RESUMO
The DNA deaminase activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) by deaminating cytidines to uridines at V region (V) genes and switch (S) regions. The mechanism by which AID is recruited to V genes and S region DNA is poorly understood. In this study, we used the CH12 B lymphoma line to demonstrate that, although S regions can efficiently recruit AID and undergo mutations and deletions, AID neither binds to nor mutates the V gene, thus clearly demonstrating intraimmunoglobulin locus specificity. Depletion of the RNA-binding protein polypyrimidine tract binding protein-2, previously shown to promote recruitment of AID to S regions, enables stable association of AID with the V gene. Surprisingly, AID binding to the V gene does not induce SHM. These results unmask a striking lack of correlation between AID binding and its mutator activity, providing evidence for the presence of factors required downstream of AID binding to effect SHM. Furthermore, our findings suggest that S regions are preferred targets for AID and, aided by polypyrimidine tract binding protein-2, act as "sinks" to sequester AID activity from other genomic regions.
Assuntos
Sequência de Bases , Citidina Desaminase/imunologia , DNA/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/imunologia , Deleção de Sequência/imunologia , Animais , Linhagem Celular Tumoral , Citidina Desaminase/genética , DNA/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Ligação ProteicaRESUMO
The cell surface receptor dystroglycan mediates interactions between oligodendroglia and laminin-211, an extracellular matrix protein that regulates timely oligodendroglial development. However, dystroglycan's precise role in oligodendroglial development and the potential mechanisms to regulate laminin-dystroglycan interactions remain unknown. Here we report that oligodendroglial dystroglycan is cleaved by metalloproteinases, thereby uncoupling oligodendroglia from laminin binding. Dystroglycan cleavage is selectively stimulated by oligodendrocyte progenitor cell attachment to laminin-211, but not laminin-111 or poly-D-lysine. In addition, dystroglycan cleavage occurs most prominently in oligodendrocyte progenitor cells, with limited dystroglycan cleavage observed in differentiating oligodendrocytes. When dystroglycan cleavage is blocked by metalloproteinase inhibitors, oligodendrocyte progenitor cell proliferation is substantially decreased. Conversely, expression of the intracellular portion of cleaved dystroglycan results in increased oligodendrocyte progenitor cell proliferation, suggesting that endogenous dystroglycan cleavage may promote oligodendrocyte progenitor cell cycle progression. Intriguingly, while matrix metalloproteinase-2 and/or -9 have been reported to be responsible for dystroglycan cleavage, we find that these two metalloproteinases are neither necessary nor sufficient for cleavage of oligodendroglial dystroglycan. In summary, laminin-211 stimulates metalloproteinase-mediated dystroglycan cleavage in oligodendrocyte progenitor cells (but not in differentiated oligodendrocytes), which in turn promotes oligodendrocyte progenitor cell proliferation. This novel regulation of oligodendroglial laminin-dystroglycan interactions may have important consequences for oligodendroglial differentiation, both during development and during disease when metalloproteinase levels become elevated.
Assuntos
Proliferação de Células/fisiologia , Distroglicanas/metabolismo , Laminina/farmacologia , Metaloproteases/fisiologia , Oligodendroglia/fisiologia , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Camundongos , Oligodendroglia/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacosRESUMO
INTRODUCTION: Transgenderism is a condition regarding the gender identity of an individual where their psychological gender is discordant with their anatomic gender. For patients transitioning from Male to Female, voice changes are created predominantly with voice therapy, with vocal surgery as an adjunct if the patient desires it. A common surgical technique is the Wendler Glottoplasty. A CO2 laser is used to de-epithelialize the anterior third of the vocal folds and the anterior one-third of the folds are sutured together. This shortens the vibratory folds and increases the fundamental frequency (F0) of the voice. We present a novel modification that incorporates use of injectable aqueous carboxy-methyl-cellulose gel (Prolaryn) to medialize the anterior aspect of the vocal folds and apply fibrin glue sealant (Tisseal) in lieu of sutures, simplifying the operative technique and a thyroarytenoid myectomy for debulking of the cords in select cases. METHOD: We present ten patients treated with our modified Wendler Glottoplasty technique. Voice assessment was based on F0 and frequency range pre and post-operatively measured via MDVP and Real-Time Pitch on the Computerized Speech Lab. RESULTS: The 10 patients had an average age of 34.0 years (range 22.2-64.3 years). The average preoperative F0 was 136.1 Hz, with an average frequency range of 108.3-282.4 Hz. Postoperatively, the average F0 was 245.9 Hz, with an average frequency range of 197.3-300.7 Hz. This led to an average F0 increase of 106.3 Hz. CONCLUSION: Our modification to the Wendler Glottoplasty successfully resulted in a significant increase in the postoperative F0. In addition, there was improved satisfaction in vocal character after the procedure, compared to their preoperative vocal character.
RESUMO
Purpose: This study aimed to determine the impact of uttering the word "quiet" on clinical workload during the overnight otolaryngology call shift and understand the factors contributing to resident busyness. Materials and Methods: A multicenter, single-blind, randomized-controlled trial was conducted. A total of 80 overnight call shifts covered by a pool of 10 residents were randomized to the quiet or to the control group. At the start of shift, residents were asked to state aloud, "Today will be a quiet night" (quiet group) or "Today will be a good night" (control group). Clinical workload, as measured by number of consults, was the primary outcome. Secondary measures included number of sign-out tasks, unplanned inpatient and operating room visits, number of phone calls and hours of sleep, and self-perceived busyness. Results: There was no difference in the number of total (P = 0.23), nonurgent (P = 0.18), and urgent (P = 0.18) consults. Tasks at signout, total phone calls, unplanned inpatient visits, and unplanned operating room visits did not differ between the control and quiet groups. While there were more unplanned operating room visits in the quiet group (29, 80.6%) compared to the control group (34, 94.4%), this was not found to be significant (P = 0.07). The majority of residents reported feeling "not busy" during control nights (18, 50.0%) compared to feeling "somewhat busy" during quiet nights (17, 47.2%; P = 0.42). Conclusion: Contrary to popular belief, there is no clear evidence that uttering the word "quiet" significantly increases clinical workload.
RESUMO
OBJECTIVE: To perform a systematic review of sensorineural hearing loss (SNHL) in hematologic malignancy; to describe an illustrative case of urgent cochlear implantation for bilateral profound SNHL and vestibular hypofunction in hyperviscosity syndrome; to suggest an approach to management of hyperviscosity syndrome-associated deafness with cochlear implantation. DATA SOURCES: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, systematic search of PubMed and Embase databases was undertaken for articles detailing clinical information about SNHL caused directly by hematologic malignancies. RESULTS: A total of 37 studies from 1989 to 2020 were qualitatively reviewed, the majority of which were case studies or case series. Causes of hearing loss in hematologic malignancy were found to include hyperviscosity syndrome, labyrinthine hemorrhage, infiltration, and infection. Patients with profound SNHL in hematologic malignancies from hyperviscosity syndrome may be candidates for cochlear implantation, and are also at increased risk for cochlear ossification. We review previous cases for their diagnostic approach, treatment paradigm, and outcomes data, and propose an approach to management. CONCLUSION: Bilateral sudden profound SNHL and vestibular hypofunction is a presenting symptom of hyperviscosity syndrome in hematologic malignancy. Although this entity is rare and previous reports have suggested improvement in hearing with oncologic treatment, cases with profound hearing loss are unlikely to recover serviceable hearing. We advocate for early magnetic resonance imaging with attention to fluid signal in the inner ear and serial audiometric follow-up to guide clinical decisions. We advise early consideration for cochlear implantation.
Assuntos
Implante Coclear , Perda Auditiva Neurossensorial , Neoplasias Hematológicas , Audição , Perda Auditiva Bilateral/cirurgia , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/cirurgia , HumanosRESUMO
BACKGROUND: Human papilloma virus testing for oropharyngeal squamous-cell carcinoma has been recommended by the National Comprehensive Cancer Network since 2012. We examine disparities, reported rates of human papillomavirus (HPV) testing, and the impact on these findings of limitations with the variable in database registries. METHODS: The HPV variable was queried for patients with oropharyngeal squamous carcinoma (OPSCC) from 2013 to 2016 in National Cancer Data Base (NCDB) and Surveillance, Epidemiology, and End Results (SEER). Multivariable regression was used to identify disparities based on sociodemographic variables. Sensitivity analyses were used to investigate limitations of the variable. RESULTS: Despite limitations in the HPV variable in the databases, there was less than 100% adherence to recommended testing, and there were significant disparities in multiple sociodemographic variables. For example, in NCDB 70% of white versus 60.4% of black patients were tested (odds ratio [OR] 0.75, confidence interval [CI] 0.66-0.85, p ≤ 0.0001); in SEER 59.8% of white and 47.6% of black patients were tested (OR 0.73, CI 0.67-0.81; p ≤ 0.0001). CONCLUSIONS: Disparities exist among patients undergoing testing for HPV-associated OPSCC and adherence to guideline recommended HPV testing has been suboptimal. In addition, the HPV variable definition, especially as it relates to p16 positivity, and use in these two registries should be improved.
Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Fidelidade a Diretrizes , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/terapia , Papillomaviridae , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
OBJECTIVE: Spontaneous vocal recovery from idiopathic vocal fold paralysis (VFP) appears to differ in time course from recovery in iatrogenic VFP. This study aimed to determine if this difference could be explained by differing mechanisms causing recurrent laryngeal nerve (RLN) dysfunction, specifically whether idiopathic VFP is consistent with a focal RLN axonal lesion. STUDY DESIGN: Case series with mathematical modeling. METHODS: A review of 1267 cases of unilateral VFP over a 10-year period yielded 114 subjects (35 idiopathic, 79 iatrogenic) with a discrete onset of spontaneous vocal recovery. The time-to-recovery data were fit to a previously described two-phase model that incorporates the Seddon classification of neuropraxia and higher grades of axonal injury. Alternatively, the data were fit to a single phase model that does not assume a focal axonal lesion. RESULTS: Time to vocal recovery in iatrogenic VFP can be reliably modeled by the assumption of a focal axonal lesion, with an early recovery group corresponding to neuropraxia and a late recovery group with more severe nerve damage. Time to recovery in idiopathic VFP can be more simply modeled in a single phase, with a time course that mirrors those in diverse biological processes such as transcription and microtubule growth. CONCLUSION: Idiopathic VFP may not be caused by a focal axonal lesion. Neuritis may be a compatible mechanism. The iatrogenic VFP data lend further support to the concept that the severity of RLN injury, not the length of axon to regenerate, is the chief determinant of recovery time after iatrogenic injury. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1520-1524, 2020.
Assuntos
Nervo Laríngeo Recorrente , Paralisia das Pregas Vocais/etiologia , Paralisia das Pregas Vocais/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças dos Nervos Cranianos/etiologia , Feminino , Humanos , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Paralisia das Pregas Vocais/complicações , Adulto JovemRESUMO
INTRODUCTION: An airway assessment often occurs prior to tracheocutaneous fistula (TCF) closure in children. Bronchoscopy (MLB) with or without fistula-occluded polysomnography (PSG) helps determine candidacy and localize potential obstruction. To date, little has been published on MLB or PSG findings in children before surgically closing a TCF. METHODS: A case series with chart review of children between 2017 and 2020 who underwent repair of a TCF after tracheostomy decannulation. RESULTS: Thirty-six children were included for review. Mean age was 5.9 years (95% CI: 4.5-7.3), 58.3% were male, and 50% had chronic lung disease. Surgery occurred 13.3 months (95% CI: 11.9-14.8) after decannulation, with 80.6% by primary closure and 19.4% by secondary intention. There was one unsuccessful closure and two patients (5.6%) presented with a postoperative complication. An MLB was performed in 97.2% of children, where 22.9% identified supraglottic pathology, 11.4% had grade 2 subglottic stenosis, and 11.4% had difficult exposure of the larynx. Further, one child had a non-obstructing subglottic cyst, one had a supraglottoplasty for redundant arytenoid mucosa, and two children had suprastomal granulomas requiring removal. A PSG was obtained in 36.1%, with a mean Apnea-Hypopnea Index of 2.4 events/hour (95% CI: 0.9-3.9), nadir Oxygen saturation of 90.5% (95% CI: 87.9-93.0), and peak end-tidal CO2 of 46.1 mmHg (95% CI: 43.7-48.5). CONCLUSION: The selection of candidates for pediatric TCF closure requires careful evaluation of the airway. Surgeons should be familiar with the potential findings on MLB and PSG prior to closure.
Assuntos
Broncoscopia , Seleção de Pacientes , Polissonografia , Ferida Cirúrgica/cirurgia , Traqueostomia , Criança , Pré-Escolar , Feminino , Humanos , Doenças da Laringe/complicações , Doenças da Laringe/diagnóstico por imagem , Masculino , Oxigênio/sangue , Complicações Pós-Operatórias/etiologia , Período Pré-Operatório , Estudos Retrospectivos , Ferida Cirúrgica/complicaçõesRESUMO
OBJECTIVE: To clarify the time course of recovery in patients with iatrogenic vocal fold paralysis. STUDY DESIGN: Retrospective chart review. METHODS: Medical records for all patients with iatrogenic vocal fold paralysis over a 10-year period were reviewed to obtain demographic and clinical information, including onset of disease and recovery of vocal function. Stroboscopic exams of patients who recovered voice were reviewed blindly to assess return of vocal fold motion. RESULTS: One hundred and two patients of 114 (89%) recovered vocal function. Time to recovery could be assessed in 39 patients who did not undergo injection augmentation. The mean time to recovery was 181.8 ± 109.3 days (left: 166.4 ± 106.7 days; right: 221.8 ± 115.6 days; P value = 0.095). Patients were analyzed according to anatomical site of surgery (skull base, carotid endarterectomy, thoracic, neck and intubation); there was no significant difference in time to recovery (P value = 0.60). Twelve of the 39 patients had recovery of vocal fold motion. The mean time to vocal recovery did not differ between patients with return of motion versus no return of motion (140.6 ± 118.0 days vs. 200.1 ± 102.2 days; P value = 0.147). CONCLUSION: Age, gender, laterality, and anatomical site of injury do not influence recovery rate in iatrogenic vocal fold paralysis. The probability of recovery decreases over time but more slowly in comparison with idiopathic vocal fold paralysis, reflecting the greater heterogeneity of injury type in the iatrogenic population. Commonly available aggregate recovery rates overstate the potential for recovery. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1159-1163, 2019.
Assuntos
Paralisia das Pregas Vocais/etiologia , Feminino , Humanos , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Prega Vocal/fisiologia , Voz/fisiologiaRESUMO
OBJECTIVES: This study aims to assess the effect of vocal fold injection augmentation (IA) on subsequent medialization laryngoplasty (ML). STUDY DESIGN: A retrospective cohort study with follow-up telephone survey was carried out. METHODS: Clinical records of patients with unilateral vocal fold paralysis or paresis (VFP) who underwent ML between April 2006 and March 2015 were reviewed. Patients who underwent IA before ML were compared with patients who did not, with respect to demographic information, symptoms, Voice Handicap Index-10 (VHI-10), etiology of VFP, and revision rate. Among patients undergoing IA, the effects of injection material and of interval from IA to ML on revision rate were assessed. Follow-up telephone surveys were conducted to evaluate long-term outcomes using VHI-10 and a condition-specific questionnaire. RESULTS: One hundred thirty-five patients (70 male:65 female) with vocal fold paralysis (125) or paresis (10) underwent ML (96 left:39 right). Sixty-six (48.9%) patients underwent concurrent arytenoid adduction. Fourteen (10.4%) patients required revision. Fifty-six (41.5%) patients had prior IA; five (8.9%) patients underwent revision. Seventy-nine (58.5%) patients did not have IA; nine (11.4%) patients required revision (P = 0.78). Neither augmentation material nor length of interval between last IA and ML affected the revision rate (P = 1.00; P ≥ 0.11 for all tested intervals, respectively). No difference in follow-up VHI-10 score was found between patients who had IA before ML and patients who had not (P = 0.73). CONCLUSIONS: IA does not appear to affect the revision rate or long-term outcome of subsequent ML.
Assuntos
Carboximetilcelulose Sódica/administração & dosagem , Durapatita/administração & dosagem , Laringoplastia , Paralisia das Pregas Vocais/terapia , Prega Vocal/cirurgia , Qualidade da Voz , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Recuperação de Função Fisiológica , Estudos Retrospectivos , Telefone , Fatores de Tempo , Resultado do Tratamento , Paralisia das Pregas Vocais/diagnóstico , Paralisia das Pregas Vocais/fisiopatologia , Prega Vocal/fisiopatologia , Adulto JovemRESUMO
OBJECTIVES/HYPOTHESIS: To clarify the time course of recovery in patients with idiopathic vocal fold paralysis. STUDY DESIGN: Retrospective chart review. METHODS: Medical records for all patients with idiopathic vocal fold paralysis over a 10-year period were reviewed to obtain demographic and clinical information, including onset of disease and recovery of vocal function. Stroboscopic exams of patients who recovered voice were reviewed blindly to assess return of vocal fold motion. RESULTS: Thirty-eight of 55 patients (69%) recovered vocal function. Time course of recovery could be assessed in 34 patients who did not undergo injection augmentation. The mean time to recovery was 152.8 ± 109.3 days (left, 179.8 ± 111.3 days; right, 105.3 ± 93.7 days; P = .088). Two-thirds of patients recovered within 6 months. Probability of recovery declined over time. Five of 22 patients who recovered voice had return of vocal fold motion; 17 did not. The mean time to recovery did not differ between these groups (return of motion, 127.4 ± 132.3 days; no return of motion, 160.1 ± 105.1 days; P = .290). CONCLUSIONS: Sixty-nine percent of patients with idiopathic vocal fold paralysis recovered vocal function, two-thirds doing so within 6 months of onset. Age, gender, laterality, use of injection augmentation did not influence recovery rate. Declining probability of recovery over time leads us to consider framework surgery after 6 months in patients with idiopathic paralysis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:148-152, 2018.
Assuntos
Paralisia das Pregas Vocais/fisiopatologia , Paralisia das Pregas Vocais/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Estroboscopia , Fatores de TempoRESUMO
Routine laboratory testing is common among hospitalized patients, with associated harm. Attitudes toward testing and drivers across clinical specialties have not been described. We performed a cross-sectional study and anonymously surveyed inpatient clinicians (nurses, advanced practice providers, and physicians) at a tertiary cancer center regarding attitudes toward unnecessary laboratory testing and its drivers across clinical specialties. A total of 837 providers completed surveys (response rate 53%). Most respondents agreed with daily testing of hospitalized patients and that daily labs generally enhance safety, and those from pediatric and surgical specialties generally valued testing less than others. Participants most commonly indentified habit and institutional culture as important drivers of unnecessary testing. There were differences in other drivers across specialties, with pediatric clinicians identifying family pressure more commonly and fear of litigation less commonly compared to others. Future interventions to reduce unnecessary inpatient laboratory testing should acknowledge different attitudes based on specialty and tailor interventions accordingly.
Assuntos
Atitude do Pessoal de Saúde , Testes Diagnósticos de Rotina/estatística & dados numéricos , Uso Excessivo dos Serviços de Saúde/estatística & dados numéricos , Médicos/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Pacientes Internados , Masculino , Padrões de Prática Médica/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
A 29-year-old otherwise healthy woman presented with a lifetime history of hoarseness because it had begun to interfere with her career. Examination of both the woman and her 60-year-old father revealed bilateral sulcus vergeture, without inflammation or lesions attributable to phonotrauma. The woman responded well to injection augmentation; the father declined treatment. Combined with existing descriptions of other family groupings, all with sulcus vergeture without signs of inflammation, clinical progression, and little or no apparent behavioral component, this report further suggests that sulcus vergeture (Ford type 2) and sulcus vocalis (Ford type 3) are entirely different entities, despite architectural similarity.
Assuntos
Rouquidão/congênito , Doenças da Laringe/congênito , Laringe/fisiopatologia , Fonação/genética , Qualidade da Voz/genética , Adulto , Durapatita/administração & dosagem , Feminino , Predisposição Genética para Doença , Hereditariedade , Rouquidão/diagnóstico , Rouquidão/fisiopatologia , Humanos , Injeções , Doenças da Laringe/diagnóstico , Doenças da Laringe/fisiopatologia , Laringoscopia , Metilcelulose/administração & dosagem , Fenótipo , Recuperação de Função Fisiológica , Estroboscopia , Resultado do TratamentoRESUMO
BACKGROUND: Treatment for osteonecrosis of the femoral head (ONFH) remains controversial. Current reviews include low-level evidence studies evaluating the treatment of both pre-collapse and collapse stages of the disease. QUESTIONS/PURPOSES: The purpose of the current study is to systematically review the literature evaluating core decompression (CD) with bone marrow mesenchymal cells (BMMCs), CD alone, and bisphosphonate treatment in pre-collapse ONFH by focusing just on randomized clinical trials (RCTs) reporting functional and radiologic outcomes. We aim to determine if the literature provides evidence supporting any single approach. METHODS: Using PubMed and EMBASE databases, we reviewed the clinical evidence of treatments for pre-collapse ONFH following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twelve RCTs met the inclusion criteria. RESULTS: Results showed that CD with BMMCs has lower risk of femoral head collapse when compared to the CD alone excluding hips lost to follow-up (relative risk (RR) [95% CI]:0.25 [0.11, 0.60]; p = 0.002) and when assumed that hips lost to follow-up experienced collapse (RR [95% CI]: 0.11 [0.03, 0.47]; p = 0.003). Neither CD nor bisphosphonate treatments showed lower risk to femoral head collapse when compared to control treatments (p = 0.46 and 0.31, respectively). CONCLUSION: Current literature shows that there is a lower risk of femoral head collapse in patients with ONFH treated with CD combined with BMMCs when compared to CD alone; however, there is no robust evidence to determine the effect on functional outcomes. More RCTs assessing new combination therapies and using standardized outcome measures are required.