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Background Intestinal Behçet's disease (BD) is a relapsing-remitting disease typically associated with punched-out ulcers in the ileocecal region. Optimal monitoring of disease activity is necessary; however, ileocolonoscopy cannot be performed on a regular basis as it is invasive, resource-intensive and causes considerable patient discomfort. Furthermore, there are risks of intestinal bleeding and perforation caused by pretreatment laxatives and air insufflation during the examination. Hence, other follow-up examinations are required. Intestinal ultrasonography (IUS) is a minimally invasive imaging method, but there are no previous reports of comparisons between IUS and endoscopy for intestinal BD. This study aimed to evaluate the usefulness of IUS in assessing the activity of ileocecal ulcers in intestinal BD. Methods This retrospective single-centre study included patients with intestinal BD who underwent colonoscopy and IUS within 2 weeks, from 2007 to 2020. Correlations between the corresponding endoscopic activity using the Sakita–Miwa classification and six IUS variables (bowel wall thickness [BWT], vascularity, bowel wall stratification, intramural and extramural abscesses, fistulas and mesenteric lymphadenopathy) were assessed and used to select the variables that should be included in the new simple score. IUS findings were also compared with biomarker (C-reactive protein [CRP]) concentrations and clinical severity indices (Crohn’s disease activity index and disease activity index for intestinal BD [DAIBD]). Results Seventy-nine IUS examinations from 53 patients were included. Univariate analysis revealed that CRP and DAIBD and the IUS findings BWT, vascularity and bowel wall stratification and intramural and extramural abscesses differed significantly according to endoscopic ulcer activity. Multivariate analysis using a logistic regression model revealed that only BWT and vascularity were statistically different; therefore, a new simple score ([2*BWT] + [5*vascularity]) was constructed. Receiver operating characteristic curve analysis revealed an area under the curve of 0.91 for detecting endoscopic activity, which was superior to those of CRP (0.80; P=0.069), Crohn’s disease activity index (0.69; P=0.002) and DAIBD (0.67; P Conclusion A new simple ultrasound activity index for intestinal BD comprising BWT and vascularity was constructed and correlated well with endoscopic disease activity. This is the first report describing the usefulness of IUS for intestinal BD, and we believe the findings will have many implications in clinical practice.

Nerve growth factor (NGF) and sensory nerves are key factors in established osteoarthritis (OA) knee pain. We investigated the time course of NGF expression and sensory nerve growth across early and late stages of OA progression in rat knees.Knee OA was induced by medial meniscectomy in rats. OA histopathology, NGF expression, and calcitonin gene-related peptide immunoreactive (CGRP-IR) nerves were quantified pre-surgery and post-surgery at weeks 1, 2, 4 and 6. Pain-related behavior was evaluated using dynamic weight distribution and mechanical sensitivity of the hind paw.NGF expression in chondrocytes increased from week 1 and remained elevated until the advanced stage. In synovium, NGF expression increased only in early stages, whereas in osteochondral channels and bone marrow, NGF expression increased in the later stages of OA progression. CGRP-IR nerve density in suprapatellar pouch peaked at week 4 and decreased at week 6, whereas in osteochondral channels and bone marrow, CGRP-IR innervation increased through week 6. Percent ipsilateral weight-bearing decreased throughout the OA time course, whereas reduced paw withdrawal thresholds were observed only in later stages.During progression of knee OA, time-dependent alterations of NGF expression and CGRP-IR sensory innervation are knee tissue specific. NGF expression increased in early stages and decreased in advanced stage in the synovium but continued to increase in osteochondral channels and bone marrow. Increases in CGRP- IR sensory innervation followed increases in NGF expression, implicating that NGF is a key driver of articular nerve growth associated with OA pain.

The porous structure of anodes in SOFCs is the key factor to improve its performance and the manufacturing method to control its design needs to be established. Additive manufacturing, so-called 3D printing technology can be a prospective method for the fabrication of electrodes of SOFCs. In this experiment, stereolithography, which is a form of 3D printing technology using UV-light with approximately 365nm wavelength and photo-curable resin, is applied. The UV-light that goes through pinholes enables the production of multiple cylindrical objects at once. As a result, the objects and the empty spaces between them make the porous structure. Moreover, by changing the size and the number of holes and distance between them, the fabrication of an anode with the desired microstructure can be expected.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Background: Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. Methods: In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636. Findings: Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. Interpretation: Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. Funding: F Hoffmann-La Roche and Genentech. © 2020 Elsevier Ltd

Beach nourishment using coral gravel and sand was proposed and implemented as an environment and user-friendly coastal conservation measure in Tuvalu. Beach monitoring was continued for two years after the construction and the adaptive coastal management with physical measure based on the monitoring data was proposed and practiced by local stakeholders. As a result, it was confirmed that the adaptive coastal management was effective in maintaining a healthy beach condition and directly enforceable by themselves.

In many high-temperature superconducting (HTS) rotating machines of radial flux type, the magnetic field from one side surface of the field pole is employed facing the armature winding. However, both side surfaces of the field pole can be effectively utilised to face the armature windings. Thus, we have applied the double armature structure in which both inner and outer armature rotors sandwiched the field pole stator in the HTS synchronous generator. We introduce the first step design and the electromagnetic study of the double armature synchronous machine for tidal current power generation. The double armatures with copper winding were adopted with a field pole composed of the HTS bulks. The power and the torque density were calculated with a low speed that depends on a 500 kW contra-rotating turbine design. In this paper, we comparatively studied three electromagnetic designs in which (1) a permanent magnet was used for the field pole, (2) the HTS bulk was employed as the field pole and (3) the field pole HTS bulk was arranged at an angle in the x-y plane, reducing torque ripple due to torque consistency and tilting of the HTS bulk plate. A generator model consistent with the input mechanical torque of the turbine was obtained from the analysis of compatibility with the 500 kW class tidal current power generation.

Rotating machine applications with superconductors attract much interest in the industry. For maintaining the operating temperature of high-temperature superconductor (HTS) field poles, a sophisticated cooling system is required. A thermosyphon (TS) is one of the ways for this purpose. The cryo-mechanical system composition is relatively simple, lightweight, and based on natural convection therefore not using any mechanical pump. It can supply the refrigerant from the static condenser part to the rotating evaporator part by using a successful rotary joint. The operating temperature of the TS cooling system depends on the refrigerant. Considering the current HTS materials, the suitable refrigerant is neon, hydrogen. Nitrogen which provides a higher operating temperature than neon and hydrogen is employed for future development. In this work, we focused on and investigated the heat transfer capacity of TS using nitrogen as the refrigerant. The heat transfer performance with rotating was also studied. As a result of the experiment, the TS cooling system could maintain the evaporator temperature by rotating. Moreover, it could transfer the 90 W heat load with rotating.

Radiation is the treatment of choice for canine nasal tumours but, in almost all cases, there is local recurrence associated with poor prognosis. This report describes the effect of endoscopic photodynamic therapy using talaporfin sodium for canine intranasal carcinoma recurring after radiation therapy. Rhinoscopic photodynamic therapy was administered after radiation therapy in three dogs with recurrent intranasal carcinoma. Two to 24 illuminations of a 665-nm diode laser were performed two hours after intravenous bolus injection of 5·0 mg/kg of talaporfin sodium. Photodynamic therapy induced almost complete remission and prolonged survival time in all cases suggesting that it might be a useful treatment for intranasal carcinomas that recur after radiation.

Background Detection of the intracellular levels of polyglutamated MTX (MTX-PGn) can predict response of MTX or possibly its adverse effects. As efficacy and toxicity of MTX differs among individual patients, we had proposed a predictive model for MTX efficacy consisting of 9 SNPs (2015 EULAR). In the present study, we measured erythrocyte MTX-PGn in RA patients with low disease activity for long time receiving a stable dose of MTX, investigated their associations with genetic polymorphisms, and speculated MTX dose required to reach possible effective MTX-PG levels. Objectives To investigate if erythrocytes MTX-PGn concentration is associated with the 9 SNPs in 7 genes reportedly related to MTX-efficacy in RA patients with low disease activity. Methods The study was cross-sectional using 121 adult patients with RA in Shinko Hospital. All patients enrolled had received a stable dose of MTX (mean 8.9±0.3 mg/week), and kept lower disease activity (DAS28-CRP Results Total PGn concentrations were 82.1±31.7 nmol/L (m±SD) and positively correlated with MTX dose (Rs =0.4104, p T was associated with PG1, PG2, and total PG, SLC19A1 c.80G>A with total PG, and SLC28A3_c.267G>A with PG3. Three SNPs (FPGS c. 192T>C, EPHX1_c.357G>A, SLC28A3_c.267G>A) were related to MTX doses. Next, we investigated roles of MTX dose and 9 SNPs in maintenance of MTX-PGn concentrations as by multiple regression analyses. As PG1 levels were related to GGH c.452C>T but not to MTX dose, PG1 levels were 38.2±19.6 and 54.8±21.5 nmol/L in CC and CT genotypes, respectively (P=0.0291). MTX dose was strongly associated with PG3 levels as well as with those of PG4. MTX-PG3 levels were regressed as follows; MTX-PG3 (nmol/L) = -0.035 +[2.04 * MTX dose] + [2.34 * SLC19A1 c.80G>A] + [-2.01 * FPGS c.*192T>C]. When upper and lower limits of them were defined, we can speculate MTX dose to reach the effective levels for individual patients. However, the ranges of effective levels were rather wide, suggesting that effectiveness of MTX may depend on not only concentrations of MTX-PG but also responsiveness to MTX-PG. Conclusions We measured erythrocyte MTX-PGn in RA patients with low disease activity and investigated for their associations with MTX dose and genetic polymorphisms. We could speculate MTX dose required to reach possible effective MTX-PG levels in individual patient. References Den Boer E, et al: Measuring methotrexate polyglutamates in red blood cells: A new LC-MS/MS-based method. Anal Bioanal Chem, 405:1673–1681, 2013. Disclosure of Interest S. Kumagai Consultant for: Sysmex CO, M. Nishida: None declared, Y. Uemura: None declared, M. Izumi: None declared, K. Abe: None declared, K. Yoneda: None declared, Y. Noda: None declared, S. Sendo: None declared, A. Ohishi: None declared, M. Shinohara: None declared, G. Tsuji: None declared

Background The association of diverticula with bowel habits is unclear. We therefore analyzed the association between diverticula and bowel habits in over 1000 Japanese individuals. Methods Japanese subjects who underwent total colonoscopies at seven centers in Japan from June to September 2013 were analyzed. Bowel habits were evaluated using the Gastrointestinal Symptom Rating Scale, and stool form was assessed using a part of the Bristol Scale and Rome ΙΙΙ criteria. Diverticula were diagnosed by colonoscopy with a transparent soft-short hood. Key Results The study evaluated 1066 subjects, 648 males and 418 females (ratio, 1.55 : 1), of mean age 63.9 ± 13.0 years. After adjusting for age and sex, the presence of constipation was associated with a significantly reduced likelihood of diverticula (odds ratio [OR] = 0.70, 95% confidence interval [CI] 0.52–0.93). When assessed according to the location of diverticula, the presence of constipation was associated with a significantly decreased likelihood of left-sided (OR = 0.39, 95% CI 0.16–0.93), but not right-sided (OR = 1.10, 95% CI 0.48–2.53), diverticula. Furthermore, stool form was unrelated with the presence or absence of diverticula. Conclusions & Inferences The wide-spread hypothesis that constipation was associated with colonic diverticula was not supported. Rather, we found that the absence of diverticula was associated with constipation, suggesting the need to reassess the etiology of colonic diverticula.

Summary The Janus kinase inhibitor tofacitinib is currently being investigated as a disease-modifying agent in rheumatoid arthritis (RA). We investigated the in-vivo effects of tofacitinib treatment for 4 weeks on elevated circulating acute-phase serum amyloid (SAA) levels in 14 Japanese patients with RA. SAA levels fell from 110·5 ± 118·5 μg/ml (mean ± standard deviation) at treatment initiation to 15·3 ± 13·3 μg/ml after 4 weeks treatment with tofacitinib. The reduction in SAA levels was greater in patients receiving tofacitinib plus methotrexate compared with those receiving tofacitinib monotherapy. Tofacitinib was also associated with reduced serum interleukin (IL)-6, but had no effect on serum levels of soluble IL-6 receptor. Patients were divided into groups with adequate (normalization) and inadequate SAA responses (without normalization). Serum IL-6 levels were reduced more in the group with adequate SAA response compared with those with inadequate SAA response. These results suggest that tofacitinib down-regulates the proinflammatory cytokine, IL-6, accompanied by reduced serum SAA levels in patients with active RA. The ability to regulate elevated serum IL-6 and SAA levels may explain the anti-inflammatory activity of tofacitinib.

Summary Janus kinase (JAK) inhibitors have been developed as anti-inflammatory agents and have demonstrated clinical efficacy in rheumatoid arthritis (RA). We investigated if JAK-3-selective inhibition alone could disrupt cytokine signalling in rheumatoid synovial fibroblasts. In-vitro studies were performed using synovial fibroblasts isolated from patients with RA. Levels of activated JAK and signal transducer and activator of transcription (STAT) proteins were detected by immunoblot analysis. Target-gene expression levels were measured by reverse transcription–polymerase chain reaction (RT–PCR) or real-time PCR. The JAK inhibitors CP-690,550 and INCB028050 both suppressed activation of JAK-1/-2/-3 and downstream STAT-1/-3/-5, as well as the expression levels of target proinflammatory genes (MCP-I, SAA1/2) in oncostatin-M (OSM)-stimulated rheumatoid synovial fibroblasts. In contrast, the JAK-3-selective inhibitor, PF-956980, suppressed STAT-1/-5 activation but did not affect STAT-3 activation in OSM-stimulated rheumatoid synovial fibroblasts. In addition, PF-956980 significantly suppressed MCP-1 gene expression, but did not block SAA1/2 gene expression in OSM-stimulated rheumatoid synovial fibroblasts. These data suggest that JAK-3-selective inhibition alone is insufficient to control STAT-3-dependent signalling in rheumatoid synovial fibroblasts, and inhibition of JAKs, including JAK-1/-2, is needed to control the proinflammatory cascade in RA.

We report Sb-NMR/NQR measurements on a valence fluctuating compound CeIrSb, which is isostructural to the Kondo semiconductors CeRhSb and CeNiSn. The nuclear spin–lattice relaxation rate divided by temperature, 1 / T 1 T has a maximum around 300 K and considerably decreases in proportion to T 2 when cooling down, followed by a 1 / T 1 T ∼ const . behavior below 20 K. These results indicate that CeIrSb has a V-shaped pseudogap with a residual density of states at the Fermi level. The size of pseudogap for CeIrSb is estimated to be about 350 K, which is one order of magnitude larger than the values of 28 K for CeRhSb and 14 K for CeNiSn. The larger size of energy gap in CeIrSb may be attributed to much stronger c – f hybridization than those for CeRhSb and CeNiSn.

An invessel neutron monitor using micro-fission chambers is one of the most important diagnostics to measure the fusion power in ITER. A single micro-fission chamber with 10 mg of 235 U to be installed in a gap between a shielding blanket module and a vacuum vessel can cover the range of the fusion power from 100 kW to 1 GW. For the low fusion power operation including D–D operation, a micro-fission chamber bundle consisting of 13 micro-fission chamber units has been designed. Nuclear heating of the micro-fission chamber for high power operations and the micro-fission chamber bundle for low power operation were analyzed by neutron transport calculations using the MCNPX code. Heat transport analyzes for the micro-fission chambers were carried out with a general purpose Finite Element Method code ANSYS 8.1, which indicated that the detector temperature might be kept less than the operational temperature limit by the thermal conduction to the vacuum vessel with the heat transfer coefficient of 100 W/m 2 K or larger.

26,27-F6-1,25(OH)2D3 has a higher potency both in vivo and in vitro systems, and longer duration of action in vivo, instead of almost equal binding to 1,25(OH)2D3 receptor and comparatively short serum half-life. To date, the mechanism of higher action is not known, but using these analogues as a mirror we might be able to elucidate the mechanism of action or the metabolism of the kidney hormone, 1,25(OH)2D3.

We fabricated bulk GdBa2Cu3O7-? (Gd123) superconductors with additions of Gd2BaCuO5 (Gd211) and Gd2Ba4CuMoOx (Gd2411). We analyzed the relation between the addition amounts of Gd211/Gd2411 particles and critical current Jc. We found Gd2411/Gd211 particles formed a band structure which resulted in the inhomogeneous distribution of Jc in the Gd123 bulks. Gd2411 particles can stably exist in the vicinity of the seed site compared to Gd211 that is easy pushed out to edge area of single domain. This enhanced the critical current Jc in the vicinity area of bulks.

According to many solar observations, the solar activity, during the Solar Cycle 23, is gradually declining to the quiet phase from the high state in 2000–2004. The Tibet air shower array has been continuing the observation of the shadow that cosmic rays make in the direction of the sun or the moon since 1991. We have shown the influence of the magnetic field around the sun, the interplanetary and the geomagnetic fields for the sun shadow at the multi-TeV region. We discuss the variation of the Sun’s shadow with the Gnevyshev gap (GG) in the maximum phase of the Solar Cycle 23. Unfortunately, the bottom in GG corresponds to off-observation period. Nonetheless, we found the anti-correlation between the significance of the Sun’s shadow and the variation of the magnetic field intensity around GG, although the statistical significance is not so high. It is expected that a detailed analysis of the Sun’s shadow will reveal interesting features of the anti-correlation.

To confirm the origin of the exchange coupling through the nano-oxide layer (NOL), the detailed analyses of the magnetization curve and the temperature dependence on magnetization for the Co 1− x Fe x -NOL samples with various oxidation processes are investigated. The field cooling effect is observed for NOL-inserted samples, which suggests the existence of the antiferromagnetic (AFM) component in the NOL. The characteristic temperature (blocking temperature) increases with increase in the Fe content for Co 1− x Fe x ( x =0.08,0.17,0.26)-NOL. These results support that NOL pinning appears higher than room temperature. Further, the twisted coupling through the NOL observed for the Co 0.50 Fe 0.50 -NOL is discussed from the viewpoint of the magnetic roughness due to the ferrimagnetic nature of the very thin NOL in specular spin valve (SPSV).

Background Although vascular changes and transplant vasculopathy have been described with cytomegalovirus, the impact of Epstein-Barr virus (EBV) on the vascular endothelium of the transplanted allograft is largely unknown. We recently reported that EBV (+) patients taken off immunosuppressive medications for periods of time had a low incidence of chronic rejection. In another report, we noted that there was expression of the "protective" antiapoptotic factor Bcl-2 in the vascular endothelium of transplant allografts from EBV (+) patients. In this report, we determined the effect of latent EBV infection on endothelial cell activation and apoptosis. Methods Cultured human umbilical vein endothelial cells (HUVEC) were either infected with EBV or transduced with EBV latent membrane protein 1 and examined for apoptosis, nuclear factor (NF)-kappaB activation, and expression of chemokines, cytokines, and adhesion molecules. Results EBV infection and latent membrane protein 1 expression in HUVEC resulted in NF-kappaB activation and increased expression of the cytokines interleukin (IL)-1alpha, IL-1beta, and IL-6; the chemokines IL-8, monocyte chemotactic protein-1, and RANTES; and the adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. There was increased expression of the antiapoptotic genes A1, c-IAP2, and TRAF1; inhibition of caspase 3; and protection from apoptosis. Conclusions Latent EBV in HUVEC results in constitutive NF-kappaB activation, protection from apoptosis, and increased basal expression of inflammatory factors. The in vivo effect of latent EBV in the vascular endothelium of the transplanted allograft and its resultant impact on transplant vasculopathy are the subject of further investigations in our laboratory.

For LRE1+x Ba2-x Cu3O7-δ (LRE: Light rare-earth superconductors, e.g., Nd, Sm and Gd), cation off-stoichiometry caused by the substitution of LRE3+/Ba2+ degrades their superconducting properties. Cooling-Rate-Control-Melt-Growth (CRCMG) method is an effective approach to suppress the substitution of RE element on Ba sites. To investigate the relationship between the cooling rate and trapped field performance in GdBa2Cu3O7-δ bulk, we fabricated some full-growth Gd1+x Ba2-x Cu3O7-δ bulks with different second-stage cooling rates (0.1, 0.3, 0.5, 0.8, and 1.0 °C/h) by the CRCMG method, and studied the correlation of the cooling rate and the trapped flux of these bulks. From the results, we found that the maximum trapped flux density and the trapped flux of all bulks have few difference at liquid nitrogen temperature, which indicates that the cooling rate seems to affect insignificantly the trapped flux property of Gd1+x Ba2-x Cu3O7-δ bulks.

Synovial fluid in inflamed joint shows a drop in pH, which activates proton-gated ion channels in nociceptors. No studies have ever tried to develop and characterize acid-induced joint pain.Rats were injected intra-articularly with pH 4.0 acidic saline twice, 5 days apart. Pain-related behaviour tests including weight-bearing asymmetry, paw withdrawal threshold and knee compression threshold were conducted. To clarify the roles of proton-gated ion channels, rats were injected intra-articularly with selective antagonists for ASIC1a, ASIC3 and TRPV1 on day 5 (before the second injection) or on day 14. Underlying peripheral and central pain mechanisms were evaluated using joint histology, interleukin-1β concentrations in the synovium, single-fibre recording of the knee afferent and expression of phosphorylated cyclic adenosine monophosphate-responsive element-binding protein (p-CREB) in the spinal dorsal horn.Repeated injections of acidic saline induced weight-bearing asymmetry, decrease in paw withdrawal threshold and knee compression threshold bilaterally, which lasted until day 28. Early administration of ASIC3 antagonist reduced the bilateral and long-lasting hyperalgesia. Neither articular degeneration nor synovial inflammation was observed. C-fibre of the knee afferent was activated by acidic saline, which was attenuated by pre-injection of ASIC3 antagonist. p-CREB expression was transiently up-regulated bilaterally on day 6, but not on day 14.We developed and characterized a model of acid-induced long-lasting bilateral joint pain. Peripheral ASIC3 and spinal p-CREB played important roles for the development of hyperalgesia. This animal model gives insights into the mechanisms of joint pain, which is helpful in developing better pain treatments.

The abstract of this paper was presented at the 14th Meeting of the International Association of Forensic Sciences, Tokyo in 1996. We report a bizarre criminal case of suspected serial homicide by injection of a muscle relaxant (succinylcholine). Five victims were found buried in a rural area. In two victims showing moderate decomposition (about three months after death), intense pulmonary oedema with pleural effusion was observed. Evidence of a puncture site was found in one of the victims. Succinylcholine could not be detected in the victims, but was identified in a syringe found near the corpses. The 40-mg ampule dose of succinylcholine administered intramuscularly to the victims, possibly causing prolonged apnea, was considered to be at least around the minimum lethal dose, although the combined effect of the sedation with hypnotics also used was not negligible.

In response to demand for clinical use, a simple noninvasive regional heating applicator system for breast hyperthermia has been developed using ferrite cores. Since the breast is positioned between a pair of ferrite cores, it is possible to regionally heat it without considering the dimension of the breast. To find a method of controlling the heating position horizontally and vertically, magnetic-held distributions are analyzed using the three-dimensional finite-element method. Theoretical analyses suggest that a conductive thin plate and a novel eddy current absorber are effective for controlling the maximum heating position. A new applicator system operates at a frequency of 4 MHz and a maximum output power of 600 W. Heating tests using an agar phantom and rabbits show a temperature rise of more than 8/spl deg/C at a depth of 8 cm after heating for 10 min without heating fatty tissue.

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is essential for EBV-mediated transformation of primary B lymphocytes. LMP1 spontaneously aggregates in the plasma membrane and enables two transformation effector sites (TES1 and TES2) within the 200-amino-acid cytoplasmic carboxyl terminus to constitutively engage the tumor necrosis factor receptor (TNFR)-associated factors TRAF1, TRAF2, TRAF3, and TRAF5 and the TNFR-associated death domain proteins TRADD and RIP, thereby activating NF-κB and c-Jun N-terminal kinase (JNK). To investigate the importance of the 60% of the LMP1 carboxyl terminus that lies between the TES1-TRAF and TES2-TRADD and -RIP binding sites, an EBV recombinant was made that contains a specific deletion of LMP1 codons 232 to 351. Surprisingly, the deletion mutant was similar to wild-type (wt) LMP1 EBV recombinants in its efficiency in transforming primary B lymphocytes into lymphoblastoid cell lines (LCLs). Mutant and wt EBV-transformed LCLs were similarly efficient in long-term outgrowth and in regrowth after endpoint dilution. Mutant and wt LMP1 proteins were also similar in their constitutive association with TRAF1, TRAF2, TRAF3, TRADD, and RIP. Mutant and wt EBV-transformed LCLs were similar in steady-state levels of Bcl2, JNK, and activated JNK proteins. The wt phenotype of recombinants with LMP1 codons 232 to 351 deleted further demarcates TES1 and TES2, underscores their central importance in B-lymphocyte growth transformation, and provides a new perspective on LMP1 sequence variation between TES1 and TES2.

Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is essential for EBV-mediated growth transformation of resting primary human B lymphocytes into indefinitely proliferating lymphoblastoid cell lines (LCLs) (30). Genetic and biochemical evidence indicates that the signal transduction pathway through which LMP1 mediates B-lymphocyte growth transformation resembles those of activated tumor necrosis factor receptors (TNFR) (26, 28, 31, 43). LMP1 consists of a 24-amino-acid N-terminal cytoplasmic domain, six transmembrane domains, and a 200-amino-acid C-terminal cytoplasmic tail (Fig. ​(Fig.1).1). Although no specific sequence of the N-terminal cytoplasmic domain is essential for growth transformation, the N terminus fulfills a critical structural role by tethering the first transmembrane domain to the cytoplasm (25, 30). The six transmembrane domains collectively enable LMP1 to self-aggregate in the plasma membrane similarly to a capped receptor. Aggregation of LMP1 in the plasma membrane causes two specific sites within the C-terminal cytoplasmic tail to constitutively mediate essential transforming signals through association with proteins that ordinarily mediate ligand-induced signals from activated TNFR family members (7, 12, 15, 16, 19, 22, 25, 31, 50, 56). These two transformation effector sites (TES1 and TES2) are within C-terminal NF-κB activating regions CTAR1 and CTAR2 (24, 42). FIG. 1 Diagram of LMP1. The Flag epitope was introduced at the amino terminus (NH2). LMP1 residues 187, 231, 352, and 386 are marked. LMP1 constitutively aggregates in the plasma membrane and associates with TRAFs, TRADD, and RIP. TES1 aggregates TRAFs to mediate ... TES1/CTAR1 (residues 187 to 231 [Fig. 1]) interacts with TNFR-associated factors (TRAFs) and is sufficient for mediating initial B-lymphocyte growth transformation (31, 43). TRAF1, TRAF2, and TRAF5 mediate NF-κB activation from TES1/CTAR1 (4, 10, 43, 49). Deletion of the TRAF interaction site results in EBV recombinants that are unable to growth transform primary B lymphocytes (26). The TES1/CTAR1 amino acid sequence is similar to sites in CD40 and CD30 that are critical for NF-κB activation (9, 40). CD40 is the receptor for a T-cell surface ligand that activates B-lymphocyte growth and differentiation (2, 8, 32, 44), and CD30 is the receptor for a T-cell surface ligand that can negatively affect heavy-chain class switching (5, 36). In retrospect, LMP1 mimicry of an activated TNFR is not surprising given the similar effects of LMP1 and CD40 on B-lymphocyte growth and gene activation (2, 8, 9, 23, 29, 32, 44, 47). TES2/CTAR2 is at the LMP1 C terminus and activates NF-κB through the TNFR1-associated death domain protein TRADD (28). The adverse consequences of mutation of the three C-terminal LMP1 codons from YYD to ID on TRADD interaction in the yeast Saccharomyces cerevisiae, on TRADD association in mammalian cells, on NF-κB activation, on TRADD synergy with LMP1 in NF-κB activation, and on B-lymphocyte growth transformation link TRADD to these TES2/CTAR2 effects (28). The tyrosines are not specifically required since substitution with codons encoding phenylalanine is indistinguishable from wild type in TRADD association in lymphocytes, in NF-κB activation, and in B-lymphocyte growth transformation (28). Thus, at this level of genetic analysis, TES2 appears to coincide with CTAR2 (15), and TRADD is a key signal-transducing intermediate. The constitutive association of LMP1 with TRADD in LCLs (28) contrasts with TNFR1, which recruits TRADD in response to ligand binding and receptor aggregation (22, 21). The objective of the experiments reported here was to investigate further the biochemistry of LMP1 TES2/CTAR2 interaction with TRADD and the expected proapoptotic effects. Since receptor-interacting protein (RIP) is implicated in TNFR1 and TRADD-mediated activation of NF-κB and apoptosis (20, 33, 51, 54), we also investigated the role of RIP in TES2/CTAR2-mediated signaling.

With progressive renal disease, structural derangement increasingly encompasses the tubulointerstitial compartment. Tubulointerstitial injury is a critical determinant of renal functional reserve and prognosis in renal disease. Interstitial cells acquiring characteristic of myofibroblasts are an important contributor to interstitial fibrosis. Caldesmon, a calmodulin or actin binding protein, is a molecular marker of differentiation in smooth muscle cells and has recently been shown by us to be a good marker of mesangial cell activation in IgA nephropathy patients. METHODS. We studied whether the expression of caldesmon in interstitium of the kidney was enhanced in the process of glomerular disease and whether it would be a marker of interstitial activation in specific disease states. We performed immunohistochemical staining with anti-caldesmon antibodies in 38 biopsy specimens from IgA nephropathy patients and analysed them quantitatively with a computer-aided manipulator. Interstitial caldesmon expression were compared with histological changes and clinical parameters.Caldesmon expression was enhanced where interstitial cell infiltration and fibrosis were found. Immunoelectron microscopy revealed that caldesmon staining in the renal interstitium was cytoplasmic, and in the processes of myofibroblast-like cells. Caldesmon expression was more prominent in the intense CD68 infiltrated group than in the low positive cells infiltrated group. Patients showing high intensity of interstitial caldesmon expression had significantly higher urinary protein excretion than those showing low intensity of caldesmon expression. Next, 15 patients were treated with glucocorticoid and heparin for 4-8 weeks and re-biopsies were performed. Caldesmon expression was reduced in concomitant with decreased interstitial cell infiltration. Follow-up of these patients (average 24 months) revealed a significant suppression of urinary protein excretion and significant improvement of creatinine clearance.These results suggest that the interstitial caldesmon expression is associated with the progression of IgA nephropathy, and glucocorticoid--heparin therapy may reverse the phenotypic change of interstitial cells during the disease process of glomerulonephritis.

having an FoF. In contrast, cognitive functions did not differ between groups. Conclusion(s): Similar to other studies, we showed that having an FoF is associated with getting older, being a woman, and the experience of falling. However, having an FoF did not appear to influence cognitive function in community-dwelling elderly adults. Implications:Our results suggest that having an FoF does not affect one’s cognitive function. Consequently, FoF may be related to psychological factors unaffected by declines in cognitive functions. However, this study was cross-sectional and cognitive function among participants was good overall. Future longitudinal studies are needed to investigate FoF in a population with poor cognitive functions.

In this study, we investigated the induction of cellular gene expression by the Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1). Previously, LMP1 was shown to induce the expression of ICAM-1, LFA-3, CD40, and EBI3 in EBV-negative Burkitt lymphoma (BL) cells and of the epidermal growth factor receptor (EGF-R) in epithelial cells. We now show that LMP1 expression also increased Fas and tumor necrosis factor receptor-associated factor 1 (TRAF1) in BL cells. LMP1 mediates NF-κB activation via two independent domains located in its C-terminal cytoplasmic tail, a TRAF-interacting site that associates with TRAF1, -2, -3, and -5 through a PXQXT/S core motif and a TRADD-interacting site. In EBV-transformed B cells or transiently transfected BL cells, significant amounts of TRAF1, -2, -3, and -5 are associated with LMP1. In epithelial cells, very little TRAF1 is expressed, and only TRAF2, -3, and -5, are significantly complexed with LMP1. The importance of TRAF binding to the PXQXT/S motif in LMP1-mediated gene induction was studied by using an LMP1 mutant that contains alanine point mutations in this motif and fails to associate with TRAFs. This mutant, LMP1(P204A/Q206A), induced 60% of wild-type LMP1 NF-κB activation and had approximately 60% of wild-type LMP1 effect on Fas, ICAM-1, CD40, and LFA-3 induction. In contrast, LMP1(P204A/Q206A) was substantially more impaired in TRAF1, EBI3, and EGF-R induction. Thus, TRAF binding to the PXQXT/S motif has a nonessential role in up-regulating Fas, ICAM-1, CD40, and LFA-3 expression and a critical role in up-regulating TRAF1, EBI3, and EGF-R expression. Further, D1 LMP1, an LMP1 mutant that does not aggregate failed to induce TRAF1, EBI3, Fas, ICAM-1, CD40, and LFA-3 expression confirming the essential role for aggregation in LMP1 signaling. Overexpression of a dominant form of IκBα blocked LMP1-mediated TRAF1, EBI3, Fas, ICAM-1, CD40, and LFA-3 up-regulation, indicating that NF-κB is an important component of LMP1-mediated gene induction from both the TRAF- and TRADD-interacting sites.

The Epstein–Barr virus latent membrane protein 1 (LMP1) is essential for the transformation of B lymphocytes into lymphoblastoid cell lines. Previous data are consistent with a model that LMP1 is a constitutively activated receptor that transduces signals for transformation through its carboxyl-terminal cytoplasmic tail. One transformation effector site (TES1), located within the membrane proximal 45 residues of the cytoplasmic tail, constitutively engages tumor necrosis factor receptor-associated factors. Signals from TES1 are sufficient to drive initial proliferation of infected resting B lymphocytes, but most lymphoblastoid cells infected with a virus that does not express the 155 residues beyond TES1 fail to grow as long-term cell lines. We now find that mutating two tyrosines to an isoleucine at the carboxyl end of the cytoplasmic tail cripples the ability of EBV to cause lymphoblastoid cell outgrowth, thereby marking a second transformation effector site, TES2. A yeast two-hybrid screen identified TES2 interacting proteins, including the tumor necrosis factor receptor-associated death domain protein (TRADD). TRADD was the only protein that interacted with wild-type TES2 and not with isoleucine-mutated TES2. TRADD associated with wild-type LMP1 but not with isoleucine-mutated LMP1 in mammalian cells, and TRADD constitutively associated with LMP1 in EBV-transformed cells. In transfection assays, TRADD and TES2 synergistically mediated high-level NF-κB activation. These results indicate that LMP1 appropriates TRADD to enable efficient long-term lymphoblastoid cell outgrowth. High-level NF-κB activation also appears to be a critical component of long-term outgrowth.

Critical-current density ( J c ) is a parameter of primary importance for potential applications of high-temperature copper oxide superconductors. It is limited principally by the breakdown of zero-resistive current due to thermally activated flux flow at high temperatures and high magnetic fields. One promising method to overcome this limitation is to introduce efficient pinning centers into crystals that can suppress the flux flow. A marked increase in J c was observed in Bi 2 Sr 2 CaCu 2 O 8+δ (Bi-2212) single crystals doped with a large amount of Pb. By electron microscopy, characteristic microstructures were revealed that probably underlie the observed enhancement in J c : thin (10 to 50 nanometers), platelike domains having a modulation-free structure appeared with spacings of 50 to 100 nanometers along the b axis.

Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) is essential for transforming primary B lymphocytes into lymphoblastoid cell lines. EBV recombinants with LMP1 genes truncated after the proximal 45 codons of the LMP1 carboxyl terminus are adequate for transformation. The proximal 45 residues include a domain that engages the tumor necrosis factor receptor associated factors (TRAFs). We investigated the importance of the TRAF binding domain by assaying the transforming ability of recombinant EBV genomes with a deletion of LMP1 codons 185–211. This mutation eliminates TRAF association in yeast and in lymphoblasts but does not affect LMP1 stability or localization. Specifically mutated recombinant EBV genomes were generated by transfecting P3HR-1 cells with overlapping EBV cosmids. Infection of primary B lymphocytes resulted in cell lines that were coinfected with an LMP1Δ185–211 EBV recombinant and P3HR-1 EBV, which has a wild-type LMP1 gene but is transformation defective due to another deletion. Despite the equimolar mixture of wild-type and mutated LMP1 genes in virus preparations from five coinfected cell lines, only the wild-type LMP1 gene was found in 412 cell lines obtained after transformation of primary B lymphocytes. No transformed cell line had only the LMP1Δ185–211 gene. An EBV recombinant with a Flag-tagged LMP1 gene passaged in parallel segregated from the coinfecting P3HR-1. These data indicate that the LMP1 TRAF binding domain is critical for primary B lymphocyte growth transformation.

The exchange bias properties of the Co/sub 1-x/Fe/sub x/ natural-oxidized nano-oxide layer (NOL) in the specular spin valve system are investigated. The exchange bias energy (J/sub ex/) increased with the Fe content of the CoFe NOL. This result suggests that the enhancement of the pinning field/energy at room temperature was induced by the inserted NOL into the pinned layer. The enhancement of both the magnetoresistance ratio and the exchange bias field was realized by increasing the Fe content in the Co/sub 1-x/Fe/sub x/ NOL.

The subchondral bone of the distal femur is a source of pain caused by osteoarthritis (OA) or spontaneous osteonecrosis of the knee. However, nociceptive phenotype of dorsal root ganglia (DRG) neurons innervating the subchondral bone in rat knee joints has not been clarified.Retrograde labelling was used to identify afferents innervating the subchondral bone of the distal femur and the knee joint in rats. The nociceptive phenotype markers [calcitonin gene-related peptide (CGRP), tyrosine receptor kinase A (TrkA), neurofilament 200 (NF200) and isolectin B4 (IB4)], segmental distribution and the soma size of backlabelled DRG neurons were examined. Furthermore, we evaluated the differences in nociceptive phenotype between the subchondral bone and the knee joint afferents.The majority (60%) of the subchondral bone afferents were localized in L3 DRGs and fewer in L4 and L5, while the knee joint afferents were localized mainly in L3 and L4. The percentage of CGRP immunoreactive (IR), TrkA-IR, NF200-IR and IB4-binding neurons in the subchondral bone afferents were 50%, 65%, 35% and 0%, respectively. The percentage of CGRP-IR and TrkA-IR neurons in the subchondral bone afferents was significantly higher than that in the knee joint afferents, respectively (p 0.05).The majority of sensory DRG neurons innervating the subchondral bone of the distal femur were CGRP-IR and TrkA-IR. It is expected that therapeutic approaches targeting CGRP and TrkA could be effective in attenuating pain from the subchondral bone in knee joints.

The Epstein-Barr virus (EBV) transforming protein LMP1 appears to be a constitutively activated tumor necrosis factor receptor (TNFR) on the basis of an intrinsic ability to aggregate in the plasma membrane and an association of its cytoplasmic carboxyl terminus (CT) with TNFR-associated factors (TRAFs). We now show that in EBV-transformed B lymphocytes most of TRAF1 or TRAF3 and 5% of TRAF2 are associated with LMP1 and that most of LMP1 is associated with TRAF1 or TRAF3. TRAF1, TRAF2, and TRAF3 bind to a single site in the LMP1 CT corresponding to amino acids (aa) 199 to 214, within a domain which is important for B-lymphocyte growth transformation (aa 187 to 231). Further deletional and alanine mutagenesis analyses and comparison with TRAF binding sequences in CD40, in CD30, and in the LMP1 of other lymphycryptoviruses provide the first evidence that PXQXT/S is a core TRAF binding motif. The negative effects of point mutations in the LMP1(1-231) core TRAF binding motif on TRAF binding and NF-kappaB activation genetically link the TRAFs to LMP1(1-231)-mediated NF-kappaB activation. NF-kappaB activation by LMP1(1-231) is likely to be mediated by TRAF1/TRAF2 heteroaggregates since TRAF1 is unique among the TRAFs in coactivating NF-kappaB with LMP1(1-231), a TRAF2 dominant-negative mutant can block LMP1(1-231)-mediated NF-kappaB activation as well as TRAF1 coactivation, and 30% of TRAF2 is associated with TRAF1 in EBV-transformed B cells. TRAF3 is a negative modulator of LMP1(1-231)-mediated NF-kappaB activation. Surprisingly, TRAF1, -2, or -3 does not interact with the terminal LMP1 CT aa 333 to 386 which can independently mediate NF-kappaB activation. The constitutive association of TRAFs with LMP1 through the aa 187 to 231 domain which is important in NF-kappaB activation and primary B-lymphocyte growth transformation implicates TRAF aggregation in LMP1 signaling.

We investigated the magnetic properties of the Co/sub 1-x/Fe/sub x/-natural oxidized nano-oxide layer (NOL) in the specular spin-valve system by precise measurement of magnetization at 77 K and M-T curves after field cooling at /spl plusmn/5 kOe. The result suggests the antiferromagnetic component behavior of the NOL and its Ne/spl acute/el temperature (T/sub N/) shifts to the higher temperature with increasing Fe composition. Below the T/sub N/, the antiparallel spin configuration at the pinned layers is stabilized by the exchange bias field induced from antiferromagnetic component of NOL by the field cooling in negative field direction.

Background Measurement of serum MMP-3 levels has been considered useful to estimate the disease activity of rheumatoid arthritis (RA). We have shown that serum MMP-3 was significantly correlated with DAS28 (CRP) and could be a useful marker in predicting joint destruction1,2. CXCL13 attracts CXCR5-expressing B and helper T cells to the follicle and probably has central roles of ongoing immune activation in RA development3. Serum MMP-3 and CXCL13 have been reported as biomarkers for detecting the disease activity and predicting the therapeutic outcomes of RA4. Objectives The aim of this study is to confirm the clinical significance of serum MMP-3 and CXCL13 measurement in the evaluation of disease activity and prediction of therapeutic outcome in RA patients treated with biologics. Methods Serum MMP-3 was serially measured by MMP-3 Latex kit (Sekisui Medical Co.) for 146 RA patients before and after treatment with biologics. Number of patients treated with each biologic were 39, 28, 19, 17, 26, and 17 patients treated with abatacept, adalimumab (ADA), etanercept, golimumab, infliximab (IFX), and tocilizumab, respectively. CXCL13 was measured by ELISA kit (Quantikine human CXCL13, R&D systems) for patients treated with ADA and IFX before and 24 weeks after treatment. The patients were classified into 61 responders (good) and 85 non-responders (moderate and none) by ACR/EULAR definition of remission criteria weeks after treatment. Results Serum MMP-3 before the treatment was significantly increased in 146 RA patients as compared with 196 healthy subjects (196.0± 197.4 vs 58.6±27.4 ng/ml, p Conclusions Serum MMP-3 and CXCL13 was shown to be useful as disease activity markers, and serial measurement were helpful to evaluate the effect of treatments with biologics. CXCL13 may be useful in evaluating and predicting the therapeutic outcome of some kinds of biologics. References Mamehara A, et al: Kobe J Med Sci. 2010, 56(3): E98–107. Uemura Y, et al: Rinsho Byori. 2015, 63(12): 1357–1364 (Japanese). Meeuwisse CM, et al: Arthritis Rheum. 2011, 63(5): 1265–1273. Greisen SR, et al: Arthritis Res Ther, 2014, 16: 434. Acknowledgement We thank Drs. Hitoshi Uga and Hirokazu Kurata of the Central Laboratories, Sysmex Co, Japan, for helpful discussion. Disclosure of Interest S. Kumagai Consultant for: Sysmex Co, Y. Uemura: None declared, T. Saito: None declared, R. UMEDA: None declared, A. Muta: None declared, M. Izumi: None declared, K. Abe: None declared, S. Sendo: None declared, G. Tsuji: None declared

A dual frequency probe using a multilayer ceramic is proposed for simultaneously obtaining a high resolution B mode and a high sensitivity Doppler mode image. This ceramic consists of two layers in which the poling directions are opposite and the individual thicknesses are different. It is possible to control the values of relative electromechanical coupling factors in the fundamental and the second harmonic by changing the thickness ratio. A thickness ratio of 1:0.7 was decided from computer simulation based on the Mason's model. A sufficient resolution has been shown from the fact that the intima of the carotid artery could be distinguished by an actually fabricated probe with dual frequencies of 3.75 and 7.5 MHz. Also, the sensitivity of this probe in the Doppler mode at 5 cm depth from the surface has been improved as much as 5 dB over that of a conventional one. >

A case of synovial chondromatosis of the temporomandibular joint in a 48-year-old woman is presented. Computed tomography and magnetic resonance imaging contributed to a clear understanding of the extent of the lesion and were helpful in both surgical treatment planning and follow-up.

Recombinant Epstein-Barr viruses (EBVs) were made with mutated latent membrane protein 1 (LMP1) genes that express only the LMP1 amino-terminal cytoplasmic and six transmembrane domains (MS187) or these domains and the first 44 amino acids of the 200-residue LMP1 carboxy-terminal domain (MS231). After infection of primary B lymphocytes with virus stocks having small numbers of recombinant virus and large numbers of P3HR-1 EBV which is transformation defective but wild type (WT) for LMP1, all lymphoblastoid cell lines (LCLs) that had MS187 or MS231 LMP1 also had WT LMP1 provided by the coinfecting P3HR-1 EBV. Lytic virus infection was induced in these coinfected LCLs, and primary B lymphocytes were infected. In over 200 second-generation LCLs, MS187 LMP1 was never present without WT LMP1. Screening of over 600 LCLs infected with virus from MS231 recombinant virus-infected LCLs identified two LCLs which were infected with an MS231 recombinant without WT LMP1. The MS231 recombinant virus could growth transform primary B lymphocytes when cells were grown on fibroblast feeders. Even after 6 months on fibroblast feeder layers, cells transformed by the MS231 recombinant virus died when transferred to medium without fibroblast feeder cells. These data indicate that the LMP1 carboxy terminus is essential for WT growth-transforming activity. The first 44 amino acids of the carboxy-terminal cytoplasmic domain probably include an essential effector of cell growth transformation, while a deletion of the rest of LMP1 can be complemented by growth on fibroblast feeder layers. LMP1 residues 232 to 386 therefore provide a growth factor-like effect for the transformation of B lymphocytes. This effect may be indicative of the broader role of LMP1 in cell growth transformation.