Citations

Abstract Classic hyperacute rejection is dependent on the activation of the terminal components of complement. Recently, xenoantibodies with limited abilities to activate the classical pathway of complement in vitro have been implicated in the acute vascular rejection of xenografts. It is unclear how these Abs affect their pathogenic activities in vivo. In this study, we demonstrate the ability of an anti-Gal-α1,3Gal (Gal) IgG1, with modest complement-activating abilities in vitro, to induce xenograft rejection. This rejection was dependent on the activation of complement, on FcγR-mediated interactions, and on the presence of NK cells. Inhibition of any one of these factors resulted in the abrogation of IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic, hyperacute rejection that was solely dependent on complement activation. Our observations implicate two types of IgG-mediated rejection; one that is dependent on complement activation, and a second that is uniquely dependent on complement, FcγR, and NK cells.

Abstract Cbl-b negatively regulates CD28-dependent T cell activation. In this report, we tested the hypothesis that CD28 and CTLA-4 have opposite roles in tuning T cell activation threshold by controlling the levels of Cbl-b protein expression. We demonstrate that CD28 costimulation potentiates TCR-induced Cbl-b degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. In support of this finding, Cbl-b expression in CTLA-4 knockout (KO) T cells is significantly reduced, and treating CTLA-4KO mice with human CTLA-4Ig to block CD28-B7 interaction restores Cbl-b expression on T cells. Furthermore, CD28 and CTLA-4 costimulatory effects are compromised in Cbl-bKO T cells. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation.

Background The study aims to compare methods of determining headache directionality (imploding, exploding, and/or ocular headaches) in women with migraine, investigate the concordance between physician assignment and patient self‐assignment of pain directionality, and evaluate whether patients assigned their headaches to the same direction when queried using different methods. Directionality of migraine headache pain (imploding, exploding, or ocular) may reflect differences in the underlying pathogenesis of individual migraine attacks among and within individuals. Emerging evidence suggests that directionality of pain in migraine sufferers may predict response to onabotulinumtoxin A . The best method of determining headache directionality in migraine sufferers has not been systematically explored. Methods We conducted a prospective cross‐sectional survey study of 198 female patients with migraine presenting to a W omen's H ealth C linic. Patients determined the directionality (imploding, exploding, and/or ocular) of their own migraine pain by choosing among 3 pictures graphically representing directionality and also by responding to a written question regarding directionality. Clinicians then classified directionality of migraine pain using structured interviews. Concordance between clinician assignment of directionality and patient self‐assignment was determined with K appa coefficients. Results Subjects were females between the ages of 18 and 77 years (mean 48 years). According to patient selection of representative pictures, 62 (31.6%) had imploding headaches with or without ocular pain, 36 (18.4%) had exploding headaches with or without ocular pain, 78 (39.8%) had ocular pain only, and 20 (10.2%) had imploding and exploding headaches with or without ocular pain. Two subjects did not respond. According to patient responses to a written question, 80 (41.0%) had imploding headaches with or without ocular pain, 53 (27.2%) had exploding headaches with or without ocular pain, 46 (23.6%) had ocular pain only, and 16 (8.2%) had imploding and exploding headaches with or without ocular pain. Three subjects did not respond. For physician assignment, 69 (34.9%) subjects had imploding headaches with or without ocular pain, 89 (45%) had exploding headaches with or without ocular pain, 14 (7.1%) had ocular pain only, and 26 (13.1%) had imploding and exploding headaches with or without ocular pain. The concordance ( K appa coefficient) between physician assignment of headache directionality with patient response to the written question was 0.33 (weak agreement), between physician assignment and patient assignment via selection of representative pictures was 0.35 (weak agreement), and between patient assignment via written question and via selection of representative pictures was 0.35 (weak agreement). Conclusions The assignment of headache directionality varied substantially depending upon the method of determination. The concordance between clinician assignment, patient‐self assignment via answering a written question, and patient self‐assignment via choosing a representative picture was weak. Improved methods of determining pain directionality are needed.

Abstract Background: Individuals with a strong family history of colorectal cancer have significant risk for colorectal cancer, although adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored telephone counseling intervention can increase adherence to colonoscopy in members of high-risk families in a randomized, controlled trial. Methods: Eligible participants were recruited from two national cancer registries if they had a first-degree relative with colorectal cancer under age 60 or multiple affected family members, which included families that met the Amsterdam criteria for hereditary non-polyposis colon cancer (HNPCC), and if they were due for colonoscopy within 24 months. Participants were randomized to receive a tailored telephone intervention grounded in behavioral theory or a mailed packet with general information about screening. Colonoscopy status was assessed through follow-up surveys and endoscopy reports. Cox proportional hazards models were used to assess intervention effect. Results: Of the 632 participants (ages 25–80), 60% were female, the majority were White, non-Hispanic, educated, and had health insurance. Colonoscopy adherence increased 11 percentage points in the tailored telephone intervention group, compared with no significant change in the mailed group. The telephone intervention was associated with a 32% increase in screening adherence compared with the mailed intervention (HR, 1.32; P = 0.01). Conclusions: A tailored telephone intervention can effectively increase colonoscopy adherence in high-risk persons. This intervention has the potential for broad dissemination to healthcare organizations or other high-risk populations. Impact: Increasing adherence to colonoscopy among persons with increased colorectal cancer risk could effectively reduce incidence and mortality from this disease. Cancer Epidemiol Biomarkers Prev; 23(4); 601–10. ©2014 AACR.

Background— Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak V O 2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. Methods and Results— RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak V O 2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and V E /V CO 2 was higher. Conclusions— AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

ObjectiveReview Mayo Clinic experience of localized tongue amyloidosis.Study DesignCase series with retrospective chart review.SettingAcademic medical center.Subjects and MethodsCases of localized tongue amyloidosis were identified from the dysproteinemia database at the Mayo Clinic in Rochester, Minnesota. Electronic records were reviewed with focus on presenting symptoms, laboratory results (ie, serum or urine immunoelectrophoresis, bone marrow biopsy, and fat aspirate analysis), treatment modality, and status of disease at follow‐up.ResultsSix cases of localized tongue amyloidosis presented to the Mayo Clinic between 1969 and 2011. Mean patient age was 69 years (range, 43‐90). Patients presented with asymptomatic tongue mass(es). Biopsy of the tongue mass in all patients showed amyloid on Congo red stains. Work‐up for systemic amyloidosis, including bone marrow biopsy, fat aspiration, and serum and urine protein immunoelectrophoresis, was negative for all 6 patients, nor was there other organ involvement. Two patients underwent resection of the lesions, and the remaining patients elected for observation. Recurrence requiring repeat excision occurred in 1 of the patients that underwent resection. Repeat evaluation for systemic involvement was performed in 3 patients 1 to 3 years after the initial diagnosis. None of these patients went on to develop systemic involvement.ConclusionsLocalized tongue amyloidosis remains a rare diagnosis and requires exclusion of systemic involvement. Localized lesions may be observed or resected; however, recurrence may occur with resection. Patients with localized tongue amyloidosis do not appear to be at increased risk of developing systemic involvement.