corrected segmentation) for the cerebellum and from 0.821 to 0.954 for the brainstem. Reducing the training set size to 2 scans only decreased the Dice coefficient ≤0.002 for the cerebellum and ≤ 0.005 for the brainstem compared to the use of training set size of 5 scans in corrective learning. The method was also robust in handling differences between the training set and the test set in head coil usage and the amount of brain atrophy, which reduced spatial overlap only by <0.01. These results suggest that the combination of automated segmentation and corrective learning provides a valuable method for accurate and efficient segmentation of the cerebellum and brainstem, particularly in large-scale neuroimaging studies, and potentially for segmenting other neural regions as well.


Assuntos
Ataxia/diagnóstico por imagem , Mapeamento Encefálico , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Neuroimagem , Tremor/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Ataxia/patologia , Ataxia/fisiopatologia , Ataxia/psicologia , Mapeamento Encefálico/métodos , Mapeamento Encefálico/normas , Tronco Encefálico/patologia , Calibragem , Estudos de Casos e Controles , Cerebelo/patologia , Síndrome do Cromossomo X Frágil/patologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Processamento de Imagem Assistida por Computador/normas , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Neuroimagem/normas , Tremor/patologia , Tremor/fisiopatologia , Tremor/psicologia , Adulto Jovem
9.
Mol Genet Metab Rep ; 1: 407-411, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27896114

RESUMO

Heterozygous mutations in the UBIAD1 gene cause Schnyder corneal dystrophy characterized by abnormal cholesterol and phospholipid deposits in the cornea. Ubiad1 protein was recently identified as Golgi prenyltransferase responsible for biosynthesis of vitamin K2 and CoQ10, a key protein in the mitochondrial electron transport chain. Our study shows that silencing UBIAD1 in cultured human hepatocellular carcinoma cells causes dramatic morphological changes and cholesterol storage in the mitochondria, emphasizing an important role of UBIAD1 in mitochondrial function.

10.
J Biol Chem ; 288(50): 36106-15, 2013 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-24187140

RESUMO

Choline is a precursor for the synthesis of phosphatidylcholine through the CDP-choline pathway. Saccharomyces cerevisiae expresses a single high affinity choline transporter at the plasma membrane, encoded by the HNM1 gene. We show that exposing cells to increasing levels of choline results in two different regulatory mechanisms impacting Hnm1 activity. Initial exposure to choline results in a rapid decrease in Hnm1-mediated transport at the level of transporter activity, whereas chronic exposure results in Hnm1 degradation through an endocytic mechanism that depends on the ubiquitin ligase Rsp5 and the casein kinase 1 redundant pair Yck1/Yck2. We present details of how the choline transporter is a major regulator of phosphatidylcholine synthesis.


Assuntos
Colina/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/metabolismo , Fosfatidilcolinas/biossíntese , Transporte Biológico Ativo , Regulação para Baixo , Endocitose , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Mutação , Estabilidade Proteica , Transporte Proteico , Proteólise , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Vacúolos/metabolismo
11.
J Minim Invasive Gynecol ; 15(3): 301-7, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18439501

RESUMO

STUDY OBJECTIVE: To compare perioperative pain and institutional use for women undergoing transcatheter uterine artery embolization (UAE) and transcatheter uterine artery occlusion (UAO) for the treatment of heavy uterine bleeding associated with uterine leiomyomas. DESIGN: A pilot double-blind, randomized clinical trial (Canadian Task Force classification I). SETTING: Large, university-affiliated community hospital with multiple residency programs including obstetrics and gynecolgoy and radiology. PATIENTS: Premenopausal women with heavy uterine bleeding related to uterine leiomyomas were enrolled. INTERVENTIONS: Either a standard UAE with microspheres or UAO using vascular coils was used. The main outcome measures were analgesic use, institutional stay, and postprocedural numeric pain scales. MEASUREMENTS AND MAIN RESULTS: Sixteen women were enrolled and 14 underwent study procedures (UAE n = 8, UAO n = 6). Baseline Aberdeen Menorrhagia Severity Scale scores, also known as the Ruta scores, were similar in each group (UAE = 54, UAO = 53). Median preprocedural uterine volume was similar for each group (UAE = 557 mL, UAO = 612 mL). The median postprocedural pain scale was less for UAO than UAE (UAO 1, UAE 5; p <.05). Six patients with UAE and no patients with UAO required parenteral narcotic analgesia in the recovery room (p <.05) (median UAO 0 and UAE 1). Patients with UAE used 6 hospital nights and patients with UAO used 1 hospital night (p =.09) (median UAO 0 and UAE 1). Three-month Aberdeen Menorrhagia Severity Scale scores were reduced to a similar degree in each group (UAE = 58%, UAO = 63%). CONCLUSION: Transcatheter UAO is a promising alternative transcatheter technique for the treatment of symptoms related to uterine leiomyomas, with less postprocedural pain, reduced requirements for analgesics, and shorter hospital stays than transcatheter UAE. Although the results of the study are promising, larger-scale trials with longer follow-up are needed to both confirm these results and evaluate the long-term efficacy of transcatheter UAO.


Assuntos
Embolização Terapêutica/instrumentação , Leiomiomatose/irrigação sanguínea , Leiomiomatose/cirurgia , Menorragia/cirurgia , Neoplasias Uterinas/cirurgia , Adulto , Cateterismo/métodos , Embolização Terapêutica/métodos , Feminino , Hospitais Universitários , Humanos , Complicações Intraoperatórias , Pessoa de Meia-Idade , Dor , Projetos Piloto , Complicações Pós-Operatórias , Radiografia Intervencionista/métodos , Útero/irrigação sanguínea
12.
J Clin Oncol ; 25(4): 384-9, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17264334

RESUMO

PURPOSE: Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. PATIENTS AND METHODS: Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. RESULTS: Sixty-five patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. CONCLUSION: The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.


Assuntos
Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/cirurgia , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento
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