Chisako Fujiwara

Possible association of elevated serum collagen type IV level with skin sclerosis in systemic sclerosis

Collagen type IV is the primary collagen in the basement membranes around blood vessels and in the dermoepidermal junction in the skin. Perivascular collagen type IV is synthesized by endothelial cells and pericytes, and contributes to the homeostasis and remodeling of blood vessels. It has been well recognized that elevated serum collagen type IV levels are associated with the liver fibrosis. The objective was to examine serum collagen type IV levels and their clinical associations in patients with systemic sclerosis (SSc), and to examine the expression of collagen type IV in the fibrotic skin in SSc. Serum collagen type IV levels in SSc patients and diffuse cutaneous type SSc patients were significantly higher than those in healthy individuals. Serum collagen type IV levels were positively correlated with modified Rodnan total skin score. Serum collagen type IV levels in early stage (disease duration ≤3 years) diffuse cutaneous SSc patients were significantly elevated. Serum collagen type IV levels in SSc patients with digital ulcers (DU) were significantly elevated. In immunohistochemical staining, the expression of collagen type IV around dermal small vessels in the affected skin was reduced compared with those of normal individuals. These results suggest that elevated serum collagen type IV levels may be associated with the skin sclerosis in the early stage of SSc. The measurement of serum collagen type IV levels in SSc patients may be useful as a disease activity marker in skin sclerosis and DU.

Trigeminal trophic syndrome: Analysis of the number of peripheral nerve fibres and blood vessels in the lesional skin

examination requires the patient undergo a general skin examination by a non-skin specialist. No currently available laboratory tests adequately detect leprosy. It is most likely that this patient contracted the disease during his most recent visit to Nepal and then re-entered Australia, evading early detection; no doubt aided by the often subtle manifestations of the tuberculoid variant. There have been a few reported leprosy cases in nonmigrants who have not travelled, but these have predominantly been in Indigenous Australians. There is a real human cost of not detecting this disease. Not only does the patient experience disruptions to work and travel plans, but all close contacts require periodic health assessment for at least 5 years. It is fortunate that this patient had the tuberculoid variant, as his transmission risk was comparatively less. In all, 190 000 people immigrated to Australia from 2014 to 2015, representing a fourfold increase from 1984 to 1985, with most originating from leprosy-endemic India. There were 36 notified cases of leprosy in the last 3 years as opposed to 27 in the previous four, representing a 33% increase. We propose that the immigration department consider specific leprosy questioning and the examination of uncertain skin rashes by a skin specialist, especially for immigrants from endemic countries.

Inhibitory Regulation of Skin Fibrosis in Systemic Sclerosis by Apelin/APJ Signaling

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).

Protective effect of mesenchymal stem cells on the pressure ulcer formation by the regulation of oxidative and endoplasmic reticulum stress

Cutaneous ischemia-reperfusion (I/R) injury is associated with the early pathogenesis of cutaneous pressure ulcers (PUs). The objective of this study was to investigate the effect of mesenchymal stem cells (MSCs) injection on the formation of PUs after I/R injury and determine the underlying mechanisms. We found that the subcutaneous injection of MSCs into areas of I/R injured skin significantly suppressed the formation of PUs. I/R-induced vascular damage, hypoxia, oxidative DNA damage, and apoptosis were decreased by MSCs injection. Oxidative stress signals detected after I/R in OKD48 (Keap1-dependent oxidative stress detector, No-48-luciferase) mice were decreased by the injection of MSCs. In cultured fibroblasts, MSCs-conditioned medium significantly inhibited oxidant-induced reactive oxygen species (ROS) generation and apoptosis. Furthermore, endoplasmic reticulum (ER) stress signals detected after I/R in ERAI (ER stress-activated indicator) mice were also decreased by the injection of MSCs. These results suggest that the injection of MSCs might protect against the development of PUs after cutaneous I/R injury by reducing vascular damage, oxidative cellular damage, oxidative stress, ER stress, and apoptosis.

Pyogenic granuloma possibly associated with capecitabine therapy

developed 1 week prior. Physical examination demonstrated cyanosis and cutaneous ulcers in the toes (Fig. 1d,e). There were diffuse itchy erythema on the trunk and extremities, concomitant with brown pigmentation and red papules persisting for years (Fig. 1a–c). Laboratory tests showed abnormalities, such as serum creatinine (3.01 mg/dL), eosinophilia (60%, 5580/lL), thymus and activation-regulated chemokine (TARC) (15 120 pg/mL) and immunoglobulin E (3475 IU/mL). Because computed tomography angiography was not performed due to his severe renal dysfunction, mural thrombi were not assessed. Although skin biopsy was not performed from blue toes, a skin biopsy of erythema on his right abdomen showed characteristic needle-shaped clefts in the subcutaneous fat layer (data not shown). He had not taken any anticoagulants or undergone interventional vascular treatment before this episode. Histopathological findings of CC in the skin, blue toes, exacerbation of renal function and eosinophilia resulted in a diagnosis of CCE. CC was also detected in the kidney. Additional biopsies were obtained from the left abdomen and the both thighs (Fig. 1a–c). CC was only detected in the deep fat layer of the left abdomen (Fig. 1f,h). Histopathological changes in the epidermis and upper dermis of four specimens were consistent with chronic eczema (Fig. 1f,g). Treatment with oral prednisolone (20 mg/day), atorvastatin (10 mg/day), omega-3-acid ethyl esters (2 g/day) and beraprost sodium (60 lg/day) for 1 month restored laboratory data and blue toes. Topical treatment with betamethasone butyrate propionate improved the eczema and normalized TARC value. In this case, it is likely that numerous CC were simultaneously scattered to several organs, such as the kidney and skin. Based on the distribution pattern, in which CC was detected in both sides of abdominal skin but not in both sides of the thighs, we thought that there was a relation between blood supply and entrapment of CC. The skin of the lower abdomen is supplied by the superficial epigastric artery (SEa), and the thighs are supplied by the descending branch of the lateral circumflex femoral artery (LCFa) (Fig. 1i). These two arteries are branches of the femoral artery, but SEa runs retrograde and LCFa anterograde. We hypothesized theoretical possibilities that a turbulent flow was more often induced by upward bloodstream in SEa than by downward bloodstream in LCFa, and CC entrapment by SEa was attributed to this turbulent flow. Although similar studies are required to confirm the findings observed in the present case with CCE, it is certain that biopsy of the unaffected abdominal skin can be performed with lower risk compared with that of the affected toes or internal organs such as kidney.

Mesenchymal stem cells-derived MFG-E8 accelerates diabetic cutaneous wound healing

BACKGROUND Diabetic wounds are intractable due to complex factors, such as the inhibition of angiogenesis, dysfunction of phagocytosis by macrophages and abnormal inflammatory responses. It is recognized that mesenchymal stem cells (MSCs) promote wound healing in diabetic mice. We previously demonstrated that MSCs produce large amounts of MFG-E8. OBJECT The objective was to ascertain the role of MSCs-derived MFG-E8 in murine diabetic wounds. METHODS MFG-E8 WT/KO MSCs or rMFG-E8 were subcutaneously injected around the wound in diabetic db/db mice, and wound areas were analyzed. Quantification of angiogenesis, infiltrating inflammatory cells, apoptotic cells at the wound area was performed by immunofluorescence staining and real-time PCR. Phagocytosis assay was performed using peritoneal macrophages from WT or db/db mice. RESULTS MFG-E8 expression in granulation tissue in diabetic mice was significantly reduced compared with that in non-diabetic mice. We next examined the effect of subcutaneous injection of MFG-E8 WT/KO MSCs around the wound. Diabetic wound healing was significantly accelerated by the injection of MSCs. Diabetic wound healing in MFG-E8 KO MSCs-injected wounds was significantly delayed compared to that in WT MSCs-injected wounds. The numbers of CD31+ EC and NG2+ pericytes, as well as M2 macrophages in wounds in KO MSCs-injected mice were significantly decreased. MFG-E8 WT MSCs treatment suppressed the number of apoptotic cells and TNF-α+ cells in wounds. In an in vitro assay, MFG-E8 WT MSCs-conditioned medium enhanced phagocytosis of apoptotic cells by peritoneal macrophages from diabetic mice. CONCLUSION MSCs-derived MFG-E8 might accelerate diabetic wound healing by promoting angiogenesis, the clearance of apoptotic cells, and the infiltration of M2 macrophages, and by suppressing inflammatory cytokines in wound area.

Pilomatricoma with bullous-like/anetodermic appearance: Possibly associated with matrix metalloproteinases

Figure 1. (a) Pilomatricoma with bullous-like/anetodermic appearance in the left axilla. (b) Few elastic fibers in the superficial dermis (elastica van Gieson [EVG], original magnification 9100). (c) CD68-positive macrophages in the superficial dermis (9400). (d) Matrix metalloproteinase (MMP)-9 was stained in fibroblasts and infiltrating inflammatory cells (9400). (e) MMP-12 was stained in infiltrating cells in the superficial dermis (9400). (f) Pilomatricoma with ordinary appearance. Subcutaneous tumor on the right eyebrow. (g) Many elastic fibers in the superficial dermis (EVG, 9100). (h) No CD68-positive macrophages in the dermis (9400). Neither (i) MMP-9 nor (j) MMP-12 was stained in the dermis (9400). (k) The results of histopathological analysis on pilomatricoma with bullous-like/anetodermic appearance and with ordinary appearance (9). –, undetectable; +, weak positivity; ++, moderate positivity; +++, strong positivity.

Fibroblastic rheumatism: A case of multiple nodules of fingers and hands, contractures of fingers and polyarthritis

Dear Editor, A 63-year-old Japanese man was referred to our department in May 2017 with a 3-month history of multiple nodules of the hands and contractures of the fingers. He also complained of arthralgia in the shoulder, knee and hip joints. Physical examination revealed swelling of the fingers with flexion contractures, and multiple reddish firm nodules located on the finger joints, palms and wrists of bilateral hands (Fig. 1a–c). Laboratory tests were normal. Antinuclear antibody, rheumatoid factor, matrix metalloproteinase-3 and anti-cyclic citrullinated peptide antibody were all negative or normal. Histological examination of the nodule in the left hand revealed a prominent dermal fibrosis (Fig. 1d,e). Dermal fibrosis was not continued directly from the synovium. Lymphocytes were infiltrated around blood vessels and between collagen fibers in the dermis (Fig. 1e). Elastica van Gieson staining showed the reduction of elastic fibers in the dermis (Fig. 1f). In immunohistochemical staining, cells in the fibrotic lesion were positive for vimentin, but not for CD34, CD68, a-smooth muscle actin and S100 protein. Magnetic resonance imaging (MRI) showed the synovitis and synovial hyperplasia of the joints and wrist in both hands, but bone edema and erosion were not identified (Fig. 1g). Based on the clinical and pathological findings, we diagnosed fibroblastic rheumatism. We initiated treatment with 30 mg/day oral prednisolone. After 1 week of corticosteroid therapy, the swelling of fingers and multiple subcutaneous nodules were significantly improved (Fig. 1i–k) and multiple arthralgia diminished. MRI showed the significant improvement of synovitis and synovial hyperplasia (Fig. 1h). However, the contractures of the right fingers remained (Fig. 1i); therefore, methotrexate (MTX, 8 mg/week) was additionally administrated. As symptoms improved, prednisolone was tapered to 15 mg/day. Exacerbation of symptoms was not observed during a 6-month follow-up period. Fibroblastic rheumatism is a rare fibroproliferative disease of unknown etiology. There have been a total of 42 reported

Possible contribution of autophagy in pyogenic granuloma

Autophagy is a “eating of self” process that is important for the sources of energy in the development and in the response to nutrient stress, hypoxia, pro-inflammatory state and so on. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles. In addition, it is generally recognized that the dysregulation of autophagy may be associated with apoptosis and cell death. There are many studies on whether autophagy in tumor cells is related to both tumor progression and suppression, suggesting that the role of autophagy in malignant tumors remains controversial. Atg5, a key regulator of autophagy required for autophagosome formation, has been shown to be cleaved by calpain, translocated into the mitochondria and to induce apoptosis. We recently reported that the staining of Atg5 was positive for endothelial cells (EC) in capecitabine-induced pyogenic granuloma (PG), suggesting that autophagy in EC may be associated with the pathogenesis of capecitabine-induced PG/PG-like lesions. However, it is unknown whether the autophagy is associated with the pathogenesis of PG. Therefore, we aimed to examine the expression of Atg5 in PG. We analyzed 15 Japanese patients with PG who visited Gunma University Hospital between 2015 and 2016, and summarize this information in Figure 1(a) (seven women and eight men; aged 53.3 6.1 years; locations, three scalp, three faces and nine fingers or toe). The study was approved by the Institutional

Milia-like idiopathic calcinosis cutis and plaque-type syringoma in a girl with Down syndrome

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