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Aim In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. Methods Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. Results In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". Conclusions Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.

Current models for the origin and constituents of Earth are based primarily on compositions of meteorites that fell recently (within the past ~1 million years) on Earth. Here we report the discover...

Background Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. Aims The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. Methods and results Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged

Aim Trefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN). Methods We investigated the renal mRNA expression of TFF3 by real-time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively. Results The renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients. Conclusion Renal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients.

We investigated differences between the pathological features of gastric signet-ring cell carcinoma (sig) and poorly differentiated adenocarcinoma (por) by examining the expressions of the trefoil factor family peptides (TFFs) and mucin core proteins (MUCs). Ninety-seven tissues of 97 gastric cancer patients were selected for this study. After gastrectomy, the major histopathologic types were determined to be sig, solid-type poorly differentiated adenocarcinoma (por1), non-solid type poorly differentiated adenocarcinoma (por2), and well-differentiated tubular adenocarcinoma (tub1). We evaluated the prevalence of positive staining for MUCs (MUC5AC and MUC2) and TFFs (TFF1 and TFF3) and assessed the correlation between MUCs and TFFs in each histopathological type. The rate of MUC2 expression significantly differed between sig and por2 (50.0% vs 11.7%, P = 0.011). TFF3 expression in sig significantly differed from TFF3 expression in both por2 (100% vs 17.6%, P

We show that every semialgebraic set admits a semialgebraic triangulation such that each closed simplex is C1 differentiable. As an application, we give a straightforward definition of the integration ∫Xω over a compact semialgebraic subset X of a differential form ω on an ambient semialgebraic manifold. This provides a significant simplification of the theory of semialgebraic singular chains and integrations without using geometric measure theory. Our results hold over every (possibly non-archimedian) real closed field.

Carcinoma with rhabdoid features is a rare malignant tumor with a poor prognosis whose molecular mechanism for aggressive behavior is unclear. We describe an undifferentiated pancreatic carcinoma with rhabdoid features that demonstrated extensive invasion and metastasis. Examination of a 63-year-old man with back pain disclosed a retroperitoneal tumor with multiple metastases. Lymph node biopsy revealed an undifferentiated carcinoma of unknown origin. Intensive chemotherapy was ineffective; the patient died 3 months after initial symptoms. Autopsy showed that the tumor displaced the retroperitoneal space: it diffusely invaded and destroyed the pancreas and duodenum. Histology demonstrated tumor cells with eccentric vesicular nuclei, large nucleoli, juxtanuclear eosinophilic inclusions, and poor cell adhesion. Immunohistochemistry showed that tumor cells expressed cytokeratin and vimentin, and electron microscopy confirmed a perinuclear mass of intermediate fibrils and lipid droplets, which indicated an undifferentiated carcinoma with rhabdoid features. Tumor tissue contained hyaluronan; tumor cells strongly expressed CD44, matrix metalloproteinase-9, hypoxia-inducible factor-1α, hyaluronan synthase 2, and acyl-CoA:cholesterol acyltransferase 1 and had a high Ki-67(+) ratio. Since hyaluronan is a ligand for CD44, formation of CD44-hyaluronan complex on the cell surface activates CD44 and this activation may explain why the tumor manifested aggressive invasion and metastasis throughout the clinical course.

AIM To investigate the potential impact of joint association of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) on insulin resistance and β-cell dysfunction in healthy Japanese individuals with a normal range of liver enzymes. METHODS This study included 1010 individuals (545 men and 465 women) aged 20-89 years who underwent an oral glucose tolerance test for health screening. Participants were divided into four groups on the basis of median values for ALT and GGT: (i) both ALT and GGT low (both-low); (ii) ALT high and GGT low (ALT-high); (iii) ALT low and GGT high (GGT-high); and (iv) both ALT and GGT high (both-high). Logistic regression analysis was used to investigate the relationship between liver enzyme and insulin dynamics, such as Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) and insulinogenic index (IGI). The insulin resistance was defined when HOMA-IR was 2.5 or more. IGI of less than 0.4 was considered to be decreased early-phase insulin secretion. RESULTS Mean values of HOMA-IR in men was 1.5 in the both-low group, 1.8 in ALT-high, 1.8 in GGT-high and 2.8 in both-high. The mean HOMA-IR in women was 1.3 in the both-low group, 1.3 in ALT-high, 1.6 in GGT-high and 2.0 in both-high. HOMA-IR in the both-high group was significantly higher than that in the both-low group regardless of the difference of sex. Multivariate analysis showed that insulin resistance occurred when the patient had high liver enzymes. CONCLUSION Combining the two liver function markers would be effective for identifying individuals with insulin resistance.

Lysophosphatidic acid (LPA) is a lipid mediator that induces various cell responses via its specific receptors. Recently, we found that orally administered LPA and phosphatidic acid (PA) ameliorate stress- or aspirin-induced stomach injury. However, the mechanisms underlying these effects have not been elucidated yet. In this study, we examined effect of LPA on prostaglandin (PG) E2 production in MKN74 cells, a gastric cell-line expressing type 2 LPA receptor (LPA2). When the cells were treated with LPA, the level of mRNA of COX-2 but not COX-1 was upregulated. The LPA effect was abolished when the cells were pretreated with pertussis toxin (PTX), suggesting the involvement of receptor(s) coupled with Gi. Pretreatment of MKN74 cells with LPA enhanced the PGE2 production triggered by calcium ionophore A23187. Again, PTX abolished the LPA effect. Fluorescent immunohistochemistry using an antibody against LPA2 showed that surface mucous cells (pit cells) in gastric mucosa of mice express LPA2 on the apical side of the plasma membrane. These results suggest that LPA in the diet or its digestion may contribute to the epithelial integrity of stomach mucosa by enhancement of PGE2 production via activation of LPA2.

A close relationship between cell death and pathological calcification has recently been reported, such as vascular calcification in atherosclerosis. However, the roles of cell death in calcification by osteoblast lineage have not been elucidated in detail. In this study, we investigated whether cell death is involved in the calcification on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hMSC) under osteogenic culture in vitro. Apoptosis and necrosis occurred in an osteogenic culture of hMSC, and cell death preceded calcification. The generation of intracellular reactive oxygen species, chromatin condensation and fragmentation, and caspase-3 activation increased in this culture. A pan-caspase inhibitor (Z-VAD-FMK) and anti-oxidants (Tiron and n-acetylcysteine) inhibited osteogenic culture-induced cell death and calcification. Furthermore, calcification was significantly promoted by the addition of necrotic dead cells or its membrane fraction. Spontaneously dead cells by osteogenic culture and exogenously added necrotic cells were surrounded by calcium deposits. Induction of localized cell death by photodynamic treatment in the osteogenic culture resulted in co-localized calcification. These findings show that necrotic and apoptotic cell deaths were induced in an osteogenic culture of hMSC and indicated that both necrotic and apoptotic cells of osteoblast lineage served as nuclei for calcification on osteoblastic differentiation of hMSC in vitro.

Aim The aim of this case–control study was to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD). Methods Twenty NAFLD patients with T2DM treated by sitagliptin were retrospectively enrolled as the sitagliptin group. These patients were given sitagliptin between January 2010 and July 2011. Another 20 NAFLD patients with T2DM treated only with diet and exercise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. Results In the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48 weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15 mg/dL at 48 weeks after the initiation of sitagliptin. The serum levels of HbA1c and FPG in the sitagliptin group decreased with statistical significance compared to those in the control group (P

The specificities of nine approved tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, and pazopanib) were determined by activity-based kinase profiling using a large panel of human recombinant active kinases. This panel consisted of 79 tyrosine kinases, 199 serine/threonine kinases, three lipid kinases, and 29 disease-relevant mutant kinases. Many potential targets of each inhibitor were identified by kinase profiling at the K(m) for ATP. In addition, profiling at a physiological ATP concentration (1 mm) was carried out, and the IC(50) values of the inhibitors against each kinase were compared with the estimated plasma-free concentration (calculated from published pharmacokinetic parameters of plasma C(trough) and C(max) values). This analysis revealed that the approved kinase inhibitors were well optimized for their target kinases. This profiling also implicates activity at particular off-target kinases in drug side effects. Thus, large-scale kinase profiling at both K(m) and physiological ATP concentrations could be useful in characterizing the targets and off-targets of kinase inhibitors.

AIM: We surveyed multiple centers to identify types and frequency of complications and mortality rate associated with radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: We distributed a questionnaire developed by members of the Chugoku-Shikoku Society for the Local Ablation Therapy of Hepatocellular Carcinoma to 20 centers and analyzed types and frequency of complications and mortality rate. RESULTS: In total, 16 346 nodules were treated in 13 283 patients between January 1999 and November 2010. Five patients (0.038%) died: two from intraperitoneal hemorrhage, and one each from hemothorax, severe acute pancreatitis and perforation of the colon. In 16 346 treated nodules, 579 complications (3.54%) were observed, including 78 hemorrhages (0.477%), 276 hepatic injuries (1.69%), 113 extrahepatic organ injuries (0.691%) and 27 tumor progressions (0.17%). The centers that treated a large number of nodules and performed RFA modifications, such as use of artificial ascites, artificial pleural effusion and bile duct cooling, had low complication rates. CONCLUSION: This study confirmed that RFA is a low-risk treatment for HCC and that sufficient experience and technical skill can reduce complications.

Aim: Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non-alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). Methods: A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow-up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan–Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. Results: The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). Conclusions: The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two-thirds in the HCV group.

J. Neurochem. (2011) 119, 497–506. Abstract Polycystic kidney disease 1-like 3 (Pkd1l3) is expressed specifically in sour-sensing type III taste cells that have synaptic contacts with afferent nerve fibers in circumvallate (CvP) and foliate papillae (FoP) located in the posterior region of the tongue, although not in fungiform papillae (FuP) or the palate. To visualize the gustatory neural pathways that originate from type III taste cells in CvP and FoP, we established transgenic mouse lines that express the transneuronal tracer wheat germ agglutinin (WGA) under the control of the mouse Pkd1l3 gene promoter/enhancer. The WGA transgene was accurately expressed in Pkd1l3-expressing type III taste cells in CvP and FoP. Punctate WGA protein signals appeared to be detected specifically in type III taste cells but not in other types of taste cells. WGA protein was transferred primarily to a subset of neurons located in close proximity to the glossopharyngeal (GL) nerve bundles in the nodose/petrosal ganglion (NPG). WGA signals were also observed in a small population of neurons in the geniculate ganglion (GG). This result demonstrates the anatomical connection between taste receptor cells (TRCs) in the FoP and the chorda tympani (CT) nerves. WGA protein was further conveyed to neurons in a rostro-central subdivision of the nucleus of the solitary tract (NST). These findings demonstrate that the approximately 10 kb 5′-flanking region of the mouse Pkd1l3 gene functions as a type III taste cell-specific promoter/enhancer. In addition, experiments using the pkd1l3-WGA transgenic mice reveal a sour gustatory pathway that originates from TRCs in the posterior region of the tongue.

Custom-made information support systems for community-based flood risk management were developed. These systems were designed to satisfy residents' needs for local flood risk and safety information in their community through the implementation of flood risk communication. To extend these support systems to an integrated support system for community-based flood risk management, the systems were combined with evacuation-support plans for individuals requiring assistance. Basic evacuation data on people requiring assistance in episodic disasters were obtained and analysed by conducting an evacuation drill in a virtual disaster scenario. It became apparent that additional temporary evacuation spots are required to ensure the safety of individuals requiring assistance and their assistants because their travelling speeds were much slower than had been supposed. The supporting systems were found to be effective in enhancing residents' awareness of the need for both self-reliance and mutual aid.

A comprehensive re-evaluation of the G protein alpha subunit genes specifically expressed in taste buds in the tongue epithelium of rodents revealed that Gq and G14 of the Gq class and Gi2 and Ggust (Gt3, also known as gustducin) of the Gi class are expressed in mammalian taste buds. Meanwhile, a database search of fish genomes revealed the absence of a gene encoding an ortholog of the mammalian Ggust gene, which mediates sweet, umami, and bitter taste signals in mammalian taste receptor cells (TRCs). Histochemical screening identified two G protein alpha subunit genes, zfGia and zfG14, expressed in subsets of TRCs in zebrafish. The expression patterns of zfGia and zfG14 in taste buds were mutually exclusive, and the expression of known T1R and T2R genes in zebrafish was restricted to a subset of zfGia-expressing TRCs. These findings highlight the existence of a novel subset of TRCs in zebrafish that is absent in mammals and suggest that unidentified G protein-coupled receptors are expressed in zfG14-expressing TRCs and in zfGia-expressing TRCs where known T1R and T2R genes were not expressed in zebrafish. The existence of not only generalized but also specialized subsets of TRCs may imply a strong connection between the evolution of the peripheral gustatory system and the evolution of particular species.

Aim: Diabetes is present in patients with chronic liver disease caused by hepatitis C virus (HCV). The aim of this case–control study is to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with chronic liver disease caused by HCV. Methods: Sixteen HCV positive patients with T2DM treated by sitagliptin were retrospectively enrolled. These patients were given sitagliptin between December 2009 and January 2010. Another 16 HCV patients with T2DM treated only with diet and excise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. Results: In the sitagliptin group, the average HbA1C level decreased approximately 0.8% at 48 weeks after the initiation of sitagliptin. Next, the average FPG level decreased approximately 20 mg/dL during follow up after the initiation of sitagliptin. All the patients were able to take sitagliptin of 50 mg/day without reduction because of sitagliptin-related side-effects. On the other hand, in the control group, the average HbA1C and FPG level did not change with statistical significance during follow up of 48 weeks. Regarding aminotransferase, there were no significant changes of average AST and ALT level during follow up of 48 weeks in both the sitagliptin group and control group. Conclusion: Our results indicate that sitagliptin is effective and safe for the treatment of T2DM complicated with HCV positive chronic liver disease.

BACKGROUND: Assessment of hepatic functional reserve is important in hepatic resection. The aim of this study was to evaluate the role of hepatic asialoglycoprotein receptor (ASGP-R) analysis in the preoperative estimation of remnant liver function in liver surgery. METHODS: One hundred and one patients undergoing hepatic resection for liver tumours were studied. Seventeen patients had preoperative percutaneous transhepatic portal vein embolization (PTPE). Function of the hepatic remnant was estimated before surgery using radioactivity in fusion images of both liver single-photon emission computed tomography and computed tomography scans using (99m)Tc-labelled diethylene triamine penta-acetate-galactosyl-human serum albumin. RESULTS: All three patients with an ASGP-R concentration below 400 nmol/l and preoperative total amount of receptor in the future remnant liver (R0-remnant) of less than 53.0 nmol per liver died. Two patients with chronic hepatitis and R0-remnant values between 53.0 and 65.0 nmol per liver and a receptor concentration lower than 600 nmol/l developed liver dysfunction. The incidence of liver failure decreased inversely with increasing R0-remnant value. CONCLUSION: A combination of receptor concentration and the amount of hepatic receptor in the future liver remnant as detected on fusion images is useful in evaluating the risk of postoperative liver failure.

Neural pathways conveying taste information from the tongue to the brain underlie gustatory information coding and processing. To visualize the gustatory neural pathways, we established transgenic mouse lines in which a transneuronal tracer, wheat germ agglutinin (WGA), was faithfully and robustly expressed in sweet/umami taste receptor cells (TRCs) under the control of mouse T1R3 gene promoter/enhancer. WGA protein was transferred not laterally to the cells with synaptic structure, but directly to a subset of neurons in the geniculate and nodose/petrosal ganglia, and further conveyed to a subpopulation of neurons in the rostro-central region of the nucleus of the solitary tract. However, no WGA immunoreactivity was observed in more central gustatory relay nuclei even in the parabrachial nucleus. These results imply that sweet/umami information from TRCs can be directly transmitted to the gustatory neurons that innervate the sweet/umami TRCs, and this study uncovered a precise map of the sweet/umami information pathway from TRCs to the nucleus of solitary tract in the brain stem.

The rodent parabrachial nucleus (PBN) is not merely a sensory relay station but also plays an important role in integrating various ascending and descending inputs together with plastic changes of neuronal responses after learning and experience. The limbic and reward systems receive ingestion-related information via the cortical areas in primates, whereas in rodents the information is sent to these systems mostly via the PBN. To explore how the rat PBN is functionally organized, we detected activation patterns of neurons mainly by means of c-fos immunohistochemistry to show neuronal activation in different situations of ingestive behavior. The expression pattern was different under nutritionally replete and deficient conditions, perceptually new and familiar conditions, and learned and unlearned conditions. As for the possible functions, the rostral part of the external lateral subnucleus is related to general visceral inputs; the caudal part of the external lateral subnucleus, aversive behavior; the dorsal lateral subnucleus, ingestive behavior; and the central medial subnucleus, taste of NaCl. Because several genes were localized in specific subnuclei, we are trying to correlate the gene expressions with possible functional significance.

Independent distributed power generation using small wind turbines is becoming more widespread as wind power generation increases. Installation of small wind turbines in densely populated urban areas is not only useful from the viewpoint of extracting wind power sources in weak-wind areas but also for making renewable energy easier to access when power supplies are closer to consumers. It is from this point of view that the authors proposed “urban wind power generation” using a collective system with a number of small vertical wind turbines, and have developed a suitable generator for low-speed vertical wind turbines such as a Savonius windmill. Based on a standard coreless generator, the proposed generator is designed to make the direction of the magnetic flux radial in order to install the magnets and coils on the outer end of the generator. The change of magnet composition and flux direction maximizes the speed of the flux change and output voltage within a limited space. With the above configuration, the power of the proposed generator is independent of the diameter. In this report, the authors describe and evaluate the fundamental performance of a prototype of the proposed generator. Based on the experiments, a maximum output power of 283 W was obtained. The obtained starting torque is small enough to begin rotation under weak wind conditions of no more than 1 m/s. Therefore, it is clear that the proposed “radial” coreless generator is suitable for self-starting and producing high power at low wind speed. © 2009 Wiley Periodicals, Inc. Electr Eng Jpn, 167(1): 26– 34, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20695

A submillimeter-scale variation of δ18O in quartz was identified in chert and Fe-oxide mesobands of the Brockman Iron Formation, Western Australia, using an in situ CO2-laser fluorination technique. The total range of variation is 11.2–23.0‰, with >5‰ variations within a single mesoband of approximately 2 cm thickness. These data contradict most previous works, which have suggested that banded iron formations are isotopically homogeneous. The present sample was obtained outside of the iron mining area, and as such is considered to have been less altered by the hydrothermal event recently shown to be responsible for the formation of the iron ore. The data suggest that the largest Paleoproterozoic banded iron formations may have formed not in a stable, quiescent sea, but instead as a result of increased influx of iron- and silica-rich solutions during periods of increased magmatism and submarine hydrothermal activity in a rift basin environment.

We report a case of hepatocellular carcinoma located just below the right hemidiaphragm that was diagnosed as having hepatitis C virus–related cirrhosis 12 years ago. Although the lesion was not clear on conventional sonography, it was clearly defined on CO2-enhanced sonography, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, extensive cauterization and complete tumor necrosis were obtained with only 1 session of treatment. The patient had no serious adverse effects and has shown no recurrence during 35 months of follow-up. © 2006 Wiley Periodicals, Inc. J Clin Ultrasound, 2007.

In order to investigate the mechanism of interferon-alpha (IFNalpha) action in the treatment of chronic myelogenous leukemia (CML), we examined surface expressions of both type I interferon receptor 1 (IFNAR1) and 2 (IFNAR2) subunits on CD34-positive cells in bone marrow (BM) in a total of 57 CML patients. Initial cell-surface IFNAR2 expression at diagnosis assessed by flow cytometry widely distributed but showed overall significantly higher expression in CML patients when compared with normal controls. In 15 fresh patients who subsequently received IFNalpha therapy, IFNAR2 expression at diagnosis was significantly higher in cytogenetic good responders than in poor responders. Down-regulation of IFNAR2 expression during IFNalpha therapy was observed only in good responders but not in poor responders. In addition to protein level, both initial high IFNAR2c mRNA expression level and its down-regulation during IFNalpha therapy, in purified CD34-positive cells, were also observed only in good responders. In contrast to IFNAR2, cell-surface IFNAR1 expression was generally lower than IFNAR2, and correlation between either the pretreatment level or down-regulation of IFNAR1 and clinical response was not evident. With in vitro IFNalpha stimulation, CD34-positive cells showed down-regulations of cell-surface IFNAR2, and IFNAR1 to a lesser extent, in one good-responder patient, but not in one poor-responder patient. Serum soluble interferon receptor (sIFNR) was higher in untreated CML patients than in normal controls, without any correlation with clinical response to IFNalpha. Thus, the pretreatment protein and mRNA expression levels of IFNAR2 and their down-regulations during IFNalpha therapy correlate well with IFNalpha response in CML patients.

Odour threshold concentrations, determined in agueous-ethanol solution, and odour qualities are reported for 18 enantiomeric and diastereomeric pairs of citronellyl derivatives [13 linear monoterpene compounds and five monocyclic α-damascone and α-ionone-related compounds (trans-2,2,6-trimethylcyclohexyl derivatives)] (98%ee). Fairly large differences in both odour strength and odour qualities were found between the monocyclic diastereomeric pairs. In four of the five cyclic compounds, the (1R, 6S)-form was found to be stronger and more sensorily active than the antipode. On the other hand, the linear enantiomeric pairs showed only small differences in both odour strength (half of them showed the same threshold values) and odour character. However, all the (3S)-forms showed milder, cleaner and a much preferable top note than the (3R)-forms except for citronellyl nitrile and the diester (citronellyl ethyl oxalate), whose (3R)-form showed a characteristic floral musk odour, although the (3S)-form showed a rose floral odour. Copyright © 2004 John Wiley & Sons, Ltd.

In glutamate-mediated excitatory neuronal cell death, immunosuppressants (FK506, Cys-A) are powerful agents that protect neurons from apoptosis. Immunosuppressants inhibit two types of enzyme, calcium/calmodulin-dependent protein phosphatase (calcineurin: CaN), and peptidyl-prolyl cis-trans-isomerase (PPIase) activity such as the FKBP family. In this study, we used a protein transduction approach to determine the functional role of CaN and to produce a potential therapeutic agent for glutamate-mediated neuronal cell death. We created a novel cell-permeable CaN autoinhibitory peptide using the 11 arginine protein transduction domain. This peptide was highly efficient at transducing into primary culture neurons, potently inhibited CaN phosphatase activities, and inhibited glutamate-mediated neuronal cell death. These results showed that CaN plays an important role in excitatory neuronal cell death and cell-permeable CaN autoinhibitory peptide could be a new drug to protect neurons from excitatory neuronal death.

The petrography, chemical, fluid inclusion and isotope analyses (O, Rb-Sr) were conducted for the shale samples of the Mount McRae Shale collected from the Tom Price, Newman, and Paraburdoo mines in the Hamersley Basin, Western Australia. The Mount McRae Shale at these mines occurs as a footwall unit of the secondary, hematite-rich iron ores derived from the Brockman Iron Formation, one of the largest banded iron formations (BIFs) in the world. Unusually low contents of Na, Ca, and Sr in the shales suggest that these elements were leached away from the shale after deposition. The δ18O (SMOW) values fall in the range of + 15.0 to +17.9 per mil and show the positive correlation with calculated quartz/sericite ratios of the shale samples. This suggests that the oxygen isotopic compositions of shale samples were homogenized and equilibrated by postdepositional event. The pyrite nodules hosted by shales are often rimmed by thin layers of silica of varying crystallinity. Fluid inclusions in quartz crystals rimming a pyrite nodule show homogenization temperatures ranging from 100 to 240dC for 47 inclusions and salinities ranging from 0.4 to 12.3 wt% NaCl equivalent for 18 inclusions. These fluid inclusion data give direct evidence for the hydrothermal activity and are comparable to those of the vein quartz collected from the BIF-derived secondary iron ores (Taylor et al, 2001). The Rb-Sr age for the Mount McRae Shale is 1,952 ± 289 Ma and at least 200 million years younger than the depositional age of the Brockman Iron Formation of ∼ 2.5 Ga in age. All the data obtained in this study are consistent with the suggestion that high temperature hydrothermal fluids were responsible for both the secondary iron ore formation and the alteration of the Mount McRae Shale.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to possess potent neurotrophic effects on dopaminergic (DA) neurons. We attempted the transplantation of encapsulated GDNF-producing cells to generate a stable supply of GDNF in the brain to promote neuroprotective and restorative effects for DA neurons. We established baby hamster kidney (BHK) cells and introduced GDNF cDNA to produce human GDNF (BHK-GDNF). These BHK-GDNF cells, or nontransfected BHK cells (BHK-Control), were encapsulated into hollow fibers, and the polymer encapsulated cells were unilaterally implanted into the striatum of adult rats, either before or after the administration of 6-hydroxydopamine into the same striatum. The encapsulated BHK-GDNF cells produced GDNF continuously in the striatum for up to 6 months. The rats that received a BHK-GDNF capsule showed a significant decrease in rotational behaviour compared to those that received a BHK-control capsule. Preservation of the nigrostriatal pathway was significantly greater in those that received a BHK-GDNF capsule than in those that received a BHK-control capsule. This indicates that encapsulated GDNF-producing cells can supply GDNF in a stable fashion and have protective and restorative effects on host DA neurons. Our results support a role for this grafting technique in the treatment of Parkinson's disease.

Objective To assess the immunological relationship between tumour and host, focusing on the production of T-cell helper (Th) subset-derived cytokines in patients with renal cell carcinoma (RCC). Patients and methods The study comprised 35 patients (19 men and 16 women, mean age 56.9 years, range 39–78) with RCC, who had undergone nephrectomy. Using enzyme-linked immunosorbent assays, the levels of Th1-derived cytokines were measured, including interleukin (IL)-2 and interferon (IFN)-γ, and Th2- derived cytokines, including IL-4, IL-5, IL-6, IL-10 and others. Results There was no detectable IL-2 or IFN-γ production (below the detection limit) except in two patients; IL-4 was produced in 18 patients (51%) and of these, 15 (43%) showed a higher level than the mean. IL-5 was produced in 12 patients (34%), all of whom showed a higher level than the mean, and IL-6 was produced in 32 (91%) of whom 10 (29%) showed a higher level than the mean. IL-10 was detected in 28 patients (80%) of whom 14 (40%) showed a higher level than the mean. The production of these cytokines was closely related to the stage and grade of malignancy. Furthermore, there were significant correlations between the levels of production of IL-4 and IL-5 (r2=0.92), IL-4 and IL-10 (r2=0.91), and IL-5 and IL-10 (r2=0.85). Conclusion The intratumoral immunological environment in patients with RCC shows a tendency to produce Th2-related cytokines in accordance with the stage and grade; this suggests a role in humoral but not in cellular immunity.

In view of a cytoprotective effect of elastase inhibitor on chemokine-mediated tissue injury, we examined the neuroprotective effect of ONO-5046, a specific inhibitor of neutrophil elastase, in rats with spinal cord injury. Standardized spinal cord compression markedly increased cytokine-induced neutrophil chemo-attractant (CINC)-1 mRNA and protein. Their increases correlated with neurologic severity of injured rats. Immunohistochemically, CINC-1 protein was detected sequentially in vascular endothelial cells at 4 h, in perivascular neutrophils at 8 h, and in neutrophils infiltrating into cord substance at 12 h. Pretreatment with ONO-5046 (50 mg/kg) markedly ameliorated motor disturbance in injured rats, and reduced CINC-1 protein and mRNA expression. ONO-5046 also significantly reduced the increase of neutrophil accumulation or infiltration estimated by myeloperoxidase activity, and the extent of vascular permeability by Evans blue extravasation in the injured cord segment in comparison to control animals receiving vehicle. These results suggest that CINC-1 contributed to inflammation in rat spinal cord injury and ONO-5046 attenuated neurologic damage partly by blocking CINC-1 production of the chemoattractant, preventing neutrophil activation and vascular endothelial cell injury.

1. We investigated the ability of a newly synthesized sugar derivative, OJ-R9188, [N-(2-tetradecylhexadecanoyl)-O-(L-alpha-fucofuranosyl)-D-seryl]-L-glutamic acid 1-methylamide 5-L-arginine salt, to block binding of selectins to their ligands in vitro and inhibit the infiltration of leukocytes in vivo. 2. OJ-R9188 prevented the binding of human E-, P- and L-selectin-IgG fusion proteins to immobilized sialyl Lewis(x) (sLe(x))-pentasaccharide glycolipid, with IC(50) values of 4.3, 1.3, and 1.2 microM, respectively. 3. In a mouse model of thioglycollate-induced peritonitis, OJ-R9188 at 10 mg kg(-1), i.v. inhibited neutrophil accumulation in the peritoneal cavity. In the IgE-mediated skin reaction, OJ-R9188 at 3 and 10 mg kg(-1), i.v. significantly inhibited extravasation of neutrophils and eosinophils into the inflammatory sites and at 10 mg kg(-1), i.v. also inhibited infiltration caused by picryl chloride-induced delayed-type hypersensitivity in mice. These results suggest that OJ-R9188 may be a useful selectin blocker, with activity against human and mouse E-, P- and L-selectins in vitro and in vivo, and that blocking selectin-sLe(x) binding is a promising strategy for the treatment of allergic skin diseases.

A total of 189 runs were completed to determine the rate of dissolved oxygen consumption in water by the reaction humic acid at 25°, 45°, and 65°C. Glass vial bottles were used as reaction vessels, and humic aicd and pure water of different intitial O2 concentration was loaded with humic acid/water weight of 0.008 and 0.009. Vials were opened periodically to measure O2 concentrations. The pH of the solution fluctuated in the early stages of the experiments and gradually decreased to a constant value. Dissolved oxygen concentration decreased, for example, from initial value of 12 mg/l to 9 mg/l at 25°C, to 5 mg/l at 45°C, and to 2 mg/l at 65°C after the reaction of 500 hours. Analyses of rates suggest that the reaction is first order, and rate constants are 8.42 × 10-9 at 25°C, 2.22 × 10-8 at 45°C, and 1.28 × 10-7 moles m-2 s-1 at 65°C.

UNLABELLED We attempted to sub-classify four cases who show temporal spikes on standard scalp electroencephalogram (EEG), using sphenoidal electrodes and the dipole localization METHOD In a case with mesial temporal epilepsy, spikes showed phase reversal in a sphenoidal electrode, and the spike dipoles were estimated to be in the mesial temporal lobe. In a case with lateral temporal epilepsy, spikes showed no phase reversal in a sphenoidal electrode, and the spike dipoles were estimated to be in the lateral temporal lobe. In two cases out of four, spikes showed phase reversal in sphenoidal electrodes, whilst the dipoles were estimated to be in the frontal lobe. Clinical features also suggested a diagnosis of frontal lobe epilepsy. In one of the two cases in which frontal lobe epilepsy was suspected, ictal dipoles as well as interictal spike dipoles indicated participation of the frontal lobe in the genesis of seizures. Nevertheless, only mesial temporal lobectomy was performed based on results obtained by invasive subdural electrodes. As a result, seizures were not controlled. Although sphenoidal electrodes were useful for differentiating between mesial and lateral temporal lobe foci, it is advisable to use them in combination with the dipole localization method to identify frontal lobe foci.

Objective To examine the levels of interleukin-18 (IL-18) bioactivity within the rheumatoid arthritis (RA) joint, and the differential effects of IL-12 and IL-18 on interferon-γ (IFNγ) production by T cell infiltrates. Methods Expression of IL-18 protein and messenger RNA (mRNA) was determined by enzyme-linked immunosorbent assay and reverse transcriptase–polymerase chain reaction, respectively. The biologic activity of IL-18 was detected on the basis of IFNγ secretion from IL-18–responding human myelomonocytic KG-1 cells. To determine the extent of inhibitory activity on binding of IL-18 to its receptor, a [125I]–IL-18 binding inhibition assay was performed, using a Chinese hamster ovary cell line transfected with a murine IL-18 receptor. Results The amount of IL-18 protein detected in both the serum and synovial fluid of RA patients was markedly larger than that detected in the serum and synovial fluid of osteoarthritis (OA) patients, and serum IL-18 levels correlated with the levels of serum C-reactive protein. IFNγ production by KG-1 cells was more strongly stimulated in synovial fluid samples from RA patients than in samples from OA patients, and this activity was largely diminished in the presence of anti–IL-18 antibody. In contrast, the activity of IL-18 binding inhibition in the serum and synovial fluid of RA patients was not significantly elevated compared with that in OA patients. RA synovial tissues showed increased expression of IL-18 mRNA and increased IL-18 protein synthesis compared with that in OA tissues. Purified CD14+ macrophages, but not activated fibroblast cell lines, from RA synovium were able to release mature IL-18, although both cell types expressed its transcripts. IL-18 alone showed a negligible effect on IFNγ production by RA synovial tissue cells, in contrast to IL-12, which was directly stimulatory. However, IL-12–induced IFNγ production was synergistically enhanced by IL-18, and yet was >50% reduced by neutralization of endogenous IL-18 with anti–IL-18 antibody. Conclusion These results indicate that IL-18, produced predominantly by tissue macrophages, primarily potentiates IL-12–induced IFNγ production by T cell infiltrates in RA synovium. Detection of significant IL-18 bioactivity in the joints, despite the presence of IL-18 binding inhibitors, supports an integral role of this cytokine in perpetuating the IFNγ-dominant T cell cytokine response in RA.

OBJECTIVE To clarify the clinical significance of autoantibodies (auto-Ab) to interleukin-1alpha (IL-1alpha) in rheumatoid arthritis (RA) with interstitial lung disease (ILD), we examined the IL-1alpha auto-Ab level in serum of patients with RA with/without ILD. METHODOLOGY We investigated the level of IL-1alpha auto-Ab in serum of 70 patients with RA with/without ILD and 40 control patients (CP). Levels of IL-1alpha auto-Ab were measured by radioimmunoassay, and serum was regarded as IL-1alpha auto-Ab positive at an auto-Ab level of more than 5 ng/mL. RESULTS Interleukin-1alpha auto-Ab was detected in the serum of 30 out of 70 RA patients (42.9%), and six out of 40 CP (15%) (P < 0.05). Interleukin-1alpha auto-Ab were detected in the serum of 18 out of 32 patients with RA with ILD (56.2%) and 12 out of 38 patients with RA without ILD (31.5%). The positive rate of these autoantibodies in RA with ILD was significantly higher than that in RA without ILD (P < 0.05). Although C-reactive protein, immunoglobulin G, rheumatoid factor and rheumatoid arthritis particle agglutination levels in serum from patients with RA with ILD were not significantly different between the IL-1alpha auto-Ab-positive and -negative groups, the lactate dehydrogenase level (LDH) and AaDO, in the IL-1alpha auto-Ab-positive group were significantly higher than those in the negative group (LDH: P < 0.001, AaDO2: P < 0.05). CONCLUSION These results suggest that IL-1alpha auto-Ab are generated in response to the immunoinflammatory process of ILD in RA, and these autoantibodies may neutralize and regulate the IL-1alpha activity.

We examined whether macrophage infiltration is associated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous melanoma. We further examined whether human melanoma cells produce angiogenic factors in response to macrophage-derived cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha). Treatment of melanoma cells with TNFalpha and IL-1alpha in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF, TNF alpha, as well as IL-1alpha, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS-activated monocytes was blocked when anti-TNF-alpha antibody or anti-IL-1alpha antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNFalpha and/or IL-1alpha secreted by activated monocytes/macrophages, influencing both tumor growth and angiogenesis in melanomas.

In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K+ currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea-pig hearts. Aprindine (3 microM) inhibited the delayed rectifier K+ current (IK) with little influence on the inward rectifier K+ current (IK1) or the Ca2+ current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). The muscarinic acetylcholine receptor-operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 microM) or by the intracellular loading of GTPgammaS. Aprindine inhibited the carbachol- and GTPgammaS-induced IK.ACh with the IC50 values of 0.4 and 2.5 microM, respectively. In atrial cells stimulated at 0.2 Hz, aprindine (3 microM) per se prolonged the action potential duration (APD) by 50+/-4%. The drug also reversed the carbachol-induced action potential shortening in a concentration-dependent manner. In isolated hearts, perfusion of carbachol (1 microM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold. Addition of aprindine (3 microM) inhibited the induction of AF by prolonging MAP and ERP. We conclude the efficacy of aprindine against AF may be at least in part explained by its inhibitory effects on IKr and IK.ACh.

Some individuals with detectable levels of Japanese cedar (Criptomeria japonica) pollen-specific immunoglobulin (Ig)E in serum have no apparent nasal symptoms during the pollen season. The response of CD4+ T-helper (Th) cells to the pollen allergen might differ fundamentally between asymptomatic and symptomatic individuals who are already sensitized to the pollen. The aim of this study was to discern the possible differences in responses of peripheral blood mononuclear cells (PBMCs) to the pollen allergen between asymptomatic and symptomatic subjects who have been sensitized to the pollen. This study included 20 non-atopic healthy volunteers (non-atopic group) and 48 patients who had detectable levels of the pollen-specific IgE before the pollen season in 1997. In the review of nasal symptoms during the pollen season 1997, 24 patients had typical symptoms of seasonal allergic rhinitis (symptomatic group), and the remainder had no seasonal aggravation of nasal symptoms (asymptomatic group). Peripheral blood mononuclear cells (1.0 x 10(7) cells/well) were obtained from each individual during the pollen season and cultured in the absence or presence of 12.5 microg of Cry j 1 for 4 days. The concentrations of IgE, interleukin-5 (IL-5), and interferon-gamma (IFN-gamma) in the culture supernatants were measured. The levels of IgE produced by Cry j 1-stimulated PBMCs of the asymptomatic and symptomatic groups were significantly higher than those of the non-atopic group, but did not differ between the asymptomatic and symptomatic groups. The levels of IL-5 produced by Cry j 1-stimulated PBMCs did not differ significantly between the non-atopic group and the asymptomatic group, but the levels of IL-5 were significantly higher in the symptomatic group than in the asymptomatic group as well as the non-atopic group. The levels of IFN-gamma produced by Cry j 1-stimulated PBMCs did not differ significantly among the three groups. In conclusion, our study has suggested that Japanese cedar pollen-induced synthesis of IL-5, but not of IgE or IFN-gamma, is likely to be a key mechanism linked to the symptomatic episode of seasonal allergic rhinitis in individuals sensitized to the pollen.