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Cilia: tuning in to the cell's antenna.

Cilia are microtubule-based organelles that project like antennae from the surface of most cells in the body. Motile cilia move fluid past cells, for example mucus in the airway. Non-motile primary cilia, however, transduce a multitude of sensory stimuli, including chemical concentrations of growth factors, hormones, odorants, and developmental morphogens, as well as osmolarity, light intensity, and fluid flow. Cilia have evolved a complex ultrastructure to accommodate these diverse functions, and an extensive molecular machinery has developed to support the assembly of these organelles. Defects in the cilia themselves, or the machinery required to assemble them, lead to a broad spectrum of human disease symptoms, including polycystic kidney disease, nephronophthisis, hydrocephalus, polydactyly, situs inversus, retinal degeneration, and obesity. While these diseases highlight the pivotal roles of cilia in physiology and development, the mechanistic link between cilia, physiology, and disease remains unclear.

Animals↗

Nasal ciliary beat after insertion of septo-valvular splints.

OBJECTIVE: At present, endonasal paraseptal splints are devices frequently employed in rhinosurgery. We evaluated the local tolerance of a newly shaped device, the Guastella/Mantovani splint (G/M-SVS), with respect to the physiological mechanism of mucociliary clearance. STUDY DESIGN AND SETTING: The study involved 20 patients who underwent septoplasty and/or turbinoplasty or other nasal surgical procedures. A sample of ciliated cells was obtained by nasal brushing and was examined ex vivo to determine the ciliary beat frequency (CBF) and morphology, before and 15 days after surgery. RESULTS: Before surgery the mean CBF was 10.87 Hz +/- 0.56 Hz and when splints were removed it was 10.25 Hz +/- 1.9 Hz. Morphological evaluation of the ciliary motion after surgery demonstrated a normal, coordinated beat. CONCLUSIONS: The G/M-SVS does not appear to interfere with the physiological mechanism of mucociliary clearance since CBF remain within a normal range. SIGNIFICANCE: This is the first study that demonstrates an optimal tolerability and safety of the septo-valvular splints on nasal mucosa.

Adult↗

Cilia, primary ciliary dyskinesia and molecular genetics.

Primary ciliary dyskinesia (PCD) is a phenotypically and genetically heterogeneous condition in which three genetic mutations have already been identified. The primary defect is in the ultrastructure or function of cilia, highly complex organelles that are structurally related to the flagella of sperm and protozoa. The clinical features of PCD include recurrent sinopulmonary infections, subfertility and laterality defects; the latter due to ciliary dysfunction at the embryological node. Completion of the human genome sequence has accelerated the identification and characterisation of disease genes, and the current molecular strategy in PCD includes candidate gene analysis, positional cloning, model organism analysis and proteomic analysis. The identification of these genes will provide new insights into the molecular mechanisms involved in the assembly and function of cilia and the pathway that determines left-right axis in man. This may also allow the development of new methods for diagnosis, prevention and treatment of PCD.

Animals↗

Obstructive azoospermia associated with chronic sinopulmonary infection and situs inversus totalis.

We describe 2 cases of obstructive azoospermia associated with situs inversus and sinopulmonary infection due to ciliary defects. Electron microscopy of testicular sperm flagella demonstrated normal morphology with nine peripheral doublets surrounding a central pair and complete sets of inner and outer dynein arms. Electron microscopy of the nasal mucosa revealed partial defects of the dynein arms of cilia, although the "9+2" morphology was preserved. Our cases were considered unique variants of Young's syndrome but also had characteristic features of Kartagener syndrome, and thus support the hypothesis that Young's syndrome has a genetic etiology similar to that of Kartagener syndrome.

Adult↗

[Primary ciliary dyskinesia. Clinical presentation and diagnosis].

UNLABELLED: Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. OBJECTIVE: We analyzed the main clinical features and test results of PCD in order to evaluate their usefulness for diagnosis. PATIENTS AND METHODS: Retrospective study of 35 cases of PCD evaluated by the same team, with nasal brushings in all cases (special light microscopy) and electron microscopy and/or by isotopic mucociliary clearance study in some. RESULTS: In a cohort of 145 patients with suspected PCD, the diagnosis of PCD was established in 35 cases using a combination of compatible clinical features coupled with the study of nasal brushings: 13 females and 22 males, average age at time of diagnosis 25 years, situs inversus in 12 patients (34%). CONCLUSION: In the absence of consensus in the literature for diagnosis of PCD, we propose the association of the following diagnostic criteria: upper airway and bronchopulmonary infections beginning often early in the life, more inconstantly situs inversus, familial cases of PCD, consanguinity, infertility and permanent and ubiquitous abnormalities of ciliary structure/function. Nasal brushing with ciliary study (special light microscopy) seems to be an easy and reliable diagnostic criterion. Electron microscopy is necessary for proving ultrastructural abnormalities.

Adult↗

Living-donor lobar lung transplantation for primary ciliary dyskinesia.

A ventilator-dependent patient with primary ciliary dyskinesia underwent successful living-donor lobar lung transplantation. The case was a 24-year-old woman who had developed recurrent lower respiratory infection and became ventilator-dependent due to severe bronchiectasis. Transmission electron microscopy of the resected bronchus demonstrated inner dynein arm deficiency.

Adult↗

Contralateral lung transplantation: a left lung implanted in the right thorax.

Since the inception of lung transplantation in 1982, it has been standard practice to implant donor lungs on the ipsilateral side in the recipient. The development of the techniques of lobar and bilateral lobar transplantation has shown that lung morphology may adapt to the shape of the thorax. Thus, variations in implantation have become possible. We describe a case of a 30-year-old man with severe bronchiectasis due to ciliary dyskinesis which required a left lower lobectomy at the age of 11 years and a left completion pneumonectomy 10 years later. His disease progressed and he was listed for a right lung transplantation. At the time of transplantation, the donor right lung was noted to be edematous and unfit for transplantation. This required grafting the donor left lung in the right thorax of the recipient. Follow-up at 7 years shows good exercise capacity and excellent functional tests without evidence of rejection.

Adult↗

Isolation of several human axonemal dynein heavy chain genes: genomic structure of the catalytic site, phylogenetic analysis and chromosomal assignment.

Dynein heavy chains (DHCs) are the main components of multisubunit motor ATPase complexes called dyneins. Axonemal dyneins provide the driving force for ciliary and flagellar motility. Recent molecular studies demonstrated that multiple DHC isoforms are produced by separate genes. We describe the isolation of five human axonemal DHC genes. Analysis of the human genomic clones revealed the existence of intronic sequences that were used to demonstrate that human axonemal DHC genes are located on different chromosomes. The cloned human DHC sequences were integrated into an evolutionary approach based on phylogenetic analysis. Tissue expression studies showed that these human axonemal DHCs are expressed in testis and/or trachea, two tissues with axonemal structures that can be altered in primary ciliary dyskinesia, making DHC genes strong candidates in the genesis of these human diseases.

Amino Acid Sequence↗

Chronic cough and infertility: a report of two cases.

OBJECTIVE: To report two cases of infertility caused by primary ciliary dyskinesia in patients who presented with an associated complaint of a chronic cough. DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): Two patients presenting with unexplained infertility and an associated history of long-term chronic cough. INTERVENTION(S): Patients underwent a nasal mucosal biopsy by an otolaryngologist. Electron microscopy (EM) examination of biopsy specimens was performed. MAIN OUTCOME MEASURE(S): Diagnosis and appropriate treatment for functional tubal factor infertility. RESULT(S): Both patients were diagnosed with primary ciliary dyskinesia based on EM of the nasal biopsy specimens. Given this diagnosis, they immediately underwent IVF-ET. Both patients became pregnant with their first IVF-ET cycle. CONCLUSION(S): Other investigators have shown that almost 20% of patients with a chronic cough will have EM evidence of ciliary dyskinesia. Patients presenting with idiopathic infertility and an associated unexplained chronic cough should be referred for nasal biopsy with EM evaluation to rule out primary ciliary dyskinesia. Infertility in these cases, which is due to a functional tubal factor, is best treated with IVF-ET rather than superovulation and intrauterine insemination treatments.

Adult↗

Birth after intracytoplasmic sperm injection with use of testicular sperm from men with Kartagener/immotile cilia syndrome.

OBJECTIVE: To describe two cases of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with testicular sperm in men with immotile cilia syndromes. DESIGN: Case report. SETTING: A university-based male infertility clinic and assisted reproduction unit. PATIENT(S): Two couples with male factor infertility due to Kartagener/immotile cilia syndrome. INTERVENTION(S): IVF/ICSI with testicular sperm. MAIN OUTCOME MEASURE(S): Semen characteristics, sperm viability, fertilization rate, and pregnancy. RESULT(S): With testicular sperm, the two pronuclear fertilization rates were 63% and 60% in two cases. One case resulted in the birth of normal healthy girl. CONCLUSION(S): With testicular sperm, successful oocyte fertilization after ICSI in couples with male Kartagener/immotile cilia syndrome is possible despite the lack of sperm motility.

Adult↗

Familial ciliary dyskinesis: a cause of infertility without respiratory disease.

Two brothers were found to have primary infertility and nonmotile sperm secondary to ultrastructural defects, which included absent central doublets and peripheral microtubular translocation. No personal or family history of sinobronchial disease was obtained. Although sporadic cases of this type of ciliary dyskinesis have been reported, our patients constitute the first known occurrence of familial association.

Adult↗

Aplasia of nasal cilia with situs inversus, azoospermia and normal sperm flagella: a unique variant of the immotile cilia syndrome.

A 23-year-old man with situs inversus and bronchiectasis was investigated because of azoospermia. Serum levels of testosterone and pituitary gonadotropins were normal. Scrotal exploration revealed no abnormalities of the testes, epididymides or vasa deferentia. Electron microscopy of a testicular biopsy specimen revealed a normal sperm flagellum structure, including the presence of dynein arms but 2 separate biopsies of the nasal mucosa revealed complete ciliary aplasia. This case, which bears a striking resemblance to Young's syndrome (bronchiectasis and azoospermia), represents a unique variant of the immotile cilia syndrome.

Adult↗

Head and neck manifestations of cystic fibrosis and ciliary dyskinesia.

Cystic fibrosis and the various conditions associated with ciliary dysmotility are well known to the otolaryngologist. Although the underlying pathophysiology and clinical courses of these diseases are quite different, they both involve chronic and acute infection in the paranasal sinuses. Some patients may suffer from persistent ear disease beyond early childhood. A high index of suspicion and early diagnosis are key to managing these conditions. The otolaryngologist often is the first to suspect and confirm the diagnosis and may have an important role in the overall management of these patients.

Ciliary Motility Disorders↗

Risk factors associated with the development of chronic lung disease in children.

By better understanding the intrinsic and extrinsic factors that predispose children to chronic lung disease, strategies to prevent its development can be proposed. This article addresses conditions, such as bronchiolitis, croup, hyaline membrane disease, hydrocarbon ingestion, and near-drowning, that have been found to result in long-term changes in lung physiology. Also considered are the possible relationships of common respiratory infection, asthma, smoking, and air pollution to the development of chronic respiratory infection.

Age Factors↗

Electron microscopy in the diagnosis of pediatric disease.

Electron microscopy, although not able to solve all diagnostic dilemmas, is an essential adjunct to the analysis of pathologic processes. The importance of correct specimen handling for ultrastructural study is highlighted. Some diseases encountered in pediatrics, in which the ultrastructural findings are well established, are illustrated. New technologies that show promise for wider application to problems in pathology also are considered in this article.

Child↗