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Cryptococcus deneoformans is an opportunistic fungal pathogen that infects the lungs via airborne transmission and frequently causes fatal meningoencephalitis. Claudins (Cldns), a family of proteins with 27 members found in mammals, form the tight junctions within epithelial cell sheets. Cldn-4 and 18 are highly expressed in airway tissues, yet the roles of these claudins in respiratory infections have not been clarified. In the present study, we analyzed the roles of Cldn-4 and lung-specific Cldn-18 (luCldn-18) in host defense against C. deneoformans infection. luCldn-18-deficient mice exhibited increased susceptibility to pulmonary infection, while Cldn-4-deficient mice had normal fungal clearance. In luCldn-18-deficient mice, production of cytokines including IFN-γ was significantly decreased compared to wild-type mice, although infiltration of inflammatory cells including CD4+ T cells into the alveolar space was significantly increased. In addition, luCldn-18 deficiency led to high K+ ion concentrations in bronchoalveolar lavage fluids and also to alveolus acidification. The fungal replication was significantly enhanced both in acidic culture conditions and in the alveolar spaces of luCldn-18-deficient mice, compared with physiological pH conditions and those of wild-type mice, respectively. These results suggest that luCldn-18 may affect the clinical course of cryptococcal infection indirectly through dysregulation of the alveolar space microenvironment.

Human papillomavirus (HPV) causes cervical cancer, anal cancer, vulvar cancer, vaginal cancer, penile cancer, and oropharyngeal cancer. Squamous cell carcinoma (SCC) in the genital region in particular is recognized to be caused by HPV infection, and intraepithelial lesions of the penis and vulva are termed penile intraepithelial neoplasia and vulvar intraepithelial neoplasia, respectively. Although SCC of the nail apparatus is recognized as being associated with high-risk HPVs, it is not well-known in general medicine, and its analysis has been insufficient. In this article, we reviewed 136 cases of HPV-associated nail SCC and SCC in situ and delineated their clinical characteristics. We found that half of the cases were high-risk HPV-associated. Almost all of the types were high-risk α-HPVs. This disease had a male dominance and left hand digit 3 and right hand digits 1-3 were typically affected. In this review, 24% of the cases of nail SCC had a history of other HPV-associated diseases, suggesting the possibility of genitodigital transmission. We propose that nail SCC is a hidden high-risk HPV-associated reservoir and should be recognized as a sexually transmitted infection.

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.

Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl β-cyclodextrin (HP-β-CD) promotes the excretion of cholesterol and prolongs the life span in animal models of NPC disease, it requires extremely high dose. We developed acid-labile β-CD-based polyrotaxanes (PRXs) comprising multiple β-CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of β-CD in NPC disease. The acid-labile PRXs dissociate under the acidic lysosomes and release threaded β-CDs in lysosomes, which promotes cholesterol excretion in NPC disease model cells at lower concentration than HP-β-CD. In this study, the therapeutic effect of the PRXs in a mouse model of NPC disease was investigated. Weekly administration of the PRXs significantly prolonged the life span and suppressed neurodegeneration in mice, even at a dose of 500mg/kg, a markedly lower dose than previously reported for HP-β-CD. Detailed analysis of tissue cholesterol revealed that PRX treatment markedly suppressed the tissue accumulation of cholesterol in the NPC mouse model, but did not alter cholesterol content in wild-type mice. Acid-labile PRX is therefore a promising candidate for potentiating the efficacy of β-CD in the treatment of NPC disease.

Pneumothorax is a possible complication of tracheostomy. We report a rare case of bilateral pneumothoraces resulting from tracheostomy in an advanced laryngeal cancer patient. A 59-year-old man was referred to our clinic for evaluation and treatment of laryngeal tumor. Laryngeal endoscopy showed limited movement of bilateral vocal cords, and computed tomography revealed a tumor lesion extending from the vocal cords to the subglottic area. Three days after the first visit, the patient developed respiratory difficulty, and we elected to perform emergency tracheostomy for airway management. Immediately after the start of the procedure, he began hyperventilating, and complained of respiratory discomfort and chest pain. We then recognized a mediastinal air leak, and we suspected pneumothorax resulting from the tracheostomy. Chest X-ray showed bilateral pneumothoraces; therefore, we inserted bilateral chest drainage tubes, which stabilized his respiratory condition. We speculated that the pathogenesis of the bilateral pneumothoraces was weakened alveolar walls secondary to long-term smoking, and a significant rise in airway pressure because of airway constriction by the neck-extended position and hyperventilation, during tracheostomy.

Approximately one-third of Lassa virus (LASV)-infected patients develop sensorineural hearing loss (SNHL) in the late stages of acute disease or in early convalescence. With 500,000 annual cases of Lassa fever (LF), LASV is a major cause of hearing loss in regions of West Africa where LF is endemic. To date, no animal models exist that depict the human pathology of LF with associated hearing loss. Here, we aimed to develop an animal model to study LASV-induced hearing loss using human isolates from a 2012 Sierra Leone outbreak. We have recently established a murine model for LF that closely mimics many features of human disease. In this model, LASV isolated from a lethal human case was highly virulent, while the virus isolated from a nonlethal case elicited mostly mild disease with moderate mortality. More importantly, both viruses were able to induce SNHL in surviving animals. However, utilization of the nonlethal, human LASV isolate allowed us to consistently produce large numbers of survivors with hearing loss. Surviving mice developed permanent hearing loss associated with mild damage to the cochlear hair cells and, strikingly, significant degeneration of the spiral ganglion cells of the auditory nerve. Therefore, the pathological changes in the inner ear of the mice with SNHL supported the phenotypic loss of hearing and provided further insights into the mechanistic cause of LF-associated hearing loss. IMPORTANCE Sensorineural hearing loss is a major complication for LF survivors. The development of a small-animal model of LASV infection that replicates hearing loss and the clinical and pathological features of LF will significantly increase knowledge of pathogenesis and vaccine studies. In addition, such a model will permit detailed characterization of the hearing loss mechanism and allow for the development of appropriate diagnostic approaches and medical care for LF patients with hearing impairment.

Neuroleptic malignant syndrome (NMS) is rare but sometimes causes life-threatening conditions. We report the case of a 53-year-old male patient who developed NMS following cardiac surgery. He was diagnosed with schizophrenia and pre- scribed blonanserin, chlorpromazine, and biperiden. From postoperative day 3, hyperthermia, disturbed consciousness, and involuntary movement were observed. Subsequently, his serum creatine phosphokinase (CPK) levels increased. After NMS was suspected, chlorpromazine and biperiden were stopped. From postoperative day 7, intravenous administration of dant- rolene was initiated. Following this treatment, his serum CPK levels gradually decreased, and the other symptoms improved. The treatment of NMS remains controversial. There is no evidence that dantrolene is effective for treating NMS; however, it may be one of the important options for treating NMS. We present the case and discuss the diagnosis and management of NMS following cardiac surgery. [Arch Clin Exp Surg 2017; 6(2.000): 117-119]

Background: Spatial disorientation is one of the most frequent causes of aircraft accidents, and is thus a major problem affecting air safety. Although a number of studies have examined spatial disorientation, the precise physiological changes occurring as a direct result of spatial disorientation and motion sickness remain unclear. The present study sought to investigate electrodermal activity (EDA) and subjective autonomic symptoms during spatial disorientation training, and to develop an indicator of physiological changes for pilot candidates. Methods: In the current study, we investigated changes in EDA measured using a wrist-worn device, and subjective autonomic nervous system symptoms during spatial disorientation training for pilot candidates. We then used the Graybiel diagnostic criteria to develop a novel physiological biomarker. Results: We found that maximum EDA change and peak amplitude were significantly increased in participants with a Graybiel score of ≥3 points compared with those who scored < 2 points. Furthermore, for symptoms of cold sweating and saliva secretion (from the seven Graybiel diagnostic criteria), the maximum EDA change in participants with scores ≥1 point was significantly higher than that of participants scoring 0 points. Conclusion: Our results indicate that EDA data measured with a wrist-worn device could provide a useful method for objective evaluation of the severity of spatial disorientation and motion sickness.

Noninvasive low-level laser therapy (LLLT) is neuroprotective, but the mechanism of this effect is not fully understood. In this study, the use of LLLT as a novel treatment for noise-induced hearing loss (NIHL) is investigated. Sprague-Dawley rats were exposed to intense noise and their right ears were irradiated with an 808nm diode laser at an output power density of 110 or 165mW/cm(2) for a 30min period for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with LLLT compared with the non-treatment group at days 2, 4, 7 and 14 after noise exposure. Morphological observations also revealed a significantly higher outer hair cell survival rate in the LLLT groups. Immunohistochemical analyses for inducible nitric oxide synthase (iNOS) and cleaved caspase-3 were used to examine oxidative stress and apoptosis. Strong immunoreactivities were observed in the inner ear tissues of the non-treatment group, whereas these signals were decreased in the LLLT group at 165mW/cm(2) power density. Our findings suggest that LLLT has cytoprotective effects against NIHL via the inhibition of iNOS expression and apoptosis.

Objectives: The prevalence of aortic valve disease is increasing. The purpose of this study was to compare the outcomes of patients undergoing ministernotomy versus conventional full sternotomy for aortic valve replacement (AVR). Materials and Methods: Between May 2009 and November 2013, 59 consecutive patients underwent AVR in our institution; 27 patients received upper ministernotomy (Group M), and 32 received conventional median full sternotomy (Group F). Pre-operative characteristics, aortic valve pathology, and left ventricular function in both groups were similar. Results: No differences were found in mean operation time, volume of blood loss, mean cardiopulmonary time, aortic clamp time, transfusion rate, or mortality and morbidity rates. However, the amount of red blood cells used in transfusion was significantly less in Group F than in Group M (7.3 +/- 4.5 vs. 4.6 +/- 3.3 units, P = 0.015). Conclusions: Although ministernotomy can be safely used for AVR without prolonging operative or cardiopulmonary time, no significant advantages were discerned for choosing ministernotomy over conventional full median sternotomy. [Arch Clin Exp Surg 2015; 4(2.000): 69-73]

The transfer of sweat to the skin surface without leakage is important for the homeostatic regulation of skin and is impaired in atopic dermatitis. Although the precise composition of the leakage barrier remains obscure, there is a large contribution from claudins, the major components of tight junctions. In humans, claudin-1, -3, and -15 are expressed on sweat ducts, and claudin-3 and -10 are expressed on secretory coils. Although only two claudins are expressed in murine sweat glands, we found that the expression of claudin-3 is conserved. Atopic dermatitis lesional skin had decreased claudin-3 expression in sweat glands, which was accompanied by sweat leakage. This critical role in water barrier function was confirmed in Cldn3-/- and Cldn3+/- mice and those with experimentally decreased claudin-3. Our results show the crucial role of claudin-3 in preventing sweat gland leakage and suggest that the pathogenesis of dermatoses accompanied by hypohidrosis involves abnormally decreased claudin-3.

The development of drugs and medical devices is necessary for medical progress; however, safety measures need to be put in place to protect the health of the population. In order to ensure the safety of drugs and medical devices, it is important to determine measures for appropriate management of risks at any time during the development phase, the regulatory review and the post-marketing phase. Adverse events detected in clinical trials are limited due to the restricted numbers of patients enrolled in the trials. Therefore, it is almost impossible to predict rare serious adverse events during the post-marketing phase. The revised Pharmaceutical Affairs Act was established in Japan in November 20, 2013. The new act focuses on increased safety of drugs and medical devices. The Pharmaceuticals and Medical Devices Agency (PMDA) is the regulatory authority in Japan that promotes safety measures from the development phase through to the post-marketing phase. In the post-marketing phase, the PMDA collects information from the medical product companies and healthcare professionals, as well as instructing and advising them with regard to post-marketing safety measures for each drug and medical device. Since Japan has a national health insurance system, a new drug or a medical device is available throughout the country when the drug price or medical fee is listed in the National Health Insurance price list. Healthcare professionals in medical institutions must learn about the drugs and medical devices they handle, and should make an effort to maintain patient safety. The PMDA medi-navi is a very useful electronic mail delivery service that provides critical information for protecting patients from health hazards caused by adverse events. The 'risk management plan' is also important as it contains important information about safety profile and post-marketing measures of a new drug.

A 17-year-old high school boy who complained of severe positional vertigo visited our hospital. He belonged to an American football team in high school, and his head often hit opponents during games. The vertigo was strongest when his left ear was down in the supine position. Physical examination and computed tomography revealed no abnormalities. However, positional testing revealed apogeotropic direction-changing horizontal nystagmus. Rightward nystagmus in the left-ear-down supine position was stronger than leftward nystagmus in the right-ear-down supine position. Additionally, in the supine position, a null point for horizontal nystagmus was identified, beyond which the nystagmus changed direction. This null point was evident when the head was turned 10 degrees to the side. The diagnosis was right lateral canal type of BPPV caused by cupulolithiasis. He was treated with the Gufoni maneuver and reported a decreased incidence of positional vertigo upon re-evaluation.

Polyrotaxanes (PRXs) composed of threading methylated cyclodextrins exhibit a temperature-dependent reversible phase transition across the lower critical solution temperature (LCST) in water. In this study, a variety of methylated β-cyclodextrin (β-CD)-threaded PRXs (Me-PRXs) with different number of methyl groups modified on the β-CD and with different compositions of axle polymers (i.e., Pluronic, PEG-b-PPG-b-PEG) were synthesized, and the relationship between the LCST value and structural parameters was investigated. The LCST values of the Me-PRXs decreased with an increasing the methylation degree of the threading β-CD. Differential scanning calorimetric measurements demonstrated that the temperature-induced phase transition of the Me-PRXs occurred due to the dehydration of the threading methylated β-CD moieties and the subsequent hydrophobic interactions. Interestingly, the Me-PRXs formed coacervate droplets above their LCST. Altogether, we concluded that the LCST values of the Me-PRXs varied accordi...

Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1 Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.

Photobiomodulation (PBM) is a noninvasive treatment that can be neuroprotective, although the underlying mechanisms remain unclear. In the present study, we assessed the mechanism of PBM as a novel treatment for noise-induced hearing loss, focusing on the nuclear factor (NF)-κB signaling pathway. Sprague-Dawley rats were exposed to 1-octave band noise centered at 4kHz for 5h (121dB). After noise exposure, their right ears were irradiated with an 808nm diode laser beam at an output power density of 165mW/cm(2) for 30min a day for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with PBM compared with the non-treatment group at 4, 7, and 14 days after noise exposure. Immunofluorescent image analysis for inducible nitric oxide synthase and cleaved caspase-3 showed lesser immunoreactivities in outer hair cells in the PBM group compared with the non-treatment group. However, immunofluorescent image analysis for NF-κB, an upstream protein of inducible nitric oxide synthase, revealed greater activation in the PBM group compared with the naïve and non-treatment groups. Western blot analysis for NF-κB also showed stronger activation in the cochlear tissues in the PBM group compared with the naïve and non-treatment groups (p0.01, each). These data suggest that PBM activates NF-κB to induce protection against inducible nitric oxide synthase-triggered oxidative stress and caspase-3-mediated apoptosis that occur following noise-induced hearing loss.

Helicobacter cinaediis a rare human pathogen which has various clinical manifestations such as cellulitis, bacteremia, arthritis, meningitis, and infectious endocarditis. We report an abdominal aortic aneurysm infected withHelicobacter cinaedi, treated successfully with surgical repair and long-term antimicrobial therapy.

Tight junctions (TJs) connect epithelial cells and form a semipermeable barrier that only allows selective passage of ions and solutes across epithelia. Here we show that mice lacking EpCAM, a putative cell adhesion protein frequently overexpressed in human cancers, manifest intestinal barrier defects and die shortly after birth as a result of intestinal erosion. EpCAM was found to be highly expressed in the developing intestinal epithelium of wild-type mice and to localize to cell–cell junctions including TJs. Claudin-7 colocalized with EpCAM at cell–cell junctions, and the two proteins were found to associate with each other. Claudins 2, 3, 7, and 15 were down-regulated in the intestine of EpCAM mutant mice, with claudin-7 being reduced to undetectable levels. TJs in the mutant intestinal epithelium were morphologically abnormal with the network of TJ strands scattered and dispersed. Finally, the barrier function of the intestinal epithelium was impaired in the mutant animals. These results suggest that EpCAM contributes to formation of intestinal barrier by recruiting claudins to cell–cell junctions.

Objectives: Early and mid-term results of stent graft (SG) treatment for thoracic aortic aneurysms (thoracic endovascular aneurysm repair: TEVAR) were retrospectively compared with open surgical treatment. Methods: The records of 213 patients in whom single thoracic aortic aneurysm repairs had been performed in our department from January 2006 through August 31, 2009 were reviewed. Acute aortic dissection was excluded. Each case was reviewed for indications for TEVAR from an anatomical standpoint. Among 62 cases in which TEVAR was indicated, 30 (SG group) were treated by TEVAR and 32, by open surgery (OP group). Early and mid-term results were analyzed retrospectively in both groups. Results: There were no operative deaths in either group. The SG group demonstrated significantly less operative bleeding, a shorter operative time, and shorter postoperative hospital stay compared with the OP group. There were 3 deaths in the SG group and 4 in the OP group, which occurred within an average of 656.4 days during the follow up period. The 3 year actuarial survival rate was 88.7% in the SG group and 87.1% in the OP group, and there were no significant differences between the groups. Conclusion: Although early and mid-term results of TEVAR and open surgery were similar, TEVAR is generally less invasive and may be preferable for high-risk patients, compared with open surgical repair. (English Translation of Jpn J Vasc Surg 2010; 19: 51-56.)

Objective: This paper aims to comprehensively document a rare case of sensorineural hearing loss accompanied by hemophagocytic syndrome which could be one of the causes of cochlear dysfunction. Methods: A 63-year-old man presented with right-sided sudden hearing loss and dizziness and pure-tone audiometry showed a right-sided sensorineural hearing loss. The patient was treated with steroid pulse infusion therapy, ATP and vitamin B12. Results: Bone marrow specimen revealed hemophagocytic cells and the diagnosis of hemophagocytic syndrome was made. A blood culture grew Capnocytophaga. The prognosis for hearing recovery was poor. Conclusion: Although viral infection and cochlear circulatory dysfunction have been suggested to be associated with sudden sensorineural hearing loss, hemophagocytic syndrome due to bacterial infection which produces high cytokine levels might cause dysfunction of the inner ear.

Background & Aims In the small intestine, the paracellular transport of Na + is thought to be critical for luminal Na + -homeostasis and the transcellular absorption of nutrients by Na + -driven transporters. Na + is supplied to the intestinal lumen from the submucosa and serum through tight junctions, which form a paracellular barrier between the cells of epithelial sheets. However, the molecular basis for this paracellular transport of Na + is not well understood. Here, we examined this mechanism by performing loss-of-function studies of claudin-2 and claudin-15, two tight-junctional membrane proteins that are specifically and age-dependently expressed in the villi and/or crypts of small intestinal epithelia. Methods Knockout mice for claudin-2 or claudin-15 were subjected to histologic, cell biologic, electrophysiologic, and physiologic analyses. Results Examination of the knockout mice revealed that both claudin-2 and claudin-15 play crucial roles in the transepithelial paracellular channel-like permselectivity for extracellular monovalent cations, particularly Na + , in infants and adults. Especially in Cldn15 −/− adults, the luminal Na + concentration in the small intestine measured directly in vivo was abnormally low, and glucose absorption was impaired, as assessed by the oral glucose tolerance test and estimation of unabsorbed glucose. Conclusions We propose that the "Na + -leaky" claudin-15 is indispensable in vivo for the paracellular Na + permeability, luminal Na + -homeostasis, and efficient glucose absorption in the small intestine, but claudin-2 is indispensable for only the first of these functions. Claudin-15 knockout leads to Na + deficiency and glucose malabsorption in the mouse adult small intestine.

Tight junctions are the main intercellular junctions of podocytes of the renal glomerulus under nephrotic conditions. Their requisite components, claudins, still remain to be identified. We have measured the mRNA levels of claudin subtypes by quantitative real-time PCR using isolated rat glomeruli. Claudin-5 was found to be expressed most abundantly in glomeruli. Mass spectrometric analysis of membrane preparation from isolated glomeruli also confirmed only claudin-5 expression without any detection of other claudin subtypes. In situ hybridization and immunolocalization studies revealed that claudin-5 was localized mainly in glomeruli where podocytes were the only cells expressing claudin-5. Claudin-5 protein was observed on the entire surface of podocytes including apical and basal domains of the plasma membrane in the normal condition and was inclined to be concentrated on tight junctions in puromycin aminonucleoside nephrosis. Total protein levels of claudin-5 in isolated glomeruli were not significantly upregulated in the nephrosis. These findings suggest that claudin-5 is a main claudin expressed in podocytes and that the formation of tight junctions in the nephrosis may be due to local recruitment of claudin-5 rather than due to total upregulation of the claudin protein levels.

Arteriovenous malformation (AVM) is a structural vascular abnormality with no proliferation of cellular components. We report on a 53-year-old man who presented with a 15-year history of a progressively enlarging nodule on his lower lip. A dark-reddish, easy-bleeding nodule diagnosed as AVM was resected to reduce the volume and troublesome bleeding. Histologically, the nodule revealed that the proliferating cellular area was composed of endothelial cells and pericytes in addition to the area of dilated vessels. We speculated that the cell proliferation developed secondary to AVM. We also discuss the histological differential diagnosis of spindle cell hemangioma and pseudo-Kaposi's sarcoma.

Background: Dermatofibrosarcoma protuberans (DFSP) is an uncommon infiltrative tumor of the\ndermis and subcutaneous tissue. Recent cytogenetic studies have demonstrated a chromosomal translocation\nof the collagen type I alpha 1 (COL1A1)gene on chromosome 17 to the platelet-derived growth\nfactor B-chain (PDGFB) gene on chromosome 22. Various exons of the COL1A1 gene have been\nreported to be involved in the fusion with exon 2 of the PDGFB gene. M ethod: The COL1A1-PDGFB\nfusion transcript was detected by reverse transcriptase-polymerase chain reaction (RT-PCR)using frozen\ntissue from 4 DFSP patients. Nucleotide sequence analyses were carried out using the PCR products to\nidentify the breakpoints. Results : COL1A1-PDGFB fusion transcripts were detected in all tumor\nspecimens. Sequence analyses revealed that the end of exon 25, 45, 32, or 11 in the COL1A1 gene was\nfused with the start of exon 2 in the PDGFB gene. Conclusion : Detection of this aberrant fusion\ntranscript can be useful as a diagnostic method for DFSP.

Summary Background As Bowen’s disease of the nail apparatus is quite rare, there have been only a few reports on the prevalence of human papillomavirus (HPV) infection in this condition. Objectives The purpose of this study was to clarify the association of HPV with this disease involving the nail apparatus. Methods Five patients with Bowen’s disease of the nail apparatus were investigated clinically, virologically and histologically. Total DNAs extracted from excised skin lesions were analysed using polymerase chain reaction (PCR) for the presence of HPV DNA and the amplified products were subjected to DNA sequence analyses. Histological localization of HPV DNA was examined by in situ hybridization. Results In three of five patients, HPV was detected by PCR amplification, and subsequent sequence analyses of the PCR products showed the sequences of HPV type 56. A common clinical feature of the three HPV-positive patients was longitudinal melanonychia. In contrast, the two HPV-negative patients presented with a convex nail deformity and a periungual ulcerative lesion. In two of three positive cases, there was a silent point mutation in the L1 gene of each HPV. In the remaining one case, the nucleotide sequence was consistent with the consensus sequence of HPV 56. Sequence analyses of the E6 gene revealed the infection of different variants of HPV 56 among the three cases. The viral genomes were located in keratinocyte nuclei upon in situ hybridization. Conclusions HPV 56 may be involved in the carcinogenesis of Bowen’s disease affecting the nail matrix with longitudinal pigmentation.

We report a 72-year-old man with nevoid basal cell carcinoma syndrome (NBCCS) who presented with 25 skin cysts on his trunk and extremities. Fourteen of 25 skin cysts (56%) were observed on his hands. Histological examination demonstrated that most of the excised cysts had an epithelial wall with typical epidermal keratinization. However, 4 skin cysts (4/16; 25%) showed a corrugated or festooned inner surface of wall without a granular cell layer, which resembled an odontogenic keratocyst, a characteristic feature of skin cysts in NBCCS. A review of the literature suggested that acral localization of skin cysts is a distinctive feature of NBCCS. In addition, the histological findings of skin cysts resembling an odontogenic keratocyst might be a hallmark of NBCCS.

We report a 58-year-old man with mycosis fungoides (MF) and occupational systemic sclerosis (SSc) induced by silica exposure. He was engaged in tunnel construction from the age of 18 to 33 years. He developed MF at the age of 30. Diagnosis of silicosis was made at the age of 52 and SSc at the age of 58. Physical examinations revealed sclerotic skin changes on his forearms and fingers and poikiloderma on the left popliteal fossa and inguinal region. Both antinuclear antibody and antitopoisomerase-I antibody were positive. We could find no apparent difference between his clinical features and those of idiopathic SSc except for the presence of silicosis and MF. Systemic therapy with interferon-gamma for MF did not improve the skin sclerosis. We discuss the relationship of silica exposure to both MF and SSc.

We reported two patients with refractory eosinophilic fasciitis (EF) and provided a systematic review of the literature to determine the clinical variables associated with prognosis of EF. We enrolled 88 cases, whose clinical characteristics were analyzed by separating the patients into two or three groups based on outcome. The incidence of certain clinical and pathological features differed among the groups. In particular, the incidence of morphea-like skin lesions in patients with refractory fibrosis was significantly higher than in patients without refractory fibrosis (p = 0.003). Patients with morphea-like skin lesions were 1.9 times more likely to develop persistent fibrosis than patients without these lesions (95% confidence intervals, 1.5-2.5). A younger age (under 12 years) at onset was associated with a 1.6 times greater risk of residual fibrosis (95% confidence interval, 1.1-2.2). Trunk involvement was associated with a 1.4 times greater risk of residual fibrosis (95% confidence interval, 1.0-2.0). Histopathologically, the presence of dermal fibrosclerosis was associated with a 1.4 times greater risk of refractory fibrosis (95% confidence interval, 1.0-2.1). We consider these clinical characteristics, notably the presence of morphea-like skin lesions may be an important risk factor for developing residual fibrosis in EF patients.

The treatment of severe lymphedema is a difficult challenge. We performed lymphaticovenular anastomosis on two patients with secondary skin lesions of chronic lymphedema; one patient exhibited acquired lymphangioma circumscriptum of the vulva and the other presented elephantiasis nostras verrucosa of the lower leg. Both patients obtained a remarkable improvement in skin lesions and also in the reduction of lymphedema of the lower extremity. During a 6-month-follow-up period, constant reduction in the circumference of the lower extremities without exacerbation of skin lesions was achieved in both patients. Lymphaticovenular anastomosis is a useful surgical treatment for secondary lymphedema in the lower extremities. In addition, this surgical treatment is effective for secondary lesions of lymphedema, including acquired lymphangioma circumscriptum and elephantiasis nostras verrucosa.

Cholangiopathies share common features, including bile duct proliferation, periportal fibrosis, and intrahepatic cholestasis. Damage of biliary epithelium by autoimunne disorder, virus infection, toxic compounds, and developmental abnormalities causes severe progressive hepatic disorders responsible for high mortality. However, the etiologies of these cholestatic diseases remain unclear because useful models to study the pathogenic mechanisms are not available. In the present study, we have found that ezrin knockdown (Vil2kd/kd) mice develop severe intrahepatic cholestasis characterized by extensive bile duct proliferation, periductular fibrosis, and intrahepatic bile acid accumulation without developmental defects of bile duct morphology and infiltration of inflammatory cells. Ezrin is a membrane cytoskeletal cross-linker protein, which is known to interact with transporters, scaffold proteins, and actin cytoskeleton at the plasma membrane. We found that the normal apical membrane localizations of several transport proteins including cystic fibrosis transmembrane conductance regulator (CFTR), anion exchanger 2 (AE-2), aquaporin 1 (AQP1), and Na+/H+ exchanger regulatory factor were disturbed in bile ducts of Vil2kd/kd mice. Stable expression of a dominant negative form of ezrin in immortalized mouse cholangiocytes also led to the reduction of the surface expression of CFTR, AE-2, and AQP1. Reduced surface expression of these transport proteins was accompanied by reduced functional expression, as evidenced by the fact these cells exhibited decreased CFTR-mediated Cl− efflux activity. Furthermore, bile flow and biliary HCO3− concentration were also significantly reduced in Vil2kd/kd mice. Conclusion: Dysfunction of ezrin mimics important aspects of the pathological mechanisms responsible for cholangiopathies. The Vil2kd/kd mouse may be a useful model to exploit in the development and testing of potential therapies for cholangiopathies. (Hepatology 2015;61:1660-1671)

Niemann-Pick type C (NPC) disease is characterized by the lysosomal accumulation of cholesterols and impaired autophagic flux due to the inhibited fusion of autophagosomes to lysosomes. We have recently developed β-cyclodextrin (β-CD)-threaded biocleavable polyrotaxanes (PRXs), which can release threaded β-CDs in response to intracellular environments as a therapeutic for NPC disease. The biocleavable PRXs exhibited effective cholesterol reduction ability and negligible toxic effect compared with hydroxypropyl-β-CD (HP-β-CD). In this study, we investigated the effect of biocleavable PRX and HP-β-CD on the impaired autophagy in NPC disease. The NPC patient-derived fibroblasts (NPC1 fibroblasts) showed an increase in the number of LC3-positive puncta compared with normal fibroblasts, even in the basal conditions; the HP-β-CD treatment markedly increased the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts, indicating that autophagic flux was further perturbed. In sharp contrast, the biocleavable PRX reduced the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts through an mTOR-independent mechanism. The mRFP-GFP-LC3 reporter gene expression experiments revealed that the biocleavable PRX facilitated the formation of autolysosomes to allow for autophagic protein degradation. Therefore, the β-CD-threaded biocleavable PRXs may be promising therapeutics for ameliorating not only cholesterol accumulation but also autophagy impairment in NPC disease.

Summary Background Although digital ulcerations frequently occur in patients with systemic sclerosis (SSc), there have been few reports on the macrovascular involvement. Objectives To evaluate the macrovascular involvement in patients with SSc exhibiting digital ulceration or gangrene. Methods Transfemoral catheter arteriography of the upper and/or lower extremities was performed in eight patients (one man and seven women, age range 42–71 years) with SSc exhibiting digital ulceration or gangrene. The background of the patients, such as autoantibody profiles and vascular risk factors including smoking habits, was also investigated. Results Macrovascular involvement was detected in seven of eight patients. In three of seven patients who underwent arteriography of the upper extremity, occlusion was limited to the digital arteries. Obliteration of the ulnar artery and superficial palmar arch was detected in three of seven patients, and the radial artery in one patient. Only one of five patients who underwent arteriography of the lower extremity showed the occlusion limited to digital arteries of the foot. Occlusion of the posterior tibial artery, dorsalis pedis artery and arcuate artery was detected, each in one patient. Two patients showed occlusion of the plantar arch. Overall, the occlusion of arteries proximal to the digits was demonstrated in four of eight patients. Three of the four patients were positive for antitopoisomerase-1 antibody and had diffuse cutaneous SSc (dcSSc) with multiple skin ulcers or gangrene. Conclusions Macrovascular involvement as detected with arteriography is not rare in SSc patients with digital ulceration or gangrene. Moreover, the vascular occlusion proximal to the digits seemed to be frequent in antitopoisomerase-1 antibody-positive dcSSc patients with multiple skin ulcers or gangrene.

A 73-year-old man with silico-asbestosis responded to steroid therapy. Chest CT scans showed diffuse micronodular opacities and ground glass opacities bilaterally throughout the entire lung fields, as well as progressive massive fibrosis in the bilateral upper lung fields. Diagnostic thoracoscopic biopsy revealed mixed dust pneumoconiosis with silicotic nodules, as well as fibrosis similar to that of Usual Interstitial Pneumonia (UIP) with many fibroblastic foci and alveolitis. Many asbestos bodies were also detected by iron staining.

Bullous pemphigoid (BP) is an acquired autoimmune blistering disease which predominantly affects the elderly. It is rare in children and infants. We reported a 14-year-old girl presenting with a month history of relapsing tense bullae on the face and extremities. Histopathological examination of the lesional skin revealed a subepidermal bulla with infiltration of eosinophils, neutrophils, and lymphocytes. Direct immunofluorescence showed linear deposits of IgM and C3 at the basement membrane zone. Indirect immunofluorescence using normal human skin sections as a substrate detected IgG anti-basement membrane zone antibodies in the patient's serum and that using 1M NaCl split skin sections showed that the patient's antibodies bound to the epidermal side of the split skin. Immunoblot analysis using normal human epidermal extracts demonstrated the presence of autoantibodies against the 230-kDa BP antigen. Furthermore, the patient's serum reacted with the recombinant protein of the NC16a domain of the 180-kDa BP antigen by immunoblot analysis and enzyme-linked immunosorbent assay. Our patient showed significant improvement of the skin lesions with systemic administration of diaminodiphenyl sulfone.

We present a 79-year-old man who suffered from extramammary Paget's disease (EMPD) with bowenoid histological features accompanied by an ectopic EMPD lesion on his abdomen. He had had an erythematous plaque on his genital region for three years. Based on a biopsy specimen, he was referred to our hospital with the histological diagnosis of Bowen's disease. The histological findings of the genital lesion obtained by surgical resection showed typical areas of Paget's cells adjacent to areas characteristic of Bowen's disease. Immunohistochemical findings showed CEA and CK7 positive tumor cells in both areas, so the atypical cells showing the bowenoid pattern could be regarded as tumor cells of Paget's disease. Immunohistochemical staining for CEA and CK7 along with multiple biopsies can be helpful in making the diagnosis of Paget's disease with bowenoid histologic features.

Loss of gastric acid secretion is pathologically known as achlorhydria. Acid-secreting parietal cells are characterized by abundant expression of ezrin (Vil2), one of ezrin/radixin/moesin proteins, which generally cross-link actin filaments with plasma membrane proteins. Here, we show the direct in vivo involvement of ezrin in gastric acid secretion. Ezrin knockout (Vil2−/−) mice did not survive >1.5 wk after birth, making difficult to examine gastric acid secretion. We then generated ezrin knockdown (Vil2kd/kd) mice by introducing a neomycin resistance cassette between exons 2 and 3. Vil2kd/kd mice born at the expected Mendelian ratio exhibited growth retardation and a high mortality. Approximately 7% of Vil2kd/kd mice survived to adulthood. Ezrin protein levels in Vil2kd/kd stomachs decreased to