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BackgroundTakayasu arteritis (TAK), a granulomatous large vessel vasculitis, mainly involves the aorta and its proximal branches and commonly occurs in young females. However, studies of pregnancy in women with TAK are sparse and limited, probably due to the rarity of the disease.ObjectivesThe purpose of this study was to understand the status quo of medical treatments of the primary disease and outcomes of pregnancy in patients with TAK, and birth outcomes of the children in Japan.MethodsPatients with TAK who conceived after the onset of the disease and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) were retrospectively enrolled in this study. The following information was collected from patients who had a live-born baby: age at diagnosis of TAK, disease classification, age at delivery, treatments before and during pregnancy, complications during pregnancy, birth outcomes of the children, and changes in disease activity during pregnancy and after delivery.ResultsFifty-one cases and 69 pregnancies from 19 ethics committee-approved centers were enrolled during the study period 2019–2021. Of these, 49 cases and 66 pregnancies (95.7%) resulted in delivery and live-born babies. The Numano classification of the 49 cases was as follows: type I, 11; type IIa, 15; type IIb,12; type III, 1; type IV, 1; type V, 9; with type IIa being the most common. The age of diagnosis was 22 years (13–37 years, year of diagnosis 1965–2017), the median age of the delivery of 66 pregnancies was 31 years (year of delivery 1969-2021), and the median duration of illness at delivery was nine years. There were 34 planned pregnancies (51.5%, including four pregnancies by artificial insemination/ovulation induction). Preconception therapy included prednisolone (PSL) in 51 pregnancies (77.3%, median dose 7.5 mg (range 4–30 mg)/day), immunosuppressive drugs in 18 pregnancies (27.3%, azathioprine 8, tacrolimus 7, methotrexate 4, cyclosporin A 1, and colchicine 1), biologics in 12 pregnancies (18.1%, infliximab 6, tocilizumab 5, and adalimumab 1), antihypertensive drugs in 5 pregnancies (7.6%). Surgical treatment had been performed before pregnancy in 6 cases (aortic root replacement 2, subclavian artery dilatation 1, subclavian artery bypass 1, subclavian artery stenting 1, and ascending aorta semicircular artery replacement 1). Medications used during the course of pregnancy included PSL in 48 pregnancies (72.7%, median dose 8 mg (range 4–30 mg)/day, increased in 13 pregnancies, decreased in 1 pregnancy), immunosuppressants in 13 pregnancies (19.7%, azathioprine 6, tacrolimus 6, and cyclosporin A 1), biologics 9 pregnancies (13.6%, infliximab 4, tocilizumab 4, and adalimumab 1). Immunosuppressants and biologics were discontinued in five and four pregnancies after conception. Complications during pregnancy were observed in 20 pregnancies (30.3%), with hypertension being the most common. Complications related to TAK or its treatment were severe infections in two pregnancies and aneurysm enlargement due to increased circulating plasma volume in one pregnancy. Aortic arch replacement was performed after delivery for the latter case. Relapse of TAK was observed in 4 pregnancies (6.1%) during pregnancy and in 8 pregnancies (12.1%) after delivery. One pregnancy resulted in restenosis of subclavian artery for which dilatation procedure was performed prior to the pregnancy. There were 13/66 (19.7%) preterm infants and 17/59 (28.8%) low birth weight infants; all but one had a birth weight of more than 2,000 g and no had serious postnatal abnormalities. Forty-three (82.7%) of the 52 confirmed infants were breastfeed fully or mixed.ConclusionMost of the pregnancies in patients with TAK were successfully delivered while they had low disease activity at a dose of less than 10 mg/day of PSL. Relapse occurred during pregnancy and after delivery in some cases. The babies tended to have low birth weight, but 82.7% of them were breastfed without serious complications.Disclosure of InterestsTakako Miyamae: None declared, Yusuke Manabe: None declared, takahiko sugihara Speakers bureau: TS has received honoraria from Abbvie Japan Co., Ltd., AsahiKASEI Co., Ltd., Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co., Grant/research support from: TS has received research grants from AsahiKASEI Co., Ltd., Daiichi Sankyo., Chugai Pharmaceutical Co., Ltd., and Ono Pharmaceutical., Natsuka Umezawa: None declared, Hajime Yoshifuji Speakers bureau: HY has received lecture fees from Janssen and Chugai., Naoto Tamura: None declared, Yoshiyuki Abe: None declared, Shunsuke Furuta Speakers bureau: Chugai Pharmaceutical Co.,Ltd.DaiichiSankyo Co.,Ltd.Asahi-Kasei Pharma Corporation, Manami Kato: None declared, Takashi Kumagai: None declared, Kaito Nakamura: None declared, Hiroko Nagafuchi: None declared, Jun Ishizaki: None declared, Naoko Nakano: None declared, Tatsuya Atsumi Speakers bureau: Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., AbbVie Inc., Eisai Co. Ltd., Daiichi Sankyo Co., Ltd., Bristol-Myers Squibb Co., UCB Japan Co. Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd.,TAIHO PHARMACEUTICAL CO., LTD., Consultant of: AstraZeneca plc., MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Pfizer Inc., AbbVie Inc., ONO PHARMACEUTICAL CO. LTD.,Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd., Grant/research support from: Astellas Pharma Inc., TAIHO PHARMACEUTICAL CO., LTD.AbbVie Inc., Nippon Boehringer Ingelheim Co., Ltd.,Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co., Ltd. and Pfizer Inc. Alexion Inc., TEIJIN PHARMA LIMITED., Kohei Karino: None declared, Koichi Amano Speakers bureau: AbbVie GK, Asahi-Kasei Pharma, Astellas, Chugai Pharmaceutical Co.Ltd., Eisai, Eli Lilly, GlaxoSmithKlein, Janssen Pharma, Pfizer Japan, Grant/research support from: Asahi-Kasei Pharma,Chugai Pharmaceutical Co.Ltd., Takahiko Kurasawa: None declared, Shuichi Ito: None declared, Ryusuke Yoshimi: None declared, Noriyoshi Ogawa: None declared, Shogo Banno: None declared, Taio Naniwa Speakers bureau: Chugai, Tanabe, Abbbvie, Eisai, Grant/research support from: Chugai, Tanabe, Abbbvie, Eisai, Satoshi Ito Speakers bureau: SI has received speaker’s fees from pharmaceutical companies., Akinori Hara: None declared, Shinya Hirahara: None declared, Haruhito A. Uchida: None declared, Yasuhiro Onishi: None declared, Yohko Murakawa Speakers bureau: Astellas, UCB, Chugai, AbbVie, Grant/research support from: Chugai, AbbVie, Yoshinori Komagata: None declared, Yoshikazu Nakaoka: None declared, Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Novartis Japan, Pfizer Japan Inc., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd and UCB Japan., Consultant of: MH is a consultant for AbbVie, Boehringer-Ingelheim, Kissei Pharmaceutical Co., Ltd., and Teijin Pharma.

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Background To clarify the influence of hypertension and blood pressure ( BP ) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐ RHYTHM Registry was performed. Methods and Results A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05–2.21, P =0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73–1.52, P =0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow‐up (Q1, CI 1.75–4.74, P CI 1.02–2.53, P =0.041) after adjustment for components of CHA 2 DS 2 ‐ VAS c score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. Conclusions BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000001569.

This prospective study, in the very early phase after initiation of glucocorticoid (GC) treatment, showed that alendronate was effective in suppressing accelerated bone resorption and subsequent decrease in bone mineral density (BMD) at the lumbar spine of patients with high-dose GC treatment. How bisphosphonates affect bone metabolism and BMD of patients with high-dose GC in the early phase, especially within 1 month is unclear. We examined the prospective effects of daily 5 mg alendronate on bone metabolism and BMD in 20 patients with high-dose GC (at least 40 mg prednisolone/day) and compared them to 34 high-dose GC-treated patients without alendronate. Serum levels of calcium decreased at day 28 in the alendronate group. Urinary calcium excretion significantly increased after day 7 in both groups. The increase in serum parathyroid hormone (PTH) level at day 7 in the control group was not observed in the alendronate group, but PTH levels increased at day 28 and month 3 in the alendronate group. As for the bone turnover markers, the serum osteocalcin level decreased in both alendronate and control groups, but serum bone-type alkaline phosphatase levels did not show significant changes. Although the urinary type I collagen cross-linked N-telopeptide (NTX) level showed significant increases on days 7 and 28 in the control group; such early increases in urinary NTX were not observed in the alendronate group. Thereafter, the urinary NTX levels fell slowly in the alendronate group significantly. BMD at the lumbar spine significantly decreased from month 1 in the control group, whereas in the alendronate group, BMD at the lumbar spine maintained almost the same level at all time points observed. Alendronate was effective in suppressing bone resorption and subsequent BMD decrease at the lumbar spine in patients with high-dose GC treatment.

Excitotoxic glutamate release occurs in several neurological disorders. One source is derived from the hydrolysis of the neuropeptide N-acetyl aspartyl glutamate (NAAG) by glutamate carboxypeptidase II (GCPII, also known as NAALADase). Drugs that attenuate glutamate transmission have been shown to relieve neuropathic pain, however side effects have limited their clinical use. It appears that GCPII is exclusively recruited to provide a glutamate source in hyperglutamatergic, excitotoxic conditions and therefore would be devoid of such side effects. Here we report on the therapeutic effects of an orally bio-available GCP II inhibitor on established painful and sensory neuropathy in the spontaneously diabetic BB/Wor rat. It significantly improved hyperalgesia, nerve conduction velocity and underlying myelinated fiber atrophy. The data suggest that GCP II inhibition may provide a meaningful and effective approach to the treatment of painful diabetic neuropathy.

In traditional Japanese smelting and forging, three characteristic technologies can be identified that may provide a basis for a new process concept in the production of iron and steel. First, ironsand, the use of which is problematic in modern ironmaking, was used instead of ironstone. The titanium oxide present was effective for keeping the slag fluid and increasing the carbon content of the product, thereby decreasing the activity coefficient of FeO in the slag. Second, two types of operation were carried out with almost the same type of furnace. In one of the operations, mainly molten pig iron was produced and, in the other, steel bloom (>50 wt-% of total product) and molten pig iron. The main controlling factors were the type of raw material (titanium content of ironsand) and the oxidising potential in the furnace, which influenced the degree of carburisation and decarburisation of the iron. Third, it is thought that traditional Japanese steel is the best material for Japanese swordmaking. Th...

Aims/Hypothesis: Hyperglutamatergic activity induced by ischemia is believed to underlie neuronal damage in a variety of neurological disorders, including neuropathic pain. Since ischemia is believed to be a prominent mechanism involved in diabetic polyneuropathy (DPN), we investigated the effect of the glutamate carboxypeptidase II (GCPII, EC #3.4.17.21; previously termed NAALADase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG to NAA and glutamate, on the development of DPN in type 1 diabetic BB/Wor rats. Methods: Diabetic animals were treated with 10 mg/kg/day i.p. of the selective GCPII inhibitor GPI-5232 from onset of diabetes for 6 months. Hyperalgesia to thermal stimulation and nerve conduction velocity (NCV)) were measured monthly. The effect on structural DPN was assessed by scoring of single, teased myelinated fibers, myelinated fiber morphometry and ultrastructural examination of C-fibers at 6 months. Results: GCPII inhibition showed significant but partial effects on hyperalgesia (p

We observed de Haas-van Alphen (dHvA) oscillation in both the normal and superconducting mixed states of a heavy-fermion superconductor CeCoIn5. The Fermi surfaces are found to consist of nearly cylindrical Fermi surfaces and small ellipsoidal ones, reflecting the unique tetragonal crystal structure. The detected cyclotron masses of 5-87 m0 for these Fermi surfaces are extremely large, and correspond to a large electronic specific heat coefficient of about 1000 mJ K-2 mol-1. The cyclotron masses are also found to be field dependent in both the normal and mixed states.

Cross-linking of the human homologue of the murine MEL-14 lymph node homing receptor (Selectin-1, LECAM-1, Leu 8) on both T and B cells results in modification of cell function. To investigate this phenomenon, we performed studies to determine if the Leu 8 molecule influences T cell activation via the TCR/CD3 complex. In initial studies, we treated T cells with immobilized anti-CD3 (OKT3 mAb) in the presence or absence of immobilized Leu 8 mAb. We found that although Leu 8 mAb alone had no effect on T cell proliferation, this antibody markedly augmented immobilized OKT3 mAb-induced proliferation. In further studies, we immunoprecipitated surface radioiodinated T cell lysates with OKT3 and Leu 8 mAb to determine if molecules in the TCR/CD3 complex associate with Leu 8 molecules. Although Leu 8 mAb immunoprecipitated only a single protein of approximately 80 kDa from T cell lysates treated with Nonidet P-40 under reducing condition, it coimmunoprecipitated additional proteins of 48, 42, 28, 24, and 22 kDa from T cell lysates treated with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate. These additional proteins were identified as the alpha-, beta-, gamma-, delta-, and epsilon-chains of the TCR/CD3 complex by one-dimensional and two-dimensional diagonal SDS-PAGE. Densitometric scanning showed that, on average, 18% of the TCR/CD3 complex associates with Leu 8. In a final study, we showed by immunoblotting analysis using anti-zeta peptide antibody that Leu 8 mAb coimmunoprecipitates the zeta-chain of CD3. These results indicate that the human lymph node homing receptor homologue (Leu 8) participates in the activation of T cells, probably via its association with the TCR/CD3 complex.

We, RSi (Robot Service Initiative) organization, have been developing a common network based robot service platform, named RSNP (Robot Service Network Protocol) since 2004. As spreading actual use of RSNP, strong requirements are raised on the push communication in limited conditions such as fewer operators and/or limited resources, and on the robot service integration with various devices supported by the other robot platform, such as RTM (Robot Technology Middleware), particularly. In this paper, we clarified these requirements and solved them by pseudo PUSH communication method, by introducing multimedia/sensor profile and by building RSi/RTM gateway. Moreover, we evaluate the effectiveness of the proposed scheme through the performance experiments. And also these results have been also reflected in RSNP 2.0, the latest specification.

SUMMARY The autologous mixed lymphocyte reaction (AMLR) represents the activation, proliferation and differentiation of T cells in response to signals from autologous non-T cells. Using monoclonal anti-Leu8 antibody to isolate subpopulations of human CD4+ and CD8+ T cells, we have investigated the role of these subpopulations in the T cell activation cascade during the course of AMLR. In normal subjects, CD4+ Leu8+ cells are necessary for the initiation of the AMLR response, and sequentially lead to activation and proliferation of both CD4+ Leu8- cells and CD8+ Lcu8+ cells. The activated CD8+Lcu8+ cells, in turn, induce CD8+ Leu8- cells to generate proliferation of the latter cells. Soluble mediators could be involved in the T cell activation cascade induced by the AMLR. Patients with active rheumatoid arthritis have a profound defect in the AMLR. Further analysis indicates that rheumatoid arthritis CD8+ T cells are markedly defective as responding cells in the AMLR. The impaired AMLR response by CD8+ cells cannot be reconstituted with AMLR-derived supernatants from normal T cells. The data suggest that the defective CD8+ T cell function may contribute to the pathogenesis of the disease.

Previous studies have shown that a subpopulation of circulating human B cells expresses the Leu 8 peripheral lymph node homing receptor homologue and that these B cells are capable of producing Ig in response to staphylococcus A Cowan I (SAC). In the present study the effect of a signal delivered via the Leu 8 molecule (using anti-Leu 8 mAb) on B cells was examined. Initially, it was shown that immobilized anti-Leu 8 suppressed IgM and IgG secretion of B cells activated by SAC + IL-2 but not that by PWM-prestimulated B cells or B cells stimulated with PWM in the presence of CD4+, Leu 8- T cells (a source of helper cells). It was also shown that anti-Leu 8 did not suppress SAC + IL-2-stimulated B cell proliferation or expression of IL-2R alpha-chain or c-myc mRNA in B cells. The addition of T cells, monocytes, purified IL-2, rIL-1, rIL-6, or human B cell growth factor did not overcome the inhibitory effect of anti-Leu 8 on SAC-stimulated B cell Ig production, and the inhibitory effect of anti-Leu 8 was not blocked by anti-TGF-beta. Finally, inhibition of B cell differentiation occurred even when anti-Leu 8 was added up to 72 hrs after initiation of cell culture. Thus, anti-Leu 8 is unique among inhibitors of B cell function in that it can down-regulate immunoglobulin synthesis without affecting B cell proliferation. These findings suggest that a natural ligand for Leu 8 could affect not only homing of B cells, but also B cell differentiation.

Eighty-seven male Japanese subjects taking prednisoloneor = 5 mg for more than 6 months and 132 age- and body mass index (BMI)-matched control subjects were examined. Multiple regression analysis adjusted for age and BMI showed that spinal bone mineral density (BMD) in the prednisolone group was not associated with prevalent vertebral fractures (VFs).Glucocorticoid (GC) treatment is known to increase the risk for bone fractures. However, the association between VFs and BMD in GC-treated male patients remains unclear.Eighty-seven male subjects taking prednisoloneor = 5 mg for more than 6 months and 132 age- and BMI-matched control subjects were examined using lateral thoracic and lumbar spine radiographs and spine dual energy X-ray absorptiometry.The presence of GC use was an independent risk factor for VFs adjusted for age and BMI (odds ratio 10.93, P0.001). By receiver operating characteristic analysis, the absolute BMD values for detecting VFs were higher and the sensitivity and specificity were lower in the GC group than in the control group (0.936 vs 0.825 g/cm(2) and 53.5% vs 74.0%, respectively). Multiple regression analysis adjusted for age and BMI showed that spinal BMD in the GC group was not associated with prevalent VFs, even after adding current and past maximum GC doses as independent variables.These results show that lumbar BMD values are not associated with prevalent VFs in GC-treated male patients, suggesting that bone fragility in male GC users is affected by bone quality rather than by BMD.

We propose a learning mechanism to learn how to select hypotheses from a set of abducibles (possible hypotheses) on abductive reasoning. Abductive reasoning is to infer an explanation of why observations could have occurred. In abduction this explanation is called a hypothesis which is selected from a set of the given possible hypotheses. This selection follows the plausible heuristics (ME-minimal explanation) criterion, LPE (least presumptive explanation) criterion, or basic criterion). Abduction is characterized by these semantic selection principles which is different from the MDL on induction. This learning mechanism is to learn preferentially propositions or rules that are selected by the heuristics. We try to integrate abductive learning and inductive learning by the number of examples for learning.

A printed circuit board (PCB) consisting of conductor (Cu) and glass epoxy material laminated on metal aluminum plate has been used commonly for high power on-board power supplies. Reducing unit size has been required, particularly for the application to communication equipment. To miniaturize the improvement of efficiency and increasing the frequency have been important subjects, but in addition to these, such technology as bringing the unit to high density is becoming very important. In this case, a multilayer with good thermal conductivity has been required for the high power on-board power supply, however, a PCB having glass epoxy (insulation) has a problem due to insufficient thermal conductivity in the case of the multilayer system. Therefore, we developed a high power on-board power supply using a Cu-alumina PCB with good thermal conductivity in addition to the employment of thermal vias.

Hemophagocytosis is a histiocytic proliferative condition associated with underlying disorders such as infection, lymphoma and autoimmune disease. We describe here a patient with systemic sclerosis who developed MPO-ANCA positive necrotizing vasculitis and hemophagocytosis concomitantly. Vasculitis supervened on a prior systemic sclerosis, and no causative disorder of hemophagocytosis could be found other than active vasculitis, suggesting that an occurrence of hemophagocytosis is associated with underlying vasculitis. Immunosuppressive therapy resulted in excellent improvement of both the hemophagocytosis and vasculitis. On the other hand, this case shows the elevated serum levels of IL-1beta, IL-6 and M-CSF which may be involved in the pathogenesis of hemophagocytosis. To our knowledge, this is the first demonstration indicating the possibility of vasculitis-associated hemophagocytosis.

Mutations in the p53 gene were detected in 27 of the 107 (25%) cases of non-Hodgkin's lymphoma (NHL), examined by assaying the transcriptional activity of p53 in yeast. A relatively high mutation rate of p53 was observed in B-cell intermediate-grade NHL and in T-cell high-grade immunoblastic NHL, in contrast to the relatively low mutation rate observed in other pathological classifications. However, retrospective analyses of all 76 cases revealed that the survival profile and therapeutic responses were very similar in NHL patients bearing lymphomas with a mutant p53 or with the wild-type p53 even within the subclasses characterized by frequent p53 mutation. In patients with high-intermediate grade tumors, the median survival period was 24 months in mutated p53 cases and 14 months in wild-type cases. Complete remission (CR) was observed in 9 of the 17 patients (53%) with mutated forms of p53 and 18 of the 35 patients (51%) with wild-type p53 genes. Our analyses of NHL patients revealed that the presence of p53 mutations may influence pathological grades of NHL, but did not strongly correlate with poor prognosis or reduced chemo/radiosensitivity in NHL. Hence, mutations of p53 do not serve as a prognostic, or chemo/radiosensitivity marker in NHL.

OBJECTIVE: Troglitazone was recently reported to specifically promote the differentiation of pre-adipocytes into adipocytes in vitro in subcutaneous fat only, indicating a relation to insulin-resistance-improving action of troglitazone. To expand on this finding, we investigated at the clinical level how long-term administration of troglitazone influences the body fat distribution in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Troglitazone (400 mg/day) was administered for 6 months to 30 type 2 diabetic patients whose glycemic control was poor. A total of 18 patients received diet therapy alone (in the single-treatment group, BMI 26.0 +/- 4.6, HbA1c 8.2 +/- 1.7%), and 12 patients concomitantly received glibenclamide (1.25-7.5 mg/day) (in the concomitant sulfonylurea group, BMI 25.4 +/- 4.7, HbA1c 9.2 +/- 1.2%). BMI, HbA1c, serum lipid level, and body fat distribution, which were determined by computed tomography (CT) scan at the umbilical level, were measured and compared before and after troglitazone treatment. RESULTS: During the 6-month troglitazone treatment, HbA1c levels decreased and BMI increased in both groups. As for body fat distribution in the single-treatment group, visceral fat area (VFA) decreased (from 118.3 +/- 54.3 to 101.1 +/- 50.8 cm2; P < 0.001), and subcutaneous fat area (SFA) increased (from 189.7 +/- 93.3 to 221.6 +/- 101.6 cm2; P < 0.001), resulting in a decrease in visceral/subcutaneous (V/S) ratio (from 0.74 +/- 0.48 to 0.50 +/- 0.32; P < 0.001). In the concomitant sulfonylurea group, VFA was unchanged (from 108.1 +/- 53.5 to 112.5 +/- 59.9 cm2), while SFA increased (from 144.6 +/- 122.0 to 180.5 +/- 143.5 cm2; P < 0.01), thereby decreasing the V/S ratio (from 0.91 +/- 0.46 to 0.77 +/- 0.44; P < 0.01). The serum triglyceride level and the area under glucose curve during the 75-g oral glucose tolerance test decreased significantly in the single-treatment group. CONCLUSIONS: According to our data, troglitazone appears to promote fat accumulation in the subcutaneous adipose tissue rather than in the visceral adipose tissue in mildly obese Japanese people with type 2 diabetes. This shift of energy accumulation from the visceral to subcutaneous adipose tissue may greatly contribute to the troglitazone-mediated amelioration of insulin resistance.

Adhesion molecules play important roles and involve in many aspects of cell-cell or cell-extracellular matrix interactions in collagen diseases. In the present article, we describe the role of adhesion molecules in the pathogenesis of collagen diseases. Adhesion molecules on endothelial cells participate in leukocyte recruitment in collagen diseases. Adhesion molecules on RA synoviocytes which interact with MNCs and destroy chondrocytes by pannus formation. In PSS, adhesion molecules on fibroblasts play important roles to form fibrosis by interacting with MNCs or collagen fibrils. We further mention on adhesion molecules in interaction between MNCs and muscle fibers in myositis, those in vasculitis in SLE and other diseases, and autoantibodies inducing adhesion molecules on endothelial cells in PSS and Wegener's granulomatosis.

We report a patient with myasthenia gravis (MG) accompanied by invasive thymoma which we treated with cyclosporin. The patient was a 42-year-old woman who was admitted to our hospital because of diplopia and left blepharoptosis. Thymectomy was undertaken but it was incomplete because the thymoma had already invaded other tissues. Following thymectomy, the antibody level for acetylcholine receptors (AChR) gradually increased and generalized weakness and dyspnea emerged. The symptoms did not improve with ADOC chemotherapy and steroid pulse. Treatment with cyclosporin (200 mg/day) was initiated after plasmapheresis and the symptoms improved and AChR antibody levels subsided. There has not been a recurrence of the thymoma after 28 months. In conclusion, treatment with cyclosporin may be more effective than other treatments in patients with inveterate MG that is accompanied by thymoma.

To clarify the local immune responses in inflammatory myopathies, we examine recent studies on expression of adhesion and costimulatory molecules. Adhesion molecules participate in MNC influx from blood vessels into muscle tissues and interactions of inflamed muscle cells with surrounded MNC. These antigens may work as costimulatory molecules in antigen presenting process by muscle cells, as well as in augmentation of inflammation by infiltrating MNCs.

The GI absorption of recombinant human insulin-like growth factor-I (rhIGF-I) and its improvement were investigated in rats. The 125I-rhIGF-I rapidly degraded to the trichloroacetic acid-soluble form in the small-intestinal contents, but it was relatively stable in the gastric and large-intestinal contents and in the subcellular fraction of the small-intestinal mucosa. To protect rhIGF-I from degradation in the small-intestinal contents, the effect of some adjuvants was examined and their degradation was markedly inhibited by the presence of aprotinin or casein. After p.o. administration of 125I-rhIGF-I at the dose of 1.0 mg/kg, trichloroacetic acid-precipitable radioactivity in the plasma was periodically determined. We found that a considerable amount of rhIGF-I was absorbed into the systemic circulation and that the bioavailability was 9.3%, which is much greater than that of insulin. The coadministration of aprotinin and that of casein enhanced the bioavailability further: 46.9% and 67.0%, respectively. Radioimmunoassay using a monoclonal antibody for rhIGF-I confirmed the high bioavailability of immunoreactive rhIGF-I. From gel chromatography of plasma, the radioactivity in the plasma was found to be in the form of high-molecular-weight complexes. The mechanism for the uptake of rhIGF-I by intestinal mucosa may be absorptive-mediated endocytosis.

Reactive hemophagocytosis is characterized by the activation of histiocytes with prominent hemophagocytosis in the reticuloendothelial system, and usually occurs in association with underlying disorders such as viral or bacterial infection and malignancy. We describe 3 cases of adult onset Still's disease (AOSD) who developed hemophagocytosis in bone marrow. Extensive studies could not identify any viral infection or other known underlying disorders for reactive hemophagocytosis except for active AOSD. Although the causative mechanisms of reactive hemophagocytosis in AOSD are not clear, our cases suggest the possibility of AOSD associated hemophagocytosis.

Feed restriction was attempted for the control of mortality at broiler farms. Respiratory signs were observed in both restricted-feed flocks and fully fed flocks, but they were less severe in the restricted-feed flocks. The death rate in the fully fed flocks began to rise at the age of 4 wk but did not do so in the restricted-feed flocks. Mortality in the restricted-feed flocks was significantly lower than in the fully fed flocks aged from 3 to 7 wk. The economic performance with restriction feeding was better than that with full feeding as a result of improvements in viability and feed conversion rates. Feed restriction appeared to be beneficial in decreasing the death losses.

We studied the clinical significance of the extent of p53 protein expression by immunohistochemical analysis and p53 mutations by functional analysis of p53 in 42 patients with high and intermediate grade of Non-Hodgkin's Lymphoma (NHL). Neither p53 expression nor mutation correlated with short survival or resistance to chemoradiotherapy, implying that p53 mutation is not a prognostic factor in NHL.

Common commercial strain male broilers were intratracheally inoculated with 0.3 ml of fluid containing 10(3.7) embryo infective doses of infectious bronchitis virus (IBV) at 14 days of age and 7.5 x 10(6) colony-forming units of Escherichia coli at 18 days of age. Ascites was detected in 15 out of 100 infected birds, which was significantly higher than in a control group of 100 mock-infected birds (P0.01). Some parabronchi were blocked by copious exudate containing heterophils and fibrin in the infected birds at 22 days of age although these findings were not seen in the infected birds at 35 days of age or in birds with ascites. The erythrocyte packed cell volume and right ventricle/total ventricle (RV/TV) ratio of birds with ascites were higher than in birds without ascites. The RV/TV weight ratio for the infected group at the age of 35 days was higher than that of the control group. No IBV or E. coli were recovered from the ascitic birds. These findings suggest that these infectious agents induce ascites in the broilers, and then disappear until the birds suffer from ascites.

A 7-month-old girl weighing 5.3 kg, presented with atrial septal defect (ASD) and paroximal supraventricular tachycardia (PSVT). The preoperative electrophysiological study could not be performed because of the severe heart failure. On suspicion of a concealed Wolff-Parkinson-White (WPW) syndrome, whose accessory pathways conduct in the retrograde direction only, the operation was performed. The intraoperative epicardial and endocardial mappings revealed the presence of a left-posterior retrograde accessory pathway. This accessory pathway was successfully ablated by a cryoablation using transseptal superior approach. The postoperative course was uneventful without a permanent heart block. We report a successful surgical repair for an infant with concealed WPW syndrome, who revealed severe heart failure because of PSVT and ASD.

To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 +/- 1.5 to 4.4 +/- 1.6 J (3.1 +/- 1.2 micrograms/ml)]. Mexiletine tended to increase DFT [from 4.6 +/- 1.2 to 6.1 +/- 2.0 J (1.8 +/- 0.6 micrograms/ml); p0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 +/- 3%). Flecainide increased DFT from 4.2 +/- 1.3 to 6.1 +/- 1.5 J at a plasma level of 1.04 +/- 0.37 micrograms/ml (p0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 +/- 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.

Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.

Cell surface MHC H-2K antigens expressed on various types of B16 melanoma cells of C57BL/6 mouse origin were stained by the avidin-biotinylated enzyme complex (ABC) technique. The low metastatic B16F1 cell line, which demonstrates high levels of H-2K antigen, stained strongly, while the high metastatic B16F10 cell line with no H-2K antigen was not stained. Metastatic colonies which developed in lungs after intravenous (i.v.) injection proved to be negative in both cases. Therefore, in consideration of decreased expression of H-2K antigen in the metastatic process both in vivo and in vitro, antisense oligonucleotides against the class I H-2K gene were transfected into B16F1 cells with H-2K antigens. Subsequent immunohistochemical assessment revealed lack of H-2K antigen expression in the cells, but nevertheless they still could not metastasize to lungs when i.v. injected. This may suggest that any link between the two is not directly causal.

We have previously shown that when patients with active rheumatoid arthritis (RA) were examined for the ability of their lymphocytes to respond in the autologous mixed lymphocyte reaction (AMLR), profoundly reduced AMLR responses were found in the RA patients. The defects were mainly due to the impaired response of CD8+ and CD4+ Law8- subsets; however, both CD4+Leu8+ and CD4+ + Leu8- cells functioned normally as responding cells. The present study demonstrated that the abnormalities of RA CD8+ T cells in the AMLR were corrected when the AMLR cultures were set up in the presence of methyl-B12. In addition, a main target of the methyl-B12 effect observed was both CD8+Leu8+ and CD8+Leu8- cells. Thus, methyl-B12 may become a potential agent that would be able to control the pathophysiology of RA.

Forty-three patients with advanced cancer were evaluated for the changes of absolute counts of peripheral blood lymphocytes and lymphocyte subsets during chemotherapy or chemoimmunotherapy. In 27 patients who did not respond to the therapy, whole lymphocytes, T cells, helper/inducer T cells and NK cells decreased significantly in number. In contrast, they showed little decrease in 16 cases responded to the therapy. In situ immunohistochemical analysis of the tumor infiltrating lymphocytes was performed on the carcinoma tissues obtained from 25 gastric cancer patients. T cell infiltration, in which helper/inducer T cells were predominant over suppressor/cytotoxic T cells, and NK cell infiltration were found in most of the tissues comprised various carcinoma types of histology. Furthermore, an analysis of a gastric cancer patient treated with systemic administration of 3 BRMs and intratumoral injection of OK-432 indicated that infiltration of cytotoxic T cells and NK cells augmented by cytokines such as IFN-gamma produced from activated helper/inducer T cells and NK cells. Therefore, it is suggested that movements of helper/inducer T cells and NK cells relate to the response to chemotherapy and participate in prognosis of advanced cancer patients.

SUMMARY. Feed restriction was attempted for the control of mortality at broiler farms. Respiratory signs were observed in both restricted-feed flocks and fully fed flocks, but they were less severe in the restricted-feed flocks. The death rate in the fully fed flocks began to rise at the age of 4 wk but did not do so in the restricted-feed flocks. Mortality in the restricted-feed flocks was significantly lower than in the fully fed flocks aged from 3 to 7 wk. The economic performance with restriction feeding was better than that with full feeding as a result of improvements in viability and feed conversion rates. Feed restriction appeared to be beneficial in decreasing the death losses.

SUMMARY. Common commercial strain male broilers were intratracheally inoculated with 0.3 ml of fluid containing 103.7 embryo infective doses of infectious bronchitis virus (IBV) at 14 days of age and 7.5 x 106 colony-forming units of Escherichia coli at 18 days of age. Ascites was detected in 15 out of 100 infected birds, which was significantly higher than in a control group of 100 mock-infected birds (P < 0.01). Some parabronchi were blocked by copious exudate containing heterophils and fibrin in the infected birds at 22 days of age although these findings were not seen in the infected birds at 35 days of age or in birds with ascites. The erythrocyte packed cell volume and right ventricle/total ventricle (RV/TV) ratio of birds with ascites were higher than in birds without ascites. The RV/TV weight ratio for the infected group at the age of 35 days was higher than that of the control group. No IBV or E. coli were recovered from the ascitic birds. These findings suggest that these infectious agents induce ascites in the broilers, and then disappear until the birds suffer from ascites.

A review was made of 62 operations in the elderly patients over the age of 65 years from 1972 to 1974. Seventy-seven percent of the patients were female. Twenty-eight operations were done to the femoral neck or trochanteric fractures. Internal fixations were ordinary done to the trochanteric fracture and the primary prosthetic replacements were performed in 11 cases out of 15 of the femoral neck fracture. Preoperative condition revealed hypertension in 18 patients, in whom cardiac disturbance was 5 and 27 patients had some pathologic ECG. Postoperative complication was urinary infection in 11, acute renal insufficiency, paralytic ileus and serum hepatitis in 2, respectively. No postoperative thromboembolism was observed.

From Nov. 1977 to Oct. 1979, meniscus lesions were diagnosed in 61 knees by means of clinical symptoms and signs. In all cases both arthrographic and arthroscopic examinations were performed, and in some cases explorative arthrotomies were done. Meniscectomies were done in 50 knees. Retrospective observation of arthrograms revealed some abnormal findings that had been overlooked before.

From April in 1975 to June in 1979, 74 cases of the femoral neck fracture were treated in the Red Cross Hospital of Fukuoka.The type of the fractures were; 23 medial and 51 lateral fractures.Compression hip screw was used in 7 cases of 23 medial fractures and 21 of 51 lateral fractures. At an average follow-up of some 2 years, the rate of good result was about 80%.

From May, 1979, We examined 28 injured ankle joints by means of stress roentgenograms and arthrograms. Of 28 ankle joints, 6 cases were treated surgically. Indication for surgical treatment is as follows:1. Positive leakage of the contrast medium into the peroneal tendon sheath.2. Marked talar tilt and positive anterior drawer test.3. Painful, unstable ankle joints.In almost all cases, good results were obtained.

Normal immunoregulation depends on a complex set of cellular interactions in which interleukin 2 (IL 2) appears to play an important role. We have examined the IL 2 activity in patients with systemic lupus erythematosus (SLE). IL 2 production by phytohemagglutinin (PHA)-stimulated T cells for 48 hr was measured by the ability of their culture fluid to induce proliferation of normal human T cells that had been activated for more than 20 days by PHA plus IL 2. To measure IL 2 responsiveness, T cells were blasted by preincubation with concanavalin A for 96 hr and stimulated for another 72 hr with lectin-free standard IL 2. SLE T cells failed to produce normal levels of IL 2 in vitro compared with normal control T cells. This failure resided in both OKT4+ and OKT8+ cells. Furthermore, the abnormality was due neither to soluble inhibitory factors produced by SLE T cells nor to active suppressor cells that might be induced by PHA-stimulation. Responsiveness to IL 2 of T cells from some, but not all, SLE patients was decreased significantly from that of normal controls. Absorption studies as well as studies with anti-Tac antibody demonstrated that the impaired responsiveness of T cells in the specific patients with SLE was due to inadequate expression of IL 2 receptors on the T cells upon activation. This defect was exclusively ascribed to the dysfunction of OKT4+, but not OKT8+, cells. The above defects in production of and responsiveness to IL 2 observed in patients with SLE were present at all times regardless of the disease activity or of corticosteroid therapy. Thus, the deficient IL 2 activity may be intrinsic to SLE lymphocytes and may contribute to impaired immunoregulation and to the development of SLE.

The autologous mixed lymphocyte reaction (MLR) is thought to be part of a regulatory role of T cells on B cell function. OKT4+, but not OKT8+, cells can proliferate in response to autologous non-T cells. Moreover, the OKT4+ cell population activated early in the course of autologous MLR functioned as inducer cells for the differentiation of B cells, whereas later in the response, the activated OKT4+ cells were particularly enriched in suppressor cells. A part of the autologous MLR appears to be an important pathway for the activation of feedback suppression mechanisms among cells contained within the OKT4+ populations. Patients with systemic lupus erythematosus (SLE) were studied with regard to the following OKT4+ cell functions in vitro after activation in the autologous MLR: a) proliferative response, and b) helper and suppressor activities for differentiation of B cells. A marked reduction in the proliferative response of OKT4+ cells was observed in SLE patients. SLE OKT4+ cells activated in the autologous MLR could function as helper cells but could not exert any suppressor activity. This OKT4+ cell abnormality was present regardless of the disease activity, and occurred in the absence of autoantibodies including anti-T cell antibodies. Instead, SLE anti-T cell antibodies could preferentially eliminate cells bearing the OKT8+ phenotype characteristic of suppressor cells in populations of normal T cells. These results suggest that the defect in the suppressor circuits among OKT4+ cell populations is intrinsic to SLE lymphocytes and that the OKT8+ suppressor T cell defect is caused by antibodies produced by the B cells of SLE patients.

Displacements of the tibial tubercle were performed to various patello-femoral conditions, that is, painful patella partita, chondromalacia patellae, subluxation or luxation of the patella and patello-femoral osteoarthritis in 12 knees in 12 patients. Age ranged from 15 to 68 years old, with an average 38. Good results were obtained in 10 of 12 knees after more than 6 months. For the lateral patellofemoral osteoarthritis, lateral open wedge bone graft to the tibial tubercle was introduced.

Concanavalin A (Con A)-activated T lymphocytes from patients with active, but not inactive, systemic lupus erythematosus (SLE) failed to express normal suppressor activity, regardless of the phenotype of CD4+ or CD8+. Con A-activated CD4+ or CD8+ T lymphocytes from the SLE patients and from normal controls were further separated into two populations, using the autologous erythrocyte rosette technique. One population very rich in cells capable of forming rosettes with autologous erythrocytes from the active patients showed the same degree of suppressor activity, as did that from normal controls; the CD4+ or CD8+ population poor in autorosetting cells derived from Con A-activated T lymphocytes from both the controls and patients did not express suppressor activity. Moreover, when autorosetting T cells from the active patients and nonrosetting cells from the same patients were mixed at a normal ratio (4:6), normal suppressor activity could be restored. It was notable that the frequency of autorosette-forming cells was markedly reduced in the Con A-activated T lymphocytes from the active, but not inactive, SLE patients, regardless of the phenotype of CD4+ or CD8+. These findings indicate the presence of a normally functioning suppressor T cell population in patients with active SLE. It seems that the lack of suppressor T cell function in patients with active SLE is due to the dilution of a few normal suppressor T cells by large numbers of nonsuppressor T lymphocytes.