Sumihisa Imakado

Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation

Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function. When we ablated Keap1, Keap1-deficient mice died postnatally, probably from malnutrition resulting from hyperkeratosis in the esophagus and forestomach. Nrf2 activity affects the expression levels of several squamous epithelial genes. Biochemical data show that, without Keap1, Nrf2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes. Breeding to Nrf2-deficient mice reversed the phenotypic Keap1 deficiencies. These experiments show that Keap1 acts upstream of Nrf2 in the cellular response to oxidative and xenobiotic stress.

Expression of angiogenic factors in neurofibromas

Abstract:  We studied the expression of angiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, platelet‐derived growth factor and hepatocyte growth factor) in cutaneous neurofibroma samples from patients with neurofibromatosis‐1. Immunohistochemical staining and the reverse transcribed polymerase chain reaction (RT‐PCR) method demonstrated that vascular endothelial and basic fibroblast growths factor are highly expressed in neurofibroma cells at both the protein and mRNA level. These data suggest that vascular endothelial and basic fibroblast growth factors may contribute to both the angiogenesis and hypervascularity of neurofibromas.

Eccrine syringofibroadenoma in a patient with a burn scar ulcer

A 72‐year‐old woman with a burn scar on the calves of both legs developed an ulcer on her right heel, surrounded by multiple verrucous nodules and plaques. She had experienced similar verrucous lesions on both legs in the burn scar areas. Although the clinical diagnosis was Marjolins ulcer, histologically the ulcer region showed thick fibrous tissue without any atypical epithelial cells. The verrucous lesions were consistent with the diagnosis of eccrine syringofibroadenoma (ESFA). Moreover, an ESFA‐like growth pattern was seen in the elevated margin of the ulcer. Our findings suggest that these lesions developed as a result of reactive eccrine duct hyperplasia followed by skin tissue remodelling.

PDGF-BB induces MAP kinase phosphorylation and VEGF expression in neurofibroma-derived cultured cells from patients with neurofibromatosis 1.

Neurofibromas of neurofibromatosis 1 (NF1) are highly vascular. Because the number of PDGF β receptors in neurofibroma‐derived cultured cells (NF‐derived cells) has been reported to be increased, we tested whether platelet‐derived growth factor BB (PDGF‐BB) could induce expression of vascular endothelial growth factor (VEGF) in NF‐derived cells. When analysed by reverse transcription‐polymerase chain reaction, VEGF mRNA expression was found to be stimulated by PDGF‐BB and TGF‐β1. Those growth factors stimulated the secretion of VEGF from NF‐derived cells. PDGF‐BB furthermore induced the mitogen‐activated protein kinase phosphorylation in NF‐derived cells from patients with NF1. In conclusion, PDGF‐BB stimulated VEGF secretion in NF‐derived cells, and this stimulation is probably important in neurofibroma hypervascularization.

Hereditary complement (C9) deficiency associated with dermatomyositis

A 28‐year‐old Japanese woman with hereditary complement (C9) deficiency and dermatomyositis is reported. She had a 3‐year history of facial erythema and a 1‐month history of progressive muscle weakness. Clinical and laboratory findings were suggestive of dermatomyositis; muscle biopsy confirmed an inflammatory myopathy. An unexpected finding, however, was the low titre of serum haemolytic complement (CH50). Treatment with prednisolone resulted in marked clinical improvement but did not affect the CH50 titre. Further investigation revealed a selective and total absence of the ninth complement component (C9), with direct DNA sequence analysis revealing a non‐sense mutation at Arg95 of the C9 gene. This case demonstrates that the muscle lesions of dermatomyositis can occur in the presence of a complement defect that would prevent the formation of the C5b‐9 membrane attack complex.

Two cases of subungual melanoma in situ

Melanonychia, which is characterized by brown or black pigmentation within the nail plate, includes heterogeneous conditions such as pigmented nevus, subungual melanoma and lentigo. We treated two cases of subungual melanoma in situ. One case was a 58‐year‐old woman who suffered from a malignant melanoma in situ of the left third fingernail, who had also suffered from melanonychia of the fingers for more than 30 years. She had a past history of carcinoma of the uterine cervix. The other patient was a 42‐year‐old man, who suffered from a malignant melanoma in situ of the right fifth fingernail. He had a past history of carcinoma of the stomach for which he had undergone surgery 2 years earlier. Both cases were accompanied by Hutchinsons sign on the fingertip skin, and the presence of this sign led to the correct diagnosis of subungual melanoma in situ. Judging from previously reported cases, it is unlikely that patients with malignant melanoma have an increased risk of carcinoma of the uterine cervix or of the stomach.

A probable case of Muckle–Wells syndrome

Muckle–Wells syndrome is a rare autosomally dominant disorder belonging to the group of periodic fever syndromes. Three main features of the disease are: (i) urticarial eruptions; (ii) progressive perceptive deafness; and (iii) amyloid nephropathy. A 26‐year‐old Japanese woman had suffered at birth from an urticarial rash and episodic fever. The fever was frequently associated with chills and ill‐defined malaise. There was no familial history of urticarial rash or fever. Although she did not recognize hearing loss, audiometry revealed perceptive deafness. She also had hepatosplenomegaly and hyperimmunoglobulinemia, but did not have persistent arthritis, or any neurological or gastrointestinal disorder. No growth retardation was observed. Skin biopsy specimens from her buttock showed a sparse perivascular and interstitial infiltrate of neutrophils in the papillary dermis. Periodic fever syndrome was diagnosed. Muckle–Wells syndrome was most likely, although no amyloid nephropathy was observed and no gene mutations of CIAS1 (T785C, C778T, G907A, G1315A, G1075C) were detected. We treated her with prednisolone, which had a partial effect. Previous treatment with colchicines, antihistamines, dapsone, clarithromycin, minocycline hydrochloride and loxoprofen sodium had been unsuccessful. Muckle–Wells syndrome may go undiagnosed for many years or be misdiagnosed as refractory urticaria. Therefore, we should consider the possibility of periodic fever syndrome when we see patients with refractory urticaria and episodic fever.

Cutaneous malignant fibrous histiocytoma of the face.

An 88‐year‐old Japanese female visited our department with an asymptomatic nodule on the right cheek. Other than treatment for hypertension for 15 years, the patient had been healthy. She had noticed the nodule one year earlier, and it had slowly enlarged to 25 × 25 × 5 mm, with redness, an irregular‐surface with ulcer formation, and was bony‐hard with no tenderness ( Fig. 1 ). There were no regional lymphadenopathies. These clinical features suggested a soft tissue tumor or basal cell carcinoma. Histopathological examinations revealed that the tumor was visible from the upper dermis beneath the flattered and partly eroded epidermis, and showed atypical and pleomorphic tumor cells with large, irregularly shaped nuclei, and variable amounts of cytoplasm ( Fig. 2 ). Some had bizarre nuclei, and occasional mitotic figures. These histopathological findings were suggestive of malignant fibrous histiocytoma. Magnetic resonance imaging showed that the tumor extended from the upper dermis to the subcutaneous tissue, was attached to the right maxillary bone, and involved the right orbit inferior margin. Apparent invasion to the bone was not seen. The tumor was resected and included skin, subcutaneous tissue, lower orbital adipose tissue, and fascia. A skin graft was taken from the thigh to cover the tumor resection. The resected tumor specimen measured 28 × 28 × 15 mm. Although the histopathological examination results were similar to the biopsy results, the tumor cells were arranged in irregular, intertwining bands, known as a storiform pattern in some areas, and focal necrosis was also seen. The tumor cells were markedly atypical with bizarre nuclei. Subcutaneous fat tissue was widely involved, and the tumor extended into the muscle tissue. In addition, the margin was positive for tumor cells in the deeper area of the tumor. Two weeks after the first operation, the patient had developed a small, firm nodule in the center of the skin graft that rapidly enlarged to form a 10‐mm tumor, which was likely the regrowth of the remaining tumor cells. A wide excision was considered, but because of her age and the extensiveness of the excision, containing maxillary bone, alternative treatment was pursued. Radiation therapy was performed five times per week, with a total dose of 60 gray. During the radiation therapy, the tumor enlargement stopped, and a skin ulcer on the grafted skin was made. The tumor started to decrease in size 1 month after the radiation therapy, and it continued to reduce in size until no tumor mass was seen by magnetic resonance imaging. No recurrence and no metastasis have occurred during the 3 years since cessation of the radiation therapy ( Fig. 3 ).

Cutaneous Bronchogenic Cyst of the Chin

A 30-year-old woman who was otherwise healthy visited our hospital for treatment of an asymptomatic subcutaneous cystic mass on her chin. It was noticed from her childhood but had recently increased in size. Physical examination revealed a nonadhesive, nontender, soft cystic mass measuring 20 ! 16 mm in the subcutaneous tissue of the center of the chin. The overlying skin appeared normal (fig. 1a). The cyst was surgically enucleated, and no connection to deeper structures was found. It was unilocular and contained a gelatinous yellowish mucoid material. On pathological findings, the cyst wall was lined with a ciliated pseudostratified columnar epithelium (fig. 1b). Phosphotungstic acid hematoxylin stain revealed a ciliated lining inside the cyst (fig. 1c). Some epithelial cells were also found to be Alcian blue positive and had diastase-resistant PAS-positive granules in their cytoplasms. They were thought to be goblet cells. There was no cartilage, thyroid tissue, smooth muscle, seromucinous glands, lymphoid follicles or salivary glands in or around the cyst. An electron-microscopic view showed ciliated cells with cilia, brush cells with microvilli and mucous cells with many mucinous granules without cilia or microvilli (fig. 2). All of them are equivalent to the normal components of bronchial epithelial [1]. This finding is evidence that the cyst was of bronchial origin. A cross-section revealed the structure of cilia, which consisted of 2 central microtubules surrounded by 9 paired microtubules, as previously reported [2]. We diagnosed the cyst as a cutaneous bronchogenic cyst in light of the above microscopic and electron-microscopic findings and in light of its anatomical location. The bronchogenic cyst is one of several cysts of embryonic foregut origin. Enteric cysts and esophageal cysts are also known as foregut origin cysts, but they rarely appear in the skin. Bronchogenic cysts usually occur in the mediastinum or pulmonary parenchyma, and they too are rarely found in the skin. Seybold and Clagett [3] first described a case of a cutaneous bronchogenic cyst in 1945. Subsequently, a total of 56 cases, including ours, have been reported in the

Disseminated Mycobacterium marinum infection in a patient with diabetic nephropathy

Abstract A patient with diabetic nephropathy who presented with multiple tender subcutaneous nodules caused by Mycobacterium marinum infection is presented.