Increased epidermal thickness and abnormal epidermal differentiation in keloid scars

Background: The pathogenesis underlying keloid formation is still poorly understood. Research has focused mostly on dermal abnormalities, while the epidermis has not yet been studied. Objectives: To identify differences within the epidermis of mature keloid scars compared with normal skin and mature normotrophic and hypertrophic scars. Methods: Rete ridge formation and epidermal thickness were evaluated in tissue sections. Epidermal proliferation was assessed using immunohistochemistry (Ki67, keratins 6, 16 and 17) and with an in vitro proliferation assay. Epidermal differentiation was evaluated using immunohistochemistry (keratin 10, involucrin, loricrin, filaggrin, SPRR2, SKALP), reverse-transcriptase polymerase chain reaction (involucrin) and transmission electron microscopy (stratum corneum). Results: All scars showed flattening of the epidermis. A trend of increasing epidermal thickness correlating to increasing scar abnormality was observed when comparing normal skin, normotrophic scars, hypertrophic scars and keloids. No difference in epidermal proliferation was observed. Only the early differentiation marker involucrin showed abnormal expression in scars. Involucrin was restricted to the granular layer in healthy skin, but showed panepidermal expression in keloids. Normotrophic scars expressed involucrin in the granular and upper spinous layers, while hypertrophic scars resembled normotrophic scars or keloids. Abnormal differentiation was associated with ultrastructural disorganization of the stratum corneum in keloids compared with normal skin. Conclusions: Keloids showed increased epidermal thickness compared with normal skin and normotrophic and hypertrophic scars. This was not due to hyperproliferation, but possibly caused by abnormal early terminal differentiation, which affects stratum corneum formation. Our findings indicate that the epidermis is associated with keloid pathogenesis and identify involucrin as a potential diagnostic marker for abnormal scarring

A more active lifestyle in persons with a recent spinal cord injury benefits physical fitness and health

Study design:A prospective cohort study. Objectives:To study the longitudinal relationship between objectively measured everyday physical activity level, and physical fitness and lipid profile in persons with a recent spinal cord injury (SCI).Setting:A rehabilitation centre in the Netherlands and the participant's home environment. Methods:Data of 30 persons with a recent SCI were collected at the start of active rehabilitation, 3 months later, at discharge from inpatient rehabilitation, and 1 year after discharge. Physical activity level (duration of dynamic activities as % of 24 h) was measured with an accelerometry-based activity monitor. Regarding physical fitness, peak oxygen uptake (VO2peak) and peak power output (POpeak) were determined with a maximal wheelchair exercise test, and upper extremity muscle strength was measured with a handheld dynamometer. Fasting blood samples were taken to determine the lipid profile. Results:An increase in physical activity level was significantly related to an increase in VO2peak and POpeak, and an increase in physical activity level favourably affected the lipid profile. A nonsignificant relation was found with muscle strength. Conclusion:Everyday physical activity seems to have an important role in the fitness and health of persons with a recent SCI. An increase in physical activity level was associated with an increase in physical fitness and with a lower risk of cardiovascular disease.Spinal Cord advance online publication, 6 December 2011; doi:10.1038/sc.2011.152

Continuous heating of a giant X-ray flare on Algol

Giant flares can release large amounts of energy within a few days: X-ray emission alone can be up to ten percent of the star's bolometric luminosity. These flares exceed the luminosities of the largest solar flares by many orders of magnitude, which suggests that the underlying physical mechanisms supplying the energy are different from those on the Sun. Magnetic coupling between the components in a binary system or between a young star and an accretion disk has been proposed as a prerequisite for giant flares. Here we report X-ray observations of a giant flare on Algol B, a giant star in an eclipsing binary system. We observed a total X-ray eclipse of the flare, which demonstrates that the plasma was confined to Algol B, and reached a maximum height of 0.6 stellar radii above its surface. The flare occurred around the south pole of Algol B, and energy must have been released continously throughout its life. We conclude that a specific extrastellar environment is not required for the presence of a flare, and that the processes at work are therefore similar to those on the Sun.Comment: Nature, Sept. 2 199

Can AMP induce sputum eosinophils, even in subjects with complete asthma remission?

<p>Abstract</p> <p>Background</p> <p>The definition of <b>"</b>clinical asthma remission" is based on absence of symptoms and use of medication. However, in the majority of these subjects airway inflammation is still present when measured. In the present study we investigated whether "complete asthma remission", additionally defined by the absence of bronchial hyperresponsiveness (BHR) and the presence of a normal lung function, is associated with the absence of airway inflammation.</p> <p>Methods</p> <p>Patients with a former diagnosis of asthma and a positive histamine provocation test were re-examined to identify subjects with complete asthma remission (no asthma symptoms or medication, PC₂₀histamine > 32 mg/ml, FEV₁> 90% predicted). Patients with PC₂₀histamine ≤ 32 mg/ml were defined as current asthmatics and were divided in two groups, i.e. asthmatics with and without BHR to adenosine 5'monophoshate (AMP). Sputum induction was performed 1 week before and 1 hour after AMP provocation. Sputum induction and AMP provocation were previously shown to be sensitive markers of airway inflammation.</p> <p>Results</p> <p>Seven patients met criteria for complete asthma remission. Twenty-three were current asthmatics, including twelve without hyperresponsiveness to AMP. Subjects with complete asthma remission showed no AMP-induced sputum eosinophilia (median (range) 0.2 (0 - 4.6)% at baseline and 0.2 (0 - 2.6)% after AMP). After AMP, current asthmatics had a significant increase in sputum eosinophils (0.5 (0 - 26.0)% at baseline and 2.6 (0 - 32.0) % after AMP), as had the subgroup of current asthmatics without hyperresponsiveness to AMP (0.2 (0 - 1.8)% at baseline and 1.3 (0 - 6.3)% after AMP).</p> <p>Conclusions</p> <p>Subjects with complete asthma remission, in contrast to subjects with current asthma, do not respond with eosinophilic inflammation in sputum after AMP provocations. These data lend support to the usefulness of the definition of complete asthma remission.</p

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility