Citations

Increasing the lifespan of a population is often a marker of a country's success. With the percentage of the population over 65 yr of age expanding, managing the health and independence of this population is an ongoing concern. Advancing age is associated with a decrease in cognitive function that ultimately affects quality of life. Understanding potential adverse effects of aging on brain blood flow and cognition may help to determine effective strategies to mitigate these effects on the population. Exercise may be one strategy to prevent or delay cognitive decline. This review describes how aging is associated with cardiovascular disease risks, vascular dysfunction, and increasing Alzheimer's disease pathology. It will also discuss the possible effects of aging on cerebral vascular physiology, cerebral perfusion, and brain atrophy rates. Clinically, these changes will present as reduced cognitive function, neurodegeneration, and the onset of dementia. Regular exercise has been shown to improve cognitive function, and we hypothesize that this occurs through beneficial adaptations in vascular physiology and improved neurovascular coupling. This review highlights the potential interactions and ideas of how the age-associated variables may affect cognition and may be moderated by regular exercise.

Abstract A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Context HepPar-1 and Arginase-1 are urea cycle enzymes used to distinguish hepatocellular carcinoma from other carcinomas. HepPar-1, but not Arginase-1, is known to be immunoreactive with normal human small intestine. Objectives To better define and compare the immunohistochemical staining patterns of HepPar-1 and Arginase-1 in adenocarcinomas arising in the small intestine, including the ampullary region. Design Staining for HepPar-1 and Arginase-1 was performed on 20 nonampullary small intestinal adenocarcinomas and 32 adenocarcinomas from the ampullary region. Ampullary adenocarcinomas were divided into intestinal morphology (15), pancreatobiliary morphology (14), and unclassifiable (3). Nonneoplastic small intestinal mucosa and colorectal adenocarcinomas were used as control groups. Results HepPar-1 stained 12 of 20 nonampullary small intestinal adenocarcinomas, with a median of 63% of cells staining in positive cases. It also stained 11 of 15 ampullary carcinomas with intestinal morphology, with a median of 75% of cells staining in positive cases. Two of 14 ampullary carcinomas with pancreatobiliary morphology were positive for HepPar-1. Arginase-1 showed positivity in 2 ampullary region carcinomas and diffuse positivity in 1 duodenal adenocarcinoma. Two of 22 colorectal carcinomas stained for HepPar-1 with none positive for Arginase-1. Conclusions HepPar-1, but not Arginase-1, usually shows positivity in small intestinal adenocarcinomas and ampullary adenocarcinomas with intestinal morphology, but only rarely shows positivity in ampullary adenocarcinomas with pancreatobiliary morphology. HepPar-1 positivity in metastatic adenocarcinoma with intestinal morphology is suggestive of an upper gastrointestinal primary site.

Intravenous recombinant tissue plasminogen activator was first approved for the treatment of acute ischemic stroke in the United States in 1996. Thrombolytic therapy has been proven to be effective in acute ischemic stroke treatment and shown to improve long-term functional outcomes. Its use is associated with an increased risk of symptomatic intracerebral hemorrhage as well as orolingual angioedema. Our goal is to outline the management strategies for these postthrombolysis complications.

Abstract Rationale Most immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to tuberculosis (TB) reactivation. However, current diagnostic tools cannot reliably distinguish nonprogressing from progressing patients a priori, and thus LTBI therapy must be prescribed with suboptimal patient specificity. We hypothesized that LTBI diagnostics could be improved by generating immunomarker profiles capable of categorizing distinct patient subsets by a combinatorial immunoassay approach. Objectives A combinatorial immunoassay analysis was applied to identify potential immunomarker combinations that distinguish among unexposed subjects, untreated patients with LTBI, and treated patients with LTBI and to differentiate risk of reactivation. Methods IFN-γ release assay (IGRA) was combined with a flow cytometric assay that detects induction of CD25+CD134+ coexpression on TB antigen–stimulated T cells from peripheral blood. The combinatorial immunoassay analysis was based on receiver operating characteristic curves, technical cut-offs, 95% bivariate normal density ellipse prediction, and statistical analysis. Risk of reactivation was estimated with a prediction formula. Measurements and Main Results Sixty-five out of 150 subjects were included. The combinatorial immunoassay approach identified at least four different T-cell subsets. The representation of these immune phenotypes was more heterogeneous in untreated patients with LTBI than in treated patients with LTBI or unexposed groups. Patients with IGRA(+) CD4+CD25+CD134+ T-cell phenotypes had the highest estimated reactivation risk (4.11 ± 2.11%). Conclusions These findings suggest that immune phenotypes defined by combinatorial assays may potentially have a role in identifying those at risk of developing TB; this potential role is supported by risk of reactivation modeling. Prospective studies will be needed to test this novel approach.