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In patients with autoimmune coagulation factor deficiency (AiCFD), the production of autoantibodies that inhibit coagulation factors in the blood reduces the activity of those relevant coagulation factors, resulting in severe bleeding symptoms. Recently, reports of patients with AiCFD have noted the concomitant detection of lupus anticoagulant (LA), a risk factor for thrombosis. LA-positive patients may show bleeding symptoms due to decreased activity of coagulation factor II (FII) caused by autoantibodies against FII, in addition to thrombotic symptoms, a condition termed LA-hypoprothrombinemia syndrome (LAHPS). Anti-FII antibodies in LAHPS cases are frequently cleared antibodies that can be detected using immunological techniques, such as enzyme-linked immunosorbent assay (ELISA). Recently, several cases of coagulation FV inhibitors, known as autoimmune FV deficiency, have been reported. Some of these cases may be complicated by LA, which can cause thrombosis. False-positive results for anticoagulant inhibitors are known to occur in LA cases; therefore, immunological confirmation of antibodies against coagulation factors is recommended. Additionally, acquired hemophilia A (AHA), caused by autoantibodies against FVIII, is a typical acquired hemorrhagic diathesis, although affected patients may present with thrombosis associated with LA. Thus, it is important to remember that hemorrhagic diathesis due to autoantibodies against clotting factors can also result in thrombosis, as demonstrated by the co-detection of LA. When clotting factor inhibitors are detected in LA-positive individuals, it is important to confirm the presence of autoantibodies against coagulation factors using immunological methods, such as ELISA, to avoid false-positive results.

Increasing number of patients with ulcerative colitis (UC) have received biologic treatment during the last decade. The association between endoscopic healing (EH) and biologic treatment failure remains understudied. Medical information of UC patients who started biologic treatment was retrospectively collected. EH was defined as Mayo endoscopic subscore of 0 or 1. Loss of response (LOR)-free drug continuation rate was compared between patients who achieved EH and those who did not using Kaplan-Meier estimator. Fifty-two patients received 53 biologic treatments and underwent follow-up colonoscopies within 2 years. Thirty-three patients achieved EH, all of which remained on the same treatment without LOR during the observational period. Twenty patients did not achieve EH, 8 of which ultimately discontinued the treatment due to LOR to biologic agents. Kaplan-Meier estimator found a significantly lower drug continuation rate in patients without EH (p < 0.001; log-rank test). A Cox regression analysis identified EH as an independent factor associated with a reduced risk of LOR-related biologic treatment failure irrespective of the types of biologic agents (Hazard Ratio = 0.0324, p < 0.001). EH within 2 years is associated with a reduced risk of LOR-related biologic treatment failure in patients with UC., (© 2024. The Author(s).)

Background: Adverse reactions to metal debris are significant complications after metal-on-metal total hip arthroplasty. Recently, late appearances of adverse reactions to metal debris and subsequent need for reoperations have been reported with small-diameter head metal-on-metal devices. We retrospectively investigated mid-term clinical outcomes of small-head metal-on-metal total hip arthroplasty., Methods: We reviewed 159 hips in 139 patients who had a small-head metal-on-metal total hip arthroplasty (M2a Taper; Biomet, Warsaw, IN) with a minimum 5-year follow-up and documented postoperative complications., Results: Focal osteolysis in either the femur or acetabulum was observed in 12 hips (7.5%, 44 months after surgery on average), with pseudotumor observed in 8 hips (5%, 120 months after surgery on average). Four hips (2.5%) had dislocations (84 months after surgery on average) and six hips (3.8%, 122 months after surgery on average) underwent reoperation., Conclusion: Small-head metal-on-metal total hip arthroplasty is associated with a high degree of complications at mid-term follow-up period. Considering this, we discourage the use of metal-on-metal total hip arthroplasty regardless of head size., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Mesalazine formulations are essential for treating ulcerative colitis (UC), and intolerance to these formulations complicates the treatment of this condition. Some cases of mesalazine formulation intolerance are caused by the excipients rather than the active ingredient mesalazine. Therefore, mesalazine administration can be continued in such cases by changing the mesalazine formulation. This report describes a case of intolerance to mesalazine in which UC was effectively treated by switching mesalazine formulations. A drug-induced lymphocyte stimulation test suggested that allergy to the additive povidone was the cause of mesalazine formulation intolerance. This is the first case study to identify an additive that caused mesalazine formulation intolerance.

Background: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials., Methods: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed., Results: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found., Conclusion: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC., Trial Registration: JapicCTI-132072; JapicCTI-132073., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy., Clinical Trial Registration Number: JapicCTI-132072., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Diphenylarsinic acid (DPAA) was a major compound found in the arsenic poisoning incident that occurred in Kamisu, Ibaraki, Japan in 2003. People exposed to DPAA via contaminated well water suffered from several neurological disorders, including cerebellar symptoms. We previously reported that DPAA induces cellular activation in cultured rat cerebellar astrocytes, dose-dependent promotion of cell growth (low DPAA), cell death (high DPAA), and increased phosphorylation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2). Moreover, DPAA induces up-regulation of oxidative stress-counteracting proteins, activation of CREB phosphorylation, increased protein expression of c-Jun and c-Fos, and aberrant secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Here, we explored the role of MAP kinases in DPAA-induced activation of astrocytes using specific MAP kinase signaling inhibitors [SB203580 (p38MAPK), SP600125 (SAPK/JNK), SCH772984 (ERK1/2), and U0126 (MEK1/2, a kinase for ERK1/2)]. DPAA-induced activation of MAP kinases had little contribution to DPAA-induced cell growth and death. On the other hand, a power relationship among MAP kinases was also observed, in which p38MAPK suppressed DPAA-induced SAPK/JNK and ERK1/2 activation, whereas ERK1/2 and MEK1/2 facilitated p38MAPK and SAPK/JNK activation. In addition, SAPK/JNK had minimal effects on the activation of other MAP kinases. DPAA-induced activation of transcription factors and secretion of brain-active cytokines were submissively but intricately dominated by MAP kinases. Collectively, our results indicate that DPAA-induced activation of MAP kinases is neither a cell growth-promoting response nor a cytoprotective one but leads to transcriptional disruption and aberrant secretion of brain-active cytokines in cerebellar astrocytes., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC., Methods: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety., Results: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab., Conclusions: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression., Trial Registration Number: JapicCTI-132073., Competing Interests: Competing interests: MN received honoraria from Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical and AstraZeneca. MN also has been a consultant/advisor for Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Pfizer, Bristol-Myers Squibb and Daiichi Sankyo, and received research funding from Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma and AstraZeneca. THid received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb and Clovis. THid also received research funding from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Clovis, Eisai, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo and Astellas Pharma. SA received honoraria from Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, and Bristol-Myers Squibb. SA also received funding from AstraZeneca and Taiho Pharmaceutical for participating in a speakers' bureau. SA also received research funding from Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Merck Serono, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Yakult and Eli Lilly. HSakai received honoraria and funding to participate in a speakers' bureau from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly and Bristol-Myers Squibb. KN received honoraria from Astellas Pharma, AstraZeneca, EPS Holdings, Ono Pharmaceutical, Kyowa Hakko Kirin, Showa Yakuhin Kako, SymBio Pharmaceuticals, Daiichi Sankyo, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Pfizer and Bristol-Myers Squibb. KN also received research funding from Chugai Pharmaceutical, MSD, Ono Pharmaceutical, EPS Associates, Quintiles, Daiichi Sankyo, Japan Clinical Research Operations, Eisai, PPD-SNBL, Pfizer, Takeda Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Kyowa Hakko Kirin and OncoTherapy Science. TTak received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Eli Lilly, Chugai Pharmaceutical and Ono Pharmaceutical. TTak also received research funding from AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Takeda Pharmaceutical, Taiho Pharmaceutical and MSD. NN received honoraria from Astellas Pharma, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim and Pfizer. HSaka received research funding from AstraZeneca, Daiichi Sankyo, Ono Pharmaceutical, Eli Lilly, Bayer, Taiho Pharmaceutical, MSD, Linical, Bristol-Myers Squibb and Sanofi. MT received honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Kyowa Hakko Kirin, Ono Pharmaceutical and Taiho Pharmaceutical. MT also received research funding from Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis and Ono Pharmaceutical. MM received honoraria from AstraZeneca, Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb and Eli Lilly. MM also received research funding from Boehringer Ingelheim. YO’s immediate family member is an employee of Chugai Pharmaceutical. YO also has an immediate family member with an ownership of interest with Ono Pharmaceutical. YO received honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, Nippon Kayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Clovis and Sanofi. YO has also been a consultant/advisor for AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Ono Pharmaceutical and Novartis, and received funding from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Kyorin Pharmaceutical, Dainippon Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis and Merck Serono. YO has also been paid by AstraZeneca to provide expert testimony. HN received honoraria from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Bristol-Myers Squibb and Chugai Pharmaceutical. HN also received research funding from Merck Serono, Pfizer, Taiho Pharmaceutical, Eisai, Chugai Pharmaceutical, Eli Lilly, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult, Quintiles, Astellas Pharma, AstraZeneca, Boehringer Ingelheim and Ono Pharmaceutical. THir received research funding from MSD, AstraZeneca, Ono Pharmaceutical, Eisai, Daiichi Sankyo, Merck Serono, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Kyowa Hakko Kirin and Takeda Pharmaceutical. HT received research funding from Eli Lilly, AstraZeneca, MSD, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical and Boehringer Ingelheim. KT received honoraria from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo and Kyowa Hakko Kirin. KT also has been a consultant/advisor for AstraZeneca, Eli Lilly and Novartis, and received research funding from AstraZeneca, Chugai Pharmaceutical, Eisai, Bristol-Myers Squibb, Eli Lilly, Ono Pharmaceutical, Kyowa Hakko Kirin, Boehringer Ingelheim and Merck Serono. KG received honoraria from Daiichi Sankyo, Nippon Kayaku, Kyowa Hakko Kirin, Bristol-Myers Squibb, AstraZeneca, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Eli Lilly and Boehringer Ingelheim. KG also has been a consultant/advisor for Taiho Pharmaceutical, Chugai Pharmaceutical, and Daiichi Sankyo, and received research funding from MSD, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, GlaxoSmithKline, OxOnc, Dainippon Sumitomo Pharma, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, Kyowa Hakko Kirin, Astellas Pharma, Eisai, Eli Lilly, Amgen Astellas BioPharma, Pizer, Riken Genesis and Bristol-Myers Squibb. MS received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Boehringer Ingelheim Novartis and MSD. MS also received research funding from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Novartis, MSD and Astellas Pharma. HI received funding to participate in a speakers' bureau from AstraZeneca, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai Pharmaceutical and Boehringer Ingelheim. KM received research funding from Ono Pharmaceutical and Chugai Pharmaceutical. NS is an employee of Ono Pharmaceutical. TTam received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Eisai, Yakult, Novartis, Daiichi Sankyo and Astellas Pharma.

Although osteoarthritis (OA) is the most prevalent aging-related joint disease, the understanding of mechanisms of OA pathogenesis remains limited. Key features include the progressive degradation of articular cartilage, synovial hyperplasia, and angiogenesis in joint tissues. CD9, a member of the tetraspanin family, is localized in the cell membranes and partly in the endosomes of all mammalian cell types. CD9 is associated with inflammation and angiogenesis through cell adhesion, migration, and signal transduction. This study examined the role of CD9 in OA development in three different mouse models: an aging model, a surgical model and antigen-induced arthritis (AIA) model, using CD9 deficient mice. Our study showed that CD9 deficiency reduced the severity of hallmarks of OA including cartilage degradation and soft tissue inflammation in aged mice. In the AIA model, cartilage damage and inflammation were also reduced in CD9 -/- mice. This was in contrast to the surgical OA model where disease severity was similar in wild-type and CD9 -/- mice. Col2a1 and Aggrecan expression was increased in chondrocytes of CD9 -/- mice compared with those of wild-type mice. Our results indicate that the suppression of cartilage degradation in CD9 -/- could be in part related to an increase in the expression of the two main cartilage extracellular matrix proteins aggrecan and type II collagen.

Object: The occurrence of compressive cervical myelopathy (CCM) increases in adults over 50 years of age. In addition, diabetes mellitus (DM) is a frequent comorbidity for people of this age and may impact the severity of CCM. The authors assessed motor pathway function in diabetic patients with CCM to investigate the correlation between electrophysiological parameters and clinical symptoms., Methods: Motor evoked potentials (MEPs) were measured from the abductor digiti minimi muscle (ADM) and the abductor hallucis muscle (AH) following transcranial magnetic stimulation, as were M- and F-waves following electrical stimulation of the ulnar and tibial nerves, in 22 patients with CCM and diabetes mellitus (DM) who had not experienced symptomatic diabetic neuropathy (CCM-DM group), in 92 patients with CCM alone (CCM group), and in 24 healthy adults (control group). The peripheral conduction time (PCT; measured from the ADM and AH) was calculated as follows: (M-wave latency + F-wave latency -1)/2. The central motor conduction time (CMCT; measured from the ADM and AH) was calculated by subtracting the PCT from the onset latency of the MEPs. The Japanese Orthopaedic Association (JOA) score for cervical myelopathy was obtained before and 1 year after surgery as a clinical outcome measure., Results: MEP, PCT, and CMCT parameters in the CCM-DM and CCM groups were significantly longer than those in the control group (p = 0.000-0.007). The PCTs in the CCM-DM group were significantly longer than those in the CCM group (p = 0.001-0.003). No significant differences were detected in the MEP and CMCT parameters between the CCM-DM and CCM groups (p = 0.080-1.000). The JOA score before surgery in the CCM-DM group was 10.7 ± 2.0 points and was significantly lower than that in the CCM group (12.2 ± 2.5 points, p = 0.015). In the CCM-DM group, JOA scores before surgery correlated with MEP-AH (r = -0.610, p = 0.012) and PCT-AH (r = -0.676, p = 0.004) values, but not with CMCT values, while the JOA scores were related to both MEP and CMCT parameters in the CCM group. The JOA scores improved to 13.8 ± 2.2 points after surgery (p = 0.001) and correlated with MEP-AH (r = -0.667, p = 0.005) and PCT-AH (r = -0.611, p = 0.012) in the CCM-DM group., Conclusions: The results suggest that MEP, PCT, and CMCT parameters each reveal abnormalities in the upper and lower motor neurons even in patients with DM. The results also show a prolonged PCT in CCM-DM patients, despite having no history of diabetic neuropathy. Corticospinal tract impairments are similar between CCM and CCM-DM patients, while the JOA score of the CCM-DM patients is lower than that in the CCM patients. The JOA score in CCM-DM patients may be influenced by additional impairments in peripheral nerves or other diabetic complications. These electrophysiological studies may be useful for screening motor pathway function for CCM in patients with DM.

The NF2 gene product Merlin is a protein containing ezrin, radixin, and moesin domains; it is a member of the 4.1 protein superfamily associated with the membrane cytoskeleton and also interacts with cell surface molecules. The mammalian Hippo cascade, a downstream signaling cascade of merlin, inactivates the Yes-associated protein (YAP). Yes-associated protein is activated by loss of the NF2 gene and functions as an oncogene in meningioma cells; however, the factors controlling YAP expression, phosphorylation, and subcellular localization in meningiomas have not been fully elucidated. Here, we demonstrate that merlin expression is heterogeneous in 1 NF2 gene-negative and 3 NF2 gene-positive World Health Organization grade I meningiomas. In the NF2 gene-positive meningiomas, regions with low levels of merlin (tumor rims) had greater numbers of cells with nuclear YAP versus regions with high merlin levels (tumor cores). Merlin expression and YAP phosphorylation were also affected by cell density in the IOMM-Lee and HKBMM human meningioma cell lines; nuclear localization of YAP was regulated by cell density and extracellular matrix (ECM) stiffness in IOMM-Lee cells. These results suggest that cell density and ECM stiffness may contribute to the heterogeneous loss of merlin and increased nuclear YAP expression in human meningiomas.

We previously demonstrated that activated microglia release excessive glutamate through gap junction hemichannels and identified a novel gap junction hemichannel blocker, INI-0602, that was proven to penetrate the blood-brain barrier and be an effective treatment in mouse models of amyotrophic lateral sclerosis and Alzheimer disease. Spinal cord injury causes tissue damage in two successive waves. The initial injury is mechanical and directly causes primary tissue damage, which induces subsequent ischemia, inflammation, and neurotoxic factor release resulting in the secondary tissue damage. These lead to activation of glial cells. Activated glial cells such as microglia and astrocytes are common pathological observations in the damaged lesion. Activated microglia release glutamate, the major neurotoxic factor released into the extracellular space after neural injury, which causes neuronal death at high concentration. In the present study, we demonstrate that reduction of glutamate-mediated exitotoxicity via intraperitoneal administration of INI-0602 in the microenvironment of the injured spinal cord elicited neurobehavioral recovery and extensive suppression of glial scar formation by reducing secondary tissue damage. Further, this intervention stimulated anti-inflammatory cytokines, and subsequently elevated brain-derived neurotrophic factor. Thus, preventing microglial activation by a gap junction hemichannel blocker, INI-0602, may be a promising therapeutic strategy in spinal cord injury.

Rapidly destructive coxarthrosis (RDC) is rare and develops unusual clinical course. Recent studies suggest multiple possible mechanisms of the development of RDC. However the exact mechanism of RDC is still not clear. The difficulty of the study on RDC is attributed to its rareness and the fact that the data before the onset of RDC is normally unavailable. In this report, we presented the patient having the radiographic data before the onset who had rapid osteoarthritis (OA) development after contralateral THA, which meets the current criteria of RDC. We thought that the increased posterior tilt of the pelvis after THA reinforced the stress concentration at pre-existed anterior acetabular cyst, thereby the destruction of the cyst was occurred. As a result the rapid OA was developed. We think that there is the case of rapid osteoarthritis developing due to alternating load concentration by posterior pelvic tilt on preexisting anterior acetabular cyst such as our patient among the cases diagnosed as RDC without any identifiable etiology. The recognition of sagittal alignment changes and anterior acetabular cyst may play important role in prediction and prevention of the rapid hip osteoarthritis development similar to RDC.

Japanese General Rules presented by the Japanese Breast Cancer Society have been long time applied in Japan. This classification uniquely adds subtypes into the group of invasive ductal carcinomas (IDC) and reported to be correlated to patients' clinical course. The latest St. Gallen consensus meeting reported the use of 5 molecules, and introduced alternative definition in the breast cancer classification. The purpose of this study is to relate the Japanese subgrouping of IDC with the 5 subtypes and to investigate whether these classifications could predict early and late recurrence and whether cytological diagnosis is influenced by the tumor phenotypes. Analyzing 127 cases, we observed that the Ki-67 labeling index (LI) of the 5 subtypes, luminal A, luminal B-Her2--/- Her2+, Her2-subtype and basal-like, is increased in this order. Though the Japanese histological groups, papillotubular, solid-tubular and scirrhous, included more or less those subtypes, the luminal types were more represented in papillotubular and scirrhous subtypes, and the solid-tubular type in non luminal subtypes. The Ki-67 LI 14% served as a cutoff for differentiating invasive from non-invasive ductal carcinomas. Breast cancers recur within 5 years after the clinical onset when the Ki-67 LI exceeded 14%. These data suggest that, (1) the intrinsic subtyping is an accurate modality in diagnosing breast cancers, (2) it can predict the recurrence duration, (3) the solid-tubular type of the Japanese classification is likely an aggressive form among breast cancers, and (4) the cytological diagnosis is presently a powerful tool in determining malignancy.

Glial scar formation is the major impedance to axonal regrowth after spinal cord injury (SCI), and scar-modulating treatments have become a leading therapeutic goal for SCI treatment. In this study, human neural stem cells (NSCs) encoding interferon-β (INF-β) gene were administered intravenously to mice 1 week after SCI. Animals receiving NSCs encoding IFN-β exhibited significant neurobehavioral improvement, electrophysiological recovery, suppressed glial scar formation, and preservation of nerve fibers in lesioned spinal cord. Systemic evaluation of SCI gliosis lesion site with lesion-specific microdissection, genome-wide microarray, and MetaCore pathway analysis identified upregulation of toll-like receptor 4 (TLR4) in SCI gliosis lesion site, and this led us to focus on TLR4 signaling in reactive astrocytes. Examination of primary astrocytes from TLR4 knockout mice, and in vivo inhibition of TLR4, revealed that the effect of IFN-β on the suppression of glial scar formation in SCI requires TLR4 stimulation. These results suggest that IFN-β delivery via intravenous injection of NSCs following SCI inhibits glial scar formation in spinal cord through stimulation of TLR4 signaling.

Cell surface heparan sulfate proteoglycans (HSPGs) play significant roles in the regulation of developmental signaling, including vascular endothelial growth factor (VEGF), fibroblast growth factor, Wnt and bone morphogenetic protein signaling, through modification of their sulfation patterns. Recent studies have revealed that one of the functions of heparan sulfate 6-O-endosulfatase (Sulf) is to remove the sulfate from the 6-O position of HSPGs at the cell surface, thereby regulating the binding activities of heparan sulfate (HS) chains to numerous ligands and receptors in animal species. In this study, we focused on the sea urchin Hemicentrotus pulcherrimus homolog of Sulf (HpSulf), and analyzed its expression pattern and functions during development. HpSulf protein was present throughout development and localized at cell surface of all blastomeres. In addition, the HS-specific epitope 10E4 was detected at the cell surface and partially colocalized with HpSulf. Knockdown of HpSulf using morpholino antisense oligonucleotides (MO) caused abnormal morphogenesis, and the development of MO-injected embryos was arrested before the hatched blastula stage, indicating that HpSulf is necessary for the early developmental process of sea urchin embryos. Furthermore, we found that injection of HpSulf mRNA suppressed the abnormal skeleton induced by overexpression of HpVEGF mRNA, whereas injection of an inactive form of HpSulf mRNA, containing mutated cysteines in the sulfatase domain, did not have this effect. Taken together, these results suggest that HpSulf is involved in the regulation of various signal transductions, including VEGF signaling, during sea urchin development., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Zinc finger protein ZPR1 (ZPR1) binds to eukaryotic translation elongation factor 1alpha (eEF1alpha) in response to growth stimuli, and is also involved in transcription and cell cycle regulation. In this study, we characterized the interaction of ZPR1 and eEF1alpha and generated a ZPR1 mutant that constitutively interacted with eEF1alpha. ZPR1-DeltaA (Delta193-246) bound to eEF1alpha independently of Zn(2+) in vivo. This study indicates that ZPR1-DeltaA (Delta193-246) is a useful tool to provide structural insights into ZPR1 and to investigate the biological significance of the interaction between ZPR1 and eEF1alpha.

The nanos genes play important roles in the development of primordial germ cells in animal species. In the sea urchin, Hemicentrotus pulcherrimus, small micromere descendants specifically express HpNanos mRNA and this expression continues in the left coelomic pouch, which produces the major component of the adult rudiment. In this study, we showed that morpholino knockdown of HpNanos resulted in a delay of primary mesenchyme cell ingression and a decrease in the number of cells comprising the left coelomic pouch. Knockdown analysis in chimeras and whole embryos revealed the disappearance of small micromere descendants from the archenteron tip. Furthermore, the expression of HpNanos mRNA was induced in other cell lineages in the HpNanos-knockdown and micromere-deleted embryos. Taken together, our results suggest that HpNanos is involved in the inductive interaction of small micromere descendants with other cell lineages, and that HpNanos is required for the survival of small micromere descendants.

A differential display was performed to analyze differential gene expression in the brains of mice in association with dietary high beef-tallow. Consumption of a high beef-tallow diet downregulated the expression of ADP-ribosylation factor-like protein 8B (Arl8B) mRNA in the brain. Arl8B mRNA was widely expressed in the mouse brain, including primary neuronal cells. The current study indicates that green fluorescent protein-fused Arl8B protein accumulated at the growth cones in primary neuronal cells, and that protrusions of human embryonic kidney 293 (HEK293) cells were significantly elongated by overexpression of Arl8B, suggesting an important role of Arl8B in neurite formation.

A differential display was performed to analyze differential gene expression in the brain of mice in association with dietary high beef tallow. Consumption of a high beef tallow diet up-regulated the expression of zinc finger protein ZPR1 mRNA in the brain. Expression of ZPR1 mRNA in the cerebellum and hippocampus was elevated in response to the high beef tallow diet. The increased ZPR1 expression in the neuronal, Neuro-2A cells, caused a significant increase in H(2)O(2)-induced cell death. These results suggest that a high beef tallow diet up-regulates ZPR1 mRNA expression in the brain and might increase the vulnerability to oxidative stress.

Previous studies have suggested that docosahexaenoic acid (DHA), contained in fish oil, prevents brain disease. In the current study, the effect of fish oil feeding on gene expression in the brain was investigated by suppression subtractive hybridization. We found that pyruvate dehydrogenase E1 alpha (PDHE1alpha) mRNA expression is down-regulated by fish oil feeding. We examined whether the expression of PDHE1alpha mRNA is altered by DHA treatment in differentiated PC12 cells. PDHE1alpha mRNA was reduced by supplementation of DHA with a significant decrease in cellular ATP level. These results indicate that fish oil feeding might modulate energy metabolism in the brain.

A hierarchial co-culture, in which rat hepatocytes and non-parenchymal liver cells (NPLCs) were separated by a collagen layer and which was designed to mimic the in vivo microenvironment, was carried out with the aim of developing a module for bio-artificial liver support. Compared with a monolayer co-culture and hepatocytes cultured alone in a monolayer, higher urea synthesis activity was maintained for 6 d in the hierarchical co-culture. When a rat hepatoma cell line H4-II-E-C3, which retains the induction of tyrosine aminotransferase (TAT), was co-cultured in a monolayer with NPLCs, dose-dependent stimulation of TAT induction was observed. In a hierarchical co-culture, NPLCs further stimulated TAT induction in H4-II-E-C3 cells. Since peritoneal macrophages could stimulate TAT induction in hepatocytes in both monolayer and hierarchical co-cultures, bone marrow cells, which can proliferate and differentiate into macrophages in vitro, were investigated as a possible substitute for NPLCs. Bone marrow cells isolated from rat femurs were cultivated in the presence of IL-3 and macrophage colony-stimulating factor (M-CSF), and co-cultured with hepatocytes. Urea synthesis and TAT induction of hepatocytes were stimulated in the co-culture. The co-culture of bone marrow and H4-II-E-C3 cells, both of which have proliferation ability in vitro, was also shown to be effective in stimulating liver functions. The hierarchical configuration, in which two cell types can communicate with the soluble factor(s) through a collagen layer, was found to be more effective than a monolayer in long-term co-culture.

Multicellular spheroids of hepatocytes are known to maintain liver functions for a long period. Rat hepatocytes were isolated to form spheroids by rotation culture and immobilized within calcium alginate. Immobilized spheroids had a much higher extent of tyrosine aminotransferase induction, which is one of the liver-specific differentiated functions, than immobilized non-aggregated cells, while the spheroids secreted significantly less prothrombin than non-aggregated cells. Co-culture of hepatocytes and non-parenchymal liver cells in a monolayer enhanced tyrosine aminotransferase induction and suppressed prothrombin secretion, while conditioned medium prepared from non-parenchymal cells greatly stimulated tyrosine aminotransferase induction and suppressed the prothrombin secretion and DNA synthesis in monolayer-cultured hepatocytes. Prothrombin secretion in hepatocytes was subjected to cell-density-dependent regulation. In a similar manner to other growth-related functions, prothrombin secretion was stimulated at low cell density. It has been reported that thrombin activates the zymogen of hepatocyte growth factor activator [Shimomura, T., Kondo, J., Ochiai, M., Naka, D., Miyazawa, K., Morimoto, Y. & Kitamura, N. (1993) J. Biol. Chem. 268, 22,927-22,932]. Therefore, prothrombin secretion could be one of the growth-related functions and involved in wound healing and liver regeneration.

The utilization of a 4:2:1 mixture of glucose, fructose, and xylitol (GFX) was studied by indirect calorimetry in patients undergoing abdominal surgery. Sixteen patients undergoing gastrectomy under general anesthesia received GFX intravenously at 0.25 g/kg h-1 during surgery. VO2, VCO2, and RQ were measured continuously for 150 min using an Engström metabolic computer, and urea nitrogen excretion was determined at 30-min intervals during surgery. Blood levels of glucose, fructose, and xylitol plateaued after 1 h. The RQ decreased over the first 90 min from 0.84 +/- 0.06 to 0.75 +/- 0.05 and then gradually increased to 0.79 +/- 0.04 at 150 min. VO2 did not change significantly over the 150-min period. From the RQ, VO2, and nitrogen excretion data, carbohydrate oxidation was estimated. The amount of carbohydrate oxidized was 9.7 +/- 6.9 g during the first 30-min period, 3.5 +/- 5.2 g during the 60 to 90-min period, and 7.5 +/- 4.5 g in the 120 to 150-min study period. Simultaneously, lipid oxidation increased. These observations suggest that the GFX solution is adequately metabolized during surgery and therefore may be a suitable energy source for patients.

In view of vasodilating action of prostaglandin E1 (PGE1) and dibutyryl cyclic AMP (DBcAMP) we investigated the effect of each agent on hemodynamics after weaning from cardiopulmonary bypass (CPB) comparing with the effect in control group. PGE1 and DBcAMP were administered to patients who underwent valve replacement surgery with continuous low dose infusion at an average rate of 0.026 micrograms.kg-1.min-1 and 7.25 micrograms.kg-1.min-1 respectively. Following result was obtained. In PGE1 administered group, a significant reduction in pulmonary vascular resistance (PVR) and a significant decrease in mean arterial pressure (MAP) were observed during CBP, while there were no significant differences in other parameters, such as platelet counts, differences between core and peripheral temperature (delta T), urine output, systemic vascular resistance (SVR), cardiac index (CI), right-to-left shunt (Qs/Qt), oxygen delivery (DO2) and oxygen consumption (VO2). However, CI and platelet counts tended to increase but delta T and SVR tended to decrease. In DBcAMP administered group, there were no significant differences in all parameters compared with those of control group, showing a tendency of less improvement in hemodynamics than in PGE1 group. We have shown that the use of PGE1 rather than DBcAMP as vasodilator agent seems advantageous during open-heart surgery in patients especially with severe pulmonary hypertension, but it tends to cause severe hypotension during CPB.

Multiple gestation pregnancies are accompanied with risks for both mother and fetuses. Morbidity and mortality of both of them are increased compared with singleton pregnancies. We have presented a case of a 30-year-old parturient with quadruplets. The pregnancy had been complicated by premature labour, anemia, toxemia, coagulopathy, pulmonary congestion and malpresentation. On the 29th week of pregnancy, an elective Caesarean section was scheduled. There is no ideal anesthetic technique for quadruplets. In this case general anesthesia was chosen, because she had coagulopathy. The anesthesia and postoperative course were uneventful. The patient and the four babies had no complication nor sequela on their discharge. The anesthetic considerations for multiple gestation pregnancies were also discussed.

Although fibrosis and gelatinous transformation of bone marrow stroma are well known, there have been few histopathological descriptions in the literature. We studied 16 cases of acute leukemia, and describe the myxomatous changes of bone marrow stroma observed at 2 or 3 weeks following chemotherapy. We analyzed the extracellular matrix components immunohistochemically, using monoclonal or polyclonal antibodies raised against collagens, proteoglycans (PG), fibronectin and laminin. We found that the major components of the myxomatous matrix were chondroitin 6-sulfate PG and large PG. The stainability resembles that of extracellular matrix components in long-term bone marrow culture. We suppose that the myxomatous matrix provides favorable conditions for hematopoiesis, because hematopoietic cells proliferate and differentiate as soon as such stromal changes occur.

Anesthetic management of patients with thoracic aneurysm is discussed. During a period of two years, 11 cases were observed; 7 cases of dissecting aneurysm and 4 cases of true aneurysm. Dissecting aneurysms were of DeBakey's type 1 in 5 cases and of DeBakey's type 2 in 2 cases. Four cases had hypertension. As many of these patients often have hypertension, it is important not to change the circulatory dynamics during induction of anesthesia. We employed high dose fentanyl in 9 cases and used nitroglycerin or nitroprusside to control systolic blood pressure at about 100-120 mmHg. Massive bleeding can occur during intraoperative period and it is important to secure a sufficient number of intravenous routes to protect the central nervous system during cardio-pulmonary bypass.