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Notes: Abstract OPLL (ossification of the posterior longitudinal ligament of the spine) is a common form of human myelopathy with a prevalence of as much as 4% in a variety of ethnic groups. To clarify the genetic factors that predispose to OPLL, we have studied ttw (tiptoe walking), a mouse model that presents ectopic ossification of the spinal ligaments similar to OPLL and have found that the ttw phenotype is caused by the nonsense mutation of the gene encoding nucleotide pyrophosphatase (NPPS), a membrane-bound glycoprotein thought to produce inorganic pyrophosphate, a major inhibitor of calcification and mineralization. To investigate a possible role of NPPS in the etiology of OPLL, we have examined its genetic variations in OPLL patients. A total of 323 OPLL patients was screened by means of polymerase chain reaction/single-strand conformation polymorphism analysis covering all the exons and their surrounding introns, plus about 1.5-kb of the promoter region. We identified ten nucleotide variations in the NPPS gene; five of the alterations caused amino-acid substitutions, and two of them were found specifically in OPLL patients. Subsequently, we performed an association study using these variations and found a significant association of an allele, viz., a deletion of T at a position 11 nucleotides upstream from the splice acceptor site of intron 20 (IVS20–11delT), with OPLL; the proportion of the individuals having this deletion was significantly higher (P = 0.0029) in OPLL patients than in controls, indicating that those who have this variation may be more susceptible to the abnormal ossification of the spinal ligaments. Thus, our study suggests that NPPS plays an important role in the etiology of human OPLL.

Notes: Human herpesvirus type 8 (HHV-8, Kaposi's sarcoma-associated herpesvirus)-positive lymphoma taking anaplastic large cell morphology in the skin is described in a 46-year-old man with AIDS. Multiple erythematous nodules appeared on the trunk and extremities during the treatment of AIDS. Histological examination of cutaneous nodules showed dense infiltration of CD30 + atypical lymphoid cells in the deep dermis. Immunoglobulin JH gene rearrangement was detected in these lymphoma cells. Both Epstein–Barr virus-encoded small RNA and HHV-8 mRNA (T1.1/nut-1) were detected in these lymphoma cells by in situ hybridization. Remarkable retention of the pericardial fluid was observed at the same time that cutaneous lesions grew, and lymphoma cells in the pericardial fluid showed the same phenotype as the cutaneous lymphoma. Chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone effectively reduced both the cutaneous nodules and pericardial fluid. However, the patient died 4 months after diagnosis because of cytomegalovirus infection. As far as we know, this is the first report of an HHV-8-positive cutaneous lymphoma taking anaplastic large cell morphology. This case suggests the association of AIDS-related anaplastic large cell lymphoma with HHV-8.

Notes: Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon–intron structures of the gene and produced a CHAC model mouse introducing no. 60–61 exon deletion corresponding to a human disease mutation by a gene-targeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.

Notes: It is well known that two different photobiologic processes mainly take place when the human skin is exposed to ultraviolet (UV) light. The long waves of UVA and visible light (320–400 nm) irradiation causes skin tanning by melanocytic activation and the short waves of UVB (280–320 nm) can elicit variety of biologic action in cutaneous keratinocytes, melanocytes and other skin component cells. The sensitivity to the UV lights is generally depending on the three kinds of the skin type classified by the proposal of Pathak et al. [1]. The skin sensitivity of Japanese population, however, seems to be different from that of Caucasian's population because of the differences in genetic background and skin color, as indicated by Satoh and Kawada [2]. They tried to classify into three groups as J-I (always burn and rarely tan), J-II (moderately burn and moderately tan) and J-III (never burn and always tan) by the skin types to UV lights for the sun-tanning and sun-burning. Comparing these two criteria, a general concern indicates that J-I–III may correspond to the skin type II–IV of the Fitzpatrick's classification, respectively. Based on the Japanese skin types, the incidence of skin cancers and precancerous lesions related to the long-term exposure of sun-light was epidemiologically estimated by Araki et al. [3]. According to their results for several years (1992–1998), the overall number of skin cancers and precancerous states in Japanese was demonstrated to be small in comparison with the incidence of Caucasian's population, even though the people sets in areas of higher ambient solar radiation. However, working outdoors having J-I and/or a history of severe sunburn during childhood were found to be important risk factors, particularly among people of over 60 years of age. Regarding skin cancers and sun-exposed areas, we compared between 20 patients with skin cancers (males 13 and females seven) (average 65 years old) (〈link href="#t1-14"〉Table I) and 24 controls (males 10 and females 14), who were selected as similar ages to the patients at random, in their skin types and life environments by a questionnaire system. The skin types of the patients were J-I (15%), J-II (40%), and J-III (35%) and those of controls were J-I (4.2%), J-II (62.5%), and J-III (4.2%), respectively. The patient group tended not to protect from sun exposure and most of them were farmers. UV exposure is known to induce modulation of the skin immune system which Langerhans cells decrease in number in the epidermis, and on the other hand it is supposed that interleukin IL-10 producing macrophages (CD11b+) expand in the dermis. Not only IL-10, but also tumor necrosis factor (TNF)-α from macrophages and mast cells in the dermis seem to increase and suppress Th1 immune responses of the epidermis and Th2 immune responses might be induced by UV irradiation [4]. Recently, it has been reported, however, that in patients with polymorphous light eruption (PLE), the expression of TNF-α, IL-4, and IL-10 is reduced by UVB irradiation and that PLE appearance is related to UVB-induced immunosuppression [5].〈tabular xml:id="t1-14"〉I〈title type="main"〉 Twenty patients with skin cancers (average ages: 65 years old) (Department of Dermatology, Fukushima Medical University Hospital, 2001–2002) 〈table frame="topbot"〉〈tgroup cols="2" align="left"〉〈colspec colnum="1" colname="col1"/〉〈colspec colnum="2" colname="col2"/〉〈thead valign="bottom"〉〈row rowsep="1"〉Skin cancersNumber of patients〈tbody valign="top"〉Malignant melanoma8Squamous carcinoma4Bowen's disease4Basal cell carcinomas3Eccrine porocarcinoma1Location of skin cancersSun-exposed areas9Non-exposed areas11Then, we attempted to study UVB effects on atopic disease and chronic inflamed skin diseases in the therapeutic advantage, although it is harmful for the patients to be cutaneous carcinogenesis. The epidermal keratinocytes are capable of producing CC chemokines in the local Th2 response, as seen in atopic dermatitis, mycosis fungoides, etc. [6]. Thymus and activated-related chemokine (TARC) is one of the chemokines produced by keratinocytes which selectively activate lymphocytes of Th2 subset expressing CCR4 (receptor for TARC) [7]. Accumulating evidence has suggested that these chemokines have primary pathogenic importance in Th2 skin diseases. In order to find the effects of UVB irradiation on the production of TARC, we used a human keratinocyte HaCaT cell line. As assessed by RT-PCR and ELISA, UVB irradiation significantly decreased the expression of TARC mRNA and protein in HaCaT cells stimulated with interferon-γ (IFN-γ) and TNF-α in a dose-dependent manner. The down-regulation of TARC expression may be mediated in part by activation of the particular transcription, signal transducer and activator of transcription 1 (STAT 1), since it has shown that STAT 1 DNA-binding was down-regulated by UVB irradiation. Our results suggest that STAT 1 and other transcription factors play an important biological role in immune system of human skin irradiated by UVB and may support the results of Kolgen et al. [5].In this point of view, UVB irradiation will be a therapeutic tool for skin diseases related to Th2 type reaction, such as atopic dermatitis, mycosis fungoides, etc., although we need to optimize adequately the use of UVB in patients with J-I skin type or those of whom have the episode of severe sun-burn after UVB irradiation.〈section xml:id="abs1-1"〉〈title type="main"〉References1. Pathak, M.A., Nghiem, P. and Fitzpatrick, T.B. Acute and chronic effects on the skin. In: Fitzpatrick's Dermatology in General Medicine, 5th edn (Freedberg, I.M., Eisen, A.Z., Wolf, K., Austen, K.F., Goldsmith, L.A., Katz, S.I. and Fitzpatrick, T.B. eds), pp. 1598–1607. McGraw-Hill, New York (1999).2. Satoh, Y. and Kawada, A. Action spectrum for melanin pigmentation to ultraviolet light, and Japanese skin typing. In: Brown Melanoderma: Biology and Diseases of Epidermal Pigmentation (Fitzpatrick, T.B., Wick, M.M. and Toda, K. eds), pp. 87–95. University of Tokyo Press, Tokyo (1986).3. Araki, K., Nagano, T., Ueda, M., Washio, F., Watanabe, S., Yamaguchi, N. and Ichihashi, M. Incidence of skin cancers and precancerous lesions in Japanese- Risk factors and prevention. J. Epidemiol. 9, S14–S21 (1999).4. Teunissen, M. B., Piskin, G., Nuzzo, S. et al. Ultraviolet B radiation induces a transient appearance of IL-4+ neutrophils, which support the development of Th2 responses. J Immunol. 168, 3732–3739 (2002).5. Kolgen, W., van Meurs, M., Jongsma, M. et al. Differential expression of cytokines in UVB-exposed skin of patients with polymorphous light eruption. Arch. Dermatol. 140, 295–302 (2004).6. Kakinuma, T., Sugaya, M., Nakamura, K., Kaneko, F., Wakugawa, M., Matsushima, K. and Tamaki, K. Thymus and activation-regulated chemokine (TARC/CCL17) in mycosis fungoides: serum TARC levels reflect the disease activity of mycosis fungoides. J. Am. Acad. Dermatol. 48, 23–30 (2003).7. Imai, T., Nagira, M., Tkagi, S. et al. Selective recruitment of CCR4-binding Th2 cells toward antigen-presenting cells by the CC chemokins thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol. 11, 81–88 (1999).

Notes: We study single-carrier traps in a GaAs/AlxGa1−xAs heterostructure by observing random telegraph signals (RTSs), which are caused by the traps having energy levels within a few kBT of the Fermi level. RTSs are observed in a split gate device while a narrow channel is shifted by independently controlling the voltage applied to each part of the split gate. This measurement reveals the variations of the energy levels of traps with the channel position. From these variations the locations and the energy distributions of the traps are demonstrated. The strength of the confinement potential around the trap is also discussed. © 1995 American Institute of Physics.

Notes: Background. Systemic lupus erythematosus (SLE) is designated by the Japanese government as one of the intractable diseases and all patients, who suffer from these diseases, are registered to get financial aid for treatment. Using newly registered SLE patients, a case-control study was conducted to evaluate potential risk factors. Methods. Two-hundred and eighty-two women SLE patients, newly registered to receive financial aid for treatment, and 292 randomly selected health examination participants at public health centers (controls) were surveyed from April 1988 through March 1990. By means of a self-administered questionnaire, data concerning demographic variables, smoking and drinking habits, past medical and reproductive history, and family history were collected. Results. Based on unconditional logistic regression analysis, the risk of SLE was significantly increased for current smokers (age-adjusted odds ratio (OR) = 2.31, 95% confidence interval (CI) (1.34–3.97). Alcohol and milk intake were inversely associated with risk. Family histories of asthma and collagen diseases, including SLE, were associated with significantly elevated risk of SLE (OR = 2.07, 95% ci 1.14–3.77; OR = 5.20, 95% CI 1.08–24.95, respectively). Regarding reproductive function, women with menarche at age 15 or later had significantly higher risk than those, who started menstruating before age 12 (OR = 3.82, 95% CI 1.66–8.81 for menarche at 〉 15 years and OR = 2.90, 95% a 1.14–7.39 for menarche at 〈inlineGraphic alt="geqslant R: gt-or-equal, slanted" extraInfo="nonStandardEntity" href="urn:x-wiley:00119059:IJD333:ges" location="ges.gif"/〉 16y). Conclusions. Our study suggests several risk factors, including smoking, family history, and reproductive history that may increase the risk of SLE.

Notes: Abstract Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia-derived factor (ADF), which we originally defined as an IL-2 receptor alpha-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)-transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress-induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein-nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of "redox regulation" is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.