Low-intensity pulsed ultrasound for 'no-option' chronic/critical limb-threatening ischaemia in a patient with Buerger disease: a case report.

Background: Buerger disease, also known as Winiwarter-Buerger disease or thromboangiitis obliterans (TAO), is a non-specific inflammation of small- and medium-sized arteries with thrombus obliteration and without atherosclerotic changes. Patients with TAO can develop chronic limb-threatening ischaemia (CLTI) and are at risk of limb amputation despite smoking cessation and exercise therapy recommendations. Case summary: A 72-year-old Japanese man presented with painful discolouration of toes and renal impairment. He was diagnosed with Rutherford classification Stage 6 CLTI with immunoglobulin A nephropathy. He refused limb amputation. Clinical symptoms reduced after treatment with low-intensity pulsed ultrasound (LIPUS). LIPUS is a non-invasive option to alleviate peripheral arterial disease symptoms. Despite the initiation of conventional therapy measures, there was a worsening of the limb condition. The non-invasive investigational treatment option of LIPUS was initiated after the poor clinical outcomes of the conventional therapy measures. The patient's symptoms in the bilateral lower limbs, ulcers, and the blue-coloured toes gradually lessened. After 1 year of treatment with LIPUS, he had achieved better walking independence with improved quality of life. Discussion: Low-intensity pulsed ultrasound is a non-invasive option for therapeutic angiogenesis with the potential to improve ischaemic limb conditions in patients with peripheral arterial disease and to avoid major amputation procedures.

Spindle Cell Variant of Ameloblastic Carcinoma: Another Example in a Japanese Male.

Spindle cell variant of ameloblastic carcinoma (SpCAC) is a rare subtype of ameloblastic carcinoma. Herein, we describe an additional case of SpCAC of the mandible of a 76-year-old Japanese male. We discuss diagnostic problems we encountered in this case, focusing on unusual expression of myogenic/myoepithelial markers, such as smooth muscle actin and calponin.

Association of alcohol consumption with the incidence of proteinuria and chronic kidney disease: a retrospective cohort study in Japan.

BACKGROUND: The difference in the clinical impact of alcohol consumption on kidney function based on sex remains to be elucidated. This study aimed to assess the association between the dose of alcohol consumption and the incidence of proteinuria and chronic kidney disease stratified by sex. METHODS: This retrospective cohort study included 26,788 workers (19,702 men and 7086 women) with normal renal function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2) at annual health examinations between January 2010 and March 2015 in Japan. The main exposure was alcohol consumption. The primary outcomes were the incidence of proteinuria (dipstick urinary protein ≥ 1) and incidence of low estimated glomerular filtration rate (eGFR; rate < 60 mL/min per 1.73 m2; decreased from the baseline eGFR by 25%). RESULTS: During a median observational period of 4 years (interquartile range: 2-6), 1993 (10.1%) men and 462 (6.5%) women developed proteinuria, whereas 667 (3.4%) men and 255 (3.6%) women developed low eGFR. After adjustment for clinically relevant factors using a Cox proportional hazards model, alcohol consumption of ≥ 46 g/day in females was significantly associated with the incidence of proteinuria (hazard ratio, 1.57; 95% confidence interval, 1.10-2.26) and low eGFR (hazard ratio, 1.62; 95% confidence interval, 1.04-2.53). However, no significant association between alcohol consumption and primary outcomes was observed in men. CONCLUSIONS: In conclusion, daily higher alcohol consumption was significantly associated with a higher incidence of proteinuria and low eGFR among women. Women might be prone to high alcohol consumption with kidney dysfunction.

Anhidrosis accompanied by cholinergic urticaria-like rash and dermal pain in a patient with Sjögren's syndrome.

Cholinergic urticaria (CholU)-like rash and dermal pain on sweating occur in patients with acquired idiopathic generalized anhidrosis (AIGA). However, it is unclear whether these are symptoms specific to AIGA among the various types of acquired generalized anhidrosis/hypohidrosis (AGAH). Moreover, the pathogenesis underlying CholU-like rash and dermal pain observed with anhidrosis remains to be clarified. A 20-year-old Japanese man with Sjögren's syndrome (SS) presented with anhidrosis. Transient stinging pain on the skin and pinpoint wheals were observed when his body temperature increased. Thermoregulatory sweat testing revealed anhidrotic areas covering 69% of the body surface area with a symmetrical distribution. A high concentration of histamine was detected (506 ng/mL) in the sweat. A skin biopsy specimen from the anhidrotic area showed the inflamed secretory portion of eccrine glands. This suggested inflammation-mediated damage to sweat glands, consistent with AGAH related to SS. Furthermore, immunohistochemical analysis revealed an ectopic distribution of dermcidin, a sweat-specific peptide, in the dermal tissue surrounding the secretory portion of eccrine glands. The expression of claudin-3, a tight junction (TJ) component of sweat glands, decreased or distributed in a mottled manner in the secretory portion. No decreased expression of muscarinic cholinergic receptor M3 was detected. These results suggested that sweat had leaked into the dermis in association with impaired TJ in the secretory portion, along with the damage to inflamed sweat glands related to SS. Collectively, CholU-like rash and dermal pain on sweating were observed in an AGAH patient with SS. The sweat leakage into the dermis may contribute to the development of the rash and pain.

Malignant melanoma with in-transit metastases refractory to programmed cell death-1 inhibitor successfully treated with local interferon-ß injections: A case report.

In-transit metastases (ITMs) in patients with malignant melanoma (MM) are associated with poor prognosis and a worse disease burden compared with MM without ITMs. A substantial population of patients with ITMs show no or only poor responses to newly developed therapies, such as immune checkpoint inhibitors or molecular-targeted agents. It is difficult to control the exudate and bleeding from ITMs when these medications are ineffective. In Japan, local injection of interferon-ß (IFN-ß) has been licensed for years as adjuvant therapy for MM. However, the evidence for IFN-ß effectiveness for ITMs remains low. The present report describes a case of MM with multiple ITMs that did not respond to a programmed cell death-1 inhibitor and local injections of IFN-ß at 3 million IU/day for 5 days/4 weeks but remitted upon increasing the amount of IFN-ß injections to 10 consecutive days/4 weeks. Local IFN-ß therapy could be an option for improving the quality of life of patients.

Calculation of practical skin donor area for meshed skin grafting in real-world surgery.

Meshed skin grafting is a common technique in operations to minimize surgery on the donor site area. However, the donor site area is empirically determined by surgeons due to the lack of a reliable formula to calculate the donor area required to cover a skin defect. To determine the minimal size for donor skin, the expansion rates of 1.5:1, 3:1, and 6:1 meshed skin graft and the area actually covered by them were investigated in real-world operations. About 51 patients who received 57 operations with meshed skin grafts were enrolled in this study. The average clinical coverage rates of area in cases in which 1.5:1, 3:1, or 6:1 meshed skin grafting was performed were 1.02, 1.29, or 2.18, respectively. Those rates were notably low when recipient sites were concave. The average expansion rates of 1.5:1, 3:1, and 6:1 meshed skin grafts were about 1.16, 1.61, and 2.32, respectively. These results indicate that the size of donor skin should be about 85%, 60%, and 45% size of the recipient site to achieve the target 1.5:1, 3:1, and 6:1 meshed skin graft, respectively. In addition, the donor area should be adjusted in consideration of the shape of the recipient sites.

Exploration of biomarkers to predict clinical improvement of atopic dermatitis in patients treated with dupilumab: A study protocol.

BACKGROUND: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab. METHODS: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment." DISCUSSION: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

Histamine- or vascular endothelial growth factor-induced tissue factor expression and gap formation between vascular endothelial cells are synergistically enhanced by lipopolysaccharide, tumor necrosis factor-α, interleukin (IL)-33 or IL-1ß.

The pathogenesis of chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, has been considered to be associated with the activation of the extrinsic blood coagulation cascade. However, the trigger for the extrinsic coagulation cascade in patients with CSU remains unclear. We previously reported that histamine and lipopolysaccharide (LPS) synergistically induced the expression of tissue factor (TF), a trigger for the extrinsic coagulation cascade, in human umbilical vein endothelial cells (HUVEC). Because the elevation of tumor necrosis factor (TNF)-α, interleukin (IL)-33, IL-1ß and vascular endothelial growth factor (VEGF) in serum has also been observed in patients with CSU, we examined the effects of LPS, TNF-α, IL-33, IL-1ß, VEGF and histamine on TF expression in HUVEC by reverse transcription polymerase chain reaction and flow cytometry, as well as examining the activity that triggers the extrinsic coagulation cascade and induces intercellular gap formation of HUVEC in the presence of plasma by Actochrome® TF activity assay and impedance sensor, respectively. The expression of TF mRNA and surface protein of TF on HUVEC in response to histamine or VEGF were synergistically enhanced by the treatment with LPS, TNF-α, IL-33 or IL-1ß. Moreover, the activation of the extrinsic coagulation pathway and intercellular gap formation of HUVEC in response to histamine or VEGF were also synergistically increased in the presence of TNF-α and LPS. Thus, TF expression on vascular endothelial cells was strongly enhanced by co-stimulation with CSU-related molecules in blood. Blocking a common pathway of LPS, TNF-α, IL-33 and IL-1ß, and/or that of VEGF and histamine may be an effective therapeutic measure for patients with severe and refractory CSU.

Rechallenge of programmed cell death 1 inhibitor after an interval with dacarbazine treatment may be effective for advanced malignant melanoma.

Immune checkpoint inhibitors (ICI) have been administrated as a standard medication in many cases of malignant melanoma (MM). They may be effective even for MM in advanced stages. However, it is still challenging to reduce the burden of MM, which were or became refractory to ICI, especially those without BRAF gene mutation. Re-administration of ICI after other modalities of treatment may be an option of treatment, but the efficacy and safety of retreatment with ICI have not been well established. We experienced four patients with advanced MM retreated with programmed cell death 1 (PD-1) inhibitor. All cases were refractory to the first PD-1 inhibitor, nivolumab, and then treated with dacarbazine (DTIC), followed by pembrolizumab. Two of the four cases achieved a partial response by switching to pembrolizumab as the second PD-1 inhibitor, and the other two cases resulted in progressive disease. In all cases, no new severe adverse events developed upon PD-1 inhibitor retreatment. Even if the first PD-1 inhibitor proves to be ineffective, it is worth re-administrating PD-1 inhibitor following a bridging therapy with DTIC.

Palmitate induces apoptosis and inhibits osteogenic differentiation of human periodontal ligament stem cells.

OBJECTIVE: The aim of the present study was to investigate the effect of palmitate on human periodontal ligament stem cells (PDLSCs). DESIGN: PDLSCs were isolated from the third molars of healthy adult donors, and cultured in normal or osteogenic medium supplemented with palmitate (0, 100, or 250 µM) for 21 days. Cell proliferation was evaluated by measuring the amount of formazan at 6, 24, 48, and 72 h. Apoptosis was detected by ELISA and terminal deoxynucleotidyl transferase dUTP nick end labeling assay at days 3 and 7. Osteogenic differentiation was evaluated by measuring the alkaline phosphatase (ALP) activity, production of procollagen type I C-peptide and osteocalcin, mineralization, and mRNA expression of Runx2 at days 3, 7, 14, and 21. In addition, mRNA expression of IL-6 and IL-8 was measured at day 3. RESULTS: Palmitate inhibited the proliferation, ALP activity, production of procollagen type I C-peptide and osteocalcin, mineralization, and mRNA expression of Runx2 in the cultured PDLSCs. Palmitate also induced apoptosis and mRNA expression of IL-6 and IL-8 in the PDLSCs. CONCLUSIONS: The results of the present study demonstrate that palmitate induces apoptosis and inhibits osteogenic differentiation of PDLSCs. These findings may help clarify the relationship between palmitate and periodontal tissue regeneration.

Non-contrast computed tomography and magnetic resonance imaging features of mucoepidermoid carcinoma in the salivary glands.

BACKGROUND: Use of contrast-enhanced cross-sectional imaging is considered standard practice for investigating mucoepidermoid carcinoma (MEC) in the salivary glands. The purpose of this study was to present the common features of MEC on computed tomography (CT) and magnetic resonance imaging (MRI) without contrast enhancements, and to investigate the possibility of discriminating between MEC and pleomorphic adenoma based on the features observed on both modalities. METHODS: Twenty cases of biopsy-confirmed MEC originating in the salivary glands were reviewed and characterized by two oral and maxillofacial radiologists with regard to the following aspects: detectability, margin, border, encapsulation, content, contrast between lesion and masticator muscle, and bone changes. RESULTS: Ninety percent of bone changes caused by MEC were detected by CT and sixty-nine percent of tumor existences were detected by MRI. The lesion border could provide a clue to distinguish MEC from pleomorphic adenoma. CONCLUSIONS: Observation of MEC features was possible by both CT and MRI. Among the features, the lesion border could be a clue to distinguish MEC from pleomorphic adenoma.

Calcifying cystic odontogenic tumor accompanied by a dentigerous cyst: A case report.

A calcifying cystic odontogenic tumor (CCOT) is a proliferation of odontogenic epithelium and scattered nests of ghost cells and calcifications that may form the lining of a cyst, or present as a solid mass. It was previously described by Gorlin et al in 1962 as a calcifying odontogenic cyst. Dentigerous cysts are developmental odontogenic jaw cysts, commonly manifesting in the second and third decades of life. The present study reports an asymptomatic case in a 13-year-old boy who was referred to the outpatient clinic of the Osaka Dental University Hospital (Osaka, Japan) for additional investigation of an area of radiolucency in the lower right jaw. X-ray demonstrated a unilocular, well-circumscribed, radiolucent lesion in the mandible, which measured 30×20 mm, with radiopaque structures within it. Enucleation of the lesion with tooth extraction was performed, which histopathologically revealed features of a CCOT and a cyst. To the best of our knowledge, the occurrence of such a lesion has not been previously identified. The present study examined the significance of the case with a brief review of the literature.

Retraction:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: A case presented brain calcification and corpus callosum atrophy from over 10 years before the onset of dementia.

This article was retracted by author's request.

Differential diagnosis of well-differentiated squamous cell carcinoma from non-neoplastic oral mucosal lesions: New cytopathologic evaluation method dependent on keratinization-related parameters but not nuclear atypism.

BACKGROUND: The cytology of oral squamous cell carcinoma (SCC) is challenging because oral SCC cells tend to be well differentiated and lack nuclear atypia, often resulting in a false negative diagnosis. The purpose of this study was to establish practical cytological parameters specific to oral SCCs. METHODS: We reviewed 123 cases of malignancy and 53 of non-neoplastic lesions of the oral mucosa, which had been diagnosed using both cytology and histopathology specimens. From those, we selected 12 SCC and 4 CIS cases that had initially been categorized as NILM to ASC-H with the Bethesda system, as well as 4 non-neoplastic samples categorized as LSIL or ASC-H as controls, and compared their characteristic findings. After careful examinations, we highlighted five cytological parameters, as described in Results. Those 20 cytology samples were then reevaluated by 4 independent examiners using the Bethesda system as well as the 5 parameters. RESULTS: Five cytological features, (i) concentric arrangement of orangeophilic cells (indicating keratin pearls), (ii) large number of orangeophilic cells, (iii) bizarre-shaped orangeophilic cells without nuclear atypia, (iv) keratoglobules, and (v) uneven filamentous cytoplasm, were found to be significant parameters. All malignant cases contained at least one of those parameters, while none were observed in the four non-neoplastic cases with nuclear atypia. In reevaluations, the Bethesda system did not help the screeners distinguish oral SCCs from non-neoplastic lesions, while use of the five parameters enabled them to make a diagnosis of SCC. CONCLUSION: Recognition of the present five parameters is useful for oral SCC cytology. Diagn. Cytopathol. 2017;45:406-417. © 2017 Wiley Periodicals, Inc.

Sodium chloride promotes tissue inflammation via osmotic stimuli in subtotal-nephrectomized mice.

Chronic inflammation, which is often associated with high all-cause and cardiovascular mortality, is prevalent in patients with renal failure; however, the precise mechanisms remain unclear. High-salt intake was reported to induce lymphangiogenesis and autoimmune diseases via osmotic stimuli with accumulation of sodium or chloride. In addition, sodium was recently reported to be stored in the extremities of dialysis patients. We studied the effects and mechanisms of high salt loading on tissue and systemic inflammation in subtotal-nephrectomized mice (5/6Nx) and in cultured cells. Macrophage infiltration in the peritoneal wall (P<0.001), heart (P<0.05) and para-aortic tissues (P<0.001) was significantly higher in 5/6Nx with salt loading (5/6Nx/NaCl) than in 5/6Nx without salt loading (5/6Nx/Water); however, there were no significant differences in blood pressure and renal function between the groups. Tissue interleukin-6, monocyte chemotactic protein-1 (MCP-1), serum- and glucocorticoid-inducible kinase 1 (Sgk1) and tonicity-responsive enhancer binding protein (TonEBP) mRNA were significantly elevated in the peritoneal wall and heart with 5/6Nx/NaCl when compared with 5/6Nx/Water. Sodium was stored in the abdominal wall, exerting high-osmotic conditions. Reversal of salt loading reduced macrophage infiltration associated with decreased TonEBP in 5/6Nx/NaCl. Macrophage infiltration associated with fibrosis induced by salt loading was decreased in the 5/6Nx/NaCl/CC chemokine receptor 2 (CCR2, receptor of MCP-1)-deficient mice when compared with 5/6Nx/NaCl/Wild mice, suggesting that CCR2 is required for macrophage infiltration in 5/6Nx with NaCl loading. In cultured mesothelial cells and cardiomyocytes, culture media with high NaCl concentration induced MCP-1, Sgk1 and TonEBP mRNA, all of which were suppressed by TonEBP siRNA, indicating that both MCP-1 and Sgk1 are downstream of TonEBP. Our study indicates that high NaCl intake induces MCP-1 expression leading to macrophage infiltration via the TonEBP-MCP-1 pathway in 5/6Nx/NaCl mice, and that TonEBP has a central role in inflammation in patients with renal failure taking high salt.

Differential expression of the epithelial mesenchymal transition factors Snail, Slug, Twist, TGF-ß, and E-cadherin in ameloblastoma.

Epithelial mesenchymal transition (EMT), the transition of epithelial cells into motile mesenchymal cells, plays an important role in embryogenesis, cancer invasion, and metastasis. Ameloblastomas are common epithelial odontogenic tumors, occurring exclusively in the mandible with locally invasive growth. Thirty-seven ameloblastoma cases were evaluated for the involvement of EMT by immunohistochemical staining and western blotting using antibodies against Slug, Snail, Twist, TGF-ß, and E-cadherin. Double immunostaining was also performed. Slug and TGF-ß were expressed in the nuclei of peripheral and stellate reticulum cells of ameloblastoma nests. Twenty cases of Snail, 36 of Slug, 8 of Twist, and 19 of TGF-ß showed strong expression in tumor cells in follicular and plexiform patterns. Expression of Slug and TGF-ß increased in regions where the expression of E-cadherin was reduced. EMT was found to be associated with the local invasive growth of ameloblastoma. These data suggest that reduced expression of E-cadherin and over-expression of Slug, Snail, and TGF-ß induce EMT. Given that ameloblastomas are characterized by local invasiveness, EMT might be related to their development. Thus, strong expression of Slug and TGF-ß and reduced expression of E-cadherin might be related to the local invasiveness of ameloblastoma.