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The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals. By examining the patterns of muscle activity produced by modulating the excitability of V2a neurons, we provide evidence that V2a neurons supply tonic drive to phrenic circuits rather than increase rhythmic inspiratory drive at the level of the brainstem. Our results demonstrate that the V2a class of neurons contribute to recovery of respiratory function following injury. We propose that altering V2a excitability is a potential strategy to prevent respiratory motor failure and promote recovery of breathing following spinal cord injury.
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Diafragma , Traumatismos de la Médula Espinal , Animales , Ratones , Tronco Encefálico , Cafeína , Neuronas , NiacinamidaRESUMEN
Vertebrate podocytes and Drosophila nephrocytes display slit diaphragms, specialised cell junctions that are essential for the execution of the basic excretory function of ultrafiltration. To elucidate the mechanisms of slit diaphragm assembly we have studied their formation in Drosophila embryonic garland nephrocytes. These cells of mesenchymal origin lack overt apical-basal polarity. We find that their initial membrane symmetry is broken by an acytokinetic cell division that generates PIP2-enriched domains at their equator. The PIP2-enriched equatorial cortex becomes a favourable domain for hosting slit diaphragm proteins and the assembly of the first slit diaphragms. Indeed, when this division is either prevented or forced to complete cytokinesis, the formation of diaphragms is delayed to larval stages. Furthermore, although apical polarity determinants also accumulate at the equatorial cortex, they do not appear to participate in the recruitment of slit diaphragm proteins. The mechanisms we describe allow the acquisition of functional nephrocytes in embryos, which may confer on them a biological advantage similar to the formation of the first vertebrate kidney, the pronephros.
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Citocinesis , Drosophila , Animales , División Celular , Corteza Cerebral , DiafragmaRESUMEN
In many organs, small openings across capillary endothelial cells (ECs) allow the diffusion of low-molecular weight compounds and small proteins between the blood and tissue spaces. These openings contain a diaphragm composed of radially arranged fibers, and current evidence suggests that a single-span type II transmembrane protein, plasmalemma vesicle-associated protein-1 (PLVAP), constitutes these fibers. Here, we present the three-dimensional crystal structure of an 89-amino acid segment of the PLVAP extracellular domain (ECD) and show that it adopts a parallel dimeric alpha-helical coiled-coil configuration with five interchain disulfide bonds. The structure was solved using single-wavelength anomalous diffraction from sulfur-containing residues (sulfur SAD) to generate phase information. Biochemical and circular dichroism (CD) experiments show that a second PLVAP ECD segment also has a parallel dimeric alpha-helical configuration-presumably a coiled coil-held together with interchain disulfide bonds. Overall, ~2/3 of the ~390 amino acids within the PLVAP ECD adopt a helical configuration, as determined by CD. We also determined the sequence and epitope of MECA-32, an anti-PLVAP antibody. Taken together, these data lend strong support to the model of capillary diaphragms formulated by Tse and Stan in which approximately ten PLVAP dimers are arranged within each 60- to 80-nm-diameter opening like the spokes of a bicycle wheel. Passage of molecules through the wedge-shaped pores is presumably determined both by the length of PLVAP-i.e., the long dimension of the pore-and by the chemical properties of amino acid side chains and N-linked glycans on the solvent-accessible faces of PLVAP.
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Diafragma , Células Endoteliales , Diafragma/metabolismo , Células Endoteliales/metabolismo , Proteínas Portadoras/metabolismo , Endotelio Vascular/metabolismo , Disulfuros/metabolismo , Dicroismo CircularRESUMEN
BACKGROUND & AIMS: Abdominal distention results from abdominophrenic dyssynergia (ie, diaphragmatic contraction and abdominal wall relaxation) in patients with disorders of gut-brain interaction. This study aimed to validate a simple biofeedback procedure, guided by abdominothoracic wall motion, for treating abdominal distention. METHODS: In this randomized, parallel, placebo-controlled trial, 42 consecutive patients (36 women and 6 men; ages 17-64 years) with meal-triggered visible abdominal distention were recruited. Recordings of abdominal and thoracic wall motion were obtained using inductance plethysmography via adaptable belts. The signal was shown to patients in the biofeedback group, who were taught to mobilize the diaphragm. In contrast, the signal was not shown to the patients in the placebo group, who were given a placebo capsule. Three sessions were performed over a 4-week intervention period, with instructions to perform exercises (biofeedback group) or to take placebo 3 times per day (control group) at home. Outcomes were assessed through response to an offending meal (changes in abdominothoracic electromyographic activity and girth) and clinical symptoms measured using daily scales for 7 days. RESULTS: Patients in the biofeedback group (n = 19) learned to correct abdominophrenic dyssynergia triggered by the offending meal (intercostal activity decreased by a mean ± SE of 82% ± 10%, anterior wall activity increased by a mean ± SE of 97% ± 6%, and increase in girth was a mean ± SE of 108% ± 4% smaller) and experienced improved clinical symptoms (abdominal distention scores decreased by a mean ± SE of 66% ± 5%). These effects were not observed in the placebo group (all, P < .002). CONCLUSIONS: Abdominothoracic wall movements serve as an effective biofeedback signal for correcting abdominophrenic dyssynergia and abdominal distention in patients with disorders of gut-brain interaction. ClincialTrials.gov, Number: NCT04043208.
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Biorretroalimentación Psicológica , Electromiografía , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Biorretroalimentación Psicológica/métodos , Adolescente , Adulto Joven , Resultado del Tratamiento , Pared Abdominal/fisiopatología , Pared Torácica/fisiopatología , Diafragma/fisiopatología , Diafragma/inervación , Pletismografía , Dilatación PatológicaRESUMEN
Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analog, ALY688-SR, remodels the diaphragm of murine model of DMD on DBA background (D2.mdx) mice treated from days 7-28 of age during early stages of disease. ALY688-SR also lowered interleukin-6 (IL-6) mRNA but increased IL-6 and transforming growth factor-ß1 (TGF-ß1) protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also attenuated fibrosis, fiber type-specific atrophy, and in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling, and force-generating properties during the very early stages of disease progression in murine model of DMD on DBA background (D2.mdx) mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2.mdx mice partially prevents fibrosis and fiber type-specific atrophy and lowers force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations.NEW & NOTEWORTHY There are limited therapies for the treatment of Duchenne muscular dystrophy. As fibrosis involves an accumulation of collagen that replaces muscle fibers, antifibrotics may help preserve muscle function. We report that the novel adiponectin receptor agonist ALY688-SR prevents fibrosis in the diaphragm of D2.mdx mice with short-term treatment early in disease progression. These responses were related to altered inflammation and mitochondrial functions and serve as a foundation for the development of this class of therapy.
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Distrofia Muscular de Duchenne , Animales , Ratones , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Adiponectina/genética , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Peróxido de Hidrógeno/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Ratones Endogámicos DBA , Músculo Esquelético/metabolismo , Diafragma/metabolismo , Fibrosis , Inflamación/metabolismo , Progresión de la Enfermedad , Atrofia/metabolismo , Atrofia/patologíaRESUMEN
Mechanical ventilation (MV) is an essential life-saving technique, but prolonged MV can cause significant diaphragmatic dysfunction due to atrophy and decreased contractility of the diaphragm fibres, called ventilator-induced diaphragmatic dysfunction (VIDD). It is not clear about the mechanism of occurrence and prevention measures of VIDD. Irisin is a newly discovered muscle factor that regulates energy metabolism. Studies have shown that irisin can exhibit protective effects by downregulating endoplasmic reticulum (ER) stress in a variety of diseases; whether irisin plays a protective role in VIDD has not been reported. Sprague-Dawley rats were mechanically ventilated to construct a VIDD model, and intervention was performed by intravenous administration of irisin. Diaphragm contractility, degree of atrophy, cross-sectional areas (CSAs), ER stress markers, AMPK protein expression, oxidative stress indicators and apoptotic cell levels were measured at the end of the experiment.Our findings showed that as the duration of ventilation increased, the more severe the VIDD was, the degree of ER stress increased, and the expression of irisin decreased.ER stress may be one of the causes of VIDD. Intervention with irisin ameliorated VIDD by reducing the degree of ER stress, attenuating oxidative stress, and decreasing the apoptotic index. MV decreases the expression of phosphorylated AMPK in the diaphragm, whereas the use of irisin increases the expression of phosphorylated AMPK. Irisin may exert its protective effect by activating the phosphorylated AMPK pathway.
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Proteínas Quinasas Activadas por AMP , Apoptosis , Diafragma , Estrés del Retículo Endoplásmico , Fibronectinas , Animales , Masculino , Ratas , Proteínas Quinasas Activadas por AMP/metabolismo , Diafragma/metabolismo , Fibronectinas/metabolismo , Contracción Muscular , Estrés Oxidativo , Ratas Sprague-Dawley , Respiración Artificial/efectos adversosRESUMEN
Skeletal muscle has a broad range of biomechanical functions, including power generation and energy absorption. These roles are underpinned by the force-velocity relationship, which comprises two distinct components: a concentric and an eccentric force-velocity relationship. The concentric component has been extensively studied across a wide range of muscles with different muscle properties. However, to date, little progress has been made in accurately characterising the eccentric force-velocity relationship in mammalian muscle with varying muscle properties. Consequently, mathematical models of this muscle behaviour are based on a poorly understood phenomenon. Here, we present a comprehensive assessment of the concentric force-velocity and eccentric force-velocity relationships of four mammalian muscles (soleus, extensor digitorum longus, diaphragm and digastric) with varying biomechanical functions, spanning three orders of magnitude in body mass (mouse, rat and rabbits). The force-velocity relationship was characterised using a hyperbolic-linear equation for the concentric component a hyperbolic equation for the eccentric component, at the same time as measuring the rate of force development in the two phases of force development in relation to eccentric lengthening velocity. We demonstrate that, despite differences in the curvature and plateau height of the eccentric force-velocity relationship, the rates of relative force development were consistent for the two phases of the force-time response during isovelocity lengthening ramps, in relation to lengthening velocity, in the four muscles studied. Our data support the hypothesis that this relationship depends on cross-bridge and titin activation. Hill-type musculoskeletal models of the eccentric force-velocity relationship for mammalian muscles should incorporate this biphasic force response. KEY POINTS: The capacity of skeletal muscle to generate mechanical work and absorb energy is underpinned by the force-velocity relationship. Despite identification of the lengthening (eccentric) force-velocity relationship over 80 years ago, no comprehensive study has been undertaken to characterise this relationship in skeletal muscle. We show that the biphasic force response seen during active muscle lengthening is conserved over three orders of magnitude of mammalian skeletal muscle mass. Using mice with a small deletion in titin, we show that part of this biphasic force profile in response to muscle lengthening is reliant on normal titin activation. The rate of force development during muscle stretch may be a more reliable way to describe the forces experienced during eccentric muscle contractions compared to the traditional hyperbolic curve fitting, and functions as a novel predictor of force-velocity characteristics that may be used to better inform hill-type musculoskeletal models and assess pathophysiological remodelling.
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Contracción Muscular , Músculo Esquelético , Humanos , Ratas , Ratones , Animales , Conejos , Conectina , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Terapia por Ejercicio , Diafragma , MamíferosRESUMEN
Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease.NEW & NOTEWORTHY Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.
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Resistencia de las Vías Respiratorias , Diafragma , Mucopolisacaridosis III , Alveolos Pulmonares , Animales , Diafragma/fisiopatología , Diafragma/patología , Diafragma/metabolismo , Rendimiento Pulmonar , Ratones , Alveolos Pulmonares/patología , Alveolos Pulmonares/fisiopatología , Alveolos Pulmonares/metabolismo , Mucopolisacaridosis III/patología , Mucopolisacaridosis III/fisiopatología , Mucopolisacaridosis III/metabolismo , Mucopolisacaridosis III/genética , Contracción Muscular/fisiología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Fuerza Muscular , Pulmón/patología , Pulmón/fisiopatología , Pulmón/metabolismo , MasculinoRESUMEN
RATIONALE: Endoscopic lung volume reduction improves lung function, quality of life and exercise capacity in severe emphysema patients. However, its effect on the diaphragm function is not well understood. We hypothesised that endoscopic lung volume reduction increases its strength by modifying its shape. OBJECTIVES: To investigate changes in both diaphragm shape and strength induced by the insertion of endobronchial valves. METHODS: In 19 patients, both the diaphragm shape and strength were investigated respectively by 3D Slicer software applied on CT scans acquired at functional residual capacity and by transdiaphragmatic pressure measurements by bilateral magnetic stimulation of the phrenic nerves before and 3 months after unilateral valves insertion. MEASUREMENTS AND MAIN RESULTS: After lung volume reduction (median (IQR), 434 mL (-597 to -156], p<0.0001), diaphragm strength increased (transdiaphragmatic pressure: 3 cmH2O (2.3 to 4.2), p<0.0001). On the treated side, this increase was associated with an increase in the coronal (16 mm (13 to 24), p<0.0001) and sagittal (26 mm (21 to 30), p<0.0001) lengths as well as in the area of the zone of apposition (62 cm2 (3 to 100), p<0.0001) with a decrease in the coronal (8 mm (-12 to -4), p<0.0001) and sagittal (9 mm (-18 to -2), p=0.0029) radii of curvature. CONCLUSIONS: Endoscopic lung volume reduction modifies the diaphragm shape by increasing its length and its zone of apposition and by decreasing its radius of curvature on the treated side, resulting in an increase in its strength. TRIAL REGISTRATION NUMBER: NCT05799352.
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Diafragma , Neumonectomía , Enfisema Pulmonar , Tomografía Computarizada por Rayos X , Humanos , Diafragma/diagnóstico por imagen , Masculino , Neumonectomía/métodos , Femenino , Persona de Mediana Edad , Anciano , Enfisema Pulmonar/cirugía , Enfisema Pulmonar/fisiopatología , Enfisema Pulmonar/diagnóstico por imagen , Broncoscopía/métodos , Fuerza Muscular/fisiología , Capacidad Residual Funcional/fisiologíaRESUMEN
BACKGROUND: Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD. METHODS: Scoring criteria for diaphragmatic apnoea (dA) and hypopnoeas (dH) have been defined by the authors considering the pattern observed on cardiorespiratory polygraphy (CR) and the dSDB pathophysiology.10 sleep professionals (physiologists, consultants) blinded to each other were involved in a two-round Delphi survey to rate each item of the proposed dSDB criteria (Likert scale 1-5) and to recognise dSDB among other SDB. The scorers' accuracy was tested against the authors' panel.Finally, CR previously conducted in DMD in clinical setting were rescored and diaphragmatic Apnoea-Hypopnoea Index (dAHI) was derived. Pulmonary function (forced vital capacity per cent of predicted, FVC%pred), overnight oxygen saturation (SpO2) and transcutaneous carbon dioxide (tcCO2) were correlated with dAHI. RESULTS: After the second round of Delphi, raters deemed each item of dA and dH criteria as relevant as 4 or 5. The agreement with the panel in recognising dSDB was 81%, kappa 0.71, sensitivity 77% and specificity 85%.32 CRs from DMD patients were reviewed. dSDB was previously scored as obstructive. The dAHI negatively correlated with FVC%pred (r=-0.4; p<0.05). The total number of dA correlated with mean overnight tcCO2 (r 0.4; p<0.05). CONCLUSIONS: dSDB is a newly defined sleep disorder that correlates with DMD progression. A prospective study to evaluate dSDB as a respiratory measure for DMD in clinical and research settings is planned.
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Técnica Delphi , Diafragma , Distrofia Muscular de Duchenne , Síndromes de la Apnea del Sueño , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/fisiopatología , Humanos , Síndromes de la Apnea del Sueño/fisiopatología , Síndromes de la Apnea del Sueño/diagnóstico , Síndromes de la Apnea del Sueño/etiología , Síndromes de la Apnea del Sueño/complicaciones , Diafragma/fisiopatología , Masculino , Polisomnografía , Índice de Severidad de la Enfermedad , Progresión de la Enfermedad , Capacidad Vital , Adolescente , NiñoRESUMEN
The vertebrate endocytic receptor CUBAM, consisting of three cubilin monomers complexed with a single amnionless molecule, plays a major role in protein reabsorption in the renal proximal tubule. Here, we show that Drosophila CUBAM is a tripartite complex composed of Amnionless and two cubilin paralogues, Cubilin and Cubilin2, and that it is required for nephrocyte slit diaphragm (SD) dynamics. Loss of CUBAM-mediated endocytosis induces dramatic morphological changes in nephrocytes and promotes enlarged ingressions of the external membrane and SD mislocalisation. These phenotypes result in part from an imbalance between endocytosis, which is strongly impaired in CUBAM mutants, and exocytosis in these highly active cells. Of note, rescuing receptor-mediated endocytosis by Megalin/LRP2 or Rab5 expression only partially restores SD positioning in CUBAM mutants, suggesting a specific requirement of CUBAM in SD degradation and/or recycling. This finding and the reported expression of CUBAM in podocytes suggest a possible unexpected conserved role for this endocytic receptor in vertebrate SD remodelling.
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Proteínas de Drosophila/genética , Endocitosis/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Receptores de Superficie Celular/genética , Proteínas de Unión al GTP rab5/genética , Animales , Diafragma/crecimiento & desarrollo , Diafragma/metabolismo , Drosophila melanogaster/genética , Uniones Intercelulares/genética , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Morfogénesis/genética , Complejos Multiproteicos/genética , Podocitos/metabolismoRESUMEN
Congenital diaphragmatic hernia (CDH) is a developmental disorder associated with diaphragm defects and lung hypoplasia. The etiology of CDH is complex and its clinical presentation is variable. We investigated the role of the pulmonary mesothelium in dysregulated lung growth noted in the Wt1 knockout mouse model of CDH. Loss of WT1 leads to intrafetal effusions, altered lung growth, and branching defects prior to normal closure of the diaphragm. We found significant differences in key genes; however, when Wt1 null lungs were cultured ex vivo, growth and branching were indistinguishable from wild-type littermates. Micro-CT imaging of embryos in situ within the uterus revealed a near absence of space in the dorsal chest cavity, but no difference in total chest cavity volume in Wt1 null embryos, indicating a redistribution of pleural space. The altered space and normal ex vivo growth suggest that physical constraints are contributing to the CDH lung phenotype observed in this mouse model. These studies emphasize the importance of examining the mesothelium and chest cavity as a whole, rather than focusing on single organs in isolation to understand early CDH etiology.
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Diafragma/embriología , Epitelio/patología , Hernias Diafragmáticas Congénitas/genética , Pulmón/embriología , Proteínas WT1/genética , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Tórax/anatomía & histologíaRESUMEN
BACKGROUND: Inspiratory muscle fatigue has been shown to have effects on limbs blood flow and physical performance. This study aimed to evaluate the influence of an inspiratory muscle fatigue protocol on respiratory muscle strength, vertical jump performance and muscle oxygen saturation in healthy youths. METHODS: A randomized and double-blinded controlled clinical trial, was conducted. Twenty-four participants aged 18-45 years, non-smokers and engaged in sports activity at least three times a week for a minimum of one year were enrolled in this investigation. Participants were randomly assigned to three groups: Inspiratory Muscle Fatigue (IMFG), Activation, and Control. Measurements of vertical jump, diaphragmatic ultrasound, muscle oxygen saturation, and maximum inspiratory pressure were taken at two stages: before the intervention (T1) and immediately after treatment (T2). RESULTS: The IMFG showed lower scores in muscle oxygen saturation and cardiorespiratory variables after undergoing the diaphragmatic fatigue intervention compared to the activation and control groups (p < 0.05). For the vertical jump variables, intragroup differences were found (p < 0.01), but no differences were shown between the three groups (p > 0.05). CONCLUSIONS: Inspiratory muscle fatigue appears to negatively impact vertical jump performance, muscle oxygen saturation and inspiratory muscle strength in healthy youths. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT06271876. Date of registration 02/21/2024. https://clinicaltrials.gov/study/NCT06271876 .
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Inhalación , Fatiga Muscular , Fuerza Muscular , Músculos Respiratorios , Humanos , Músculos Respiratorios/fisiología , Fatiga Muscular/fisiología , Fuerza Muscular/fisiología , Masculino , Adolescente , Adulto Joven , Femenino , Adulto , Inhalación/fisiología , Saturación de Oxígeno/fisiología , Persona de Mediana Edad , Diafragma/fisiología , Método Doble CiegoRESUMEN
PURPOSE: We aimed to evaluate the safety and efficacy of hyperthermic intraoperative thoraco-abdominal chemotherapy (HITAC) and cytoreductive surgery (CRS) for peritoneal carcinomatosis (PC) patients who underwent diaphragm resection. METHODS: PC patients who underwent CRS with diaphragm resection were selected from a prospectively established database and were divided into hyperthermic intraperitoneal chemotherapy (HIPEC) and HITAC groups. The clinicopathological characteristics, treatment-related variables, perioperative adverse events (AEs), and survival outcomes were compared between the two groups. RESULTS: Of 1168 CRS + HIPEC/HITACs, 102 patients were enrolled-61 HITAC patients and 41 HIPEC patients. In the HITAC and HIPEC groups, the incidence of grade III-V AEs was 29.5% versus 34.1% (p = 0.621). The pleural progression rates were 13.2 versus 18.9% (p = 0.462) and the median overall survival (OS) was 50.5 versus 52.7 months (p = 0.958). Median time to progression (TTP) in thoracic disease was not reached. There was no significant difference in perioperative AEs, TTP, and OS for total patients and the completeness of cytoreduction (CC) score subgroups (p > 0.05). Age ≥ 60 years (hazard ratio [HR] 4.162, p = 0.026) was an independent risk factor influencing pleural progression, and primary malignant peritoneal mesothelioma (MPM; HR 2.749, p = 0.016) and the presence of two or more serious AEs (SAEs; HR 7.294, p = 0.001) were independent risk factors influencing OS. CONCLUSIONS: HITAC can be performed in carefully selected PC patients who underwent diaphragm resection, with no worsening of the safety profile and a possible benefit for pleural progression. In those patients, age ≥ 60 years is associated with a shorter TTP of thoracic disease, while primary MPM and two or more perioperative SAEs are associated with worse OS.
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Hipertermia Inducida , Neoplasias Peritoneales , Humanos , Persona de Mediana Edad , Neoplasias Peritoneales/patología , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Diafragma/patología , Quimioterapia del Cáncer por Perfusión Regional , Tasa de SupervivenciaRESUMEN
BACKGROUND: The most common surgery for non-small cell lung cancer is lobectomy, which can be performed through either thoracotomy or video-assisted thoracic surgery (VATS). Insufficient research has examined respiratory muscle function and exercise capacity in lobectomy performed using conventional thoracotomy (CT), muscle-sparing thoracotomy (MST), or VATS. This study aimed to assess and compare respiratory muscle strength, diaphragm thickness, and exercise capacity in lobectomy using CT, MST, and VATS. METHODS: The primary outcomes were changes in respiratory muscle strength, diaphragm thickness, and exercise capacity. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were recorded for respiratory muscle strength. The 6-min walk test (6MWT) was used to assess functional exercise capacity. Diaphragm thickness was measured using B-mode ultrasound. RESULTS: The study included 42 individuals with lung cancer who underwent lobectomy via CT (n = 14), MST (n = 14), or VATS (n = 14). Assessments were performed on the day before surgery and on postoperative day 20 (range 17-25 days). The decrease in MIP (p < 0.001), MEP (p = 0.003), 6MWT (p < 0.001) values were lower in the VATS group than in the CT group. The decrease in 6MWT distance was lower in the MST group than in the CT group (p = 0.012). No significant differences were found among the groups in terms of diaphragmatic muscle thickness (p > 0.05). CONCLUSION: The VATS technique appears superior to the CT technique in terms of preserving respiratory muscle strength and functional exercise capacity. Thoracic surgeons should refer patients to physiotherapists before lobectomy, especially patients undergoing CT. If lobectomy with VATS will be technically difficult, MST may be an option preferable to CT because of its impact on exercise capacity.
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Diafragma , Tolerancia al Ejercicio , Neoplasias Pulmonares , Fuerza Muscular , Neumonectomía , Músculos Respiratorios , Cirugía Torácica Asistida por Video , Toracotomía , Humanos , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Femenino , Fuerza Muscular/fisiología , Diafragma/fisiopatología , Diafragma/diagnóstico por imagen , Diafragma/cirugía , Neumonectomía/métodos , Persona de Mediana Edad , Cirugía Torácica Asistida por Video/métodos , Anciano , Músculos Respiratorios/fisiopatología , Toracotomía/métodos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Estudios de Seguimiento , PronósticoRESUMEN
Pulmonary hypertension (PH) is a chronic, progressive condition in which respiratory muscle dysfunction is a primary contributor to exercise intolerance and dyspnea in patients. Contractile function, blood flow distribution, and the hyperemic response are altered in the diaphragm with PH, and we sought to determine whether this may be attributed, in part, to impaired vasoreactivity of the resistance vasculature. We hypothesized that there would be blunted endothelium-dependent vasodilation and impaired myogenic responsiveness in arterioles from the diaphragm of PH rats. Female Sprague-Dawley rats were randomized into healthy control (HC, n = 9) and monocrotaline-induced PH rats (MCT, n = 9). Endothelium-dependent and -independent vasodilation and myogenic responses were assessed in first-order arterioles (1As) from the medial costal diaphragm in vitro. There was a significant reduction in endothelium-dependent (via acetylcholine; HC, 78 ± 15% vs. MCT, 47 ± 17%; P < 0.05) and -independent (via sodium nitroprusside; HC, 89 ± 10% vs. MCT, 66 ± 10%; P < 0.05) vasodilation in 1As from MCT rats. MCT-induced PH also diminished myogenic constriction (P < 0.05) but did not alter passive pressure responses. The diaphragmatic weakness, impaired hyperemia, and blood flow redistribution associated with PH may be due, in part, to diaphragm vascular dysfunction and thus compromised oxygen delivery which occurs through both endothelium-dependent and -independent mechanisms.
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Diafragma , Hipertensión Pulmonar , Ratas Sprague-Dawley , Vasodilatación , Animales , Femenino , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/etiología , Arteriolas/fisiopatología , Diafragma/fisiopatología , Diafragma/irrigación sanguínea , Modelos Animales de Enfermedad , Vasodilatadores/farmacología , Endotelio Vascular/fisiopatología , Vasoconstricción , Monocrotalina/toxicidad , RatasRESUMEN
INTRODUCTION: Computed tomography (CT) is routinely employed on the evaluation of dyspnea, yet limited data exist on its assessment of diaphragmatic muscle. This study aimed to determine the capability of CT in identifying structural changes in the diaphragm among patients with ultrasound-confirmed diaphragmatic dysfunction. METHODS: Diaphragmatic ultrasounds conducted between 2018 and 2021 at our center in Marseille, France, were retrospectively collected. Diaphragmatic pillars were measured on CT scans at the L1 level and the celiac artery. Additionally, the difference in height between the two diaphragmatic domes in both diaphragmatic dysfunction cases and controls was measured and compared. RESULTS: A total of 65 patients were included, comprising 24 with diaphragmatic paralysis, 13 with diaphragmatic weakness, and 28 controls. In the case group (paralysis and weakness) with left dysfunctions (n = 24), the CT thickness of the pillars at the level of L1 and the celiac artery was significantly thinner compared with controls (2.0 mm vs. 7.4 mm and 1.8 mm vs. 3.1 mm, p < 0.001 respectively). Significantly different values were observed for paralysis (but not weakness) in the right dysfunction subgroup (n = 15) (2.6 mm vs. 7.4 mm and 2.2 mm vs. 3.8 mm, p < 0.001 respectively, for paralysis vs. controls). Regardless of the side of dysfunction, a significant difference in diaphragmatic height was observed between cases and controls (7.70 cm vs. 1.16 cm and 5.51 cm vs. 1.16 cm, p < 0.001 for right and left dysfunctions, respectively). Threshold values determined through ROC curve analyses for height differences between the two diaphragmatic domes, indicative of paralysis or weakness in the right dysfunctions, were 4.44 cm and 3.51 cm, respectively. Similarly for left dysfunctions, the thresholds were 2.70 cm and 2.48 cm, respectively, demonstrating good performance (aera under the curve of 1.00, 1.00, 0.98, and 0.79, respectively). CONCLUSION: In cases of left diaphragmatic dysfunction, as well as in paralysis associated with right diaphragmatic dysfunction, CT revealed thinner pillars. Additionally, a notable increase in the difference in diaphragmatic height demonstrated a strong potential to identify diaphragmatic dysfunction, with specific threshold values.
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Diafragma , Debilidad Muscular , Humanos , Diafragma/diagnóstico por imagen , Estudios Retrospectivos , Ultrasonografía/métodos , Parálisis , Tomografía Computarizada por Rayos X , TomografíaRESUMEN
BACKGROUND: Respiratory disorders remain incompletely described in multiple sclerosis (MS), even though they are a frequent cause of death. METHODS: The objective was to describe respiratory disorders in MS patients with Expanded Disability Status Score (EDSS) ⩾ 6.5. Diaphragm dysfunction was defined by at least two of the seven criteria: clinical signs, inspiratory recruitment of neck muscles during wakefulness, reduced upright vital capacity (VC) < 80%, upright-to-supine VC ⩾ 15% of upright VC, decrease in Maximal Inspiratory Pressure < 60%, phasic activation of inspiratory neck muscles during sleep, and opposition of thoracic and abdominal movements during sleep. Cough weakness was defined by a peak cough flow < 270 L/min and/or need for cough assist. Sleep apnea syndrome was defined by an apnea-hypopnea index ⩾ 15. RESULTS: Notably, 71 MS patients were included: median age 54 [48, 61] years; median disease duration 21.4 [16.0, 31.4] years. Of these, 52 patients had one or more respiratory disorders; diaphragm dysfunction was the most frequent (n = 34). Patients with diaphragm dysfunction and cough weakness were more disabled. The fatigue score and the cognitive evaluations did not differ between the groups. Five patients required non-invasive ventilation. CONCLUSION: Respiratory disorders are frequent in severe MS, mostly diaphragm dysfunction. Of interest, instrumental interventions are available to address these disorders.
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Esclerosis Múltiple , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/fisiopatología , Trastornos Respiratorios/etiología , Trastornos Respiratorios/fisiopatología , Diafragma/fisiopatología , Tos/fisiopatología , Tos/etiología , Índice de Severidad de la Enfermedad , Síndromes de la Apnea del Sueño/fisiopatología , AdultoRESUMEN
Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.
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Acetilcisteína , Diafragma , Modelos Animales de Enfermedad , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne , Animales , Acetilcisteína/farmacología , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/fisiopatología , Masculino , Ratones , Diafragma/efectos de los fármacos , Diafragma/fisiopatología , Ratones Endogámicos C57BL , Músculos Respiratorios/efectos de los fármacos , Músculos Respiratorios/fisiopatología , Respiración/efectos de los fármacos , Antioxidantes/farmacología , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/fisiopatología , Sistema Respiratorio/metabolismoRESUMEN
INTRODUCTION/AIMS: Point-of-care ultrasound of the diaphragm is highly sensitive and specific in the detection of neuromuscular diaphragmatic dysfunction. In some patients with neuromuscular diaphragmatic dysfunction, paradoxical thinning of the diaphragm during inspiration is observed on ultrasound; however, its frequency, electrodiagnostic associations, and prognostic significance remain uncertain. METHODS: Medical records of patients presenting to two electrodiagnostic laboratories (Mayo Clinic, Rochester, Minnesota and University of Alberta, Edmonton, Alberta) from January 1, 2022 to December 31, 2022, for evaluation of suspected neuromuscular respiratory failure, were reviewed. RESULTS: 214 patients were referred and 19 patients excluded due to incomplete information. Of 195 patients (384 hemidiaphragms), 104 had phrenic neuropathy, 12 had myopathy, and 79 had no evidence of neuromuscular disease affecting the diaphragm. Paradoxical thinning occurred in 31 (27%) patients with neuromuscular diaphragmatic dysfunction and was unilateral in 30, the majority (83%) having normal contralateral ultrasound. Phrenic nerve conduction studies and diaphragm electromyography results did not distinguish patients with paradoxical thinning versus without. Most patients (71%) with paradoxical thinning required non-invasive ventilation (NIV), including 16 with unilateral paradoxical thinning. Paradoxical thinning and BMI ≥30 kg/m2 were risk factors for requiring NIV in multivariable logistic regression analysis, with odds ratios of 2.887 (95% CI:1.166, 7.151) and 2.561 (95% CI: 1.186, 5.532), respectively. DISCUSSION: Paradoxical thinning of the diaphragm occurs in patients with prominent neuromuscular diaphragmatic dysfunction, most commonly from phrenic neuropathy, and is a significant risk factor for requiring NIV. Unilateral paradoxical thinning is sufficient for needing NIV. BMI ≥30 kg/m2 additionally increases risk of requiring NIV in patients with neuromuscular diaphragmatic dysfunction.