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Biomedical subjects

M Akiyama

Publications and source records attributed to M Akiyama.

At least 19 recordsLinked to original sources
PubMed2007

Plectin defects in epidermolysis bullosa simplex with muscular dystrophy.

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD, MIM 226670) is caused by plectin defects. We performed mutational analysis and immunohistochemistry using EBS-MD (n = 3 cases) and control skeletal muscle to determine pathogenesis. Mutational analysis revealed a novel homozygous plectin-exon32 rod domain mutation (R2465X). All plectin/HD1-121 antibodies stained the control skeletal muscle membrane. However, plectin antibodies stained the cytoplasm of type II control muscle fibers (as confirmed by ATPase staining), whereas HD1-121 stained the cytoplasm of type I fibers. EBS-MD samples lacked membrane (n = 3) but retained cytoplasmic HD1-121 (n = 1) and plectin staining in type II fibers (n = 3). Ultrastructurally, EBS-MD demonstrated widening and vacuolization adjacent to the membrane and disorganization of Z-lines (n = 2 of 3) compared to controls (n = 5). Control muscle immunogold labeling colocalized plectin and desmin to filamentous bridges between Z-lines and the membrane that were disrupted in EBS-MD muscle. We conclude that fiber-specific plectin expression is associated with the desmin-cytoskeleton, Z-lines, and crucially myocyte membrane linkage, analogous to hemidesmosomes in skin.

Adult↗
PubMed2006

Eccrine porocarcinoma and Bowen's disease arising in a seborrhoeic keratosis.

An association between seborrhoeic keratosis (SK) and malignant tumours is considered to be rare. We observed a case of eccrine porocarcinoma and Bowen's disease (BD) occurring synchronously, forming one lesion in a SK on the abdomen. It is controversial whether malignant neoplasms arising in SK occur only by chance or if pre-existing SK plays a role in pathogenesis. This case suggests an implication of pre-existing SK in the subsequent development of both BD and eccrine porocarcinoma.

Aged, 80 and over↗
PubMed2006

PDGF isoforms induce and maintain anagen phase of murine hair follicles.

BACKGROUND: It is known that platelet-derived growth factor (PDGF) receptors are expressed in hair follicle (HF) epithelium. OBJECTIVES: The aim of the present study was to clarify the effects of PDGF-AA and -BB on the cyclic growth of HFs. METHODS: PDGF-AA or -BB was injected into the dorsal skin of C3H mice during the second telogen phase once daily for five consecutive days, or PDGF-AA or -BB dissolved in hyaluronic acid was injected only once. In order to confirm the effects of different PDGF isoforms, anti-PDGF-AA antibody or anti-PDGF-BB antibody was injected just after each injection of PDGF-AA or -BB. In addition, anti-PDGF antibodies were injected into the skin of C3H mice during the second anagen phase once daily for 5 days. We studied expression of signaling molecules in the skin where anagen phase had been induced by PDGF injection by real-time RT-PCR. RESULTS: Both PDGF-AA and -BB injection experiments immediately induced the anagen phase of the hair growth cycle at the injection sites. The induction of anagen was interfered by anti-PDGF antibody treatment. Real-time RT-PCR using extracted RNA from the PDGF injected sites of skin samples showed upregulated expression of HF differentiation-related key signaling molecules, Sonic hedgehog (Shh), Lef-1 and Wnt5a. CONCLUSIONS: These results indicate that both PDGF-AA and -BB are involved in the induction and maintenance of the anagen phase in the mouse hair cycle. Local application of PDGF-AA and -BB might therefore prove to be an effective treatment option for alopecia associated with early catagen induction and elongated telogen phase.

Animals↗
PubMed2006

Hair follicle stem cell-targeted gene transfer and reconstitution system.

Gene transfer to hair follicle (HF) epithelium is an attractive approach for not only treating skin diseases, but also many systemic disorders. In this study, we attempted to develop a gene transfer system for HF epithelial stem cells to maximize the beneficial therapeutic effects. For persistent and stable transgene expression in HF stem cells, we transferred retroviral vectors encoding reporter genes into cultured HF stem cells. In addition, these cells were mixed with cultured dermal papilla cells and transplanted on to immunodeficient mice. We succeeded in reconstituting HFs and their appendages in which these cells harbored a transgene reporter. The transgene expression was observed in all skin epithelial compartments including the HF epithelium, sebaceous gland and epidermis. In addition, transgene expression was observed for at least 6 months. This HF stem cell-targeted gene transfer and reconstitution system provides reliable gene-function analysis and gene therapy.

Animals↗
PubMed2006

Childhood epidermolysis bullosa acquisita with autoantibodies against the noncollagenous 1 and 2 domains of type VII collagen: case report and review of the literature.

Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal bullous disease characterized by IgG autoantibodies to type VII collagen, a major component of anchoring fibrils. Most patients with EBA are adult and develop autoantibodies to the noncollagenous (NC) 1 domain of type VII collagen. We describe a 4-year-old Japanese boy presenting pruritic vesicles and tense blisters over his whole body. Immunofluorescence studies revealed linear IgG/C3 deposits along the dermal-epidermal junction of the patient's skin, and circulating IgG autoantibodies mapping to the dermal side of 1 M NaCl-split skin. By immunoblotting analysis using dermal extracts as a substrate, the patient's IgG antibodies labelled a 290-kDa protein corresponding to type VII collagen. Immunoblotting studies using recombinant proteins demonstrated that the patient's circulating autoantibodies recognized not only the NC1 but also the NC2 domain of type VII procollagen. Review of the previously reported cases and the present case suggested that patients with EBA with autoantibodies to regions other than the NC1 domain are all children younger than 10 years of age with clinical features of an inflammatory phenotype.

Autoantibodies↗
PubMed2006

Bacterial infection-induced generalized Hailey-Hailey disease successfully treated by etretinate.

Hailey-Hailey disease (HHD; familial benign chronic pemphigus) is a hereditary blistering disorder characterized by episodic maceration and erosions mainly in intertriginous areas, and generalized eruptions are rarely seen. We report here a 51-year-old woman with generalized HHD who was successfully treated with oral etretinate. The present case suggests that oral etretinate is effective against the generalized eruptions even in cases in which bacterial infection has triggered the generalization of HHD.

Administration, Topical↗
PubMed2006

Drug eruptions to contrast media in Japan.

BACKGROUND: In Japan, drug eruptions to nonionic iodinated contrast media have been reported since the products appeared on the market in 1986. OBJECTIVES: To evaluate this clinical finding, we analysed the number of patients with drug eruption to contrast media in our hospital from 1989 to 2003. METHODS: In total, 117 patients suspected of such drug eruptions were patch and intradermal tested with contrast media (as commercially sold). Those who tested positive were evaluated. RESULTS: Of the 117 patients, 69 patients (19 men; 50 women, mean +/- SD age 51.4 +/- 16.5 years, range 17-86) showed positive reactions to contrast media. The number was 6-13 annually from 1989 to 1995, and 1-4 annually from 1996 to 2003. CONCLUSION: Although our data suggest (but do not prove) that patients with drug eruption to contrast media decreased in number, this condition is still not rare in Japan. Higher annual exposure to contrast media, including pretesting, could play an important role in this observation.

Adolescent↗
PubMed2005

Multiple intracranial subarachnoid osteomas.

OBJECTIVE AND IMPORTANCE: Intracranial osteomas, which have no connections with the dura or the skull, are very rare. Here we report one case of multiple intracranial subarachnoid osteomas. CLINICAL DESCRIPTION: A 24-year-old gentleman, who had no previous history of systemic disease, meningitis or head injury, presented with a 6-month history of non-specific intermittent headache over the whole head. Neuro-imaging showed multiple ossified lesions in the right frontal area, which were found to compress the underlying cerebral hemisphere. The patient underwent a right frontal craniotomy. The masses were dissected from the depressed brain along the intact pial planes, however, all of the white bone-hard masses tightly adhered to the superficial cortical veins. The masses were removed and the cortical veins were sacrificed. The patient had headaches and was nauseous for three days after the surgery due to venous congestion; however, the patient was neurologically intact on discharge. Pathological diagnosis was osteoma. CONCLUSION: To our knowledge, this is the first report of multiple intracranial subarachnoid osteomas. Surgical findings strongly support the hypothesis of the origin of the tumour that the primitive mesenchymal cells from the connective tissue might have migrated into the subarachnoid space accompanying the intracerebral blood vessels.

Adult↗
PubMed2005

Direct injection of plasmid DNA into the skin induces dermatitis by activation of monocytes through toll-like receptor 9.

BACKGROUND: Direct injection of naked DNA into skin can be efficiently used to transfer genes into keratinocytes in vivo. However, bacterial DNA is known to be a potent stimulus for vertebrate immune cells and immune systems. Towards the clinical use of this method, this study examined whether the application of plasmid DNA by direct injection induces any adverse skin effects. METHODS: Several plasmid preparations were prepared and directly injected into rat and human skin. Migration, IL-6 production, and reactive oxygen production assays were performed to determine the type of the primary cells responsible for the reaction. Involvement of toll-like receptor (TLR) 9 was examined by experiments using TLR9-knockout mice. RESULTS: Injection of several plasmid preparations into rat and human skin resulted in an inflammatory reaction at the treated site. Contamination by endotoxin in the plasmid preparation was shown to worsen this skin inflammation reaction. Immunohistochemical analysis showed that the infiltrating cells in the skin lesions were predominantly monocytes and neutrophils. Further experiments examining migration, IL-6 production, and reactive oxygen production indicated that the primary responsible cells were monocytes rather than neutrophils. Since it was recently shown that cytosine-guanosine dinucleotide (CpG) motif is critical for immune reaction induction in bacterial DNA and cellular responses were mediated by TLR9, we injected plasmids into the ear skin of TLR9-knockout mice. A decrease in ear swelling was noted in the knockout mice, compared to controls, suggesting that plasmid-DNA-induced dermatitis was mediated mostly by TLR9. CONCLUSIONS: This study demonstrates that injection of plasmid DNA induces skin inflammation initiated by monocyte activation via TRL9. We should therefore attempt to counteract this dermatitis during the clinical use of the naked DNA injection method in skin.

Animals↗
PubMed2005

Rapid damping of food-entrained circadian rhythm of clock gene expression in clock-defective peripheral tissues under fasting conditions.

Restricted feeding-induced free-running oscillation of clock genes in the liver was studied in homozygous Clock-mutant (Clock/Clock) mice. Similar to wild-type mice, Clock/Clock mice showed robust food-anticipatory behavioral activity in accordance with a restricted feeding schedule. Also, the peak of all clock gene mRNAs tested was phase-advanced in the liver of Clock/Clock mice as well as wild-type mice, although the amplitude of clock gene expression was low in Clock/Clock mice. The food-anticipatory behavioral rhythm in Clock/Clock mice maintained a period similar to wild-type mice during 2-day fasting after the cessation of restricted feeding. However, during the fasting days after temporal feeding cues were removed, the oscillation of clock genes in the liver and heart, excluding the suprachiasmatic nuclei, appeared to result in arrhythmicity in Clock/Clock mice. Thus, although the CLOCK-based molecular mechanism is not required for the expression of food-anticipatory activity, intact CLOCK protein might be involved in sustaining several cycles of peripheral circadian oscillations after restricted feeding-induced resetting.

ARNTL Transcription Factors↗
PubMed2005

Beta defensin-3 engineered epidermis shows highly protective effect for bacterial infection.

Defensins are small cationic proteins that harbor broad-spectrum microbicidal activity against bacteria, fungi and viruses. This study examines the effects on pathogens of the epidermis engineered to express human beta-defensin 3 (HBD3) to combat bacterial infections. First, we examined the localization of HBD3 in the epidermis and observed HBD3 in the intercellular spaces and lamellar bodies of the upper epidermal layers. This result showed HBD3 expressed and assembled in the outer layers of the epidermis was suspected to counter the invading microorganisms. Next, we established a keratinocyte cell line that stably expressed HBD3 and found that the culture medium showed antibacterial activity. Furthermore, we prepared an epidermal sheet of these cells with the HBD3 gene and grafted this onto a dermal wound on a nude rat. The HBD3 engineered epidermis demonstrated significant antimicrobial activity. Skin ulcers without epidermis are constantly exposed to invading microorganisms. Biopsy samples of re-epithelizing epidermis from patients with skin ulcers were collected, and HBD3 mRNA level measured in the epidermis. The epidermal samples from the ulcer skin expressed 2.5 times higher levels of HBD3 transcript than those in the control skin. These results, taken together, indicate that the therapeutic introduction of the HBD3 gene into somatic cells may provide a new gene therapy strategy for intractable infectious diseases.

Animals↗
PubMed2005

Detection of 1733insC mutations in an Asian family with Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant genodermatosis characterized by skin tumours, including multiple fibrofolliculomas, trichodiscomas and acrochordons. BHD patients also may suffer from associated renal and colonic carcinomas. The defective gene in BHD has been recently identified and is suspected of being a tumour suppressor gene. Several mutations of the BHD gene have been reported only in Caucasian patients. OBJECTIVES: This study reports the first Asian family that has been demonstrated to carry a BHD mutation. PATIENTS/METHODS: The proband was a 26-year-old Japanese man with multiple asymptomatic, soft skin-coloured papules on his face, neck and trunk, which were clinically thought to be acrochordon. His father was also affected. Histopathologically, the papules revealed a fibrofolliculoma that had a circumscribed proliferation of fibroblasts and collagen fibres surrounding an abnormal hair follicle. RESULTS: Mutational analysis of the BHD gene of the proband and the father detected 1733insC, a cytosine insertion mutation in an eight-cytosine tract (nucleotides 1733-1740) in exon 11. Analysis of fibrofolliculoma in the proband showed heterozygous 1733insC mutation, suggesting the absence of loss of heterozygosity. Interestingly, previous mutational analysis in Caucasian patients revealed that both1733insC and 1733delC mutations were hot spots. CONCLUSIONS: This study is the first to find the same hot-spot 1733insC mutation in Asian kindred. The mutations in this polycytosine tract may have a wide, global distribution despite their arising from a different ethnic background.

Adult↗
PubMed2005

Ichthyosis bullosa of Siemens: its correct diagnosis facilitated by molecular genetic testing.

Ichthyosis bullosa of Siemens (IBS, MIM 146800) is a unique congenital ichthyosis characterized by mild epidermal hyperkeratosis over flexural areas, blister formation and the development of superficially denuded areas of hyperkeratotic skin. It is clinically difficult to distinguish severe IBS from mild bullous congenital ichthyosiform erythroderma (BCIE, MIM 113800). In the current literature, 19 IBS families with keratin 2e (K2e) mutations have been reported, despite only five IBS families having been reported before the first identification of K2e mutation in 1994. We studied four patients from three Japanese IBS families. They had previously been misdiagnosed as having BCIE before the correct diagnosis was made after mutation detection. To detect the pathogenic mutations, we performed direct sequencing of the entire coding regions of KRT2E encoding K2e in the patients and healthy family members. K2e mutations, a 1469T-->C transition (L490P) and a 1477G-->A transition (E493K) within the conserved 2B helix termination motif of the rod domain were detected in the families and the definite diagnosis of IBS was made in the four cases. The present results indicate that IBS is not such a rare entity as was previously thought, and accurate diagnosis is now available by mutation analysis.

Adult↗
PubMed2005

Prenatal exclusion of harlequin ichthyosis; potential pitfalls in the timing of the fetal skin biopsy.

BACKGROUND: Harlequin ichthyosis (HI) is a severe and usually fatal congenital skin disorder with autosomal recessive inheritance. Several cases of HI prenatal diagnosis have been performed using fetal skin biopsy, mainly at around 23 weeks estimated gestational age (EGA), and reported in the literature. However, prenatal testing must be done earlier than 21 weeks EGA in several countries including Japan where the present HI families live, because termination is legally allowed only until 22 weeks EGA. OBJECTIVES: We report the successful prenatal exclusion of HI in two fetuses from two independent families and discuss the technical difficulties and potential pitfalls in the prenatal exclusion of HI at early gestation stages. METHODS: Fetal skin biopsy specimens and amniotic fluid samples at 19 and 20 weeks EGA from two fetuses at risk of HI were examined by light and electron microscopy. RESULTS: For the prenatal diagnosis in case 1, the fetal skin biopsy samples were obtained at 20 weeks EGA and showed normal keratinization in the hair canals; no abnormalities were observed in the keratinized cells. In case 2, the interfollicular epidermis and the hair follicles in the samples obtained at 19 weeks EGA had not differentiated enough to show proper keratinization. However, lamellar granules were normally formed in the inner root sheath cells of the late bulbous hair pegs. From these ultrastructural findings, the case 1 fetus was diagnosed as unaffected with HI, and the case 2 fetus was diagnosed as unlikely to be affected. Subsequently, both were born as healthy, unaffected babies. CONCLUSIONS: The timing of biopsies at 19 weeks EGA is not ideal for fetal skin biopsy because the samples are not always sufficiently differentiated for the prenatal diagnosis of HI. However, morphological observations of lamellar granules gives us important additional information useful for HI prenatal diagnosis.

Amniotic Fluid↗
PubMed2005

Structural, enzymatic and molecular studies in a series of nonbullous congenital ichthyosiform erythroderma patients.

Causative gene defects have not been demonstrated in the majority of nonbullous congenital ichthyosiform erythroderma (NBCIE) cases. The purpose of this study was to further elucidate the pathogenesis of NBCIE. Immunohistochemical and ultrastructural observations, transglutaminase activity assays and sequencing of TGM1 were performed in five patients from four NBCIE families. Transglutaminase 1 (TGase 1), involucrin and loricrin expression and in situ transglutaminase activity were present in all of the cases. Ultrastructurally, two cases out of five showed incomplete thickening of the cornified cell envelope (CCE) during keratinization and the other three exhibited abnormal lipid droplets in the cornified cells and malformed lamellar granules. No TGM1 mutation was found in any of the four families by direct sequence analysis. NBCIE cases with normal TGase 1 seemed to have two distinct patterns of abnormality, one with abnormal lipid droplets and malformed lamellar granules and the other with defective CCE formation.

Adult↗
PubMed2005

Two cases of atypical membranous aplasia cutis with hair collar sign: one with dermal melanocytosis, and the other with naevus flammeus.

We report two atypical cases of membranous aplasia cutis surrounded by a rim of hairs, one case associated with dense dermal melanocytosis and the other with naevus flammeus, with characteristic clinical features. A rim of hypertrichosis, 'hair collar' sign, is proposed to have a close association with neuroectodermal defects. A failure of the normal closure of the cranial neural tube might have affected foetal skin development, including melanoblast migration and capillary network formation. The changes in the present cases, as well as the hair collar sign may suggest a complex hamartomatous nature of membranous aplasia cutis.

Ectodermal Dysplasia↗
PubMed2005

Two cases of atypical melanocytic lesions in recessive dystrophic epidermolysis bullosa infants.

Summary Atypical melanocytic lesions (AtML) are known to be associated with epidermolysis bullosa (EB), mainly with the junctional subtype. We report two cases of AtML in two female infants with recessive dystrophic epidermolysis bullosa (RDEB). Both lesions were dark brown- to black-coloured, asymmetric-shaped macules, 3-4 cm in size, with an irregular border and were located on the forearms of two unrelated, 1-year-old female infants. On a clinical and pathological basis, the pigmented macules were diagnosed as AtML in EB patients. There are only a few reports describing in detail the clinical and histopathological features of AtML in RDEB, especially in infant cases. AtML may easily be misdiagnosed as malignant melanoma and, even in infant patients with RDEB, this should be included as one of the differential diagnosis of pigmented lesions.

Diagnosis, Differential↗