Age-dependent effects of APOE ε4 in preclinical Alzheimer's disease.

Objective: The ε4 allele of apolipoprotein E (APOE) is the strongest known common genetic risk factor for Alzheimer's disease (AD) and alters age of onset in retrospective studies. Here, we longitudinally test the effects of APOE ε4 genotype and age during progression from normal cognition to AD.

Methods: Using data from 5381 cognitively normal older individuals and Cox proportional hazards models, we longitudinally tested the effects of APOE genotype on progression from normal cognition to mild cognitive impairment (MCI) or AD in four age strata (<60, 60-70, 70-80, 80 + ) and with a sliding window approach between ages 60 and 85.

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas.

Background: Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).

Methods: We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model-based and model-free linkage analyses, using S.

A novel approach for next-generation sequencing of circulating tumor cells.

Background: Next-generation sequencing (NGS) of surgically resected solid tumor samples has become integral to personalized medicine approaches for cancer treatment and monitoring. Liquid biopsies, or the enrichment and characterization of circulating tumor cells (CTCs) from blood, can provide noninvasive detection of evolving tumor mutations to improve cancer patient care. However, the application of solid tumor NGS approaches to circulating tumor samples has been hampered by the low-input DNA available from rare CTCs.

Pulsatile Load Components, Resistive Load and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Left ventricular (LV) afterload is composed of systemic vascular resistance (SVR) and components of pulsatile load, including total arterial compliance (TAC), and reflection magnitude (RM). RM, which affects the LV systolic loading sequence, has been shown to strongly predict HF. Effective arterial elastance (E) is a commonly used parameter initially proposed to be a lumped index of resistive and pulsatile afterload.

Associations Between Cardiovascular Events and Nonergot Dopamine Agonists in Parkinson's Disease.

Background: Knowledge of possible cardiovascular risks from Parkinson's disease (PD) medications is critical to informing safe and effective treatment decisions. The objective of our study was to determine whether PD patients treated with nonergot dopamine agonists (DAs) are at increased risk of adverse cardiovascular or cerebrovascular outcomes, relative to PD patients receiving other treatments.

Methods: Matched case-control studies were conducted within a cohort of 14,122 inpatients receiving treatment for PD who were identified in the Cerner Health Facts database.

Memantine and Cognition in Parkinson's Disease Dementia/Dementia With Lewy Bodies: A Meta-Analysis.

Background: The aim of this work was to utilize meta-analysis in examining the effects of memantine on neuropsychological functioning in patients with Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB).

Methods: Included studies fulfilled these criteria: included objective cognitive measures, a comparison group of participants not taking memantine, and provided sufficient data for calculation of effect size. We examined effect sizes across global cognition and five specific neuropsychological domains.

CAP2 in cardiac conduction, sudden cardiac death and eye development.

Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.

Processing ambiguity in a linguistic context: decision-making difficulties in non-aphasic patients with behavioral variant frontotemporal degeneration.

Some extent of ambiguity is ubiquitous in everyday conversations. For example, words have multiple meaning and very common pronouns, like "he" and "she" (anaphoric pronouns), have little meaning on their own and refer to a noun that has been previously introduced in the discourse. Ambiguity triggers a decision process that is not a subroutine of language processing but rather a more general domain resource.

Desmin common mutation is associated with multi-systemic disease manifestations and depletion of mitochondria and mitochondrial DNA.

Desmin (DES) is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders.

68Ga DOTATATE PET/CT is an Accurate Imaging Modality in the Detection of Culprit Tumors Causing Osteomalacia.

Objectives: Tumor-induced osteomalacia (TIO) is generally caused by small benign mesenchymal tumors producing fibroblast growth factor-23 (FGF-23). The only curative therapy of the disease is resection of the causative tumors. However, these tumors are extremely difficult to detect using conventional imaging modalities.

The impact of vitamin D3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial.

Objectives: We tested the hypothesis that daily vitD3 supplementation increases neuromuscular motor skills, jump power, jump energy, muscular force, and muscular strength.

Methods: This was a secondary analysis of a randomized controlled trial of 12-months of oral 7,000 IU/day vitD3 supplementation or placebo among 56 persons living with HIV aged 9-25 years. Neuromuscular motor skills were quantified using the Bruininks-Oseretsky Test of Motor Proficiency.

Individualized treatment with transcranial direct current stimulation in patients with chronic non-fluent aphasia due to stroke.

While evidence suggests that transcranial direct current stimulation (tDCS) may facilitate language recovery in chronic post-stroke aphasia, individual variability in patient response to different patterns of stimulation remains largely unexplored. We sought to characterize this variability among chronic aphasic individuals, and to explore whether repeated stimulation with an individualized optimal montage could lead to persistent reduction of aphasia severity. In a two-phase study, we first stimulated patients with four active montages (left hemispheric anode or cathode; right hemispheric anode or cathode) and one sham montage (Phase 1).

If so many are "few," how few are "many"?

The scope of reference of a word's meaning can be highly variable. We present a novel paradigm to investigate the flexible interpretation of word meaning. We focus on quantifiers such as "many" or "few," a class of words that depends on number knowledge but can be interpreted in a flexible manner.

Rare variants at 16p11.2 are associated with common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients.

Objective: We sought to seek novel associations of genes and genetic variants with CVID.

Imputation of TPMT defective alleles for the identification of patients with high-risk phenotypes.

Background: The activity of thiopurine methyltransferase (TPMT) is subject to genetic variation. Loss-of-function alleles are associated with various degrees of myelosuppression after treatment with thiopurine drugs, thus genotype-based dosing recommendations currently exist. The aim of this study was to evaluate the potential utility of leveraging genomic data from large biorepositories in the identification of individuals with TPMT defective alleles.

Copy number variation analysis in the context of electronic medical records and large-scale genomics consortium efforts.

The goal of this paper is to review recent research on copy number variations (CNVs) and their association with complex and rare diseases. In the latter part of this paper, we focus on how large biorepositories such as the electronic medical record and genomics (eMERGE) consortium may be best leveraged to systematically mine for potentially pathogenic CNVs, and we end with a discussion of how such variants might be reported back for inclusion in electronic medical records as part of medical history.