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Persisting adaptive humoral immunity relies on two key cell types: memory B lymphocytes and long-lived plasma cells. Independently from the specific Ig class they produce, those cells can on one side maintain immunity but on the other side account for dysimmune conditions or hypersensitivity. Stringent control is thus required for both their generation and their survival. Among Ig classes, IgE carries the most powerful pro-inflammatory properties, even at minimal concentration. IgE responses and memory, although protecting against parasites and certain venoms, can inversely mediate devastating effects. The long-term memory of anaphylactic responses against allergens thus stands as the black side of IgE responses, accounting for chronic conditions punctuated with dramatic acute adverse events, some eventually lethal. To manage both their value and their danger, the immune system has evolved with multiple and drastic safeguards around IgE responses, notably ensuring a “B-cell self control” which could now be exploited and reinforced by new specific therapeutic strategies., La persistance de l’immunité humorale adaptative repose particulièrement sur 2 acteurs clés : les lymphocytes B mémoires et les plasmocytes à longue durée de vie. Indépendamment de la classe d’immunoglobuline produite, ces cellules peuvent maintenir tant la protection contre des pathogènes que des manifestations d’hypersensibilité ou d’immunopathologie. Elles requièrent donc une régulation stricte de leur génération comme de leur survie. Parmi toutes les classes d’immunoglobuline produites, l’IgE constitue l’anticorps aux propriétés les plus puissantes, pouvant déclencher des réactions inflammatoires majeures même à doses infimes. Les réponses et la mémoire de classe IgE, au rôle protecteur contre les parasites et certains venins ou toxines, sont conservées par l’évolution chez la quasi-totalité des mammifères. Cependant, les réponses anaphylactiques aux venins peuvent à l’inverse être dramatiques et la mémoire à long terme des sensibilisations et des réactions anaphylactiques contre les allergènes constitue le côté obscur des IgE, responsable de pathologies chroniques ponctuées d’évènements aigus parfois fatals. Face à leur utilité mêlée de dangerosité, l’évolution du système immunitaire a entouré les réponses IgE des cellules B de multiples et stricts garde-fous, un self-control naturel en renfort duquel s’ouvrent aujourd’hui de nouvelles voies thérapeutiques.

Background For cardiac resynchronization therapy (CRT), patients with chronic heart failure (HF) and wide (>150msec) QRS duration (QRSd) received class I/A indication. However, its beneficial effect seemed to be limited for those with mid- (120–150msec) QRSd. Recent studies demonstrated that QRSd normalized to left ventricular end-diastolic volume (QRSd/ LVEDV) improved prediction of clinical outcome in patients with CRT. Therefore, we sought to investigate predictive value of QRSd/LVEDV for responding to CRT in patients with mid-QRSd. Methods This was retrospective multi-center observational cohort study. A total 506 consecutive patients who underwent CRT implantation in Tohoku University Hospital and National Cerebral and Cardiovascular Center were evaluated. Exclusion criteria were QRSd less than 120ms, upgrade procedures from other implanted non-CRT devices and bradycardia requiring pacing. We evaluated clinical variables, data of electrocardiogram and transthoracic echocardiography at baseline and 6 months after CRT implantation. Primary endpoint was a HF hospitalization after CRT implantation. Distribution of free from HF hospitalization during follow-up was calculated using Kaplan-Meier curves, and the effects of covariate on the time to endpoint were investigated using a Cox proportional hazards model. Results After 199 patients were excluded based on exclusion criterion, remaining 307 patients were included for the analysis. Mean age was 62±14 [SD] years, and 238 (77%) were male. Mean LVEF and LVEDV were 25±9% and 234±82ml, respectively, and 24% of patients had ischemic etiology of HF. During the median 948 days of follow-up, CRT patients with mid QRSd (n=126; 136±10msec), as compared with those with wide QRSd (n=181; 174±17msec), tended to have higher incidence of HF hospitalization (Wilcoxon p=0.03). Multivariate analysis showed that QRSd and QRSd/LVEDV were significant predictors for HF hospitalization in CRT patients with mid QRSd, and cut-off values (137msec of QRSd and 0.65 of QRSd/LVEDV), which was calculated by receiver operative curve analysis, was used for risk stratification. QRSd Conclusion The present study demonstrates that QRSd normalized to left ventricular end-diastolic volume (QRSd/ LVEDV) could be clinical value in predicting outcome in CRT patients with mid-QRSd. These findings indicate normalized QRSd reflects myocardial conduction properties and contribute to risk stratification. Funding Acknowledgement Type of funding sources: None.

Summary Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte–macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.

Background Sarcoidosis is a systemic inflammatory syndrome of unknown etiology and cardiac involvement has been reported to be an important prognostic factor in this disease. An autopsy study has reported that the frequency of this cardiac involvement (cardiac sarcoidosis: CS) varies in the different countries and races and very frequent in Japanese patients. We therefore performed the nationwide questionnaire survey and try to clarify the clinical characteristics and corticosteroid effect in CS, especially focused on arrhythmic events in this disease. Methods Total of 757 Japanese patients from 57 hospitals who diagnosed CS were examined. Patients who unsatisfied the criteria of the Japanese new guidelines, or who underwent cardiac transplantations were excluded, and 420 patients (287 females, median follow-up periods 1864 days [interquartile range: 845–3159 days]) were analyzed. The clinical outcome and corticosteroid effect were evaluated. Results Clinical characteristics at diagnosis was as follows: female dominant (68%), mean age of 60±13 years old, mean left ventricular ejection fraction was 49±16%. Arrhythmic events were very frequently observed as an initial cardiac manifestation in 263 patients (62%) of CS, of which atrioventricular block (AVB) in 174 (41%), ventricular tachycardia (VT) in 73 (17%) and AVB with VT in 17 (4%) (Figure 1A). Pacemaker was implanted in 166 patients (40%) and defibrillators was 137 patients (33%). Corticosteroid was prescribed in 144 (83%) of 174 patients with AVB and in 62 (85%) of 73 patients with VT. Initial dose was mean 47.9 mg and maintenance dose of mean 7.3 mg. Corticosteroid improved VT as good as AVB (27% vs. 29%). However, corticosteroid sometimes worsened VT events compared with AVB (10% vs. 2%) (Figure 1B). During the course of follow-up, 32 patients were needed to increase corticosteroid in 23 of AVB and 10 of VT cases. However, there were no difference in mortality between the groups, whether or not to increase corticosteroid. All survival rate was 92% (5-year mortality), 83% (10-year mortality) and free from all cause death and defibrillator charge was 81% (5 year), 71% (10 year). Conclusion Fatal arrhythmia is commonly observed in CS as a primary symptom. Corticosteroid sometimes worsen ventricular arrhythmia and appropriate defibrillator discharge was common. Thus, careful attention for activating ventricular arrhythmia would be needed during the follow-up period even after corticosteroid therapy. Funding Acknowledgement Type of funding source: None

Background “Age” is one of the major concerns and determinants of the indications for catheter ablation (CA) of atrial fibrillation (AF). There are little safety data on CA of AF according to the age. This study aimed to assess the safety of CA in elderly patients undergoing CA of AF. Methods and results We investigated the complication rate of CA of AF for the different age groups ( Conclusions The frequency of complications was significantly higher according to a higher age. We should take note of the indications and procedure for CA of AF in aged patients. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Intramural Research Fund 17 (Kusano) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center

Background Sarcoidosis is a systemic non-caseating granulomatous disease of unknown etiology. Cardiac involvement (cardiac sarcoidosis, CS) has been reported to be an important prognostic factor in this disease because of heart failure and/or ventricular arrhythmia, and corticosteroid therapy is usually prescribed to prevent cardiac events. However, little is known about the relationship of cardiac function and concomitant corticosteroid therapy on later cardiac events in CS. Objective We evaluated the relationship between prognosis and left ventricular ejection fraction (LVEF) at the time of diagnosis in CS patients from the Japanese nationwide questionnaire survey. Methods Total of 757 Japanese patients from 57 hospitals who diagnosed CS were examined. Patients who unsatisfied the criteria of the Japanese new guidelines, or who underwent cardiac transplantations were excluded, and 420 patients (287 females, mean age 60±13 years old, median follow-up periods 1864 days [interquartile range: 845–3159 days]) were analyzed. The relationship of adverse events (all-cause death, cardiovascular death, and appropriate ICD [Implantable Cardioverter Defibrillator] discharge) and LVEF (with corticosteroid 84%) (low LVEF: LVEF≤35% n=98 [with corticosteroid in 78%], moderate LVEF: LVEF 35–50% n=104 [with corticosteroid in 93%], normal LVEF: 50≤LVEF n=218 [with corticosteroid in 83%]) were evaluated respectively. Results 89 CS patients developed all-cause death (n=50), cardiovascular death (n=30) or appropriate ICD discharge (n=48). The frequency of corticosteroid therapy was not different in the each LVEF group, but Kaplan-Meier analysis revealed that all-cause death, cardiovascular death, and all cardiovascular adverse events were more observed in lower LVEF group (log-rank p Conclusion This Japanese nationwide questionnaire survey data showed that initial LVEF was an independent and strong prognostic predictor in CS, therefore primary prevention would be needed even after starting corticosteroid in patients with decreased cardiac function. Funding Acknowledgement Type of funding source: None

Background Catheter ablation of atrial fibrillation (AF) is associated with risks of silent cerebral events. However, the timing of intraprocedural micro-embolic events or differences between open-irrigated radiofrequency (RF) and cryoballoon (Cryo) ablation are unclear. Newly developed real-time carotid artery Doppler is a simple non-invasive method to detect micro-embolic signals (MESs) during ablation. Objective We investigated the timing of detecting MESs during RF and Cryo ablation of AF. Methods During the first pulmonary vein isolation (PVI) session of AF, MESs were monitored by real-time carotid artery Doppler monitoring throughout the procedure. The MES counts were collected and evaluated separately during the different steps of the procedure (Figure). Results Thirty-three AF patients (RF/Cryo: 22/11 cases, 9 females, 69.5±11.6 y.o) were included. PVI was successfully accomplished in all patients with no major complications. The MES count was significantly greater in the RF group than Cryo group (table). In both groups, left atrial (LA) access (interatrial puncture) and sheaths insertion to the LA generated a significant number of MESs (RF: 1690 of 9116 MESs [18.5% of the total MESs], Cryo: 793 of 2285 MESs [34.7%]). In the RF group, MESs were observed incessantly during PVI (Figure). The LA dwell time was significantly longer in the RF group than Cryo group (table). In the RF group, the MES count was significantly greater in the longer LA dwell time group (LA dwell time >130min) than the shorter group (464.2±179.7 vs 302.6±138.2: P=0.049). During the cryo-applications in the Cryo group, the MESs were greatest during the first cryoballoon application (625 of 2285 MESs [27.4%]). Conclusions There were more MESs during RF ablation than cryoablation. MESs were recorded during a variety of steps throughout the procedure. In the RF group, most of MESs were recorded incessantly during radiofrequency ablation and greater number of MESs were recorded in patients with longer LA dwell time. In the Cryo group, most of MESs occurred during phases with a high probability of gaseous emboli. Funding Acknowledgement Type of funding source: None

Background Prior ventricular tachycardia (VT) and low left ventricular ejection fraction (LVEF) are the most important prognostic factors in cardiac sarcoidosis (CS). Recently diagnosis of CS was renewed according to Japanese new guidelines. Patients with preserved cardiac function often have VT events, thus new guidelines recommends to assess the implantable cardioverter defibrillator (ICD) implantation for CS patients with preserved LVEF (35%≤LVEF Objective In CS patients with preserved LVEF, we evaluated the prognosis between VT manifestation and non-VT manifestation groups at CS diagnosis from Japanese nationwide questionnaire survey. Methods Total of 757 Japanese patients from 57 hospitals who diagnosed CS were examined. Patients who unsatisfied the criteria of the Japanese new guidelines, who had LVEF≤35%, LVEF>50%, or who underwent cardiac transplantations were excluded. 104 patients with LVEF 35–50% (67 females, mean age 60±15 years old, median follow-up periods 2134 days [interquartile range: 758–2935 days]) were analyzed. The prognosis between VT manifestation and non-VT manifestation groups at CS diagnosis were evaluated. Results 30 patients had VT manifestation at CS diagnosis and 24 patients (80%) received ICDs. 74 patients had no VT manifestation at CS diagnosis and 19 patients (44%) received ICDs during follow up period. All-cause mortality was not different between two groups (Figure). Appropriate ICD therapy of non-VT manifestation group was significantly lower compared with that of VT manifestation group (log-rank p=0.001), however considerable number (n=7, 15%) of non-VT manifestation group had appropriate ICD therapy event during follow-up period. Cox hazard analysis revealed that concomitant non-sustained VT (NSVT) with atrioventricular block (AVB) was a predictor of appropriate ICD therapy in non-VT manifestation group. Conclusion This nationwide survey showed that considerable number of CS patients with preserved LVEF had VT events, independent of VT manifestation. Concomitant NSVT with AVB was a predictor of VT events, and ICD implantation should be assessed. Funding Acknowledgement Type of funding source: None

Background The prognosis, the underlying substrate and clinical outcomes of treatment are unclear in patients with cardiac sarcoidosis (CS)-related ventricular tachycardia (VT). Objective This study investigated the prognosis and the relationship between electroanatomical mapping (EAM) and imaging findings in patients with CS-related VT. Methods A total of 203 CS patients (Age 68.1±11.6 years, 87 males) were enrolled at two tertiary care medical centers between 2000 and 2018. All met the 2016 Japanese Circulation Society guidelines for diagnosis of CS. They were followed for a composite of major adverse cardiac events (MACE) including cardiac death, heart transplantation, unscheduled hospitalization for heart failure, and life-threatening ventricular arrhythmias. Distribution of late gadolinium enhancement (LGE) on cardiac MRI (CMR) and/or an abnormal myocardial 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography at diagnosis were examined. The relationship between EAM and the image findings were also analyzed in patients with radiofrequency ablation (RFA) for VT. Results During a median follow-up of 53 months, 87 of the 203 patients (43%) experienced a MACE. Baseline factors associated with MACE were presence of sustained VT (HR, 2.43, 95% CI 1.54–3.85, P Conclusions In our 203 CS patients, sustained VT and abnormal FDG uptake were associated with worse cardiac outcomes. The prevalence of abnormal FDG uptake was significantly higher in patients with CS-related VT, LGE on CMR was more frequent within localized areas of an abnormal EGM, suggesting that both scar itself and the associated inflammation were involved in the pathogenesis of CS-related VT. Successful RFA of CS-related VT is still challenging, and recurrence is common. Preprocedural CMR can be useful in detecting abnormal EGMs that are potential targets for substrate ablation. Funding Acknowledgement Type of funding source: None

In mammals, the endocannabinoid anandamide is biosynthesized from N-arachidonoyl-phosphatidylethanolamine by the enzyme N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD). Importantly, NAPE-PLD also produces other bioactive N-acylethanolamines, including anti-inflammatory palmitoylethanolamide and appetite-suppressive oleoylethanolamide, from their corresponding N-acyl-phosphatidylethanolamines (NAPEs). The analyses of NAPE-PLD-deficient mice revealed remarkable accumulation of NAPEs in brain and several peripheral tissues, suggesting the central role in NAPE degradation. On the other hand, the endogenous levels of N-acylethanolamines, including anandamide, were significantly decreased or almost unchanged, probably depending on co-existing NAPE-PLD-independent alternative pathways. The phenotypes of NAPE-PLD-deficient mice suggested the physiological and pathophysiological roles of NAPE-PLD in appetite, energy metabolism, and inflammation. So far, the reported inhibitors are not highly specific for NAPE-PLD, and potent specific inhibitors are under development.

The agricultural and agroindustrial sector are great waste generator, among them the filter cake, derived from the processing of sugarcane biomass. The inappropriate disposal of this residue can cause large impacts to the environment, however using it as an additional source of nutrients for the soil and consequently for the agricultural crops presents itself as a sustainable alternative. Therefore, the purpose of this work was to analyze the influence of the application of the filter cake, associated or not with mineral fertilization, on the chemical characteristics of the soil. The experimental design was a randomized complete block design with 4treatments and 4 repetitions: T1 - filter cake (25 ton.ha-1), T2 - filter cake (25 ton.ha-1) plus mineral fertilization(139 kg.ha-1 of formulation 04 %, 30 % and 10 % of NPK), T3 - mineral fertilization (257 kg.ha-1 of formulation 04 %, 30 % and 10 % of NPK) and T4 - control. After 90 days of treatments application the soil chemical characteristics were evaluated: V% (base saturation), CEC (cation exchange capacity), sum of bases, organic matter, carbon, macronutrients (P, K, Ca, Mg, Ca + Mg) and micronutrients (Cu, Zn, Fe, Mn and Na). Data haS been submitted to analysis of variance and the results have been compared by the Scott-Knott test at 5% level of significance. The chemical characteristics of the soil, the parameters that presented significant difference were CEC, sum of bases and Ca + Mg, with emphasis on treatments T2 and T3 for the first two parameters and T1, T2 and T3 for Ca + Mg. In this way, it was observed that the use of the filter cake in the soil, under the conditions of this experiment, presents itself as a sustainable practice. Since the disposal of this residue in soil did not cause negative changes in the evaluated parameters, as the results showed, it can be used as a source of nutrients, reducing the dependence of producers on mineral fertilizers, and consequently a more sustainable agriculture.

The objectives of this work were: to evaluate the physico-chemical properties in the composting process of the organic residues, filter cake and sugarcane bagasse, as well as to evaluate the time necessary for the organic compound to reach maturity, and to evaluate the performance of the different substrates in the germination of lettuce seeds. The temperature inside the pile, electrical conductivity (EC) and pH were evaluated in composting process. To evaluate the maturation of the compounds the stabilization of the temperature and EC values and the C / N ratio at the end of the process were analyzed. The data were analyzed in DIC (4x3). The treatments were: T0 - 100% FC (filter cake); T1 -100% sugarcane bagasse (SB); T2 - 50% FC and 50% SB; and T3 - 70% FC and 30% SB. For the production of the substrates from the organic compounds, the treatments were: S1 = 100% of the compound T0, S2 = 50% of T0 and 50% of the ashes of the boiler, S3 = 100% of T1, S4 = 50% of T1 and 50% of boiler ash, S5 = 100% of T2, S6 = 50% of T2 and 50% of boiler ash, S7 = 100% of T3, S8 = 50% of T3 and 50% of boiler ash, S9 = Commercial Substrate (Lupa®). The design was DIC (9x30). The percentage of germination of lettuce seeds in each of the substrates was evaluated weekly, until 30 days after sowing. At the end of each stage the data were submitted to analysis of variance and the means were compared by the Scott-Knott test, at the 5% level of significance. It was concluded that the compounds reached maturity at 90 days for treatments T0, T2, T3 and T4 and it is possible to formulate substrates for the making of lettuce seedlings from the residues of the sucroenergy sector evaluated.

The “macaúba” (Acrocomia aculeata) is a Brazilian palm tree that represents a promising alternative for the production of biodiesel. The kernel and the almond of the fruits are rich in oil. Its oil has interesting physicochemical characteristics for the production of biodiesel. It consists mainly of triacylglycerols and small amounts of mono and diacylglycerols, and it has a high content of unsaturated fatty acids, mainly oleic acid. However, it has a high content of free fatty acids which prevents reactions with basic catalysis for biodiesel production. The use of solid catalysts to improve the biodiesel production processes is considered as a promising alternative in this case. In addition, the solid catalysts have the highest reaction rate when compared to acid catalysts. The aim of this study was to obtain ethyl esters of crude oil from A. aculeate withhigh acid value (45.3 mg KOH g-1), using heterogeneous catalyst, with low reaction temperature. Thereactions were done in an under-pressurized Parr 4843 reactor. For the reaction, the factorial design is 2 elevated to 2 and response surface methodology was used. The variables studied were: temperature (T), molar ratio (MR) (ethanol:oil) and catalyst Amberlyst 15 (C, wt%). The response was obtained into yield (%) of ethyl esters and conversion (%) of free fatty acid, which were quantified by gas chromatography (GC). The response surface indicated the reaction at temperature 80-100 °C, molar ratio ethanol:oil 9.0:1 and catalyst 9- 11 wt% presented an yield in 32.8% of fatty acid ethyl esters (FAEE) and 72.0% of conversion, with 48.8 of selectivity index. The Amberlyst 15 catalyst showed little selectivity for yield in terms of FAEE, but a greater conversion of free fatty acids (FFAs) to the respective ethyl esters occurred. The surface response graph indicated that the reaction medium at temperature 60-70 °C, ethanol:oil 8.0:1-9.0:1 and catalyst 2-4% wt provided 83.8% of FFA conversion. This result is expected for oils with high FFA content, since conversion occurs at lower temperatures, while good yields occur at elevated temperatures.

Dyes are used in several industrial sectors; the methylene blue, specifically, is often used in manufacture of paper and other materials such as nylons and polyesters. Given this, many researches related to the treatment of these effluents frequently appear. A process widely used in the treatment of industrial wastewater involving dyes is the adsorption. It presents high efficiency and does not require high initial investments. In order to reduce the costs of the adsorption process, biomasses can be used as adsorbent materials. Cassava is a crop of easy adaptation, being cultivated in all states of Brazil. In this research the ability of cassava bark residue (CBR) to remove methylene blue from aqueous solution was evaluated. Its physical characteristics were studied by scanning electron microscope (SEM) and potential zeta analysis. Methylene blue biosorption studies were performed in batch experiments, isothermally at 25 °C. The contact time was determined by the study of kinetics of the process. It was also performed an acid and alkaline treatment to improve methylene blue removal in aqueous solution. Biosorption of methylene blue using CBR with alkaline modification presented 97.99% removal after 24 h. The use of the CBR was confirmed as a good biosorbent for methylene blue removal, and could be considered as a new alternative for the treatment of wastewater, presenting an application for the destination of residue of manioc bark.

Background Recent studies had proven that the genetic backgrounds of ANCA associated vasculitis (AAV) were dependent on ANCAs. We and other groups had shown the differences between MPO-ANCA positive Granulomatosis with polyangitis (MPO-GPA) and Microscopic polyangitis (MPA) (1–3). It is not clear what determine these two phenotypes. Objectives To elucidate the etiologies of two phenotypes, we compared the backgrounds and comorbidities between MPO-GPA and MPA. Methods Retrospectively we recruited MPO-GPA and MPA patients through the two multi-center cohorts (Cohort A: 2001–2012, Cohort B: 2012–2016). We classified patients with EMEA classification and ANCA. We found 40 MPO-GPA and 126 MPA cases without overlaps. We compared those backgrounds, comorbidities, organ involvements and outcomes. Results The average age of MPO-GPA group was similar to that of MPA (69.1 years old vs 72.1 years old). But MPO-GPA preferentially affected female patients (80.0% vs 52.8%) with lower creatinine levels (1.03mg/dl vs 2.7mg/dl). Two year survivals of MPO-GPA were significantly better than MPA (95.8% vs 73.2%, p=0.0424). Interestingly MPO-GPA patients had less atherosclerotic risk factors, i.e. smoking history (6.3% vs 38.4%), hypertension (10.4% vs 30.5%) and diabetes (12.5% vs 17.9%). Instead these patients had more upper respiratory inflammations (chronic sinusitis, chronic otitis media and allergic rhinitis, 33.3% vs 6.6%) before the disease onset. Conclusions We found that MPA had more atherosclerotic risk factors, and MPO-GPA had more upper respiratory inflammations. These factors may determine MPA or GPA phenotypes in MPO-ANCA positive AAV. References Ono N at al. Characteristics of MPO-ANCA-positive granulomatosis with polyangiitis: a retrospective multi-center study in Japan. Rheumatol Int. 2015 Mar;35(3):555–9. Miloslavsky EM et al. MPO-ANCA-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener9s): Distinct Patient Subsets. Arthritis Rheumatol. 2016 Dec;68(12):2945–2952. Schirmer JH at al. MPO-ANCA-Positive Granulomatosis With Polyangiitis (Wegener9s) Is a Clinically Distinct Subset of ANCA-Associated Vasculitis: A Retrospective Analysis of 315 Patients From a German Vasculitis Referral Center. Arthritis Rheumatol. 2016 Dec;68(12):2953–2963. Acknowledgements We gratefully acknowledge the work of people who helped to correct patients data. Disclosure of Interest None declared

A flow cytometry cross-match (FCXM) test is the gold standard for detection of human leukocyte antigen (HLA) antibodies in renal transplantation because of its high sensitivity. However, this technique can produce false-positive results when non-HLA antibodies or low-titer donor-specific antibodies (DSA) are detected. To determine the clinical relevance of the recently introduced novel cross-match test termed immunocomplex capture fluorescence analysis (ICFA), we retrospectively compared the results of ICFA and FCXM, including a single-antigen bead test for detection of DSA in renal transplant recipients. We found a correlation of 71.4% (235/329) between the results of ICFA-I and FCXM-T, whereas that between ICFA-II and FCXM-B was 41.1% (134/326). Ninety-four patients were ICFA-I negative and FCXM-T positive, and 188 were ICFA-II negative and FCXM-B positive, whereas 46.8% (44/94) and 61.7% (116/188) were found to be DSA-I and DSA-II negative, respectively, which classified them into the non-HLA antibody and low-titer DSA groups, respectively. The mean value of molecules of equivalent soluble fluorochrome for DSA-I was 22,994 in the ICFA-I-positive group, which was significantly higher than 2117 in the negative group (P < .0001), whereas there was no significant difference for DSA-II between the ICFA-II-positive and ICFA-II-negative groups. Graft survival in the ICFA-I-negative group was significantly higher than that in the ICFA-I-positive group (P = .0058). Our results indicate that ICFA-I does not respond to non-HLA antibodies or low-titer DSA, which have influence on graft survival. Therefore, this novel hybrid test, which combines cross-match testing and HLA antibody detection functions, may be useful for clinical pretransplantation evaluation of renal transplantation patients.

A number of reports have shown that the efficacy of mycophenolate mofetil (MMF) is superior to that of azathioprine (AZP) for long-term kidney allograft survival. We conducted a retrospective single-center study to evaluate renal function more than 2 years after conversion from AZP to MMF in kidney transplant recipients several years after transplantation.AZP was converted to MMF in 51 recipients at 17.0 ± 0.8 years after kidney transplantation who were followed up for more than 2 years after conversion. Estimated glomerular filtration rate (eGFR) was determined using the Formula of the Japanese Society of Nephrology.The eGFR was significantly greater at 1 year before conversion (41.72 ± 1.91 mL/min/1.73 m(2)) as compared with the day of conversion (39.04 ± 1.82 mL/min/1.73 m(2); P.05). After conversion, eGFR plateaued to 39.30 ± 2.01 mL/min/1.73 m(2) at 1 year and 38.24 ± 2.42 mL/min/1.73 m(2) at 2 years after conversion. The average eGFR slopes were -2.96 ± 0.36 mL/min/1.73 m(2) per year for AZP and 1.22 ± 0.10 mL/min/1.73 m(2) per year for MMF (P.0001). Cyclosporine (CSA) was reduced from 176 ± 9.3 to 165 ± 9.8 mg/d (P = .0394) after the switch, whereas the CSA trough level was increased from 77.3 ± 6.6 to 118 ± 9.8 ng/mL (P = .0017). Furthermore, the daily dose of tacrolimus (TAC) was decreased from 3.5 ± 0.3 to 3.1 ± 0.3 mg/d (P = .0083).Our findings demonstrated the safety of conversion from AZP to MMF even in the patients who underwent renal transplantation several years prior. In addition, these short-term results indicated the improvement in allograft function following conversion.

Background: In SABCS 2009, we reported that the high level of serum anti-p53 antibody titers was associated with response to preoperative chemotherapy in cases with primary breast cancer (SABCS 2009). Prognostic meaning of pathological complete response (pCR) after preoperative chemotherapy differs among various subtype, and there is a close relationship between pCR and prognosis in cases with HER2 positive or triple negative disease. The aim of this study is to evaluate the association between the high level of serum anti-p53 antibody titers and pCR in patients with HER2-positive or triple negative breast cancer. Patients and Methods: In this study, we analyzed 196 women with operable early stage breast cancer (T1-T3, N0-1) treated with preoperative chemotherapy and definitive curative surgery since 2002 to 2011. All of the patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). The serum anti-p53 antibody titers were assessed by ELISA with the anti-p53 EIA Kit II (MESACUP anti-53 Test: MBL) in the pre-treatment serum samples. The test's cut-off value was determined to be 1.3 IU/ml based on reference distribution in healthy control individuals. The association between serum anti-p53 antibody titers and pCR was analyzed. Results: The subtype of tumors of 196 patients were classified to 86 of ER+/HER2−, 24 of ER+/HER2+, 29 of ER−/HER2+ and 57 of ER−/HER2−. The pCR was achieved 49 of 196 patients (25%). The pCR rate were 7%(6/86), 33%(8/24), 48%(14/29) and 37%(21/57) in the subtype of ER+/HER2−, ER+/HER2+, ER−/HER2+ and ER−/HER2− respectively. The range of serum anti-p53 antibody titers in the serum samples of 196 patients was between 0.40 and 5610 (the median was 0.40 and the average was 85.2). Excluding 86 cases with ER+/HER2−, relationship between serum anti-p53 antibody titers and pCR was evaluated. According to serum anti-p53 antibody titers with the patients of pCR, cut-off value of serum anti-p53 antibody titers was set to be 6 IU/ml. The pCR was observed in nine of 12 cases (75%) with high serum anti-p53 antibody titers, which was significantly higher than those with low titers (35%: 34/98; p = 0.01). Multivariate analysis showed that the only high anti-p53 antibody titer was an independent predictive factor for pCR due to preoperative chemotherapy (p = 0.01). Conclusion: p53 mutation analysis using serum anti-p53 antibody titers might be a useful predictive test for response to preoperative chemotherapy in patients especially with HER2 positive or triple negative breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-26.

Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.

The aim of this study was to investigate N-acetyltransferase 2 (NAT2) genetic polymorphism and enzyme activity in Serbs, and to examine the influence of NAT2 genotype, sex, and smoking on the phenotype. Genotyping for 190C>T, 282C>T, 341T>C, 403C>G, 411T>A, 481C>T, 590G>A, 803A>G, and 857G>A in the NAT2 gene, was performed in 140 healthy Serbs. NAT2 activity was determined as AFMU/ (AFMU + 1X + 1U) urinary ratio in 100 subjects using caffeine as a probe. The most frequent NAT2 haplotypes were NAT2*5B (38.2%), NAT2*6A (26.0%), and NAT2*4 (24.4%). The log-transformed NAT2 activity indices exhibited trimodal distribution with 9%, 36%, and 55% of slow, intermediate, and rapid acetylators, respectively. Significant NAT2 genotype-phenotype correlation was observed (P < .0001). The frequency of NAT1*10 and NAT1*11 were 27.5% and 6.9%, respectively. There was no significant influence of sex or cigarette smoking on NAT2 enzyme activity. Eight subjects displayed rapid NAT2 acetylators phenotype despite being homozygous for NAT2 slow alleles, and NAT1 fast acetylators genotype (NAT1*10 and NAT1*11) had no implication. In contrast to other white populations described hitherto, rapid acetylator is the predominant NAT2 phenotype in Serbs. NAT2 genotype, but not sex and cigarette smoking, influence enzyme activity. NAT1 fast acetylators genotypes do not contribute for NAT2 genotype-phenotype discordance.

Background The role of microchimerism found in the peripheral blood of renal transplant recipients remains a matter of debate. We assessed the frequency of microchimerism after kidney transplantation and examined its influence on clinical courses over a 12-month follow-up period. Patients and Methods Ten single-kidney recipients underwent microchimerism detection at 2 days, 2 weeks, and 1, 3, 6, and 12 months after transplantation, with mismatch human leukocyte antigen (HLA)-A, -B, and -C used as markers. Results Microchimerism was detected in 8 (80%) patients at 2 days after kidney transplantation. In 3 of those, microchimerism became negative within 3 months after transplantation, whereas it remained present for up to 12 months in 3 patients (33 %). There was 1 acute rejection episode in a patient in whom microchimerism became negative within 3 months. Protocol renal graft biopsy specimens obtained 3 months after transplantation revealed no acute cellular-mediated rejection (ACMR) or acute antibody-mediated rejection (AAMR) in the 5 patients positive for microchimerism at 3 months. Conclusions Microchimerism was frequently detected after kidney transplantation. Microchimerism that remained for more than 3 months post-transplantation might be correlated with a lower incidence of rejection, thus its monitoring may help identify recipients with a low rejection risk.

We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1–3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration

The impact of packaging-induced circuit performance changes for a small-scale integrated circuit (IC) smaller than 1.0 mm 2 has been evaluated by a new method with specially designed test chips. Analog circuits such as power management ICs for portable electronic devices are small-scale chips and require high-accuracy operation. Multiple test chips with different resistor locations have been fabricated and measured by die-to-die correspondence, after which one distribution chart was reproduced from all of the measurement results. The present method enables the characteristic distribution on the chip surface to visualize not only the electrical parametric distribution but also the residual stress distribution, even though small-scale ICs have a limited number of bonding pads. In addition, a new method for evaluating the circuit performance change of an analog circuit due to stress-induced parametric changes is presented.

For the purpose of a nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens in patients in Japan, the Japanese Society of Chemotherapy conducted their second year survey, during the period from January to August, 2007. A total of 1178 strains were collected from clinical specimens obtained from adult patients with well-diagnosed respiratory tract infections. Susceptibility testing was evaluable for 1108 strains (226 Staphylococcus aureus, 257 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 206 Haemophilus influenzae, 120 Moraxella catarrhalis, 122 Klebsiella pneumoniae, and 171 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 beta-lactams (four penicillins, three penicillins in combination with beta-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standards Institute (CLSI). The incidence of methicillinresistant Staphylococcus aureus (MRSA) was high, at 59.7%, and the incidences of penicillin-intermediateresistant and -resistant Streptococcus pneumoniae (PISP and PRSP) were 30.4% and 5.1%, respectively. Among Haemophilus influenzae strains, 19.9% of them were found to be beta-lactamase-non-producing ampicillin (ABPC)-intermediately-resistant (BLNAI), 29.1% to be beta-lactamasenon-producing ABPC-resistant (BLNAR), and 6.7% to be beta-lactamase-producing ABPC-resistant (BLPAR) strains. Extended-spectrum beta-lactamase-producing Klebsiella pneumoniae was not isolated. Two isolates (1.2%) of Pseudomonas aeruginosa were found to be metallo-beta-lactamase-producing strains, including one (0.6%) suspected multidrug-resistant strain showing resistance to imipenem, amikacin, and ciprofloxacin. These data will be a useful reference for future periodic surveillance studies and for investigations to control resistant infections as well. Continued surveillance is required to prevent the further spread of these antimicrobial resistances.

言語獲得理論に関する生得論的立場のChomskyによる経験論的立場のSkinner批判(Chomsky、1959)以降、言語獲得が人間特有な心的構造によって達成されるという認識が一般化している(照井・高橋、2006)。しかし、近年、コンピュータサイエンスを含む分野からの反証や認知言語学からの提案など、Chomsky派の言語獲得仮説が見直される流れがあるのも事実である。そこで、本稿では、生得性への反証も加えて考察し、それによって、第二言語習得に有効な資料を得ようと試みるものである。考察は、まず生得性の根拠を確認し、次いで批判的検討を加え、生得性の容認度合を推測する。最終的に、外国語教育に有効な基底的な学習仮説と原理を考察するものである。なお、本稿は、一篇の独立した論考ではなく、別稿にて考察が継続される「日本における有効な英語教育構築に関する論文」の中心的課題となる問題提起を提示する'preliminary study' (予備的考察)という位置付けにある。