Notes: Although many antihistamines are now in clinical use, few studies directly compare their pharmacodynamic and sedative activities in humans in vivo. We designed a double-blind, placebo-controlled, crossover study to compare the inhibitory effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced flare-and-wheal response. Systemic sedative effects and impaired psychomotor activities by these drugs were also evaluated. Bepotastine (10 mg twice a day), cetirizine (10 mg once a day), fexofenadine (60 mg twice a day), and olopatadine (5 mg twice a day) or placebo was given in a double-blind manner to seven healthy volunteers before histamine challenge by iontophoresis. At 0, 1, 2, 4, 8, 12, and 24 h following the oral administration of these drugs, histamine iontophoresis-induced wheal-and-flare response was measured. Sedative effects by the drugs were also evaluated by a visual analogue scale for subjective sedation, and by word processor test for psychomotor activity. Each volunteer was tested with all of the drugs (including placebo), administered in a random order with a washout period of at least 1 week. Histamine iontophoresis induced marked wheal-and-flare response in all participants. Bepotastine, cetirizine, fexofenadine, and olopatadine yielded significant reduction of histamine-induced wheal-and-flare response compared to placebo (P 〈 0.01). Among the drugs, olopatadine and cetirizine suppressed most markedly and persistently histamine-induced wheal-and-flare response, while bepotastine and fexofenadine produced a significant, but less persistent suppression. Olopatadine, fexofenadine, and cetirizine showed a significant systemic sedative effect in this order with bepotastine showing the least sedative effect. Moreover, olopatadine affected psychomotor performance most markedly, which was followed by fexofenadine and cetirizine. These results indicate that bepotastine, cetirizine, fexofenadine, and olopatadine inhibit histamine-induced wheal-and-flare response of humans in vivo and induce a variable systemic sedative effect and impaired psychomotor activity. Although olopatadine and cetirizine showed the strongest and most persistent suppression of histamine-induced wheal-and-flare response, olopatadine showed a considerable sedative effect with impaired psychomotor performance.

Notes: Erythrokeratoderma (EK) variabilis is a heterogeneous group of diseases characterized by migratory erythematous patches and hyperkeratotic plaques. Mutations in connexin 31 have recently been found to underlie several cases of EK variabilis. We describe a Japanese girl with extensive lesions that appeared to be a form of EK variabilis, clinically resembling genodermatose en cocardes (Degos). Our patient had characteristic migratory rosette or target-like erythematous keratotic plaques with peripheral scaling in addition to relatively fixed keratotic plaques. Sequencing of the connexin 31 gene did not detect mutations. Skin biopsy showed parakeratotic hyperkeratosis with hypergranulosis. Immunohistochemically, suprabasal keratins, involucrin and profilaggrin were unequivocally expressed, while loricrin expression was greatly diminished and deiminated K1 was undetectable. Our results confirm aetiological heterogeneity in EK. The histological features suggest disruption of keratinocyte terminal differentiation at a very late stage.

Notes: Abstract: Cell envelopes (CEs) are insoluble, chemically and mechanically tough structures formed during terminal differentiation of keratinocytes, providing skin with a protective barrier against the environment. They are 15 to 20 nm thick structures beneath the plasma membrane and continuous with desmosomal attachment plaques. Sequential deposition of several proteins including involucrin and loricrin leads to a gradual increase in envelope thickness and rigidity. Cross-linking of demosomal components to other CE-proteins has been demonstrated and desmosomes in the cornified cells have been demonstrated and desmosomes in the cornified cells have been regarded as a part of CEs. Our previous immunoelectron microscopy studies showed that desmosomal areas of granular cells were loricrin-positive, but those in cornified cells were negative. We asked whether this is due to epitope masking and applied trypsin digestion of the electron microscopy sections to retrieve the possibly masked epitopes. Since this treatment made desmosomal structures obscure, one side of the sections was stained with anti-desmoglein antibody as an indicator of desmosomes. Trypsin was applied on the other side followed by immunolabeling with anti-loricrin antibody. Trypsin digestion indeed unmasked the loricrin epitopes in the desmoglein-positive desmosomal areas of CEs. It seems therefore that loricrin is first accumulated at the desmosomes before the CE-assembly and cross-linking of loricrin occurs at the desmosomal areas of CEs as well as at the non-desmosomal areas.

Notes: Using pig skin organ culture in vitro, we compared the effects of antipsoriatic and anti-metabolic agents on the beta-adrenergic response of epidermis. After a 24-h incubation with these chemicals, the beta-adrenergic response of epidermis was shown to be increased to various degrees. Among the chemicals, colchicine, actinomycin D, and puromycin had the most marked effect, and were followed by Ro 10–1670 and hydrocortisone, and then by anthralin, cycloheximide and N-5’(N-(3,4-dimethyloxycinnamoyl) anthranilic acid). Methotrexate and hydroxyurea apparently had no (or rather decreasing) effects on the beta-adrenergic response of epidermis. After the same treatment in vitro, thymidine incorporation of epidermal keratinocytes was compared. In the latter system, the inhibitory effects of puromycin, cycloheximide and actinomycin D were most marked, and were followed by those of colchicine and Ro ro-1670, and then hydrocortisone and anthralin. n-s' had no effect and hydroxyurea increased thymidine incorporation of keratinocytes. Our data indicate that most (but not all) anti-psoriatic agents do augment the beta-adrenergic response of epidermis, which might be associated with the clinical efficacy of these agents in psoriasis where a defective beta-adrenergic response is well documented. The augmentation effects of these chemicals, however, did not correlate with their inhibitory effects on keratinocyte proliferation, at least in the thymidine incorporation system in epidermal keratinocytes in vitro.

Notes: Incubation of unfixed skin slices in RPMI 1640 medium for 24—48 h resulted in two types of histological change in psoriatic-involved epidermis. The degenerative change was the major finding in 7 out of 11 psoriatic-involved epidermis, whereas the acantholytic change was observed in the remaining four cases. Neither degenerative nor acantholytic changes were observed in psoriatic-uninvolved epidermis (11 cases) or in normal human epidermis (5 cases). The acantholytic change was observed after only a 12-h incubation and was significantly (but not completely) inhibited by the addition of soybean trypsin inhibitor, which had no effect on the degenerative change of keratinocytes. The addition of hydrocortisone in the incubation medium had no effect on cither degenerative or acantholytic changes of keratinocytes. Our results indicate that a significant population of psoriatic-involved epidermis reveals acantholysis during organ culture in vitro, which might be, at least in part, induced by serine-type protease, the activity of which is known to be increased in the psoriatic-involved epidermis.

Notes: Three cases of a benign follicular tumour of infundibular origin are reported. The neoplasms were solitary, verrucous, slowly-growing papules or nodules on the face, which were diagnosed clinically as verruca vulgaris or seborrhoeic keratoses. Histologically, several epithelial lobules were seen, mainly above the level of the surface of the surrounding skin, with characteristic funnel-shaped invaginations. The tumours occasionally contained vellus hairs or were connected with sebaceous glands and/or hair follicles at their bases, indicating their follicular origin. The tumour masses consisted of peripherally arranged basaloid and inner squamoid cells. The latter cells contained more glycogen and appeared paler with haematoxylin and eosin (H&E), stains than the normal inter-follicular squamous cells. Neither clear cells nor squamous eddies were observed. Palisading of the basaloid cells was not a prominent feature. The name‘infundibular keratosis'is proposed for such tumours, which probably represent the prototype of infundibular tumours of the hair follicle.

Notes: A group of hereditary palmoplantar keratodermas due to heterozygous mutation in the loricrin gene has recently been identified. Of five reported pedigrees, four presented as mutilating keratoderma with ichthyosis (variant Vohwinkel syndrome), and one as progressive symmetric erythrokeratoderma. We report a new Japanese pedigree of loricrin keratoderma. A 14-year-old male and his 11-year-old female sibling had both been born as collodion babies and were initially diagnosed as having non-bullous congenital ichthyosiform erythroderma, but later developed palmoplantar keratoderma with pseudoainhum. Their father was similarly affected. Direct sequencing of genomic DNA revealed a G residue insertion at codon 230–231 of the loricrin gene. Antibody studies confirmed the presence of mutant loricrin in the retained nuclei. We conclude that loricrin gene mutation may present as congenital ichthyosiform erythroderma, and should be included in the differential diagnosis of collodion baby.

Notes: Psoriatic hyperproliferative epidermis is characterized by a regular elongation of rete ridges, accompanied by altered keratinization. Another notable finding is close positioning of the vasculature to the suprapapillary epidermis. These architectural/morphological changes are naturally described by a concept of epidermal remodelling based on decreased epidermal turnover time. The recently described positioning of stem cells to the tips of dermal papillae fits nicely with this concept.