Atopic Dermatitis: Recent Therapeutic Advances

New treatments were recently proposed for the management of severe atopic dermatitis (AD). They all act on some component of the immune reaction. Oral cyclosporine reduces the number of CD4+ cells, the secretion of interleukins, and the function of Langerhans cells. Although the action of oral cyclosporine at moderately high dosages is regular and rapid, the risk of serious side effects and the reappearance of progressive disease after stopping treatment limits the use of this drug in AD. Thymic hormone extracts in patients with severe AD affect the deficit of cellular immunity. gamma-Interferon inhibits IgE synthesis induced by interleukin-4, increases expression of Fc gamma receptors, and increases superoxide production by circulating monocytes. More recently, two other treatments were published: complexes of allergen and specific antibodies to Dermatophagoides pteronyssinus, and interleukin-2. All of these modalities have only a transitory effect, but they can help to modify a flare of severe AD.     

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth

Type XIX collagen is a minor collagen that localizes to basement membrane zones, together with types IV, XV, and XVIII collagens. Because several NC1 COOH-terminal domains of other chains from basement membrane collagens were reported to exhibit antitumor activity, we decided to study the effects of the NC1(XIX) collagen domain on tumor progression using an experimental in vivo model of mouse melanoma. We observed a 70% reduction in tumor volume in NC1(XIX)-treated mice compared with the corresponding controls. Histologic examination of the tumors showed a strong decrease in tumor vascularization in treated mice. In vitro, NC1(XIX) inhibited the migrating capacity of tumor cells and their capacity to invade Matrigel. It also inhibited the capacity of human microvascular endothelial cells to form pseudotubes in Matrigel. This effect was accompanied by a strong inhibition of membrane type-1 matrix metalloproteinase (matrix metalloproteinase-14) and vascular endothelial growth factor expression. Collectively, our data indicate that the NC1 domain of type XIX collagen exerts antitumor activity. This effect is mediated by a strong inhibition of the invasive capacities of tumor cells and antiangiogenic effects. NC1(XIX) should now be considered as a new member of the basement membrane collagen-derived matrikine family with antitumor and antiangiogenic activity.     

Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease

Progressive photoreceptor degeneration resulting from genetic and other factors is a leading and largely untreatable cause of blindness worldwide. The object of this study was to find a cell type that is effective in slowing the progress of such degeneration in an animal model of human retinal disease, is safe, and could be generated in sufficient numbers for clinical application. We have compared efficacy of four human-derived cell types in preserving photoreceptor integrity and visual functions after injection into the subretinal space of the Royal College of Surgeons rat early in the progress of degeneration. Umbilical tissue-derived cells, placenta-derived cells, and mesenchymal stem cells were studied; dermal fibroblasts served as cell controls. At various ages up to 100 days, electroretinogram responses, spatial acuity, and luminance threshold were measured. Both umbilical-derived and mesenchymal cells significantly reduced the degree of functional deterioration in each test. The effect of placental cells was not much better than controls. Umbilical tissue-derived cells gave large areas of photoreceptor rescue; mesenchymal stem cells gave only localized rescue. Fibroblasts gave sham levels of rescue. Donor cells were confined to the subretinal space. There was no evidence of cell differentiation into neurons, of tumor formation or other untoward pathology. Since the umbilical tissue-derived cells demonstrated the best photoreceptor rescue and, unlike mesenchymal stem cells, were capable of sustained population doublings without karyotypic changes, it is proposed that they may provide utility as a cell source for the treatment of retinal degenerative diseases such as retinitis pigmentosa.     

Normo or hypobaric hypoxic tests: propositions for the determination of the individual susceptibility to altitude illnesses

Assessment of individual susceptibility to altitude illnesses and more particularly to acute mountain sickness (AMS) by means of tests performed in normobaric hypoxia (NH) or in hypobaric hypoxia (HH) is still debated. Eighteen subjects were submitted to HH and NH tests (PIO₂=120 hPa, 30 min) before an expedition. Maximal and mean acute mountain sickness scores (AMSmax and mean) were determined using the self-report Lake Louise questionnaire scored daily. Cardio-ventilatory (f, V_T, PetO₂ and PetCO₂, HR and finger pulse oxymetry SpO₂) were measured at times 5 and 30 min of the tests. Arterial (PaO₂, PaCO₂, pH, SaO₂) and capillary haemoglobin (Hb) measurements were performed at times 30 min. Hypoxic ventilatory (HVR) and cardiac (HCR) responses, peripheral O₂ blood content (CpO₂) were calculated. A significant time effect is found for ΔSpO₂ (P = 0.04). Lower PaCO₂ (P = 0.005), SaO₂ (P = 0.07) and higher pH (P = 0.02) are observed in HH compared to NH. AMSmax varied from 3 to12 and AMSmean between 0.6 and 3.5. In NH at 30 min, AMSmax is related to PetO₂ (R = 0.61, P = 0.03), CpO₂ (R = −0.53, P = 0.02) and in HH to CpO₂ (R = −0.57, P = 0.01). In NH, AMSmean is related to Δf (R = 0.46, P = 0.05), HCR (R = 0.49, P = 0.04), CpO₂ (R = −0.51, P = 0.03) and, in HH at 30 min, to V_T (R = 0.69, P = 0.01) and a tendency for CpO₂ (R = −0.43, P = 0.07). We conclude that HH and NH tests are physiologically different and they must last 30 min. CpO₂ is an important variable to predict AMS. For practical considerations, NH test is proposed to quantify AMS individual susceptibility using the formulas: AMSmax = 9.47 + 0.104PetO₂(hPa)–0.68CpO₂ (%), (R = 0.77, P = 0.001); and AMSmean = 3.91 + 0.059Δf + 0.438HCR–0.135CpO₂ (R = 0.71, P = 0.017).     

The use of physical hydrogels of chitosan for skin regeneration following third-degree burns

Skin repair is an important field of the tissue engineering, especially in the case of extended third-degree burns, where the current treatments are still insufficient in promoting satisfying skin regeneration. Bio-inspired bi-layered physical hydrogels only constituted of chitosan and water were processed and applied to the treatment of full-thickness burn injuries. The aim of the study was at assessing whether this material was totally accepted by the host organism and allowed in vivo skin reconstruction of limited area third-degree burns. A first layer constituted of a rigid protective gel ensured good mechanical properties and gas exchanges. A second soft and flexible layer allowed the material to follow the geometry of the wound and ensured a good superficial contact. To compare, highly viscous solutions of chitosan were also considered. Veterinary experiments were performed on pig's skins and biopsies at days 9, 17, 22, 100 and 293, were analysed by histology and immuno-histochemistry. Only one chitosan material was used for each time. All the results showed that chitosan materials were well tolerated and promoted a good tissue regeneration. They induced inflammatory cells migration and angiogenetic activity favouring a high vascularisation of the neo-tissue. At day 22, type I and IV collagens were synthesised under the granulation tissue and the formation of the dermal-epidermal junction was observed. After 100 days, the new tissue was quite similar to a native skin, especially by its aesthetic aspect and its great flexibility.     

The safety and efficacy of an injectable bone substitute in dental sockets demonstrated in a human clinical trial

This study is the first report of a clinical evaluation of an injectable bone substitute (IBS). This IBS was prepared by suspending biphasic calcium phosphate (BCP) particles with diameters ranging between 80 and 200 microm in a water-soluble cellulose polymer carrier phase. It was used for filling bone defects after tooth extractions in 11 patients. The first objective of the study was to investigate the safety of the filler material. The second objective was to investigate the efficacy of the material for filling human tooth sockets and preventing alveolar bone loss. Radiographic density measurements of the surgical sites gradually increased to those of the surrounding host bone. Three years after surgery, small biopsies of the implanted areas were harvested and analyzed by using micro-computed tomography, non-decalcified histology and histomorphometry. The BCP granules appeared in direct contact with mineralized bone tissue, thereby supporting bone growth. A gradual substitution of the filler by bone tissue was observed thus preserving the height of the alveolar bone crest.     

Anti-alpha-actinin antibodies: a new marker of lupus nephritis

The exact role of anti-ds (double stranded) DNA antibodies in the pathogenesis of kidney injury in lupus nephritis remains a focus of continuing investigation. One theory explaining the pathogenicity of anti-dsDNA antibodies in lupus nephritis is direct cross-reactivity with renal antigens. Several years ago, alpha-actinin was identified as a major cross-reactive target for pathogenic anti-dsDNA antibodies in murine SLE. Indeed, binding of a nephritogenic murine anti-dsDNA antibody was stronger to the alpha-actinin derived from a lupus prone mouse mesangial cell line as compared to alpha-actinin in a non-autoimmune mouse mesangial cell line. Furthermore, we recently showed that immunization of non-autoimmune mice with alpha-actinin induces anti-chromatin antibodies, glomerular IgG deposition and proteinuria. In humans, anti-alpha-actinin autoantibodies (Ab) were associated with anti-dsDNA Ab in SLE. In those patients, anti-alpha-actinin rather than anti-dsDNA Ab were significantly associated with glomerulonephritis and disease activity. The anti-alpha-actinin reactivity was associated with high avidity anti-dsDNA Ab. Moreover, the anti-alpha-actinin response was related to the actin-binding site of alpha-actinin. Taken together, these studies indicate that detection of anti-alpha-actinin Ab, in association with anti-dsDNA Ab, may constitute a new marker in lupus nephritis.     

MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient mice

Peroxisome proliferator-activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they are also involved in inflammatory processes. Three PPAR isotypes have been identified: alpha, beta (or delta) and gamma. The development of PPAR transgenic mice offers a promising tool for prospective therapeutic studies. This study used MRI to assess the role of PPARalpha and PPARbeta in the development of stroke. Permanent middle cerebral artery occlusion induced focal ischemia in wild-type, PPARalpha-null mice and PPARbeta-null mice. T(2)-weighted MRI was performed with a 7 T MRI scan on day 0, 1, 3, 7 and 14 to monitor lesion growth in the various genotypes. General Linear Model statistical analysis found a significant difference in lesion volume between wild-type and PPAR-null mice for both alpha and beta isotypes. These data validate high-resolution MRI for monitoring cerebral ischemic lesions, and confirm the neuroprotective role of PPARalpha and PPARbeta in the brain.     

Determinants of excessive daytime sleepiness in a French community-dwelling elderly population

Epidemiological studies have suggested that excessive daytime sleepiness (EDS) is associated with depression, but the association between EDS and other psychiatric disorders has not been investigated. The aim of this study was to investigate the association of EDS with a wide range of psychiatric disorders and health-related conditions in the elderly population. Two thousand two hundred and fifty-nine non-institutionalised persons aged 65-years and over randomly recruited from the Montpellier district, France, completed the Epworth Sleepiness Scale (ESS). Psychiatric status was assessed by the Mini International Neuropsychiatric Interview and demographic and other health information was obtained. This cross-sectional study was conducted from March 1999 to February 2001. Men were significantly more likely to report EDS (ESS score>10) compared with women (12.0% versus 6.0% respectively). EDS was significantly associated in univariate analyses with chronic diseases, early awakening, snoring, severity of depression and lifetime prevalence of manic and hypomanic episodes. A multivariate analysis revealed that the lifetime prevalence of manic and hypomanic episodes, snoring and gender (male) were independently associated with EDS. No independent association with other psychiatric disorders was found.