Unaffected Subjects Research Articles

Testing the extreme male brain theory of autism spectrum disorder in a familial design.

Autism Spectrum Disorder (ASD) may be an extreme manifestation of some male-typical traits in both neuroanatomy and cognition. Using the ratio of the second to fourth digit (2D:4D) and digit length as biomarkers of (pre- and postnatal) testosterone levels, examined was whether hypermasculinized digit ratios and/or lengths were familial traits in ASD and investigated their relation to sexually dimorphic cognitive abilities. 2D:4D ratios and digit lengths of 216 children with ASD, 202 unaffected siblings, and 360 parents were compared with those of 174 control children and their 146 parents. Generalized Estimation Equations, Generalized Linear Models, and Linear Mixed Models were used to investigate parent-offspring relationships and group differences. In ASD probands and their relatives alike, digit length relative to overall height was significantly increased in comparison to controls. No significant group differences were found between affected and unaffected subjects, or between males and females. Additionally, 2D:4D ratios increased with age. No (consistent) associations were found between 2D:4D ratio or digit lengths and systemizing and empathizing skills. The findings emphasize the role of familially based elevated pre- and postnatal testosterone levels in the liability for ASD, but challenge the use of 2D:4D ratio as a proxy of prenatal testosterone exposure solely. Given that many genes influence digit length, the exact mechanisms underlying a familial predisposition toward increased digit length in ASD are as yet unknown and needs to be explored in future studies.

Studies of genes involved in craniofacial development and tumorigenesis: FGF3 contributes to isolated oral clefts and may interact with PAX9

Objective. Previous studies suggest individuals born with oral clefts and their families have a higher susceptibility for cancer, which raises the hypothesis that these two conditions share common molecular pathways. This study evaluated the association between oral clefts and polymorphisms in genes that play a role in craniofacial and tumor development. Materials and methods. Four hundred and ninety-seven subjects born with oral clefts and 823 unaffected subjects were recruited. Twenty-nine markers in 13 genes were genotyped by the Taqman method. Chi-square was used to compare allele and genotype frequencies. Bonferroni correction for multiple testing was used and the established alpha was 0.0003. This study also used logistic regression to test if genetic variants were associated with oral clefts using positive family history of cancer and age as covariates. Results. There was no association between family history of cancer and oral clefts (p = 0.51). None of the 1320 study participants had a diagnosis of cancer at the time of participation in the study. The marker rs4980700 in FGF3 was associated with oral clefts (p = 0.0002). Logistic regression analysis also provided evidence for gene–gene interaction between FGF3 (rs4980700) and PAX9 (rs2073242), increasing the risk for isolated oral clefts (p = 0.0003). Conclusion. FGF3 is associated with oral clefts and may interact with PAX9.

Randomized Controlled Trial of a Protein Substitute with Prolonged Release on the Protein Status of Children with Phenylketonuria

Objective: To examine whether a phenylalanine-free protein substitute with prolonged release may be beneficial to the protein status of children with phenylketonuria (PKU) compared to conventional substitutes. Methods: Sixty children with PKU, 7 to 16 years of age, were randomly allocated to receive either a prolonged-release (test) or the current conventional protein substitute for 30 days. Subjects were additionally sex and age matched with 60 subjects with mild hyperphenylalaninemia and 60 unaffected subjects. The protein status in children with PKU was assessed by albumin, transthyretin, and retinol-binding protein (RBP), and changes throughout the trial period were the primary outcome measures. Results: Children with PKU did not differ in anthropometry from children with mild hyperphenylalaninemia or unaffected children but they ingested lower amounts of proteins (p < 0.01). No differences occurred throughout the trial between or within children with PKU who received the test or conventional substitute for macronutrient intake. Albumin and RBP concentrations were within the age-specific reference range for all children. The rate of protein insufficiency (transthyretin concentration less than 20 mg/dL) did not differ statistically between children receiving test or conventional substitute (recruitment 51.8% vs 53.6%; end of the trial 44.4% vs 50.0%) but mean transthyretin recovered over 20 mg/dL in children who received the test substitute, increasing from 19.1 to 20.7 mg/dL (mean change, 1.6 mg/dL; 95% confidence interval 0.4 to 2.8 mg/dL). In children receiving conventional substitute mean transthyretin changed from 19.0 to 19.2 mg/dL (0.2; −0.2 to 0.6) mg/dL. Conclusions: Protein substitutes with prolonged release might be beneficial to protein status in children with phenylketonuria.

Nutrients Utilization in Obese Individuals with and without Hypertriglyceridemia

Background: Low fat utilization is linked to weight gain and to the presence of certain atherosclerosis markers. It is not clear whether the presence of hyperlipidemia can further affect nutrients utilization. The main objective of this study was to investigate the fasting fuel utilization of obese subjects suffering from hypertriglyceridemia, and to compare it with that of individuals that are solely obese. Method: We recruited 20 obese individuals with hypertriglyceridemia and 20 matched individuals not affected by hypertriglyceridemia. The fuel utilization (respiratory quotient) was measured by respiratory gas exchange, by Indirect Calorimetry. Results: There was a significant difference in fuel utilization and HDL-cholesterol between cases and controls (respiratory quotient 0.89 ± 0.07 vs. 0.84 ± 0.06; p = 0.020 respectively). The univariate and multivariate linear regression analysis confirmed that hypertrygliceridemia was positively correlated to the respiratory quotient (p = 0.035). Conclusion: obese subjects with hypertriglyceridemia had a higher respiratory quotient in comparison to unaffected subjects. This could suggest a limitation in the beta-oxidation mechanisms; this could actually imply that fatty acids may be redirected from oxidation to reesterification into triglycerides. The study could suggest the presence of different mechanisms unrelated to obesity and also a potential new therapeutic target for hypertriglyceridemia management.

Deletion of exons 1–3 of the MEN1 gene in a large Italian family causes the loss of menin expression

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disease, characterized by parathyroid adenomas, endocrine gastroenteropancreatic tumors and pituitary adenomas, due to inactivating mutations of the MEN1 gene (chromosome 11q13). MEN1 mutations are mainly represented by nonsense, deletions/insertions, splice site or missense mutations that can be detected by direct sequencing of genomic DNA. However, MEN1 patients with large heterozygous deletions may escape classical genetic screening and may be misidentified as phenocopies, thereby hindering proper clinical surveillance. We employed a real-time polymerase chain reaction application, the TaqMan copy number variation assay, to evaluate a family in which we failed to identify an MEN1 mutation by direct sequencing, despite a clear clinical diagnosis of MEN1 syndrome. Using the TaqMan copy number variation assay we identified a large deletion of the MEN1 gene involving exons 1 and 2, in three affected family members, but not in the other nine family members that were to date clinically unaffected. The same genetic alteration was not found in a group of ten unaffected subjects, without family history of endocrine tumors. The MEN1 deletion was further confirmed by multiplex ligation-dependent probe amplification, which showed the deletion extended from exon 1 to exon 3. This new approach allowed us to correctly genetically diagnose three clinical MEN1 patients that were previously considered as MEN1 phenocopies. More importantly, we excluded the presence of genetic alterations in the unaffected family members. These results underline the importance of using a variety of available biotechnology approaches when pursuing a genetic diagnosis in a clinically suggestive setting of inherited endocrine cancer.

Fast urinary screening of oligosaccharidoses by MALDI-TOF/TOF mass spectrometry

BackgroundOligosaccharidoses, which belong to the lysosomal storage diseases, are inherited metabolic disorders due to the absence or the loss of function of one of the enzymes involved in the catabolic pathway of glycoproteins and indirectly of glycosphingolipids. This enzymatic deficiency typically results in the abnormal accumulation of uncompletely degraded oligosaccharides in the urine. Since the clinical features of many of these disorders are not specific for a single enzyme deficiency, unambiguous screening is critical to limit the number of costly enzyme assays which otherwise must be performed.MethodsHere we provide evidence for the advantages of using a MALDI-TOF/TOF (matrix-assisted laser desorption ionization time-of-flight) mass spectrometric (MS) method for screening oligosaccharidoses. Urine samples from previously diagnosed patients or from unaffected subjects were randomly divided into a training set and a blind testing set. Samples were directly analyzed without prior treatment.ResultsThe characteristic MS and MS/MS molecular profiles obtained allowed us to identify fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, Sandhoff disease, α-mannosidosis, sialidosis and mucolipidoses type II and III.ConclusionsThis method, which is easily run in less than 30 minutes, is performed in a single step, and is sensitive and specific. Invaluable for clinical chemistry purposes this MALDI-TOF/TOF mass spectrometry procedure is semi-automatizable and suitable for the urinary screening of oligosacharidoses.

Association between CCND1 and XPC polymorphisms and bladder cancer risk: a meta-analysis based on 15 case–control studies

Perturbations in cell cycle and DNA repair genes might affect susceptibility to cancer. The aim of this meta-analysis is to generate large-scale evidence to determine the degree to which common Cyclin D1 (CCND1) G870A (dbSNP: rs603965) and xeroderma pigmentosum group C (XPC) Ala499Val (dbSNP: rs2228000) polymorphisms are associated with susceptibility to bladder cancer. The electronic databases PubMed, Embase, Web of Science, and CNKI were searched for relevant studies (with an upper date limit of July 25, 2013). The principal outcome measure for evaluating the strength of association was crude odds ratios (ORs) along with their corresponding confidence intervals (95%CIs). We found and reviewed nine case-control studies on CCND1 G870A with a total of 6,823 subjects and seven studies on XPC Ala499Val with a total of 7,674 subjects. Our meta-analysis provides evidence that the variant genotype of CCND1 G870A showed a significant association in the occurrence of invasive bladder tumors in former and current smokers. The XPC Ala499Val polymorphism correlated with significant differences between patients and unaffected subjects, but when the groups were stratified by ethnicity, the magnitude of the overall effect was similar only among Caucasian populations. Results from our meta-analysis support the view that the G870A polymorphism may modulate the risk of bladder cancer in conjunction with tobacco smoking and that the Ala499Val polymorphism may contribute to the susceptibility to bladder cancer in Caucasian populations. Our findings, however, warrant larger well-designed studies to investigate the significance of these two polymorphisms as markers of susceptibility to bladder cancer.

A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism

Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.

Congenital heart defects after maternal fever

The purpose of this study was to evaluate whether maternal febrile illnesses in early pregnancy are associated with increased risk for congenital heart defects in the offspring and whether such risk is mitigated by multivitamin supplement use. From a multistate population-based case-control study (National Birth Defects Prevention Study), we compared maternal reports of first-trimester febrile illness from 7020 subjects with heart defects and 6746 unaffected control subjects who were born from 1997 through 2005. Relative risks were computed with no fever or infection during the first trimester as reference group and were adjusted for potential confounders. First-trimester febrile illness was reported by 7.4% of control mothers (1 in 13). Febrile genitourinary infections were associated with selected heart defects, particularly right-sided obstructive defects (odds ratios, >3) and possibly others, whereas common respiratory illnesses were associated with low-to-negligible risks for most heart defects. When risk estimates were elevated, they tended to be mitigated when multivitamin supplements had been taken in the periconceptional period. The source of fever and the use of supplements appear to influence the risk for heart defects. This information can be helpful in counseling and research, in particular with regard to primary prevention.

Autism traits in the RASopathies

BackgroundMutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous...

Variations in inflammatory genes are associated with periodontitis

BackgroundPeriodontitis is a multi-factorial disease and several risk-factors such as infections, inflammatory responses, oral hygiene, smoke, aging and individual predisposition are involved in the disease. Pathogens trigger chronic inflammation with cytokines release which in turn leads to the destruction of the connective and the teeth supporting bone. The identification of genetic factors controlling oral inflammation may increase our understanding of genetic predisposition to periodontitis.Single nucleotide polymorphisms in the promoter region of Vascular Endothelial Growth Factor, Alpha-1-Antichymotripsin, hydroxy-methyl-glutaryl CoA reductase, Interferon alpha, Interleukin-1 Beta, Interleukin 10, Interleukin 6 and Tumor Necrosis Factor- alpha genes from a case/control study were investigated.ResultsThe C allele of Vascular Endothelial Growth Factor, A allele of Interleukin 10 and GG genotype of Tumor Necrosis Factor-α were individually associated with chronic periodontitis. However, the concomitant presence of the three genetic markers in the same subjects appeared to play a synergistic role and increased several folds the risk of the disease.ConclusionsOur findings offer new tools to implement the screening of unaffected subjects with an increased susceptibility of periodontitis and increase our understanding regarding the genetic inflammatory background related to familiarity of the disease.

Chemical shift-based MRI to measure fat fractions in dystrophic skeletal muscle

The relationship between fat fractions (FFs) determined based on multiple TE, unipolar gradient echo images and (1) H magnetic resonance spectroscopy (MRS) was evaluated using different models for fat-water decomposition, signal-to-noise ratios, and excitation flip angles. A combination of single-voxel proton spectroscopy ((1) H-MRS) and gradient echo imaging was used to determine muscle FFs in both normal and dystrophic muscles. In order to cover a large range of FFs, the soleus and vastus lateralis muscles of 22 unaffected control subjects, 16 subjects with collagen VI deficiency (COL6), and 71 subjects with Duchenne muscular dystrophy (DMD) were studied. (1) H-MRS-based FF were corrected for the increased muscle (1) H2 O T1 and T2 values observed in dystrophic muscles. Excellent agreement was found between coregistered FFs derived from gradient echo images fit to a multipeak model with noise bias correction and the relaxation-corrected (1) H-MRS FFs (y = 0.93x + 0.003; R(2) = 0.96) across the full range of FFs. Relaxation-corrected (1) H-MRS FFs and imaging-based FFs were significantly elevated (P < 0.01) in the muscles of COL6 and DMD subjects. FFs, T2 , and T1 were all sensitive to muscle involvement in dystrophic muscle. MRI offered an additional advantage over single-voxel spectroscopy in that the tissue heterogeneity in FFs could be readily determined.

P.16.9 Epigenetic variability is a modifier of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is strongly associated with epigenetic changes of the 4q35 D4Z4 macrosatellite. FSHD pathology requires the misexpression and missplicing of the DUX4 (double homeobox 4) gene encoded within the repeat array resulting in production of a pathogenic protein, DUX4-FL. We have analyzed DUX4 mRNA and protein expression in a large collection of myogenic cells and muscle biopsies derived from muscles of FSHD1 affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adults yet to show clinical manifestations of the disease; however, there was great individual and familial variation in the levels of DUX4-FL. In addition, we found DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology. To investigate if subtle differences in the epigenetic status of the 4q35 region could account for the wide variation in DUX4-fl expression among FSHD1 subjects and potentially the spurious expression in certain unaffected controls, family cohorts of myogenic cells from FSHD1 subjects were tested for their sensitivity to small molecules that can alter the chromatin state. We find that myogenic cells from FSHD1 subjects are overall epigenetically poised to express DUX4 compared with unaffected subjects; however, FSHD1 subjects show individual differences in their capacity to express DUX4-fl in response to DNA demethylation and blocking histone deacetylation. Therefor, individual differences in the epigenetic status likely impacts progression of disease pathology, variability in age of onset, disease severity, and asymmetry of affected muscles.

P.5.12 A mutation in TNPO3 causes LGMD1F and characteristic nuclear pathology

Limb-girdle muscular dystrophy 1F (LGMD1F) is an autosomal dominant muscular disease affecting a Spanish family. Using whole genome sequencing, we identified a single nucleotide deletion (c.2771del) in transportin-3 gene ( TNPO3 ) in a LGMD1F patient. The mutation disrupts the termination codon of TNPO3 and causes a reading frame shift. Transportin-3 is a nuclear protein, and mediates import of serine–arginine rich proteins into nucleus, which is important for mRNA splicing. This study aimed to investigate the significance of transportin-3 in the pathogenesis of LGMD1F. We performed dideoxy-sequencing of TNPO3 in 24 affected and 23 unaffected family members. Muscle specimens from 4 patients were analyzed by conventional stains and immunohistochemistry. Direct sequence of TNPO3 revealed that all patients carried a heterozygous mutation, and none of the unaffected subjects had the mutation. Hematoxylin-eosin (HE) stained muscle revealed nuclei (10.7 ± 3.0%; mean ± SD) with central pallor in all patients studied. Immunohistochemistry with anti-transportin-3 antibody showed colocalization with nuclei in control subjects. In patients, transportin-3 was also observed within nuclei, but was often unevenly distributed in periphery, a staining pattern similar to that seen by HE. Genetic and histological studies in a Spanish family strongly support the hypothesis that TNPO3 is the causative gene of LGMD1F. Pathological study also indicates that the subcellular distribution of transportin-3 is disrupted and affects the structure of nuclei.

SAT0098 Seropositivity of anti-cyclic citrullinated peptide antibody is more prevalent in unaffected first-degree relatives with multicases families of rheumatoid arthritis

ObjectivesThis study elucidates the prevalence of seropositivity and determinants for rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and anti-mutated citrullinated vimentin (anti-MCV) antibodies in unaffected first-degree relatives (FDRs) of rheumatoid...

Skeletal Muscles of Ambulant Children with Duchenne Muscular Dystrophy: Validation of Multicenter Study of Evaluation with MR Imaging and MR Spectroscopy

To validate a multicenter protocol that examines lower extremity skeletal muscles of children with Duchenne muscular dystrophy (DMD) by using magnetic resonance (MR) imaging and MR spectroscopy in terms of reproducibility of these measurements within and across centers. This HIPAA-compliant study was approved by the institutional review boards of all participating centers, and informed consent was obtained from each participant or a guardian. Standardized procedures with MR operator training and quality assurance assessments were implemented, and data were acquired at three centers by using different 3-T MR imaging instruments. Measures of maximal cross-sectional area (CSAmax), transverse relaxation time constant (T2), and lipid fraction were compared among centers in two-compartment coaxial phantoms and in two unaffected adult subjects who visited each center. Also, repeat MR measures were acquired twice on separate days in 30 boys with DMD (10 per center) and 10 unaffected boys. Coefficients of variation (CVs) were computed to examine the repeated-measure variabilities within and across centers. CSAmax, T2 from MR imaging and MR spectroscopy, and lipid fraction were consistent across centers in the phantom (CV, <3%) and in the adult subjects who traveled to each site (CV, 2%-7%). High day-to-day reproducibility in MR measures was observed in boys with DMD (CSAmax, CV = 3.7% [25th percentile, 1.3%; 75th percentile, 5.1%]; contractile area, CV = 4.2% [25th percentile, 0.8%; 75th percentile, 4.9%]; MR imaging T2, CV = 3.1% [25th percentile, 1.2%; 75th percentile, 4.7%]; MR spectroscopy T2, CV = 3.9% [25th percentile, 1.5%; 75th percentile, 5.1%]; and lipid fraction, CV = 4.7% [25th percentile, 1.0%; 75th percentile, 5.3%]). The MR protocol implemented in this multicenter study achieved highly reproducible measures of lower extremity muscles across centers and from day to day in ambulatory boys with DMD.

Human Photoreceptor Outer Segments Shorten During Light Adaptation

Best disease is a macular dystrophy caused by mutations in the BEST1 gene. Affected individuals exhibit a reduced electro-oculographic (EOG) response to changes in light exposure and have significantly longer outer segments (OS) than age-matched controls. The purpose of this study was to investigate the anatomical changes in the outer retina during dark and light adaptation in unaffected and Best disease subjects, and to compare these changes to the EOG. Unaffected (n = 11) and Best disease patients (n = 7) were imaged at approximately 4-minute intervals during an approximately 40-minute dark-light cycle using spectral domain optical coherence tomography (SD-OCT). EOGs of two subjects were obtained under the same conditions. Automated three-dimensional (3-D) segmentation allowed measurement of light-related changes in the distances between five retinal surfaces. In normal subjects, there was a significant decrease in outer segment equivalent length (OSEL) of -2.14 μm (95% confidence interval [CI], -1.77 to -2.51 μm) 10 to 20 minutes after the start of light adaptation, while Best disease subjects exhibited a significant increase in OSEL of 2.07 μm (95% CI, 1.79-2.36 μm). The time course of the change in OS length corresponded to that of the EOG waveform. Our results strongly suggest that the light peak phase of the EOG is temporally related to a decreased OSEL in normal subjects, and the lack of a light peak phase in Best disease subjects is associated with an increase in OSEL. One potential role of Bestrophin-1 is to trigger an increase in the standing potential that approximates the OS to the apical surface of the RPE to facilitate phagocytosis.

MEFV Variants in Patients with PFAPA Syndrome in Japan

Background: The pathogenesis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is unknown as yet. In order to understand whether genes implicated in other auto-inflammatory diseases might be involved in the pathogenesis of PFAPA, all variants in the genes causing familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Hyper IgD syndrome were analyzed in children with PFAPA.Patients and Methods: All variants in MEFV, TNFRSF1A, and MVK were analyzed in 20 patients with PFAPA. PFAPA were diagnosed by previous published criteria. The findings of all analyses in PFAPA patients were compared with those of unaffected normal subjects (n=62).Results: In the 13 children of 20 with PFAPA, the heterozygous variants of MEFV (5 patients: E148Q-L110P, 2 patients: E148Q, 1 patient: E148Q-L110P/E148Q, 1 patient: E148Q-P369S-R408Q-E84K, 1 patient: E148Q-L110P-P369S-A408G, 1 patient: R202Q, 1 patient: P115R) were found. No variants belonging to TNFRSF1A or MVK were detected in children with PFAPA. The frequency of the E148Q-L110P variants in children with PFAPA was significantly higher than that observed in unaffected normal subjects (7/20 versus 8/62). The duration of the episodes of illness in PFAPA children with MEFV variants was shorter than that of patients without variants.Conclusion: Genes involved in the development and progression of MEFV may affect the incidence and the phenotype of PFAPA in children.

The Idiopathic Pulmonary Fibrosis Honeycomb Cyst Contains A Mucocilary Pseudostratified Epithelium

BackgroundWe previously identified a MUC5B gene promoter-variant that is a risk allele for sporadic and familial Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP). This allele was strongly associated with increased MUC5B gene expression in lung tissue from unaffected subjects. Despite the strong association of this airway epithelial marker with disease, little is known of mucin expressing structures or of airway involvement in IPF/UIP.MethodsImmunofluorescence was used to subtype mucus cells according to MUC5B and MUC5AC expression and to identify ciliated, basal, and alveolar type II (ATII) cells in tissue sections from control and IPF/UIP subjects. Staining patterns were quantified for distal airways (Control and IPF/UIP) and in honeycomb cysts (HC).ResultsMUC5B-expressing cells (EC) were detected in the majority of control distal airways. MUC5AC-EC were identified in half of these airways and only in airways that contained MUC5B-EC. The frequency of MUC5B+ and MUC5AC+ distal airways was increased in IPF/UIP subjects. MUC5B-EC were the dominant mucus cell type in the HC epithelium. The distal airway epithelium from control and IPF/UIP subjects and HC was populated by basal and ciliated cells. Most honeycombing regions were distinct from ATII hyperplasic regions. ATII cells were undetectable in the overwhelming majority of HC.ConclusionsThe distal airway contains a pseudostratified mucocilary epithelium that is defined by basal epithelial cells and mucus cells that express MUC5B predominantly. These data suggest that the HC is derived from the distal airway.

Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants

BackgroundCDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a...