Kazunori Kishiyama

Modulation of pig epidermal adenylate-cyclase responses by protein-synthesis inhibitors: Its relation to glucocorticoid and colchicine effects

SummaryThe effects of protein-synthesis inhibitors (actinomycin D, puromycin, and cycloheximide) on epidermal adenylate-cyclase responses were investigated. When pig skin (epidermis) was incubated in RPMI-1640 medium, the β-adrenergic adenylatecyclase response (epinephrine-induced cyclic-AMP accumulations) decreased, whereas the adenosine and histamine responses increased after long-term (up to 48 h) incubation. The addition of actinomycin D or puromycin to the incubation medium resulted in a marked increase in epinephrine-induced cyclic-AMP accumulations and a decrease in adenosine- and histamine-induced cyclic-AMP accumulations. Cycloheximide had a weak effect on the epinephrine response, and had apparently stronger effects on the adenosine and histamine responses than actinomycin D or puromycin. Histologically, various degenerative changes of keratinocytes (with or without acantholytic changes) were observed after long-term incubation with these protein-synthesis inhibitors. Both low- and high-Kmcyclic-AMP phosphodiesterase activities were moderately decreased by the protein-synthesis inhibitors. However, augmentation effects on the β-adrenergic response were also observed in the presence of the cyclic-AMP phosphodiesterase inhibitor, theophylline. We have described previously similar augmentation effects on the β-adrenergic response caused by glucocorticoids and colchicine. Comparison of the effects of these chemicals with those of protein-synthesis inhibitors revealed that the most marked effects on the β-adrenergic response were produced by actinomycin D, puromycin and colchicine; glucocorticoid had a moderate effect (hydrocortisone), while cycloheximide had only a weak effect. Furthermore, the simultaneous addition of actinomycin D (or puromycin) and colchicine (or hydrocortisone) at their optimal concentrations produced a more marked (additive or synergistic) increase in the β-adrenergic response than the addition of each chemical alone. The simutaneous addition of actinomycin D and puromycin at their optimal concentrations resulted in neither an additive nor a synergistic effect. Our results indicate that, as well as being affected by glucocorticoids and colchicine, epidermal adenylatecyclase responses are affected by various protein-synthesis inhibitors, the mechanism of which seems to be independent of that of glucocorticoids or colchicine.

CLINICAL OBSERVATIONS ON A CASE OF IMMUNODEFICIENCY AND THYMOMA (GOOD'S SYNDROME) ASSOCIATED WITH CHRONIC MUCOCUTANEOUS CANDIDIASIS

A 50 year‐old woman with immunodeficiency and thymoma (Goods syndrome) associated with chronic muco‐cutaneous candidiasis (CMCC) was observed. Immunological treatment with transfer factor (TF), supplements of γ‐globulin and anti‐candidal agents was maintained for six years. Because of the association of pure red cell aplasia in the clinical course, systemic steroid therapy was added to the treatment. Although the patient gradually improved, further immunological therapy was considered to be necessary for the tongue lesions due to candidiasis and the agammaglobulinemia.

Case of generalized eosinophilic pustular folliculitis induced by allopurinol.

Dear Editor, Eosinophilic pustular folliculitis (EPF) is a chronic inflammatory skin disease characterized by circularly arranged, sterile, recurrent follicular pustularized papules. While EPF is classified into classic, immunosuppression-associated and infancy-associated subtypes, the pathomechanism has not been fully elucidated. The hematological or immunosuppressive disorders are related with exacerbation of EPF, suggesting the involvement of immunological imbalance. Drug-induced EPF is relatively rare, and herein we report a case of generalized EPF induced by allopurinol. A 74-year-old Japanese woman presented with itchy, bright red, disseminated follicular papules on her face, back and four extremities without any mucosal lesion (Fig. 1a–d). The facial follicular papules were circularly arranged and formed erythematous plaques (Fig. 1a). Allopurinol administration had been initiated against her hyperuricemia for a month. Except hypereosinophilia, blood test did not show any abnormality in cell counts (8540/lL white blood cells, 1530/lL lymphocytes, 1550/ lL eosinophils), biochemistry, immunoglobulin E (25.4 IU/mL) or viral antibodies including anti-HIV antibody. Computed tomography did not detect any visceral involvement. Histopathology showed destroyed hair follicles with perifollicular dense infiltration of inflammatory cells mainly composed of lymphocytes and eosinophils (Fig. 1e–g). After discontinuation of allopurinol, oral prednisolone (PSL; 1 mg/kg/day) for 10 days was not sufficiently effective, but addition of indomethacin (50 mg/day) led to immediate improvement of eosinophilia and the pruritic eruptions in a few days. The dose of PSL and indomethacin was gradually tapered and terminated in 10 weeks without any recurrence of the symptoms. The patch test to allopurinol was negative, while drug-induced lymphocyte stimulation test for allopurinol was positive (stimulation index, 199%). These findings and the clinical course led to the diagnosis of EPF induced by allopurinol. To date, only six cases of EPF induced by medications, such as minocycline, indeloxazine hydrochloride and carbamazepine, have been reported. This is the seventh case of drug-induced EPF. Compared with classical EPF, the drug-induced EPF frequently shows generalized and disseminated lesions, which are usually controlled by discontinuation of the causative drugs and oral corticosteroid. Recent study suggests that eotaxin-3-expression induced by prostaglandin D2 in sebocytes is involved in the pathomechanism of EPF, and this finding can explain the effectiveness of indomethacin against EPF. In our case, combined administration of PSL and indomethacin was effective. The drugs eliciting EPF seem to overlap with those eliciting drug-induced hypersensitivity syndromes, in which the period between drug intake and the onset of eruption is generally longer than the other type of drug eruption. In drug-induced

Squamous cell carcinoma in a chronic myelogenous leukemia patient treated with imatinib mesylate

Dear Editor, Imatinib mesylate is a multi-tyrosine kinase inhibitor, especially targeted at chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors, in which the bcr-abl fusion protein, c-Kit receptor and platelet-derived growth factor receptor play a critical tumorigenic role. Here, we report a case of paradoxical squamous cell carcinoma (SCC) during the treatment of imatinib mesylate for CML. A 70-year-old Japanese man had been administrated imatinib mesylate (300 mg daily) against his CML for 6 years. While his CML was well controlled, a small nodule emerged and rapidly developed into a 1-cm, ulcerated, reddish nodule with an erythematous halo on his back within 1 month (Fig. 1a). Histopathology showed an asymmetrical, cup-shaped tumor composed of atypical keratinocytes and filled with keratinized material, somehow simulating keratoacanthoma (KA) (Fig. 1b). The nests of atypical keratinocytes with hyperchromatic nuclei and prominent nucleoli showed highly differentiated features but irregularly invaded deep into the reticular dermis with multiple mitoses (Fig. 1c). No swollen lymph node or visceral involvements were detected by computed tomography. Immunohistochemistry disclosed that these tumor nests in the invading front were strongly positive for Ki-67, podoplanin (PDPN) and phospho-signal transducer and activator of transcription (p-STAT3) (Fig. 1d–f). The clinical and histopathological findings led to the diagnosis of SCC simulating features of KA. Additional resection with 2-cm margin from the postoperative scar was performed, and so far no recurrence or distant metastasis has been detected. Skin tumors also may be sensitive to imatinib, and regression of SCC during the treatment of CML with imatinib was reported. On the other hand, a secondary skin tumor during

Erythema multiforme‐type drug eruption with prominent keratinocyte necrosis induced by long‐term administration of telmisartan

(Fig. 1a). Lesional biopsy revealed atypical keratinocytes in the basal layer of the epidermis, and solar elastosis in the dermis indicative of solar keratosis. The arsenic level in the patient’s hair was normal. In subsequent years, multiple solar keratotic lesions and squamous cell carcinoma (SCC) developed on the extremities and abdomen (Fig. 1b–f). All lesions were excised but, after six of nine excision procedures, postoperative wounds were infected with methicillin-resistant Staphylococcus aureus, with resultant cellulitis. Lymphocyte stimulation tests with phytohemagglutinin or concanavalin A revealed the absence of systemic immunosuppression. Ultimately, 15 solar keratotic lesions and 10 SCC lesions were detected, on both sunexposed and non-exposed areas, as shown in Figure 1(b). In our patient, multiple skin cancers had developed after long-term PUVA therapy, which is known to raise, slightly, the risk of malignancy. The incidence of skin cancer increases when the cumulative dose of ultraviolet (UV)-A exceeds 1000 J/ cm or after more than 400 treatments. However, Asian patients with more than 20 malignancies after PUVA therapy are rare. Ataxia telangiectasia-mutated protein (ATM) is activated by UV-A and ataxia telangiectasiaand Rad3-related protein kinase (ATR) is involved at the early stage of UV-mediated carcinogenesis. We stained specimens with antibodies against products of kinases whose expression is associated with DNA damage. One antibody was directed against phosphorylated ATM (Abcam, Cambridge, UK) and one was directed against phospho-histone H2A.X (Ser139) (Merck Millipore, Billerica, MA, USA), which is involved in pathways downstream of both ATM and ATR. While solar keratotic lesions on the back and on the right ankle were immunostained with these antibodies (Fig. 1g–j), apparently normal epidermis adjacent to solar keratotic lesions was immunonegative. Positive immunostaining with the first antibody might have been due to activation of the ATM signaling pathway in response to dsDNA breakage during carcinogenesis. Our results suggest that DNA damage was not ubiquitous in epidermal cells and that elimination of recent DNA damage was limited to local areas of epidermis, for example, epidermal stem cells. Wound infections recurred after surgery. Thus, probably, local immunosuppressive conditions existed in our patient’s skin. However, the involvement of photoaging in antimicrobialbarrier disruption remains to be clarified. Stress-induced senescence due to UV light yields cells with a senescenceassociated secretory phenotype (SASP) that secrete interleukin (IL)-6, IL-8 and matrix metalloproteinase (MMP). MMP may inactivate certain antimicrobial proteins. Such factors might have mediated the recurrent infections after surgery and the development of multiple malignancies.

Immunocytochemical studies on inflammatory infiltrates in psoriasis.

Deposits of immunoglobulins (Igs) and complement components can be demonstrated in the stratum corneum (SC) of psoriatic lesions by immunofluorescent (IF) technique. In this paper, the underlying inflammation in the lesional dermis, which may affect the immune reactions in the SC, was investigated by immunocytochemical and IF techniques.