Assessment of ciliary phenotype in primary ciliary dyskinesia by micro-optical coherence tomography.
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ABSTRACT:
SUBMITTER: Solomon GM
PROVIDER: S-EPMC5333960 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chest computed tomography (CT) is the gold standard for detecting structural abnormalities in patients with primary ciliary dyskinesia (PCD) such as bronchiectasis, bronchial wall thickening and mucus plugging. There are no studies on quantitative assessment of airway and artery abnormalities in children with PCD. The objectives of the present study were to quantify airway and artery dimensions on chest CT in a cohort of children with PCD and compare these with control children to analyse the influence of covariates on airway and artery dimensions. Chest CTs of 13 children with PCD (14 CT scans) and 12 control children were collected retrospectively. The bronchial tree was segmented semi-automatically and reconstructed in a three-dimensional view. All visible airway-artery (AA) pairs were measured perpendicular to the airway centre line, annotating per branch inner and outer airway and adjacent artery diameter and computing inner airway diameter/artery ratio (AinA ratio), outer airway diameter/artery ratio (AoutA ratio), wall thickness (WT), WT/outer airway diameter ratio (Awt ratio) and WT/artery ratio. In the children with PCD (38.5% male, mean age 13.5 years, range 9.8-15.3) 1526 AA pairs were measured versus 1516 in controls (58.3% male, mean age 13.5 years, range 8-14.8). AinA ratio and AoutA ratio were significantly higher in children with PCD than in control children (both p<0.001). Awt ratio was significantly higher in control children than in children with PCD (p<0.001). Our study showed that in children with PCD airways are more dilated than in controls and do not show airway wall thickening.
| S-EPMC7487358 | biostudies-literature
Project description:Cilia play essential roles in normal human development and health; cilia dysfunction results in diseases such as primary ciliary dyskinesia (PCD). Despite their importance, the native structure of human cilia is unknown, and structural defects in the cilia of patients are often undetectable or remain elusive because of heterogeneity. Here we develop an approach that enables visualization of human (patient) cilia at high-resolution using cryo-electron tomography of samples obtained noninvasively by nasal scrape biopsy. We present the native 3D structures of normal and PCD-causing RSPH1-mutant human respiratory cilia in unprecedented detail; this allows comparisons of cilia structure across evolutionarily distant species and reveals the previously unknown primary defect and the heterogeneous secondary defects in RSPH1-mutant cilia. Our data provide evidence for structural and functional heterogeneity in radial spokes, suggest a mechanism for the milder RSPH1 PCD phenotype and demonstrate that cryo-electron tomography can be applied to human disease by directly imaging patient samples.
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Project description:Clinical manifestations of cystic fibrosis (CF) result from an increase in the viscosity of the mucus secreted by epithelial cells that line the airways. Particle-tracking microrheology (PTM) is a widely accepted means of determining the viscoelastic properties of CF mucus, providing an improved understanding of this disease as well as an avenue to assess the efficacies of pharmacologic therapies aimed at decreasing mucus viscosity. Among its advantages, PTM allows the measurement of small volumes, which was recently utilized for an in situ study of CF mucus formed by airway cell cultures. Typically, particle tracks are obtained from fluorescence microscopy video images, although this limits one's ability to distinguish particles by depth in a heterogeneous environment. Here, by performing PTM with high-resolution micro-optical coherence tomography (?OCT), we were able to characterize the viscoelastic properties of mucus, which enables simultaneous measurement of rheology with mucociliary transport parameters that we previously determined using ?OCT. We obtained an accurate characterization of dextran solutions and observed a statistically significant difference in the viscosities of mucus secreted by normal and CF human airway cell cultures. We further characterized the effects of noise and imaging parameters on the sensitivity of ?OCT-PTM by performing theoretical and numerical analyses, which show that our system can accurately quantify viscosities over the range that is characteristic of CF mucus. As a sensitive rheometry technique that requires very small fluid quantities, ?OCT-PTM could also be generally applied to interrogate the viscosity of biological media such as blood or the vitreous humor of the eye in situ.
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Project description:The mammalian cochlea has historically resisted attempts at high-resolution, non-invasive imaging due to its small size, complex three-dimensional structure, and embedded location within the temporal bone. As a result, little is known about the relationship between an individual's cochlear pathology and hearing function, and otologists must rely on physiological testing and imaging methods that offer limited resolution to obtain information about the inner ear prior to performing surgery. Micro-optical coherence tomography (μOCT) is a non-invasive, low-coherence interferometric imaging technique capable of resolving cellular-level anatomic structures. To determine whether μOCT is capable of resolving mammalian intracochlear anatomy, fixed guinea pig inner ears were imaged as whole temporal bones with cochlea in situ. Anatomical structures such as the tunnel of Corti, space of Nuel, modiolus, scalae, and cell groupings were visualized, in addition to individual cell types such as neuronal fibers, hair cells, and supporting cells. Visualization of these structures, via volumetrically-reconstructed image stacks and endoscopic perspective videos, represents an improvement over previous efforts using conventional OCT. These are the first μOCT images of mammalian cochlear anatomy, and they demonstrate μOCT's potential utility as an imaging tool in otology research.
| S-EPMC5025881 | biostudies-literature
Project description:Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of cilia structure, function, and biogenesis leading to chronic infections of the respiratory tract, fertility problems, and disorders of organ laterality. The diagnosis can be challenging, using traditional tools such as characteristic clinical features, ciliary function, and ultrastructural defects and newer screening tools such as nasal nitric oxide levels and genetic testing add to the diagnostic algorithm. There are 32 known PCD-causing genes, and in the future, comprehensive genetic testing may screen young infants before developing symptoms, thus improving survival. Therapies include surveillance of pulmonary function and microbiology, in addition to airway clearance, antibiotics, and early referral to bronchiectasis centers. As with cystic fibrosis (CF), standardized care at specialized centers using a multidisciplinary approach likely improves outcomes. In conjunction with the CF foundation, the PCD foundation, with experienced investigators and clinicians, is developing a network of PCD clinical centers to coordinate the effort in North America and Europe. As the network grows, clinical care and knowledge will improve.
| S-EPMC4873960 | biostudies-literature
Project description:Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 ± Hz at 25°C), but an abnormal, circular beat pattern.The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.
| S-EPMC3983840 | biostudies-literature
Project description:Purpose:To image, track and map the nerve fiber distribution in excised rabbit corneas over the entire stromal thickness using micro-optical coherence tomography (µOCT) to develop a screening tool for early peripheral neuropathy. Methods:Excised rabbit corneas were consecutively imaged by a custom-designed µOCT prototype and a commercial laser scanning fluorescence confocal microscope. The µOCT images with a field of view of approximately 1 × 1 mm were recorded with axial and transverse resolutions of approximately 1 µm and approximately 4 µm, respectively. In the volumetric µOCT image data, network maps of hyper-reflective, branched structures traversing different stromal compartments were segmented using semiautomatic image processing algorithms. Furthermore, the same corneas received ?III-tubulin antibody immunostaining before digital confocal microscopy, and a comparison between µOCT image data and immunohistochemistry analysis was performed to validate the nerval origin of the tracked network structures. Results:Semiautomatic tracing of the nerves with a high range of different thicknesses was possible through the whole corneal volumes, creating a skeleton of the traced nerves. There was a good conformity between the hyper-reflective structures in the µOCT data and the stained nerval structures in the immunohistochemistry data. Conclusions:This article demonstrates nerval imaging and tracking as well as a spatial correlation between µOCT and a fluorescence corneal nerve standard for larger nerves throughout the full thickness of the cornea ex vivo. Translational Relevance:Owing to its advantageous properties, µOCT may become useful as a noncontact method for assessing nerval structures in humans to screen for early peripheral neuropathy.
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Project description:Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance.
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Project description:Diagnosis of corneal disease and challenges in corneal transplantation require comprehensive understanding of corneal anatomy, particularly that of the posterior cornea. Micro-optical coherence tomography (µOCT) is a potentially suitable tool to meet this need, owing to its ultrahigh isotropic spatial resolution, high image acquisition rate and depth priority scanning mode. In this study, we explored the ability of µOCT to visualize micro-anatomical structures of the posterior cornea ex vivo and in vivo using small and large animals. µOCT clearly delineated cornea layers and revealed micro-anatomical structures, including not only polygonal endothelial cells, stellate keratocytes, collagen fibres and corneal nerve fibres but also new structures such as the dome-shaped basolateral side of endothelial cells and lattice structures at the interface between endothelium and Descemet's membrane. Based on these observations, a short post-harvest longitudinal study was conducted on rat cornea to test the feasibility of using µOCT to monitor the quality of endothelial cells. This study successfully reveals a series of morphological features and pathological changes in the posterior cornea at the cellular level in situ and in real time with µOCT. These findings enrich knowledge of corneal anatomy and suggest that µOCT may be a promising imaging tool in corneal transplantation.
| S-EPMC5589810 | biostudies-literature
Project description:ObjectivesAmong patients with non-cystic fibrosis bronchiectasis, 1-18% have an underlying diagnosis of primary ciliary dyskinesia (PCD) and it is suspected that there is under-recognition of this disease. Our intention was to evaluate the specific features of PCD seen on computed tomography (CT) in the cohort of bronchiectasis in order to facilitate the diagnosis.Materials and methodsOne hundred and twenty-one CTs performed in patients with bronchiectasis were scored for the involvement, type, and lobar distribution of bronchiectasis, bronchial dilatation, and bronchial wall thickening. Later, associated findings such as mucus plugging, tree in bud, consolidations, ground glass opacities, interlobular thickening, intralobular lines, situs inversus, emphysema, mosaic attenuation, and atelectasis were registered. Patients with PCD (n = 46) were compared to patients with other underlying diseases (n = 75).ResultsIn patients with PCD, the extent and severity of the bronchiectasis and bronchial wall thickness were significantly lower in the upper lung lobes (p<0.001-p = 0.011). The lobar distribution differed significantly with a predominance in the middle and lower lobes in patients with PCD (<0.001). Significantly more common in patients with PCD were mucous plugging (p = 0.001), tree in bud (p <0.001), atelectasis (p = 0.009), and a history of resection of a middle or lower lobe (p = 0.047). Less common were emphysematous (p = 0.003) and fibrotic (p<0.001) changes. A situs inversus (Kartagener's Syndrome) was only seen in patients with PCD (17%, p <0.001).ConclusionTypical imaging features in PCD include a predominance of bronchiectasis in the middle and lower lobes, severe tree in bud pattern, mucous plugging, and atelectasis. These findings may help practitioners to identify patients with bronchiectasis in whom further work-up for PCD is called for.
| S-EPMC5800555 | biostudies-literature