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An association between kidney disease and direct-acting antivirals against hepatitis C (DAAs) has been suggested, however the warning on the package insert (PI) of the drug varies among DAAs. In this study, the risk of decreased kidney function associated with DAAs marketed in Japan was investigated to determine whether the risk of kidney disease is a common adverse event and class effect of DAAs. Data for patients who were new users of DAAs marketed in Japan, with eGFR ≥ 45 mL/min/1.73 m2 and without specific risk factors, were extracted from the MID-NET® medical information database network in Japan. Changes from the baseline on estimated glomerular filtration rate (eGFR) categories (eGFR ≥ 90, 90 > eGFR ≥ 60, 60 > eGFR ≥ 45, 45 > eGFR ≥ 30, 30 > eGFR ≥ 15, 15 > eGFR; unit: mL/min/1.73 m2) were used for evaluating the risk of decreased kidney function. Exposure groups for DAAs and relevant concomitant drugs were categorized into 10 patterns based on the PI. Among the 10 patterns, a significant increase in the incidence rate ratio (P

Background Rituximab is conditionally approved in Japan for use in patients with refractory nephrotic syndrome. To meet the conditions of approval, an all-case post-marketing surveillance study was conducted to confirm the real-world safety and efficacy of rituximab in patients of all ages with refractory nephrotic syndrome. Methods All patients scheduled to receive rituximab treatment for refractory nephrotic syndrome were eligible to register (registration: August 29, 2014 through April 15, 2016); the planned observation period was 2 years from the initiation of rituximab treatment (intravenous infusion, 375 mg/m2 once weekly for four doses). The study was conducted at 227 hospitals throughout Japan. Adverse drug reactions (ADRs) were collected for safety outcomes. The efficacy outcomes were relapse-free period and the degree of growth in pediatric ( Results In total, 997 (447 pediatric) patients were registered; 981 (445) were included in the safety analysis set; 852 (402) completed the 2-year observation period; and 810 (429) were included in the efficacy analysis set. Refractory nephrotic syndrome had developed in childhood for 85.0% of patients, and 54.6% were aged ≥15 years. ADRs were observed in 527 (53.7%) patients, treatment-related infection/infestation in 235 (24.0%) patients, and infusion reactions in 313 (31.9%) patients. The relapse-free period was 580 days (95% confidence interval, 511–664). There was a significant change in height standard deviation score (pediatric patients; mean change, 0.093; standard deviation, 0.637; P = 0.009). Conclusion The safety and efficacy of rituximab treatment in patients with refractory nephrotic syndrome were confirmed in the real-world setting. Clinical trial registration UMIN000014997.

Background Previous studies suggested that direct-acting antivirals (DAAs) against hepatitis C increased the blood coagulability of patients on warfarin. This study aims to descriptively investigate the effects of DAAs on the blood coagulability and liver function of patients on warfarin in Japan. Methods The Medical Information Database Network (MID-NET®) was used as data source. Fluctuations of blood coagulability and liver function were examined before and after DAA treatment in patients who were prescribed both DAAs and warfarin at least once during the study period from January 1, 2010, to December 31, 2017. Results For the 16 eligible patients, the mean values of both PT-INR and WSI (warfarin sensitivity index) defined as the value obtained by dividing the PT-INR by the warfarin daily dose slightly decreased at the date of completion of the DAA treatment in comparison with those at the date of initiation and subsequently increased at 12 weeks after treatment completion. In contrast, the warfarin daily dose increased at the date of completion of the DAA treatment, followed by a decrease at 12 weeks after its completion. Several laboratory tests related to the liver function also revealed a similar decrease at the end of the DAA treatment. Conclusion The analysis of MID-NET® data provides useful information on drug safety assessment of real-world patients. The results of this study imply that fluctuation of the liver function test results may relate to the fluctuation of blood coagulability in patients on both DAA and warfarin. This study contributes to a deeper understanding of the usefulness and limitations of real-world data in MID-NET® for regulatory purposes.

Background Immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (NS) because of their high risk of severe infections. Vaccinations may precipitate relapses of NS, but there is no available data regarding inactivated influenza (flu) virus vaccines. Methods We retrospectively reviewed the medical records of children with NS who had received flu vaccines between 2002 and 2015. The day of flu vaccination was defined as day 0, and the period between the pre-vaccination and the post-vaccination days was defined as − X to + Y. The risk ratios and their 95% confidence intervals for NS relapse rate were estimated by generalized estimating equation (GEE) Poisson regression. Results A total of 104 pediatric patients received 208 flu vaccines. The mean age at onset of NS was at 4.85 ± 3.87 years old. There were 261 NS relapses between days − 180 and + 180. Compared with the relapse rate in the − 180 to 0 interval (1.19 times/person-year), those in 0 to + 30 (1.23), + 31 to + 60 (1.58), + 61 to + 90 (1.41), + 91 to + 120 (1.41), and + 121 to + 180 (1.32) days groups were slightly increased, but without significance. Multivariate analysis using GEE Poisson regression also showed no significant increase in relapse rate in each day group compared with days − 180 to 0. Risk ratios for NS relapse were significantly higher in children who were treated with steroids at the first vaccination. Conclusions Our results suggest that flu vaccines should not be avoided in children with NS based on the potential for NS relapses. Electronic supplementary material The online version of this article (10.1007/s10157-020-01930-8) contains supplementary material, which is available to authorized users.

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Although asthma attacks are known adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use, few studies have quantified these risks. The objectives of this study were to utilize an epidemiological approach to quantitatively evaluate the risk of acute asthma attacks associated with NSAID prescription in Japan and to compare the risks among NSAIDs according to their cyclooxygenase (COX)-2 selectivity.We conducted a self-controlled case series study using Japanese health insurance claims data. Exposed cases were identified as those who had experienced both NSAID prescription and acute asthma attack, which was defined as the combination of an inhalation procedure and the prescription of any inhaled βWe identified 9769 subjects, more than 95% of whom were younger than 60 years. There was a significantly higher risk of acute asthma attacks during the NSAID prescription period when compared with the baseline period. The quantified IRRs were, in descending order, 93.94 (95% CI, 90.10-97.95) for the prescription start date, 3.96 (95% CI, 3.63-4.33) for 1 to 9 days after the prescription start date, 3.01 (95% CI, 2.78-3.25) for 7 days after the prescription end date, 2.19 (95% CI, 1.82-2.65) for9 days after the prescription start date, and 1.44 (95% CI, 1.29 -1.61) for 7 days before the prescription start date. There were lower asthmatic risks for COX-2 selective NSAIDs compared with nonselective NSAIDs.The use of NSAIDs in Japan was associated with an increased risk of acute asthma attacks. However, this risk was lower in COX-2 selective NSAIDs.

Steroid-sparing drugs, such as cyclosporine, are recommended as treatment for children with frequently relapsing nephrotic syndrome (FRNS) and steroid-related toxicities. We recently reported a high rate of relapsing nephrotic syndrome 2 years after discontinuation of cyclosporine treatment, suggesting that long-term treatment is necessary. Cyclosporine-associated nephrotoxicity (CAN) is a potential side effect of long-term cyclosporine treatment. We retrospectively reviewed pediatric patients with FRNS treated with cyclosporine for ≥3 years at a single center between 1999 and 2012. The cyclosporine dose was adjusted to maintain the whole-blood cyclosporine trough level at 80–100 ng/ml for 6 months, at 60–80 ng/ml for 18 months, and then at around 50–60 ng/ml thereafter. Maintenance dose of prednisolone was not prescribed. CAN was graded in terms of arteriolar hyalinosis and the degree of interstitial fibrosis. Thirty-six children (28 males) were enrolled in the study. The median age at the start of long-term cyclosporine treatment was 9.4 years. The median duration of the longest period of cyclosporine treatment was 4.5 years. Most CAN cases were characterized by arteriolar hyalinosis. The frequency of CAN was positively correlated with the duration of cyclosporine treatment, with an odds ratio (95% confidence interval) for CAN of 3.84 (0.79–18.74) after 2–5 years and 6.60 (1.18–36.94) after >5 years of cyclosporine treatment (vs. 0–2 years). Although the frequency of CAN was correlated with the duration of cyclosporine treatment in our pediatric patient population, most cases of CAN involved arteriolar hyalinosis. We conclude that long-term cyclosporine treatment is useful for treating FRNS in children, providing its dose is controlled and kidney biopsies are regularly performed.

To study discoid meniscus in children who underwent arthroscopic surgery at our center.Thirty-four patients (39 knees) younger than 15 years with discoid lateral meniscus (mean age, 12.9 years; 13 males, 21 females) who underwent arthroscopic surgeries since 2007 were studied. The surgical procedure consisted of, in principle, saucerization with additional suture repair in the case of meniscal instability at the peripheral rim of the residual meniscus. The mechanisms of symptom onset, symptoms, complications and postoperative outcome in these cases were examined. In addition, Lysholm scores were obtained before surgery and at the last postoperative follow-up in all patients.Symptom onset was associated with sports in 18 knees, fall in 3 knees, and no definitive trigger in the remaining knees. The presenting symptoms were pain in 32 knees, catching in 11 knees, and locking in 6 knees. According to Watanabe classification, 26 knees were complete type and 13 knees were incomplete type. The modes of tear included horizontal tear in 10 knees and longitudinal tear in 10 knees, while no definitive tear was present on the knee joint surface. The surgical procedures included saucerization only in 22 knees, partial meniscectomy in 10 knees, and saucerization with suture repair in 5 knees. The mean Lysholm score was 63.9 before surgery, and improved significantly to 92.3 at the last follow-up. Only two knees developed osteochondritis dissecans after surgery. Two knees required reoperation; one knee underwent subtotal meniscectomy and one knee had partial meniscectomy with suturing.Although the short-term outcome after saucerization with or without suture repair for discoid meniscus is favorable, degenerative change or change of lower limb alignment may occur in the long term. Further long-term study is required.

Little is known regarding the epidemiology of idiopathic nephrotic syndrome (INS) in East Asia. Previous studies have suggested higher incidence of INS in Asian children, though decreasing trend of its incidence has also been shown. We conducted a nationwide study of Japanese children aged 6 months to 15 years with INS. Children who were newly diagnosed with INS between 1 January 2010 and 31 December 2012 were eligible. Children with congenital nephrotic syndrome or nephrotic syndrome secondary to nephritis were excluded. A total of 2099 children were initially diagnosed with INS and were followed for up to 4 years. The estimated incidence of INS was 6.49 cases/100,000 children per year, without clear correlation with geographical region. The male:female ratio was 1.9 and approximately 50 % of children were

Background In Japan, several large healthcare databases have become available for research since the early 2000’s. However, validation studies to examine the accuracy of these databases remain scarce. We conducted a validation study in order to estimate the positive predictive value (PPV) of local or ICD-10 codes for acute myocardial infarction (AMI) in Japanese claims. In particular, we examined whether the PPV differs between claims in the Diagnosis Procedure Combination case mix scheme (DPC claims) and in non-DPC claims. Methods We selected a random sample of 200 patients from all patients hospitalized at a large tertiary-care university hospital between January 1, 2009 and December 31, 2011 who had an inpatient claim assigned a local or ICD-10 code for AMI. We used a standardized data abstraction form to collect the relevant information from an electronic medical records system. Abstracted information was then categorized by a single cardiologist as being either definite or not having AMI. Results In a random sample of 200 patients, the average age was 67.7 years and the proportion of males was 78.0%. The PPV of the local or ICD-10 code for AMI was 82.5% in this sample of 200 patients. Further, of 178 patients who had an ICD-10 code for AMI based on any of the 7 types of condition codes in the DPC claims, the PPV was 89.3%, whereas of the 161 patients who had an ICD-10 code for AMI based on any of 3 major types of condition codes in the DPC claims, the PPV was 93.8%. Conclusion The PPV of the local or ICD-10 code for AMI was high for inpatient claims in Japan. The PPV was even higher for the ICD-10 code for AMI for those patients who received AMI care through the DPC case mix scheme. The current study was conducted in a single center, suggesting that a multi-center study involving different types of hospitals is needed in the future. The accuracy of condition codes for DPC claims in Japan may also be worth examining for conditions other than AMI such as stroke.

Structural changes in nucleus pulposus cells induce intervertebral disc (IVD) degeneration as a consequence of cytokine generation, biochemical products, and changes in the local environment. We have previously shown that inflammatory cytokines induce murine IVD (mIVD) angiogenesis and macrophage migration. Although the physiological roles of thrombin, a known proinflammatory factor, are documented, its relationship to IVD degeneration remains largely unexplored. Thrombin mediates cellular responses via the activation of protease-activated receptors such as PAR1 which has been studied in numerous cell types, but not extensively in IVD cells. This study was designed to investigate the endogenous expression of thrombin, tissue factor, and PAR1 in cultured coccygeal mIVDs. Thrombin exclusively induced MCP-1 via the MAPK-ERK and PI3K-AKT pathways. MCP-1 produced by mIVDs induced macrophage migration and thrombin treatment increased MMP-3 production to induce mIVD degeneration. These effects of thrombin on mIVDs were abrogated by a PAR1 inhibitor and suggest that thrombin may be a novel factor capable of stimulating cytokine activity implicated in the regulation several aspects of mIVDs. Mechanisms governing mIVDs, which are regulated by thrombin/PAR1 signaling, require elucidation if our understanding of IVD degenerative mechanisms is to advance.

To investigate the frequency of meniscal tear and the location of tear associated with anterior cruciate ligament (ACL) injury.We studied 549 patients (552 knees) who were diagnosed with ACL injury by arthroscopy at our center between January 2006 and March 2014 (8 years and 3 months). The subjects comprised 289 males and 263 females ranging in age from 13 to 66 (mean 26.1) years. The cause of injury was sports-related in 89.1 %, and the mean interval from injury to initial arthroscopy was 23 months. The patients were divided into two groups: arthroscopy performed within 8 weeks after injury (acute group; 256 knees) and more than 8 weeks after injury (chronic group; 296 knees). Frequency of meniscal tear and location of tear were compared between two groups.The incidence of meniscal tear diagnosed by arthroscopic examination was 79.2 % (437 of 552 knees) in all subjects; 72.7 % (186 of 256 knees) in acute group and 84.8 % (251 of 296 knees) in chronic group, and was significantly higher in chronic group. Regarding the locations of meniscal tears, in acute group (186 knees), medial meniscal tear only was found in 20 knees (10.8 %), lateral meniscal tear only in 129 knees (69.4 %), and bilateral (including medial and lateral) meniscal tears in 37 knees (19.9 %). In chronic group (251 knees), medial meniscal tear only was found in 62 knees (24.7 %), lateral meniscal tear only in 85 knees (33.9 %), and bilateral meniscal tears in 104 knees (41.4 %). Lateral meniscal tear was commonly associated with acute ACL injury, while medial meniscal tear with chronic ACL injury. Bucket handle tear was observed in 25 knees (medial: 17 knees, lateral: 8 knees) in acute group, and 81 knees (medial: 69 knees, lateral: 12 knees) in chronic group, and was more common in the chronic group.The incidence of meniscal tear associated with ACL injury is higher in chronic cases; the number of medial meniscal tears is particularly high, many of which require meniscectomy. Early ACL reconstruction is recommended also for the prevention of secondary meniscal tear.

The long-term outcome of pediatric IgA nephropathy (IgAN) is unclear. Objective IgAN remission criteria were proposed by the Japanese Society of Nephrology in 2013. Children with newly developed IgAN followed for >5 years were analyzed. They were divided into two groups based on histological findings at initial kidney biopsy: the focal mesangial proliferation group (Focal group) and diffuse mesangial proliferation group (Diffuse group). The primary outcome was the remission rate according to the newly proposed IgAN remission criteria. The patients comprised 53 children (31 boys; mean age at IgAN onset, 10.0 years). The Focal and Diffuse groups comprised 21 and 32 patients, respectively. No significant differences in patient characteristics were found between the groups except for steroid administration. The median follow-up period from onset was 9.9 years. Sixteen patients in the Diffuse group and 10 in the Focal group had not achieved remission at the last observation. Patient conditions 2 years after the initial treatment were almost identical to those at the last observation. Multivariate analysis revealed that proteinuria, particularly

Background This study aimed to evaluate risk factors for resistance to proton-pump inhibitor (PPI) therapy among patients with reflux esophagitis (RE) and nonerosive reflux disease (NERD) in gastroesophageal reflux disease (GERD) using a standardized questionnaire in Japan: the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG).

To investigate the long-term outcome in children with frequently relapsing nephrotic syndrome (FRNS) we conducted a follow-up of a previous randomized controlled trial (RCT) 10 years after the initiation of the treatment protocol.We previously conducted an RCT on the efficacy of cyclosporine for treating children with FRNS. After 2 years of treatment, a recommended a management protocol of steroids, and immunosuppressants was provided.Valid information was available for 46 of the 56 patients (82.1 %) enrolled in the original RCT. The median follow-up period was 10.3 years from the start of protocol treatment with cyclosporine. At last follow-up (mean age 18.7 years), only ten patients (21.7 %) showed disease-free remission (no relapse for at least 2 years). In contrast, 23 (50.0 %) continued to relapse frequently or were on immunosuppressants, eight patients (17.4 %) had infrequent relapses without immunosuppressants. Adverse effects attributable to treatment included short stature (6 patients), osteoporosis (six patients), obesity (4 patients), cataracts (3 patients) and hypertension (3 patients). No lethal event or renal dysfunction occurred during follow-up.This 10-year follow-up study shows that most children with FRNS experience relapses after 2 years of cyclosporine treatment, in adolescence and into adulthood. Outcomes in terms of life expectancy and renal function are favorable.

The (pro)renin receptor ((P)RR) is expressed in several tissues including kidney, heart and brain, and is thought to regulate the tissue renin–angiotensin system (RAS) through the non-proteolytic activation of prorenin. (P)RR is cleaved by furin to generate soluble (P)RR (s(P)RR), which is secreted into the extracellular space. s(P)RR is a candidate biomarker reflecting the status of the tissue RAS. Here, we investigated the relationship between background factors and serum s(P)RR levels. We measured s(P)RR levels in 122 patients with essential hypertension (EH) and assessed the relationships between background factors and s(P)RR levels. Serum s(P)RR levels were 19.0 ± 4.9 ng ml−1. Single regression analyses showed that age (r =0.251, P

The present study sought to establish a standard third-line eradication regimen for Helicobacter pylori in Japan.Subjects were 204 patients with H. pylori infection in whom the standard Japanese first- and second-line eradication therapies had proven unsuccessful. Patients were randomly assigned to one of the following third-line eradication therapy groups: (1) LA group: lansoprazole (LPZ) 30 mg 4 times a day (qid) + amoxicillin (AMPC) 500 mg qid for two weeks; (2) LAL group: LPZ 30 mg twice a day (bid) + AMPC 750 mg bid + levofloxacin (LVFX) 300 mg bid for one week; (3) LAS group: LPZ 30 mg bid + AMPC 750 mg bid + sitafloxacin (STFX) 100 mg bid for one week. Patients for whom these therapies failed underwent a crossover fourth-line eradication regimen. Drug sensitivity was also tested for AMPC, clarithromycin (CAM), MNZ, LVFX, and STFX.Drug resistance rates prior to third-line eradication therapy were 86.4 % for CAM, 71.3 % for MNZ, 57.0 % for LVFX, 8.2 % for AMPC, and 7.7 % for STFX. Intention-to-treat analysis of third-line eradication therapy eradication rates showed a significantly higher rate in the LAS group (70.0 %) compared with the LA group (54.3 %; p0.05) and the LAL group (43.1 %; p0.001). The significantly lower rate in the LAL group than the LAS group was caused by bacterial resistance to LVFX.The findings suggest that triple therapy with PPI, AMPC, and STFX for one week would be an effective standard third-line eradication regimen for H. pylori in Japan.

Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5α-androstane-3β,17β-diol (3β-diol), which is inactive androgen metabolized from DHT. 3β-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3β-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3β-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3β-diol, by the inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3β-diol to DHT was catalysed by 3β-HSD and abiraterone could inhibit this activity of 3β-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3β-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3β-HSD activity could be a new approach to castration-resistant prostate cancer treatment.

Reactive oxygen species (ROS) are strongly implicated in melanoma development, and treatment with antioxidants has shown efficacy in suppressing malignant transition and progression. Here, we investigated the significance of the glutamate-L: -cysteine ligase catalytic subunit (GCLC) expression, a key regulator of glutathione synthesis, for malignant melanoma. A large set of melanoma cell lines (n = 36) was analyzed, and higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation. Moreover, treatment with the antioxidant N-acetylcysteine efficiently reduced the growth speed of several investigated malignant cells. In addition GCLC expression was significantly linked to a prominent set of cellular antioxidants, accounting for the observed lower basal levels of oxidative stress and higher antioxidative capacity. Key attributes defining the malignant phenotype of melanoma cells including survival, invasiveness, and switch from E-cadherin to N-cadherin expression were more prominent in cells with lower GCLC expression. Our findings were further corroborated by observations in Rag2(-/-)γc(-/-)mice, in which melanoma cells with lower GCLC expression depicted a dramatically stronger tumor growth. Furthermore, prognostic significance of GCLC expression was investigated in patients (n = 28) with advanced malignant melanoma. High tumor immunoreactivity for GCLC was a significant determinant for better 5-year overall survival. Conclusively, we show for the first time that GCLC may serve a dual role, as a surrogate marker for cellular redox state as well as malignant potential of melanoma cells. These promising results regarding its prognostic significance as well as its potential as a pharmacological target require further in-depth investigations.

Acute pulmonary embolism (APE) is a serious disease. Recently, multidetector-row computed tomography (MDCT) has proven to be valuable in detecting APE and deep vein thrombosis. APE is classified as massive, submassive, and nonmassive. The incidence of submassive APE and the number of therapeutic approaches for clinically diagnosed critical submassive APE have both increased. However, most strategies for submassive APE have been conservative, e.g., transvenous catheter pulmonary embolectomy, and there are few reports on surgical pulmonary embolectomy. We examined the surgical outcomes in four cases of submassive APE with a floating thrombus in the right atrium (RA) from August 2003 to July 2008. All patients appeared to have no neurological complications and showed an event-free survival of up to 65 months (37 ± 25 months). Surgical pulmonary embolectomy was effective for submassive APE with a floating thrombus in the RA.

Ménétrier's disease has been reported to be associated with Helicobacter pylori infection. The aim of this study was to investigate the genetic characteristics of various virulence factors and cytokine expression profiles in Helicobacter pylori isolated from patients with Ménétrier's disease. The genotyping of virulence factors was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Induction of various cytokines in MKN45 cells or gastric fibroblasts by Helicobacter pylori stimulus was measured by real-time reverse transcription-PCR. We found that the Helicobacter pylori strain isolated from a patient with Ménétrier's disease was different from other strains in the MseI-RFLP pattern of the ureC gene. Helicobacter pylori isolated from a patient with Ménétrier's disease showed the highest hepatocyte growth factor (HGF) and TNF-alpha mRNA expressions from gastric fibroblasts, and the highest TNF-alpha expression from MKN45 cells. The results in this study suggest that the difference in cytokine production, depending on the difference in bacteria components, plays an important role in the development of Ménétrier's disease.

In Japanese healthy CYP2C19 extensive metabolizers, rabeprazole 10 mg shows a faster onset of action and stronger inhibition of acid secretion than does omeprazole 20 mg on the first 3 days of administration. We evaluated gastric ulcer improvement after 1 week's treatment with rabeprazole or omeprazole in relation to CYP2C19 polymorphism. A 6-mm rubber disc was placed temporarily at the side of the ulcer for measurement of the ulcer area. The improvement ratios of ulcer area in homozygous extensive metabolizers (homoEMs), heterozygous extensive metabolizers (heteroEMs) and poor metabolizers (PMs) treated with rabeprazole 10 mg were 60.8, 65.0 and 55.3%, respectively, and these values are not significantly different. Corresponding values with omeprazole 20 mg were 46.3, 61.7 and 63.2%, respectively, and the value of homoEMs was significantly smaller than that of heteroEMs. The improvement ratios with rabeprazole in homoEMs and heteroEMs were significantly greater than that with omeprazole in homoEMs.

Purpose. Previously, we suggested that alkylglucoside can be aneffective vector for renal-specific drug delivery (Suzuki et al., J. Pharmacol.Exp. Ther., 288:57–61, 1999). The purpose of the present study is tocharacterize the membrane protein which is recognized by thisalkylglucoside.

Background. Urinary mononuclear cells (UMCs) were studied in IgA nephropathy (IgAN) in relation to clinical and histopathological parameters. Methods. A two-color flow-cytometry analysis was used to phenotype and quantitate UMCs in patients with IgAN (n = 37) and those with other kidney diseases (n = 27). Results. The IgAN patients had higher numbers of UMCs than the patients with other kidney diseases. Macrophages (CD14+; P < 0.0001) and T lymphocytes (CD3+; P = 0.0001; CD4+, P < 0.0001) were predominantly found. In the IgAN patients, the quantities of urinary CD3+, CD14+ cells correlated with impaired renal function; namely, serum creatinine, creatinine clearance, and urinary protein excretion. The UMCs were associated with histopathological changes such as glomerular segmental lesions (r = 0.511; P < 0.01 for CD3+; r = 0.623, P < 0.0001 for CD4+, and r = 0.552; P < 0.001 for CD14+) and the index of glomerular hypercellularity (r = 0.405; P = 0.01 for CD3+ T cells and r = 0.392, P = 0.01 for CD14+ macrophages). Moreover, the UMCs reflected the severity of pathology, as estimated by the glomerular score (r = 0.424; P < 0.01 for CD3+; r = 0.458; P < 0.01 for CD4+; r = 0.500, P = 0.001 for CD14+ cells). UMCs were weakly correlated with tubulointerstitial changes. Conclusion. UMCs were associated with the clinical stage of IgAN and mirrored the extent of histopathology in the kidney. Flow-cytometry analysis of UMCs may help to predict the course of the disease.

Purpose. We have previously shown Glc-S-C7-Me (octyl β-D-thioglucoside) exhibits renal targeting potential in vivo in addition to its specific binding to the renal membrane fraction in vitro. Thus, 'alkylglycoside' is considered to be a novel targeting vector for the kidney (1,2). The present study is designed to clarify the structural requirements for alkylglycoside as a renal targeting vector.

A B16 melanoma-specific CD8+ T cell line (AB1) was established from the spleen cells of C57BL/6 mice cured of B16 melanoma with interleukin (IL)-12 treatment. The AB1 line exclusively used T cell receptor Vbeta11. The AB1 cells exhibited a cytolytic activity against both syngeneic B16 melanoma and allogeneic P815 mastocytoma, whereas a cold inhibition assay revealed specificity of the AB1 cells against B16 melanoma. Their lostability to kill a class I loss variant of B16 melanoma was restored by the transfection of H-2Kb gene. In addition, their interferon (IFN)-gamma production was significantly suppressed by the addition of anti-H-2Kb monoclonal antibody, and RT-PCR analysis showed that the AB1 line expressed the mRNA encoding IFN-gamma, but not IL-4 or IL-10. The experiment using synthetic peptides of tyrosinase-related protein-2 (TRP-2) revealed that the AB1 cells could recognize TRP-2(181-188) peptide. Moreover, the AB1 cells showed an in vivo antitumor effect against established pulmonary metastases of B16 melanoma. Overall, these results indicate that the Tc1-type Vbeta11+ AB1 cells exert an antitumor activity against syngeneic B16 melanoma through recognition of TRP-2(181-188) peptide in an H-2Kb-restricted manner.

On diagnosis of Stanford type A acute aortic dissection with an aberrant right subclavian artery, emergency operation was performed. Aortic arch replacement was undertaken with additional 'elephant trunk' procedure to cover the entry site and decrease the blood flow through the false lumen. We consider this technique will become one of the effective procedures for acute aortic dissection involving an aberrant right subclavian artery.

Dolichos biflorus agglutinin (DBA) binding was examined in 32 cases of intracranial human germ-cell tumors. In embryonal carcinomas, intense DBA binding sites were found on the free surface and cytoplasm of embryonal cells. In teratomas, glandular structures often had positive DBA binding sites. Yolk sac carcinomas and choriocarcinomas showed negative DBA affinity. Of 19 cases of germinomas, 10 showed no DBA-positive cells, while sporadically and/or collectively distributed-DBA positive cells were found in the other 9 cases. Common brain tumors such as gliomas, neurinomas and meningiomas were negative for DBA staining. Considering the cellular carbohydrate structure, these findings suggest that DBA-positive cells in germinoma might be evidence of differentiation into embryonal or some somatic components. In addition, because of the absence of DBA binding sites in the common brain tumors, the identification of such binding sites in brain tumors might act as a marker for embryonal or somatic components, especially among germ-cell tumors.

Most esophageal cancers are either squamous cell carcinomas or Barrett’s mucosa-derived adenocarcinomas. A 64-year-old man with a long history of alcohol drinking and smoking was found to have a tumor in the cervical esophagus on screening esophagography. Subsequent work-up revealed double primary cancer of the esophagus consisting of adenocarcinoma arising from ectopic gastric mucosa in the cervical esophagus and squamous cell carcinoma in the abdominal esophagus. He underwent subtotal esophagectomy. On microscopic examination of the resected specimen, the Ip tumor in the cervical esophagus was confirmed to be an adenocarcinoma derived from ectopic gastric mucosa that had invaded the muscularis mucosa, and the 0-IIb tumor located near the esophagogastric junction was confirmed to be a squamous cell carcinoma that had invaded the proper mucosal layer. No lymph node metastases were noted. Adenocarcinoma from ectopic gastric mucosa is rare, and its coexistence with squamous cell carcinoma is extremely rare.

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multifunctional cytokine that regulates cell growth, migration, and survival principally through a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14). However, its physiological roles in bone are largely unknown. We herein report various effects of TWEAK on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed Fn14 and produced RANTES (regulated upon activation, healthy T cell expressed and secreted) upon TWEAK stimulation through PI3K-Akt, but not nuclear factor-κB (NF-κB), pathway. In addition, TWEAK inhibited bone morphogenetic protein (BMP)-2-induced expression of osteoblast differentiation markers such as alkaline phosphatase through mitogen-activated protein kinase (MAPK) Erk pathway. Furthermore, TWEAK upregulated RANKL (receptor activation of NF-κB ligand) expression through MAPK Erk pathway in MC3T3-E1 cells. All these effects of TWEAK on MC3T3-E1 cells were abolished by mouse Fn14-Fc chimera. We also found significant TWEAK mRNA or protein expression in osteoblast – and osteoclast-lineage cell lines or the mouse bone tissue, respectively. Finally, we showed that human osteoblasts expressed Fn14 and induced RANTES and RANKL upon TWEAK stimulation. Collectively, TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in MC3T3-E1 cells. TWEAK may thus be a novel cytokine that regulates several aspects of osteoblast function.

The authors reviewed 5 cases of histopathologically verified malignant cerebellar astrocytic tumours (2 anaplastic astrocytomas and 3 glioblastomas) in children admitted to our department. All cases exhibited symptoms and signs of increased intracranial pressure and of a cerebellar lesion. Brain stem symptoms were present in 4 cases. All of the tumours were located in or near the midline of the cerebellum with no large cyst. Surgical removal (70 to 90% removal) of the tumour was performed in 4 cases. In one case only a biopsy was done. Even with subsequent follow-up treatment including radiotherapy, chemotherapy, and/or immunotherapy, the course of the disease could not be reversed, and all of the children died 3 to 13 months (mean 7 months) after admission due to tumour re-growth or recurrence. Tumour dissemination along the walls of the ventricular system was seen in 2 cases, and was considered to be a peculiar, fatal form of tumour recurrence in patients with this type of tumour. Malignant cerebellar astrocytic tumours in children have an extremely poor prognosis. Until, improved therapy is available to counteract this tragic consequence, it will remain so.