Incidence of retinal detachment associated with atopic dermatitis in Japan: review of cases from 1992 to 2011.

PURPOSE: The present study aims to investigate the number and characteristics of retinal detachment with atopic dermatitis (AD) in these 20 years, and the number of the first visit AD outpatients in almost the same period. METHODS: A retrospective review of 101 consecutive surgically treated retinal detachments with AD patients from 1992 to 2011 was conducted. Retinal detachments were divided into two groups: eyes operated on from 1992 to 2001 (former AD group, n=63) and eyes operated on from 2002 to 2011 (recent AD group, n=38). We also reviewed the records of the first visit AD outpatients from 1993 to 2011 except 1998. RESULTS: The percentage of bilateral detachment was significantly higher in the former AD group (14/63) than that in the recent AD group (0/38) (P=0.0002). In addition, patients in the recent AD group were significantly older than those in the former AD group (P=0.0084). The annual cases with non-AD retinal detachment remained invariant for 20 years. The ratio of the retinal detachment with AD for the total retinal detachment was significantly lower in the recent (38/847) AD group than that in the former (63/796) AD group (P=0.0038). The number of the first visit AD outpatients linearly decreased in these 19 years (153 cases in 1993 and 65 cases in 2011). CONCLUSION: Our study indicates an apparent decrease in retinal detachment with AD in the recent 10 years, and might suggest the importance of dermatitis control for prevention of retinal detachment with AD.

Immunological parameters in prophylactic sublingual immunotherapy in asymptomatic subjects sensitized to Japanese cedar pollen.

BACKGROUND: This study aims to examine the immunological parameters, focusing IL-10 productivity, in prophylactic sublingual immunotherapy (SLIT) in asymptomatic subjects sensitized to Japanese cedar pollen (JCP). METHODS: This study was conducted as part of a randomized, double-blind, placebo-controlled, multiple center trial, and was performed for two consecutive pollen seasons in 2012 and 2013. The present results were based only on our institution. We recruited 29 participants with specific IgE against JCP of at class 2 and higher levels without history of the pollinosis symptoms at the time of JCP scattering. The SLIT group received standardized JCP extract for five months over the pollen season. We observed and judged development of the symptoms in the pollen season. The percentage of IL-10 producing CD4(+) T (Trl) cells, B cells and monocytes were analyzed by flow cytometry. JCP specific IgE and total IgE were also measured. RESULTS: The ratio of development of cedar pollinosis was significantly lower in the SLIT group compared to the placebo group in 2013. In 2012, the percentage of circulating Tr1 cells and IL-10 producing monocytes significantly increased in the SLIT group. In 2013, the percentage of circulating Tr1 cells and IL-10 producing B cells increased significantly in the SLIT group. The percentage of circulating IL-10 producing monocytes significantly decreased in the placebo group. CONCLUSIONS: Prophylactic SLIT is effective for prevention of the development of pollinosis. Induction of IL-10 producing T cells, B cells and monocytes is an important mechanism of SLIT for prevention of pollinosis in asymptomatic but sensitized subjects.

Single step modified ink staining for Tzanck test: quick detection of herpetic giant cells in Tzanck smear.

Tzanck test has been recently re-evaluated as a method for the diagnosis of herpes virus infection. Giemsa staining for the Tzanck test is time-consuming and laborious. There is a need to develop simple and quick staining methods for bedside diagnosis of this disease. We report a single step and quick method for staining herpes giant cells in Tzanck smears using routinely available inks and physiological saline. A keratinocyte cell line (HaCaT) was cultured on a slide glass and stained with various commercially available blue, blue-black and black inks serially diluted with physiological saline. Clinical smear samples from herpes lesions were also stained with these solutions without specific pretreatment. The nuclei of HaCaT were clearly stained showing high contrast with the cytoplasm using 5% Parker-Quink blue-black ink saline solution. Concentration of ink solution higher or lower than 5% resulted in less contrast. Blue or black inks or other manufacturers' inks can also be used, but staining of the cultured keratinocytes was less clear. Smear of clinical samples from herpes lesions were also stained with 5% ink solution. The nuclei of the multinucleated giant cells were clearly stained, and the sample could be immediately used for microscopic examination. One step staining of Tzanck smear using this diluted ink solution is an inexpensive and a convenient bedside diagnostic tool for the dermatologist.

The role of cytokines/chemokines in the pathogenesis of atopic dermatitis.

Atopic dermatitis (AD) is the most common and relapsing allergic disease of the skin. AD is characterized by a predominant expression of Th2-type cytokines associated with increased cellular infiltration in the skin, elevated circulating levels of IgE and eosinophilia. These findings are positively correlated with interleukin (IL)-4 and IL-13 expression in CD4+ T cells. In AD patients, Th2 cells, eosinophils, mast cells and dendritic cells are markedly increased in the skin lesions. However, Th1 cells are also involved in the development of AD lesions. In fact, Th1 cytokine mRNA expressions including γ-interferon and IL-12 are elevated in the chronic lesions as well as elevated Th2 cytokines in the acute AD lesions. The discovery of Th17 lineage and regulatory T (T(reg)) cells shifted the simple Th1/Th2 balance concept into a 4-way balance system. Th17/22 cells, Foxp3+ T(reg) and IL-10-producing T cells (Tr1) are involved in the mechanism of a local and systemic immunological milieu. In addition, super Th1 cells arranged from Th1 cells in high IL-18 milieu are also involved in the development of mouse AD lesions. Correction of Th2 cytokine predominance by Th1 inducers shows effectiveness in experimental models. However, fine-tuning of the delicate 4-way balance among Th1, Th2, Th17/22 and T(reg) cells is required for the control of AD. Efficacy of some biological agents in AD has been reported. However, further investigations are required to make possible the therapeutic application of biologicals, antigen-specific immunotherapy, non-antigen-specific immunotherapy, antagonists and biological response modifiers in the clinic. These novel approaches may constitute a potential curative therapy for AD.

High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma.

In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (T(HS)) cells were CD4(+) in CD4(+) mycosis fungoides (MF), CD8(+) in CD8(+) MF, and contained only clonal T cells in patients with identifiable malignant Vß clones. T(HS) cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal T(HS) cells correlated with skin disease in patients followed longitudinally. Clonal T(HS) cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

SLIT improves cedar pollinosis by restoring IL-10 production from Tr1 and Monocytes∼IL-10 productivity is critical for becoming allergic∼.

BACKGROUND: Allergen-specific immunotherapy (SIT) is currently used for several allergic disorders and IL-10-producing regulatory T cells (Tr1) induced by SIT suppress allergic reactions. We investigated the relation between IL-10 production and acquiring allergy. METHODS: A prospective study was undertaken to evaluate the effect of SIT on IL-10 production in T cells and other cell fractions in children with pollinosis. In addition, blood samples were collected from non-allergic healthy controls and patients with pollinosis to compare the levels of IL-10 production. PBMC were cultured with pollen peptides or control allergens, and the IL-10 production from monocyte and CD4 T cell was analyzed. RESULTS: Monocytes and CD4 T cells from SIT group of patients produced high levels of IL-10, suggesting that the induction of IL-10 is essential for inducing T cell tolerance. IL-10 production from monocytes and T cells was significantly increased in non-allergic controls compared to patients with pollinosis. This high IL-10 production was observed even when PBMC were stimulated with antigens other than pollen peptides. CONCLUSIONS: IL-10 is critical for induction of specific T cell tolerance, and increased production of IL-10 by monocytes and T cells during inflammatory responses or after SIT may influence effector cells in allergy. Present data implicates that the low productivity of IL-10 by monocytes and T cells is closely related with sensitivity to multiple allergens, and resistance to allergic diseases. Augmentation of constitutive IL-10 production from immune system is a potential therapeutic approach for allergic disorders.

Japanese spotted fever with acute hepatic failure: was it associated with Epstein-Barr virus?

BACKGROUND: An 81-year-old female experiencing high fever, fatigue, and loss of appetite was admitted to our hospital and diagnosed with acute cholecystitis. Her condition did not improve and an eschar and erythema subsequently appeared. We then diagnosed Japanese spotted fever (JSF). She recovered immediately after the administration of minocycline. This case differed from other cases because the patient had a remarkably acute hepatic failure. METHODS: Considering that the present case might be associated with other factors, we performed a repeat polymerase chain reaction (PCR) test on the patient's blood that had been collected on admission and stored. RESULTS: Epstein-Barr virus (EBV) was detected in her blood by PCR. CONCLUSION: We consider this case might be associated with EBV.

Immunohistochemical study of cytokeratin expression in nevus sebaceous.

BACKGROUND: The histogenesis of nevus sebaceous (NS) is unclear. METHODS: To elucidate the histogenesis of NS, cytokeratin (CK) profiles were examined immunohistochemically using 10 anti-keratin antibodies in the three stages of NS. RESULTS: In the first stage, stratified differentiated keratins (CK1 and 10) were reduced, and basal keratin (CK14) was increased in the epidermis and primitive follicular structure (PFS). In the second stage, in addition to reduced CK1 and CK10 expressions and increased CK14 expression, CK17 expression was strongly expressed in the sebaceous ducts in proportion to the development of sebaceous gland. In the third stage, CK14, CK17 and CK19 were expressed in secondary tumors. CK16 was not detected throughout all stages of NS. CONCLUSION: These results suggest that NS is not hyperproliferative but involves hamartomatous differentiation with undifferentiated keratins.

Restoration of peripheral blood T cell repertoire complexity during remission in advanced cutaneous T cell lymphoma.

In advanced stages, cutaneous T cell lymphomas (CTCL) are associated with increased mortality from infections and also increased susceptibility to skin malignancies. In this study, we analyzed the complexity of the peripheral blood T cell repertoire with a sensitive b-variable (BV) complementarity-determining region 3 (CDR3) spectratyping analysis and flow cytometry in three-stage IV CTCL/Sezary syndrome patients who achieved complete clinical remission after therapy. The T cell repertoire of peripheral blood T cells before treatment was profoundly abnormal across multiple BV subfamilies. Following treatment, CDR3 spectratype patterns showed dramatic restoration of normal diversity and complexity. However, absolute CD4 counts across multiple BV families remained low for many months, even after identifiable circulating malignant T cell populations were eliminated. These data suggest that the diversity of the T cell repertoire can be recovered after successful treatment of even advanced CTCL.

Primary cutaneous apocrine carcinoma arising within a congenital nevus: Keratins and filaggrin expression suggesting differentiation into the secretory cells of apocrine glands.

Primary cutaneous apocrine carcinoma (PCAC) is a rare neoplasm of skin appendages. To determine the differentiation of apocrine carcinoma, we studied the expression of epithelial keratins and filaggrin immunohistochemically using 10 anti-keratin antibodies againt keratin (K) 1, 7, 8, 10, 14, 15, 16, 17, 18, 19 and the anti-filaggrin antibody. PCAC demonstrated strong positivity for K7, K8, K18 and K19. These keratins are distributed in secretory cells of normal apocrine glands. The tumor cells were negative for K14 and K17. The two keratins exist in myoepithelial cells in normal apocrine glands. Results suggest that PCAC shows differentiation into secretory cells of apocrine glands, although it does not differentiate into myoepithelial cells. K14 is also known as undifferentiated keratin, whereas K17 is considered to be a hyperproliferative keratin. Absence of the expression of K14 and K17 may reflect an indolent clinical course of PCAC.

Pilomatricoma can differentiate not only towards hair matrix and hair cortex, but also follicular infundibulum, outer root sheath and hair bulge.

Pilomatricoma is believed to differentiate towards the hair matrix and hair cortex. To elucidate the origin of differentiation in pilomatricoma, we studied the expression of epithelial keratin (K) and filaggrin (filament aggregating protein) in pilomatricoma. An immunohistochemical study has been made of 53 cases of pilomatricoma using 10 monospecific anti-keratin antibodies and anti-filaggrin antibody. Basophilic cells, transitional cells and shadow cells did not react with epithelial keratins and filaggrin antibodies as well as hair matrix and hair cortex. Instead, infundibular-type epithelium was positive for K1, K10 and filaggrin. Epithelium showing trichilemmal keratinization was positive for K14 and K16. The hair bulge-like structure was positive for K19. The differentiation of pilomatricoma is diversified, and is heterogeneous in epithelial keratin and filaggrin expression. Our results for keratin and filaggrin expression suggested that pilomatricoma can differentiate not only towards hair matrix and hair cortex, but also follicular infundibulum, outer root sheath and hair bulge.

Leg ulcer caused by Mycobacterium ulcerans ssp. shinshuense infection.

BACKGROUND: An 81-year-old man presented with a skin ulcer on the left forearm caused by infection with Mycobacterium ulcerans ssp. shinshuense. The patient first noticed the subcutaneous nodule with an undermined ulcer and areola on the left forearm without any episode of trauma. METHODS: The rod-shaped and acid-fast bacteria taken from the ulcerative lesion were positive for Ziehl-Neelsen staining. The bacterial colony was cultured on Ogawa slant egg medium at 28 degrees C. RESULTS: A clinical diagnosis of Mycobacterium infection was made. For therapy, in addition to oral clarithromycin, topical sulfadiazine silver and hyperthermia were used. One month after starting treatment, topical treatment was changed to U-pasta (sucrose, povidone-iodine). Four months after the onset of the disease, bacterial colonies composed of scotochromogens were identified as Mycobacterium marinum by the DNA-DNA hybridization (DDH) method. The growth speed and characteristics of the bacterial colonies were different from those of Mycobacterium marinum. CONCLUSIONS: This pathogenetic bacterium was finally identified as Mycobacterium ulcerans ssp. shinshuense by the polymerase chain reaction method and 16S rRNA gene sequencing. Nine months after the onset of the disease, the ulcer was re-epithelialized with a residual scar.

Protective role of interleukin-18 against Fas-mediated liver injury.

Interleukin (IL)-18 plays an important role in the pathogenesis of several liver diseases as well as Fas-mediated apoptosis. However, the effects of IL-18 on Fas-mediated liver injury have not been well elucidated. Therefore, we examined the effects of IL-18 on Fas-mediated apoptosis in in vitro and in vivo experiments. We found that recombinant IL-18 protected mouse hepatocellular carcinoma cell lines, BNL5, from Fas-mediated apoptosis in a dose-dependent manner with up-regulation of both nuclear factor (NF) kappaB and X-linked inhibitors of apoptosis (XIAP). IL-18 transgenic (Tg) mice were also protected from Fas-mediated liver injury and this was further confirmed by histological study and TUNEL staining. In IL-18 Tg mice, up-regulation of XIAP and down-regulation of caspase 3 were observed after injection of anti-Fas, which was consistent with the in vitro findings. These results suggest that IL-18 suppresses Fas-mediated apoptosis of hepatocytes by up-regulation of NFkappaB and XIAP, following inhibition of caspase-3 activity. This observation raises the possibility that IL-18 could be a therapeutic strategy for Fas-mediated liver injury as a negative regulator of XIAP.

Keratin and filaggrin expression in keratoacanthoma.

To clarify the histogenesis of keratoacanthoma, we studied keratin (K) expression in keratoacanthoma (KA) using 10 different anti-keratin antibodies against K1, K7, K8, K10, K14, K15, K16, K17, K18 and K19 and anti-filaggrin (filament aggregating protein) antibody. In the centre of KA, K1 and K10 expressions were declined, and K14 and K16 were detected in the tumour cells, suggesting differentiation towards the outer root sheath beneath the orifice of the sebaceous duct. These results suggest that KA differentiates towards the outer root sheath beneath the opening of the sebaceous duct.

Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression.

BACKGROUND: Cutaneous lymphocyte-associated antigen (CLA) is a surface glycoprotein expressed by skin-homing T cells. This carbohydrate moiety expressed on mucin-like surface glycoproteins, including P-selectin glycoprotein ligand 1 and CD43, confers binding activity to dermal endothelial E-selectin and is critical for T-cell recruitment to the skin. Vitamin A (retinoic acid [RA]) and the active form of vitamin D3 (1,25 dihydroxyvitamin D3 [1,25D(3)]) have been used to treat certain T cell-mediated inflammatory skin diseases, as well as cutaneous T-cell lymphomas; however, their effect on CLA expression has not been studied. OBJECTIVE: We analyzed the effects of RA and 1,25D(3) on expression of CLA and other lymphocyte-homing receptors on human T cells. METHODS: We cultured human T cells with 1,25D(3) and RA and analyzed the expression of CLA and other homing receptors. We also pretreated mice with either vitamin and then induced an antigen-dependent contact hypersensitivity response. RESULTS: Both RA and 1,25D(3) downregulated expression of the CLA and, in parallel, functional E-selectin ligand. Whereas RA increased expression of the gut-homing receptor alpha4beta7 and reduced L-selectin expression, 1,25D(3) had no effect on other homing receptors. In an in vivo assay treatment with RA or 1,25D(3) downregulated the skin infiltration of effector CD4+ T cells. CONCLUSION: These findings suggest that 1,25D(3) can selectively downregulate CLA expression without influencing lymphocyte migration patterns to other tissues.

Necrobiotic xanthogranuloma with paraproteinemia; an atypical case.

Necrobiotic xanthogranuloma (NXG) is a rare marker for paraproteinemia. An 86-year-old woman had a one year history of large red-yellow to brown annular plaques involving all limbs. Biopsies showed a non-palisading granuloma with numerous multinucleated giant cells showing prominent elastophagocytosis and extensive areas of necrobiosis throughout the entire dermis. Complete loss of elastic fibers was observed in the central atrophic area of an annular plaque. Small vascular thromboses were also present. Laboratory findings revealed paraproteinemia of IgG-lambda type. Immunohistochemical staining detected the presence of roughly equal numbers of IgG-lambda-and IgG-kappa-staining plasma cells in the dermis. We diagnosed NXG with paraproteinemia with monoclonal gammopathy (IgG-lambda type) of unknown significance.

A case of Adamantiades-Behçet disease with ischemic optic neuritis (posterior optic neuropathy).

Adamantiades-Behçet disease (ABD) may present with cutaneous and ophthalmologic findings. A 29-year old woman complained of fever and general fatigue, along with erythema nodosum and vesiculo-pustular lesions on the legs, acneiform lesions, genital ulcerations and painful oral ulcers. She also complained of reduced visual acuity, visual disturbance and blurred vision in the left eye. Her left visual acuity was 6/20. Light reflex in the left eye was reduced. The relative afferent pupillary defect (RAPD) was positive in the left eye where a central scotoma was present. The vitreous was clear; the optic disc, macula, retina and iris were all normal. Uveitis was not observed. The patient was diagnosed with ischemic optic neuritis (posterior optic neuropathy) with ABD. Histopathological findings taken from a blister on the leg showed subepidermal bulla, dense dermal neutrophil infiltration, and extravasation of erythrocytes, suggesting leukocytoclastic vasculitis. She was treated orally with high-dose corticosteroids (methylprednisolone 500 mg/d) for three days. Her general condition and ophthalmic symptoms resolved completely. Optic neuropathy with ABD is very rare; we know of two previous cases [1, 2] of ABD with ischemic posterior optic neuritis.