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Visual contrast sensitivity in Alzheimer's disease, mild cognitive impairment, and older adults with cognitive complaints
(Elsevier, 2013) Risacher, Shannon L.; WuDunn, Darrell; Pepin, Susan M.; MaGee, Tamiko R.; McDonald, Brenna C.; Flashman, Laura A.; Wishart, Heather A.; Pixley, Heather S.; Rabin, Laura A.; Paré, Nadia; Englert, Jessica J.; Schwartz, Eben; Curtain, Joshua R.; West, John D.; O’Neill, Darren P.; Santulli, Robert B.; Newman, Richard W.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
Deficits in contrast sensitivity (CS) have been reported in Alzheimer's disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.
A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53
(Springer Nature, 2013) Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L.; Le, Nhung X. H.; Bertelsen, Sarah; Budde, John P.; Harari, Oscar; Koller, Daniel L.; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I.; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor; Johnson, Eric O.; Kang, Sun; Kapoor, Manav; Kramer, John; Kuperman, Samuel; Madden, Pamela A. F.; Manz, Niklas; Martin, Nicholas G.; McClintick, Jeanette N.; Montgomery, Grant W.; Nurnberger, John I., Jr.; Rangaswamy, Madhavi; Rice, John; Schuckit, Marc; Tischfield, Jay A.; Whitfield, John B.; Xuei, Xiaoling; Porjesz, Bernice; Heath, Andrew C.; Edenberg, Howard J.; Bierut, Laura J.; Goate, Alison M.; Medical and Molecular Genetics, School of Medicine
Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.
Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus
(American Association for the Advancement of Science, 2012-10-23) Liu, Yan; Liu, Fan; Yu, Hao; Zhao, Xinyang; Sashida, Goro; Deblasio, Anthony; Harr, Michael; She, Qing-Bai; Chen, Zhenbang; Lin, Hui-Kuan; Di Giandomenico, Silvana; Elf, Shannon E.; Yang, Youyang; Miyata, Yasuhiko; Huang, Gang; Menendez, Silvia; Mellinghoff, Ingo K.; Rosen, Neal; Pandolfi, Pier Paolo; Hedvat, Cyrus V.; Nimer, Stephen D.; Pediatrics, School of Medicine
The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16(Ink4a) and the tumor suppressor p19(Arf). Bmi1 plays a key role in oncogenesis and stem cell self-renewal. We report that phosphorylation of human Bmi1 at Ser³¹⁶ by Akt impaired its function by triggering its dissociation from the Ink4a-Arf locus, which resulted in decreased ubiquitylation of histone H2A and the inability of Bmi1 to promote cellular proliferation and tumor growth. Moreover, Akt-mediated phosphorylation of Bmi1 also inhibited its ability to promote self-renewal of hematopoietic stem and progenitor cells. Our study provides a mechanism for the increased abundance of p16(Ink4a) and p19(Arf) seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.
Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension
(Springer Nature, 2012-10-24) Aljadhey, Hisham; Tu, Wanzhu; Hansen, Richard A.; Blalock, Susan J.; Brater, D. Craig; Murray, Michael D.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.
Methods: We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.
Results: Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.
Conclusion: Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
The Association between Metabolic Syndrome and Colorectal Neoplasm: Systemic review and Meta-analysis
(Wolters Kluwer, 2013) Jinjuvadia, Raxitkumar; Lohia, Prateek; Jinjuvadia, Chetna; Montoya, Sergio; Liangpunsakul, Suthat; Medicine, School of Medicine
Background: There has been constant speculation about the association between metabolic syndrome (MetS) and colorectal neoplasia (CN); however, the published results are conflicting. The aims of this study are to conduct a systematic search, and assess the literature to determine the available evidence on the association between these two conditions.
Methods: Meta-analysis was conducted based on relevant studies identified through a systematic literature review from PubMed, OvidSP, and Cochrane database during January 1980 to July 2011. A combined analysis was performed, followed by a subgroup analyses stratified by the study design, type of colorectal lesions, and sex. Publication bias was assessed using the Begg and Egger tests and visual inspection of funnel plot.
Results: Eighteen studies were included in the final analysis. Overall, MetS was associated with 34% increase in the risk of CN [summary relative risk (RR), 1.34; 95% confidence interval (CI), 1.24-1.44]. The association between MetS and CN was found to be statistically significant in separate analysis for both case-control studies (summary RR, 1.58; 95% CI, 1.44-1.73) and cohort studies (summary RR, 1.21; 95% CI, 1.13-1.29). The association remained significant when analyses were restricted by type of colorectal lesions (colorectal cancer: RR, 1.30; 95% CI, 1.18-1.43; colorectal adenoma: RR, 1.37; 95% CI, 1.26-1.49). Further subgroup analysis by sex showed significant association between MetS and CN in both male and female population.
Conclusions: Our meta-analysis showed significant association between presence of MetS and CN. These results may help in identifying high-risk individuals at early stage, who might benefit from targeted colorectal cancer screening intervention.