Mechanisms of neutrophil damage to human alveolar extracellular matrix: the role of serine and metalloproteases.

Many syndromes of lung injury are associated with accumulation of neutrophils within the pulmonary parenchyma. These neutrophils have the capacity to produce lung injury by products including proteases and reactive oxygen species (ROS). We examined the ability of activated neutrophils to solubilize human alveolar extracellular matrix (ECM), and by use of scavengers and inhibitors, evaluated the role of ROS and proteases in this process. Supernatants of phorbol myristate acetate-activated neutrophils routinely solubilized 10.2% +/- 0.8% (n = 30) of collagen in human alveolar ECM, as measured by hydroxyproline release. Scavengers of ROS had no significant effect on ECM solubilization. Inhibitors of metalloproteases partially inhibited ECM solubilization (38.5% +/- 4.6% inhibition by ethylenediaminetetraacetic acid [n = 6], and 37.0% +/- 14.7% by 1,10-phenanthroline [n = 6]; p less than 0.05). Inhibitors of the neutrophil serine proteases, elastase and cathepsin G, markedly inhibited ECM solubilization (100.9% +/- 3.7% by alpha 1-protease inhibitor [alpha 1-PI] [n = 6] and 81.9% +/- 0.1% by soybean trypsin inhibitor [n = 6]; p less than 0.01). Since alpha 1-PI completely inhibited solubilization, metalloprotease activity appeared to be related to serine protease activity. This finding was confirmed by the observation that addition of a metalloenzyme activator, p-aminophenylmercuric acetate, in the presence of alpha 1-PI, restored solubilization to the same level as that inhibited by metal chelators. We conclude that human neutrophil metalloproteases and serine proteases directly solubilize human alveolar ECM. Furthermore, neutrophil serine proteases activate latent metalloproteases. However, ROS were not demonstrated to play a major role in ECM solubilization in our system.     

Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family

Hereditary hearing impairment affects about 1 in 1000 newborns. In most cases hearing loss is non-syndromic with no other clinical features, while in other families deafness is associated with specific clinical abnormalities. Analysis of large families with non-syndromic and syndromic deafness have been used to identify genes or gene locations that cause hearing impairment. The present report describes a large Norwegian family with autosomal dominant non-syndromic, progressive high tone hearing loss with linkage to 1q21-q23. A maximum LOD score of 7.65 (theta = 0.00) was obtained with the microsatellite marker D1S196. Analysis of recombinant individuals maps the deafness gene (DFNA7) to a 22 cM region between D1S104 and D1S466. The region contains several attractive candidate genes. This report supports the idea of extensive genetic heterogeneity in hereditary hearing impairment and represents the first localization of a deafness gene in a Norwegian family.      

Gross and cellular analysis of 6-mercaptopurine-induced cleft palate in hamster

The present study analyzes the morphological, histochemical, and ultrastructural aspects of the pathogenesis of 6-mercaptopurine (6MP)-induced cleft palate in hamster fetuses. Gross and light microscopic observations indicated that 6MP stunts the growth of vertical palatal shelves and thus induces cleft palate. Ultrastructural analysis showed that, in contrast to controls, 6MP-induced alterations were first seen in the mesenchymal cells 24 hr after drug administration. The initial alterations were characterized by swelling of the nuclear membrane. During the next 12 hr, lysosomes were seen first in the mesenchymal cells and then in the cells of the medial edge epithelium (MEE) of the developing palatal primordia. The appearance of lysosomes was temporally abnormal and was interpreted as a sublethal response to 6MP treatment. Subsequently, the nuclear alterations and the lysosomes diminished; and 48 hr after 6MP administration, they were absent from the palatal tissues. Ninety hours after 6MP administration, unlike the controls (in which the palatal shelves were already fused), changes were seen at the epithelial-mesenchymal interface in the developing cleft palatal shelves. These changes were characterized by breakdown of the basal lamina and epithelial-mesenchymal contacts. Eventually, at term, the MEE of the vertical shelf stratified. It was suggested that 6MP affected cytodifferentiation in the palatal tissues during the critical phase of early vertical shelf development and thereby induced cleft palate.     

Lubrication and surface chemical properties of ophthalmic solutions

Surface chemical and lubrication parameters such as contact angle, surface tension, and coefficient of friction, together with viscosity, were measured for commercial ophthalmic solutions. A sensitive friction-testing instrument was employed to measure the coefficient of friction between low-energy polymeric surfaces, e.g., polymethylmethacrylate (PMMA). The viscosity of ten commercial tear substitutes employed in the present study ranged from 2 to 25 cp. The results showed that there is no correlation between the coefficient of friction and viscosity, surface tension, or contact angle of these tear substitutes. The coefficient of friction of tear substitutes appears to depend upon the structure, conformation, and adsorption characteristics of polymer as well as surface characteristics of sliding surfaces. A systematic study was undertaken to evaluate the effect of speed and load on the coefficient of friction between different sliding surfaces, namely PMMA/nylon and PMMA/PMMA. The analysis of data established that our system was operating in the region of "boundary lubrication." In general, a PMMA/PMMA system exhibited a lower coefficient of friction as compared with the PMMA/nylon system.     

Correction to: Time and lexicographic preferences in the valuation of EQ-5D-Y with time trade-off methodology

The European Journal of Health Economics -     

Congenital Pseudarthrosis of Femur and Sciatic Nerve Palsy with Congenital Constriction Band Syndrome: Report of the First Case in Literature

Congenital constriction band syndrome has varied clinical presentations ranging from small, incomplete skin deep constriction band to in utero amputation. Pseudarthrosis of underlying bone most commonly tibia has been reported by many authors. We report the first case of congenital pseudarthrosis of the femur with congenital constriction band syndrome. Nine-day-old female presented with the constriction band in the left thigh with open pseudarthrosis of the femur. The left femur had gross recurvatum deformity and the posterior apex of the pseudarthrosis was exposed via skin ulceration. She had an ipsilateral paralytic clubfoot. She was treated with single-stage excision of constriction band and Z-plasty. Spontaneous union of the femur was achieved at 3 months. Procurvatum deformity of the femur improved gradually over 3 years. This happens to be the first and only reported case of congenital pseudarthrosis of the femur with sciatic nerve palsy due to congenital constriction band.     

Variability in cesarean delivery rates among individual labor and delivery nurses compared to physicians at three attribution time points

ObjectiveTo examine the variability in the cesarean delivery (CD) rates of individual labor and delivery nurses compared with physicians at three attribution time points.Data SourcesMedical record data from nine hospitals in Washington State from January 2016 through September 2018.Study DesignRetrospective, observational cohort design using an aggregated database of birth records.Data Collection/Extraction MethodsChart‐abstracted clinical data from a subset of nulliparous, term, singleton, vertex births attributed at admission, labor management, and delivery to nurses and physicians. Two classification methods were used to categorize nurse‐ and physician‐level CD rates at three attribution time points and the reliability of these methods compared.Principal FindingsThe sample included 12 556 births, 319 nurses, and 126 physicians. Overall, variation in nurse‐level CD rates did not differ significantly across the three attribution time points, and the extent of variation was similar to that observed in physicians. However, agreement between attribution time points varied between 35 percent and 65 percent when classifying individual nurses into the top and bottom deciles. The average reliability of nurse‐level CD rates was 32 percent at admission (IQR 22.0 percent to 38.7 percent), 32.6 percent at labor (IQR 23.1 percent to 40.9 percent), and 29.3 percent (IQR 20.9 percent to 35.8 percent) at delivery. The average reliability of physician‐level CD rates was higher: 54.2 percent (IQR 38.7 percent to 71.4 percent) at admission, 62.5 percent (IQR 49.0 percent to 79.6 percent) at labor management, and 66.1 percent (IQR 53.7 percent to 81.2 percent) at delivery.ConclusionFeedback on nurse‐level CD rates as part of routine clinical quality audits can provide insight into nurse performance in the context of other individual‐level and unit‐level information. To reliably distinguish individual nurse performance, larger sample sizes are needed.     

Human V5/MT+: comparison of functional and cytoarchitectonic data

To date, the delineation of the human visual “motion area” still relies on functional paradigms originally devised to identify monkey area MT. Using fMRI, we have identified putative human area V5/MT+ in normals by modelling the BOLD responses to alternating radially moving and stationary dot patterns. Functional activations were compared with cytoarchitectonic probability maps of its putative correlate area hOc5, which was calculated based upon data from histological sections of ten human post-mortem brains. Bilateral visual cortex activations were seen in the single subject dynamic versus stationary contrasts and in the group random-effects analysis. Comparison of group data with area hOc5 revealed that 19.0%/39.5% of the right/left functional activation was assigned to the right/left hOc5. Conversely, 83.2%/53.5% of the right/left hOc5 was functionally activated. Comparison of functional probability maps (fPM) with area hOc5 showed that 28.6%/18.1% of the fPM was assigned to hOc5. In turn, 84.9%/41.5% of the area hOc5 was covered by the respective fPM. Thus, random-effects data and fPMs yielded similar results. The present study shows for the first time the correspondence between the functionally defined human V5/MT+ and the post-mortem cytoarchitectonic area hOc5.