Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR?

The increase in numbers of adults with cystic fibrosis (CF) has allowed us to identify previously unrecognized chronic complications of CF, as well as appreciate unique presentations of cystic fibrosis-related diseases. Do these chronic complications and unique presentations provide us with new insight into cystic fibrosis transmembrane conductance regulator (CFTR) function? Current data suggest that the 'chronic complications' reveal mainly the effect of a long-term absence of previously recognized CFTR functions. In contrast, the 'unique presentations' provide new insight into the role of CFTR in different tissues

Large genomic rearrangements in the CFTR gene contribute to CBAVD

<p>Abstract</p> <p>Background</p> <p>By performing extensive scanning of whole coding and flanking sequences of the <it>CFTR (Cystic Fibrosis Transmembrane Conductance Regulator</it>) gene, we had previously identified point mutations in 167 out of 182 (91.7%) males with isolated congenital bilateral absence of the vas deferens (CBAVD). Conventional PCR-based methods of mutation analysis do not detect gross DNA lesions. In this study, we looked for large rearrangements within the whole <it>CFTR </it>locus in the 32 CBAVD patients with only one or no mutation.</p> <p>Methods</p> <p>We developed a semi-quantitative fluorescent PCR assay (SQF-PCR), which relies on the comparison of the fluorescent profiles of multiplex PCR fragments obtained from different DNA samples. We confirmed the gross alterations by junction fragment amplification and identified their breakpoints by direct sequencing.</p> <p>Results</p> <p>We detected two large genomic heterozygous deletions, one encompassing exon 2 (c.54-5811_c.164+2186del8108ins182) [or <it>CFTRdele2</it>], the other removing exons 22 to 24 (c.3964-3890_c.4443+3143del9454ins5) [or <it>CFTRdele 22_24</it>], in two males carrying a typical CBAVD mutation on the other parental <it>CFTR </it>allele. We present the first bioinformatic tool for exon phasing of the <it>CFTR </it>gene, which can help to rename the exons and the nomenclature of small mutations according to international recommendations and to predict the consequence of large rearrangements on the open reading frame.</p> <p>Conclusion</p> <p>Identification of large rearrangements further expands the <it>CFTR </it>mutational spectrum in CBAVD and should now be systematically investigated. We have designed a simple test to specifically detect the presence or absence of the two rearrangements identified in this study.</p

Lipoxin A4 Stimulates Calcium-Activated Chloride Currents and Increases Airway Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia

Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl− secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA4 is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA4 are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA4 produced a rapid and transient increase in intracellular Ca2+. We have investigated, the effect of LXA4 on Cl− secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA4 stimulated a rapid intracellular Ca2+ increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA4 stimulated whole-cell Cl− currents which were inhibited by NPPB (calcium-activated Cl− channel inhibitor), BAPTA-AM (chelator of intracellular Ca2+) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA4 increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA4 effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl− secretion. The LXA4 stimulation of intracellular Ca2+, whole-cell Cl− currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA4 in the stimulation of intracellular Ca2+ signalling leading to Ca2+-activated Cl− secretion and enhanced ASL height in non-CF and CF bronchial epithelia

Validity of self-assessment of hallux valgus using the Manchester scale

<p>Abstract</p> <p>Background</p> <p>Hallux valgus (HV) is a common condition involving the progressive subluxation of the first metatarsophalangeal joint due to lateral deviation of the hallux and medial deviation of the first metatarsal. The objective of this study was to evaluate the re-test reliability and validity of self-assessment of HV using a simple clinical screening tool involving four standardised photographs (the Manchester scale), in order to determine whether this tool could be used for postal surveys of the condition.</p> <p>Methods</p> <p>HV was assessed with the Manchester scale in 138 people aged 65 to 93 years of age (102 women and 36 men) as part of a larger randomised controlled trial. At the six month follow-up assessment, HV was reassessed to determine re-test reliability, and participants were asked to self-assess their degree of HV independent of the examiners. Associations between (i) baseline and follow-up assessments of the examiners and (ii) participant and examiner assessments were performed using weighted kappa statistics. Analyses were then repeated after HV was dichotomised as present or absent using unweighted kappa, and sensitivity and specificity of self-assessment of HV was determined.</p> <p>Results</p> <p>Re-test reliability of the examiners was substantial to almost perfect (weighted kappa = 0.78 to 0.90), and there was a substantial level of agreement between observations of the participants and the examiners (weighted kappa = 0.71 to 0.80). Overall, there was a slight tendency for participants to rate their HV as less severe than the examiners. When the Manchester scale scores were dichotomised, agreement was substantial to almost perfect for both re-test comparisons (kappa = 0.80 to 0.89) and substantial for comparisons between participants and examiners (kappa = 0.64 to 0.76). The sensitivity and specificity of self-assessment of HV using the dichotomous scale were 85 and 88%, respectively.</p> <p>Conclusions</p> <p>The Manchester scale demonstrates high re-test reliability, and self-assessment scores obtained by participants are strongly associated with scores obtained by examiners. These findings indicate that the tool can be used with confidence in postal surveys to document the presence and severity of HV.</p> <p>Trial registration</p> <p>ACTRN12608000065392</p

Characterising the biophysical properties of normal and hyperkeratotic foot skin

BACKGROUND: Plantar foot skin exhibits unique biophysical properties that are distinct from skin on other areas of the body. This paper characterises, using non-invasive methods, the biophysical properties of foot skin in healthy and pathological states including xerosis, heel fissures, calluses and corns. METHODS: Ninety three people participated. Skin hydration, elasticity, collagen and elastin fibre organisation and surface texture was measured from plantar calluses, corns, fissured heel skin and xerotic heel skin. Previously published criteria were applied to classify the severity of each skin lesion and differences in the biophysical properties compared between each classification. RESULTS: Calluses, corns, xerotic heel skin and heel fissures had significantly lower levels of hydration; less elasticity and greater surface texture than unaffected skin sites (p &lt; 0.01). Some evidence was found for a positive correlation between hydration and elasticity data (r ≤ 0.65) at hyperkeratotic sites. Significant differences in skin properties (with the exception of texture) were noted between different classifications of skin lesion. CONCLUSIONS: This study provides benchmark data for healthy and different severities of pathological foot skin. These data have applications ranging from monitoring the quality of foot skin, to measuring the efficacy of therapeutic interventions. KEYWORDS: Biophysical parameters; Callus; Corns; Dry skin; Heel fissures; Plantar foot skin hyperkeratosis; Quantification; Skin classification (SELs); Xerosi

Foot pain and functional limitation in healthy adults with hallux valgus: a cross-sectional study

Background Hallux valgus (HV) is a very common deformity of the first metatarsophalangeal joint that often requires surgical correction. However, the association between structural HV deformity and related foot pain and disability is unclear. Furthermore, no previous studies have investigated concerns about appearance and difficulty with footwear in a population with HV not seeking surgical correction. The aim of this cross-sectional study was to investigate foot pain, functional limitation, concern about appearance and difficulty with footwear in otherwise healthy adults with HV compared to controls. Methods Thirty volunteers with HV (radiographic HV angle >15 degrees) and 30 matched controls were recruited for this study (50 women, 10 men; mean age 44.4 years, range 20 to 76 years). Differences between groups were examined for self-reported foot pain and disability, satisfaction with appearance, footwear difficulty, and pressure-pain threshold at the first metatarsophalangeal joint. Functional measures included balance tests, walking performance, and hallux muscle strength (abduction and plantarflexion). Mean differences (MD) and 95% confidence intervals (CI) were calculated. Results All self-report measures showed that HV was associated with higher levels of foot pain and disability and significant concerns about appearance and footwear (p < 0.001). Lower pressure-pain threshold was measured at the medial first metatarsophalangeal joint in participants with HV (MD = -133.3 kPa, CI: -251.5 to -15.1). Participants with HV also showed reduced hallux plantarflexion strength (MD = -37.1 N, CI: -55.4 to -18.8) and abduction strength (MD = -9.8 N, CI: -15.6 to -4.0), and increased mediolateral sway when standing with both feet with eyes closed (MD = 0.34 cm, CI: 0.04 to 0.63). Conclusions These findings show that HV negatively impacts on self-reported foot pain and function, and concerns about foot appearance and footwear in otherwise healthy adults. There was also evidence of impaired hallux muscle strength and increased postural sway in HV subjects compared to controls, although general physical functioning and participation in physical activity were not adversely affected

Stomata morphological traits in two different genotypes of Populus nigra L.

Populus nigra L. (black poplar) possesses amphistomatic leaves, with large (giant) and normal sized stomata. The role of giant stomata in leaf development, and the consequences on stomatal density in adult leaves remains elusive. This paper describes the characteristics of ordinary and giant stomata in leaves of two black poplar genotypes (58-861 with large leaves from northern Italy, and Poli with small leaves from southern Italy). Stomatal traits in both genotypes were studied using light microscopy on mature leaf adaxial and abaxial epidermal impressions. Moreover, scanning electron microscopy was applied to study giant and normal stomata in early, young, and mature leaves. Leaf abaxial surfaces in the two genotypes revealed variable sizes and patterns of stomata related to differences in intrinsic water use efficiency (Wi). These observations provided evidence of different stomatal types in mature black poplar leaves, and new information regarding the presence and potential role of giant stomata in black poplar leaves