RESUMO
Pseudomonas aeruginosa is a common opportunistic pathogen that can cause chronic infections in multiple disease states, including respiratory infections in patients with cystic fibrosis (CF) and non-CF bronchiectasis. Like many opportunists, P. aeruginosa forms multicellular biofilm communities that are widely thought to be an important determinant of bacterial persistence and resistance to antimicrobials and host immune effectors during chronic/recurrent infections. Poly (acetyl, arginyl) glucosamine (PAAG) is a glycopolymer that has antimicrobial activity against a broad range of bacterial species, and also has mucolytic activity, which can normalize the rheological properties of cystic fibrosis mucus. In this study, we sought to evaluate the effect of PAAG on P. aeruginosa bacteria within biofilms in vitro, and in the context of experimental pulmonary infection in a rodent infection model. PAAG treatment caused significant bactericidal activity against P. aeruginosa biofilms, and a reduction in the total biomass of preformed P. aeruginosa biofilms on abiotic surfaces, as well as on the surface of immortalized cystic fibrosis human bronchial epithelial cells. Studies of membrane integrity indicated that PAAG causes changes to P. aeruginosa cell morphology and dysregulates membrane polarity. PAAG treatment reduced infection and consequent tissue inflammation in experimental P. aeruginosa rat infections. Based on these findings we conclude that PAAG represents a novel means to combat P. aeruginosa infection, and may warrant further evaluation as a therapeutic.
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Fibrose Cística , Infecções por Pseudomonas , Animais , Antibacterianos/farmacologia , Biofilmes , Fibrose Cística/microbiologia , Glucosamina/farmacologia , Glucosamina/uso terapêutico , Humanos , Pulmão/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/fisiologia , RatosRESUMO
Defective airway mucus clearance is a defining characteristic of cystic fibrosis lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using microoptical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in cystic fibrosis. We found that ARINA-1 significantly augmented mucociliary transport rates, both alone and with CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared with PBS vehicle control. Analysis of mucus reflectivity and particle-tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases in mucociliary transport rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o- cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o- F508del cells treated with VX-809 and primary human bronchial epithelial cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on cystic fibrosis mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in cystic fibrosis.
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Ácido Ascórbico/farmacologia , Bicarbonatos/farmacologia , Fibrose Cística/tratamento farmacológico , Glutationa/farmacologia , Transporte de Íons/efeitos dos fármacos , Depuração Mucociliar/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , HumanosRESUMO
OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.
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Aborto Espontâneo/economia , Aborto Espontâneo/prevenção & controle , Progesterona/economia , Progestinas/economia , Hemorragia Uterina/tratamento farmacológico , Aborto Espontâneo/etiologia , Adolescente , Adulto , Análise Custo-Benefício , Método Duplo-Cego , Feminino , Humanos , Nascido Vivo/economia , Gravidez , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicina Estatal , Resultado do Tratamento , Reino Unido , Hemorragia Uterina/complicações , Hemorragia Uterina/economia , Adulto JovemRESUMO
BACKGROUND: Cystic fibrosis (CF) is a genetic disorder of the epithelial CFTR apical chloride channel resulting in multi-organ manifestations, including pancreatic exocrine secretion. In the pancreas, CFTR abnormality results in abnormally viscous secretions that obstruct proximal ducts leading to fibrotic injury and ultimately pancreatic insufficiency in 85% of the CF population. CFTR modulators, including the potentiator ivacaftor, augment channel gating to restore 30-50% of CFTR-mediated anion transport. While CFTR modulation has been shown to alkalinize the pH of the alimentary tract and potentially augment pancreatic enzyme activity, the effect of ivacaftor on recurrent pancreatitis is emerging. Here we describe a case of a patient with CF (R117H/7 T/F508del) who presented with recurrent pancreatitis who was effectively treated with ivacaftor in the absence of respiratory symptoms. CASE PRESENTATION: A 24-year-old white male with past medical history of recurrent acute pancreatitis presented for evaluation following a referral from an outside hospital. The patient reported a lifetime of gastrointestinal symptoms requiring over 20 hospitalizations for pancreatitis in the last 10 years. Prior U/S and CT imaging for pancreatitis ruled out gallstones or anatomical etiologies. Family history included a brother with CF carrier status who suffered from recurrent acute pancreatitis. Sweat chloride testing was suggestive of CFTR dysfunction (57 mmol/L). Genetic testing demonstrated disease causing CFTR mutations: R1117H/7 T/F508del. Patient was prescribed pancrelipase, however, he reported worsened gas and diarrhea symptoms. Pancrelipase was discontinued and the patient was prescribed ivacaftor 150 mg BID. After 6 weeks of ivacaftor treatment, patient reported improved gastrointestinal symptoms. For an additional 19 months, patient reported no episodes of pancreatitis until he discontinued ivacaftor. Over the next 3 weeks, patient experienced progressive nausea and sharp epigastric pain and laboratory studies confirmed pancreatitis. Patient was subsequently lost to follow up. CONCLUSIONS: These findings support a possible relationship between the use of CFTR modulators, such as ivacaftor, in the management of recurrent pancreatitis in the setting of patients with cystic fibrosis and a CFTR mutation with residual CFTR activity or otherwise known to be responsive in vitro. Ivacaftor may be useful for recurrent pancreatitis, even in the absence of respiratory morbidity.
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Aminofenóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Pancreatite Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Humanos , Masculino , Pancreatite Crônica/genética , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Pyruvate kinase deficiency (PKD) is a rare disease and understanding of its epidemiology and associated burden remains limited. With no current curative therapy, clinical manifestations can be life threatening, clinically managed by maintaining adequate hemoglobin levels through transfusion and subsequent support, but with frequent complications. Treatment goals are to maintain/improve the patient's quality of life. With new therapies, reliable, valid, and relevant patient-reported outcome (PRO) tools are required for use in clinical trials. METHODS: Systematic literature search identified no current PRO tools for capturing/measuring the impact of PKD and treatments in clinical trials. Therefore, the search strategy was revised to consider conditions analogous to PKD in terms of symptoms and impacts that might serve as parallels to the experience in PKD; this included sickle cell anemia, thalassemia, and hemolytic anemia. Psychometric properties, strengths, and weakness of selected appropriate PRO instruments were compared, and recommendations made for choice of PRO tools. RESULTS: In adult populations, EORTC QLQ C30 and SF-36v2 are recommended, the former being a basic minimum, covering generic HRQoL, and core symptoms such as fatigue. In pediatric populations, PedsQL Generic Core Scale to measure HRQoL and PedsQL MFS scale to measure fatigue are recommended. CONCLUSIONS: Some symptoms/life impacts may be unique to PKD and not observable in analogous conditions. A 'Physico-Psychosocial Model' derived from the 'Medical Model' is proposed to form the basis for a hypothesized conceptual framework to address the development of PKD-specific PRO instruments.
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Anemia Hemolítica Congênita não Esferocítica/diagnóstico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Medidas de Resultados Relatados pelo Paciente , Psicometria/métodos , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/diagnóstico , Qualidade de Vida/psicologia , Anemia Hemolítica Congênita não Esferocítica/patologia , Humanos , Erros Inatos do Metabolismo dos Piruvatos/patologiaRESUMO
OBJECTIVE: To describe the ultrasound findings and natural history of pregnancies implanted within or on Cesarean section scars in the first trimester of pregnancy. METHODS: This was a prospective observational study of 10 women diagnosed with a pregnancy implanted in or on a Cesarean section scar in the first trimester, who declined medical intervention because of their desire to continue the pregnancy. The study population comprised women at < 12 weeks' gestation who were seen in our early pregnancy unit between January 2011 and September 2013. Nine women were followed up by serial ultrasound examinations and had detailed care plans for delivery at King's College Hospital (KCH). One woman was followed up and delivered at another teaching hospital. The first-trimester ultrasound findings were compared with the clinical outcome of the pregnancy. RESULTS: The nine patients who were followed up at KCH developed ultrasound findings of morbidly adherent placenta (MAP) in the second and third trimesters. All 10 patients were diagnosed with MAP at the time of delivery by Cesarean section. The gestational age at delivery ranged from 26 to 38 weeks. The uterus was conserved in five patients, and Cesarean hysterectomy was performed in the remaining five. All three women with complete implantation of the gestational sac within the scar and two of three cases with placental lakes in the first trimester had hysterectomies. The two cases with bulging of the gestational sac out of the uterine contour had a preterm emergency hysterectomy due to placenta percreta. Histology confirmed placenta accreta in the five hysterectomy specimens. There were no fetal or neonatal complications. CONCLUSIONS: Implantation of a pregnancy on or in a Cesarean section scar is a precursor of MAP; however, the degree of morbidity associated with this implantation is variable and difficult to predict based on first-trimester ultrasound findings only. The assessment of ongoing pregnancies implanted in Cesarean scars is most beneficial when performed between 7 and 9 weeks' gestation. Complete implantation within the myometrial defect, bulging of the trophoblast from the uterine contour and large placental lakes in the first trimester are ultrasound findings that may predict severe placenta accreta or percreta and consequently a poor outcome.
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Cesárea , Cicatriz , Doenças Placentárias/etiologia , Complicações Pós-Operatórias , Primeiro Trimestre da Gravidez , Gravidez Ectópica/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto , Cicatriz/etiologia , Feminino , Seguimentos , Humanos , Doenças Placentárias/diagnóstico por imagem , Doenças Placentárias/cirurgia , Gravidez , Resultado da Gravidez , Gravidez Ectópica/cirurgia , Estudos ProspectivosRESUMO
OBJECTIVE: To review the success rate of expectant management in a series of interstitial pregnancies. METHODS: We identified all women with an ultrasound diagnosis of interstitial pregnancy seen within a 9-year period (January 2004 to April 2013). The clinical history, ultrasound findings and biochemical results were reviewed. The outcome of all interstitial pregnancies managed conservatively was recorded. Treatment was considered as successful when the serum ß-human chorionic gonadotropin (ß-hCG) level declined below 20 IU/L without the need for further intervention. RESULTS: A total of 48 interstitial pregnancies were diagnosed during the study period. Surgery was the first-line treatment in nine (18.8%) cases. Thirty-eight (79.2%) women were offered non-surgical management: 19 (39.6%) had methotrexate (MTX) and 19 (39.6%) were managed expectantly. One (2.1%) woman returned to her local hospital following diagnosis and we were unable to obtain any follow-up information regarding her care. The median initial serum ß-hCG level and ectopic size were not significantly different between any of the groups according to initial treatment. The overall success rate of expectant management was 89.5%. There were no cases of ectopic rupture in this group. Length of follow-up ranged from 7 to 141 days with a median duration of follow-up of 50.6 days. CONCLUSION: Our data show that expectant management is an option for selected women with non-viable interstitial pregnancies and declining serum ß-hCG levels, irrespective of ectopic mass size and initial serum ß-hCG levels.
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Abortivos não Esteroides/uso terapêutico , Aborto Terapêutico/métodos , Gonadotropina Coriônica Humana Subunidade beta/sangue , Metotrexato/uso terapêutico , Gravidez Ectópica/terapia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Gravidez , Gravidez Ectópica/sangue , Gravidez Ectópica/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia Pré-NatalRESUMO
Industrial back support exoskeletons (BSEs) are a promising approach to addressing low back pain (LBP) which still affect a significant proportion of the workforce. They aim to reduce lumbar loading, the main biomechanical risk factor for LBP, by providing external support to the lumbar spine. The aim of this study was to determine the supporting effect of one active (A1) and two passive (P1 and P2) BSEs during different manual material handling tasks. Kinematic data and back muscle activity were collected from 12 subjects during dynamic lifting and static holding of 10 kg. Mean and peak L5/S1 extension moments, L5/S1 compression forces and muscle activation were included in the analysis. During dynamic lifting all BSEs reduced peak (12-26 %) and mean (4-17 %) extension moments and peak (10-22 %) and mean (4-15 %) compression forces in the lumbar spine. The peak (13-28 %) and mean (4-32 %) activity of the back extensor muscles was reduced accordingly. In the static holding task, analogous mean reductions for P1 and P2 of L5/S1 extension moments (12-20 %), compression forces (13-23 %) and muscular activity (16-23 %) were found. A1 showed a greater reduction during static holding for extension moments (46 %), compression forces (41 %) and muscular activity (54 %). This pronounced difference in the performance of the BSEs between tasks was attributed to the actuators used by the different BSEs.
Assuntos
Remoção , Dor Lombar , Vértebras Lombares , Suporte de Carga , Humanos , Fenômenos Biomecânicos , Masculino , Adulto , Suporte de Carga/fisiologia , Dor Lombar/fisiopatologia , Vértebras Lombares/fisiologia , Exoesqueleto Energizado , Feminino , Músculos do Dorso/fisiologia , Músculo Esquelético/fisiologiaRESUMO
HYPOTHESIS: We aimed to identify practice trends and association between physician training and administration of perioperative steroids for cochlear implantation (CI) as it relates to hearing preservation. BACKGROUND: Perioperative steroid therapy regimens are postulated to protect residual hearing and improve hearing preservation outcomes in CI. METHODS: A 27-question online survey was developed by the senior authors using the Qualtrics Survey Tool, then distributed via email from September to November 2022 to otolaryngologists specializing in otology or neurotology and who practice in the United States or Canada. RESULTS: The survey was sent to 463 physicians, 162 (35.0%) of whom completed the survey. One hundred forty-four (31.1%) responses underwent analysis. All physicians administering preoperative steroids (n = 31) prefer preoperative oral prednisone. Of 143 physicians administering intraoperative steroids, 54.5% prefer intraoperative intravenous dexamethasone. More than half (77.6%) of 85 physicians administering postoperative steroids prefer postoperative oral prednisone. Postoperative steroid administration (p < 0.006) and taper utilization (p < 0.041) were greater among physicians who complete greater than 40 CIs annually (n = 47 [71.2%]; n = 30 [49.2%]) than physicians who complete up to 40 CIs annually (n = 37 [48.7%]; n = 20 [31.3%]), respectively. Physicians practicing for 5 to 20 years after residency are more prevalent in using postoperative steroid tapers than physicians practicing for fewer than 5 years after and more than 20 years after residency (n = 37 [51.4%] versus n = 14 [25.5%], p < 0.001). CONCLUSION: Consensus is needed about the optimal steroid treatment for CI patients. LEVEL OF EVIDENCE: 4.
Assuntos
Implante Coclear , Implantes Cocleares , Humanos , Estados Unidos , Prednisona/uso terapêutico , Audição , Glucocorticoides , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: The incidence and risk factors for facial nerve dysfunction (FND) following CyberKnife® therapy for vestibular schwannoma (VS) remain poorly understood. This study investigates whether differential radiation doses to vulnerable segments of the facial nerve may be associated with FND outcomes. METHODS: Patients were identified who underwent CyberKnife® radiosurgery for VS at a single institution. Basic demographics, tumor characteristics, and facial nerve function were collected. Total radiation doses to tumor, internal auditory canal (IAC), and labyrinthine segment of facial nerve (LSFN) were evaluated. RESULTS: Six out of 64 patients experienced FND following CyberKnife® treatment for VS (9.38%, 6/64). Patients with FND were compared to those without FND (control). Of the 64 patients, complete radiation records were obtained for 30 patients (6 FND vs. 24 control). There were no significant differences in demographic or tumor characteristics between control and FND cohorts. More severe FND (HB ≥ 4) had significantly larger tumors (3.74 vs. 1.27 cm3, p = 0.037) with directionally decreased time to FND (3.50 vs. 33.5 months, p = 0.106) than patients with HB < 4, respectively. There were directionally, nonsignificant differences between maximum radiation doses to the LSFN (2492.4 vs. 2557.0 cGy, p = 0.121) and IAC (2877.3 vs. 2895.5 cGy, p = 0.824) between the control and FND cohorts, respectively. CONCLUSIONS: FND may represent an underrecognized sequelae of CyberKnife® radiosurgery for VS that can occur many months following treatment. Further studies are needed to elucidate the effect of differential radiation exposure to the facial nerve with FND following treatment. LEVEL OF EVIDENCE: III (Retrospective Cohort Study) Laryngoscope, 2024.
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BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.
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OBJECTIVE: To determine the clinical significance of a chorionic bump diagnosed by ultrasound in women attending an early pregnancy unit in a teaching hospital. METHODS: This was a retrospective case-control study over an 8-year period (2003-2010). Cases of chorionic bump were identified by searching our early pregnancy database and were matched to controls in a ratio of 1:3. The primary outcome measure was miscarriage vs ongoing pregnancy. Secondary outcomes were gestational age at delivery and the presence or absence of fetal abnormality. RESULTS: A total of 37 798 pregnancies were examined over the study period and 57 pregnancies with a chorionic bump were identified, giving an estimated prevalence of 1.5 per 1000 pregnancies (0.15%; 95% CI, 0.01-0.73%). Of the 52 women with follow-up data, 20 (38.5%; 95% CI, 26.4-52.1%) miscarried vs 31/151 (20.5%; 95% CI, 14.8-27.7%) in the control group (P = 0.01). There were four second-trimester miscarriages in the study group and none in the controls (P < 0.01). Out of 52 pregnancies in the study group there were 32 live births (62%; 95% CI, 47.9-73.6%) vs 118/151 (78%; 95% CI, 70.9-84.0%) in the control group (P = 0.02). There were no differences in preterm delivery rates or fetal anomalies. No significant relationship was found between size of the bump or location in relation to the umbilical cord insertion and risk of miscarriage. CONCLUSIONS: Women presenting to early pregnancy units with a chorionic bump discovered at first-trimester ultrasound examination had approximately double the risk of miscarriage compared with matched controls, the difference being due to a greater number of miscarriages during the second trimester of pregnancy.
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Córion/diagnóstico por imagem , Feto/anormalidades , Idade Gestacional , Saco Gestacional/diagnóstico por imagem , Resultado da Gravidez , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-NatalRESUMO
Non-bacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, has been reported to occur in 0.3-9.3% of the adult population at autopsy. NBTE associated with malignancy is an underrecognised cause of thromboembolic disorders. The clinical spectrum encountered and investigation results can be non-specific, often mimicking other acute conditions such as infective endocarditis. We describe the case of a 34-year-old woman with non-localising and multifocal neurological symptoms, who was subsequently diagnosed with NBTE secondary to a resectable primary lung adenocarcinoma.
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Adenocarcinoma/diagnóstico , Endocardite não Infecciosa/diagnóstico , Neoplasias Pulmonares/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Adenocarcinoma/complicações , Adenocarcinoma de Pulmão , Adulto , Diagnóstico Diferencial , Endocardite não Infecciosa/complicações , Feminino , Humanos , Neoplasias Pulmonares/complicações , Doenças do Sistema Nervoso/complicaçõesRESUMO
The stria vascularis (SV) has been shown to play a critical role in the pathogenesis of many diseases associated with sensorineural hearing loss (SNHL), including age-related hearing loss (ARHL), noise-induced hearing loss (NIHL), hereditary hearing loss (HHL), and drug-induced hearing loss (DIHL), among others. There are a number of other disorders of hearing loss that may be relatively neglected due to being underrecognized, poorly understood, lacking robust diagnostic criteria or effective treatments. A few examples of these diseases include autoimmune inner ear disease (AIED) and/or autoinflammatory inner ear disease (AID), Meniere's disease (MD), sudden sensorineural hearing loss (SSNHL), and cytomegalovirus (CMV)-related hearing loss (CRHL). Although these diseases may often differ in etiology, there have been recent studies that support the involvement of the SV in the pathogenesis of many of these disorders. We strive to highlight a few prominent examples of these frequently neglected otologic diseases and illustrate the relevance of understanding SV composition, structure and function with regards to these disease processes. In this study, we review the physiology of the SV, lay out the importance of these neglected otologic diseases, highlight the current literature regarding the role of the SV in these disorders, and discuss the current strategies, both approved and investigational, for management of these disorders.
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Surdez , Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Doenças do Labirinto , Doença de Meniere , Humanos , Estria Vascular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Doenças do Labirinto/diagnóstico , Doenças do Labirinto/patologia , Doença de Meniere/diagnóstico , Surdez/patologiaRESUMO
HYPOTHESIS: Analysis of human temporal bone specimens of patients with Menière's disease (MD) may demonstrate altered expression of gene products related to barrier formation and ionic homeostasis within cochlear structures compared with control specimens. BACKGROUND: MD represents a challenging otologic disorder for investigation. Despite attempts to define the pathogenesis of MD, there remain many gaps in our understanding, including differences in protein expression within the inner ear. Understanding these changes may facilitate the identification of more targeted therapies for MD. METHODS: Human temporal bones from patients with MD (n = 8) and age-matched control patients (n = 8) were processed with immunohistochemistry stains to detect known protein expression related to ionic homeostasis and barrier function in the cochlea, including CLDN11, CLU, KCNJ10, and SLC12A2. Immunofluorescence intensity analysis was performed to quantify protein expression in the stria vascularis, organ of Corti, and spiral ganglion neuron (SGN). RESULTS: Expression of KCNJ10 was significantly reduced in all cochlear regions, including the stria vascularis (9.23 vs 17.52, p = 0.011), OC (14.93 vs 29.16, p = 0.014), and SGN (7.69 vs 18.85, p = 0.0048) in human temporal bone specimens from patients with MD compared with control, respectively. CLDN11 (7.40 vs 10.88, p = 0.049) and CLU (7.80 vs 17.51, p = 0.0051) expression was significantly reduced in the SGN. CONCLUSION: The results of this study support that there may be differences in the expression of proteins related to ionic homeostasis and barrier function within the cochlea, potentially supporting the role of targeted therapies to treat MD.
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Doença de Meniere , Humanos , Doença de Meniere/patologia , Cóclea/patologia , Estria Vascular/patologia , Osso Temporal/patologia , Homeostase , Membro 2 da Família 12 de Carreador de SolutoRESUMO
Endocochlear potential, which is generated by the stria vascularis, is essential to maintain an environment conducive to appropriate hair cell mechanotransduction and ultimately hearing. Pathologies of the stria vascularis can result in a decreased hearing. Dissection of the adult stria vascularis allows for focused single-nucleus capture and subsequent single-nucleus sequencing and immunostaining. These techniques are used to study stria vascularis pathophysiology at the single-cell level. Single-nucleus sequencing can be used in the setting of transcriptional analysis of the stria vascularis. Meanwhile, immunostaining continues to be useful in identifying specific populations of cells. Both methods require proper stria vascularis dissection as a prerequisite, which can prove to be technically challenging.
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Mecanotransdução Celular , Estria Vascular , Camundongos , Animais , Estria Vascular/patologia , Estria Vascular/fisiologia , Audição , Cóclea/fisiologiaRESUMO
Extramedullary hematopoiesis (EMH) is the formation and development of blood cells outside the medullary spaces of the bone marrow. Although widely considered an epiphenomenon, secondary to underlying primary disease and lacking serious clinical or diagnostic implications, the presence of EMH is far from incidental on a molecular basis; rather, it reflects a well-choreographed suite of changes involving stem cells and their microenvironment (the stem cell niche). The goals of this review are to reconsider the molecular basis of EMH based on current knowledge of stem cell niches and to examine its role in the pathophysiologic mechanisms of EMH in animals. The ability of blood cells to home, proliferate, and mature in extramedullary tissues of adult animals reflects embryonic patterns of hematopoiesis and establishment or reactivation of a stem cell niche. This involves pathophysiologic alterations in hematopoietic stem cells, extracellular matrix, stromal cells, and local and systemic chemokines. Four major theories involving changes in stem cells and/or their microenvironment can explain the development of most occurrences of EMH: (1) severe bone marrow failure; (2) myelostimulation; (3) tissue inflammation, injury, and repair; and (4) abnormal chemokine production. EMH has also been reported within many types of neoplasms. Understanding the concepts and factors involved in stem cell niches enhances our understanding of the occurrence of EMH in animals and its relationship to underlying disease. In turn, a better understanding of the prevalence and distribution of EMH in animals and its molecular basis could further inform our understanding of the hematopoietic stem cell niche.
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Microambiente Celular/fisiologia , Hematopoese Extramedular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Modelos Biológicos , Transdução de Sinais/fisiologia , Nicho de Células-Tronco/fisiologia , Animais , Quimiocinas/metabolismo , Matriz Extracelular/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Especificidade da Espécie , Células Estromais/fisiologiaRESUMO
The stay-suture technique (SST) helps ensure safe replacement of the tracheostomy tube after accidental decannulation. We describe a patient found to have a retained stay suture in the glottis 2 weeks post-decannulation. It is important to appreciate the possible complications associated with SST, including airway compromise, infection, and laryngospasm.
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OBJECTIVE: To identify genes implicated in sudden sensorineural hearing loss (SSNHL) and localize their expression in the cochlea to further explore potential pathogenic mechanisms and therapeutic targets. STUDY DESIGN: Systematic literature review and bioinformatics analysis. DATA SOURCES: The following sources were searched from inception through July 2, 2020: PubMed-NCBI, MEDLINE, Embase, CINAHL, Cochrane Library, ClinicalTrials.gov, OpenGrey, GreyNet, GreyLiterature Report, and European Union Clinical Trials Registry. PubMed-NCBI and MEDLINE were additionally searched for human temporal bone histopathologic studies related to SSNHL. METHODS: Literature review of candidate SSNHL genes was conducted according to PRISMA guidelines. Existing temporal bone studies from SSNHL patients were analyzed to identify the most commonly affected inner ear structures. Previously published single-cell and single-nucleus RNA-Seq datasets of the adult mouse stria vascularis, as well as postnatal day 7 and 15 mouse cochlear hair cells and supporting cells, were utilized for localization of the SSNHL-related genes curated through literature review. CONCLUSIONS: We report 92 unique single nucleotide polymorphisms (SNPs) in 76 different genes that have been investigated in relation to SSNHL in the literature. We demonstrate that a subset of these genes are expressed by cell types in the adult mouse stria vascularis and organ of Corti, consistent with findings from temporal bone studies in human subjects with SSNHL. We highlight several potential genetic targets relevant to current and possible future SSNHL treatments.
Assuntos
Orelha Interna , Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Animais , Cóclea/patologia , Orelha Interna/patologia , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Súbita/patologia , Humanos , Camundongos , RNARESUMO
PURPOSE OF REVIEW: This article reviews the current literature regarding the pathogenesis of immune-mediated sensorineural hearing loss, utilizes previously published single-nucleus transcriptional profiles to characterize cytokine and cytokine receptor expression in the adult stria vascularis cell types to support immune system interaction with the stria vascularis and reviews the current literature on immunomodulatory agents currently being used for hearing-restoration treatment. RECENT FINDINGS: The literature review highlights recent studies that elucidate many cytokines and immune markers, which have been linked to various immune-mediated disease processes that have been observed with sensorineural hearing loss within the stria vascularis and highlights recent publications studying therapeutic targets for these pathways. SUMMARY: This review highlights the current literature regarding the pathogenesis of immune-mediated hearing loss. The role of cochlear structures in human temporal bones from patients with immune-mediated sensorineural hearing loss are highlighted, and we review cytokine signalling pathways relevant to immune-mediated sensorineural hearing loss and localize genes encoding both cytokine and cytokine receptors involved in these pathways. Finally, we review immunomodulatory therapeutics in light of these findings and point to opportunities for the application of novel therapeutics by targeting these signalling pathways.