Citations

AbstractBackgroundApolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([11C]PiB PET) has not been assessed.MethodsNinety‐six Alzheimer's Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1–40 and Aβ1–42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [11C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ1–40, Aβ1–42, and Aβ1–40/Aβ1–42 with [11C]PiB uptake.ResultsIn APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1–40/Aβ1–42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1–40/Aβ1–42 improved the explained variance in [11C]PiB binding compared with using APOE and plasma Aβ1–40/Aβ1–42 as separate terms.ConclusionsThe results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.

AbstractObjectiveA National Institute on Aging–sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy‐one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross‐sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory‐sensitive measures and longitudinal design.

Targeting co‐stimulatory molecules to modulate the immune response has been shown to have useful therapeutic effects for autoimmune diseases. Among the co‐stimulatory molecules, CD2 and CD58 are very important in the early stages of generation of an immune response. Our goal was to utilize CD2‐derived peptides to modulate protein–protein interactions between CD2 and CD58, thereby modulating the immune response. Several peptides were designed based on the structure of the CD58‐binding domain of CD2 protein. Among the CD2‐derived peptides, peptide 6 from the F and C β‐strand region of CD2 protein exhibited inhibition of cell–cell adhesion in the nanomolar concentration range. Peptide 6 was evaluated for its ability to bind to CD58 in Caco‐2 cells and to CD48 in T cells from rodents. A molecular model was proposed for binding a peptide to CD58 and CD48 using docking studies. Furthermore, in vivo studies were carried out to evaluate the therapeutic ability of the peptide to modulate the immune response in the collagen‐induced arthritis (CIA) mouse model. In vivo studies indicated that peptide 6 was able to suppress the progression of CIA. Evaluation of the antigenicity of peptides in CIA and transgenic animal models indicated that this peptide is not immunogenic.

BackgroundThe purpose of this study was to report the treatment outcomes of patients with advanced oropharyngeal cancer treated with transoral laser microsurgery (TLM) followed by radiation therapy (RT) at Mayo Clinic in Arizona.MethodsA retrospective study of 80 patients treated from January 1, 2000 to November 7, 2011 was performed. All patients had stage III/IV oropharyngeal tumors and underwent TLM with neck dissection. Adjuvant RT was then given. Thirty‐seven patients received concurrent adjuvant chemotherapy. The primary outcome was locoregional control.ResultsMedian follow‐up was 47.3 months (range, 9.7–139.2 months). The 3‐year locoregional control, recurrence‐free survival, and overall survival rates were 98.6% (95% confidence interval [CI], 91% to 100%), 91.1% (95% CI, 81% to 96%), and 93.7% (95% CI, 84% to 98%), respectively. There were a total of 5 treatment failures, 1 regional and 4 distant. Twenty‐six patients underwent neck only RT with exclusion of the primary site.ConclusionTLM followed by RT for advanced oropharyngeal cancer results in excellent locoregional control rates. © 2013 Wiley Periodicals, Inc. Head Neck 36: 220–225, 2014

Central nervous system inflammatory demyelinating disease can affect patients across the life span. Consensus definitions and criteria of all of the different acquired demyelinating diseases that fall on this spectrum have magnetic resonance imaging criteria. The advances of both neuroimaging techniques and important discoveries in immunology have produced an improved understanding of these conditions and classification. Neuroimaging plays a central role in the accurate diagnosis, prognosis, disease monitoring and research efforts that are being undertaken in this disease. This review focuses on the imaging spectrum of acquired demyelinating disease.

Podocyturia, the shedding of live podocytes, is present at delivery in women with preeclampsia. The aim of this study was to test whether podocyturia is present earlier in pregnancy and predicts for preeclampsia. We also aimed to compare test characteristics of podocyturia with those of angiogenic factors previously implicated in the pathogenesis of this disorder. We prospectively enrolled 315 women who provided blood and urine samples at the end of the second trimesters of their pregnancies (median, 27 gestational weeks) and within 24 hours of their deliveries (median, 39.5 gestational weeks). Blood samples were analyzed for angiogenic markers, including placental growth factor, the soluble receptor fms-like tyrosine kinase receptor-1 for vascular endothelial growth factor, and endoglin. The urine sediments were analyzed for podocytes, identified by staining for podocin after culturing the urinary sediments for 24 hours. This analysis included all women who developed preeclampsia (n=15), gestational hypertension (n=15), and a subsample of women who remained normotensive throughout pregnancy (n=44), matched for maternal age and number of previous pregnancies to those who developed preeclampsia. At the second trimester collection, all women who developed preeclampsia had podocyturia, compared with none of those who remained normotensive or were diagnosed with gestational hypertension. Podocyturia in the second trimester had a significantly greater sensitivity and specificity for the subsequent diagnosis of preeclampsia than any single angiogenic marker or a combination thereof. Screening for podocyturia at the end of the second trimester may allow for accurate identification of pregnant women at risk for preeclampsia.

The treatment of exudative age-related macular degeneration (AMD) has been completely transformed by the development of drugs that bind vascular endothelial growth factor (VEGF). The antibody-based VEGF inhibitors bevacizumab and ranibizumab usually prevent the enlargement of choroidal neovascular membranes, reduce vascular permeability, and improve visual acuity. The newest VEGF inhibitor, aflibercept, is a soluble fusion protein that binds all isoforms of VEGF-A, VEGF-B, and placental growth factor with high affinity. Preclinical studies demonstrated aflibercept's ability to prevent experimental neovascularization and tumor growth in animal models. In phase 3 trials for exudative AMD, patients who received aflibercept avoided moderate vision loss and experienced improved visual acuity comparable to those who received ranibizumab. Additionally, patients who were treated with aflibercept 2 mg every 8 weeks (after 3 monthly loading doses) had similar visual results to those treated every 4 weeks. When treated as needed during the second year of the trials, patients were able to last an average of 3 months between aflibercept injections. Since its regulatory approval, aflibercept has also been found to perform well as a salvage therapy for eyes that respond incompletely to ranibizumab and bevacizumab. Because aflibercept can be administered less frequently than ranibizumab, it promises to decrease the frequency of patients’ visits to physicians’ offices in addition to the overall cost of AMD therapy.