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The study aimed to investigate the clinical implications and natural history of primary intraparenchymal lesions in patients with neurofibromatosis type 2. Radiological findings of 15 neurofibromatosis type 2 cases were retrospectively collected. Twenty-seven primary intraparenchymal lesions were observed in 7 out of 15 patients (47%). Cortical/subcortical T2 hyperintense lesions and enlarged Virchow–Robin spaces were the most common findings in five and four patients, respectively. During the follow-up period (median 84 months), one new primary intraparenchymal lesion was identified and increased lesions were observed in two cases on contrast-enhanced MRI. Surgical resection was performed in one case pathologically diagnosed with atypical meningioma. Twenty-five other lesions without contrast enhancement presented no apparent growth during follow-up. Although most primary intraparenchymal lesions are benign, a subset of cases would present newly developed or increased lesions on contrast-enhanced MRI. Careful monitoring is necessary for such cases, and pathological confirmation should be considered.

Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. Cases comprised six females and two males, with a median age of 56.5 years (range, 46–71 years) and a median disease duration of 62.5 months (range, 0.6–252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for GFAP: (i) astrocyte lysis: extensive loss of astrocytes with fragmented and/or dust-like particles; (ii) progenitor recruitment: loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (iii) protoplasmic gliosis: presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (iv) fibrous gliosis: lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD.

Introduction Thyroid storm is a rare life-threating condition. We report a case of thyroid storm after radical nephrectomy for renal cell carcinoma with inferior vena cava tumor thrombus. Case presentation A 76-year-old man with a left renal tumor and tumor thrombus extending into the inferior vena cava underwent left radical nephrectomy and thrombectomy. After the surgery, his postoperative course rapidly deteriorated, including central nervous system disturbance, fever, tachycardia, congestive heart failure, and hepatic manifestation. Thyroid function test revealed perioperative hyperthyroidism. Corticosteroids and inorganic iodide improved his condition, suggesting that he developed thyroid storm after surgery. He was discharged 5 months after surgery and has been free from disease recurrence for more than 2 years. Conclusion Thyroid storm after surgery is rare. However, this postoperative complication is important because it is fatal if not diagnosed and treated properly.

Objectives Although many studies have examined locomotive syndrome (LS) among elderly people, few studies have examined LS in young‐ and middle‐aged adults. This study aimed to provide basic data on the epidemiological characteristics of LS, including in young‐ and middle‐aged adults. Method We conducted a cross‐sectional survey of a nonrandom sample of 852 adults aged 18–64 (678 males, 174 females) working in five companies in Japan, between December 2015 and February 2018. LS stage was determined using the criteria proposed by the Japanese Orthopaedic Association (JOA). LS stage 0 was defined as No‐LS, and stages 1 and 2 were defined as LS. Multiple logistic regression analysis was used to investigate the independent relationship between LS and sociodemographic, smoking, alcohol drinking (AD), frequency of breakfast consumption (FBC), dietary variety score (DVS), and the University of California Los Angeles (UCLA) activity score after adjusting for age and sex. Results We found that 23.1% of participants were evaluated as LS, including 21.5% of males and 29.3% of females (P

The majority of oligodendroglial tumors harbor mutations in the telomerase reverse transcriptase (TERT) gene (TERT) promoter and the isocitrate dehydrogenase 1/2 (IDH1/2) gene (IDH1/2), as well as 1p/19q codeletion. Generally, TERT promoter mutations, C250T and C228T, are mutually exclusive. We present a case of oligodendroglioma harboring both C250T and C228T mutations in TERT promoter. A 38-year-old man presented with grand mal seizures and underwent a resection surgery for a left frontal lobe tumor. He was pathologically diagnosed as having oligodendroglioma and was carefully observed. At 48 years of age, he underwent another resection surgery due to tumor regrowth, with the pathological diagnosis of anaplastic oligodendroglioma. Genetic analysis of the initial tumor specimen revealed IDH1 R132H mutation and both C250T and C228T mutations in TERT promoter. Using mutation-specific primers, two mutations were considered to be distributed in different alleles. In the tumor specimen obtained during the second surgery, IDH1 R132H mutation was detected to be similar to that of the initial specimen; however, only C228T mutation was detected in TERT promoter. The 1p/19q codeletion was detected in both the initial and recurrent tumor specimens. According to the sequencing data from the two tumor specimens, although TERT promoter mutation has been considered to be an early genetic event in the tumorigenesis of oligodendroglial tumors, it is likely that the C250T and C228T mutations in TERT promoter are subclonally distributed in the same tumor specimen of the present case.

// Naoko Ishida 1 , Motoi Baba 1 , Yutaka Hatanaka 2, 3 , Kanako Hagio 1 , Hiromi Okada 2 , Kanako C. Hatanaka 3 , Kenichi Togashi 4 , Yoshihiro Matsuno 2, 3 and Hiroko Yamashita 1 1 Department of Breast Surgery, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan 2 Department of Surgical Pathology, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan 3 Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan 4 Roche Diagnostics K.K., Konan, Minato-ku, Tokyo 108-0075, Japan Correspondence to: Hiroko Yamashita, email: hirokoy@huhp.hokudai.ac.jp Keywords: breast cancer; estrogen receptor; PIK3CA; AKT Ser473; ERα Ser167 Received: June 27, 2017 Accepted: February 28, 2018 Published: April 03, 2018 ABSTRACT Although endocrine therapy is the most important treatment option in estrogen receptor (ER)-positive breast cancer, new strategies, such as molecular targeted agents together with endocrine therapy are required to improve survival. PIK3CA is the most frequent mutated gene in ER-positive early breast cancers, and PIK3CA mutation status is reported to affect activation of AKT and ERα. Moreover, recent studies demonstrate that patients had a better prognosis when tumors expressed ER, androgen receptor (AR), and vitamin D receptor (VDR). In this study, we examined expression of AR and VDR, phosphorylation of AKT serine (Ser) 473 (AKT phospho-Ser473) and ERα Ser167 (ERα phospho-Ser167) by immunohistochemistry in ER-positive, HER2-negative early breast cancer. PIK3CA gene mutations were also detected in genomic DNA extracted from tumor blocks. Correlations between these biological markers, clinicopathological factors and prognosis were analyzed. Levels of AKT phospho-Ser473 were significantly higher in premenopausal women than in postmenopausal women. In contrast, AR expression was significantly higher in postmenopausal women than in premenopausal women. PIK3CA mutations were detected in 47% in premenopausal women and 47% in postmenopausal women. Postmenopausal women with PIK3CA wild-type tumors had significantly worse disease-free survival than patients with PIK3CA mutant tumors. Low levels of AKT phospho-Ser473 and high levels of ERα phospho-Ser167 were strongly associated with increased disease-free survival in postmenopausal women. Evaluation of ERα activation, in addition to PIK3CA mutation status, might be helpful in identifying patients who are likely to benefit from endocrine therapy alone versus those who are not in postmenopausal ER-positive early breast cancer.

Background Muir–Torre syndrome (MTS) is a rare autosomal dominant genodermatosis caused by mutations in mismatch repair genes. It is characterized by the presence of at least one sebaceous skin tumor associated with internal malignancies. Whether positron emission tomography/computed tomography (PET/CT) is useful for the detection of malignancies in patients with MTS has not been determined. We herein report two cases in which PET/CT was useful for the diagnosis and follow-up of internal malignancies in patients with MTS. Case presentation In case 1, a 57-year-old woman underwent excision of a sebaceous carcinoma on the left upper eyelid. She underwent follow-up PET/CT once yearly thereafter. Forty-two months after the eyelid surgery, PET/CT showed intense tracer uptake in the right lower abdomen. An ascending colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. In case 2, a 77-year-old man presented for evaluation of three continuous papules with telangiectasia on his right cheek. Examination of a skin biopsy specimen of the cheek papule revealed a sebaceous carcinoma. He underwent PET/CT to detect other malignancies. PET/CT showed intense tracer uptake in the sigmoid colon. A sigmoid colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. Both patients underwent resection of their tumors, and both were still free of recurrence of the sebaceous and colon carcinomas at the time of this writing. Conclusion PET/CT is a reliable imaging modality for the detection of internal malignancies and is useful for the diagnosis and follow-up of MTS.

This study surveyed that the relationship between the frequencies of intake of taurine-contained nutritional drinks (TCND), and lifestyle and the purposes of intake it. The study was conducted a cross-sectional survey using 265 people (203 male, 62 female) aged 18–64 worked in two companies in Mie Prefecture, Japan between December 2017 and February 2018. The questionnaires gathered characteristics, demographic, socioeconomic, lifestyle habits and purpose of TCND intake. We divided the frequency of intake of TCND of at least a few times every month as the high-frequency TCND (HF-TCND) group, and the remaining as the low-frequency TCND (LF-TCND) group. Multivariate logistic regression analysis was used to investigate the relationship between characteristics, demographic, socioeconomic, lifestyle habits and purpose of TCND intake and HF-TCND after controlling for individual variables. Of all participants, 13.4% was evaluated as HT-CND. 16.3% for male or 4.3% for female were evaluated as HF-TCND (p < 0.05). The most reason for frequent choosing a TCND was fatigue recovery. Logistic regression analysis showed that sex, occupation, purpose of TCND intake and stressful are related to HF-TCND. Our study indicates that purpose of TCND intake, such as fatigue recovery and reducing stress, may partly affect the frequency of intake of TCND. Therefore, we must continue to show scientific evidence for taurine by enlightenment activity etc.

The aim of the present study was to investigate the clinicopathological features of cystic lesions in the eyelid. Clinicopathological profiles were retrospectively searched based on medical records of 35 patients with cystic lesions of the eyelids, which were surgically resected from January 2003 to June 2016. The cohort consisted of 16 men and 19 women. The mean age of the patients was 57±24 years. The main locations of the cysts were the upper eyelid in 22 patients, followed by the lower eyelid in 5 patients. Eyelid skin and its appendages were the most common as the origin of cysts, followed by the tarsus, palpebral conjunctiva and lacrimal gland. The histopathological diagnoses were 16 epidermal cysts, 5 intratarsal keratinous cysts, 3 conjunctival cysts, 2 trichilemmal cysts, 1 dermoid cyst, 1 apocrine hidrocystoma, 1 lacrimal gland cyst and 6 unclassifiable cysts. All cysts did not recur following resection. In summary, cystic lesions of the eyelid were frequently observed in the upper eyelid. The most frequent diagnoses were epidermal cysts, followed by intratarsal keratinous cysts, while a definitive diagnosis in some cysts could not be pathologically determined, as they lacked epithelia and/or the contents or they resembled apocrine hidrocystoma and intratarsal keratinous cysts with atypical findings. The results of the current study indicate that the incidence and differential diagnosis of eyelid cystic lesions may contribute to the application of appropriate treatment for patients with eyelid tumors.

BACKGROUND Family members of children with cancer experience various long-term effects as a result of cancer diagnosis and treatment. Therefore, comprehensive and long-term support is needed. As the employment rate of women has increased in recent years, support for working mothers with children diagnosed with cancer is also required. OBJECTIVE We investigated the following issues and relevant changes that working mothers of children diagnosed with cancer must deal with: (1) work change, (2) stress, (3) social support, (4) work motivation, and (5) employment status after diagnosis. METHODS A cross-sectional exploratory study design was used. Data were collected from 62 mothers of children who were diagnosed with cancer using self-report questionnaires. RESULTS Of the 32 mothers who worked at the time of diagnosis, 10 continued to work, 12 took an extended leave, and 10 quit working, and 70% lost motivation for work following diagnosis. Half of mothers who continued to work during treatment reported financial reasons. CONCLUSIONS These findings indicate that mothers who quit work following diagnosis did not initially consider a long leave of absence. Even mothers who continued to work during treatment desired a long leave of absence to care for their children. IMPLICATIONS FOR PRACTICE Nurses should provide mothers with explanations of the prospects after the completion of cancer treatment and determine their expectations for their lifestyle and work during treatment. We recommend that nurses confirm mothers' willingness to take a long leave of absence from work and give relevant advice about seeking financial assistance.

Current tumor therapies, including immunotherapies, focus on passive eradication or at least reduction of the tumor mass. However, cancer patients quite often suffer from tumor relapse or metastasis after such treatments. To overcome these problems, we have developed an NKT cell-targeted immunotherapy focusing on active engagement of the patient’s immune system, but not directly targeting the tumor cells themselves. Natural Killer T (NKT) cells express an invariant antigen receptor α chain encoded by Trav11 (Vα14)-Traj18 (Jα18) gene segments in mice and TRAV10 (Vα24)-TRAJ18 (Jα18) in humans and recognize glycolipid ligand in conjunction with a monomorphic CD1d molecule. The NKT cells play a pivotal role in the orchestration of antitumor immune responses by mediating adjuvant effects that activate various antitumor effector cells of both innate and adaptive immune systems and also aid in establishing a long-term memory response. Here, we established NKT cell-targeted therapy using a newly discovered NKT cell glycolipid ligand, RK, which has a stronger capacity to stimulate both human and mouse NKT cells compared to previous NKT cell ligand. Moreover, RK mediates strong adjuvant effects in activating various effector cell types and establishes long-term memory responses, resulting in the continuous attack on the tumor that confers long-lasting and potent antitumor effects. Since the NKT cell ligand presented by the monomorphic CD1d can be used for all humans irrespective of HLA types, and also because NKT cell-targeted therapy does not directly target tumor cells, this therapy can potentially be applied to all cancer patients and any tumor types.

Background High-density Lipoprotein (HDL) attenuates endothelial cell apoptosis induced by different cell-death stimuli such as oxidation or growth factor deprivation. HDL is the main plasma carrier of the bioactive lipid sphingosine 1-phosphate (S1P), which it is a signaling molecule that promotes cell survival in response to several apoptotic stimuli. In HDL, S1P is bound to Apolipoprotein M (ApoM), a Lipocalin that is only present in around 5% of the HDL particles. The goal of this study is to characterize ApoM-bound S1P role in endothelial apoptosis protection and the signaling pathways involved. Methods Human umbilical vein endothelial cells (HUVEC) cultures were switched to serum/grow factor deprivation medium to induce apoptosis and the effect caused by the addition of ApoM and S1P analyzed. Results The addition of HDL+ApoM or recombinant ApoM-bound S1P promoted cell viability and blocked apoptosis, whereas HDL-ApoM had no protective effect. Remarkably, S1P exerted a more potent anti-apoptotic effect when carried by ApoM as compared to albumin, or when added as free molecule. Mechanistically, cooperation between S1P1 and S1P3 was required for the HDL/ApoM/S1P-mediated anti-apoptotic ability. Furthermore, AKT and ERK phosphorylation was also necessary to achieve the anti-apoptotic effect of the HDL/ApoM/S1P complex. Conclusions Altogether, our results indicate that ApoM and S1P are key elements of the anti-apoptotic activity of HDL and promote optimal endothelial function. Electronic supplementary material The online version of this article (doi:10.1186/s12944-017-0429-2) contains supplementary material, which is available to authorized users.

The staphylococcal superantigen-like protein (SSL) family is composed of 14 exoproteins sharing structural similarity with superantigens but no superantigenic activity. Target proteins of four SSLs have been identified to be involved in host immune responses. However, the counterparts of other SSLs have been functionally uncharacterized. In this study, we have identified porcine plasma prothrombin as SSL10-binding protein by affinity purification using SSL10-conjugated Sepharose. The resin recovered the prodomain of prothrombin (fragment 1 + 2) as well as factor Xa in pull-down analysis. The equilibrium dissociation constant between SSL10 and prothrombin was 1.36 × 10−7 m in surface plasmon resonance analysis. On the other hand, the resin failed to recover γ-carboxyglutamic acid (Gla) domain-less coagulation factors and prothrombin from warfarin-treated mice, suggesting that the Gla domain of the coagulation factors is essential for the interaction. SSL10 prolonged plasma clotting induced by the addition of Ca2+ and factor Xa. SSL10 did not affect the protease activity of thrombin but inhibited the generation of thrombin activity in recalcified plasma. S. aureus produces coagulase that non-enzymatically activates prothrombin. SSL10 attenuated clotting induced by coagulase, but the inhibitory effect was weaker than that on physiological clotting, and SSL10 did not inhibit protease activity of staphylothrombin, the complex of prothrombin with coagulase. These results indicate that SSL10 inhibits blood coagulation by interfering with activation of coagulation cascade via binding to the Gla domain of coagulation factor but not by directly inhibiting thrombin activity. This is the first finding that the bacterial protein inhibits blood coagulation via targeting the Gla domain of coagulation factors.

The development of next-generation sequences has brought not only high-throughput sequencing but also new possibilities for various kinds of analysis methods of genetic information. Dr. Hayashizaki et al. developed new technologies to construct the full-length cDNA library and applied them to high-throughput sequencing technologies for large-scale transcriptome analysis. These analysis results overturned the conventional assumption the 2% of the genome is transcribed by showing that 70% or more of the genome is transcribed as RNA through FANTOM activities which was founded in 2000 on their initiative. Further, the existence of 23,000 non-protein coding RNAs was confirmed. These new findings redefine the central dogma into a new picture containing new interaction cascade and the unexpected complexity of combined omics. The neo central dogma shows that there are three types of final products derived from genes; long ncRNA, small ncRNA, and protein. They play essential roles by forming complexes with each other to maintain life. Long ncRNA and small ncRNA play a role as a ligand with sequence information. Long ncRNA and protein play a role as a functional molecule. Here, I would like to introduce the neo central dogma concept and some of the mechanisms of ncRNAs.

Background: Although asbestos acts as a potent carcinogen in pleural mesothelial and pulmonary epithelial cells, it still remains unclear whether asbestos causes specific and characteristic gene alterations in these different kinds of target cells, because direct comparison in an identical patient is not feasible. We experienced a rare synchronous collision tumor composed of malignant pleural mesothelioma (MPM) and primary pulmonary adenocarcinoma (PAC) in a 77-year-old man with a history of long-term smoking and asbestos exposure, and compared the DNA copy number alteration (CNA) and somatic mutation in these two independent tumors. Methods: Formalin-fixed paraffin-embedded (FFPE) tissues of MPM and PAC lesions from the surgically resected specimen were used. Each of these MPM and PAC lesions exhibited a typical histology and immunophenotype. CNA analysis using SNP array was performed using the Illumina Human Omni Express-12_FFPE (Illumina, San Diego, CA, USA) with DNA extracts from each lesion. Somatic mutation analysis using next-generation sequencing was performed using the TruSeq Amplicon Cancer Panel (Illumina). Results: The CNA analysis demonstrated a marked difference in the frequency of gain and loss between MPM and PAC. In PAC, copy number (CN) gain was detected more frequently and widely than CN loss, whereas in MPM there was no such obvious difference. PAC did not harbor CNAs that have been identified in asbestos-associated lung cancer, but did harbor some of the CNAs associated with smoking. MPM exhibited CN loss at 9p21.2-3, which is the most common genetic alteration in mesothelioma. Conclusion: In this particular case, asbestos exposure may not have played a primary role in PAC carcinogenesis, but cigarette smoking may have contributed more to the occurrence of CN gains in PAC. This comparative genetic analysis of two different lesions with same amount of asbestos exposure and cigarette smoke exposure has provided information on differences in the cancer genome related to carcinogenesis.

Background: Vitreoretinal lymphoma (VRL) is a life- and sight-threatening disorder. The aim of this study was to analyze the usefulness of the cell block method for diagnosis of VRL. Methods: Sixteen eyes in 12 patients with VRL, and 4 eyes in 4 patients with idiopathic uveitis presenting with vitreous opacity were enrolled in this study. Both undiluted vitreous and diluted fluids were isolated during micro-incision vitrectomy. Cell block specimens were prepared in 19 eyes from diluted fluid containing shredding vitreous. These specimens were then submitted for HE staining as well as immunocytological analyses with antibodies against the B-cell marker CD20, the T-cell marker CD3, and cell proliferation marker Ki67. Conventional smear cytology was applied in 14 eyes with VRL using undiluted vitreous samples. The diagnosis of VRL was made based on the results of cytology, concentrations of interleukin (IL)-10 and IL-6 in undiluted vitreous, and immunoglobulin heavy chain gene rearrangement analysis. Results: Atypical lymphoid cells were identified in 14 out of 15 cell block specimens of VRL (positive rate: 93.3 %), but in 5 out of 14 eyes in conventional smear cytology (positive rate: 35.7 %). Atypical lymphoid cells showed immunoreactivity for CD20 and Ki67. Seven cell block specimens were smear cytology-negative and cell block-positive. The cell block method showed no atypical lymphoid cells in any patient with idiopathic uveitis. Conclusions: Cell block specimens using diluted vitreous fluid demonstrated a high diagnostic sensitivity and a low pseudo-positive rate for the cytological diagnosis of VRL. The cell block method contributed to clear differentiation between VRL and idiopathic uveitis with vitreous opacity., 背景：眼内リンパ腫（VRL）は視力・生命予後に影響を及ぼす疾患である。本研究ではVRLの診断における細胞塊（セルブロック）標本の有用性を検討することを目的とした。症例と方法：北海道大学病院眼科および他院を受診したVRL12例16眼、および硝子体混濁を呈した特発性ぶどう膜炎4例4眼を対象とした。小切開硝子体手術により、無希釈硝子体液および硝子体灌流液を採取した。19眼で、硝子体灌流液を用いたセルブロック標本を作製した。これらの標本を用いて特殊染色、およびB細胞マーカーである抗CD20抗体の免疫細胞化学的検討を行った。14眼では無希釈硝子体液を用いた塗抹細胞診を併せて行った。VRLの診断は、細胞診、無希釈硝子体液のIL-10, -6濃度、灌流液沈殿物から遺伝子再構成部位のモノクローナリティについて検討して行った。結果：VRLの15眼中14眼でセルブロック標本にて悪性リンパ腫細胞が検出された（陽性率：93.3％）。一方、塗抹細胞診では5眼で悪性細胞が検出された（陽性率：35.7％）。塗抹細胞診で陰性、セルブロックで陽性を示したIOL症例は7例8眼であった。特発性ぶどう膜炎では、悪性細胞が検出された症例はなかった（陽性率：0％）。VRL細胞はCD20陽性を示したが、特発性ぶどう膜炎ではCD20陽性細胞は検出されなかった。結語：硝子体灌流液を用いたセルブロック細胞診は、これまでの塗抹細胞診よりVRLの陽性率が高く、偽陽性も無かった。セルブロックは、VRLとぶどう膜炎との鑑別にも有用であることが示唆された。

An increased expression of plasminogen activator inhibitor type-1 (PAI-1) has been implicated in accelerating atherogenesis and coronary artery disease in patients with type 2 diabetes. Transforming growth factor (TGF)-β increases its expression. An increased PAI-1 appears to predispose also to augmented fibrosis potentially contributing to negative left ventricular remodeling and heart failure after myocardial infarction. Diabetes is well known to induce oxidative stress. To elucidate molecular mechanisms underlying an increased PAI-1 production, the effects of TGF-β and oxidative stress implicated as agonists of PAI-1 synthesis were characterized with the use of human liver-derived HepG2 cells.PAI-1 mRNA was assayed by real-time PCR, and PAI-1 protein was assayed by western blotting. PAI-1 promoter (-825 -+42 bp) activity was assessed with the luciferase assay. The role of the 3'-untranslated region was delineated with the use of luciferase constructs containing the 3'-untranslated region. Oxidative stress was measured after loading carboxy-2,7-dichlorodihydrofluorescein into cells.TGF-β increased oxidative stress, which was accompanied by increases in NADPH oxidase 3 mRNA and membrane translocation of Rac proteins. TGF-β-inducible increases in the PAI-1 promoter activity involved Smad-binding elements and a nuclear factor-κB-binding site. TGF-β did not increase the activity of the PAI-1 mRNA 3'-untranslated region. TGF-β-inducible PAI-1 expression was attenuated by simvastatin and curcumin, a natural polyphenol.TGF-β can increase the expression of PAI-1 through multiple mechanisms involving Smad and nuclear factor-κB pathways and oxidative stress. As both oxidative stress and PAI-1 production were reduced by simvastatin and curcumin, modulation of oxidative stress and PAI-1 production are attractive targets for pharmacotherapy of cardiovascular disorders associated with an increased PAI-1 including type 2 diabetes and its associated consequences including accelerated coronary artery disease and an increased fibrosis that may exacerbate adverse left ventricular remodeling after myocardial infarction.

Insulin increases, through several molecular mechanisms, expression of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis. This phenomenon has been implicated as a cause of accelerated coronary artery disease and the increased incidence of acute coronary syndromes associated with type 2 diabetes. We have previously reported that physiologic and pharmacologic concentrations of insulin induce PAI-1 synthesis in human HepG2 cells and that simvastatin can attenuate its effects. This study was performed to further elucidate mechanisms responsible for the insulin-induced PAI-1 production.Concentrations of PAI-1 mRNA were determined by real-time PCR, and PAI-1 protein was assayed by western blotting. PAI-1 promoter (-829 to +36 bp) activity was assayed with the use of luciferase reporter assays. The potential role of the 3'-untranslated region (UTR) in the PAI-1 gene was assayed with the use of luciferase constructs containing the 3'-UTR. Oxidative stress was measured by loading cells with carboxy-2,7 dichlorodihydrofluorescein.Insulin increased PAI-1 promoter activity, PAI-1 mRNA, and accumulation of PAI-1 protein in the conditioned media. Insulin-inducible PAI-1 promoter activity was attenuated by simvastatin. Experiments performed with luciferase reporters containing the 3'-UTR showed that insulin increased luciferase activity through this region. Insulin also increased oxidative stress. Both insulin-inducible luciferase activity through the 3'-UTR and oxidative stress were attenuated by simvastatin.Insulin can increase PAI-1 expression through multiple mechanisms including induction mediated by the 3'-UTR of the PAI-1 gene. Accordingly, beneficial pleiotropic effects of statins on coronary artery disease may be attributable, in part, to attenuation of overexpression of PAI-1 mediated by the 3'-UTR in syndromes of insulin resistance (such as the metabolic syndrome) and type 2 diabetes.

Protein S (PS) is a member of the vitamin K-dependent protein family containing similar γ-carboxyglutamic acid (Gla) domains, although only PS has a thrombin-sensitive region (TSR), which is located between the Gla domain and the first epidermal growth factor-like domain. In this study, a novel PROS1 mutation was identified at the last nucleotide in intron C (c.260-1G>A) in a patient suffering from recurrent deep vein thrombosis associated with PS deficiency. To investigate the molecular mechanisms of PS deficiency caused by the novel PROS1 mutation, we characterized the mutant mRNA, and the secretion and function of the mutant PS molecule associated with the mutation. RT-PCR was used to detect the aberrant mRNA in the patient's platelets, the amount of which was markedly reduced and lacked the region corresponding to exon 4 coding the TSR of the PS molecule. The recombinant mutant PS lacking the TSR (TSR-lack PS) showed a markedly reduced transient expression/secretion level, 37.9% of that of wild-type (WT) PS. Activated protein C (APC) cofactor activity assay showed that TSR-lack PS had no cofactor activity. Moreover, binding assays of monoclonal antibodies recognizing the PS Gla domain and the Gla residues indicated that the bindings of TSR-lack PS to both of these antibodies were clearly weaker than those of WT PS. These findings suggest that the novel mutation leading to the absence of the TSR not only affected the secretion of mutant PS, but was also responsible for impairment of the Gla domain conformation required for the γ-carboxylation to express APC cofactor activity.

Many people have suffered and died due to a lot of large-scale disasters such as earthquake, fire, and terrorism, etc. In disasters where most evacuators become panic, two things are necessary for their immediate evacuation. The first is to estimate the location of the disaster occurrence. The second is to construct an evacuation support system that searches for safe and efficient evacuation routes. In this paper, we propose Emergency Rescue Urgent Communication — Evacuation Support System (EUC-ESS) based on Mobile Ad-hoc networks (MANET) composed of many mobile terminals. Using experiments and computer simulations, we show that this system would support evacuators in determining appropriate routes for survivors.

Introduction Genetic deficiencies of PROS1, PROC, and SERPINC1 (antithrombin) are risk factors for deep vein thrombosis (DVT). Diagnosis of the inherited deficiencies of these three genes is sometimes difficult because of the phenotypic variability. This study was undertaken to reveal the frequency of nonsynonymous mutations of these three genes in Japanese DVT patients. Patients/Methods One hundred seventy-three DVT patients were registered by the Sub-group of Blood Coagulation Abnormality, from the Study Group of Research on Measures for Intractable Diseases. We sequenced the entire coding regions of the three genes in all DNA samples and identified the nonsynonymous mutations. Results and Conclusions For PROS1 we identified 15 nonsynonymous mutations in 28 DVT patients; for PROC, 10 nonsynonymous mutations in 17 patients; and for SERPINC1, 13 nonsynonymous mutations in 14 patients. Five patients had two mutations in PROS1 and PROC, and all of them had PROS1 K196E mutation. We previously identified one patient with a large PROS1 gene deletion. Thus, 55 out of 173 patients (32%) carried at least one genetic defect in the three genes. The PROS1 K196E mutation found in 15 Japanese DVT patients was the most prevalent. Mutations of PROC K193del and V339M were the second, each found in four patients. Our data suggested that the PROC K193del mutation caused the loss of the anticoagulant activity but not the amidolytic activity. Our effort is the first DNA resequencing study to identify the genetic variations in DVT patients without any consideration of their plasma activities and antigens. To minimize selection bias in a future evaluation of the contribution of genetic deficiency to DVT, we must recruit patients consecutively.

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protease inhibitor that inhibits the tissue factor-initiated blood coagulation cascade reactions. Based on these anticoagulant functions of TFPI, we hypothesized that genetic variations in TFPI may alter the TFPI expression or impair the anticoagulant function and could predispose persons to deep vein thrombosis (DVT). This study was undertaken to examine whether the genetic polymorphisms in TFPI are associated with the plasma TFPI levels and risk for DVT. We sequenced the entire coding regions of TFPI in 175 Japanese DVT patients and identified 12 genetic variants, including one missense mutation, Asn221Ser. The missense mutation occurred at the site presumably attached to the glycosylphosphatidylinositol anchor in the TFPI-beta form. The allele frequency of the mutant Ser-coding allele of the Asn221Ser mutation was 8% in the Japanese general population consisting of 1684 individuals. The Asn221Ser mutation was significantly associated with the total TFPI levels (Asn/Asn, n = 108, total TFPI = 56.57 +/- 0.88 ng/ml (mean +/- SD) vs. Asn/Ser + Ser/Ser, n = 16, total TFPI = 63.44 +/- 2.28 ng/ml, P = 0.0058). The genotype was not associated with the free TFPI level. This Asn221Ser mutation was not associated with DVT. Thus, the Asn221Ser mutation occurring in the TFPI-beta form was associated with the total TFPI level, but not a risk for DVT. The absence of the putative glycosylphosphatidylinositol anchor in TFPI-beta under pathological conditions remains to be studied.

Thymic epithelial cells can produce many kinds of cytokines, and interleukin (IL)-6-producing thymic carcinoma cases have been reported. However, a cytokine-producing human thymic tumor cell line has not previously been established. In this paper, we report a novel, multiple inflammatory cytokine-productive cell line that was established from a patient with thymic carcinoma. This cell line, designated ThyL-6, positively expressed epithelial membrane antigen, cytokeratins, vimentin intermediate filament and CD5, although hematological markers were not present in the cells. Cytokine antibody array analysis showed that the cells secreted several cytokines including IL-1alpha, IL-6, IL-8, RANTES, soluble TNFalpha-receptor 1, VEGF and CTLA into the culture medium. The addition of ThyL-6-cultured supernatant supported the growth of human myeloma ILKM-3 cells, which require the presence of IL-6 in the culture medium for the maintenance of cell growth, suggesting that the secreted IL-6 from ThyL-6 cells was biologically active. Chromosome analysis demonstrated that ThyL-6 cells had complex karyotype anomalies, including der(16)t(1;16); the latter has been recognized in thymic squamous cell carcinoma and thymic sarcomatoid carcinoma cases, as well as in several other kinds of malignancies. Heterotransplantation of the cells into nude mice showed tumorigenesis with neutrophil infiltration and liquefactive necrosis. These findings suggest that ThyL-6 cells will provide us with a new experimental tool for investigating not only the pathogenesis, biological behavior, chromo-somal analysis and therapeutic reagents of human thymic carcinoma, but also for studying cytokine-chemokine network systems.

SummarySeveral studies have indicated that approximately 25% of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8%). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.Supplementary Material to this article is available at www.thrombosis-online.com.

Background: Due to variations in location and size, laparoscopic surgery for paraaortic or paracaval neurogenic tumors is challenging. We evaluated the surgical outcomes, as well as surgical tips and tricks. Methods: Between 2000 and 2015, 25 procedures were performed in 24 patients. One patient underwent second surgery due to the recurrence of paraganglioma. Data were collected on the tumor diameter, tumor location, perioperative outcomes, pathology, and last known disease status. Regarding the operative procedures, we reviewed the operative charts or videos to identify surgical tips and tricks. Results: The median tumor diameter was 5.0 cm (range, 1.5-10). The tumor location was suprahilar in 10, hilar in 6, and infrahilar in 9. Regarding the approach, a transperitoneal approach was selected in 24 cases and retroperitoneal approach in 1. The median operative time and blood loss were 208 minutes (range, 73-513) and 10 mL (range, 0-1,020), respectively. No patient required blood transfusion or conversion to open surgery. Pathological examination revealed paraganglioma in 12, ganglioneuroma in 7, and schwannoma in 6. At the last follow-up, 23 patients were free of disease, while one patient developed metastatic multiple recurrence of paraganglioma 54 months after the second laparoscopic surgery. A review of the surgical records revealed several tips and tricks, including taping the vena cava/ renal vein (n=2) being helpful for detaching a retrocaval tumor from these great vessels, or rotating the kidney to provide a favorable operative view of tumors behind the renal hilum (n=2). In recent cases, 3D-CT was helpful for preoperative planning. Conclusion: Laparoscopic resection of paraaortic or paracaval neurogenic tumors is feasible in experienced hands. Surgeons should be familiar with detaching maneuvers around great vessels and the mobilization of adjacent organs. Careful preoperative planning is mandatory.

Summary Eight distinct and potentially causative mutations were identified in eight unrelated Japanese patients with protein S (PS) deficiency, by direct DNA sequencing of the protein Sa (PSa) gene-specific polymerase chain reaction products of all 15 exons and exon/intron boundaries. There were five missense mutations, including two novel mutations (Cys80Tyr and Arg314His), and three showed a major impact on the expected gene products: novel mutations of a 5-bp deletion (delCTCTG887:Cys206Stop) and a nonsense mutation (Glu208Stop), as well as a previously reported splice site (exon 10 +5 A fi G) mutation. One of the patients showed compound heterozygosity for delCTCTG887 and 732A fi G. Investigation for the cosegregation state of these two mutations with PS deficiency in the patient’s family suggested that the delCTCTG887 mutation was responsible for the abnormal phenotype and that the 732A fi G (Lys155Glu) mutation did not appear to play a key role. However, we also identified the same 732A fi G (Lys155Glu) mutation in an unrelated patient with apparent PS deficiency with severe pulmonary embolism, and found that this mutation seemed to cosegregate with a PS-deficient state in her family members. These data implied that unknown factor(s) other than the 732A fi G mutation itself might influence phenotypic expression of PS status in different individuals.

Light chain-associated (AL) amyloidosis is a common and fatal systemic amyloidosis. AL amyloid fibrils (fAL) are composed of intact or fragmental monoclonal light chains (AL proteins). To elucidate the molecular mechanisms of fAL formation from AL proteins, we purified fAL and AL proteins from the amyloid-deposited organs of five AL amyloidosis patients. By electron microscopy and fluorometric thioflavin T method, we observed optimal fibril extension at pH 2.0-3.5 for the fibrils obtained from four patients, while at pH 7.5-8.0 for those obtained from one patient. Fragmental AL proteins were more efficient in the extension reaction than intact AL proteins. The fibrils obtained from all five patients showed clear fibril extension electron microscopically at pH 7.5. The extension of the fibrils obtained from all five patients could be explained by a first-order kinetic model, i.e., fibril extension proceeds via the consecutive association of AL proteins onto the ends of existing fibrils. Fibril extension was accelerated by dermatan sulfate proteoglycan, and inhibited by apolipoprotein E, alpha1-microglobulin, fibronectin, and an antioxidant nordihydroguaiaretic acid. These findings contribute to our understanding of the molecular mechanism underlying the pathogenesis of AL amyloidosis, and will be useful for developing a therapeutic strategy against the disease.

In this study, we focus on Pedestrian-Vehicular Collision Avoidance Support System (P-VCASS). P-VCASS is a system to support collision avoidance between vehicles and pedestrians. P-VCASS grasps the relative locations of vehicles and pedestrians by exchanging the GPS information with each other. P-VCASS warns drivers if it estimates the possibility of their collisions. The former P-VCASS is intended for adult pedestrians who are sensible to dangerous actions. In this paper, we propose a new activity estimation method of pupil/infant pedestrians who are not sensible to dangerous actions with coordination between intersections in P-VCASS. This method has two advantages. First, it is able to prevent the jumping out accidents of the pedestrians. Second, it is able to apply to the complex intersections by sharing a traffic situation between intersections. We show the validity of the proposed method by experiments using a vehicle which carries an in-vehicle apparatus in a intersection with roadway and sidewalk. As a results, we found that the recognition of a vehicle driver is possible before pedestrian jumps out to roadway in a complex intersections.

The Fe2+-binding property and its binding site on xanthan were investigated in connection with the synergistic antioxidation to soybean oil in the presence of tocopherols. Xanthan significantly inhibited Fe2+-induced oxidation of soybean oil in emulsion at pH 7.0 or 4.0. The binding parameters (Kd, n) between xanthan and Fe2+ ion were obtained at pH values of 4.0, 5.0, 6.0, and 6.5 by using the Scatchard equation. The maximum,number (about 0.6 mol/kg of xanthan) of high-affinity binding sites agreed with the pyruvate residue content in xanthan. 1H-NMR spectra indicated that xanthan bound Fe2+ through a pyruvate residue. These results suggest that xanthan chelates Fe2+ ions and consequently suppresses oil peroxidation synergistically in the presence of tocopherols by inactivation of the Fe2+ ion.

Vast number of victims have damaged and died due to a lot of large-scale disasters (earthquake, fire, and terrorism, etc.) up to the present time. In disasters that most victims become panic, two matters are necessary to evacuate efficiently. The first is to estimate the location of the disaster occurrence. The second is to construct the evacuation support system that searches a safe and efficient evacuation route. In this paper, we propose Emergency Rescue Urgent Communication - Evacuation Support System (EUC-ESS) based on Mobile Ad-hoc NETworks (MANETs) composed of a lot of mobile terminals. By computer simulation, we show that this system would work to support the disaster victims regardless of situations (indoor, urban, basement, etc.)

Leaking glaucoma filtering blebs with scleral perforation were successfully repaired in two patients using amniotic membrane transplantation. The amniotic membrane was placed into the subconjunctival space to cover the perforated scleral area. The edge of the limbal conjunctiva was sutured to the peripheral cornea with conjunctival advancement over the amniotic membrane. The bleb leaks were successfully closed. In addition, good and functioning filtration was maintained during a follow-up period of 12 months in both cases. Amniotic membrane transplantation may be effective for the surgical management of high risk of leaking glaucoma blebs with scleral perforation.

The L-rhamnose isomerase gene (L-rhi) encoding for L-rhamnose isomerase (L-RhI) from Bacillus pallidus Y25, a facultative thermophilic bacterium, was cloned and overexpressed in Escherichia coli with a cooperation of the 6xHis sequence at a C-terminal of the protein. The open reading frame of L-rhi consisted of 1,236 nucleotides encoding 412 amino acid residues with a calculated molecular mass of 47,636 Da, showing a good agreement with the native enzyme. Mass-produced L-RhI was achieved in a large quantity (470 mg/l broth) as a soluble protein. The recombinant enzyme was purified to homogeneity by a single step purification using a Ni-NTA affinity column chromatography. The purified recombinant L-RhI exhibited maximum activity at 65 degrees C (pH 7.0) under assay conditions, while 90% of the initial enzyme activity could be retained after incubation at 60 degrees C for 60 min. The apparent affinity (K(m)) and catalytic efficiency (k(cat)/K(m)) for L-rhamnose (at 65 degrees C) were 4.89 mM and 8.36 x 10(5) M(-1) min(-1), respectively. The enzyme demonstrated relatively low levels of amino acid sequence similarity (42 and 12%), higher thermostability, and different substrate specificity to those of E. coli and Pseudomonas stutzeri, respectively. The enzyme has a good catalyzing activity at 50 degrees C, for D: -allose, L-mannose, D-ribulose, and L-talose from D-psicose, L-fructose, D-ribose and L-tagatose with a conversion yield of 35, 25, 16 and 10%, respectively, without a contamination of by-products. These findings indicated that the recombinant L-RhI from B. pallidus is appropriate for use as a new source of rare sugar producing enzyme on a mass scale production.

OBJETIVO: o presente trabalho de pesquisa analisou os efeitos da tração reversa da maxila associada à anquilose intencional dos caninos decíduos superiores, mediante o emprego da cefalometria. METODOLOGIA: o protocolo de tratamento incluiu: 1) anquilose intencional dos caninos decíduos superiores; 2) expansão rápida da maxila e 3) tração reversa da maxila, imediatamente após o término da fase ativa da expansão. A amostra foi composta de 18 crianças nos estágios de dentadura decídua e dentadura mista, com idade média inicial de 7 anos e 1 mês. O intervalo médio de tratamento com a tração reversa da maxila foi de 1 ano e 1 mês. As telerradiografias laterais foram obtidas na documentação inicial e após a correção da Classe III. RESULTADOS E CONCLUSÕES: os resultados demonstram que os ângulos representativos da convexidade facial, NAP e ANB, aumentaram de 0º para 6,6º e 3,5º, respectivamente. Isso significa dizer que a face transformou-se de reta ou côncava, peculiar na Classe III, para uma face convexa, característica de normalidade no estágio avaliado. Essa melhora na convexidade facial é atribuída ao avanço da maxila, registrado tanto na região alveolar (ângulo SNA e as distâncias Co-A e NPerp-A) como na região basal (ângulo SN.ENA). A maxila deslocou-se para frente, enquanto a redução do ângulo SNB de 80,56º para 79,61º demonstrou um retroposicionamento mandibular. Além da mudança no sentido sagital, houve rotação da mandíbula no sentido horário, com aumento dos ângulos SN.GoGn e SN.Gn. Somado aos efeitos ortopédicos, houve inclinação vestibular dos incisivos superiores. AIM: the current article analyses the effects of maxillary protraction associated to the intentional ankylosis of the deciduous canines on the basis of cephalometric measurements. METHODS: the treatment protocol included: 1) intentional ankylosis of the upper deciduous canines; 2) rapid palatal expansion and 3) maxillary protraction performed immediately after the end of the expansion. The sample was comprised of 18 patients equally divided according to gender, in the primary and mixed dentition. The mean treatment time with maxillary protraction was 1 year. The lateral radiographs were taken in the beginning of the treatment and after correction of the Class III malocclusion. RESULTS AND CONCLUSION: the results show that the facial convexity angles - NAP and ANB - increased from 0º to 6.6º and 3.5º, respectively. This means that the patients’ profile changed from straight or concave, which is typical in the Class III malocclusion, to convex, which is typical in normal occlusion. Such an improvement in the facial convexity is due to the maxillary advancement, evidenced both in the dentoalveolar (SNA angle and Nperp-A measurement) and in the basal areas (SN.ANS angle). The maxilla was anteriorly displaced while the reduction of the SNB angle from 80.56º to 79.61º demonstrated a mandibular retropositioning. Besides the sagittal alterations, the mandible presented a clockwise rotation, with increase in the SN.GoGn and SN.Gn angles. Dental compensation was also noticed, represented by the buccal inclination of the upper incisors.

The D2194G mutation is responsible for increased levels of FV1 in carriers of the factor V R2 haplotype

Investigation on water balance, water temperature, dissolved oxygen and other chemical analyses were made for Lake Saino-ko, Nikko, from May 1980 to April 1983.The results are as follows :(1) As estimated by electric prospecting of geology around the lake, the lake was dammed by coarse gravel from the river. Because of this permeable material in the downstream section, the water level of the lake shows a wide seasonal variation. The level falls by about 11m in winter compared with early summer, then the water surface area and the water volume decrease to 1/2 and 1/6, respectively, in winter.(2) The rate of leakage from the lake is estimated from water balance in winter when noticeable inflows are not observed. A high rate of leakage is obtained at a high water level and vice versa.(3) In summer, water balance calculated including the effect of water level has a close relationship to the effective precipitation. The equilibrium water level in summer is estimated to be 13.3m.(4) Water circulation is effective in shallow layers as deduced from dissolved oxygen and water temperature. This may be influenced by the position of leakage. A phenomenal circulation was observed during and after floods.