Akiko Sekiguchi

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.

Langerhans cell histiocytosis masquerading as hidradenitis suppurativa

Dear Editor, A 42-year-old Japanese man presented with a 22-year history of painful nodules and ulcers with recurrent draining sinuses on the axillary and perianal regions. He developed a pneumothorax at the age of 25 years, which was diagnosed as eosinophilic granuloma. His axillary and perianal lesions had been treated with surgical drainage of the abscesses in other hospitals. Because the lesions had enlarged, he visited our hospital. A physical examination revealed brownish indurated plaques with reddish-purplish papules, ulcers and fistulas, and active purulent drainage on the bilateral axillaries (Fig. 1a). The perianal region showed multiple ulcers and fistulas with scars due to repeated surgical drainage over the past 20 years (Fig. 1b). At that time, we clinically diagnosed these ulcers and fistulas as hidradenitis suppurativa. Bacterial culture revealed a small number of Staphylococcus aureus and Prevotella disiens. We performed debridement and split-thickness skin grafting on the axillary lesions. A pneumothorax developed on postoperative day 2, which was treated with a partial pneumonectomy. Histological examination revealed sinuses lined with epidermis in the dermis (Fig. 1d) and a dense infiltration of histiocytic mononuclear cells and multinucleated giant cells from the dermis to subcutaneous tissue (Fig. 1e). The histiocytic cell populations expressed CD1a (Fig. 1f) and S-100 proteins (Fig. 1g). The hypermetabolic lesions of F-fluorodeoxyglucose positron emission tomography/computed tomography were confirmed in the soft tissue from the right neck to the back, thyroid (Fig. 1h), perianal region and adductor magnus muscle. The histological findings of the resected lung tissue and needle biopsies from the thyroid and soft tissue of the neck were compatible with those of Langerhans cell histiocytosis (LCH). The results of a plain-film bone survey and bone marrow puncture were normal. Finally, we established the diagnosis of adult-onset LCH with multisystem involvement. He was treated

Erythema induratum of Bazin associated with bacillus Calmette–Guérin vaccination: Implication of M1 macrophage infiltration and monocyte chemotactic protein-1 expression

1 Lehman H, Rushinek H. A rare case of Ramsay Hunt syndrome following temporomandibular joint surgery. Int J Oral Maxillofac Surg 2015; 44: 1038–1040. 2 Hunt JR. On herpetic inflammation of the geniculate ganglion. A new syndrome and its complications. J Nerv Ment Dis 1907; 34: 73–96. 3 Yamamoto S, Tada R, Shimomura Y et al. Detecting varicellazoster virus DNA in iridocyclitis using polymerase chain reaction: a case of zoster sine herpete. Arch Ophthalmol 1995; 113: 1358–1359.

Successful treatment of Raynaud's phenomenon and digital ulcers in systemic sclerosis patients with botulinum toxin B injection: Assessment of peripheral vascular disorder by angiography and dermoscopic image of nail fold capillary

We recently identified the efficacy and safety of a botulinum toxin (BTX)‐A/B in Raynauds phenomenon (RP) and digital ulcers (DU) in Japanese patients with systemic sclerosis (SSc). Detailed assessments of peripheral vascular disorder using angiography and dermoscopic images of nail fold capillaries have not been performed previously. This study aimed to evaluate the effect of BTX‐B on SSc‐associated peripheral vascular disorder. Two SSc patients who suffered with RP and DU were treated with a BTX‐B injection, and thereafter the symptoms of RP were improved and DU healed in both patients. Furthermore, angiography showed an increased blood flow to the palm and fingers, and dermoscopic images of nail fold capillary changes showed improvement. These results suggest that a BTX‐B injection may increase peripheral blood flow and improve RP and DU in SSc patients.

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.