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1.
Am J Rhinol Allergy ; : 19458924211041438, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34546814

RESUMO

BACKGROUND: Intranasal corticosteroids (INCS), oral antihistamines (POAH), and allergen-specific immunotherapy (ASIT) are widely used in the treatment of allergic rhinitis (AR); however, appraisal of treatment effect has been heterogenous, and few studies have interpreted these outcomes in context with measures of nasal airflow. OBJECTIVE: To provide a systematic review and meta-analysis of randomized placebo-controlled trials for common therapy classes for AR to assess standardized treatment effect on validated patient-reported outcomes and physiologic measures of airflow. METHODS: A systematic search was performed in PubMed, Scopus, OVID, and Cochrane library databases to identify randomized controlled trials meeting inclusion criteria. Treatment effects of INCS, POAH, and ASIT on total nasal symptom score (TNSS), visual analog scale (VAS), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and peak nasal inspiratory flow (PNIF) were analyzed by meta-analysis. RESULTS: Twenty-two studies with 4673 AR patients were identified, with 5 INCS, 8 POAH, and 9 ASIT trials. INCS improved TNSS (mean difference [MD] 0.90; P = .002) and PNIF (MD 13.31 L/min [P = .0007]. POAH improved quality of life assessed by RQLQ [MD 0.36; P < .001], but no improvement was found in PNIF. ASIT improved RQLQ [MD 0.65; P < .001], with a trend toward improvement in TNSS. CONCLUSION: Overall, INCS resulted in a clinically and statistically meaningful improvement in symptom scores and physiologic measures in AR. POAH and ASIT both improved symptom scores and quality of life, but their impacts upon nasal airflow are uncertain. There is a lack of studies assessing the effect of INCS on quality of life and the effect of POAH on symptom severity, particularly for mild AR. Future studies should assess the effect of treatment for each of these patient-reported measures.

2.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437090

RESUMO

The ability to perceive and respond to environmental stimuli emerges in the absence of sensory experience. Spontaneous retinal activity prior to eye opening guides the refinement of retinotopy and eye-specific segregation in mammals, but its role in the development of higher-order visual response properties remains unclear. Here, we describe a transient window in neonatal mouse development during which the spatial propagation of spontaneous retinal waves resembles the optic flow pattern generated by forward self-motion. We show that wave directionality requires the same circuit components that form the adult direction-selective retinal circuit and that chronic disruption of wave directionality alters the development of direction-selective responses of superior colliculus neurons. These data demonstrate how the developing visual system patterns spontaneous activity to simulate ethologically relevant features of the external world and thereby instruct self-organization.


Assuntos
Fluxo Óptico , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Visão Ocular/fisiologia , Vias Visuais , Potenciais de Ação , Células Amácrinas/fisiologia , Animais , Animais Recém-Nascidos , Axônios/fisiologia , Proteínas do Citoesqueleto/genética , Camundongos , Movimento (Física) , Mutação , Piridazinas/farmacologia , Receptores de GABA-A/metabolismo , Retina/crescimento & desenvolvimento , Análise Espaço-Temporal , Colículos Superiores/fisiologia
3.
Otol Neurotol ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34420022

RESUMO

OBJECTIVE: To examine audiologic outcomes and operative considerations for patients undergoing subtotal petrosectomy (STP) followed by implantable hearing restoration. STUDY DESIGN: Retrospective review. SETTING: Tertiary academic referral hospital. PATIENTS: All patients who underwent STP and implantable hearing restoration from 2014 to 2020. INTERVENTIONS: Single or staged STP with cochlear implantation (CI) or placement of an osseointegrated hearing implant (OHI). MAIN OUTCOME MEASURES: Indications for STP and CI or OHI; postoperative complication and reoperation rates; audiologic outcomes through speech recognition thresholds, AzBio sentence scores, and consonant-nucleus-consonant scores. RESULTS: Twenty-six adults (age 33-85) and six children (age 1-17) underwent 37 STP procedures with 33 CIs and four OHI. Thirty-one cases were planned single-stage, but six (16%) cases required revision surgery postoperatively due to refractory postauricular infection and breakdown of wound closure. Therefore, 25 cases were single procedures and 12 were staged. Indications for staged procedures included extensive cholesteatoma (n = 5, 42%), chronic middle ear inflammation (n = 5, 42%), and osteoradionecrosis (n = 2, 17%). No patients with OHI required revision surgery. For patients undergoing CI, the mean speech recognition thresholds improved from 80 ±â€Š21 dB to 31 ±â€Š9 dB (p < 0.001), mean aided AzBio scores improved from 11% to 43% (p = 0.002) and aided consonant-nucleus-consonant word scores improved from 6% to 47% (p < 0.001) in quiet. CONCLUSIONS: Subtotal petrosectomy is effective for creating a safe, dry ear in patients with chronic inflammation or anatomically challenging ears. Rehabilitative hearing options following STP can be achieved safely, restoring hearing to an acceptable level with CI. Careful consideration should be undertaken to approach as a single or staged procedure.

4.
Ear Hear ; 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34282088

RESUMO

OBJECTIVE: To examine the prevalence of hearing impairment in children with hypothyroidism, and to characterize clinical and subclinical hearing loss by examining cochlear function, auditory brainstem pathways, and integration of the auditory system as a whole. DESIGN: An electronic search was conducted using PubMed, Scopus, and Cochrane Library databases. This systematic review was performed in accordance with the PRISMA guidelines. Original observational studies that utilized audiological tests for auditory system evaluations in hypothyroidism were included. A total of 2004 studies were found in the search, with 23 studies meeting the inclusion criteria. RESULTS: The pooled prevalence of hearing loss was 16.1% [95% confidence interval 10.7, 22.4] for children with congenital hypothyroidism. Hearing thresholds at pure-tone averages (0.5-2 kHz) were 1.6 dB [95% confidence interval 1.7, 4.8] higher for children with hypothyroidism compared to age-matched controls. Cochlear dysfunction was detected at middle frequencies (1-3 kHz) by otoacoustic emission testing, indicating abnormalities of hair cell function or cochlear integration. Retrocochlear involvement was detected on auditory brainstem response (ABR), with prolonged Wave I indicating a peripheral conduction abnormality localized to the middle or inner ear and eighth cranial nerve. CONCLUSIONS: Children with hypothyroidism have a higher prevalence of hearing loss than children without hypothyroidism. For children with congenital hypothyroidism, evidence of subclinical abnormalities at the level of the cochlea and eighth cranial nerve are present despite early initiation of levothyroxine therapy. Dysfunction of the auditory system might begin with predominance of peripheral conduction abnormalities early in development.

5.
Otolaryngol Head Neck Surg ; : 1945998211029527, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34253107

RESUMO

OBJECTIVE: To determine the impact of treatment for patients with nasal obstruction secondary to allergic rhinitis (AR) and nasal septal deviation (NSD) on sleep quality. DATA SOURCES: Primary studies were identified though PubMed, Scopus, Cochrane Library, and Web of Science. REVIEW METHODS: A systematic review was performed by querying databases for articles published through August 2020. Studies were included that reported on objective sleep parameters (apnea-hypopnea index) and sinonasal and sleep-specific patient-reported outcome measures: Rhinoconjunctivitis Quality of Life Questionnaire, Nasal Obstruction Symptom Evaluation, Epworth Sleepiness Scale (EpSS), and Pittsburgh Sleep Quality Index (PSQI). RESULTS: The database search yielded 1414 unique articles, of which 28 AR and 7 NSD studies were utilized for meta-analysis. A total of 9037 patients (8515 with AR, 522 with NSD) were identified with a mean age of 35.0 years (35.3 for AR, 34.0 for NSD). Treatment for AR and NSD significantly improved subjective sleep quality. For AR, the EpSS mean difference was -1.5 (95% CI, -2.4 to -0.5; P = .002) and for the PSQI, -1.7 (95% CI, -2.1 to -1.2; P < .00001). For NSD, the EpSS mean difference was -3.2 (95% CI, -4.2 to -2.2; P < .00001) and for the PSQI, -3.4 (95% CI, -6.1 to -0.6; P = .02). CONCLUSION: Subjective sleep quality significantly improved following treatment for AR and NSD. There were insufficient data to demonstrate that objective metrics of sleep quality similarly improved.

6.
Head Neck Pathol ; 15(3): 935-944, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33788136

RESUMO

In a previous study, we found interobserver agreement among 88 board-certified pathologists evaluating perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) was fair, and participants most often used the following criteria: (1) tumor invading the perineurium, (2) tumor surrounding a nerve. In this study, we aimed to determine whether application of these most commonly used criteria may improve interobserver agreement. 512 pathologists were invited to participate in a web-based survey. Participants were asked to assess the presence/absence of PNI in a set of OSCC photomicrographs by applying each of the two criteria above. The survey was completed by 84 board-certified pathologists [mean age: 52 years (range 31-81), mean years in practice: 19 (range 1-56)]. Interobserver agreement was moderate (k = 0.46, 95% CI 0.45-0.46) when using definition #1 (tumor invading the perineurium) and fair (k = 0.24, 95% CI 0.23-0.25) when using definition #2 (tumor surrounding a nerve). By comparison, interobserver agreement was fair (k = 0.36, 95% CI 0.35-0.37) among phase 1 participants asked to evaluate these photomicrographs as they would in their pathology practice. Differences in kappa between definition #1 and phase 1, definition #2 and phase 2, and definition #1 and #2 were statistically significant (p < 0.001). Compared to our prior study based on pathologists' personal views, the current study shows improved interobserver agreement with application of the criterion, "tumor invading the perineurium." However, further work is needed to delineate concise, objective, and more reproducible criteria for histopathologic assessment of PNI.

7.
Int Forum Allergy Rhinol ; 11(9): 1367-1377, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33773058

RESUMO

BACKGROUND: Rhinologists often encounter a broad spectrum of allergic rhinitis (AR) and nonallergic rhinitis (NAR) patients, who can be variably classified based upon timing and severity of disease. Our understanding of the varied quality of life (QOL) impact in different classifications of rhinitis is limited. Thus a more comprehensive understanding of the impact of rhinitis upon our patients, as measured by both patient reported outcome measures (PROMs) and clinical physiologic measures, as well as unique factors associated with disease severity is needed. METHODS: A systematic search of databases was performed to identify AR and NAR studies reporting Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), total nasal symptom score (TNSS), or visual analogue scale (VAS) scores, and physiologic measures including peak nasal inspiratory flow (PNIF) and nasal airflow. Relationships between PROMs, physiologic measures, and associated factors (e.g., allergic status, disease duration) were assessed by weighted correlations and meta-regressions. RESULTS: A total of 171 studies reporting on 33,843 patients were included. Symptoms were more severe in AR than NAR on VAS (p < 0.001). Classification based upon Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines demonstrated differences in PROM severity. There was no significant correlation between PROMs and demographic factors, comorbidities, or physiologic measures. Meta-regression identified a correlation between worse RQLQ scores and shorter disease duration (r = -0.4, p < 0.001). CONCLUSION: Rhinitic patients have more severe impact upon QOL in the presence of allergy with variable impact upon specific symptom subdomains. PROMs do not correlate with common demographic factors, comorbidities, or physiologic measures of nasal airflow.

8.
J Neurosci ; 41(7): 1489-1504, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33397711

RESUMO

Intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit melanopsin-dependent light responses that persist in the absence of rod and cone photoreceptor-mediated input. In addition to signaling anterogradely to the brain, ipRGCs signal retrogradely to intraretinal circuitry via gap junction-mediated electrical synapses with amacrine cells (ACs). However, the targets and functions of these intraretinal signals remain largely unknown. Here, in mice of both sexes, we identify circuitry that enables M5 ipRGCs to locally inhibit retinal neurons via electrical synapses with a nonspiking GABAergic AC. During pharmacological blockade of rod- and cone-mediated input, whole-cell recordings of corticotropin-releasing hormone-expressing (CRH+) ACs reveal persistent visual responses that require both melanopsin expression and gap junctions. In the developing retina, ipRGC-mediated input to CRH+ ACs is weak or absent before eye opening, indicating a primary role for this input in the mature retina (i.e., in parallel with rod- and cone-mediated input). Among several ipRGC types, only M5 ipRGCs exhibit consistent anatomical and physiological coupling to CRH+ ACs. Optogenetic stimulation of local CRH+ ACs directly drives IPSCs in M4 and M5, but not M1-M3, ipRGCs. CRH+ ACs also inhibit M2 ipRGC-coupled spiking ACs, demonstrating direct interaction between discrete networks of ipRGC-coupled interneurons. Together, these results demonstrate a functional role for electrical synapses in translating ipRGC activity into feedforward and feedback inhibition of local retinal circuits.SIGNIFICANCE STATEMENT Melanopsin directly generates light responses in intrinsically photosensitive retinal ganglion cells (ipRGCs). Through gap junction-mediated electrical synapses with retinal interneurons, these uniquely photoreceptive RGCs may also influence the activity and output of neuronal circuits within the retina. Here, we identified and studied an electrical synaptic circuit that, in principle, could couple ipRGC activity to the chemical output of an identified retinal interneuron. Specifically, we found that M5 ipRGCs form electrical synapses with corticotropin-releasing hormone-expressing amacrine cells, which locally release GABA to inhibit specific RGC types. Thus, ipRGCs are poised to influence the output of diverse retinal circuits via electrical synapses with interneurons.


Assuntos
Inibição Neural/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Células Amácrinas/fisiologia , Animais , Hormônio Liberador da Corticotropina/fisiologia , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Junções Comunicantes/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Optogenética , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Opsinas de Bastonetes/metabolismo , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia
9.
Ann Otol Rhinol Laryngol ; 130(3): 245-253, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32627567

RESUMO

OBJECTIVE(S): Negative pressure pulmonary edema (NPPE) is a rare perioperative complication with a potentially fatal outcome. The aim of this study was to perform a systematic review of NPPE in adult otolaryngology procedures with the goal of identifying risk factors, clinical presentation, diagnosis, management and outcomes. METHODS: Systematic review performed using PubMed, Scopus, Web of Science, and Cochrane databases. RESULTS: Sixty-nine studies including data from 87 individual patients were included in this review. Fifty-six (68%) patients were male and the average patient age was 37 years old. Type 1 NPPE occurred in 63 (72%) cases, while type 2 NPPE accounted for 20 (23%) cases. The most common procedures leading to NPPE were septoplasty, rhinoplasty or sinus surgery (n = 22, 25%), directly laryngoscopy or bronchoscopy (n = 13, 15%), and tracheostomy or cricothyroidotomy (n = 11, 13%). The most employed treatment options included diuretics (n = 55, 63%) and mechanical ventilation (n = 54, 62%). Seventy-eight (90%) patients made a full recovery with an average time to NPPE resolution of 33 hours and an average length of hospitalization of 5.6 days. Five (6%) patients had a long-term morbidity and four (5%) patients died, with age and ICU stay increasing risk for death and long-term morbidity (OR 1.044 and 7.42, respectively, P < .05). CONCLUSION: Septoplasty, rhinoplasty and sinus surgery account for the majority of NPPE cases in adult otolaryngology procedures. Young, healthy patients are the most commonly involved with a slight male predominance. The vast majority of patients recover fully, however there is a significant risk for morbidity and mortality.


Assuntos
Procedimentos Cirúrgicos Otorrinolaringológicos , Complicações Pós-Operatórias/epidemiologia , Edema Pulmonar/epidemiologia , Manuseio das Vias Aéreas , Obstrução das Vias Respiratórias/complicações , Anestesia Geral , Broncoscopia , Cuidados Críticos , Cianose/fisiopatologia , Dispneia/fisiopatologia , Endoscopia , Hemoptise/fisiopatologia , Humanos , Hipóxia/fisiopatologia , Intubação Intratraqueal , Laringismo/complicações , Laringoscopia , Procedimentos Cirúrgicos Nasais , Oxigenoterapia , Seios Paranasais/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/terapia , Pressão , Edema Pulmonar/etiologia , Edema Pulmonar/fisiopatologia , Edema Pulmonar/terapia , Insuficiência Respiratória/fisiopatologia , Rinoplastia , Tórax , Traqueostomia
10.
Int Forum Allergy Rhinol ; 11(7): 1074-1086, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33275331

RESUMO

BACKGROUND: Rhinologic disease can be responsible for systemic symptoms affecting mood, cognition, and sleep. It is unclear whether sleep disturbance in specific rhinologic disorders (chronic rhinosinusitis [CRS], rhinitis, and nasal septal deviation [NSD]) is an obstructive phenomenon or due to other mechanisms. In this review we examine the impact of CRS, rhinitis, and NSD on objective and subjective sleep outcome metrics and draw comparisons to normal controls and patients with known obstructive sleep apnea (OSA). METHODS: A systematic review of 4 databases (PubMed, Scopus, Cochrane Library, and Web of Science) was performed. Studies reporting on objective (apnea-hypopnea index [AHI], respiratory disturbance index [RDI], oxygen nadir) and subjective (Epworth Sleepiness Scale [EpSS], Pittsburgh Sleep Quality Index [PSQI], Fatigue Severity Scale [FSS]) sleep parameters and disease-specific patient-reported outcome measures (PROMs; 22-item Sino-Nasal Outcome Test [SNOT-22], Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ], Nasal Obstruction Symptom Evaluation [NOSE]) were included. RESULTS: The database search yielded 1414 unique articles, of which 103 were included for analysis. Baseline PROMs were at the high end of normal to abnormal for all 3 conditions: EpSS: CRS (9.8 ± 4.0), rhinitis (9.7 ± 4.3), and NSD (8.9 ± 4.6); and PSQI: CRS (11.0 ± 4.5), rhinitis (6.1 ± 3.7), and NSD (8.6 ± 3.5). Objective measures demonstrated a mild to moderate OSA in the studied diseases: AHI: CRS (10.4 ± 11.5), rhinitis (8.6 ± 8.8), and NSD (13.0 ± 6.9). There were significant differences when compared with reported norms in all measured outcomes (p < 0.001). CONCLUSION: Sleep quality is impacted by rhinologic (CRS, rhinitis, NSD) disease. There is likely a mild obstructive component contributing to poor sleep, but other contributing factors may be involved.

12.
Anesth Analg ; 130(6): 1516-1523, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384341

RESUMO

BACKGROUND: Postoperative cognitive dysfunction (POCD) and delirium are the most common perioperative cognitive complications in older adults undergoing surgery. A recent study of cardiac surgery patients suggests that physical frailty is a risk factor for both complications. We sought to examine the relationship between preoperative frailty and postoperative delirium and preoperative frailty and POCD after major noncardiac surgery. METHODS: We performed a prospective cohort study of patients >65 years old having major elective noncardiac surgery with general anesthesia. Exclusion criteria were preexisting dementia, inability to consent, cardiac, intracranial, or emergency surgery. Preoperative frailty was determined using the FRAIL scale, a simple questionnaire that categorizes patients as robust, prefrail, or frail. Delirium was assessed with the Confusion Assessment Method for the intensive care unit (CAM-ICU) twice daily, starting in the recovery room until hospital discharge. All patients were assessed with neuropsychological tests (California Verbal Learning Test II, Trail Making Test, subtests from the Wechsler Adult Intelligence Scale, Logical Memory Story A, Immediate and Delayed Recall, Animal and Vegetable verbal fluency, Boston Naming Test, and the Mini-Mental Status Examination) before surgery and at 3 months afterward. RESULTS: A total of 178 patients met inclusion criteria; 167 underwent major surgery and 150 were available for follow-up 3 months after surgery. The median age was 70 years old. Thirty-one patients (18.6%) tested as frail, and 72 (43.1%) prefrail before surgery. After adjustment for baseline cognitive score, age, education, surgery duration, American Society of Anesthesiologists (ASA) physical status, type of surgery, and sex, patients who tested frail or prefrail had an estimated 2.7 times the odds of delirium (97.5% confidence interval, 1.0-7.3) when compared to patients who were robust. There was no significant difference between the proportion of POCD between patients who tested as frail, prefrail, or robust. CONCLUSIONS: After adjustment for baseline cognition, testing as frail or prefrail with the FRAIL scale is associated with increased odds of postoperative delirium, but not POCD after noncardiac surgery.


Assuntos
Transtornos Cognitivos/prevenção & controle , Delírio/complicações , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Fragilidade/complicações , Complicações Cognitivas Pós-Operatórias , Idoso , Cognição , Interpretação Estatística de Dados , Eletroencefalografia , Feminino , Seguimentos , Idoso Fragilizado , Avaliação Geriátrica , Humanos , Masculino , Rememoração Mental , Testes Neuropsicológicos , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários
13.
Aesthet Surg J ; 40(5): NP314-NP319, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-31600380

RESUMO

BACKGROUND: YouTube is increasingly being utilized as a major educational resource by patients. It is important for plastic surgeons to understand the quality and characteristics of videos that patients are likely to view about procedures of interest. OBJECTIVES: The aim of this study was to evaluate the quality of the videos that patients are most likely to encounter when searching YouTube for the most common cosmetic plastic surgery procedures. METHODS: Based on Google Trends data, the most searched medical and colloquial terms were identified for common cosmetic surgery procedures: "abdominoplasty," "tummy tuck," "breast augmentation," "boob job," "liposuction," "lipo," "mastopexy," "breast lift," "reduction mammoplasty," and "breast reduction." On YouTube, videos were searched by relevance (default) and view count; the top 10 results were collected in each group and rated according to the DISCERN criteria. Each video was assigned an overall and bias DISCERN score (DS). A score of 1 indicates high bias and low overall quality and a score of 5 indicates the opposite. RESULTS: In total, 143 unique videos were identified, which resulted in a mean bias DS of 2.29 and mean overall DS of 2.44. Seventy-two videos included US board-certified plastic surgeons and 58 were classified as patient experience. Videos had 667,373,209 total views and were an average of 4.27 years old. Videos including US board-certified plastic surgeons were of significantly higher quality and showed lower bias than videos without these practitioners (P < 0.05). CONCLUSIONS: Overall, YouTube videos showed high bias and low quality. Plastic surgeons should be aware of this popular resource and counsel patients about the bias that is often present. Plastic surgeons and academic plastic surgery organizations should strive to upload high-quality, unbiased videos to provide patients with a more appropriate resource.


Assuntos
Mídias Sociais , Cirurgiões , Cirurgia Plástica , Pré-Escolar , Humanos , Disseminação de Informação , Gravação em Vídeo
14.
Sci Transl Med ; 11(512)2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578241

RESUMO

Tumor necrosis factor receptor 2 (TNFR2) is the alternate receptor for TNF and can mediate both pro- and anti-inflammatory activities of T cells. Although TNFR2 has been linked to enhanced suppressive activity of regulatory T cells (Tregs) in autoimmune diseases, the viability of TNFR2 as a target for cancer immunotherapy has been underappreciated. Here, we show that new murine monoclonal anti-TNFR2 antibodies yield robust antitumor activity and durable protective memory in multiple mouse cancer cell line models. The antibodies mediate potent Fc-dependent T cell costimulation and do not result in significant depletion of Tregs Corresponding human agonistic monoclonal anti-TNFR2 antibodies were identified and also had antitumor effects in humanized mouse models. Anti-TNFR2 antibodies could be developed as a novel treatment option for patients with cancer.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/terapia , Modelos Animais de Doenças , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
15.
Cancer Res ; 79(15): 3928-3939, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31189649

RESUMO

Fibroblast activation is a crucial step in tumor growth and metastatic progression. Activated fibroblasts remodel the extracellular matrix (ECM) in primary tumor and metastatic microenvironments, exerting both pro- and antitumorigenic effects. However, the intrinsic mechanisms that regulate the activation of fibroblasts are not well-defined. The signaling axis comprising the calcium-activated Ser/Thr phosphatase calcineurin (CN), and its downstream target nuclear factor of activated T cells, has been implicated in endothelial (EC) and immune cell activation, but its role in fibroblasts is not known. Here, we demonstrate that deletion of CN in fibroblasts in vitro altered fibroblast morphology and function consistent with an activated phenotype relative to wild-type fibroblasts. CN-null fibroblasts had a greater migratory capacity, increased collagen secretion and remodeling, and promoted more robust EC activation in vitro. ECM generated by CN-null fibroblasts contained more collagen with greater alignment of fibrillar collagen compared with wild-type fibroblast-derived matrix. These differences in matrix composition and organization imposed distinct changes in morphology and cytoskeletal architecture of both fibroblasts and tumor cells. Consistent with this in vitro phenotype, mice with stromal CN deletion had a greater incidence and larger lung metastases. Our data suggest that CN signaling contributes to the maintenance of fibroblast homeostasis and that loss of CN is sufficient to promote fibroblast activation. SIGNIFICANCE: Calcineurin signaling is a key pathway underlying fibroblast homeostasis that could be targeted to potentially prevent fibroblast activation in distant metastatic sites.


Assuntos
Calcineurina/metabolismo , Fibroblastos/metabolismo , Animais , Progressão da Doença , Humanos , Camundongos , Fenótipo
16.
Psychon Bull Rev ; 25(6): 2245-2253, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29582377

RESUMO

Observers perceive objects in the world as stable over space and time, even though the visual experience of those objects is often discontinuous and distorted due to masking, occlusion, camouflage, or noise. How are we able to easily and quickly achieve stable perception in spite of this constantly changing visual input? It was previously shown that observers experience serial dependence in the perception of features and objects, an effect that extends up to 15 seconds back in time. Here, we asked whether the visual system utilizes an object's prior physical location to inform future position assignments in order to maximize location stability of an object over time. To test this, we presented subjects with small targets at random angular locations relative to central fixation in the peripheral visual field. Subjects reported the perceived location of the target on each trial by adjusting a cursor's position to match its location. Subjects made consistent errors when reporting the perceived position of the target on the current trial, mislocalizing it toward the position of the target in the preceding two trials (Experiment 1). This pull in position perception occurred even when a response was not required on the previous trial (Experiment 2). In addition, we show that serial dependence in perceived position occurs immediately after stimulus presentation, and it is a fast stabilization mechanism that does not require a delay (Experiment 3). This indicates that serial dependence occurs for position representations and facilitates the stable perception of objects in space. Taken together with previous work, our results show that serial dependence occurs at many stages of visual processing, from initial position assignment to object categorization.


Assuntos
Percepção Espacial/fisiologia , Percepção Visual/fisiologia , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
17.
Neurology ; 89(15): 1633-1642, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-28916533

RESUMO

OBJECTIVE: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)-in patients clinically diagnosed with these conditions. METHODS: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models. RESULTS: Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04-1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81-1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRN mutation carriers) revealed a higher prevalence of female patients with GRN-related FTD (RR 1.33, 95% CI 1.09-1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95-1.55). CONCLUSIONS: Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression.


Assuntos
Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Demência Frontotemporal/epidemiologia , Mutação/genética , Proteína C9orf72 , Bases de Dados Bibliográficas/estatística & dados numéricos , Feminino , Demência Frontotemporal/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Progranulinas , Proteínas/genética , Fatores Sexuais
18.
J Biopharm Stat ; 27(6): 933-944, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28296570

RESUMO

Noninferiority multiregional clinical trials (MRCTs) have recently received increasing attention in drug development. While a major goal in an MRCT is to estimate the global treatment effect, it is also important to assess the consistency of treatment effects across multiple regions. In this paper, we propose an intuitive definition of consistency of noninferior treatment effects across regions under the random-effects modeling framework. Specifically, we quantify the consistency of treatment effects by the percentage of regions that meet a predefined treatment margin. This new approach enables us to achieve both goals in one modeling framework. We propose to use a signed likelihood ratio test for testing the global treatment effect and the consistency of noninferior treatment effects. In addition, we provide guidelines for the allocation rule to achieve optimal power for testing consistency among multiple regions. Extensive simulation studies are conducted to examine the performance of the proposed methodology. An application to a real data example is provided.


Assuntos
Aprovação de Drogas/estatística & dados numéricos , Saúde Global/estatística & dados numéricos , Modelos Estatísticos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Aprovação de Drogas/métodos , Humanos , Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tamanho da Amostra , Resultado do Tratamento
19.
J Vis ; 16(15): 16, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28006066

RESUMO

Object identities somehow appear stable and continuous over time despite eye movements, disruptions in visibility, and constantly changing visual input. Recent results have demonstrated that the perception of orientation, numerosity, and facial identity is systematically biased (i.e., pulled) toward visual input from the recent past. The spatial region over which current orientations or face identities are pulled by previous orientations or identities, respectively, is known as the continuity field, which is temporally tuned over the past several seconds (Fischer & Whitney, 2014). This perceptual pull could contribute to the visual stability of objects over short time periods, but does it also address how perceptual stability occurs during visual discontinuities? Here, we tested whether the continuity field helps maintain perceived object identity during occlusion. Specifically, we found that the perception of an oriented Gabor that emerged from behind an occluder was significantly pulled toward the random (and unrelated) orientation of the Gabor that was seen entering the occluder. Importantly, this serial dependence was stronger for predictable, continuously moving trajectories, compared to unpredictable ones or static displacements. This result suggests that our visual system takes advantage of expectations about a stable world, helping to maintain perceived object continuity despite interrupted visibility.


Assuntos
Movimentos Oculares/fisiologia , Reconhecimento Facial/fisiologia , Orientação/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Mascaramento Perceptivo/fisiologia , Adulto , Feminino , Humanos , Masculino , Desempenho Psicomotor , Psicofísica , Adulto Jovem
20.
MAbs ; 7(1): 42-52, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25484041

RESUMO

Antibody-targeted nanoparticles have the potential to significantly increase the therapeutic index of cytotoxic anti-cancer therapies by directing them to tumor cells. Using antibodies or their fragments requires careful engineering because multiple parameters, including affinity, internalization rate and stability, all need to be optimized. Here, we present a case study of the iterative engineering of a single chain variable fragment (scFv) for use as a targeting arm of a liposomal cytotoxic nanoparticle. We describe the effect of the orientation of variable domains, the length and composition of the interdomain protein linker that connects VH and VL, and stabilizing mutations in both the framework and complementarity-determining regions (CDRs) on the molecular properties of the scFv. We show that variable domain orientation can alter cross-reactivity to murine antigen while maintaining affinity to the human antigen. We demonstrate that tyrosine residues in the CDRs make diverse contributions to the binding affinity and biophysical properties, and that replacement of non-essential tyrosines can improve the stability and bioactivity of the scFv. Our studies demonstrate that a comprehensive engineering strategy may be required to identify a scFv with optimal characteristics for nanoparticle targeting.


Assuntos
Citotoxinas , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Anticorpos de Cadeia Única , Substituição de Aminoácidos , Animais , Anticorpos Antineoplásicos/química , Anticorpos Antineoplásicos/genética , Anticorpos Antineoplásicos/imunologia , Anticorpos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Camundongos , Neoplasias/imunologia , Proteínas Recombinantes , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia
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