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Scientific Reports Nov 2023Fetal growth restriction (FGR) remains one of the main obstetrical problems worldwide, with consequences beyond perinatal life. Animal models with developmental and...
Fetal growth restriction (FGR) remains one of the main obstetrical problems worldwide, with consequences beyond perinatal life. Animal models with developmental and structural similarities to the human are essential to understand FGR long-term consequences and design novel therapeutic strategies aimed at preventing or ameliorating them. Herein, we described the long-term consequences of FGR in pulmonary function, structure, and gene expression, and characterized neurodevelopmental sequelae up to preadolescence in a rabbit model. FGR was induced at gestational day 25 by surgically reducing placental blood supply in one uterine horn, leaving the contralateral horn as internal control. Neonatal rabbits born near term were assigned to foster care in mixed groups until postnatal day (PND) 21. At that time, one group underwent pulmonary biomechanical testing followed by lung morphometry and gene expression analysis. A second group underwent longitudinal neurobehavioral assessment until PND 60 followed by brain harvesting for multiregional oligodendrocyte and microglia quantification. FGR was associated with impaired pulmonary function and lung development at PND 21. FGR rabbits had higher respiratory resistance and altered parenchymal biomechanical properties in the lungs. FGR lungs presented thicker alveolar septal walls and reduced alveolar space. Furthermore, the airway smooth muscle content was increased, and the tunica media of the intra-acinar pulmonary arteries was thicker. In addition, FGR was associated with anxiety-like behavior, impaired memory and attention, and lower oligodendrocyte proportion in the frontal cortex and white matter. In conclusion, we documented and characterized the detrimental pulmonary function and structural changes after FGR, independent of prematurity, and beyond the neonatal period for the first time in the rabbit model, and describe the oligodendrocyte alteration in pre-adolescent rabbit brains. This characterization will allow researchers to develop and test therapies to treat FGR and prevent its sequelae.
Topics: Infant, Newborn; Animals; Child; Rabbits; Pregnancy; Female; Humans; Fetal Growth Retardation; Placenta; Lung; Obstetrics; Infant, Premature; Lagomorpha
PubMed: 38017239
DOI: 10.1038/s41598-023-48174-6 -
Laryngoscope Investigative... Oct 2023Anterior active rhinomanometry (AAR) is widely used in Swedish routine clinical practice to decide if septoplasty is necessary. The scientific basis for the method needs...
OBJECTIVES
Anterior active rhinomanometry (AAR) is widely used in Swedish routine clinical practice to decide if septoplasty is necessary. The scientific basis for the method needs to be strengthened. Therefore, the aims were to evaluate nasal airway resistance (NAR), paradoxical reactions to pharmacological decongestion, and test-retest characteristics of the Rhino-Comp® AAR in healthy subjects.
METHODS
A prospective longitudinal design was used. AAR was performed before and after decongestion at baseline and after ≥6 months on 60 healthy volunteers. The relationships between NAR, height, weight, BMI, sex, and allergic rhinitis were evaluated by regression analyses. Descriptive statistics were used to evaluate paradoxical reactions. Test-retest and repeatability characteristics were evaluated with intra-class coefficients (ICC), Cronbach's α, and standard error of measurement.
RESULTS
No statistically significant differences were found between genders or nasal cavity sides. NAR was statistically significantly related to height. Short- and long-term test-retest characteristics were good with ICC and Cronbach's > .75. The minimal significant difference in NAR Log10V2 values between the two measurements was 0.11 and 0.09 (long- and short-term). Paradoxical reactions to pharmacological decongestion were rare, mostly weak, and not evidently reproducible.
CONCLUSION
In this study, we report reference data for healthy subjects, test-retest capabilities, and the minimal relevant difference between two measurements for the Rhino-Comp® AAR, information that is vital and necessary for the appropriate use of AAR in clinical practice. An effective method for pharmacological decongestion is described and recommended for future studies and clinical practice. Paradoxical reactions to pharmacological decongestants exist but maybe without clinical significance.
LEVEL OF EVIDENCE
NA.
PubMed: 37899860
DOI: 10.1002/lio2.1157 -
Computers in Biology and Medicine Dec 2023Understanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby...
BACKGROUND AND OBJECTIVE
Understanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby contributing to the enhancement of the therapeutic efficacy of inhaled drug delivery. This study demonstrates the potential effects of inhaler resistance on particle deposition characteristics in an anatomically realistic human oropharynx and the United States Pharmacopeia (USP) throat using computational fluid dynamics (CFD).
METHOD
Magnetic resonance (MR) imaging was performed on a healthy volunteer biting on a small mockup inhaler mouthpiece. Three-dimensional geometry of the oropharynx and mouthpiece were reconstructed from the MR images. CFD simulations coupled with discrete phase modelling were conducted. Inhaled polydisperse particles under two different transient flow profiles with peak inspiratory flow rates (PIFR) of 30 L/min and 60 L/min were investigated. The effect of inhaler mouthpiece resistance was modelled as a porous medium by varying the initial resistance (Ri) and viscous resistance (Rv). Three resistance values, 0.02 kPaminL, 0.035 kPaminL and 0.05 kPa minL, were simulated. The inhaler outlet velocity was set to be consistent across all models for both flow rate conditions to enable a meaningful comparison of models with different inhaler resistances.
RESULT
The results from this study demonstrate that investigating the effect of inhaler resistance by solely relying on the USP throat model may yield misleading results. For the geometrically realistic oropharyngeal model, both the pressure and kinetic energy profiles at the mid-sagittal plane of the airway change dramatically when connected to a higher-resistance inhaler. In addition, the geometrically realistic oropharyngeal model appears to have a resistance threshold. When this threshold is surpassed, significant changes in flow dynamics become evident, which is not observed in the USP throat model. Furthermore, this study also reveals that the impact of inhaler resistance in a geometrically realistic throat model extends beyond the oral cavity and affects particle deposition downstream of the oral cavity, including the oropharynx region.
CONCLUSION
Results from this study suggest that key mechanisms underpinning the working principles of inhaler resistance are intricately connected to their complex interaction with the pharynx geometry, which affects the local pressure, local variation in velocity and kinetic energy profile in the airway.
Topics: Humans; Administration, Inhalation; Aerosols; Dry Powder Inhalers; Computer Simulation; Pharynx; Hydrodynamics; Particle Size; Equipment Design
PubMed: 37956626
DOI: 10.1016/j.compbiomed.2023.107673 -
Biofilm Dec 2023The viscoelastic properties of biofilms are correlated with their susceptibility to mechanical and chemical stress, and the airway environment in muco-obstructive...
The viscoelastic properties of biofilms are correlated with their susceptibility to mechanical and chemical stress, and the airway environment in muco-obstructive pulmonary diseases (MOPD) facilitates robust biofilm formation. Hyperconcentrated, viscoelastic mucus promotes chronic inflammation and infection, resulting in increased mucin and DNA concentrations. The viscoelastic properties of biofilms are regulated by biopolymers, including polysaccharides and DNA, and influence responses to antibiotics and phagocytosis. We hypothesize that targeted modulation of biofilm rheology will compromise structural integrity and increase antibiotic susceptibility and mucociliary transport. We evaluate biofilm rheology on the macro, micro, and nano scale as a function of treatment with a reducing agent, a biopolymer, and/or tobramycin to define the relationship between the viscoelastic properties of biofilms and susceptibility. Disruption of the biofilm architecture is associated with altered macroscopic and microscopic moduli, rapid vector permeability, increased antibiotic susceptibility, and improved mucociliary transport, suggesting that biofilm modulating therapeutics will improve the treatment of chronic respiratory infections in MOPD.
PubMed: 36711323
DOI: 10.1016/j.bioflm.2023.100104 -
Frontiers in Veterinary Science 2023In veterinary medicine, airway management of cats under general anesthesia is performed with an endotracheal tube (ETT) or supraglottic airway device (SGAD). This study...
INTODUCTION
In veterinary medicine, airway management of cats under general anesthesia is performed with an endotracheal tube (ETT) or supraglottic airway device (SGAD). This study aims to describe the use of computational fluid dynamics (CFD) to assess the velocities, pressures, and resistances of cats with ETT or SGAD.
METHODS
A geometrical reconstruction model of the device, trachea, and lobar bronchi was carried out from computed tomography (CT) scans that include the head, neck, and thorax. Twenty CT scans of cats under general anesthesia using ETT ( = 10) and SGAD ( = 10) were modeled and analyzed. An inspiratory flow of 2.4 L/min was imposed in each model and velocity (m/s), general and regional pressures (cmHO) were computed. General resistance (cmHO/L/min) was calculated using differential pressure differences between the device inlet and lobar bronchi. Additionally, regional resistances were calculated at the device's connection with the breathing circuit (region A), at the glottis area for the SGAD, and the area of the ETT exit (bevel) (region B) and the device itself (region C).
RESULTS
Recirculatory flow and high velocities were found at the ETT's bevel and at the glottis level in the SGAD group. The pressure gradient (Δp) was more enhanced in the ETT cases compared with the SGAD cases, where the pressure change was drastic. In region A, the Δp was higher in the ETT group, while in regions B and C, it was higher in the SGAD group. The general resistance was not statistically significant between groups ( = 0.48). Higher resistances were found at the region A ( = <0.001) in the ETT group. In contrast, the resistance was higher in the SGAD cases at the region B ( = 0.001).
DISCUSSION
Overall, the provided CT-based CFD analysis demonstrated regional changes in airway pressure and resistance between ETT and SGAD during anesthetic flow conditions. Correct selection of the airway device size is recommended to avoid upper airway obstruction or changes in flow parameters.
PubMed: 37818391
DOI: 10.3389/fvets.2023.1183223 -
Pneumologie (Stuttgart, Germany) Nov 2023Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a...
Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a mean pulmonary arterial pressure (PAPm) > 20 mmHg, a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance of ≤ 5 Wood units (WU). Both the non-severe (PVR ≤ 5 WU) and much more the severe PH (PVR > 5 WU) have an unfavorable prognosis.If PH is suspected, it is recommended to primarily check whether risk factors for pulmonary arterial hypertension (PAH, group 1 PH) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4 PH) are present. If risk factors are present or there is a suspicion of severe PH in lung patients, it is recommended that the patient should be presented to a PH outpatient clinic promptly.For patients with severe PH associated with lung diseases, personalized, individual therapy is recommended - if possible within the framework of therapy studies. Currently, a therapy attempt with PH specific drugs should only be considered in COPD patients if the associated PH is severe and a "pulmonary vascular" phenotype (severe precapillary PH, but typically only mild to moderate airway obstruction, no or mild hypercapnia and DLCO < 45 % of predicted value) is present. In patients with severe PH associated with interstitial lung disease phosphodiesterase-5-inhibitors may be considered in individual cases. Inhaled treprostinil may be considered also in non-severe PH in this patient population.
Topics: Humans; Hypertension, Pulmonary; Lung; Vascular Resistance; Prognosis; Lung Diseases, Interstitial
PubMed: 37963481
DOI: 10.1055/a-2145-4756 -
BMC Pulmonary Medicine May 2024Assessing mechanical properties of the respiratory system (C) during mechanical ventilation necessitates an end-inspiration flow of zero, which requires an...
BACKGROUND
Assessing mechanical properties of the respiratory system (C) during mechanical ventilation necessitates an end-inspiration flow of zero, which requires an end-inspiratory occlusion maneuver. This lung model study aimed to observe the effect of airflow obstruction on the accuracy of respiratory mechanical properties during pressure-controlled ventilation (PCV) by analyzing dynamic signals.
METHODS
A Hamilton C3 ventilator was attached to a lung simulator that mimics lung mechanics in healthy, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) models. PCV and volume-controlled ventilation (VCV) were applied with tidal volume (V) values of 5.0, 7.0, and 10.0 ml/kg. Performance characteristics and respiratory mechanics were assessed and were calibrated by virtual extrapolation using expiratory time constant (RC).
RESULTS
During PCV ventilation, drive pressure (DP) was significantly increased in the ARDS model. Peak inspiratory flow (PIF) and peak expiratory flow (PEF) gradually declined with increasing severity of airflow obstruction, while DP, end-inspiration flow (EIF), and inspiratory cycling ratio (EIF/PIF%) increased. Similar estimated values of C and airway resistance (R) during PCV and VCV ventilation were obtained in healthy adult and mild obstructive models, and the calculated errors did not exceed 5%. An underestimation of C and an overestimation of R were observed in the severe obstruction model.
CONCLUSION
Using the modified dynamic signal analysis approach, respiratory system properties (C and R) could be accurately estimated in patients with non-severe airflow obstruction in the PCV mode.
Topics: Humans; Airway Resistance; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Respiratory Distress Syndrome; Tidal Volume; Respiratory Mechanics; Lung; Lung Compliance; Models, Biological; Adult
PubMed: 38769572
DOI: 10.1186/s12890-024-03061-2 -
Frontiers in Veterinary Science 2023Cranial and upper-airway anatomy of short-nosed, flat-faced brachycephalic dogs predisposes them to brachycephalic obstructive airway syndrome (BOAS). Periodic apnoea...
INTRODUCTION
Cranial and upper-airway anatomy of short-nosed, flat-faced brachycephalic dogs predisposes them to brachycephalic obstructive airway syndrome (BOAS). Periodic apnoea increased inspiratory resistance, and an inability to thermoregulate effectively are characteristic of BOAS, but internationally accepted objective markers of BOAS severity are missing. The objective of this study was to compare the selected blood parameters between non-brachycephalic (NC) and brachycephalic (BC) dogs, exploring the possibility of developing a blood test for BOAS severity grading in the future.
METHODS
We evaluated blood biochemistry, complete blood cell counts, red blood cell (RBC) indices, reticulocyte counts, a blood-born marker of intermittent hypoxia (glutathione, NO production), RBC hydration, deformability, and blood markers of metabolic changes and stress between BC ( = 18) and NC (meso- and dolichocephalic, = 22) dogs.
RESULTS
Reticulocyte counts and the abundance of middle-fluorescence immature reticulocytes were significantly ( < 0.05) higher in BC dogs compared to NC dogs. BC dogs had significantly more NO-derived NO/NO in plasma than NC dogs. RBCs of BC dogs were shedding significantly more membrane, as follows from the intensity of eosin maleimide staining, and had a significantly higher mean corpuscular hemoglobin concentration than NC dogs. Intracellular reduced glutathione content in RBCs of BC dogs was significantly lower, while plasma lactate was significantly higher in BC dogs compared to NC dogs. Plasma cholesterol and triglycerides were significantly lower, and cortisol was significantly higher in BC dogs compared to NC dogs. Eosinophil counts were significantly lower and the neutrophil-to-lymphocyte ratio was higher in BC dogs compared to NC dogs.
DISCUSSION
Taken together, our findings suggest that the brachycephalic phenotype in dogs is associated with alterations at the level of blood cells and, systemically, with oxidation and metabolic changes. The parameters identified within this study should be further investigated for their potential as objective indicators for BOAS.
PubMed: 37649563
DOI: 10.3389/fvets.2023.1166032 -
BioRxiv : the Preprint Server For... Mar 2024Versatility in carbon source utilization assists in its adaptation to various niches. Recently, we characterized the role of malonate, an understudied carbon source, in...
UNLABELLED
Versatility in carbon source utilization assists in its adaptation to various niches. Recently, we characterized the role of malonate, an understudied carbon source, in quorum sensing regulation, antibiotic resistance, and virulence factor production in . These results indicate that global responses to malonate metabolism remain to be uncovered. We leveraged a publicly available metabolomic dataset on human airway and found malonate to be as abundant as glycerol, a common airway metabolite and carbon source for . Here, we explored and compared adaptations of UCBPP-PA14 (PA14) in response to malonate or glycerol as a sole carbon source using transcriptomics and phenotypic assays. Malonate utilization activated glyoxylate and methylcitrate cycles and induced several stress responses, including oxidative, anaerobic, and metal stress responses associated with increases in intracellular aluminum and strontium. Some induced genes were required for optimal growth of in malonate. To assess the conservation of malonate-associated responses among strains, we compared our findings in strain PA14 with other lab strains and cystic fibrosis isolates of . Most strains grew on malonate as a sole carbon source as efficiently as or better than glycerol. While not all responses to malonate were conserved among strains, formation of biomineralized biofilm-like aggregates, increased tolerance to kanamycin, and increased susceptibility to norfloxacin were the most frequently observed phenotypes. Our findings reveal global remodeling of gene expression during its growth on malonate as a sole carbon source that is accompanied by several important phenotypic changes. These findings add to accumulating literature highlighting the role of different carbon sources in the physiology of and its niche adaptation.
IMPORTANCE
is a notorious pathogen that causes local and systemic infections in immunocompromised individuals. Different carbon sources can uniquely modulate metabolic and virulence pathways in , highlighting the importance of the environment that the pathogen occupies. In this work, we used a combination of transcriptomic analysis and phenotypic assays to determine how malonate utilization impacts as recent evidence indicates this carbon source may be relevant to certain niches associated within the human host. We found that malonate utilization can induce global stress responses, alter metabolic circuits, and influence various phenotypes of that could influence host colonization. Investigating the metabolism of malonate provides insight into adaptations to specific niches where this substrate is abundant, and how it can be leveraged in the development of much-needed antimicrobial agents or identification of new therapeutic targets of this difficult-to-eradicate pathogen.
PubMed: 38585990
DOI: 10.1101/2024.03.26.586813 -
Respiratory Research Jul 2023Pulmonary arterial hypertension (PAH) encompasses a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling and...
BACKGROUND
Pulmonary arterial hypertension (PAH) encompasses a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling and inflammation. Bromodomain and extra-terminal (BET) proteins are required for the expression of a subset of NF-κB-induced inflammatory genes which can be inhibited by the BET mimic JQ1+. We hypothesised that JQ+ would supress TNFα-driven inflammatory responses in human pulmonary vascular cells from PAH patients.
METHODS
Immunohistochemical staining of human peripheral lung tissue (N = 14 PAH and N = 12 non-PAH) was performed for the BET proteins BRD2 and 4. Human pulmonary microvascular endothelial cells (HPMEC) and pulmonary artery smooth muscle cells (HPASMC) from PAH patients (N = 4) and non-PAH controls (N = 4) were stimulated with TNFα in presence or absence of JQ1+ or its inactive isomer JQ1-. IL-6 and -8 mRNA was measured by RT-qPCR and protein levels by ELISA. Chromatin immunoprecipitation analysis was performed using EZ-ChIP™ and NF-κB p65 activation determined using a TransAm kit. MTT assay was used to measure cell viability.
RESULTS
Nuclear staining of BRD2 and BRD4 was significantly (p < 0.0001) increased in the lung vascular endothelial and smooth muscle cells from PAH patients compared to controls with normal lung function. TNFα-driven IL-6 release from both HPMECs and HPASMCs was greater in PAH cells than control cells. Levels of CXCL8/IL-8 protein release was higher in PAH HPASMCs than in control cells with similar release observed in HPMECs. TNFα-induced recruitment of activated NF-κB p65 to the IL-6 and CXCL8/IL-8 promoters were similar in both cell types and between subject groups. JQ1+ suppressed TNFα-induced IL-6 and CXCL8/IL-8 release and mRNA expression to a comparable extent in control and PAH HPMECs and HPASMCs. JQ1 had a greater efficacy on IL-6 release in HPMEC and on CXCL8/IL-8 release in HPASMC.
CONCLUSION
BET inhibition decreases TNFα driven inflammation in primary pulmonary vascular cells. The anti-inflammatory actions of JQ1 suggests distinct cell-specific regulatory control of these genes. BET proteins could be a target for future therapies for PAH.
Topics: Humans; Pulmonary Arterial Hypertension; Tumor Necrosis Factor-alpha; Interleukin-8; Endothelial Cells; Interleukin-6; NF-kappa B; Nuclear Proteins; Transcription Factors; Familial Primary Pulmonary Hypertension; Cell Cycle Proteins
PubMed: 37516840
DOI: 10.1186/s12931-023-02499-y