Citations

AbstractBackgroundLow HCV has recently been qualified by the European Medicines Agency as a biomarker for enrichment of clinical trials in predementia stages of Alzheimer's disease. For automated methods to meet the necessary regulatory requirements, it is essential they be standardized and their performance be well characterized.MethodsThe within‐image and between‐field strength reproducibility of automated hippocampal volumetry using the Learning Embeddings for Atlas Propagation (or LEAP) algorithm was assessed on 153 Alzheimer's Disease Neuroimaging Initiative subjects.ResultsTests/retests at 1.5 T and 3 T, and a comparison between 1.5 T and 3 T, yielded average unsigned variabilities in HCVs of 1.51%, 1.52%, and 2.68%. A small bias between field strengths (mean signed difference, 1.17%; standard deviation, 3.07%) was observed.ConclusionsThe measured reproducibility characteristics confirm the suitability of using automated magnetic resonance imaging analyses to assess HCVs quantitatively and to represent a fundamental characterization that is critical to meet the regulatory requirements for using hippocampal volumetry in clinical trials and health care.

AbstractBackgroundRegulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development.MethodsThe Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data.ResultsThe literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011.ConclusionsWe summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

AbstractBackgroundApolipoprotein E ε4 (APOE ε4) is a risk factor for β‐amyloid deposition in Alzheimer's disease dementia. Its influence on β‐amyloid deposition in speech and language disorders, including primary progressive aphasia (PPA), is unclear.MethodsOne hundred thirty subjects with PPA or progressive speech apraxia underwent APOE genotyping and Pittsburgh compound B (PiB) PET scanning. The relationship between APOE ε4 and PiB status, as well as severity and regional distribution of PiB, was assessed.ResultsForty‐five subjects had an APOE ε4 allele and 60 subjects were PiB‐positive. The odds ratio for a subject with APOE ε4 being PiB‐positive compared with a subject without APOE ε4 being PiB‐positive was 10.2 (95% confidence interval, 4.4–25.5; P < .0001). The APOE ε4 allele did not influence regional PiB distribution or severity.ConclusionAPOE ε4 increases the risk of β‐amyloid deposition in PPA and progressive speech apraxia but does not influence regional β‐amyloid distribution or severity.

BackgroundAneurysm of the left atrial appendage is rare. We sought to systematically review the published literature on left atrial appendage aneurysm (LAAA) to address its demographic features, clinical characteristics, treatment, complications, and outcomes.MethodologyA systematic electronic search of Medline, PubMed, and EMBASE for case reports, case series, and related articles of LAAA published from 1962 until July 2013 was carried out. Statistical analysis was done using SPSS version 20.0. Logistic Regression Analysis was used to identify the independent predictors of LAAA‐related thrombus formation and embolism.ResultsEighty‐two cases of LAAA were identified. There was a slight female preponderance and most of the patients presented in their third decades. Palpitation, dyspnea or both were most common clinical symptoms associated with LAAA. Echocardiography was the main diagnostic modality used and the mean size of aneurysm was 7.08 ± 3.03 × 5.75 ± 2.36 cm. Surgical resection of the aneurysm was performed in most patients with favorable results. Systemic embolism and atrial tachyarrhythmias were the two common complications associated with untreated LAAA. Presence of atrial fibrillation/flutter was the only significant predictor of thrombus formation/embolic events.ConclusionAneurysm of left atrial appendage is rare and often an incidental diagnosis during echocardiography. It is important to recognize this entity since it is associated with cardiovascular morbidity and mortality by predisposing to atrial tachyarrhythmia and thromboembolism. Surgical resection is the standard of treatment in the current literature. Medical management is directed toward the treatment of thromboembolism and atrial tachyarrhythmia.

AbstractAn estimated 22 350 patients had multiple myeloma diagnosed in 2013, representing 1.3% of all new cancers; 10 710 deaths are projected, representing 1.8% of cancer deaths. Approximately 0.7% of US men and women will have a myeloma diagnosis in their lifetime, and with advances in therapy, 77 600 US patients are living with myeloma. The 5-year survival rate was 25.6% in 1989 and was 44.9% in 2005. The median age at diagnosis is 69 years, with 62.4% of patients aged 65 or older at diagnosis. Median age at death is 75 years. The rate of new myeloma cases has been rising 0.7% per year during the past decade. The most common indication for autologous stem cell transplantation in the United States is multiple myeloma, and this article is designed to provide the specifics of organizing a transplant program for multiple myeloma. We review the data justifying use of stem cell transplantation as initial management in myeloma patients. We provide selection criteria that minimize the risks of transplantation. Specific guidelines on mobilization and supportive care through the transplant course, as done at Mayo Clinic, are given. A review of the data on tandem vs sequential autologous transplants is provided.

Abstract Pretreatment evaluation is performed to determine the number, location, and size of the brain metastases and magnetic resonance imaging (MRI) is the recommended imaging technique, particularly in patients being considered for surgery or stereotactic radiosurgery. A contiguous thin-cut volumetric MRI with gadolinium with newer gadolinium-based agents can improve detection of small brain metastases. A systemic workup and medical evaluation are important, given that subsequent treatment for the brain metastases will also depend on the extent of the extracranial disease and on the age and performance status of the patient. Patients with hydrocephalus or impending brain herniation should be started on high doses of corticosteroids and evaluated for possible neurosurgical intervention. Patients with moderate symptoms should receive approximately 4–8 mg/d of dexamethasone in divided doses. The routine use of corticosteroids in patients without neurologic symptoms is not necessary. There is no proven benefit of anticonvulsants in patient without seizures. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

This viewpoint commentary, written from the perspective of a teacher who has helped to educate students in a wide variety of educational environments, is a reaction to the article published in Anatomical Sciences Education on developing of core syllabuses for the anatomical sciences. After reflecting on the definitions of both curriculum and syllabus and their importance as roadmaps for effective instruction, the value of core knowledge and core syllabuses in anatomical sciences was explored. Encouragement for the pursuit of the project proposed in the original article was provided; however, the reminder to not allow any curriculum or syllabus to prevent instructional flexibility was emphasized. Several constructive questions (regarding democracy in curriculum development, the proposed rating scale, and the desirability of reaching local or national consensus before seeking global agreement) were advanced for consideration. Anat Sci Educ 7 326–328. © 2014 American Association of Anatomists.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients.

Adipose tissue macrophage (ATM) recruitment and activation play a critical role in obesity-induced inflammation and insulin resistance (IR). The mechanism regulating ATM activation and infiltration remains unclear. In this study, we found receptor interacting protein 140 (RIP140) can regulate the dynamics of ATM that contribute to adipose tissue remodeling. A high-fat diet (HFD) elevates RIP140 expression in macrophages. We generated mice with RIP140 knockdown in macrophages using transgenic and bone marrow transplantation procedures to blunt HFD-induced elevation in RIP140. We detected significant white adipose tissue (WAT) browning and improved systemic insulin sensitivity in these mice, particularly under an HFD feeding. These mice have decreased circulating monocyte population and altered ATM profile in WAT (a dramatic reduction in inflammatory classically activated macrophages [M1] and expansion in alternatively activated macrophages [M2]), which could improve HFD-induced IR. These studies suggest that reducing RIP140 expression in monocytes/macrophages can be a new therapeutic strategy in treating HFD-induced and inflammation-related diseases.