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Objectives It has been known that the use of moisturizers is useful in preventing the onset and maintaining remission of atopic dermatitis (AD). We recently focused on the moisturizing effect of natural mineral dissolved water and have conducted various studies. In this study, we investigated whether the bath treatment using natural mineral dissolved water can improve dry skin in AD patient in prospective nonblind, nonrandomized controlled study. Methods Thirteen adults with almost clear to moderate AD took bath therapy using tap water for 13 days, followed by bath therapy using natural mineral dissolved water for 13 days. Changes in the severity scoring, patient‐oriented eczema measure, pruritus numerical rating scale, transepidermal water loss (TEWL) and hydration were evaluated at day1, 14 and 28. Results Tap water using bath treatment did not change the severity scoring and itch associated score, and it partially decrease TEWL when compared with baseline condition. Bath treatment using natural mineral dissolved water slightly decrease eczema area and severity index (EASI) score and significantly decrease TEWL with respect to baseline condition. Moreover, in relatively severe AD analysis, bath treatment with mineral dissolved water significantly decreased EASI and TEWL. Conclusions Based on these results, bathing with natural mineral dissolved water may be effective in improving the dry skin of atopic dermatitis. Further studies are needed to evaluate its effects more clearly.

A 37-year-old Japanese man with a 3-year history of diffuse cutaneous systemic sclerosis was admitted to our hospital with high fever, arthralgia, myalgia, and muscle weakness. A physical examination revealed facial erythema, Gottron's sign, and mechanic's hands in addition to skin sclerosis. Laboratory data revealed significantly elevated levels of creatine kinase and decreased complement. Anti-RNP, anti-Smith, anti-DNA, anti-β2 -glycoprotein 1, anti-polymyositis (PM)/Scl75, and anti-PM/Scl100 antibodies were detected. He also had urinary protein, interstitial lung disease, pericarditis, multifocal cerebral infarctions, and leukoencephalopathy. Thus, a diagnosis of overlap syndrome of diffuse cutaneous systemic sclerosis, dermatomyositis, and systemic lupus erythematosus with antiphospholipid syndrome was made. Because of the intractable course, he was treated with multiple immunosuppressive and immunomodulatory drugs, including three rounds of 1000 mg methylprednisolone pulse therapy. This is the first case report of anti-PM/Scl antibody-positive overlap syndrome of three major connective tissue diseases.

Oxidative stress has been reported to play an important role in the pathogenesis of skin fibrosis in systemic sclerosis (SSc). We previously identified that botulinum toxin (BTX) injection suppresses pressure ulcer formation in a cutaneous ischemia-reperfusion injury mouse model by regulation of oxidative stress. However, the therapeutic possibility of BTX administration for preventing skin fibrosis in SSc is unclear. The objective of this study was to investigate the effect of BTX-B on skin fibrosis in a murine model of SSc and determine the underlying mechanism. We found that BTX-B injection significantly reduced dermal thickness and inflammatory cell infiltration in bleomycin-induced skin fibrosis lesion in mice. We also identified that the oxidative stress signal detected through bioluminescence in OKD48 mice after bleomycin injection in the skin was significantly decreased by BTX-B. Additionally, mRNA levels of oxidative stress associated factors (NOX2, HO-1, Trx2) were significantly decreased by BTX-B. Apoptotic cells in the lesional skin of bleomycin-treated mice were significantly reduced by BTX-B. Oxidant-induced intracellular accumulation of reactive oxygen species in SSc fibroblasts was also inhibited by BTX-B. In conclusion, BTX-B might improve bleomycin-induced skin fibrosis via the suppression of oxidative stress and inflammatory cells in the skin. BTX-B injection may have a therapeutic effect on skin fibrosis in SSc.

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud's phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8 ± 1.1 vs 8.5 ± 0.5 µmol/L, P < 0.01). Presence of mechanic's hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen-6 (KL-6), surfactant protein-D and creatine kinase levels, and anti-aminoacyl-tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic's hand, ILD and anti-ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL-6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti-ARS Ab, and further examination is required.

Objective Several studies have demonstrated that the secreted glycoprotein and integrin ligand milk fat globule-associated protein with epidermal growth factor- and factor VIII-like domains (MFG-E8) negatively regulates fibrosis in the liver, lungs, and respiratory tract. However, the mechanisms and roles of MFG-E8 in skin fibrosis in systemic sclerosis (SSc) have not been characterized. We undertook this study to elucidate the role of MFG-E8 in skin fibrosis in SSc. Methods We assessed expression of MFG-E8 in the skin and serum in SSc patients. We examined the effect of recombinant MFG-E8 (rMFG-E8) on latent transforming growth factor β (TGFβ)-induced gene/protein expression in SSc fibroblasts. We examined the effects of deficiency or administration of MFG-E8 on fibrosis mouse models. Results We demonstrated that MFG-E8 expression around dermal blood vessels and the serum MFG-E8 level in SSc patients (n = 7 and n = 44, respectively) were lower than those in healthy individuals (n = 6 and n = 28, respectively). Treatment with rMFG-E8 significantly inhibited latent TGFβ-induced expression of type I collagen, α-smooth muscle actin, and CCN2 in SSc fibroblasts (n = 3-8), which suggested that MFG-E8 inhibited activation of latent TGFβ as well as TGFβ signaling via binding to αv integrin. In a mouse model of bleomycin-induced fibrosis (n = 5-8) and in a TSK mouse model (a genetic model of SSc) (n = 5-10), deficient expression of MFG-E8 significantly enhanced both pulmonary and skin fibrosis, and administration of rMFG-E8 significantly inhibited bleomycin-induced dermal fibrosis. Conclusion These results suggest that vasculopathy-induced dysfunction of pericytes and endothelial cells, the main cells secreting MFG-E8, may be associated with the decreased expression of MFG-E8 in SSc and that the deficient inhibitory regulation of latent TGFβ-induced skin fibrosis by MFG-E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients.

Objective Apelin/APJ signaling has been determined to regulate cardiac and arterial fibrosis and to be involved in the pathogenesis of pulmonary arterial hypertension. Our objective was to elucidate the role of apelin in skin fibrosis in systemic sclerosis (SSc). Methods Expression of apelin/APJ in normal and SSc fibroblasts was compared. Effects of small interfering RNA depletion and the addition of apelin in fibroblasts were analyzed. The effect of apelin injections on bleomycin-induced dermal fibrosis in mice was investigated. We analyzed the effects of the biased agonist of APJ, MM07, on skin fibrosis in vitro and in vivo. Results The expression of apelin in SSc fibroblasts was significantly lower than that in normal fibroblasts. Serum apelin levels were negatively correlated with the modified Rodnan skin thickness score in SSc patients. Stimulation with transforming growth factor β1 (TGFβ1) inhibited apelin expression in fibroblasts, suggesting that activation of TGFβ1 signaling in SSc might be responsible for reduced apelin expression in SSc fibroblasts. Small interfering RNA depletion of apelin from fibroblasts significantly enhanced fibrosis-related gene expression, and treatment with apelin protein significantly inhibited TGFβ1 signaling in fibroblasts. Administration of apelin significantly inhibited bleomycin-induced dermal fibrosis in mice. We demonstrated that MM07 had greater potential than apelin to inhibit fibrosis in vivo and in vitro. Conclusion Collectively, TGFβ1 signaling and apelin signaling may counteract each other in the fibrotic process of SSc. Inhibitory regulation of TGFβ1-induced skin fibrosis by apelin/APJ signaling may be involved in the pathogenesis of SSc and could be a therapeutic target for fibrosis in SSc patients.

Ischaemia-reperfusion (I/R) is involved in the development of various organ diseases. There has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. However, there is no evidence-based treatment for early-stage PUs. Our objective was to assess the effects of topical steroid on the development of PUs after cutaneous I/R injury in mice. Cutaneous I/R was performed by trapping the dorsal skin between two magnetic plates for 12 h, followed by plate removal. Topical application of betamethasone butyrate propionate (BBP) in I/R areas significantly increased the size of PUs after I/R. The number of thromboses was increased, and CD31(+) vessels were decreased in the I/R area treated with topical BBP. The number of oxidative stress-associated DNA-damaged cells and apoptotic cells in the I/R area was increased by topical BBP treatment. In addition, the mRNA level of NADPH oxidase 4 (Nox4), the essential enzyme that produces reactive oxygen species, was significantly increased and that of NF-E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidant proteins, was inhibited in the I/R area treated by BBP. The number of CD68(+) macrophages and the level of transforming growth factor-beta in lesional skin were also decreased by BBP. These results suggest that a topical steroid might accelerate the formation of PUs induced by cutaneous I/R injury by aggravating oxidative stress-induced tissue damage. Topical steroids might not be recommended for the treatment of acute-phase decubitus ulcers.

Currently, there is no satisfactory treatment for Raynaud's phenomenon (RP) in systemic sclerosis (SSc). Recently, it has been reported that botulinum toxin A (BTX-A) injection was effective for the treatment of RP in SSc patients. The objective was to assess the efficacy and safety of BTX-A on RP in Japanese SSc patients. In the prospective, case series study, 10 Japanese SSc patients with RP received 10 U of BTX-A injections into the hand. The change in severity of RP, including the frequency of attacks/pain, color changes, duration time of RP and the severity of pain, was assessed by Raynaud's score and pain visual analog scale (VAS) at each visit during 16 weeks. The recovery of skin temperature 20 min after cold water stimulation was examined by thermography at baseline and 4 weeks after injection. The number of digital ulcers (DU) and adverse effects were assessed at each visit. BTX-A injection decreased Raynaud's score and pain VAS from 2 weeks after injection, and the suppressive effect was continued until 16 weeks after injection. Skin temperature recovery after cold water stimulation at 4 weeks after injection was significantly enhanced compared with that before injection. All DU in five patients were healed within 12 weeks after injection. Neither systemic nor local adverse effects were observed in all cases. We conclude that BTX-A injection significantly improved the activity of RP in SSc patients without any adverse events, suggesting that BTX-A may have possible long-term preventive and therapeutic potentials for RP in Japanese SSc patients.

Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

Patients with systemic sclerosis (SSc) usually develop Raynaud's phenomenon, persistent digital ischemia and sometimes develop digital ulcers (DU). Several studies have reported an association of carotid artery atherosclerosis with SSc by evaluating carotid intima-media thickness (IMT) in SSc patients. However, none of those studies analyzed the association between DU and carotid artery atherosclerosis in SSc patients. We examined the association of carotid artery atherosclerosis with digital ulcers by comparing SSc patients with (n = 48, 29.5%) and without (n = 206, 70.5%) DU. The demographic and clinical features of the SSc patients showed that young age, male sex, anti-topoisomerase I antibody positivity, severe skin sclerosis, interstitial lung disease complication and cardiac involvements were significantly prevalent in patients with DU. In addition, diffuse cutaneous type, anti-RNA polymerase III antibody positivity and severe skin sclerosis are more frequent in SSc patients with DU at the extensor surface of joints than SSc patients with DU at the digital tip. There were no differences in serum lipid level, carotid IMT or plaque score between SSc patients with and without DU, suggesting that atherosclerotic changes are not primarily involved in the development of DU.

Blepharochalasis is a rare disorder characterized by recurrent episodic swelling of eyelids, eventually leading to atrophy of skin. Although immunological mechanisms may be involved in the degradation of elastic fibers, the pathogenesis is not well characterized. We report a 10-year-old Japanese boy with an 11-month history of the swelling of bilateral upper eyelids with atrophic skin. Attacks of non-painful swelling in eyelids with erythema have recurred several times a month and lasted for 2-3 days. Histological examination revealed perivascular and interstitial infiltration of lymphocytes in the dermis. Elastica Van Gieson staining showed a marked decrease of elastic fibers throughout the dermis. Results of direct and indirect immunofluorescence analyses were negative. Staining of matrix metalloproteinase (MMP)-3 and MMP-9 was observed in and around infiltrating cells in the dermis, suggesting that MMP-3 and MMP-9 may play, in part, roles in the development of blepharochalasis, and that inhibitor of MMP may have a possibility of therapeutic application.

The molecular orientation of an aromatic polycarbonate containing fluorene side chains was investigated by polarized infrared spectroscopy and birefringence analyses. The copolymers were synthesized from 2,2-bis(4-hydroxyphenyl)propane (BPA), 9,9-bis(4-hydroxy-3-methylpheny)fluorene (BMPF), and phosgene by interfacial polycondensation. The 1449-cm−1 band of the uniaxially oriented films, stretched at the glass-transition temperature (Tg) plus 5 °C, was assigned to various combinations of CC stretching and CH in-plane bending vibrations in the fluorene ring, and the transition moment angle was estimated to be 90°. The intrinsic birefringence of aromatic polycarbonate films with BMPF molar ratios ranging from 0.5 to 1 was obtained with the 1449-cm−1 band. The copolymer was estimated to show zero intrinsic birefringence at the BMPF molar ratio of 0.75, and the BMPF homopolymer showed negative intrinsic birefringence. A linear relationship between the volume fraction of BMPF units and the intrinsic birefringence indicated that the two monomer units of BPA and BMPF in each copolymer were not independent, and an intrinsic birefringence could be defined even in the copolymer. The sign of the photoelastic coefficient in the homopolymer with BMPF units was positive. The different signs of the photoelastic coefficient and the intrinsic birefringence suggest that the fluorene side-chain orientation induced by stress in the glass state is quite different from the orientation of the uniaxially oriented films stretched at Tg + 5 °C. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1554–1562, 2003

A support system for hepatectomies enabling quantitative analyses of three-dimensional distances between parts or volumes of parts in an operation area to facilitate intuitive understanding of the locational relationships and three-dimensional structures inside and outside the operated area has been developed. First, imaging and measuring of the three-dimensional internal structures of the operation area have been performed using ultrasound measuring equipment. A three-dimensional sensor is installed on the ultrasonic wave probe to obtain three-dimensional locational information of tomographic images. The tomographic images are rearranged three-dimensionally in the data space, sampling is performed three-dimensionally, and three-dimensional images are reconstructed as voxel data. In addition, the three-dimensional shape of the operating area surface is image-measured and three-dimensional images are reconstructed as polygon data. Three-dimensional images of the internal structures and three-dimensional images of the surface shape are collocated three-dimensionally by superposing the coordinate systems of the two systems on the data space three-dimensionally, using measurement data of the two measurement systems with respect to established reference points. The internal structures are displayed three-dimensionally using the volume rendering method and the surface shape is three-dimensionally displayed by being superimposed on the image plane using the surface rendering method, so that the internal structures and the surface shape of the operated area can be simultaneously observed intuitively as well as quantitatively. Experimental results obtained by this system, using agar phantoms and isolated pig liver, are presented. © 2002 Wiley Periodicals, Inc. Syst Comp Jpn, 33(6): 73–82, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.1134

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease (PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon (RP), digital ulcers (DU) in systemic sclerosis (SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti-topoisomerase I antibody positivity, complications of DU, acro-osteolysis (AO) and interstitial lung disease (ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness (IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO.

Background: Enhanced production of nitric oxide (NO) is associated with various inflammatory diseases such as sepsis. Although activated neutrophils are presumably involved in septic organ injury, the expression of inducible nitric oxide synthase (iNOS) by these cells has not been elucidated. The authors investigated whether activated neutrophils in sepsis could induce mRNA for iNOS and produce NO. Methods: Peripheral blood neutrophils were obtained from healthy volunteers, and septic patients underwent a surgical operation. The neutrophils of the healthy volunteers were stimulated with lipopolysaccharide (LPS) and/or tumour necrosis factor-α (TNF-α). The iNOS expression and NO production were examined by the reverse transcription–polymerase chain reaction and Griess method, respectively. Results: Circulating neutrophils obtained from patients with sepsis expressed higher levels of iNOS mRNA than those from patients with systemic inflammatory response syndrome (SIRS). Resting neutrophils from normal controls did not express iNOS mRNA and thus did not produce NO. After in vitro stimulation with LPS and TNF-α, the neutrophils did express iNOS mRNA and thus produce NO. Conclusion: Activated neutrophils may be one source of NO production in sepsis.

We have developed a novel Z-plate with nano-scale multi-layered structure. The optically biaxial characteristics (nx