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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed ‘radial spoke defect’. We sequenced CCDC39 and CCDC40 in 54 ‘radial spoke defect’ families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice and frameshift predicting early protein truncation, which suggests this defect is caused by ‘null’ alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganisation and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as ‘IDA and nexin-dynein regulatory complex (N-DRC) defect’, rather than ‘radial spoke defect’.

Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combined IDA and ODA defects, we found that 6/38 (16%) carried biallelic mutations in the conserved zinc-finger gene BLU (ZMYND10). ZMYND10 mutations conferred dynein-arm loss seen at the ultrastructural and immunofluorescence level and complete cilia immotility, except in hypomorphic p.Val16Gly (c.47T>G) homozygote individuals, whose cilia retained a stiff and slowed beat. In mice, Zmynd10 mRNA is restricted to regions containing motile cilia. In a Drosophila model of PCD, Zmynd10 is exclusively expressed in cells with motile cilia: chordotonal sensory neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T>G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged Drosophila ZMYND10 is localized primarily to the cytoplasm, and human ZMYND10 interacts with LRRC6, another cytoplasmically localized protein altered in PCD. Using a fly model of PCD, we conclude that ZMYND10 is a cytoplasmic protein required for IDA and ODA assembly and that its variants cause ciliary dysmotility and PCD with laterality defects.

BACKGROUND: The aim was to identify susceptibility alleles for infantile hypertrophic pyloric stenosis (IHPS) in a pedigree previously linked to IHPS5 on chromosome 16q24. METHODS: We screened the positional and functional candidate gene FOXF1 by Sanger sequencing in a single affected individual. All family members for whom DNA was available were genotyped to determine co-segregation status of the putative causal variant. Immunofluorescence studies were performed to compare the cellular localisation of wildtype and mutant form of the protein. Transcriptional activity was compared using a luciferase assay. RESULTS: A single novel substitution in FOXF1 (c.416G>A) predicted to result in a missense mutation (R139Q) was shown to co-segregate with disease trait. It was not seen in 560 control chromosomes nor has it been reported in ExAC or ESP. The R139Q substitution affects a conserved arginine residue within the DNA-binding domain of FOXF1. The transcriptional activity of the mutant FOXF1 protein is significantly reduced in comparison to wild-type. CONCLUSION: These results provide strong evidence that the R139Q substitution in FOXF1 causes IHPS in this family and imply a novel pathological pathway for the condition. They further support a role for FOXF1 in the regulation of embryonic and neonatal development of the gastro-intestinal tract.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left-right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307∗), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus.

Infantile hypertrophic pyloric stenosis (IHPS) is a common cause of upper gastrointestinal obstruction during infancy. A multifactorial background of the disease is well established. Multiple susceptibility loci including the neuronal nitric oxide synthase (NOS1) gene have previously been linked to IHPS, but contradictory results of linkage studies in different materials indicate genetic heterogeneity. To identify IHPS susceptibility loci, we conducted a genome-wide linkage analysis in 37 Swedish families. In regions where the Swedish material showed most evidence in favor of linkage, 31 additional British IHPS families were analyzed. Evidence in favor of significant linkage was observed in the Swedish material to two loci on chromosome 2q24 (non-parametric linkage (NPL) =3.77) and 7p21 (NPL=4.55). In addition, evidence of suggestive linkage was found to two loci on chromosome 6p21 (NPL=2.97) and 12q24 (NPL=2.63). Extending the material with British samples did not enhance the level of significance. Regions with linkage harbor interesting candidate genes, such as glucagon-like peptide-2 (GLP-2 encoded by the glucagon gene GCG), NOS1, motilin (MLN) and neuropeptide Y (NPY). The coding exons for GLP-2, and NPY were screened for mutations with negative results. In conclusion, we could confirm suggestive linkage to the region harboring the NOS1 gene and detected additional novel susceptibility loci for IHPS.

An experiment on a heat transfer and a natural-circulation performance for an integral-type reactor have been carried out using the VISTA facility, and the calculated results using the TASS/SMR and...

Context Following a 15-week attachment in paediatrics and child health, general practice and dermatology medical students in their second clinical year at this medical school undertake a high-stakes assessment including an objective structured clinical examination (OSCE). There were 2 hypotheses. Firstly, groups of similar stations map to competency domains identifiable by factor analysis. Secondly, poor performance in individual domains is compensated for by achieving the required standard of performance across the whole assessment. Methods A total of 647 medical students were assessed by an OSCE during 5 individual examination sittings (diets) over 2 years. Ten scoring stations in the OSCE were analysed and confirmatory factor analysis performed comparing a 1-factor model (where all the stations are discrete entities related to one underlying domain) with a 3-factor model (where the stations load onto 3 domains from a previously reported exploratory factor analysis). Results The 3-factor model yielded a significantly better fit to the data (χ2 = 15.3, P

Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy. The disease is considered a paradigm for the sex-modified model of multifactorial inheritance and affects males four times more frequently than females. However, extended pedigrees consistent with autosomal dominant inheritance have been documented. We have analysed data from an extended IHPS family including eight affected individuals (five males and three females) and mapped the disease locus to chromosome 16q24 (LOD score=3.7) through an SNP-based genome wide scan. Fourteen additional multiplex pedigrees did not show evidence of linkage to this region, indicating locus heterogeneity.

We present a stratification of the genetic basis of primary ciliary dyskinesia (PCD), based on screening >230 individuals for gene mutations using various approaches including whole exome sequencing. PCD is a genetically heterogeneous recessive ciliopathy, characterized by chronic lung disease and laterality and fertility defects arising from cilia and sperm dysmotility. Most PCD is caused by loss of the ciliary outer dynein arm motors (ODA) essential for motility, arising from mutations in ODA subunits or ODA docking and targeting proteins. Gene panel resequencing of candidate ciliopathy genes in affected children from a consanguineous Bedouin-Arabic family has recently revealed a homozygous protein truncating variant in CCDC151 (c.925G>T; p.Glu308*). Parallel exome sequencing combined with autozygosity mapping in a consanguineous UK-Pakistani-origin family highlighted a large autozygous region on chr 19p13 harbouring a homozygous CCDC151 protein-truncating variant (c.1256C>T; pSer419*). Sanger sequencing of CCDC151 in 150 more PCD cases identified another individual carrying c.925G>T. Transmission electron microscopy of respiratory cilia from individuals carrying CCDC151 mutations showed loss of ODA. Consistent with laterality defects in these individuals, we find Ccdc151 expressed in vertebrate left-right organizers. Both homozygous zebrafish and mouse Ccdc151-deficient mutants display situs defects associated with complex heart defects. Immunofluorescence analysis in patients shows that CCDC151 mutations abolish assembly of CCDC151 into respiratory cilia, and furthermore cause a failure in assembly of the ODA component DNAH5 and ODA docking proteins CCDC114 and ARMC4. We conclude that CCDC151 mutations appear to cause PCD by disruption of the axonemal ODA docking complex machinery.

Nanocomposite materials, consisting of ensembles of Ag and Co nanoparticles, have been successfully fabricated, with various compositions and packing densities. The transport and magnetic characteristics of the compounds were studied. In particular, a crossover from a positive magnetoresistance (MR) at low applied magnetic fields to a negative magnetoresistance at high applied magnetic fields was observed. The behaviors could be understood by the spin-dependent tunneling mechanism, known as tunneling magnetoresistance.

A feeding trial was conducted to determine whether dietary vitamin C (200 mg/kg) and vitamin E (250 mg/kg) prevent any drops in egg shell quality under heat stress in broiler breeder hens. One hundred and sixty molted Ross broiler breeders were housed randomly in an individual cage at 83 weeks of age. Four dietary treatments with forty hens and four replications per treatment were control (no additional vitamins), vitamin C-, or vitamin E-supplemented and combined supplementation of the two vitamins. After a ten- day-adaptation period at 25°C, the ambient temperature was kept at 32°C for a three-week-testing period. Egg production dropped dramatically over week but it did not show a significant change among treatments (p

DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both Gram-positive and Gram-negative bacteria. We have reported recently that DW-116 is embryotoxic and teratogenic in rats. The present study was conducted to investigate the teratogenicity of DW-116, together with maternal toxicity and developmental toxicity using New Zealand White rabbits. The test chemical was administered by gavage to pregnant rabbits from gestational day (GD) 6 through to GD 18 at dose levels of 0, 5, 19.5 and 76.1 mg kg(-1) day(-1). All does were subjected to caesarean section on day 28 of gestation and their foetuses were examined for external, visceral and skeletal abnormalities. In the 76.1 mg kg(-1) group, a minimal maternal toxicity, as evidenced by decreased body weight gain during treatment period, was observed in pregnant rabbits. Significant embryo-foetal toxicity, including increased number of foetal deaths and delayed foetal ossification, was seen. However, no treatment-related morphological changes were detected in foetal external, visceral and skeletal examinations. There were no adverse effects on either pregnant dams or embryo-foetal development at 19.5 and 5 mg kg(-1). It was concluded that administration of DW-116 during the major organogenetic period in rabbits produced decreased maternal body weight gain, increased number of foetal deaths and foetal developmental delay but no evidence of teratogenicity. The no-observed-adverse-effect levels (NOAELs) of DW-116 are considered to be 19.5 mg kg(-1) day(-1) for does and embryo-foetuses, respectively.

We have synthesized colloidal Pt nanoparticles with a mean particle size of 2.6±0.4 nm by reducing PtCl2 dissolved in N,N-dimethylacetamide with t-BuMe2SiH. The latter compound acted both as a reducing agent and a stabilizer of the Pt nanoparticles. Pt nanoparticles were deposited onto the Au substrate and IR reflectance absorption spectroscopy (IRRAS) was applied to investigate CO adsorption and oxidation at the surface of the catalyst. The reactivity of the catalyst covered with Nafion was compared with the reactivity of the catalyst without Nafion. In addition, the reactivity of the colloidal Pt was compared with the reactivity of bulk polycrystalline Pt. We found that CO oxidation proceeds at lower over-potentials at nanoparticles than at polycrystalline Pt. The IRRAS data indicate that the difference in the reactivity may be explained by a different mechanism of the oxidation reaction; Langmuir–Hinshelwood at Pt nanoparticles and island formation and growth at polycrystalline Pt. We have also observed that a film of Nafion slows down the CO oxidation reaction. The IRRAS spectra for CO adsorbed at Pt nanoparticles covered by Nafion were significantly different from the spectra recorded for the nanoparticles in the absence of Nafion. The spectroscopic features suggest that in the presence of Nafion the nanoparticles experience regions of lower and higher proton concentration.

This study investigated the three dimensional (3D) trabecular microstructure of the alveolar and basal bone in the mandible using micro-CT and compared the morphometric values of the different sites. Ten specimens were prepared and scanned using a micro-CT system. Both the alveolar and basal trabecular bone of the premolar region in the mandible were measured for the structural analysis. Cross-sectional 1024x1024 pixel images were created. From the two-dimensional (2D) images produced, 3D structural images were reconstructed. After scanning the specimen, the volumes of interest (VOI) of the alveolar and basal bone regions were selected from the 3D reconstruction images, and the structural parameters such as bone volume fraction, bone surface density, trabecular thickness, trabecular separation, trabecular number and structural model index were analyzed. The trabecular structure showed a marked variation within the sites of the specimen, especially in the basal trabecular bone inferior to the mandibular canal. In both the alveolar and basal bone regions, a mixture of both plate-like and rod-like structures was observed. The alveolar region showed a more compact, plate-type trabecular structure than the basal regions. In parametric comparison with the basal bone, the alveolar bone generally had a higher bone volume fraction, bone trabecular thickness and trabecular number, and lower bone surface density, trabecular separation and structural model index. The alveolar bone consisted of a compact bone structure with a large amount of thick plate-type trabecular bone, which was effectively resistant to the masticatory forces. As the measurements were made closer to the basal bone, a loose structure was observed with lower bone volume and fewer, thin, rod-like trabeculae.

DW-116 is a fluoroquinolone antibacterial developed by Dong-Wha Pharmaceutical Industry Co. The aim of this study is to determine the potential adverse effects of this chemical on pregnancy, delivery and lactation of dams and on peri- and postnatal development of F1 offspring. The test chemical was orally administered to pregnant rats from day 16 of pregnancy, through parturition and throughout the period of lactation up to weaning (postnatal day 21) at dose levels of 0, 10, 50, or 250 mg/kg/day. The progeny were examined at birth and subsequently to weaning. Mortality, body weight change, physical signs of postnatal development (pinna detachment, incisor eruption, fur development, eye opening, testis descent and vaginal opening) and behavioral function (righting reflex, negative geotaxis, grip-strength, pupillary reflex, acoustic startle response, rotating rod test, open field test and water-filled T-maze test) were evaluated. When the exposed offspring reached maturity (11 weeks old) their reproductive capacity was assessed. Maternal toxicity was observed only in the highest dose group and was limited to decreased food consumption during the late stage of pregnancy. However, this change was not observed during the lactation period. There were no adverse effects on mortality, clinical signs, body weight, necropsy findings, organ weight of dams in any treatment group. No adverse effects on the offspring were seen with the low and middle doses tested, but the highest dose increased postnatal mortality. The number of stillborn was also increased at the highest dose but the difference was not statistically significant. Meanwhile, no treatment-related effects were observed in clinical sign, developmental and behavioral landmarks and necropsy findings at any dose levels tested. There were no treatment-related effects on the mating of the F1 generation and resulting F2 offspring. The results of this study indicate that the peri- and postnatal administration of DW-116 to female rats results in an increase in postnatal mortality at a minimally maternotoxic dose, i.e., 250 mg/kg/day. Under the experimental conditions, the no-observed-adverse-effect level for peri- and postnatal developmental toxicity was considered to be 50 mg/kg/day.

The purpose of this study was to investigate the potential subchronic toxicity of plant sterol esters by a 13-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 1000, 3000 and 9000 mg/kg/day for 13 weeks. At the end of treatment period, 10 rats/sex/group were sacrificed, while six rats/sex in the negative control and highest dose groups were sacrificed after a 4-week recovery period. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. Slight decreases in body weight gain were noted at lower doses but were only statistically different from the control animals in the highest dose group. In histopathological examinations, an increase in the incidence of cardiomyopathy with mononuclear cell infiltration was observed in males of the 9000 mg/kg group. Decreased body weight gain and increased incidence of cardiomyopathy observed in the highest dose group were not recovered until the end of the recovery period. There were no adverse effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights in any treatment group. Based on these results, it was concluded that the 13-week repeated oral dose of plant sterol esters resulted in the suppression of body weight gains in both sexes and cardiomyopathy in males at a dose level of 9000 mg/kg/day. The target organ was determined to be heart in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 3000 mg/kg/day for both sexes.

Flupyrazofos is a new type of pyrazole organophosporus insecticide, which has a high activity against the diamond-back moth (Plutella xylostella). The potential of this agent to induce developmental toxicity was investigated in the Sprague-Dawley rat. One hundred mated females (sperm in vaginal LAVAGE=day 0) were distributed among three treated groups and a control group. Flupyrazofos was administered by gavage to pregnant rats from days 7-17 of gestation at dose levels of 0, 5, 12 and 30 mg/kg/day. All dams were subjected to the caesarean section on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. At 30 mg/kg, maternal effects including mortality (4.3%), clinical signs of toxicity, decreased food intake, suppressed body weight, and increased weight of adrenal glands, kidney and heart were observed in dams. Litter values for corpora lutea, implantations, sex ratio and litter size were within the normal range. However, a reduction in the fetal weight and an increase in the incidence of fetal skeletal retardations were observed. At 12 mg/kg, toxic effects including mortality (4.2%), nasal discharge and some fetal skeletal retardation were observed. There were no signs of either maternal toxicity or embryotoxicity at 5 mg/kg. The results show that flupyrazofos induces fetal growth retardation only at maternally toxic doses in rats and the no-observed-adverse-effect levels (NOAELs) of this agent are considered to be 5 mg/kg for both dams and fetuses.

The present study was undertaken to investigate changes in haematology parameters over the course of normal pregnancy in New Zealand White rabbits. Blood samples were collected on gestational days (GD) 0, 4, 8, 12, 16, 20, 24, and 28. Red blood cell counts and haemoglobin concentrations on GD 20–28 were lower than those of normal non-pregnant rabbits. These values fluctuated slightly between GD 0 and 12 and subsequently decreased to reach a nadir on either GD 24 or 28. Haematocrit value in pregnant rabbits also decreased slightly in the third trimester, but the difference was not statistically noticeable. Mean corpuscular volume in pregnant rabbits increased gradually during the course of gestation and was larger on GD 24 than that in non-pregnant rabbits. There were no differences in mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration between pregnant and non-pregnant rabbits. Platelet counts on GD 24–28 were lower than that of normal non-pregnant rabbits. These values increased slightly in the first half of gestation and then decreased to reach a nadir on GD 28. Total white blood cell and lymphocyte counts on GD 24 were lower than those of normal non-pregnant rabbits. These values increased maximally by GD 4 and then decreased progressively to a minimum level on GD 24. No significant differences were observed in the numbers of neutrophils, eosinophils, basophils, and monocytes between pregnant and non-pregnant rabbits. Neutrophil counts of pregnant rabbits fluctuated minimally between GD 0 and 12 and then decreased to reach a lowest level on GD 24. Eosinophil counts increased to a maximum value on GD 4 and subsequently decreased to reach a nadir on GD 24. Basophil and monocyte counts were not different throughout the course of pregnancy. These data can be used not only as a historical database for the effective evaluation of data from reproductive toxicology studies, but also as a contribution to biological characterization of New Zealand White rabbits.

The present study was undertaken to investigate changes in haematology parameters over the course of gestation in Sprague–Dawley rats. Blood samples were alternatively collected from two groups of pregnant rats on gestational days (GD) 0, 3, 6, 9, 12, 15, 18 and 21 using a needle catheter. Red blood cell counts, haemoglobin and haematocrit on GD 6, 12, 18 and 21 were lower than those of normal non-pregnant rats. These values declined progressively during the course of gestation and reached minimum levels on GD 18 or 21. There were no differences in mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration between pregnant and non-pregnant rats. Platelet counts in pregnant rats increased gradually with advancing gestation and were much higher on GD 15 and 21 than in nonpregnant rats. Total white blood cell and lymphocyte counts on GD 0–15 were higher than those of non-pregnant rats. These values increased maximally by GD 6 and then decreased progressively to a nadir on GD 21. Neutrophil counts on GD 9–21 were higher than non-pregnant rat values. The neutrophils increased to a peak level on GD 12 and then steadily decreased. These data can be used not only as a historical database for the effective evaluation of data from reproductive toxicology studies, but also as a contribution to biological characterisation of Sprague–Dawley rats.

Primary ciliary dyskinesia (PCD), or immotile cilia syndrome (ICS), is an autosomal recessive disorder affecting ciliary movement with an incidence of 1 in 20000-30000. Dysmotility to complete immotility of cilia results in a multisystem disease of variable severity with recurrent respiratory tract infections leading to bronchiectasis and male subfertility. Ultrastructural defects are present in ciliated mucosa and spermatozoa. Situs inversus (SI) is found in about half of the patients (Kartagener syndrome). We have collected samples from 61 European and North American families with PCD. A genome-wide linkage search was performed in 31 multiplex families (169 individuals including 70 affecteds) using 188 evenly spaced (19cM average interval) polymorphic markers. Both parametric (recessive model) and non-parametric (identity by descent allele sharing) linkage analyses were used. No major locus for the majority of the families was identified, although the sample was powerful enough to detect linkage if 40% of the families were linked to one locus. These results strongly suggest extensive locus heterogeneity. Potential genomic regions harbouring PCD loci were localised on chromosomes 3p, 4q, 5p, 7p, 8q, 10p, 11q, 13q, 15q, 16p, 17q and 19q. Linkage analysis using PCD families with a dynein arm deficiency provided 'suggestive' evidence for linkage to chromosomal regions 8q, 16pter, while analyses using only PCD families with situs inversus resulted in 'suggestive' scores for chromosomes 8q, and 19q.

The transcription factor FOXJ1 (alias HFH-4 or FKHL13) of the winged-helix/forkhead family is expressed in cells with cilia or flagella, and seems to be involved in the regulation of axonemal structural proteins. The knockout mouse Foxj1–/– shows abnormalities of organ situs, consistent with random determination of left-right asymmetry, and a complete absence of cilia. The human FOXJ1 gene which maps to chromosome 17q, is thus an excellent candidate gene for Kartagener Syndrome (KS), a subphenotype of Primary Ciliary Dyskinesia (PCD), characterized by bronchiectasis, chronic sinusitis and situs inversus. We have collected samples from 61 PCD fami- lies, in 31 of which there are at least two affected individuals. Two families with complete aciliogenesis, and six families, in which the affected members have microsatellite alleles concordant for a locus on distal chromosome 17q, were screened for mutations in the two exons and intron-exon junctions of the FOXJ1 gene. No sequence abnormalities were observed in the DNAs of the affected individuals of the selected families. These results demonstrate that the FOXJ1 gene is not responsible for the PCD/KS phenotype in the families examined.

An optimal design code for centrifugal pumps has been developed to determine the geometric and fluid dynamic variables under appropriate design constraints. The optimization problem has been formulated with a non-linear objective function to minimize one, two or all of the fluid dynamic losses, the net positive suction head required and the product price of a pump stage depending on the weighting factors selected as the design compromise. The optimal solution is obtained by means of the Hooke-Jeeves direct search method. The performance analysis is based on the mean streamline analysis using the present state-of-the-art loss correlations. The optimized efficiency and design variables of centrifugal pumps are presented in this paper as a function of non-dimensional specific speed in the range, 0.5 ≤ Ns ≤ 1.3. The diagrams presented herein can be used efficiently in the preliminary design phase of centrifugal pumps.

This paper presents the mean streamline analysis using the empirical loss models for performance prediction of mixed-flow pumps with high specific speeds. A new internal loss model to describe the effect of flow separation on the characteristic head-capacity curve with a dip in the low flow range is developed and a modified recirculation loss model for calculation of parasitic loss due to flow recirculation at the impeller exit is suggested in this study. The prediction performance of the proposed method here is tested against four sets of measured total heads and efficiencies of mixed-flow pumps, and it is also compared with that based on two-dimensional cascade theory. Predicted results by the present set of loss models agree very well with experimental data for a variety of mixed-flow pumps over the normal operating conditions.

The present study has tested most of the loss models previously published in the open literature and found an optimum set of empirical loss models for a reliable performance prediction of centrifugal compressors. In order to improve the prediction of efficiency curves, this paper recommends a modified parasitic loss model. The performance analyses by using various empirical loss models are also compared with those by the two-zone modelling. Predicted performance curves by the proposed optimum set agree fairly well with experimental data for a variety of centrifugal compressors. The prediction method developed through this study can serve as a tool for preliminary design and assist the understanding of the operational characteristics of general purpose centrifugal compressors.

Pseudohypoaldosteronism type 1 (PHA1, OMIM264350) is a rare Mendelian disorder characterised byend-organ unresponsiveness to mineralocorticoids.Most steroid hormone insensitivity syndromes arisefrom mutations in the corresponding receptor, butavailable genetic evidence is against involvement ofthe mineralocorticoid receptor gene, MLR, in PHA1. Acomplete genome scan for PHA1 genes was under-taken using homozygosity mapping in 11 consan-guineous families. Conclusive evidence of linkage withheterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locusmapped to chromosome 16p12.2–13.11 in six familiesand to 12p13.1-pter in the other five families. The twochromosomal regions harbour genes for subunits ofthe amiloride-sensitive epithelial sodium channel:SCNN1B and SCNN1G on 16p and SCNN1A on 12p.Liddle’s syndrome of hypertension and pseudoaldos-teronism has been shown to arise from mutations inSCNN1B and SCNN1G . These results strongly suggestthat PHA1 and Liddle’s syndrome are allelic variantscaused by mutations in genes encoding subunits ofthis sodium channel. These genes are of broad biologi-cal interest both in relation to sodium and water home-ostasis in mammals and by virtue of their homology tothe mec genes of Caenorhabditis elegans involved inmechanosensitivity and neuronal degeneration.INTRODUCTIONPseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is anuncommon inherited disorder characterised by target-organunresponsiveness to mineralocorticoids. Since the first report byCheek and Perry in 1958 (1) over 100 cases have been reported.Marked elevation of serum aldosterone levels is present in allcases, and is associated with salt-wasting, hyponatraemia,hyperkalaemia and increased plasma renin activity. Clinicalexpression of the disease varies from severely affected infantswho may die to apparently asymptomatic individuals (2).Familial and sporadic cases have been reported. Inheritance isMendelian and may be either autosomal dominant or recessive.The inheritance pattern appears to correspond to whether thehormonal insensitivity is renal or multisystem (3). MultisystemPHA1 is more severe with salt loss from all aldosterone sensitiveend organs including salivary glands, sweat glands, colon andkidney, and is usually inherited as an autosomal recessive trait.The renal form of PHA1 is characterised by renal salt-wastingonly and is usually inherited as an autosomal dominant trait (3).The majority of reported cases falls into one of these categories(2,3). There is a high incidence of consanguinuity in autosomalrecessive PHA1.The molecular basis of PHA1 is unknown ( 4). By analogy withother end-organ hormone insensitivity syndromes a defect at the

Background Interferon (IFN) signatures are upregulated in patients with primary Sjogren9s syndrome (pSS) and interferons are considered to play a pathogenic role in pSS. Therefore, Janus kinase (JAK) which mediates interferon signaling pathway may be a good therapeutic target Objectives We set out to investigate whether a selective JAK1 inhibitor, filgotinib would ameliorate disease-related parameters in non-obese diabetic (NOD) mice, an animal model SS Methods Filgotinib (1.5mg/kg) or vehicle (saline) was intraperitoneally injected three times per week from 8 weeks after birth. Salivary flow rate (SFR) was addressed on 8, 12, 16 and 20 weeks. Histologic analysis was performed on 20 weeks. The effect of filgotinib on the expressions of B cell activating factor (BAFF) and chemokines (CXCL10 [IP-10], CXCL3 [fractalkine], CCL-2 [MCP-1]) in human salivary gland epithelial cell (SGEC) line or primary epithelial cells of patients with pSS was determined in vitro . Results The SFR of NOD mice in both groups decreased over time. Of note, SFRs of filgotinib-treated mice were greater than those of controls. Histologic evaluation of the salivary gland revealed that the lymphocytic infiltration of salivary gland was markedly reduced in the mice treated with filgotinib. Filgotinib suppressed STAT1 phosphorylation in IFN-treated SGECs. In addition, IFN-induced BAFF and chemokine production of SGECs or primary epithelial cells were abrogated by filgotinib treatment. Conclusions Filgotinib suppresses SFR decrease and lymphocytic infiltration of salivary glands of NOD mice by inhibiting inhibiting IFN signaling pathway, thus suppressing BAFF and chemokine production of salivary gland epithelial cells. JAK inhibition may be a novel therapeutic approach for SS. Disclosure of Interest None declared

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder characterised by recurrent respiratory tract infections, bronchiectasis and subfertility which arises from cilia/sperm dysmotility associated with axonemal ultrastructural abnormalities. Laterality is randomized with ~50% of patients having situs inversus. Up to 15% of PCD cases show perturbation of the 9+2 microtubule structure and loss of the inner dynein arms, and these have tended to be referred to as ‘radial spoke defect’ cases. The radial spokes are essential for axoneme motility, mediating signal transduction between the central microtubular pair and dynein arm motors. Two genes causing this specific ultrastructural defect are known: CCDC39 (Merveille et. al., Nat Genet. 2011 43:72-8) and CCDC40 (Becker-Heck et. al. Nat Genet. 2011 43:79-84). We sequenced these genes in 22 PCD families with an ultrastructural defect involving microtubule disorganisation, either with or without accompanying loss of the inner dynein arms. We found recesively inherited CCDC39 mutations in 8/22 families and CCDC40 mutations in 7/22 families in the cohort, jointly accounting for a remarkable 68% (15/22) of families. The majority of CCDC39 and CCDC40 mutations were nonsense or frameshift resulting in early protein truncation, predicted to cause major disruption to the axoneme. Furthermore, there was a preponderance of homozygous mutations accounting for disease, even in families from outbred populations. Our results highlight the key role of the CCDC39 and CCDC40 genes in PCD with radial spoke defect, and suggest that disease is associated with complete protein loss (null alleles). These two genes represent prime targets for genetic testing in this disease phenotype. Work is in progress to identify the disease genes in the remaining patients within this subgroup, by next generation whole exome sequencing.

The genetic disorder primary ciliary dyskinesia (PCD) arises from dysmotility of cilia in the respiratory tract, brain ventricles, oviduct and the embryonic node. Patients have chronic obstructive pulmonary disease, reduced fertility and situs abnormalities. PCD is genetically heterogeneous with 12 genes causing ~40% of all cases, two encoding proteins (KTU, LRRC50) involved in cytosolic axonemal dynein co-assembly. We have identified mutations in the C19ORF51 gene located within a previously mapped PCD locus. C19ORF51 encodes a protein orthologous to PF22, a Chlamydomonas protein involved in the cytoplasmic assembly of outer dynein arms preceeding their import into the axoneme. Chlamydomonas pf22 cells display a disturbance in their cytoplasm of dynein heavy chain stabilityand the co-assembly of heavy with intermediate chains, both essential for dynein arm assembly. PF22 appears to act downstream of KTU and LRRC50 in the dynein preassembly pathway. PF22 knockdown in zebrafish causes a loss of dynein arms, cilia dysmotility, and a typical ciliopathy phenotype with axis curvature, pronephric cysts, hydrocephalus and situs inversus. We propose the existance of a conserved multi-step pathway for formation of assembly-competent dynein complexes, and that PF22 (now renamed DNAAF3, “dynein axonemal assembly factor 3”) mutations cause PCD with situs inversus due to deficient cytoplasmic dynein assembly.

The locus for Unverricht-Lundborg disease, EPM 1, has recently been mapped to chromosome 21q22.3. A locus, EJM 1, predisposing to idiopathic generalised epilepsy in families of probands with juvenile myoclonic epilepsy has been localised to chromosome 6p by evidence of linkage to the HLA region. However, segregation analysis suggests a two-locus model for JME and evidence has been obtained for genetic heterogeneity within the JME/IGE phenotype. EPM 1 was therefore investigated as a candidate locus in the set of families segregating for IGE and JME which do not show linkage to markers on chromosome 6p. Linkage analysis was carried out in 25 families using three microsatellite DNA markers around the EPM 1 gene region using different models of inheritance. Multipoint linkage analysis provided definite exclusion for 20cM around PFKL, the closest linked marker to EPM 1, under three out of four models tested. These results strongly suggest that the EPM 1 gene is not linked to the phenotype expressed in these families, and therefore that Unverricht-Lundborg disease and juvenile myoclonic epilepsy are not allelic variants.

Primary ciliary dyskinesia most often arises from loss of the dynein motors that power ciliary beating. Here we show that DNAAF3 (also known as PF22), a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes before their transport into cilia. We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms. Knockdown of dnaaf3 in zebrafish likewise disrupts dynein arm assembly and ciliary motility, causing primary ciliary dyskinesia phenotypes that include hydrocephalus and laterality malformations. Chlamydomonas reinhardtii PF22 is exclusively cytoplasmic, and a PF22-null mutant cannot assemble any outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway. These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes.

The purpose of this study was to evaluate the effect of alendronates on healing of extraction sockets and healing around implants in the maxilla of rats.Twenty-four Sprague-Dawley rats were used. The rats in bisphosphonate group were subcutaneously injected with alendronate (5.0 mg kg(--1)) three times a week for 4 weeks. Both sides of the maxillary first molars were extracted, and customized titanium implants (Ø1.5 × 2.0 mm) were placed immediately into one side. Rats were killed at 3, 7, 14, or 28 days following surgery.New bone formation in extraction sockets, bone area around the implant site, and bone-implant contact were not delayed in the bisphosphonate group. The tartrate-resistant acid phosphatase positive cell count did not differ between bisphosphonate and control groups; however, empty lacunae were observed significantly more in bisphosphonate group. The differences in empty lacunae were shown at different time points between the implant sites and extraction sites: at 7 days after extraction, and at 14 and 28 days after implantation.Alendronates seemed to decrease bone resorption but not to decrease bone formation. Empty lacunae were observed significantly more at later time points in implant sites compared to extraction sockets.

Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy with a striking male preponderance. Infants present with vomiting due to gastric outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. Two loci specific to extended pedigrees displaying autosomal dominant inheritance have been identified. A genome scan identified loci on chromosomes 11q14–q22 and Xq23–q24 which are predicted to be responsible for a subset of smaller families with IHPS demonstrating non-Mendelian inheritance. The two linked chromosomal regions both harbour functional candidate genes which are members of the canonical transient receptor potential (TRPC) family of ion channels. Both TRPC5 (Xq23–q24) and TRPC6 (11q14–q22) have a potential role in smooth muscle control and hypertrophy. Here, we report suggestive evidence for a third locus on chromosome 3q12–q25 (Z max = 2.7, p

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G > A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes.

Infantile hypertrophic pyloric stenosis (IHPS) has an incidence of 1-8 per 1000 live births and is inherited as a complex sex-modified multifactorial trait with a striking male preponderance. Syndromic and monogenic forms exist, and two loci have been identified. Infants present with vomiting due to gastric-outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. A genome-wide SNP-based high-density linkage scan was carried out on 81 IHPS pedigrees. Nonparametric and parametric linkage analysis identified loci on chromosomes 11q14-q22 (Z(max) = 3.9, p0.0001; HLOD(max) = 3.4, alpha = 0.34) and Xq23 (Z(max) = 4.3, p0.00001; HLOD(max) = 4.8, alpha = 0.56). The two linked chromosomal regions each harbor functional candidate genes that are members of the canonical transient receptor potential (TRPC) family of ion channels and have a potential role in smooth-muscle control and hypertrophy.

Oxygen vacancies in ${\mathrm{TbMnO}}_{3}$ were created by monovalent ${\mathrm{Na}}^{+}$ doping. The effects of the interruption of the superexchange paths on the spin orderings were investigated. Chemical doping resulted in a much higher ordering temperature, which is probably associated with enhanced $\mathrm{Tb}\text{\ensuremath{-}}\mathrm{Tb}$ coupling because of a reduction in $\mathrm{Tb}\text{\ensuremath{-}}\mathrm{Tb}$ interatomic distances. The oxygen vacancies turned the modulated Mn spin structure into a simple commensurate one, presumably due to interruptions of the in-plane $(\mathrm{Mn}\text{\ensuremath{-}}\mathrm{O})--(\mathrm{O}\text{\ensuremath{-}}\mathrm{Mn})$ superexchange paths, which reduced the significance of the next nearest-neighbor interactions of the Mn ions. The modulated spin structure of the Mn moments was found to reappear in systems with high Na doping, indicating that the anisotropic magnetic couplings had reemerged.

Infantile hypertrophic pyloric stenosis (IHPS) is the most common form of bowel obstruction in infancy. The disease affects males four times more often than females and is considered a paradigm for the sex-modified model of multifactorial inheritance. However, pedigrees consistent with autosomal dominant inheritance have also been documented. We analyzed a 3-generation family with IHPS including 10 affected individuals (5 males and 5 females) and mapped the underlying disease locus to chromosome 16p12-p13 (LOD score 3.23) by using a single-nucleotide polymorphism–based genomewide scan. The analysis of 10 additional multiplex pedigrees yielded negative or nonsignificant LOD scores, indicating the presence of locus heterogeneity. Sequence analysis of candidate genes from the chromosome 16 disease interval excluded the presence of pathogenic mutations in the GRIN2A and MYH11 genes.

The SMART is an integral type reactor with new innovative design features aimed at achieving a highly enhanced safety and improved economics. This paper focuses on the thermal hydraulic experimental program for the development of SMART. Thermal hydraulic responses for the transient operations of the SMART-P are experimentally investigated by using an integral effect test facility. The test facility (VISTA) has been constructed to simulate the SMART-P, which is a pilot plant of the SMART. The VISTA facility is a full height and 1/96 volume scaled test facility with respect to the SMART-P with a power of 65MWt. In the present study, the VISTA facility was subjected to various transient conditions in order to understand the thermal-hydraulic responses following transients and finally to verify the system design of the SMART-P. Several experiments, including a heatup, a main coolant pump (MCP) speed change, and a power change, have been performed to investigate the heat transfer characteristics and the natural circulation performance of the primary system and the Passive Residual Heat Removal System (PRHRS) of the SMART-P by using the VISTA facility. Performance tests of a passive residual heat removal system (PRHRS) have also been carried out for its design optimization. Besides, several design basis accidents, such as an increase or a decrease of the feedwater flow, a loss of coolant flow, a control rod withdrawal, and a limited case of a loss of coolant accident (LOCA) on the line to the gas cylinder are under investigation in order to understand the thermal-hydraulic responses and finally to verify the system design of the SMART-P. Especially, the details of the experimental results for a loss of feedwater accident and a power increase accident due to a control rod withdrawal are explored in the present study.Copyright © 2006 by ASME

Rationale: Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive, genetic disorder characterized by ciliary dysfunction, sino-pulmonary disease, and situs inversus. Disease-causing mutations have been reported in DNAI1 and DNAH5 encoding outer dynein arm (ODA) proteins of cilia. Objectives: We analyzed DNAI1 to identify disease-causing mutations in PCD and to determine if the previously reported IVS1+2_3insT (219+3insT) mutation represents a "founder" or "hot spot" mutation. Methods: Patients with PCD from 179 unrelated families were studied. Exclusion mapping showed no linkage to DNAI1 for 13 families; the entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on nasal epithelial RNA in 14 families. Results: Mutations in DNAI1 including 12 novel mutations were identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutations were not identified by reverse transcriptase-polymerase chain reaction. The prevalence of mutations in families with defined ODA defect was 13%; no mutations were found in patients without a defined ODA defect. The previously reported IVS1+2_3insT mutation accounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutations occurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging asmutation clusters harboring29%(12/42) of mutant alleles. Conclusions: A total of 10% of patients with PCD are estimated to harbor mutations in DNAI1; most occur as a common founder IVS1+2_3insT or in exons 13, 16, and 17. This information is useful for establishing a clinical molecular genetic test for PCD.

The superconducting parameters of zero-dimensional In nanoparticles were studied by measuring the magnetic susceptibility, electrical resistivity, and specific heat. Significant alternations of the superconducting parameters were found for particles with diameters smaller than $120\phantom{\rule{0.3em}{0ex}}\mathrm{nm}$. The Anderson regime, where superconductivity was sharply suppressed by the discrete nature of the electronic levels, was seen for particle smaller than $7.5\phantom{\rule{0.3em}{0ex}}\mathrm{nm}$. A regime prior to the Anderson one, in which superconductivity was found to vary in accordance with alternations of the structural parameters, due to the small size effect, was also observed and characterized. A nonignorable 5 % increase in ${T}_{C}$ and a 400 times higher ${H}_{C}$ were seen for the $39\phantom{\rule{0.3em}{0ex}}\mathrm{nm}$ particles. The appearance of this regime was closely related to the structural symmetry of the system.

Received 10 January 2005; revised manuscript received 24 May 2005; published 14 September 2005We describe the transport characteristics and the observation of a type of magnetoresistive behavior innonmagnetic nanocompacts, consisting of mixtures of Ag and PbO nanoparticles packed into compact units atvarious mass compositions and compacting densities. Semiconductorlike, intermediate, and metallic transportsmay all be revealed by tuning the compacting density. Crossovers from a positive magnetoresistance MR atlow applied magnetic fields to a negative MR at high fields were observed in the loosely packed units. Noevidence of MR saturation was seen up to an applied field of 9 T. Raising the temperature suppresses the MRresponses. Surprisingly, no noticeable differences in the MR responses were found for samples with differentAg/PbO compositions. The observed transport characteristics fit well to the tunneling transport, and the MRcharacteristics may be described as being the tunneling transport between Zeeman split discrete Fermi states ofweakly linked nanoparticles.DOI: 10.1103/PhysRevB.72.113406 PACS number s : 73.63.Bd, 71.70.Ej, 73.43.Qt, 78.67.Bf

A newly developed device that enables easy intraoperative colonic irrigation and subsequent colonoscopy was introduced recently.To evaluate the efficacy of the single-stage procedure with a new device and the significance of on-table colonoscopy, 112 patients with obstructive left colon cancer were recruited.Primary anastomosis after tumor resection was performed in 104 cases. The volume of saline used for irrigation averaged 13.5 l over 12.1 min. Subsequent colonoscopic examination added an average of 10.4 min to the operative time. There were three anastomotic leaks, two wound infections, four acute renal failures, and two operative mortalities. On-table colonoscopy resulted in extended resection in 17 cases.The new device enabled safe, simple, and time-saving, single-stage surgical management of left colon cancer obstruction. The ability to perform on-table colonoscopy enabled treatment and recognition of synchronous bowel pathology.

The transport and magnetic behaviors of a series of seven two-component (Ag)/sub x/(Ni)/sub 100-x/ nanocompacts , each with a different Ag/Ni mass ratio, are studied with and without the presence of an applied magnetic field. A percolation threshold is found at 30% Ag concentration, higher than which metallic transport is observed. Using the tunneling magnetoresistance mechanism, the magnetorestrictive behaviors of the nanocompacts is investigated. It is observed that the TMR effects become diminshing in low Ni concentration nanocompacts.

Primary ciliary dyskinesia (PCD; Immotile cilia syndrome; OMIM 242650) is an autosomal recessive disorder resulting from dysmotility of cilia and sperm flagella.1 Cilia and flagella function either to create circulation of fluid over a stationary cell surface or to propel a cell through fluid.2,3 These related structures are highly complex organelles composed of over 200 different polypeptides.4,5 The core or axoneme of cilia and flagella comprises a bundle of microtubules and many associated proteins. The microtubules are formed from α and β tubulin protofilaments and are arranged in a well recognised ‘9+2’ pattern: nine peripheral microtubule doublets in a ring connected around a central pair of microtubules by radial spoke proteins. The peripheral microtubules have dynein motor proteins attached and are connected with each other by nexin links.6–8 In human beings, ciliated epithelium can be found lining the respiratory tract, including the sinuses and middle ear, the brain ependyma, the female oviduct, and the male vas deferens. Cilia in the respiratory tract play an important part in airway clearance of respiratory secretions. In primary ciliary dyskinesia, impaired mucociliary clearance causes recurrent respiratory tract infections including chronic otitis media, rhinitis, and sinusitus, often leading to permanent lung damage (bronchiectasis).9 Patients are also often subfertile due to sperm tail immotility and immotile oviduct cilia. About half of the patients have defects of laterality, usually complete mirror-image reversal of the left-right axis (situs inversus) and this association is known as Kartagener syndrome (OMIM 244400). The defects in left-right axis determination associated with primary ciliary dyskinesia are proposed to result from dysfunction of the embryonic node monocilia during development.10–12 Primary ciliary dyskinesia has an incidence of 1 in 20 000 with enrichment in certain populations.9,13 Diagnosis is made on brushings or biopsy …