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Summary: Background: Blood-based disease staging across the Alzheimer's disease (AD) continuum holds the promise to identify individuals that profit from disease-modifying therapies. We set out to identify Braak V+ (Braak V and/or VI) tau PET-positive individuals within amyloid-β (Aβ)-positive individuals using plasma biomarkers. Methods: In this cross-sectional study, we assessed 289 individuals from the TRIAD cohort and 306 individuals from the WRAP study across the AD continuum. The participants were evaluated by amyloid-PET with [18F]AZD4694 or [11C]PiB and tau-PET with [18F]MK6240 and measured plasma levels included total tau, phospho-tau isoforms (pTau) pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers using different analytic platforms to predict Braak V+ positivity in Aβ+ individuals. Findings: Highest associations with Braak V+ tau positivity in Aβ+ individuals were found for plasma pTau-217+Janssen (AUC [CI95%] = 0.97 [0.94, 1.0]) and ALZpath pTau-217 (AUC [CI95%] = 0.93 [0.86, 1.0]) in TRIAD. Plasma ALZpath pTau-217 separated Braak V+ tau PET-positive individuals in the WRAP longitudinal study (AUC [CI95%] = 0.97 [0.94, 1.0]). Interpretation: Thus, we demonstrate that using adjusted cut-offs, plasma pTau-217 identifies individuals with later Braak stage tau accumulation which will be helpful to stratify patients for treatments and clinical studies. Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR) [MOP-11-51-31; RFN 152985, 159815, 162303], Canadian Consortium of Neurodegeneration and Aging (CCNA; MOP-11-51-31 -team 1), the Alzheimer's Association [NIRG-12-92090, NIRP-12-259245], Brain Canada Foundation (CFI Project 34874; 33397), the Fonds de Recherche du Québec—Santé (FRQS; Chercheur Boursier, 2020-VICO-279314). P.R-N and SG are members of the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging. Colin J. Adair Charitable Foundation.

BCL-2 inhibition has been shown to be effective in acute myeloid leukemia (AML) in combination with hypomethylating agents or low-dose cytarabine. However, resistance and relapse represent major clinical challenges. Therefore, there is an unmet need to overcome resistance to current venetoclax-based strategies. We performed high-throughput drug screening to identify effective combination partners for venetoclax in AML. Overall, 64 antileukemic drugs were screened in 31 primary high-risk AML samples with or without venetoclax. Gilteritinib exhibited the highest synergy with venetoclax in FLT3 wild-type AML. The combination of gilteritinib and venetoclax increased apoptosis, reduced viability, and was active in venetoclax-azacitidine-resistant cell lines and primary patient samples. Proteomics revealed increased FLT3 wild-type signaling in specimens with low in vitro response to the currently used venetoclax-azacitidine combination. Mechanistically, venetoclax with gilteritinib decreased phosphorylation of ERK and GSK3B via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and proteasomal degradation. Gilteritinib and venetoclax were active in an FLT3 wild-type AML patient-derived xenograft model with TP53 mutation and reduced leukemic burden in 4 patients with FLT3 wild-type AML receiving venetoclax-gilteritinib off label after developing refractory disease under venetoclax-azacitidine. In summary, our results suggest that combined inhibition of FLT3/AXL potentiates venetoclax response in FLT3 wild-type AML by inducing MCL-1 degradation. Therefore, the venetoclax-gilteritinib combination merits testing as a potentially active regimen in patients with high-risk FLT3 wild-type AML., (© 2022 by The American Society of Hematology.)

We report the isolation and characterization of a methylene bridged "dimer" of the opioid antagonist Naloxone, previously detected in experimental Buprenorphine-Naloxone oral films. This compound was found to form via an aldol addition followed by a condensation reaction under acidic conditions between two units of Naloxone and one unit of formaldehyde. HPLC-UV-HRMS analysis revealed the formation of three individual stereoisomers during this reaction, which were separately isolated using solid-phase extraction. These isomers were shown to freely react into one another in solvent, forming an equilibrium. The structure of the unknown compound was determined via HRMS spectrometry and 1D and 2D NMR spectroscopy., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: Catheter ablation in adult congenital heart disease (ACHD) patients is a critical treatment strategy for complex arrhythmias including atrial fibrillation (AF) and atrial tachycardia (AT). In addition to vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) are increasingly used in this patient population., Objective: The purpose of this study was to assess the safety of catheter ablation in ACHD patients on uninterrupted oral anticoagulation with VKA or DOAC, examining thromboembolic, bleeding, and vascular access complications., Methods: Retrospective analysis of 234 ACHD patients with simple (n = 83), moderate (n = 66), or complex (n = 85) CHD (mean age 46 years) undergoing 368 ablation procedures on uninterrupted oral anticoagulation with VKA (45.4%) or DOAC (54.6%) was undertaken. Arrhythmias were AF in 97, right AT in 181, left AT in 65, or a combination of AF and AT in 25., Results: No thromboembolic complications occurred. Major complications occurred in 4 patients (1.1%; 1 VKA, 3 DOAC), including retroperitoneal hematoma in 2 and arteriovenous (AV) fistula requiring surgical treatment in 2. Minor bleeding or vascular access complications occurred in 46 cases (12.5%), including hematomas >5 cm in 26, AV fistulas (not requiring surgical intervention) in 13, and pseudoaneurysms in 7 (thrombin injection in 3/7). Overall, no significant difference was found between DOAC (14.9%) and VKA groups (12.0%; P = .411)., Conclusion: Catheter ablation in ACHD patients on uninterrupted oral anticoagulation with VKA or DOAC is feasible and safe. No thromboembolic events occurred, and major bleeding or vascular access complications were rare. No significant differences regarding minor bleeding or vascular access complications between patients on DOAC or VKA were found., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background/aims: Prostate specific antigen (PSA) is regulated by steroid hormones, such as testosterone, the serum levels of which are altered in patients with Alzheimer's disease (AD).This pilot study compared serum levels of the free (f) PSA between AD, mild cognitive impairment (MCI), and control subjects, and evaluated the relationship between fPSA serum levels and cognitive assessment tests and neuroimaging data. In addition, in a subgroup of AD patients, we correlated fPSA serum levels with the existing data on serum levels of amyloid-beta (Aβ), and iron-related proteins, including hepcidin and ferritin., Methods: Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of fPSA using enzyme-linked immunosorbent assay., Results: fPSA serum levels calculated as median ± SD were higher in AD males (663.6 ± 821.0 pg/ml) compared to control males (152.0 ± 207.0 pg/ml), p = 0.003. A similar Pattern emerged when comparing MCI males (310.7 ± 367.0 pg/ml) to control males (P = 0.02). Correlation studies showed a significant association between fPSA and CDR (r = 0.56, P = 0.006) and CDR-SOB (r = 0.54, P = 0.009) in AD males., Conclusion: Additional studies in a larger cohort are required for determining whether fPSA can be used as biomarker of AD disease progression and whether it has the potential to identify male subjects at risk of AD dementia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is standard of care in heart failure (HF), however this technique is associated with a non-responder rate of 30%. Multipole pacing (MPP) with a quadripolar lead may optimize CRT and responder rate by creating two electrical wave fronts in the left ventricular (LV) myocardium simultaneously in order to reduce mechanical dyssynchrony. The objective of this study was to investigate the acute impact of MPP on LV function by assessing systolic dyssynchrony index (SDI) and left ventricular ejection fraction (LVEF) via real-time three-dimensional echocardiography (RT3DE)., Methods: In 41 consecutive patients (87.8% male; mean age 66.0 ± 12.7 years) who received CRT defibrillators with a quadripolar LV lead, RT3DE datasets were acquired the day after implantation under the following pacing configurations: Baseline AAI, conventional biventricular pacing using distal or proximal LV poles and MPP. Datasets were analyzed in paired samples evaluating SDI and LVEF depending on programmed pacing modality., Results: MPP resulted in statistically significant reduction of SDI compared to baseline (6.3%; IQR 4.4-7.8 and 9.9%; IQR 8.0-12.7; p < 0.001) and to conventional biventricular pacing using distal (7.6%; IQR 6.5-9.1; p < 0.001) or proximal (7.4%; IQR 6.2-8.8; p < 0.001) LV poles respectively. MPP yielded significant increase in LVEF compared to baseline (30.6%; IQR 25.8-37.5 and 27.2%; IQR 21.1-33.6; p < 0.001) and to conventional biventricular pacing configuration with distal (28.1%; IQR 22.1-34.5; p < 0.001) or proximal (28.6%; IQR 23.2-34.9; p < 0.001) LV poles respectively., Conclusions: Multipole pacing improves mechanical dyssynchrony of the left ventricular myocardium as assessed by SDI and LVEF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Glatiramer acetate (GA) 40 mg × 3/weekly was approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). While the beneficial effect of GA 20 mg/daily in MS patients on non-conventional MRI measures has been demonstrated, the effect of GA 40 mg × 3/weekly at the microstructural tissue level has yet to be explored., Objective: To investigate the effect of switching from GA 20 mg/daily to GA 40 mg × 3/weekly on the evolution of microstructural changes in the thalamus and normal appearing white matter (NAWM), using diffusion tensor imaging (DTI)., Methods: In this observational, longitudinal, cross-over, 34-month MRI study, we recruited 150 RRMS patients that underwent MRI 12-18 months before switching (pre-index), during the switch (index) and 12-18 months after switching (post-index) from GA 20 mg/daily to GA 40 mg × 3/weekly. Regional DTI metrics and tract-based spatial statistics (TBSS) analyses were performed. Mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA) were measured in thalamus and NAWM., Results: Regional DTI measures, measures of whole brain, white and gray matter, and thalamus volumes, as well as lesion volume, showed no significant changes. However, the voxel-wise TBSS analysis showed increased FA both in the NAWM and thalamus, as well as increased MD and AD in NAWM, and decreased RD in NAWM (p < .05). Areas of increased FA and MD as well as decreased RD in the NAWM, and increased AD both in the NAWM and thalamus were detected between index to post-index (p < .05)., Conclusions: This study confirms a comparable effect of GA 40 mg × 3/weekly to GA 20 mg/daily on DTI measures over 34 months., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Weight loss and low body-mass-index (BMI) are well-known risk factors for mortality among older persons. Both items represent a reduced nutritional state but their nature is different. It is, however, unclear which of these factors is more important for prognosis and if there is interference or interaction between them., Objective: To measure the prevalence of low BMI and weight loss in nursing home residents and to analyze their impact on mortality., Methods: The nutritionDay in nursing homes is an international annual one-day cross sectional survey evaluating malnutrition and 6-months mortality. The data collected from 2007 to 2012 were analyzed. The mortality risk due to a BMI <20 kg/m(2) and weight loss >5 kg was calculated by logistic regression analysis with adjustment for confounding factors., Results: In total, 10,298 residents with a mean age of 85 years (78% female) from 191 nursing homes in 13 countries were included in the analysis. Eighteen percent (17.7%) had a low BMI < 20 kg/m(2), and 11.3% lost > 5 kg of body weight in the previous year. Low BMI <20 kg/m(2) and weight loss >5 kg were both independent and significant risk factors for 6-months mortality (OR 1.7 and 1.5; p < 0.001 in the adjusted model). In comparison to the effect size of low BMI and weight loss alone, the interaction of both factors was substantial (OR = 1.4; p = 0.056). The average 6-months mortality was 13.8%. Subjects with BMI ≥20 kg/m(2) without weight loss >5 kg presented the lowest mortality of 11.2%. In subjects with one of the two features, weight loss >5 kg or low BMI <20 kg/m(2), mortality was significantly increased to 17.4% and 19.8%, respectively. However, if both features were present simultaneously the mortality increased disproportionally to 35.7% (OR 3.5; p < 0.001). In addition, this study presents an overlap and a strong dose-effect relationship of both items with regard to the 6-month mortality., Conclusion: A BMI <20 kg/m(2) and weight loss >5 kg in one year are both independent and equally relevant risk factors for the 6-months mortality of nursing home residents aged 65 years or older. For this reason weight loss should be avoided and residents with a low BMI and weight loss should receive particular attention and nutritional care., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Electrocardiographic (ECG) identification of prior myocardial infarction (MI) during right ventricular (RV) pacing is of clinical importance. Proposed ECG criteria have been evaluated only during apical pacing. We evaluated the effect of pacing site on the predictive performance of ECG signs of prior MI., Methods: The present study is a secondary analysis of a prospective, multicenter study which randomized recipients of an implantable cardioverter defibrillator to an apical versus septal RV lead positioning. ECGs of patients with or without prior MI were analyzed for the presence of the following criteria: Cabrera sign, Chapman sign, QR pattern in leads I, aVL, V5 or V6, QR in inferior leads and notching in the descending slope of the QRS complex in inferior leads., Results: The MI group included 89 patients (55.1% apically paced), while 99 patients had no prior MI (50.5% apically paced). In the total population, the Cabrera sign presented the highest specificity (97%) and diagnostic accuracy (62.2%), with a sensitivity of 23.6%. The Cabrera sign was the only significant predictor of a prior MI [OR=9.9, (95%CI:2.8-34.5), p<0.001], among all ECG markers. Pacing site did not significantly influence the sensitivity and specificity of the Cabrera sign for detection of prior MI., Conclusions: In our study, the Cabrera sign was the only ECG marker that predicted the presence of prior MI during ventricular paced rhythm. Septal RV lead positioning did not affect the predictive performance of the Cabrera sign., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The OPTION (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator Patients Without Pacing Indications) trial sought to compare long-term rates of inappropriate shocks, mortality, and morbidity between dual-chamber and single-chamber settings in implantable cardioverter-defibrillators (ICDs) patients., Background: The use of dual-chamber ICDs potentially allows better discrimination of supraventricular arrhythmias and thereby reduces inappropriate shocks. However, it may lead to detrimental ventricular pacing., Methods: This prospective multicenter, single-blinded trial enrolled 462 patients with de novo primary or secondary prevention indications for ICD placement and with left ventricular ejection fractions ≤40% despite optimal tolerated pharmacotherapy. All patients received atrial leads and dual-chamber defibrillators that were randomized to be programmed either with dual-chamber or single-chamber settings. In the dual-chamber setting arm, the PARAD+ algorithm, which differentiates supraventricular from ventricular arrhythmias, and SafeR mode, to minimize ventricular pacing, were activated. In the single-chamber setting arm, the acceleration, stability, and long cycle search discrimination criteria were activated, and pacing was set to VVI 40 beats/min. Ventricular tachycardia detection was required at rates between 170 and 200 beats/min, and ventricular fibrillation detection was activated above 200 beats/min., Results: During a follow-up period of 27 months, the time to the first inappropriate shock was significantly longer in the dual-chamber setting arm (p = 0.012, log-rank test), and 4.3% of patients in the dual-chamber setting group compared with 10.3% in the single-chamber setting group experienced inappropriate shocks (p = 0.015). Rates of all-cause death or cardiovascular hospitalization were 20% for the dual-chamber setting group and 22.4% for the single-chamber setting group and satisfied the pre-defined margin for equivalence (p < 0.001)., Conclusions: Therapy with dual-chamber settings for ICD discrimination combined with algorithms for minimizing ventricular pacing was associated with reduced risk for inappropriate shock compared with single-chamber settings, without increases in mortality and morbidity. (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator [ICD] Patients Without Pacing Indications [OPTION]; NCT00729703)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Detrimental effects of right ventricular (RV) apical pacing have directed the interest toward alternative pacing sites such as the RV mid-septum. As safety data are scarce for implantable cardioverter defibrillator (ICD) recipients the study aims to evaluate ICD lead performance in the mid-septal position., Methods and Results: A total of 299 ICD recipients (79% male, aged 65.2 ± 12.1 years, 83% primary prevention of sudden cardiac death) were randomized to receive the RV ICD electrode either in a mid-septal (n=145) or apical (n=154) location. Event-free survival was evaluated at 3 (primary endpoint) and 12 months (secondary endpoint). Events included a composite of lead revision, suboptimal right ventricular electrode performance (including defibrillation thresholds (DFT)>25 J) or lead position not in accordance with randomized location. Event-free survival at 3 (12) months was observed in 80.6% (72.3%) of patients randomized to a mid-septal and in 82.2% (72.1%) of patients randomized to an apical lead position, p=0.726 (p=0.969). Pre-defined margins for non-inferiority were not reached at 3 or 12 months. High DFT was found in 7 patients (5.0%) of the mid-septal and in 3 (2.2%) patients of the apical group (p=0.209)., Conclusion: In ICD recipients electrode positioning to the RV mid-septum or the RV apex results in slightly different rates concerning the survival free of lead revision, suboptimal right ventricular electrode performance or non-randomized lead position. Non-inferiority of the mid-septal lead location cannot be concluded. This should be taken into consideration when a mid-septal lead position is pursued., Clinical Trial Registration: ClinicalTrials.gov identifier NCT00745745., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Data on physical activity assessed by cardiac implantable electronic devices (ICD/CRT) have been used for prognostic implications in heart failure patients, but no study has ever compared these data to validated external accelerometers., Methods: 73 ICD/CRT recipients (age 60 ± 20 years, 21% female) received a validated external accelerometer over a period of 7 days. Thereafter, data on physical activity of both ICD/CRT and external accelerometers were retrieved and compared using Spearman's rank correlation coefficient and Bland Altman plots., Results: Mean total daily activity was 276 ± 85 min (range 72-462) as assessed by the external accelerometers and 237 ± 105 min (28-575) as assessed by the ICD/CRT activity sensors (p<0.001). A strong, significant intra-individual correlation (r>0.7) between the two measurements was observed in a majority (70%) of patients (p<0.05 each). However, a Bland Altman plot revealed a broad variation of total daily activity between both methods (95% limits of agreement -225 to 147 min), resulting in differences in the duration of daily activity up to several hours. In multivariate regression analysis, no influence of age, NYHA functional class, left ventricular ejection fraction, underlying disease or type of device on these differences was observed., Conclusions: As compared to a validated external accelerometer, daily physical activity assessed by ICD/CRT devices shows strong intra-individual correlations, but differs substantially regarding the absolute amount of daily activity. Thus, using ICD/CRT activity data for more precise clinical or prognostic information without prior validation is of limited value., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Implantable cardioverter defibrillators (ICD) proved to be effective in the prevention of sudden cardiac death in adults. In children, the experience of ICD therapy is limited. This retrospective study was undertaken to review our experience with ICD implantation in children with special consideration of psychosocial impact of this therapy., Methods and Results: Sixteen children (f:5, m:11, median age 12.2 years, range 4-15.9 years) received an ICD. Eleven patients had survived sudden cardiac death with documented ventricular fibrillation (VF) and five patients had sustained ventricular tachycardia (VT) with hemodynamic significance. The underlying heart disease was congenital in 5, hypertrophic cardiomyopathy in 2, myocarditis in 2 and primary electrical in 7 patients. All leads were implanted transvenously. Mean follow up was 43.1 months (range 1-105 months). All patients are alive. In 7 patients, a total of 387 sustained VT episodes were detected by the ICD. At follow-up, 10 inappropriate shocks were delivered in four patients. One early and six late lead revisions were done in seven patients. 12/16 (75%) patients had concomitant antiarrhythmic drug therapy. About half of the adolescents showed signs of depression and/or anxiety., Conclusion: ICD therapy via transvenous access for prevention of sudden cardiac death is feasible and effective even in small children. However, the occurrence of lead complications is significant. Since about half of the adolescents showed signs of depression and/or anxiety, professional psychological surveillance should be considered in these patients.

Native high molecular weight dextran induces a thymus-independent response in BALB/c mice. When the dextran epitope is linked to a protein carrier the response becomes thymus-dependent. IgG antibodies produced after secondary immunization had epitope specificity and idiotope of myeloma M104E. The antibody of M104E (mu, lambda1) is representative for antibodies produced by mice with immunoglobulin haplotype Igh(a) in response to immunization with dextran B1355S. Myeloma product and physiological antibodies share specificity for the alpha(1-3) glucosidic linkage and have idiotopes in common. Mice with haplotypes other than Igh(a) (e.g. Igh(b)) are unable to yield this type of response. A complete rearranged immunoglobulin mu-chain gene with a VDJ-region from BALB/c (Igh(a)) myeloma protein M104E had been introduced into the genome of BALB/c congenic mice having the haplotype Igh(b). As was shown previously in our laboratory the M104E mu-chain transgene confers Igh(a)-type reactivity to Igh(b) mice. In experiments described in this report we used the thymus-dependent form of the antigen to immunize mice bearing the M104E mu-chain, either alone or together with the lambda1-chain, as a transgene on an Igh(b) genetic background. Serological analysis revealed a class switch to IgG very similar to that seen in BALB/c mice with respect to magnitude, kinetics, epitope and idiotope specificity. The pattern of IgG subclass expression was indistinguishable in mu-chain transgenic Igh(b) and normal BALB/c mice. The class switch occurred even though, as is shown here, the transgene had become incorporated in a site not linked to the Igh locus on chromosome 12. We propose a model for this apparent trans-chromosomal class switch recombination which is based on mechanisms known for conventional switch recombination.

By the use of allotypic markers on immunoglobulin molecules of isotypes IgG1 and IgG2a, in transfers of spleen cells between Igh haplotype congeneic partner strains BALB/c (Igha) and CB20 (=BALB/c-Ighb), the expression of donor and recipient lymphocytes could be followed differentially. BALB/c donor's allotype a was produced in nonirradiated CB20 recipients for months. By contrast, CB20 donor's allotype b disappeared in nonirradiated BALB/c recipients shortly after transfer. These BALB/c recipients of CB20 spleen cells ("CB20-primed") developed lymphocytes which were able to suppress the autochthoneous allotype b production of CB20 irradiated or CB20 nu/nu or neonatal F1 (BALB/c female X CB20 male) recipients immediately after transfer. Titers decreased with a half life of about 4 days, resembling that of immunoglobulin molecules. The suppression was restricted to the IgG2a isotype of allotype b. Neither the other isotype IgG1 of allotype b, nor, in the reciprocal transfer experiment, IgG1 or IgG2a of allotype a was affected. Analogous transfers between Igh congeneic partners on a C57B1/6 genomic background revealed the same susceptibility of allotype b-producing cells from C57B1/6 donors toward suppression by C57B1/6-Igha mice as recipients. Allotype suppression, induced by cell transfer, is thus unidirectional in that Igha haplotype mice react against allotype b but not vice versa, and it is isotype-specific, only directed against IgG2a, and not IgG1.

Donor's memory cell expression is reduced in nonirradiated recipients as compared to irradiated ones. This "barrier" was studied in Igh-congenic BALB/c mice as transfer partners, making use of their allotypic markers, under two aspects: (I) Does the barrier apply to naive B-cells also, not only to memory cells? (II) Does a barrier exist in nude recipient mice also? (I) Naive donor B cells were subject to a barrier in nonirradiated recipients as well as memory cells. (II) Nude recipients showed a barrier toward naive donor cells like euthymic hosts, but toward memory cells this was less stringent. The allotypically marked donor B cells survived and were active in the nonirradiated host. In some situations they even dominated the host's response. The results favor a concept of the barrier as an "intrinsic" interlymphocytic control, exerted by B cells, augmented by T cells, best explained by Jerne's theory of idiotypic interactions.