Citations

Background: Different clinical syndromes can arise from Alzheimer’s disease (AD) neuropathology, including dementia of the Alzheimer’s type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). Objective: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. Methods: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. Results: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. Conclusion: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

PurposeTo characterize peripheral nerve stimulation (PNS) of an asymmetric head‐only gradient coil that is compatible with a commercial high–channel‐count receive‐only array.MethodsTwo prototypes of an asymmetric head‐only gradient coil set with a 42‐cm inner diameter were constructed for brain imaging at 3T with maximum performance specifications of up to 85 mT/m and 708 T/m/s. Tests were performed in 24 volunteers to measure PNS thresholds with the transverse (x = left–right; y = anterior–posterior [A/P]) gradient coils of both prototypes. Fourteen of these 24 volunteers were also tested for the z‐gradient PNS in the second prototype and were scanned with high–slew‐rate echo planar imaging (EPI) immediately after the PNS tests.ResultsFor both prototypes, the y‐gradient PNS threshold was markedly higher than the x‐gradient threshold. The z‐gradient threshold was intermediate between those for the x‐ and y‐coils. Of the 24 volunteers, only two experienced y‐gradient PNS at 80 mT/m and 500 T/m/s. All volunteers underwent the EPI scan without PNS when the readout direction was set to A/P.ConclusionMeasured PNS characteristics of asymmetric head‐only gradient coil prototypes indicate that such coils, especially in the A/P direction, can be used for fast EPI readout in high‐performance neuroimaging scans with substantially reduced PNS concerns compared with conventional whole body gradient coils. Magn Reson Med 76:1939–1950, 2016. © 2015 International Society for Magnetic Resonance in Medicine

Background Patients with atrial fibrillation ( AF ) and hypertension are at high risk for stroke. Previous studies have shown elevated risk of stroke in patients with AF who have a history of hypertension (regardless of blood pressure [ BP ] control) and in patients with elevated BP . We assessed the association of hypertension and BP control on clinical outcomes. Methods and Results In ARISTOTLE (n=18 201), BP was evaluated as history of hypertension requiring treatment and elevated BP (systolic ≥140 and/or diastolic ≥90 mm Hg) at study entry and any point during the trial. Hazard ratios ( HR s) were derived from Cox proportional hazards models including BP as a time‐dependent covariate. A total of 15 916 (87.5%) patients had a history of hypertension requiring treatment. In patients with elevated BP measurement at any point during the trial, the rate of stroke or systemic embolism was significantly higher ( HR , 1.53; 95% confidence interval [ CI ], 1.25–1.86), as was hemorrhagic stroke ( HR 1.85; 95% CI , 1.26–2.72) and ischemic stroke ( HR , 1.50; 95% CI , 1.18–1.90). Rates of major bleeding were lower in patients with a history of hypertension ( HR , 0.80; 95% CI , 0.66–0.98) and nonsignificantly lower in patients with elevated BP at study entry ( HR , 0.89; 95% CI , 0.77–1.03). The benefit of apixaban versus warfarin on preventing stroke or systemic embolism was consistent among patients with and without a history of hypertension ( P interaction=0.27), BP control at baseline ( P interaction=0.43), and BP control during the trial ( P interaction=0.97). Conclusions High BP measurement at any point during the trial was independently associated with a substantially higher risk of stroke or systemic embolism. These results strongly support efforts to treat elevated BP as an important strategy to optimally lower risk of stroke in patients with AF . Clinical Trial Registration URL : https://ClinicalTrials.gov/ . Unique identifier: NCT 00412984.

BackgroundThe development of a left ventricular (LV) apical pouch in patients with apical hypertrophic cardiomyopathy (aHCM) has been thought to be the transition point that can become an apical aneurysm, which is linked to higher risk of adverse events. In our study, we sought to compare the ability of transthoracic echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) to accurately identify the presence of an apical pouch or aneurysm in patients with aHCM.MethodsWe retrospectively reviewed the charts of all consecutive patients that had features of aHCM on imaging. Data from cMRI and echo examinations were abstracted, and the ability of these diagnostic modalities to identify the presence of a LV apical pouch and aneurysm was analyzed.ResultsOf 31 patients with aHCM, 17 (54.8%) had an apical pouch and 2 were found to have apical aneurysm (6.5%) on cMRI. Echo with and without perflutren contrast was able to accurately identify both aneurysms, but only 47.1% (8/17) of apical pouches seen by cMRI. Two patients had apical thrombus that was identified by cMRI, but not by echo.ConclusionOur findings indicate that cMRI is superior to echo in identifying apical pouches in patients with aHCM. Our results also suggest that in patients undergoing echo, the use of perflutren contrast for LV opacification increases the diagnostic yield. Further study is necessary to delineate whether earlier identification of an apical pouch will be of clinical benefit for patients with aHCM by altering clinical management and avoiding adverse cardiovascular events.

AbstractBackgroundAs a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient′s native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions.MethodsConsecutive experiments were carried out between 2009 and 2013. Twenty‐one genetically modified pigs (GGTA1‐knockout/hCD46/± thrombomodulin, in one caseHLA‐E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according toISregimen:In group one (n = 10), pre‐treatment started either one (anti‐CD20) or four weeks (anti‐CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti‐thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti‐CD20.In group two (n = 11), myeloablative pre‐treatment as in multiple myeloma patients (long and short regimens) was added to extended conventionalIS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600cGY) was used to further reduce antibody‐producing cells.ResultsIn the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique orISregimen.Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12–50) days and 16 (7–35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer‐lasting grafts; myocardial histology confirmed pre‐clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy.Grafts of group 2 presented with only mild‐to‐moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due toTLI.ConclusionsLonger‐term results were difficult to achieve in this model due to theISregimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.