An observer-blinded randomized controlled pilot trial comparing localized immersion psoralen-ultraviolet A with localized narrowband ultraviolet B for the treatment of palmar hand eczema.

BACKGROUND: Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. OBJECTIVES: To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB-UVB for the treatment of chronic hand eczema unresponsive to topical steroids. METHODS: Sixty patients with hand eczema unresponsive to clobetasol propionate 0·05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary outcome measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). RESULTS: In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to-treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9·5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. CONCLUSIONS: In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.

Smothering in UK free-range flocks. Part 2: investigating correlations between disease, housing and management practices.

Smothering, when birds group together in a way that results in death from suffocation, is a welfare and economic concern for the egg industry. This questionnaire-based study explored correlations between disease, housing, management practices and smothering on free-range farms. A binomial logistic regression approach was used to test whether question responses predicted occurrence of nest box smothers (NBS) and panic and recurring smothers (PSRS) on farms. Breed (P=0.008) and nest box manufacturer (P=0.014) predicted NBS. Breed and nest box design have been previously reported to affect nesting behaviour. The affect of nest box manufacturer found in this study may illustrate the effect of nest box design features or house layouts. Nest box manufacturer (P=0.009), feeding oyster grit or grain on the litter (P<0.001) and range use on a sunny day (P<0.001) also predicted PSRS. Implementing some management practices to encourage desirable behaviours (eg ranging) may contribute to smothering, whereas some management practices such as those aimed at occupying birds may be beneficial, illustrating the delicate balance of factors involved in free-range egg production. It is hoped that these results will stimulate further work exploring the suitability of housing design and management of laying hens in light of smothering.

Successful treatment of forehead lipoma depends on knowledge of the surgical anatomy: a step-by-step guide.

We review the anatomy of the frontal scalp in relation to the clinical features and surgical management of frontalis-associated lipoma. Awareness of this entity, coupled with sound regional anatomical knowledge, is essential to achieve good outcomes.

Autoimmune pancytopenia following combination chemotherapy for chronic lymphocytic leukaemia.

Autoimmune haemolysis or thrombocytopenia can complicate purine nucleoside monotherapy for chronic lymphocytic leukaemia (CLL), but Evans syndrome is rare. This is a report of the occurrence of pancytopenia secondary to a unique combination of red cell aplasia with autoimmune thrombocytopenia and neutropenia in a patient with CLL following treatment with fludarabine and cyclophosphamide. This case is unusual for the simultaneous targeting of three haemopoietic lineages by immune dysfunction following fludarabine and cyclophosphamide, which is a treatment regimen believed to reduce autoimmune haematological toxicity in CLL.

Bakery flour dust exposure causes non-allergic inflammation and enhances allergic airway inflammation in mice.

BACKGROUND: Baker's asthma is one of the most commonly reported occupational lung diseases in countries where fresh bread is baked daily in large quantities, and is characterized by rhinitis, bronchial hyperresponsiveness, and reversible airflow obstruction. Epidemiological studies have identified pre-existing atopy as an important risk factor for developing baker's asthma, yet the aetiology and pathogenesis of baker's asthma remain poorly understood. OBJECTIVE: We sought to develop a mouse model of baker's asthma that could be used to characterize the development and progression of baker's asthma. METHODS: We were unable to sensitize mice to bakery flour dust or flour dust extract. We assessed total inflammatory cells, cellular differential, total serum IgE and the pro-inflammatory cytokine response to oropharyngeally instilled bakery flour dust or flour dust extract by itself or in the context of ovalbumin (OVA) sensitization and challenge. RESULTS: Both bakery flour dust and flour dust extract consistently elicited a neutrophilic inflammation in a Toll-like receptor 4-independent manner; suggesting that endotoxin is not playing a role in the inflammatory response to flour dust. Moreover, bakery flour dust and dust extract significantly enhance the inflammatory response in OVA-sensitized and challenged mice. CONCLUSIONS: Bakery flour dust and flour dust extract are strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation.

Subchronic endotoxin inhalation causes persistent airway disease.

The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin exposure. Physiological and biological parameters were evaluated after 1 day, 5 days, or 8 wk of exposure to endotoxin [lipopolysaccharide (LPS)] in endotoxin-sensitive (C3HeB/FeJ) and endotoxin-resistant (C3H/HeJ) mice. After 5 days or 8 wk of LPS exposure, only C3HeB/FeJ had elevated airway hyperreactivity to inhaled methacholine. Only the C3HeB/FeJ mice had significant inflammation of the lower respiratory tract after 1 day, 5 days, or 8 wk of LPS exposure. Stereological measurements of small, medium, and large airways indicated that an 8-wk exposure to LPS resulted in expansion of the submucosal area only in the C3HeB/FeJ mice. Cell proliferation as measured by bromodeoxyuridine incorporation contributed to the expansion of the submucosa and was only significantly elevated in C3HeB/FeJ mice actively exposed to LPS. C3HeB/FeJ mice had significantly elevated levels of interleukin-1beta protein in whole lung lavage after 1 day and 5 days of LPS exposure and significantly elevated protein levels of total and active transforming growth factor-beta1 in whole lung lavage fluid after 5 days of LPS exposure. Our findings demonstrate that subchronic inhalation of LPS results in the development of persistent airway disease in endotoxin-responsive mice.

Primary lung fibroblasts from the 129 mouse strain exhibit reduced growth factor responsiveness in vitro.

Lung fibroblasts are activated to proliferate and produce connective tissue during the development of lung fibrosis. The 129 mouse strain does not develop asbestos-induced fibrogenesis, whereas several other inbred strains rapidly respond to inhaled fibers. Thus, in the experiments presented here, we have compared the responses of primary lung fibroblasts isolated from 129 and C57BL/6 mice. The 129 and C57BL/6 mouse lung fibroblasts (MLFs) proliferated similarly in 10% fetal bovine serum (FBS), but after quiescence, the 129 MLFs grew more slowly in serum and responded less to the BB isoform of platelet-derived growth factor. This is consistent with our finding that the mRNA for the PDGF-a receptor exhibits reduced expression by the 129 MLFs compared to those from C57BL/6 mice. Fibroblasts from the SJL mouse strain, from a C57BL/6-129 hybrid, and from the 3T3 cell line all proliferated more vigorously than MLFs from the 129 mice. In addition, the 129 MLFs exhibited reduced expression of alpha1 procollagen mRNA consequent to treatment with tumor necrosisfactor alpha. Based on these new findings, we suggest that the reduced fibrogenesis in asbestos-exposed 129 mice is due to an intrinsic difference in the ability of the lung fibroblasts to respond to peptide growth factors.

A macro-mechanical model of the guinea pig cochlea with realistic parameters.

The post-mortem transfer function of the cochlea of the guinea pig was compared to the transfer function generated by a model with parameters derived from physical measurements of the guinea pig cochlea. Both the formulation and parameters of the model were carefully chosen to be realistic using evidence from published measurements. The fit between the transfer function of the model and recent mechanical measurements of the passive guinea pig cochlear response was good, with a root mean square ratio of 6.3 dB in amplitude and 0.33 pi rad in phase. The model was used to explore the effect of cochlear partition mode factor and duct geometry upon the mechanical response of the cochlea. Possible inadequacies of the model which could explain the remaining differences between the output of the model and measurements are discussed.

Reduced tumor necrosis factor-alpha and transforming growth factor-beta1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure.

Tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta mRNA and protein expression and the degree of fibroproliferative response to inhaled asbestos fibers are clearly reduced in the 129 inbred mouse strain as compared with typical fibrogenesis observed in the C57BL/6 inbred strain. The C57BL/6 mice showed prominent lesions at bronchiolar-alveolar duct (BAD) junctions where asbestos fibers deposit and responding macrophages accumulate. The 129 mice, however, were generally indistinguishable from controls even though the numbers of asbestos fibers deposited in the lungs of all exposed animals were the same. Quantitative morphometry of H&E-stained lung sections comparing the C57BL/6 and 129 mice showed significantly less mean cross-sectional area of the BAD junctions in the 129 animals, apparent at both 48 hours and 4 weeks after exposure. In addition, fewer macrophages had accumulated at these sites in the 129 mice. Nuclear bromodeoxyuridine immunostaining demonstrated that the number of proliferating cells at first alveolar duct bifurcations and in adjacent terminal bronchioles was significantly reduced in the 129 strain compared with C57BL/6 mice at 48 hours after exposure (P < 0.01). TNF-alpha and TGF-beta1 gene expression, as measured by in situ hybridization, was reduced in the 129 mice at 48 hours after exposure, and expression of TNF-alpha and TGF-beta1 protein, as measured by immunohistochemistry, was similarly reduced or absent in the 129 animals. We postulate that the protection afforded the 129 mice is related to reduction of growth factor expression by the bronchiolar-alveolar epithelium and lung macrophages.

TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers.

We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alphaRKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obtained by in situ hybridization showing that expression of the genes coding for transforming growth factor alpha (TGF-alpha) and platelet-derived growth factor A-chain (PDGF-A) is reduced in the TNF-alphaRKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-alphaRKO mice show no increases over unexposed control animals. In contrast, wild-type control mice exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and consequently develop fibrogenic lesions. Even though the levels of TNF-alpha gene expression and protein production were increased in the asbestos-exposed TNF-alphaRKO mice, the lack of receptor signaling protected the mice from developing fibroproliferative lesions. We agree with the view that TNF-alpha is essential for the development of interstitial pulmonary fibrosis and postulate that TNF-alpha mediates its effects through activation of other growth factors such as PDGF and TGF-alpha that control cell growth and matrix production.

Mouse lymphoblasts lose their immunogenicity and susceptibility to specific cytotoxic T lymphocyte lysis during maintenance in culture.

This study was undertaken to search for possible mechanisms by which T-cell lines become non-immunogenic and refractory to cellular-mediated lysis during culture. We demonstrate that mouse lymphoblasts (LB) lost their susceptibility to specific cytotoxic T lymphocyte (CTL)-mediated lysis following culture for more than 5 days in the presence interleukin-2 (IL-2), IL-7 but not IL-4. In contrast, the cultured lymphoblasts (CLB) were efficiently lysed by specific antibody and C' and by CTL in the presence of concanavalin A. In addition, CLB did not inhibit cytotoxicity against LB in a cold target competition assay, indicating that CLB and LB differ in the expression of certain surface molecules. Indeed, a significantly lower expression of H-2D class I antigen, the Fas antigen and the adhesion molecules intracelluar adhesion molecule-1 (ICAM-1) and very late activation antigen-4 (VLA-4) was observed on the CLB surface. Consequently, CLB could not form conjugates with specific CTL, a prerequisite for CTL-mediated lysis. In addition, there was a marked decrease in CLB immunogenicity: the cultured cells were unable to stimulate allogeneic spleen cells in mixed lymphocyte culture nor could they induce a cytotoxic response following their injection into allogeneic mice. The reduced immunogenicity enabled the prolonged survival of active CLB in an allogeneic host. We suggest that the extended survival in an allogeneic tumour-bearing host of cultured, hence weakly immunogenic, anti-tumour CTL, will enable them the in vivo implementation of their anti-tumour activity.

Analyzing the genes and peptide growth factors expressed in lung cells in vivo consequent to asbestos exposure and in vitro.

Inhalation of fibrogenic particles causes injury to the bronchiolar-alveolar epithelium. Consequently, there is a rapid proliferative response as the epithelium recovers and interstitial mesenchymal cells divide and produce connective tissue. In our model of brief (5-hr) exposure to chrysotile asbestos (approximately 1000 fibers/cc) in rats and mice, these events result in focal scarring at the bronchiolar-alveolar duct junctions in a histopathologic pattern identical to that seen in asbestos-exposed individuals. After 3 consecutive days of exposure, these lesions persist for at least 6 months postexposure. We postulate that cell proliferation and production of extracellular matrix is mediated in large part by three peptide growth factors, transforming growth factors alpha and beta (TGF-alpha and -beta), and platelet-derived growth factor (PDGF) A- and B-chains. To test this hypothesis in part, we have asked whether the genes that code for these growth factor proteins are activated at sites of asbestos-induced lung injury. If these genes were not activated, it would be reasonable to suspect that other potent growth factors and cytokines released during lung injury could be the primary mediators of fibroproliferative lung disease. In the studies reported here, we show, by in situ hybridization (ISH) and immunohistochemistry, that the four genes and their concomitant proteins are expressed within 24 hr in the bronchiolar-alveolar epithelium and underlying mesenchymal cells. RNase protection assay and ISH showed that the PDGF gene was upregulated during the first 5 hr of exposure and all the gene products remained above control levels for at least 2 weeks postexposure. TGF-alpha is a potent mitogen for epithelial cells, whereas the PDGF isoforms are potent growth factors for mesenchymal cells. TGF-beta retards fibroblast growth but stimulates extracellular matrix synthesis. Further studies using gene knockouts, appropriate antibodies, or antisense technology will be necessary to prove whether any of the growth factors are playing a significant role in fibrogenic lung disease. In addition, we have carried out a series of studies using type II alveolar epithelial cells purified from adult mouse lungs and maintained for up to 8 weeks in serum-free culture. These cells exhibit high transepithelial resistance values and they release TGF-beta 1 and -beta 2. This cell type also has been cultured from TGF-alpha knockout mice, resulting in monolayers with increased transepithelial resistance. This combination of studies in vivo and in vitro will allow us to pursue the mechanisms through which growth factors mediate lung fibrosis.

The effect of the evanescent wave upon acoustic measurements in the human ear canal.

When making acoustic measurements in a human ear canal, it is often necessary to monitor the output of a sound source with a microphone positioned within a few millimeters of that sound source. This microphone will not only measure the pressure due to the propagated acoustic wave, which we wish to measure, but also the pressure due to the evanescent wave. The pressure due to the evanescent wave can be viewed as a source of error in the measurement of the propagating acoustic wave. This paper attempts to quantify the magnitude of this error. Theoretical predictions are made of the relative level of the evanescent sound pressure in a number of source and microphone arrangements applicable to ear canal measurements. It is shown that these theoretical predictions represent an upper limit of evanescent sound pressure that can be measured experimentally. The maximum measurement error due to the presence of the evanescent wave in human ear canals below 10 kHz is predicted to be 3 dB in adults and 1.3 dB in 1 month old infants, when the loudspeaker and microphone ports are spaced more than 2 mm apart.

[Recurrent fracture of the pediatric forearm]. / Die Refraktur des kindlichen Unterarms.

In a retrospective multicenter study 28 relapse fractures of the forearm in children were reviewed. The male to female ratio was 23:5. Six children were younger than 6 years, 12 were between 6 and 10 years, and 10 were between 10 and 14 years old. The primary fracture was treated by cast fixation of 3-7 weeks duration. The refracture occurred on a average 14 weeks (4-32 weeks) after the primary fracture by a simple fall (n = 14) or a fall from height (n = 4), or during school (n = 6) or leisure-time (n = 3) sporting activities. In 84% of the patients partial consolidation, i.e. incomplete healing of one cortex of one or both forearm bones, preceded the refracture. In the majority of patients this was observed after a green stick fracture due to permanent angulation. Six patients were operated upon for irreducibility of the relapse fracture; the others were treated by conservative means. In two patients a second refracture occurred. Fifteen patients were available for a 2 year result. Definitive angulation of more than 10 degrees caused a clinically relevant limitation of pro-supination in five of six patients. To prevent relapse fractures of the forearm in children, complete circular consolidation of the original fracture has to be guaranteed. It remains unclear whether this is best achieved by special plaster techniques or by converting a greenstick fracture into a complete, unstable fracture.

Assessment of an implementation of a narrow band, neonatal otoacoustic emission screening method.

OBJECTIVE: To validate a narrow band method for the detection of transient evoked otoacoustic emissions (TEOAEs) in neonates. DESIGN: A method for the assessment of TEOAEs was implemented. The method was based upon assessing the estimated signal to noise ratio of a narrow band of TEOAEs from 1.6 kHz to 2.8 kHz. This method was tested against a commercially available broad band TEOAE test, the Otodynamics ILO88 in quickscreen mode. Trials were performed on 162 ears from a group of normal neonates aged from 3 to 6 wk. RESULTS: The sensitivity of the method was 100% and its specificity was 92%, against the ILO88 test when looking for the absence of TEOAEs. When the ILO88 test was limited in time so that the number of undetected TEOAEs from both tests were similar, the narrow band test took 40% less time than the ILO88 test. CONCLUSIONS: The narrow band TEOAE detection method, as implemented here, did not miss any neonate ears without TEOAEs. However, the narrow band test did not detect TEOAEs in 8% of the group in which TEOAEs were detected by the ILO88. With a two-stage screening test and a 0.6% incidence of sensorineural hearing loss, it is predicted that 1.9% of neonates with TEOAEs would be misclassified, by the narrow band test. (It is predicted that the ILO88 quickscreen test would misclassify 1.1% under the same conditions.) The test is faster and easier to perform than the broad band ILO88 test.

The objective assessment of transient evoked otoacoustic emissions in neonates.

OBJECTIVE: To develop a simple objective method for assessing the presence or absence of a TEOAE in recordings from neonatal ears. DESIGN: Several simple, objective methods of transient evoked otoacoustic emissions (TEOAE) assessment were tested against a verified subjective assessment method, using 200 neonatal TEOAEs recorded under clinical conditions. RESULTS: Total TEOAE level did not correlate well with the subjective assessment. Total estimated signal to noise ratio correlated better with the subjective assessment. Filtering the response between 1.5 and 2.8 kHz and windowing it between 4 and 10 msec did not degrade the correlation. In a normal population of neonates the filterd, windowed estimated signal to noise ratio method miscategorized only 4.0% of the responses as having no TEOAEs. None of the population without TEOAEs were categorized as having TEOAEs by the objective test. CONCLUSIONS: An objective TEOAE assessment (based on the signal to noise ratio of a time limited midband section of the TEOAE) performed well at detecting the presence or absence of a TEOAE.

Quantitative assessment of methods for the detection of otoacoustic emissions.

OBJECTIVE: To compare the performance of various types of signal detector commonly used to detect otoacoustic emissions (OAEs). METHOD: The signal detectors were tested with signals in various types of noise, including noise with various amplitude distributions. Commonly utilized transient evoked OAE and distortion product OAE detectors were analyzed. RESULTS: In both cases it was found that detector performance increased as the measurement bandwidth was increased. Noises of different amplitude distributions were found to affect the performance of both types of detectors. The effect of different amplitude distributions decreased as the measurement bandwidth was increased. For a given power per spectral line, the transient evoked OAE detector could detect signals 6 dB farther into gaussian noise than the distortion product OAE detector. CONCLUSIONS: An analysis of the results of practical methods of OAE measurement show that distortion product OAEs can be measured with higher power per spectral line than transient evoked OAEs. This means that in adult humans distortion product OAEs can be reliably detected in about 1/14th of the time of transient evoked OAEs. In neonatal humans distortion product OAEs can be reliably detected in about two-thirds of the time of transient evoked OAEs.

Analyses of Mössbauer mechanical measurements indicate that the cochlea is mechanically active.

Using the results of Mössbauer measurements, mechanical activity in the cochlea was tested for by comparing the measured basilar membrane (BM) transverse velocity amplitude with that calculated for a lossless mechanically passive system, derived from the measured BM velocity phase. If the cochlea is considered to be a lossless mechanically passive system, then the transverse velocity amplitude can be calculated from the group velocity and the relative variation of stiffness along the BM. The group velocity can be derived from the Mössbauer phase measurements, and the relative variation of stiffness along the BM can be derived from the frequency map of the cochlea. Making some general assumptions, the actual transverse velocity amplitudes are then compared from the Mössbauer amplitude data with those derived from the Mössbauer phase data, to determine if there is a significant transverse velocity gain. This operation was performed on several sets of Mössbauer data. From Mössbauer data showing sharp tuning, differences were found of up to 40 dB between the actual transverse velocity amplitude and the calculated lossless passive transverse velocity amplitude derived from the phase data. Examination of the assumptions made during the calculation of the lossless passive transverse velocity amplitude showed that none could account for a 40-dB transverse velocity gain. Thus, it is concluded that this transverse velocity gain can only be accounted for by the contribution to the amplitude of the transverse BM velocity by mechanically active elements along the cochlear duct. From Mössbauer data showing much less sharp tuning, it was found that the actual transverse velocity amplitude was approximately equal to the calculated lossless passive transverse velocity amplitude, basal to the characteristic place. This result is attributed to the disabling of the mechanically active elements along the cochlear duct. Apical to the characteristic place, the actual transverse velocity amplitude is shown to behave in a manner that suggests that the effective damping increases markedly in this region. This increase in effective damping is not necessarily due to an increase in viscous damping but could be due to any mechanism removing energy from the BM traveling wave. As an example, this paper discusses how this effective damping could be accounted for the transfer of energy to another mode of vibration at the characteristic place.