Mizue Fujii

Developmental alterations of physical properties and components of neonatal-infantile stratum corneum of upper thighs and diaper-covered buttocks during the 1st year of life.

BACKGROUND Although physical properties of neonatal-infantile stratum corneum (SC) change drastically after birth, precise developmental alterations of specific sites have not been fully elucidated. OBJECTIVE To determine the longitudinal alterations of neonatal-infantile SC functions and components of upper thighs and diaper-covered buttocks during the first year of life. The data were compared with those of adults. METHODS Nineteen full-term neonates and their mothers were subjected to the measurements. Skin hydration, water sorption/retention capacity, TEWL were measured. Superficial SC analyses for NMF, ester binding sebum, and free fatty acids were performed by ATR-FTIR spectrometer. Total amount of ceramides (CERs) and CER subclasses were analyzed by NPLC-ESI-MS. RESULTS SC hydration of neonatal thighs was lower than that of their mothers, which rapidly increased during the 1st month. Skin hydration of neonatal buttocks was similar to that of their mothers. This also rapidly increased during the 1st month. The neonatal TEWL was less than those of their mothers indicating more efficient barrier function at both sites, which significantly increased during the 1st year development. This was mostly correlated decreased in the ω-hydroxy fatty acid-esterified CERs. Superficial ester-binding sebum content of neonates was similar to that of their mothers, which significantly decreased during the measurement; the decrease was more marked on buttocks. Neither NMF nor FFA of the superficial SC showed significant alteration during the 1-year development. CONCLUSION Our results indicate that physical functions and components of neonatal-infantile SC show considerable alterations between diaper-covered buttocks and upper thighs during the 1st year development.

Primary cutaneous γδ-T-cell lymphoma treated with low-dose methotrexate and narrowband ultraviolet B irradiation: Report of a case with testicular involvement

Primary cutaneous γδ‐T‐cell lymphoma (CGD‐TCL) is a rare entity of cutaneous T‐cell lymphomas (CTCL) and is characterized by tumoral growth of mature γδ‐T‐cell expressing cytotoxic molecules. The prognosis of CGD‐TCL is generally worse than other CTCL. However, relatively indolent patch/plaque lesions have been described suggesting the heterogeneous nature of this entity. Here, we present a case of CGD‐TCL with various skin manifestations, such as erythematous plaques/tumors and subcutaneous panniculitis‐like lesions. During the follow up, testicular involvement was detected, which was surgically removed. Histopathology showed mixed features from epidermotropism, dermal infiltration and subcutaneous panniculitis‐like lesions depending on the clinical manifestations. The tumor cells were positive for CD3 and revealed cytotoxic markers, TIA‐1 and perforin, but not for CD4, CD8, CD20, CD56, TCRβF1 or EBER. Topical glucocorticoid ointment, narrowband ultraviolet B (NB‐UVB) irradiation and low‐dose methotrexate (MTX) were effective to control these skin lesions. No visceral involvement was detected thereafter. While CGD‐TCL is usually associated with poor prognosis, it seems to be composed of various clinical manifestations, and NB‐UVB and low‐dose MTX could be a choice for indolent patch/plaque and possibly nodular lesions, especially for the aged.

Intercellular contact augments epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3)-activation which increases podoplanin-expression in order to promote squamous cell carcinoma motility.

The transmembrane glycoprotein podoplanin (PDPN) plays an important role in cell motility. However, mechanisms regulating PDPN expression have not been fully elucidated. Here, we investigated the effect of intercellular contact on signal transduction pathways and PDPN expression in human squamous cell carcinoma (SCC) cell lines. PDPN expression was higher in confluent SCC cells than sparse cultures. This PDPN induction leads to increased SCC cell migration and invasion, which was reversed by shRNA PDPN knockdown. This cell density dependent PDPN induction required activation of epidermal growth factor receptor (EGFR) and its effector, signal transducer and activator of transcription 3 (STAT3). These observations also extend to human clinical specimens, in which PDPN expression localized to confluent basal cell layers at the invading front of in situ SCC lesions. Taken together, these results illuminate an EGFR-STAT3-PDPN pathway as a potential pharmacological opportunity to target invasive SCC cells.

The nuclear factor kappa B p50 subunit and cortactin as markers to distinguish between keratoacanthoma and well-differentiated squamous cell carcinoma.

Background.  Distinguishing keratoacanthoma (KA) from well‐differentiated squamous cell carcinoma (SCC) is sometimes difficult. Recent evidence indicates that the nuclear factor kappa B p50 subunit (p50) and cortactin might be useful to distinguish between these two conditions.

Podoplanin expression is inversely correlated with granular layer/filaggrin formation in psoriatic epidermis

1 Imai Y, Tsuda T, Aochi S et al. YKL-40 (chitinase 3-like-1) as a biomarker for psoriasis vulgaris and pustular psoriasis. J Dermatol Sci 2011; 64: 75–77. 2 Johansen JS, Jensen HS, Price PA. A new biochemical marker for joint injury. Analysis of YKL-40 in serum and synovial fluid. Br J Rheumatol 1993; 32: 949–955. 3 Bojesen SE, Johansen JS, Nordestgaard BG. Plasma YKL-40 levels in healthy subjects from the general population. Clin Chim Acta 2011; 412: 709–712. 4 Mastroianni A, Minutilli E, Mussi A et al. Cytokine profiles during infliximab monotherapy in psoriatic arthritis. Br J Dermatol 2005; 153: 531–536. 5 Jensen P, Wiell C, Milting K et al. Plasma YKL-40: a potential biomarker for psoriatic arthritis? J Eur Acad Dermatol Venereol. Published online: 23 May 2012; doi: 10.1111/j.1468-3083.2012.04570.x.

Granulocyte colony stimulating factor-producing squamous cell carcinoma of the skin

Laboratory findings were compatible with an acute FMF attack (elevated serum C-reactive protein and fibrinogen levels and increased erythrocyte sedimentation rate). The patient was diagnosed as having FMF-related erysipelas-like erythema based on the clinical and histopathological examinations. The clinical picture of many infections (erysipelas, erysipeloid) as well as inflammatory diseases (contact dermatitis, erysipeloid cutaneous metastases) may resemble erysipeloid lesion. One of the proposed mechanisms by which FMF causes skin eruption is vasculitis. Several types of vasculitis are associated with FMF: polyarteritis nodosa, Henoch–Schönlein purpura, and protracted febrile myalgia. The diagnosis of leukocytoclastic vasculitis by biopsy supports that skin eruptions related to FMF can be caused by vasculitis. It has also been implicated that erysipelas-like erythema belongs to the spectrum of neutrophilic dermatoses and it is related to abnormal inhibition of the inflammatory cascade. In addition, homozygosity for the M694V mutation is associated with erysipelas-like erythema and our patient also had M694V ⁄M694V mutations. The distinction between acute vasculitis and neutrophilic dermatoses can be difficult in some cases as in our patient. Erysipelas-like erythema can accompany FMF attacks and ELE should alert the physician to the correct diagnosis of this systemic disease. Fatma AYDIN, Ceyda OZCELIK, Ilkser AKPOLAT, Ahmet Yasar TURANLI, Tekin AKPOLAT Departments of Dermatology, Internal Medicine and Pathology, School of Medicine, Ondokuz Mayis University, Samsun, Turkey

Kaposi's varicelliform eruption presenting with extensive skin lesions and sepsis.

direct contact with contaminated water or fish through minor trauma, although the exact site of entry is not identified in approximately 20% of cases. Considering its relatively long incubation period (mean, 30.1 days; range, 5–270), it is possible that our patient had a minor trauma on the right hand, and was infected through the green spotted pufferfish in her aquarium. M. marinum infection rarely progresses to generate deeper lesions, such as arthritis and tenosynovitis, which occur mostly in immunocompromised patients. In addition to the history of diabetes, our patient had been treated with methotrexate and sulfasalazine, which might accelerate the proliferation ofM. marinum, leading to progression into deeper lesions. Another report describes a patient who had septic arthritis caused by M. marinum infection without skin lesions and had been treated with anti-tumor necrosis factor-a agents, which resulted in systemic M. marinum infection. Also, Hsiao et al. reported seven cases of septic arthritis caused by M. marinum infection, and all of these cases had arthritis in the small joints of the hands. Thus, the likelihood of M. marinum infection should be considered in patients with arthritis in the hand that is atypical of other rheumatic diseases. Furthermore, awareness of mycobacterial arthritis may be low among dermatologists. Nonetheless, dermatologists have an important role to play in the diagnosis of this condition by asking for a history of raising fish and conducting mycobacterial culture when it accompanies skin lesions before the development of irreversible joint damage. CONFLICT OF INTEREST: None declared.

Aberrant LIM‐kinase 1 expression in hyperproliferative psoriatic epidermis

Multilayered epidermis makes a robust barrier against physical and chemical stimuli from the outer environment, balancing proliferation and cornification of keratinocytes. The homeostatic balance can be altered in skin disorders, and the epidermal turnover time is shortened by one-seventh of the normal healthy epidermis in psoriasis. In these skin disorders, aberrant expression of keratinization markers, various signal transduction molecules and other characteristics are observed. While the expression of LIM-kinase 1 (LIMK1), a serine-threonine kinase associated with actin polymerization, is suppressed in psoriatic epidermis, the regulatory mechanism of LIMK1 remains unknown. Here, we analyzed the expression pattern of LIMK1 in psoriatic epidermis with/without granular layers (GL) and cytokine-treated reconstituted epidermis mimicking psoriasiform hyperproliferative epidermis. In this study, psoriatic lesional epidermis was classified into typical GL-negative markedly hyperproliferative epidermis and GL-positive stationary and/or healing epidermis. Formaldehyde-fixed paraffin-embedded sections from 30 cases who had been histopathologically diagnosed with psoriasis at the Department of Dermatology, Asahikawa Medical University hospital since 2008 (male : female, 11:4; mean age, 56.97 years [men, 56.73 [range, 25–85]; women, 56.73 [range, 18–91]) including 15 cases of GL-negative and 15 cases of GL-positive psoriasis, were analyzed by immunohistochemistry. Samples of reconstituted epidermis that had been cultured for 6 days (J-TEC; Gamagori, Aichi, Japan) were provided every other day with culture medium containing 50 ng/mL of interleukin (IL)-22 (Peprotech, Rocky Hill, NJ, USA) or IL-24 (Peprotech). Rabbit polyclonal anti-LIMK1 (Santa Cruz Biotech, Dallas, TX, USA) and mouse monoclonal anti-b-tubulin (SigmaAldrich, St Louis, MO, USA) antibodies were employed for immunostaining and immunoblotting. A primer pair of 50-AGGT GACACACCGTGAGACAG-30 and 50-ACTCTCTGGCTCCATGG GTAC-30 was used for the amplification of LIMK1 transcript in reverse transcription polymerase chain reaction. While the strong and restricted expression of LIMK1 was detected in the subcorneal layer of normal and uninvolved epidermis of psoriasis patients, the expression was remarkably downregulated in psoriatic lesional epidermis (Fig. 1a). The expression of LIMK1 was much weaker in GL-negative hyperproliferative psoriatic epidermis than in GL-positive less hyperproliferative psoriatic epidermis (P < 0.05, Mann–Whitney U-test) (Fig. 1b). The expression of LIMK1 was much more upregulated in stratified reconstituted epidermis than in conventionally cultured human epidermal keratinocytes (HEK) (Fig. 1c), and the increased expression of LIMK1 was remarkably suppressed in IL-22or IL-24-treated hyperproliferative psoriasis-mimicking reconstituted epidermis in vitro (Fig. 1c,d). The transcription level of LIMK1 was not affected by treatments with these cytokines (Fig. 1e). In this study, it was clearly shown that LIMK1 expression is negatively regulated in GL-negative psoriatic epidermis or IL-22/IL-24-treated hyperproliferative reconstituted epidermis. These findings suggest a novel regulatory mechanism and a potent role of LIMK1 in psoriatic epidermis. LIM-kinase, a serine/threonine kinase, plays an essential role in actin polymerization via inhibition of cofilin, an actin depolymerizer, and affects cell motility and morphogenesis. LIMK consists of two subtypes, LIMK1 and LIMK2. The former is expressed in a few layers beneath the horny layer of normal epidermis and the latter is expressed in the basal layer of normal epidermis. LIMK1 expression is upregulated in differentiating HEK during Ca switching, and is possibly associated with flattening of epidermal keratinocytes in subcorneal layers. However, its expression is significantly suppressed in psoriatic epidermis. In psoriatic epidermis, GL is inversely correlated with the proliferation level: GL is negative in hyperproliferative epidermis, but positive in less proliferative epidermis. In addition, constitutively active cofilin, which cannot be inhibited by LIMK1/2, results in upregulated phosphorylation of signal transducer and activator of transcription (STAT)3 deeply associated with hyperproliferating psoriatic epidermis. In this study, LIMK1 expression level was weaker in GL-negative epidermis than in GL-positive epidermis. IL-22 and IL-24 belonging to IL-20 family cytokines induce hyperproliferation of reconstituted epidermis via STAT-3 activation of keratinocytes. The strong LIMK1 expression in non-treated reconstituted epidermis was diminished by IL-22 and IL-24 treatments, suggesting an inverse correlation of LIMK1 expression and epidermal proliferation. The previous reports suggest that LIMK1 expression can be regulated by transcriptional and proteasomal mechanisms. Some E3-ubiquitin ligases, such as Rnf6, can be involved in the proteasomal degradation of LIMK. The result

Elevation of serum carcinoembryonic antigen in a case of cholinergic urticaria with failed detection of hypohidrosis by the conventional starch-iodine test.

Dear Editor, Acquired idiopathic generalized anhidrosis (AIGA) is defined as non-segmental generalized hypohidrosis/anhidrosis without any dermatological or neurological causes except limited dysfunction of the autonomic nervous system only in sweating. Idiopathic pure sudomotor failure (IPSF), the most common subtype, presents distinct features, such as sudden onset in youth, absence of any specific skin lesion and favorable response to systemic corticosteroids including repeated methylprednisolone pulse therapy; dysfunction of acetylcholine transmission can be related to the pathomechanism. Recently, serum carcinoembryonic antigen (CEA) level has been proposed as a marker reflecting the disease activity of AIGA as well as a conventional starch–iodine test. Here, we report a case of cholinergic urticaria (CU), in which serum CEA elevation and lymphocytic infiltration around eccrine sweat glands were observed but the conventional test failed to detect hypohidrosis. A 27-year-old Japanese man serving in the self-defense forces presented with sickness accompanied by a history of decreased sweating and occasional heatstroke for 7 months. In conditions usually inducing sweating, such as bathing and physical exercise, he was aware of the appearance of disseminated miliary-sized wheals on the body with itchy and prickling sensation. Blood test only showed elevated serum CEA level (19.1 ng/mL; normal, < 5.0) but no abnormality in cell counts, biochemistry, thyroid function test, immunoglobulin E and antiSSA/B antibody. No intracranial lesion was found by magnetic resonance imaging. A modified Minor test failed to detect obvious hypohidrosis, or to induce wheals or excessive hyperthermia (Fig. 1). However, histopathology showed moderate lymphocytic infiltration around the secretory portion of eccrine sweat glands, where increased CEA expression was revealed by immunohistochemistry. These findings led to the diagnosis of CU without apparent hypohidrosis detected by the conventional Minor test. Oral olopatadine hydrochloride (10 mg/day)

Serum carcinoembryonic antigen specifically increases among various serum markers of adenocarcinoma in hypohidrosis or conditions related to hypohidrosis

Anhidrosis/hypohidrosis are conditions presenting various level of sweating dysfunction. Among them, acquired idiopathic generalized anhidrosis (AIGA) presents inadequate decrease or loss of sweating without apparent neurological and dermatological symptoms except cholinergic urticaria. Recently, serum level of carcinoembryonic antigen (CEA), one of the most well‐known tumor markers, has been proposed as a clinical marker reflecting activity of AIGA. This study was performed to verify the specificity and independence of serum CEA level from the other serum tumor markers especially related to adenocarcinoma. The expression of various tumor markers in the serum collected from three healthy control subjects, four AIGA cases, and a cholinergic urticaria (CU) case with elevation of serum CEA level and history of hyperthermia was analyzed using a membrane‐based antibody array. In all AIGA and CU cases, the intensity of CEA was significantly increased (7.60–15.9 times compared with that of control), relatively well‐reflecting the serum CEA level, and the mean intensity of CEA was 11.8 times higher than the control subjects (P = 0.0011). On the other hand, the ratio of carbohydrate antigen (CA)125 and CA19‐9 was 1.93 and 0.23 times compared with the mean intensity of the control subjects, respectively, and there was no statistical significance. Immunohistochemistry on 10 AIGA cases showed increased expression of CEA but not CA19‐9 and CA125 in the eccrine sweat glands. In conclusion, the elevation of serum CEA level was independent from the other tumor markers in hypohidrotic condition represented by AIGA.