Ectopic coexpression of keratin 8 and 18 promotes invasion of transformed keratinocytes and is induced in patients with cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) results from transformation of epidermal keratinocytes. Invasion of transformed keratinocytes through the basement membrane into the dermis results in invasive cSCC with substantial metastatic potential. To better understand the mechanisms for invasion and metastasis, we compared the protein expression profiles of a non-metastatic transformed mouse keratinocyte line and its metastatic derivative. Keratin 8 (Krt8) and Krt18, not seen in normal keratinocytes, were coexpressed and formed Krt8/18 filaments in the metastatic line. The metastatic line efficiently invaded an artificial basement membrane in vitro owing to the Krt8/18-coexpression, since coexpression of exogenous Krt8/18 in the non-invasive parental line conferred invasiveness. To test whether the Krt8/18-coexpression is induced and is involved in cSCC invasion, we examined specimens from 21 pre-invasive and 24 invasive cSCC patients by immunohistochemistry, and the ectopic Krt8/18-coexpression was almost exclusively found in invasive cSCC. Further studies are needed to examine the clinical significance of ectopic Krt8/18-coexpression in cSCC.

Detection of human papillomavirus type 11 in a case of Buschke-Löwenstein tumor.

We here report a 31-year-old male affected by a papillary tumor in his pubic region. At 26 years of age, he consulted a nearby clinic and was prescribed a topical cream. Although the condition was not relieved, he left the disease untreated. The gradually growing tumor adversely affected his quality of life, and he consulted another clinic, where he was referred to our hospital for surgery. The tumor had infiltrated the tissue at the base of the penis, but not the glans. After careful examination, we performed local excision of the tumor and a split-thickness skin graft. On pathological examination, elongation of the epidermis and koilocytes in the uppermost portion of the spinous layer were observed. Moreover, PCR examination confirmed the presence of human papillomavirus (HPV) type 11 in the tumor tissue. These findings supported a diagnosis of Buschke-Löwenstein tumor (BLT).

Case of skin injuries due to stings by crown-of-thorns starfish (Acanthaster planci).

A case of skin injuries due to stings by crown-of-thorns starfish, Acanthaster planci, in a 53-year-old Okinawan woman is reported. She went to a beach to gather shellfish on 8 April 2001 and fell to the ground with her left palm on a crown-of-thorns starfish that happened to be close to her. She hurried to the emergency section of our hospital. An emergency doctor sterilized the wound and administered an antibiotic, an analgesic agent and an injection of a tetanus antitoxin. He tried to remove the remaining spines from the palm with great difficulty. Because swelling and subcutaneous indurations of the left palm had persisted thereafter, oral and topical administration of corticosteroid started on 13 April. Physical examination at the dermatology section revealed approximately 10 stab wounds of the left palm with pus, subcutaneous bleeding and many abrasions around them. X-rays of the left hand showed foreign bodies, 2-10 mm in size, located on the lesions. The patient was treated with a topical injection of 2 mg triamcinolone acetonide (Kenacort-A), diluted fivefold with 1% Xylocaine, once a week. Some of the foreign body granulomatous lesions improved but pain and subcutaneous indurations persisted in most of the lesions. Because the X-ray photographs showed many remaining spines, surgical excision to remove them was performed under local anesthesia 3 months after the injury. All the symptoms improved after the operation. Scanning electron microscopic examination of the spines revealed that their tips had fragile lattice-like structures.

Neonatal pemphigus vulgaris.

A male newborn with skin erosions was born to a 32-year-old woman who was under treatment for pemphigus vulgaris that had been diagnosed 16 months earlier. Antibodies to desmoglein (Dsg)1 and Dsg3 were analyzed by enzyme-linked immunosorbent assay. Index values of antibodies to Dsg1 and Dsg3 were 49 (normal index values, <14) and 121 (normal index values, <7), respectively. Those findings concluded a diagnosis of neonatal pemphigus vulgaris. No new vesicles or bullae appeared in the newborn after the birth. Non-corticosteroid ointments produced prompt epithelialization on the erosive lesions. All the eruptions disappeared in 3 weeks. The level of serum anti-Dsg3 autoantibodies when measured at the 76th day was negative (<5).

Case of linear immunoglobulin A bullous dermatosis associated with acquired hemophilia.

Linear immunoglobulin (Ig)A bullous dermatosis is a rare autoimmune subepidermal bullous dermatosis caused by circulating IgA autoantibodies directed against the antigens at the basement membrane zone. Most linear IgA bullous dermatosis cases are idiopathic, but some are associated with the use of certain drugs, infections, lymphoproliferative disorders, internal malignancies, autoimmune disorders, collagen diseases or, very rarely, other skin diseases, including autoimmune bullous diseases. Acquired hemophilia is also rare; it is a coagulation disease caused by anti-factor VIII IgG antibodies. Acquired hemophilia has been reported to be associated with malignant tumors, pregnancy or postpartum, drug reactions, collagen diseases such as rheumatoid arthritis, autoimmune disorders, and skin diseases such as psoriasis and pemphigus. We report a case of hemophilia acquired during the course of linear IgA bullous dermatosis and review reported cases of autoimmune bullous dermatoses associated with acquired hemophilia.

Case of chromoblastomycosis appearing in an Okinawa patient with a medical history of Hansen's disease.

Chromoblastomycosis is one of several chronic infectious skin diseases caused by various species of dematiaceous fungi. It is clinically characterized by verrucous skin eruptions and occurs most commonly in tropical and subtropical regions. In Okinawa, a subtropical area, there have been only three reported cases of chromoblastomycosis including the present one. Direct microscopic examination of crust specimens and findings of sclerotic cells in histopathology can confirm the diagnosis, and cultures of crust and/or tissue specimens can identify the causative fungi. We herein report the third case of chromoblastomycosis in Okinawa; it arose in an 87-year-old Japanese woman with a history of Hansen's disease, who lived in a leprosarium in Miyako Island. To identify the causative agent as Fonsecaea pedrosoi, we used the polymerase chain reaction and direct sequencing analysis in addition to the usual methods, which include 20% potassium hydroxide microscopy, histopathological confirmation of sclerotic cells by periodic acid-Schiff stain, culture by Sabouraud's glucose agar, slide culture method, and observation of conidia by scanning electron microscopic examination.

Case of pemphigus foliaceus that shifted into pemphigus vulgaris after adrenal tumor resection.

A 79-year-old Japanese woman visited our hospital on 6 May 2003, who had suffered from erythema and crusted vesicles located on the head, face and trunk. The eruptions first appeared in February 2003. Histopathological findings included blister formation spreading from just below the horny layers to the upper squamous layers, where acantholytic cells were observed. Direct immunofluorescence disclosed immunoglobulin G depositions in the epidermal intercellular spaces. Enzyme-linked immunosorbent assay showed an elevated titer of anti-desmoglein (Dsg)1 autoantibodies (154 index value), but almost normal levels of anti-Dsg3 autoantibodies (8 index value in serum). The diagnosis at first was made as pemphigus foliaceus (PF). Topical use of corticosteroids alone could control the eruptions well. Systemic examinations on admission revealed a right adrenal tumor that had caused Cushing's syndrome. Its resection was performed on 24 July 2003. Histopathological diagnosis of the removed tumor was a functional adrenal adenoma. The symptoms had worsened after the resection. Topical use of corticosteroids alone could no longer control the symptoms. Additional p.o. medications of minocycline hydrochloride and nicotinic acid amides improved the symptoms to some extent. However, oral cavity erosions appeared in December 2004, and the titer of anti-Dsg3 autoantibodies in serum elevated, suggesting a transition from PF to pemphigus vulgaris (PV). p.o. administration of corticosteroids started, which improved the symptoms significantly. To date, there have been no reports of pemphigus complicated with an adrenal tumor that caused Cushing's syndrome in Japan. The present case is particularly interesting in that the symptoms became worse after the tumor resection and that the first diagnosis of PF shifted into PV after the operation.

Cutaneous leishmaniasis in a Japanese returnee from West Africa successfully treated with liposomal amphotericin B.

Leishmaniasis has been occasionally reported in returnees from endemic areas. Here, we report a case of cutaneous leishmaniasis in a 33-year-old Japanese man who presented with a skin nodule after returning from an 8-year stay in West Africa including Burkina Faso. He was successfully treated with liposomal amphotericin B with no significant adverse effects. This is the first Japanese case of cutaneous leishmaniasis treated successfully with liposomal amphotericin B.

Tinea corporis caused by Microsporum gallinae: first clinical case in Japan.

We report herein a case of tinea corporis caused by Microsporum gallinae in a 96-year-old, otherwise healthy Japanese man. The patient had a long working history as a breeder of fighting cocks, and he suffered from two erythematous macules after being bitten by a cock. M. gallinae was identified as the infectious agent based on the morphology of isolates cultured on slides and analysis of DNA sequences of the internal transcribed spacers (ITS) from ribosomal DNA from cultured isolates. The patient was successfully treated with antifungal ointments. To our knowledge, this is the first case of M. gallinae infection in a human reported in Japan.

Allergic contact dermatitis due to diclofenac sodium in eye drops.

Eyelid dermatitis and/or periocular dermatitis (ED/PD) is commonly seen in a variety of skin diseases such as seborrheic dermatitis, atopic dermatitis and psoriasis, but is most often associated with allergic contact dermatitis (ACD). Here, a case of ACD in an 82-year-old man is described; he used 0.1% diclofenac sodium eye drops and exhibited pruritic erythema on the eyelids. Patch test for diclofenac sodium eye drops was positive. Further patch tests revealed a positive reaction to diclofenac sodium (monosodium 2-[2, 6-dichlorophenylamino] phenylacetate), which was the main component in the eye drop medicine. Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID), and is frequently used in everyday oral medications, topical ointments, gel agents and eye drops. Case reports on ACD caused by diclofenac sodium eye drops are extremely rare. Nevertheless, it is necessary to consider ACD due to diclofenac sodium when a patient with ED/PD has a history of use of diclofenac sodium eye drops.

Nosocomial outbreak of multidrug-resistant USA300 methicillin-resistant Staphylococcus aureus causing severe furuncles and carbuncles in Japan.

USA300 methicillin-resistant Staphylococcus aureus (MRSA) has been attracting worldwide attention as a cause of community-associated MRSA (CA-MRSA) infections in the 21st century. Nosocomial outbreaks of CA-MRSA clones have been progressively more reported in Europe and the USA, but only one very recent report from Kyoto found in Japan. In February 2008, a severe MRSA infection occurred in one immunocompromised patient and three healthy medical staff members at the Department of Dermatology, Graduate School of Medicine, University of the Ryukyus. The epidemiological and clinical pattern of the infection prompted us to characterize the molecular features of the MRSA strain involved. The causative MRSA strain belonged to the multi-locus sequence type 8, staphylococcal cassette chromosome mec (SCCmec) type IVa, spa1 (alternatively t008), agr1 and coagulase type III, and carried the Panton-Valentine leukocidin (PVL) gene and the arginine catabolic mobile element. Pulsed-field gel electrophoresis analysis showed that the MRSA responsible for the outbreak was the USA300 clone. All of the isolated USA300 clones had multiple resistance against six non-ß-lactam antimicrobial drugs. We report here the first nosocomial outbreak of multidrug-resistant USA300 MRSA infections in Japan. This report shows that the USA300 clone can manifest severe skin infections such as furuncles and carbuncles even in healthy persons, which require drainage and i.v. treatment, and suggests that the clone can spread in hospital settings worldwide.

Cytomegalovirus gastritis.

Cytomegalovirus (CMV) has been increasingly recognized as an important common pathogen in an immunocompromised state. The colon and stomach are the most common sites of its gastrointestinal infection. Symptoms of CMV gastritis are usually nonspecific and include epigastric pain, fever, nausea and bleeding. Endoscopic features are quite variable and include macroscopically normal mucosa, diffuse erythema, nodules, pseudotumors, erosions and ulcers. The bioptic detection of intranuclear inclusions is the hallmark of CMV infection. Most gastrointestinal CMV infection responds well to ganciclovir. We present endoscopic and histopathological features of CMV gastritis in a 71 year old woman receiving long-term prednisolone for pemphigus vulgaris.

Esophagitis dissecans superficialis and autoimmune bullous dermatoses: A review.

Esophagitis dissecans superficialis (EDS) is a rare and severe endoscopic finding characterized by sloughing of large fragments of esophageal mucosal lining. Although EDS has been reported in association with serious illnesses and certain medications, the pathophysiological association of autoimmune bullous dermatoses with EDS has gained remarkable attention. Among these dermatoses, pemphigus vulgaris and pemphigoid frequently present with various types of esophageal involvement including EDS. We review the pathophysiology and clinical features of this involvement with the presentation of our experiences. The importance of endoscopic evaluation of this entity is discussed.

Phaeohyphomycosis caused by Exophiala jeanselmei in a patient with polymyalgia rheumatica.

An 87-year-old man, a gardener in Okinawa, first noticed a tumor on the dorsum of his right hand in November 2005. He had been taking prednisolone for the treatment of polymyalgia rheumatica since 2000. A nearby dermatologist incised the tumor for pus drainage in February 2006. In April of the same year, the dome-like tumor reappeared. The same treatment was repeated. Because the culture of the pus revealed fungi at that time, terbinafine hydrochloride and minocycline were administrated under the diagnosis of a deep fungal infection. After a short remission, the tumor recurred in November of the same year and in May and August of 2007 regardless of the repeated incision and pus drainage. He was referred to our hospital on 27 September 2007. His first physical examination at our outpatient office showed a skin-colored, well-demarcated, multilocular, cystic subcutaneous tumor on the dorsum of his right hand. Histopathological examination revealed a pseudocyst with fibrous walls of connective tissue. Continuous, bead-like hyphae, positive with periodic acid-Schiff stain and Grocott stain, were found within the pseudocyst. Morphological and molecular biological examinations of the separately cultured specimens identified the causative agent as Exophiala jeanselmei. The entire cyst was removed under local anesthesia, and an artificial dermis made of silicon membrane was applied to the wound. Skin graft was performed in November after confirming no recurrence of the fungal infection. Terbinafine hydrochloride 125 mg/day has continued. No recurrence has been observed up to now.

Necrotizing fasciitis caused by Streptococcus pneumoniae.

A 69-year-old woman presented with shivering and pain in the lower extremities on 5 April 2006; she was referred to the dermatology division of our hospital on the following day with difficulty in walking. She had been suffering from non-viral, non-alcoholic liver cirrhosis, and was being treated by the Division of Internal Medicine. Physical examination showed edema in the lower extremities and light purpuras on the groin and legs. Low blood pressure had been observed since admission. Necrotizing fasciitis (NF) was suspected on the basis of the skin symptoms, systemic conditions, and magnetic resonance imaging. During surgical debridement under general anesthesia, cardiopulmonary arrest occurred, and the patient died 12 h after admission. NF, in its early stages, exhibits few skin changes. In order to differentiate it from other skin infections, it is necessary to take into account blood pressure, abnormal systemic conditions, and severe pain out of proportion to its minor skin changes. In the present case, Streptococcus pneumoniae was detected by blood culture. Soft tissue infectious diseases caused by S. pneumoniae, especially NF, are very rare. We have reviewed reported cases of NF caused by S. pneumoniae.

PARG1, a protein-tyrosine phosphatase-associated RhoGAP, as a putative Rap2 effector.

Rap2 belongs to the Ras family of small GTP-binding proteins, but its specific signaling role is unclear. By yeast two-hybrid screening, we have found that the Caenorhabditis elegans ortholog of Rap2 interacts with a protein containing a Rho-GTPase-activating protein (RhoGAP) domain, ZK669.1a, whose human ortholog PARG1 exhibits RhoGAP activity in vitro. ZK669.1a and PARG1 share a homology region with previously unknown function, designated the ZK669.1a and PARG1 homology (ZPH) region. Here we show that the ZPH region of PARG1 mediates interaction with Rap2. PARG1 interacted with Rap2 in a GTP-dependent manner but not with Ras or Rap1. We also show that PARG1 and its mutant lacking the ZPH region induce typical cytoskeletal changes for Rho inactivation in fibroblasts. Rap2 suppressed this in vivo action of PARG1 but not that of the mutant PARG1. These results suggest that PARG1 is a putative specific effector of Rap2 to regulate Rho.

Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase.

Little is known about the specific signaling roles of Rap2, a Ras family small GTP-binding protein. In a search for novel Rap2-interacting proteins by the yeast two-hybrid system, we isolated isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a previously described but uncharacterized isoform. Other isoforms of MAP4K4 in humans and mice are known as hematopoietic progenitor kinase (HPK)/germinal center kinase (GCK)-like kinase and Nck-interacting kinase, respectively. MAP4K4 belongs to the STE20 group of protein kinases and regulates c-Jun N-terminal kinase (JNK). MAP4K4 interacted with Rap2 through its C-terminal citron homology domain but did not interact with Rap1 or Ras. Interaction with Rap2 required the intact effector region of Rap2. MAP4K4 interacted preferentially with GTP-bound Rap2 over GDP-bound Rap2 in vitro. In cultured cells, MAP4K4 colocalized with Rap2, while a mutant MAP4K4 lacking the citron homology domain failed to do so. Furthermore, Rap2 enhanced MAP4K4-induced activation of JNK. These results suggest that MAP4K4 is a putative effector of Rap2 mediating the activation of JNK by Rap2.

The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton.

Rap2 belongs to the Ras family of small GTP-binding proteins, but its specific roles in cell signaling remain unknown. In the present study, we have affinity-purified from rat brain a Rap2-interacting protein of approximately 155 kDa, p155. By liquid chromatography tandem mass spectrometry, we have identified p155 as Traf2- and Nck-interacting kinase (TNIK). TNIK possesses an N-terminal kinase domain homologous to STE20, the Saccharomyces cerevisiae mitogen-activated protein kinase kinase kinase kinase, and a C-terminal regulatory domain termed the citron homology (CNH) domain. TNIK induces disruption of F-actin structure, thereby inhibiting cell spreading. In addition, TNIK specifically activates the c-Jun N-terminal kinase (JNK) pathway. Among our observations, TNIK interacted with Rap2 through its CNH domain but did not interact with Rap1 or Ras. TNIK interaction with Rap2 was dependent on the intact effector region and GTP-bound configuration of Rap2. When co-expressed in cultured cells, TNIK colocalized with Rap2, while a mutant TNIK lacking the CNH domain did not. Rap2 potently enhanced the inhibitory function of TNIK against cell spreading, but this was not observed for the mutant TNIK lacking the CNH domain. Rap2 did not significantly enhance TNIK-induced JNK activation, but promoted autophosphorylation and translocation of TNIK to the detergent-insoluble cytoskeletal fraction. These results suggest that TNIK is a specific effector of Rap2 to regulate actin cytoskeleton.