Methods for Detecting Cough and Airway Inflammation in Mice.

Chronic cough, which lasts for more than 8 weeks, is one of the most common complaints requiring medical attention, and patients suffer from a huge socioeconomic burden and a marked decrement in quality of life. Animal models can mimic the complex pathophysiology of the cough and are important tools for cough research. The detection of cough sensitivity and airway inflammation is of great significance for studying the complex pathological mechanism of cough. This article describes the measurement of cough using a noninvasive and real-time whole-body plethysmography (WBP) system and the normative procedures for harvesting tissue samples (including blood, lung, spleen, and trachea) of mice. It introduces some methods to assess airway inflammation, including pathological changes in hematoxylin and eosin (HE)-stained lung and trachea sections, the total protein concentration, the uric acid concentration, and the lactate dehydrogenase (LDH) activity in the supernatant of bronchoalveolar lavage fluid (BALF), and the leukocytes and differential cell counts of BALF. These methods are reproducible and serve as valuable tools to study the complex pathophysiology of cough.

Advancing cough research: Methodological insights into cough challenge in guinea pig models using double chamber vs whole-body plethysmography.

OBJECTIVE: This study compares two methods of citric acid-induced cough in guinea pigs in whole-body plethysmography (WBP) and double chamber plethysmography (DCP) to evaluate their efficacy. METHODS: Sixteen specific pathogen-free (SPF) and sixteen conventionally-bred (CON) animals were exposed to 0.4 M citric acid aerosol. They underwent cough provocation using both DCP and WBP methods. The number of coughs and latency to the first cough were recorded and analysed using statistical methods to determine significant differences between the two techniques. RESULTS: WBP resulted in significantly higher cough counts (WBP vs. DCP: 13±9 vs 2±3 for SPF; 14±8 vs 5±5 for CON; p<0.0001) and shorter latency (WBP vs. DCP: 59±6 s vs 159±14 s for SPF; 77±4 s vs 112±12 s for CON; p<0.0001) compared to DCP in both groups. CONCLUSION: Methodological differences substantially impact cough responses. WBP provides a more reliable and physiologically relevant methodology for cough assessment, suggesting the need for standardized protocols in cough research to enhance translational relevance.

Adapting Real-Time Lung Function Measurements for SARS-CoV-2 Infection Studies in Syrian Hamsters.

Pulmonary function examinations are critical to assess respiratory disease severity in patients. In preclinical rodent models of viral respiratory infections, however, disease is frequently evaluated based on virological, pathological and/or surrogate clinical parameters, which are not directly associated with lung function. To bridge the gap between preclinical and clinical readouts, we aimed to apply unrestrained whole-body plethysmography (WBP) measurements in a SARS-CoV-2 Syrian hamster challenge model. While WBP measurements are frequently used for preclinical research in mice and rats, results from studies in hamsters are still limited. During unrestrained WBP measurements, we obtained highly variable breathing frequency values outside of the normal physiological range for hamsters. Importantly, we observed that animal movements were recorded as breaths during WBP measurements. By limiting animal movement through either mechanical or chemical restraint, we improved the reliability of the lung function readout and obtained breathing frequencies that correlated with clinical signs when comparing two different variants of SARS-CoV-2 post-inoculation. Simultaneously, however, new sources of experimental variation were introduced by the method of restraint, which demands further optimalization of WBP measurements in Syrian hamsters. We concluded that WBP measurements are a valuable refinement either in combination with video recordings or if average values of measurements lasting several hours are analyzed.

Comparison of Forced Oscillation Technique, Lung Volumes by Body Plethysmography, and Spirometry in Moderate Persistent Adult Asthma.

BACKGROUND: Spirometry is used extensively, but airway oscillometry is gaining acceptance for evaluating obstructive airway disorders. Moderate persistent asthma requires daily treatment with inhaled corticosteroids (ICS). MATERIALS AND METHODS: We aimed to examine the relationship between airway oscillometry and lung volumes, which are the markers of lung physiology in obstructive airway disease and spirometry in the real-world clinical setting. A total of 72 adults with moderate persistent asthma followed up in our outpatient department from November 2021 to August 2022, and their clinical details and tests of spirometry, forced oscillation technique (FOT), and lung volumes by body plethysmography (BP) performed before and after bronchodilator administration were analyzed. RESULTS: The mean age of the study population was 40 years, and the majority (57%) were females. FOT detected airflow limitation in 12 of the 31 patients with normal spirometry. BP detected abnormalities in more patients than both spirometry and FOT (91.6 vs 73.6%, p < 0.001). Respiratory resistance 5 (R5) had a negative correlation with functional residual capacity (FRC) and total lung capacity (TLC). Reactance 5 (X5) correlated positively with inspiratory capacity (IC) and TLC and negatively with reserve volume (RV)/TLC ratio. A positive correlation was found between IC/TLC% and postbronchodilator X5 and between R5 and 19 and RV/TLC. R5 had a negative and X5 had a positive correlation with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, and maximal mid expiratory flow rates (MMEF). ∇X5 had a negative correlation with FEV1, MMEF, and FEV1/FVC. Spirometry detected postbronchodilator responsiveness in more patients than FOT when only the R5 criterion was used and in a comparable number when the X5 criterion was added. ∇X5 and R5-R19/R5 declined significantly after bronchodilators. CONCLUSION: We concluded that there is a moderate correlation between FOT and spirometry and lung volumes by BP. FOT and spirometry should be used together to identify airflow obstruction and postbronchodilator responsiveness in asthma. Lung volumes by BP identify more abnormalities in adults with asthma than both spirometry and FOT. Thresholds to define postbronchodilator responsiveness (PBDR) for ∇X5 and R5-R19 need to be defined.

Assessing breathing effort by barometric whole-body plethysmography and its relationship with prognosis in client-owned cats with respiratory distress.

BACKGROUND: Cats in respiratory distress have limited tolerance for manipulation, hindering clinical monitoring. Minute volume (MV) can be utilized to rate dyspnea in humans, but its relationship with respiratory distress in cats remains poorly investigated. HYPOTHESIS: Cats with respiratory distress will show higher MV per kg body weight (MV/BW) than normal cats, and the MV/BW increase will correlate with survival. ANIMALS: Fifty-two cats with respiratory distress from lung parenchymal disease, pleural space disease, lower airway obstruction (LAO), or upper airway obstruction were recruited since 2014. METHODS: This is a prospective observational study. Study cats were placed in a transparent chamber, allowing clinicians to easily observe their breathing status and record ventilation using barometric whole-body plethysmography (BWBP). Ventilatory variables of the 52 cats were compared with those of 14 historic control cats. Follow-up data, including disease category, clinical outcomes, and survival, were prospectively collected. RESULTS: Cats in respiratory distress demonstrated significantly higher MV/BW (397 mL/kg; range, 158-1240) than normal cats (269 mL/kg; range, 168-389; P < .001). Among the etiologies, cats with LAO, parenchymal, and pleural space disease exhibited higher-than-normal MV/BW trends. A cutoff value of 373 mL/kg (1.4-fold increase) indicated abnormally increased breathing efforts (sensitivity, 67%; specificity, 93%). MV/BW was independently associated with increased cardiorespiratory mortality in cats with respiratory distress (adjusted hazard ratio 1.17, 95% confidence interval [CI] 1.02-1.35; P = .03). CONCLUSIONS AND CLINICAL IMPORTANCE: Breathing efforts in cats can be noninvasively quantified using BWBP. Measurement of MV/BW could serve as a prognostic index for monitoring cats experiencing respiratory distress.

Influence of acclimatization time on parameters of barometric whole-body plethysmography in healthy adult cats.

BACKGROUND: Pulmonary function testing by barometric whole-body plethysmography (BWBP) is a long-established and well-accepted, non-invasive investigative procedure in cats. HYPOTHESIS/OBJECTIVES: To evaluate, if different acclimatization times influence the measurement parameters of BWBP in healthy adult cats. ANIMALS: 48 healthy adult cats. METHODS: In the prospective observational study, healthy cats were placed in a measuring chamber and BWBP was performed over 30 minutes. Parameters obtained during the three measurement units of 10 minutes each (T1, T2 and T3) were compared. RESULTS: All measurement parameters except for tidal volume per body weight changed significantly (p<0.05) over the three time periods. From T1-T2, the parameters minute volume per body weight (p<0.001), peak inspiratory flow per body weight (p<0.001), peak expiratory flow per body weight (p = 0.002), pause (p = 0.03), enhanced pause (p = 0.03) and quotient of peak expiratory flow divided by expiratory flow at end expiratory volume plus 50% tidal volume (p = 0.03) changed significantly. From the time interval T2-T3, only respiratory rate (p = 0.02), inspiratory time (p = 0.02), expiratory time (p = 0.04), and relaxation time (p = 0.01) changed significantly. All measurement parameters except for tidal volume per body weight changed significantly (p<0.05) between T1 and T3. Age had a significant influence on all parameters except for peak expiratory flow per body weight and peak inspiratory flow per body weight. The parameters were not influenced by sex. CONCLUSION AND CLINICAL IMPORTANCE: All measurement parameters except tidal volume per body weight were significantly affected by acclimatization time. Controlling for age and sex, there was still a significant influence of acclimatization time on all parameters except for tidal volume per body weight. Standardization of the acclimatization time for future studies would be appropriate in order to maintain comparability.

Airway Reactance Predicts Static Lung Hyperinflation in Severe Asthma

Background: Static lung hyperinflation (SLH) measured using body plethysmography in patients with asthma is associated with poor outcomes. The severity of SLH may be associated with small airway dysfunction (SAD), which can be measured using impulse oscillometry (IOS). Objective: This study aims to determine the correlation between SLH and SAD in patients with severe asthma and assess the improvement in SLH and SAD with treatment. Methods: We analyzed data from patients who were enrolled in the Taiwan Severe Asthma Registry, which comprises a prospective observational cohort. Plethysmography and IOS were performed regularly. The relationship between spirometry and IOS parameters was determined. Changes in the clinical outcomes in response to treatment were analyzed. Results: Of 107 patients with severe asthma, 83 (77.6%) had SLH based on an increased residual volume to total lung capacity ratio (RV/TLC). Most patients were older women with worse pulmonary function and SAD than those without SLH. SAD, defined as increased airway resistance/reactance, was significantly correlated with SLH. Airway reactance at 5 Hz (X5) ≤−0.21 kPa/(L/s) detected SLH with an area under the receiver operating characteristic curve of 0.84 (P<.0001; sensitivity, 85.2%; and specificity, 83.3%). After 12 months, patients who received add-on biologics (vs those who did not) had significantly reduced exacerbations, fractional exhaled nitric oxide level, and blood eosinophil counts, as well as improved forced expiratory volume in the first second, X5, and a trend toward reduced RV/TLC ratio. Conclusion: In severe asthma, airway reactance (X5) could be a novel parameter for assessing SLH. (AU)

Antecedentes: En el asma bronquial, la hiperinsuflación pulmonar estática (SLH) medida mediante pletismografía corporal (Pleth) se asocia a un peor pronóstico. La gravedad de la SLH podría estar asociada con la disfunción de las vías respiratorias pequeñas (SAD), que puede medirse mediante la oscilometría de impulsos (IOS). Objetivo: Este estudio pretende determinar la correlación entre el SLH y la SAD en pacientes con asma grave, y la mejora de ambos parámetros en respuesta al tratamiento. Métodos: Se analizaron los datos de los pacientes que se inscribieron en el Registro de Asma Grave de Taiwán, una cohorte observacional prospectiva. Se realizaron periódicamente mediciones de Pleth e IOS. Se determinó la relación entre los parámetros espirométricos e IOS. Se analizaron los cambios en los parámetros clínicos y funcionales en respuesta al tratamiento. Resultados: De una muestra de 107 pacientes con asma grave, 83 (77,6%) presentaban SLH, definida mediante una relación volumen residual/capacidad pulmonar total (VR/CTP) aumentada. La mayoría de los pacientes eran mujeres de edad avanzada con peor función pulmonar y SAD, en comparación con los que no tenían SLH. El SAD por aumento de la resistencia/reactancia de las vías respiratorias se correlacionó significativamente con el SLH. La reactancia de las vías respiratorias a 5 Hz (X5) ≤-0,21 [kPa/(L/s)] detectó el SLH con un área bajo la curva ROC de 0,84 (p < 0,0001, sensibilidad = 85,2% y especificidad = 83,3%). Después de 12 meses, los pacientes que recibieron tratamiento biológico adicional presentaron una reducción significativa de las exacerbaciones, del nivel de óxido nítrico exhalado, del recuento de eosinófilos en sangre, una mejora del volumen espiratorio forzado en el primer segundo, de la X5, y una tendencia a la reducción del cociente RV/TLC en comparación con los que no recibieron tratamiento biológico... (AU)

Influence of chronic hypoxia on the hypoxic ventilatory response of juvenile and adult rats.

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition - from blunting to augmenting the HVR - occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 - 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one "typical" pattern for VAH in adult rats.

Simplified Whole Body Plethysmography to Characterize Lung Function During Respiratory Melioidosis.

Surrogate animal models of disease are subject to the 3Rs of Responsible Research. There is a frequent revisiting of refinements to animal models to ensure that both animal welfare and scientific insights advance with the availability of new technologies. This article demonstrates the use of Simplified Whole Body Plethysmography (sWBP) to non-invasively study respiratory failure in a model of lethal respiratory melioidosis. sWBP has the sensitivity to detect breathing in mice through the entirety of the course of the disease, allowing for the moribund-associated symptoms (bradypnea and hypopnea) to be measured and potentially used to develop humane endpoint criteria. Some of the benefits of sWBP in the context of respiratory disease are that host breath monitoring comes the closest of any physiologic measurement at assessing dysfunction of the primary infected tissue, namely, the lung. In addition to biological significance, the use of sWBP is rapid and non-invasive, minimizing stress in research animals. This work demonstrates the use of in-house sWBP apparatus to monitor disease throughout the course of respiratory failure in the murine model of respiratory melioidosis.

Evaluation of barometric whole-body plethysmography for therapy monitoring in cats with feline lower airway disease.

OBJECTIVES: Feline lower airway disease (FLAD) is a common respiratory condition in cats. Traditionally, response to therapy is monitored only by evaluation of clinical signs and radiographic examination of the lungs. Barometric whole-body plethysmography (BWBP) is considered a non-invasive, well-tolerated form of measuring airway reactivity in cats. The aim of the study was to assess pulmonary function testing by BWBP for non-invasive evaluation of response to therapy in cats with FLAD and to investigate whether BWBP parameters correlate with clinical severity. MATERIAL AND METHODS: The prospective study included 25 client-owned cats, diagnosed with FLAD on the basis of their medical history, clinical signs, radiographic findings, and bronchoalveolar lavage fluid (BALF) examination. At three time points (day 0, 14, and 60), a standardised owner questionnaire, a clinical examination and BWBP measurements were carried out. Results of the questionnaire and the clinical examination were evaluated using a clinical 12-point score. Individual therapy was administered to all patients after diagnosis, based on the severity of disease and compliance of the cat. RESULTS: The total clinical score significantly improved over the entire study period (p<0.001). Significant improvement was detected for the frequency of coughing (p = 0.009), respiratory distress (p = 0.001), lung auscultation findings (p = 0.002), and general condition and appetite (p = 0.045). The BWBP parameter Penh, an indicator of bronchoconstriction, improved significantly under initial therapy between day 0 and 14 (p = 0.009). A significant correlation between Penh and the severity of auscultation findings was seen on day 0 (r = 0.40; p = 0.013). CONCLUSION: The study supports the role of Penh as a non-invasive parameter for monitoring initial treatment response in cats with FLAD. Further studies are needed to address whether other BWBP parameters might be suitable for non-invasive therapy monitoring of FLAD. Clinical evaluation is always essential in cats with FLAD to evaluate treatment response.

Differences in the Measurement of Functional Residual Capacity Between Body Plethysmographs of Two Manufacturers.

Body plethysmography is a fundamental method for the assessment of static lung volumes. Although equipment is provided by several manufacturers, there are no established cross-vendor tools for quality control. In the process of quality control and analysis of data on hyperinflation from the large COPD cohort COSYCONET, hints appeared that plethysmographs of different vendors might yield different values for static lung volumes. Functional residual capacity (FRC) differed about 0.67 litres between plethysmographs of the manufacturer Vyaire and Ganshorn. Absolute differences of residual lung volume (RV) and total lung capacity (TLC) were similar. It appears undeniable that differences of this magnitude have an impact on clinical interpretation. Thus, device harmonization seems to be required.

FEV1 Predicts Cardiac Status and Outcome in Chronic Heart Failure.

BACKGROUND: COPD is an established predictor of clinical outcome in patients with chronic heart failure (HF). However, little evidence is available about the predictive value of FEV1 in chronic HF. RESEARCH QUESTION: Is pulmonary function related to the progression of chronic HF? STUDY DESIGN AND METHODS: The MyoVasc study (ClinicalTrials.gov Identifier: NCT04064450) is a prospective cohort study of HF. Information on pulmonary and cardiac functional and structural status was obtained by body plethysmography and echocardiography. The primary study end point was worsening of HF. RESULTS: Overall 2,998 participants (age range, 35-84 years) with available FEV1 data were eligible for analysis. Linear multivariate regression analysis revealed an independent relationship of FEV1 (per -1 SD) with deteriorated systolic and diastolic left ventricle (LV) function as well as LV hypertrophy under adjustment of age, sex, height, cardiovascular risk factors (CVRFs), and clinical profile (LV ejection fraction: ß-estimate, -1.63% [95% CI, -2.00% to -1.26%]; E/E' ratio: ß-estimate, 0.82 [95% CI, 0.64-0.99]; and LV mass/height2.7: ß-estimate, 1.58 [95% CI, 1.07-2.10]; P < .001 for all). During a median time to follow-up of 2.6 years (interquartile range, 1.1-4.1 years), worsening of HF occurred in 235 individuals. In Cox regression model adjusted for age, sex, height, CVRF, and clinical profile, pulmonary function (FEV1 per -1 SD) was an independent predictor of worsening of HF (hazard ratio [HR], 1.44 [95% CI, 1.27-1.63]; P < .001). Additional adjustment for obstructive airway pattern and C-reactive protein mitigated, but did not substantially alter, the results underlining the robustness of the observed effect (HRFEV1, 1.39 [95% CI, 1.20-1.61]; P < .001). The predictive value of FEV1 was consistent across subgroups, including individuals without obstruction (HR, 1.55 [95% CI, 1.34-1.77]; P < .001) and nonsmokers (HR, 1.72 [95% CI, 1.39-1.96]; P < .001). INTERPRETATION: FEV1 represents a strong candidate to improve future risk stratification and prevention strategies in individuals with chronic, stable HF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04064450; URL: www.clinicaltrials.gov.

Normative reference equations of airway dynamics assessed by whole-body plethysmography during spontaneous breathing evaluated in infants, children, and adults.

Effective specific airway resistance (sReff ), its reciprocal the effective specific airway conductance (sGeff ) are computed as ratios between the integral of the resistive aerodynamic work of breathing (sWOB) and the integral of the tidal flow/volume loop, the reciprocal, respectively. Unfortunately, reference equations to obtain normative values for sReff , sGeff , and sWOB are not yet available. To assess reference equations for sWOB, sReff , and sGeff during tidal breathing at resting level in healthy infants, children, and adults by a multidimensional model. Retrospectively exported data were collected from databases of five Swiss lung function centers, in which plethysmography (Jaeger Würzburg, Germany) was performed for the assessment of airway dynamics, static lung volumes, and forced breathing flow-volume loops, in a collective of 28 healthy infants, 47 children, and 273 adults. From this cohort, reference equations were computed based on anthropometric measures, lung volumes, indices of the breathing pattern, and timing of breathing. By multi-linear modeling reference equations of sReff , sGeff , and sWOB could be defined taking as independent parameters apart from anthropometric parameters, also parameters given by the ratio between the tidal volume and functional residual capacity (FRCpleth /VT ), and the ratio between VT and inspiratory time (VT /TI ). An alternative statistical approach to define reference equations of airway dynamics reveals that apart from the subject's anthropometric measurements, parameters of the magnitude of static lung volumes, the breathing pattern, and the timing of breathing are co-variants of reference equations of airway dynamics over a large age range.

Obstructive sleep apneas naturally occur in mice during REM sleep and are highly prevalent in a mouse model of Down syndrome.

STUDY OBJECTIVES: The use of mouse models in sleep apnea study is limited by the belief that central (CSA) but not obstructive sleep apneas (OSA) occur in rodents. We aimed to develop a protocol to investigate the presence of OSAs in wild-type mice and, then, to apply it to a validated model of Down syndrome (Ts65Dn), a human pathology characterized by a high incidence of OSAs. METHODS: In a pilot study, nine C57BL/6J wild-type mice were implanted with electrodes for electroencephalography (EEG), neck electromyography (nEMG), and diaphragmatic activity (DIA), and then placed in a whole-body-plethysmographic (WBP) chamber for 8 h during the rest (light) phase to simultaneously record sleep and breathing activity. CSA and OSA were discriminated on the basis of WBP and DIA signals recorded simultaneously. The same protocol was then applied to 12 Ts65Dn mice and 14 euploid controls. RESULTS: OSAs represented about half of the apneic events recorded during rapid-eye-movement-sleep (REMS) in each experimental group, while the majority of CSAs were found during non-rapid eye movement sleep. Compared with euploid controls, Ts65Dn mice had a similar total occurrence rate of apneic events during sleep, but a significantly higher occurrence rate of OSAs during REMS, and a significantly lower occurrence rate of CSAs during NREMS. CONCLUSIONS: Mice physiologically exhibit both CSAs and OSAs. The latter appear almost exclusively during REMS, and are highly prevalent in Ts65Dn. Mice may, thus, represent a useful model to accelerate the understanding of the pathophysiology and genetics of sleep-disordered breathing and to help the development of new therapies.

The Utility of Body Composition Assessment in Nutrition and Clinical Practice: An Overview of Current Methodology.

Body composition is a key component for maintaining good general health and longevity. It can be influenced by a variety of factors, including genetics, environment, and lifestyle choices. The assessment of body composition is an essential tool for nutrition specialists to effectively evaluate nutritional status and monitor progression during dietary interventions. As humans age, there is a natural increase in fat mass coupled with a gradual decline in lean mass, specifically in bone and muscle mass. Individuals with a high body fat percentage are at a greater risk of cardiovascular diseases, type 2 diabetes, several types of cancer, and early mortality. Significant decreases in bone mineral density signify osteopenia and osteoporosis, while reductions in skeletal muscle mass increase the risk of developing sarcopenia. Moreover, undernutrition exacerbates the effects of many medical conditions and is important to address. Though weight tracking and calculation of BMI are used commonly by clinicians and dietitians, these measures do not provide insight on the relative contributions of fat mass and fat-free mass or the changes in these compartments that may reflect disease risk. Therefore, it is important that healthcare professionals have a critical understanding of body composition assessment and the strengths and limitations of the methods available.

Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor.

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.

Comportamiento de volúmenes pulmonares estáticos por pletismografía en enfermedad pulmonar obstructiva crónica con disociación clínico-espirométrica / Behavior of static lung volumes due to plethysmography in chronic obstructive pulmonary disease with clinical-spirometric dissociation

Introducción: La enfermedad pulmonar obstructiva crónica es un problema sanitario mundial por su elevada prevalencia, morbilidad y cuantioso costo económico. Objetivo: Caracterizar mediante la pletismografía a los pacientes con diagnóstico de enfermedad pulmonar obstructiva crónica que presentaron una discrepancia clínica espirométrica. Métodos: Se realizó un estudio descriptivo y transversal en 33 pacientes con diagnóstico de enfermedad pulmonar obstructiva crónica que acudieron a consulta externa del Hospital Neumológico Benéfico Jurídico y el Centro de Investigaciones Clínicas. Se les realizaron volúmenes pulmonares por pletismografía corporal y espirometría en el período comprendido de noviembre 2016 a marzo 2018. Resultados: El sexo masculino (69,7 por ciento) resultó el más frecuente y el grupo de edad predominante fue mayor de 65 años (60,6 por ciento). El 41,2 por ciento de los pacientes presentaron grado de obstrucción moderadamente severo. La capacidad pulmonar total y el volumen residual fueron normales (72,7 por ciento y 42,5 por ciento) respectivamente. El 43,8 por ciento de los pacientes presentaron hiperinsuflación leve. El grado 3 de disnea fue el que predominó en los pacientes. El 12,1 por ciento de los pacientes presentaron aumento del volumen residual dado por atrapamiento aéreo grave con la disminución del volumen espiratorio forzado en el primer segundo. Conclusiones: El comportamiento de los volúmenes pulmonares por pletismografía corporal en la enfermedad pulmonar obstructiva crónica con disociación clínico-espirométrica, evidenció la disminución del volumen espiratorio forzado en el primer segundo y el aumento del volumen residual relacionándose con el grado de disnea(AU)

Introduction: Chronic obstructive pulmonary disease is a global health problem due to its high prevalence, morbidity and high economic cost. Objective: By using plethysmography, to describe patients with diagnosis of chronic obstructive pulmonary disease that had spirometric clinical discrepancy. Methods: A descriptive and cross-sectional study was carried out in 33 patients with diagnosis of chronic obstructive pulmonary disease who attended the outpatient clinic at Benéfico Jurídico Pneumologic Hospital and the Clinical Research Centre. Lung volumes were performed by body plethysmography and spirometry from November 2016 to March 2018. Results: The male sex (69.7 percent) was the most frequent and the predominant age group was older than 65 years (60.6 percent). 41.2 percent of the patients had moderately severe degree of obstruction. Total lung capacity and residual volume were normal, 72.7 percent and 42.5 percent, respectively. 43.8 percent of the patients had mild hyperinflation. Grade 3 dyspnea was the one that predominated in the patients. 12.1 percent of the patients showed increased residual volume due to severe air trapping with decreased forced expiratory volume in the first second. Conclusions: The behavior of lung volumes by body plethysmography in chronic obstructive pulmonary disease with clinical-spirometric dissociation, evidenced decrease in forced expiratory volume in the first second and increased in residual volume related to the degree of dyspnea(AU)

Noninvasive Measurement of Pulmonary Function in Experimental Mouse Models of Airway Disease.

Mouse models have become an indispensable tool in translational research of human airway disease and have provided much of our understanding of the pathogenesis of airway disease such as asthma. In these models the ability to assess pulmonary function and particularly airway responsiveness is critically important. Existing methods for testing pulmonary function in mice in vivo include noninvasive and invasive technologies. Noninvasive head-out body plethysmography is a well-established and widely accepted technique which has been proven as a reliable method to measure lung function on repeated occasions in intact, conscious mice. We have performed several validation studies in allergic mice to compare the parameter midexpiratory flow (EF50) as a noninvasive marker of airflow limitation with invasively measured gold standard parameters of lung mechanics. The results of these studies showed a good agreement of EF50 with the invasive assessment of lung resistance and dynamic compliance with a somewhat lower sensitivity of EF50. The measurement of EF50 together with basic respiratory parameters is particularly appropriate for simple and repeatable screening of pulmonary function in large numbers of mice or if noninvasive measurement without use of anesthesia is required. Beyond known applications, head-out body plethysmography also provides a much-needed high-throughput screening tool to gain insights into the impact and kinetics of respiratory infections such as SARS-COV-2 on lung physiology in laboratory mice.

Effect of Predicted Versus Measured Thoracic Gas Volume on Body Fat Percentage in Young Adults.

The BodPod® (COSMED, Concord, CA) uses predicted (pTGV) or measured thoracic gas volume (mTGV) during estimations of percentage body fat (%BF). In young adults, there is inconsistent evidence on the variation between pTGV and mTGV, and the effect of sex as a potential covariate on this relationship is unknown. This study examined the difference between TGV assessments and its effect on %BF and potential sex differences that may impact this relationship. A retrospective analysis of BodPod® pTGV and mTGV for 95 men and 86 women ages 18-30 years was performed. Predicted TGV was lower than mTGV for men (-0.49 ± 0.7 L; p < .0001). For men, %BF derived by pTGV was lower than that by mTGV (-1.3 ± 1.8%; p < .0001). For women, no differences were found between pTGV and mTGV (-0.08 ± 0.6 L; p > .05) or %BF (-0.03 ± 0.2%; p > .05). The two-predictor model of sex and height was able to account for 57.9% of the variance in mTGV, F(2, 178) = 122.5, p < .0001. Sex corrected for the effect of height was a significant predictor of mTGV (ß = 0.483 L, p < .0001). There is bias for pTGV to underestimate mTGV in individuals with a large mTGV, which can lead to significant underestimations of %BF in young adults; this was especially evident for men in this study. Sex is an important covariate that should be considered when deciding to use pTGV. The results indicate that TGV should be measured whenever possible for both men and women ages 18-30 years.

Fibroblast growth factor 23 is an independent marker of COPD and is associated with impairment of pulmonary function and diffusing capacity.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that in recent years has been reported to have significant effects on numerous tissues. Chronic obstructive pulmonary disease (COPD) is associated with hypophosphatemia but the evidence for elevated plasma levels of FGF23 in COPD subjects is ambiguous. Recently, FGF23 has even been shown to be involved in the inflammatory pathways activated in COPD, so FGF23 could be a novel biomarker for COPD and impairment of pulmonary function. The purpose was thus to explore the association of FGF23 with COPD and measures of pulmonary function. This was a cross sectional study of 450 subjects who underwent spirometry, body plethysmography, determination of diffusing capacity (DL,CO) and biomarker analysis of FGF23, interleukin (IL)-1 receptor antagonist, IL-6 and IL-8. Forty-four participants were excluded due to missing data or renal impairment (eGFR <45 mL/min/m2). Spirometry identified 123 subjects with COPD. FGF23 levels were elevated in COPD subjects compared to non COPD subjects, and this remained significant after adjustment for age, sex and smoking habits (OR = 1.6, p = 0.02). Linear regression showed significant relationships between FGF23 and FEV1 (ß = -0.15, p = 0.003), RV/TLC (ß = 0.09, p = 0.05) and DL, CO (ß = -0.24, p < 0.001). In conclusion we found that plasma levels of FGF23 are elevated in COPD subjects even when adjusting for traditional risk factors. Furthermore, FGF23 is associated with impairment in lung function as measured by FEV1 and DL,CO. Further studies are needed to establish whether FGF23 could serve as a novel biomarker of COPD and emphysema development.