RESUMO
Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.
Assuntos
Alelos , Modelos Animais de Doenças , Proteínas Musculares , Músculo Esquelético , Mutação , Miopatias da Nemalina , Fenótipo , Sarcômeros , Peixe-Zebra , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Miopatias da Nemalina/fisiopatologia , Peixe-Zebra/genética , Animais , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Sarcômeros/genética , Sarcômeros/metabolismo , Sarcômeros/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Humanos , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) has been associated with hypertrophic cardiomyopathy and sudden cardiac arrest in juveniles. cTnT-I79N is located in the cTnT N-terminal (TnT1) loop region and is known for its pathological and prognostic relevance. A recent structural study revealed that I79 is part of a hydrophobic interface between the TnT1 loop and actin, which stabilizes the relaxed (OFF) state of the cardiac thin filament. Given the importance of understanding the role of TnT1 loop region in Ca2+ regulation of the cardiac thin filament along with the underlying mechanisms of cTnT-I79N-linked pathogenesis, we investigated the effects of cTnT-I79N on cardiac myofilament function. Transgenic I79N (Tg-I79N) muscle bundles displayed increased myofilament Ca2+ sensitivity, smaller myofilament lattice spacing, and slower crossbridge kinetics. These findings can be attributed to destabilization of the cardiac thin filament's relaxed state resulting in an increased number of crossbridges during Ca2+ activation. Additionally, in the low Ca2+-relaxed state (pCa8), we showed that more myosin heads are in the disordered-relaxed state (DRX) that are more likely to interact with actin in cTnT-I79N muscle bundles. Dysregulation of the myosin super-relaxed state (SRX) and the SRX/DRX equilibrium in cTnT-I79N muscle bundles likely result in increased mobility of myosin heads at pCa8, enhanced actomyosin interactions as evidenced by increased active force at low Ca2+, and increased sinusoidal stiffness. These findings point to a mechanism whereby cTnT-I79N weakens the interaction of the TnT1 loop with the actin filament, which in turn destabilizes the relaxed state of the cardiac thin filament.
Assuntos
Miofibrilas , Troponina T , Humanos , Miofibrilas/genética , Miofibrilas/patologia , Troponina T/genética , Troponina T/química , Actinas/genética , Mutação , Citoesqueleto de Actina/genética , Miosinas , CálcioRESUMO
B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27+ memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-ß (IKKß, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , NF-kappa B , Humanos , NF-kappa B/metabolismo , Transdução de Sinais , Linfócitos B/metabolismo , Quinase Induzida por NF-kappaB , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismoRESUMO
OBJECTIVES: Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. METHODS: Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry. RESULTS: ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. CONCLUSIONS: Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.
Assuntos
Granulomatose com Poliangiite , Interleucina-17 , Humanos , Células T de Memória , Granulomatose com Poliangiite/tratamento farmacológico , Interleucina-4 , Fator de Necrose Tumoral alfa , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismoRESUMO
PURPOSE: To investigate the biomechanical effects of tape-reinforced graft suturing and graft retensioning for all-soft tissue quadriceps tendon (ASTQT) anterior cruciate ligament reconstruction (ACLR) in a full-construct human cadaveric model. METHODS: Harvested cadaveric ASTQT grafts were assigned to either (1) double-suspensory adjustable-loop cortical button device (ALD) fixation in which both graft ends were fixed with a suspensory fixation device with (n = 5) or without (n = 5) tape-reinforced suturing or (2) single-suspensory distal tendon fixation in which only the patellar end was fixed with an ALD (n = 5) or fixed-loop cortical button device (FLD) (n = 5). All specimens were prepared using a No. 2 whipstitch technique, and tape-reinforced specimens had an integrated braided tape implant. Graft preparation time was recorded for double-suspensory constructs. Samples were tested on an electromechanical testing machine using a previously published protocol simulating rehabilitative kinematics and loading. RESULTS: Tape-reinforced graft suturing resulted in greater graft load retention after cycling (11.9% difference, P = .021), less total elongation (mean [95% confidence interval (CI)], 5.57 mm [3.50-7.65 mm] vs 32.14 mm [25.38-38.90 mm]; P < .001), greater ultimate failure stiffness (mean [95% CI], 171.9 N/mm [158.8-185.0 N/mm] vs 119.4 N/mm [108.7-130.0 N/mm]; P < .001), and less graft preparation time (36.4% difference, P < .001) when compared with unreinforced specimens. Retensioned ALD constructs had less cyclic elongation compared with FLD constructs (mean total elongation [95% CI], 7.04 mm [5.47-8.61 mm] vs 12.96 mm [8.67-17.26 mm]; P = .004). CONCLUSIONS: Tape-reinforced graft suturing improves time-zero ASTQT ACLR construct biomechanics in a cadaveric model with 83% less total elongation, 44% greater stiffness, and reduced preparation time compared with a whipstitched graft without tape reinforcement. ALD fixation improves construct mechanics when compared with FLD fixation as evidenced by 46% less total elongation. CLINICAL RELEVANCE: Tape-reinforced implants and graft retensioning using ALDs improve time-zero ACLR graft construct biomechanics in a time-zero biomechanical model. Clinical studies will be necessary to determine whether these implants improve clinical outcomes including knee laxity and the incidence of graft rupture.
Assuntos
Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior , Humanos , Ligamento Cruzado Anterior/cirurgia , Fenômenos Biomecânicos , Autoenxertos , Tendões/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , CadáverRESUMO
BACKGROUND: Body weight support (BWS) training devices are frequently used to improve gait in individuals with neurological impairments, but guidance in selecting an appropriate level of BWS is limited. Here, we aim to describe the initial BWS levels used during gait training, the rationale for this selection and the clinical goals aligned with BWS training for different diagnoses. METHOD: A systematic literature search was conducted in PubMed, Embase and Web of Science, including terms related to the population (individuals with neurological disorders), intervention (BWS training) and outcome (gait). Information on patient characteristics, type of BWS device, BWS level and training goals was extracted from the included articles. RESULTS: Thirty-three articles were included, which described outcomes using frame-based (stationary or mobile) and unidirectional ceiling-mounted devices on four diagnoses (multiple sclerosis (MS), spinal cord injury (SCI), stroke, traumatic brain injury (TBI)). The BWS levels were highest for individuals with MS (median: 75%, IQR: 6%), followed by SCI (median: 40%, IQR: 35%), stroke (median: 30%, IQR: 4.75%) and TBI (median: 15%, IQR: 0%). The included studies reported eleven different training goals. Reported BWS levels ranged between 30 and 75% for most of the training goals, without a clear relationship between BWS level, diagnosis, training goal and rationale for BWS selection. Training goals were achieved in all included studies. CONCLUSION: Initial BWS levels differ considerably between studies included in this review. The underlying rationale for these differences was not clearly motivated in the included studies. Variation in study designs and populations does not allow to draw a conclusion on the effectiveness of BWS levels. Hence, it remains difficult to formulate guidelines on optimal BWS settings for different diagnoses, BWS devices and training goals. Further efforts are required to establish clinical guidelines and to experimentally investigate which initial BWS levels are optimal for specific diagnoses and training goals.
Assuntos
Transtornos Neurológicos da Marcha , Humanos , Transtornos Neurológicos da Marcha/reabilitação , Transtornos Neurológicos da Marcha/etiologia , Peso Corporal , Marcha/fisiologiaRESUMO
BACKGROUND: Reproducible methods for determining adequate bone densities for stemless anatomic total shoulder arthroplasty (aTSA) are currently lacking. The purpose of this study was to evaluate the utility of preoperative computed tomography (CT) imaging for assessing the bone density of the proximal humerus for supportive differentiation in the decision making for stemless humeral component implantation. It was hypothesized that preoperative 3-dimensional (3-D) CT bone density measures provide objective classifications of the bone quality for stemless aTSA. METHODS: A 3-part study was performed that included the analysis of cadaveric humerus CT scans followed by retrospective application to a clinical cohort and classification with a machine learning model. Thirty cadaveric humeri were evaluated with clinical CT and micro-CT (µCT) imaging. Phantom-calibrated CT data were used to extract 3-D regions of interest and defined radiographic scores. The final image processing script was applied retrospectively to a clinical cohort (n = 150) that had a preoperative CT and intraoperative bone density assessment using the "thumb test," followed by placement of an anatomic stemmed or stemless humeral component. Postscan patient-specific calibration was used to improve the functionality and accuracy of the density analysis. A machine learning model (Support vector machine [SVM]) was utilized to improve the classification of bone densities for a stemless humeral component. RESULTS: The image processing of clinical CT images demonstrated good to excellent accuracy for cylindrical cancellous bone densities (metaphysis [ICC = 0.986] and epiphysis [ICC = 0.883]). Patient-specific internal calibration significantly reduced biases and unwanted variance compared with standard HU CT scans (P < .0001). The SVM showed optimized prediction accuracy compared with conventional statistics with an accuracy of 73.9% and an AUC of 0.83 based on the intraoperative decision of the surgeon. The SVM model based on density clusters increased the accuracy of the bone quality classification to 87.3% with an AUC of 0.93. CONCLUSIONS: Preoperative CT imaging allows accurate evaluation of the bone densities in the proximal humerus. Three-dimensional regions of interest, rescaling using patient-specific calibration, and a machine learning model resulted in good to excellent prediction for objective bone quality classification. This approach may provide an objective tool extending preoperative selection criteria for stemless humeral component implantation.
Assuntos
Artroplastia do Ombro , Densidade Óssea , Úmero , Imageamento Tridimensional , Tomografia Computadorizada por Raios X , Humanos , Artroplastia do Ombro/métodos , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Masculino , Feminino , Úmero/diagnóstico por imagem , Úmero/cirurgia , Idoso , Pessoa de Meia-Idade , Cadáver , Cuidados Pré-Operatórios/métodos , Aprendizado de Máquina , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Idoso de 80 Anos ou maisRESUMO
Muscle weakness is a hallmark of inherited or acquired myopathies. It is a major cause of functional impairment and can advance to life-threatening respiratory insufficiency. During the past decade, several small-molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review, we provide an overview of the available literature and the mechanisms of action of small-molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin. We also discuss their use in the treatment of skeletal myopathies. The first of three classes of drugs discussed here increase contractility by decreasing the dissociation rate of calcium from troponin and thereby sensitizing the muscle to calcium. The second two classes of drugs directly act on myosin and stimulate or inhibit the kinetics of myosin-actin interactions, which may be useful in patients with muscle weakness or stiffness.NEW & NOTEWORTHY During the past decade, several small molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review, we provide an overview of the available literature and the mechanisms of action of small molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin.
Assuntos
Cálcio , Sarcômeros , Humanos , Sarcômeros/fisiologia , Contração Muscular/fisiologia , Debilidade Muscular , Miosinas/genética , TroponinaRESUMO
Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force-both in vivo and in vitro-in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. In Acta1H40Y mice, treatment with tirasemtiv increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of tirasemtiv were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.
Assuntos
Actinas , Miopatias da Nemalina , Actinas/genética , Animais , Humanos , Imidazóis , Camundongos , Músculo Esquelético/patologia , Mutação , Miopatias da Nemalina/tratamento farmacológico , Miopatias da Nemalina/genética , Pirazinas/uso terapêuticoRESUMO
[Figure: see text].
Assuntos
Diafragma/metabolismo , Insuficiência Cardíaca/metabolismo , Mitocôndrias Musculares/metabolismo , Debilidade Muscular/metabolismo , Cálcio/metabolismo , Diafragma/fisiopatologia , Diafragma/ultraestrutura , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/ultraestrutura , Proteínas Musculares/metabolismo , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , NADPH Oxidases/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The high prevalence and severe consequences of poor sleep following acquired brain injury emphasises the need for an effective treatment. However, treatment studies are scarce. The present study evaluates the efficacy of blended online cognitive behavioural therapy for insomnia (eCBT-I) developed specifically for people with acquired brain injury. In a multicentre prospective, open-label, blinded end-point randomised clinical trial, 52 participants with insomnia and a history of a stroke or traumatic brain injury were randomised to 6 weeks of guided eCBT-I or treatment as usual, with a 6-week follow-up. The primary outcome measure was the change in insomnia severity between baseline and after treatment, measured with the Insomnia Severity Index. Results showed that insomnia severity improved significantly more with eCBT-I than with treatment as usual compared to baseline, both at post-treatment (mean [SEM] 4.0 [1.3] insomnia severity index points stronger decrease, d = 0.96, p < 0.003) and at follow-up (mean [SEM] 3.2 [1.5] insomnia severity index points, d = -0.78, p < 0.03). In conclusion, our randomised clinical trial shows that blended CBT is an effective treatment for insomnia, and feasible for people with acquired brain injury, regardless of cognitive and psychiatric complaints. Online treatment has major advantages in terms of availability and cost and may contribute to the successful implementation of insomnia treatment for people with acquired brain injuries.
Assuntos
Lesões Encefálicas , Terapia Cognitivo-Comportamental , Distúrbios do Início e da Manutenção do Sono , Telemedicina , Humanos , Distúrbios do Início e da Manutenção do Sono/etiologia , Distúrbios do Início e da Manutenção do Sono/terapia , Estudos Prospectivos , Terapia Cognitivo-Comportamental/métodos , Resultado do Tratamento , Lesões Encefálicas/complicaçõesRESUMO
OBJECTIVE: To provide reference values of cardiorespiratory fitness for individuals post-stroke in clinical rehabilitation and to gain insight in characteristics related to cardiorespiratory fitness post stroke. DESIGN: A retrospective cohort study. Reference equations of cardiopulmonary fitness corrected for age and sex for the fifth, 25th, 50th, 75th, and 95th percentile were constructed with quantile regression analysis. The relation between patient characteristics and cardiorespiratory fitness was determined by linear regression analyses adjusted for sex and age. Multivariate regression models of cardiorespiratory fitness were constructed. SETTING: Clinical rehabilitation center. PARTICIPANTS: Individuals post-stroke who performed a cardiopulmonary exercise test as part of clinical rehabilitation between July 2015 and May 2021 (N=405). MAIN OUTCOME MEASURES: Cardiorespiratory fitness in terms of peak oxygen uptake (VËO2peak) and oxygen uptake at ventilatory threshold (VËO2-VT). RESULTS: References equations for cardiorespiratory fitness stratified by sex and age were provided based on 405 individuals post-stroke. Median VËO2peak was 17.8[range 8.4-39.6] mL/kg/min and median VËO2-VT was 9.7[range 5.9-26.6] mL/kg/min. Cardiorespiratory fitness was lower in individuals who were older, women, using beta-blocker medication, and in individuals with a higher body mass index and lower motor ability. CONCLUSIONS: Population specific reference values of cardiorespiratory fitness for individuals post-stroke corrected for age and sex were presented. These can give individuals post-stroke and health care providers insight in their cardiorespiratory fitness compared with their peers. Furthermore, they can be used to determine the potential necessity for cardiorespiratory fitness training as part of the rehabilitation program for an individual post-stroke to enhance their fitness, functioning and health. Especially, individuals post-stroke with more mobility limitations and beta-blocker use are at a higher risk of low cardiorespiratory fitness.
Assuntos
Aptidão Cardiorrespiratória , Acidente Vascular Cerebral , Humanos , Feminino , Estudos Retrospectivos , Valores de Referência , Consumo de Oxigênio , Acidente Vascular Cerebral/complicações , Teste de Esforço , OxigênioRESUMO
Oxalate nephropathy, due to secondary hyperoxaluria has widely been described in gastrointestinal diseases. However, reports of oxalate nephropathy in newly diagnosed celiac disease are rare. A 72-year-old Caucasian male presented to the hospital with abdominal discomfort and acute renal insufficiency with a creatinine of 290 µmol/L. The clinical course, laboratory results and urinalysis were suspect for tubular injury. Renal biopsy showed calcium oxalate depositions. Elevated plasma and urine oxalate levels established the diagnosis oxalate nephropathy. The abdominal complaints with steatorrhea and positive anti-tissue transglutaminase antibodies were diagnosed as celiac disease, which was confirmed after duodenal biopsies. Treatment with prednisone, and gluten-free, low oxalate and normal calcium diet, lowered the plasma oxalate levels and improved his renal function. Decreased absorption of free fatty acids can lead to increased free oxalate in the colon due to the binding of free fatty acids to calcium, preventing the formation of the less absorbable calcium oxalate in the colon. Oxalate dispositions in the kidney can lead to acute tubular injury and chronic renal insufficiency. Celiac disease is therefore one of the intestinal diseases that can lead to hyperoxaluria and oxalate nephropathy.
Assuntos
Injúria Renal Aguda , Doença Celíaca , Hiperoxalúria , Humanos , Masculino , Idoso , Oxalato de Cálcio/urina , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Cálcio , Ácidos Graxos não Esterificados , Hiperoxalúria/complicações , Hiperoxalúria/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/complicações , OxalatosRESUMO
OBJECTIVE: We sought to validate our proposed tool for estimating channel discrimination of cochlear implant (CI) users along the full electrode array and to assess associations between place-pitch discrimination and speech perception. DESIGN: In two tests, participants identified one stimulus (probe) as the odd-one-out compared with two reference stimuli. Probe stimuli were evoked using dual electrode stimulation characterised by the current steering coefficient α. The first test measured psychometric functions (PFs) on pre-defined contacts, with just a noticeable difference (JNDα) as the outcome variable. The second test estimated channel discrimination on the full electrode array, yielding a discrimination score of Dα. We measured speech perception as free-field consonant-vowel-consonant phoneme recognition scores. STUDY SAMPLE: We included 25 adults with at least 6 months of CI experience. RESULTS: JNDα and Dα scores measured on the same contact correlated significantly (rs = 0.64, p < 0.001). Mean JNDα and speech perception scores showed significant relationships in quiet and in noise. CONCLUSIONS: Dα correlated strongly with JNDα scores obtained with the PFs. For poor performers, the full-array test may underestimate JNDα. The full-array pitch discrimination test could be a helpful clinical tool, such as for fitting regions of lesser pitch discrimination ability.
Assuntos
Implante Coclear , Implantes Cocleares , Percepção da Fala , Adulto , Humanos , Discriminação da Altura Tonal , Ruído , Percepção da Fala/fisiologiaRESUMO
PURPOSE: Clinical work-integrating care (CWIC) refers to paying attention to work participation in a clinical setting. Working patients may benefit from CWIC. The purpose of this study is to explore the extent and nature to which medical specialists provide CWIC and what policies and guidelines oblige or recommend specialists to do. METHODS: A scoping review was conducted. The databases MEDLINE, EMBASE, Psychinfo, CINAHL, and Web of Science were searched for studies on the extent and nature of CWIC and supplemented by gray literature on policies and guidelines. Six main categories were defined a priori. Applying a meta-aggregative approach, subcategories were subsequently defined using qualitative data. Next, quantitative findings were integrated into these subcategories. A separate narrative of policies and guidelines using the same main categories was constructed. RESULTS: In total, 70 studies and 55 gray literature documents were included. The main findings per category were as follows: (1) collecting data on the occupation of patients varied widely; (2) most specialists did not routinely discuss work, but recent studies showed an increasing tendency to do so, which corresponds to recent policies and guidelines; (3) work-related advice ranged from general advice to patient-physician collaboration about work-related decisions; (4) CWIC was driven by legislation in many countries; (5) specialists sometimes collaborated in multidisciplinary teams to provide CWIC; and (6) medical guidelines regarding CWIC were generally not available. CONCLUSION: Medical specialists provide a wide variety of CWIC ranging from assessing a patient's occupation to extensive collaboration with patients and other professionals to support work participation. Lack of medical guidelines could explain the variety of these practices.
RESUMO
Acquired Brain Injury and Work Participation - A Dutch Interdisciplinary Guideline for Occupational and Insurance Physicians Abstract. This article discusses the Dutch interdisciplinary guideline 'Acquired brain injury and work participation'. Its development follows the methodology of evidence-based medicine and supports all professionals involved in the vocational re-integration of workers with traumatic (e.g., traffic accident) and non-traumatic (e.g., stroke) acquired brain injury.
Assuntos
Lesões Encefálicas , Seguro , Médicos , HumanosRESUMO
KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.
Assuntos
Cardiomiopatias , Proteínas Musculares , Animais , Humanos , Camundongos , Arritmias Cardíacas , Cardiomiopatias/genética , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis , Proteínas Musculares/genética , Volume Sistólico/fisiologia , Função Ventricular EsquerdaRESUMO
OBJECTIVES: Lung- and diaphragm-protective ventilation is a novel concept that aims to limit the detrimental effects of mechanical ventilation on the diaphragm while remaining within limits of lung-protective ventilation. The premise is that low breathing effort under mechanical ventilation causes diaphragm atrophy, whereas excessive breathing effort induces diaphragm and lung injury. In a proof-of-concept study, we aimed to assess whether titration of inspiratory support based on diaphragm effort increases the time that patients have effort in a predefined "diaphragm-protective" range, without compromising lung-protective ventilation. DESIGN: Randomized clinical trial. SETTING: Mixed medical-surgical ICU in a tertiary academic hospital in the Netherlands. PATIENTS: Patients (n = 40) with respiratory failure ventilated in a partially-supported mode. INTERVENTIONS: In the intervention group, inspiratory support was titrated hourly to obtain transdiaphragmatic pressure swings in the predefined "diaphragm-protective" range (3-12 cm H2O). The control group received standard-of-care. MEASUREMENTS AND MAIN RESULTS: Transdiaphragmatic pressure, transpulmonary pressure, and tidal volume were monitored continuously for 24 hours in both groups. In the intervention group, more breaths were within "diaphragm-protective" range compared with the control group (median 81%; interquartile range [64-86%] vs 35% [16-60%], respectively; p < 0.001). Dynamic transpulmonary pressures (20.5 ± 7.1 vs 18.5 ± 7.0 cm H2O; p = 0.321) and tidal volumes (7.56 ± 1.47 vs 7.54 ± 1.22 mL/kg; p = 0.961) were not different in the intervention and control group, respectively. CONCLUSIONS: Titration of inspiratory support based on patient breathing effort greatly increased the time that patients had diaphragm effort in the predefined "diaphragm-protective" range without compromising tidal volumes and transpulmonary pressures. This study provides a strong rationale for further studies powered on patient-centered outcomes.
Assuntos
Diafragma/metabolismo , Pulmão/metabolismo , Respiração Artificial/normas , Trabalho Respiratório/fisiologia , Diafragma/fisiopatologia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Respiração Artificial/métodos , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/prevenção & controle , Insuficiência Respiratória/terapia , Trabalho Respiratório/efeitos dos fármacosRESUMO
INTRODUCTION: Macrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study. MATERIAL AND METHODS: Patients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data. RESULTS: In total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality. CONCLUSIONS: Our results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Macrófagos , Humanos , Estudos RetrospectivosRESUMO
INTRODUCTION/AIMS: Diaphragm ultrasound is increasingly used in the diagnosis of diaphragm dysfunction and to guide respiratory management in patients with neuromuscular disorders and those who are critically ill. However, the association between diaphragm ultrasound variables and demographic factors like age, sex, and body mass index (BMI) are understudied. Such relationships are important for correct interpretation of normative values and comparison with selected patients groups. The aim of this study was to determine the associations between diaphragm ultrasound variables and subject characteristics. METHODS: B-mode ultrasound was used to image the diaphragm at the zone of apposition in 83 healthy subjects. Diaphragm thickness at resting end-expiration (Tend-exp ), diaphragm thickness at maximal end-inspiration (Tmax-insp ), diaphragm thickening ratio (Tmax-insp /Tend-exp ), and diaphragm echogenicity were measured. Multivariate linear regression was used to explore the associations between diaphragm ultrasound variables and subject characteristics. RESULTS: Tend-exp , Tmax-insp , and thickening ratio do not change with age whereas diaphragm echogenicity increases with age. The thickening ratio had a weak negative association with BMI, while Tend-exp was positively associated with BMI. Men had a larger Tend-exp and Tmax-insp than women (Tend-exp 1.6 ± 0.5 and 1.4 ± 0.3 mm; p = .011, Tmax-insp 3.8 ± 1.0 and 3.2 ± 0.9 mm; p = .004), but similar thickening ratios. DISCUSSION: Diaphragm thickness, thickening, and echogenicity measured with ultrasound are associated with factors such as age, BMI, and sex. Therefore, subject characteristics should be considered when interpreting diaphragm ultrasound measurements. In the absence of normative values, matched control groups are a prerequisite for research and in clinical practice.