Children with 5′-end NF1 gene mutations are more likely to have glioma

Objective:To ascertain the relationship between the germline NF1 gene mutation and glioma development in patients with neurofibromatosis type 1 (NF1).Methods:The relationship between the type and location of the germline NF1 mutation and the presence of a glioma was analyzed in 37 participants with NF1 from one institution (Washington University School of Medicine [WUSM]) with a clinical diagnosis of NF1. Odds ratios (ORs) were calculated using both unadjusted and weighted analyses of this data set in combination with 4 previously published data sets.Results:While no statistical significance was observed between the location and type of the NF1 mutation and glioma in the WUSM cohort, power calculations revealed that a sample size of 307 participants would be required to determine the predictive value of the position or type of the NF1 gene mutation. Combining our data set with 4 previously published data sets (n = 310), children with glioma were found to be more likely to harbor 5′-end gene mutations (OR = 2; p = 0.006). Moreover, while not clinically predictive due to insufficient sensitivity and specificity, this association with glioma was stronger for participants with 5′-end truncating (OR = 2.32; p = 0.005) or 5′-end nonsense (OR = 3.93; p = 0.005) mutations relative to those without glioma.Conclusions:Individuals with NF1 and glioma are more likely to harbor nonsense mutations in the 5′ end of the NF1 gene, suggesting that the NF1 mutation may be one predictive factor for glioma in this at-risk population.</jats:sec

Influence of conditioned compensatory response on drinking and driving decision making

Title from PDF of title page (University of Missouri--Columbia, viewed on September 14, 2012).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Thesis advisor: Dr. Denis M. McCarthyIncludes bibliographical references.M. A. University of Missouri--Columbia 2012."May 2012"Perceived intoxication is a strong determinant of one's willingness to drive after drinking alcohol. When contextual cues are conditioned with the administration of alcohol, a compensatory response is elicited that decreases the impairing effects of alcohol and perceived intoxication. The authors hypothesized that a cue-induced compensatory response would decrease perceived intoxication and therefore increase willingness to drive while intoxicated. Young adults (N = 60, 81.7% male) attended a single session during which they were randomly assigned to receive a moderate dose of alcohol via either a familiar or an unfamiliar alcoholic beverage. Following consumption, participants completed cognitive and psychomotor tasks, rated their subjective experience, and reported their willingness to drive. The cues of the familiar alcoholic beverage did not increase the willingness to drive compared to the unfamiliar cues. The groups also had similar subjective experiences and cognitive and psychomotor impairment. These results are inconsistent with previous conditioned compensatory response research. These discrepant results may be a result of the observed group difference in breath alcohol concentration (BrAC), with the familiar alcoholic beverage resulting in a higher BrAC. The group difference in BrAC makes it difficult to interpret these results

A multi-method analysis of the acquired preparedness model of risk for alcohol problems

Dissertation supervisor: Dr. Denis M. McCarthy.Includes vita.The acquired preparedness model (APM) integrates both general risk factors and alcohol-related cognitive factors to understand the development of alcohol use and its associated problems. The present project utilized an innovative multi-method approach (self-report questionnaires and event-related potential [ERP] techniques) to conduct a more comprehensive and in-depth analysis of the APM. Participants were 137 young adult (M = 22 years old, SD = 3, 59% female) social drinkers recruited from a Midwest college town. Self-report measures assessed reward sensitivity (general risk factor) and alcohol outcome expectancies (cognitive factor). The P3 component of the ERP was recorded while participants responded to infrequent normal- and rotated-head oddball targets (general risk factor) and while they viewed infrequent, alcohol cues (cognitive factor). Consistent with previous research, results indicated a significant indirect path from reward hypersensitivity to drinking frequency through more positive expectancies about alcohol's effects. Positive alcohol expectancies were also found to mediate the influence of reward hypersensitivity on substance use problems, suggesting that the acquisition of more positive alcohol expectancies may reflect the formation of more positive drug-relate expectancies. A significant mediation effect for negative expectancies on the association between reward hypersensitivity and alcohol-related problems was observed. Common method variance had a marked impact on the results of mediation analyses for involving the P3 component. These findings point to the importance of accounting for method effects to reduce the likelihood of spurious results and misspecification of theoretical models.Includes bibliographical references (pages 45-62)

HAX1 Augments Cell Proliferation, Migration, Adhesion, and Invasion Induced by Urokinase-Type Plasminogen Activator Receptor

The urokinase-type plasminogen activator receptor (uPAR) is a cell surface receptor which has a multifunctional task in the process of tumorigenesis including cell proliferation, adhesion, migration, and invasion. Many of the biological functions of uPAR necessitate interactions with other proteins. We have shown previously that uPAR interacts with HAX1 protein (HS-1-associated protein X-1). In the current study, to gain insight into the possible role of HAX1 overexpression in regulation of uPAR signal transduction pathway, several function assays were used. We found that, upon stimulation of uPAR, HAX1 colocalizes with uPAR suggesting a physiological role for HAX1 in the regulation of uPAR signal transduction. HAX1 overexpression augments cell proliferation and migration in uPAR-stimulated cells. Moreover, HAX1 over-expression augmented uPAR-induced cell adhesion to vitronectin as well as cellular invasion. Our results suggest that HAX1 over-expression may underlay a novel mechanism to regulate uPAR-induced functions in cancer cells

Facility Targeting, Protection and Mission Decision Making Using the VISAC Code

The Visual Interactive Site Analysis Code (VISAC) has been used by DTRA and several other agencies to aid in targeting facilities and to predict the associated collateral effects for the go, no go mission decision making process. VISAC integrates the three concepts of target geometric modeling, damage assessment capabilities, and an event/fault tree methodology for evaluating accident/incident consequences. It can analyze a variety of accidents/incidents at nuclear or industrial facilities, ranging from simple component sabotage to an attack with military or terrorist weapons. For nuclear facilities, VISAC predicts the facility damage, estimated downtime, amount and timing of any radionuclides released. Used in conjunction with DTRA's HPAC code, VISAC also can analyze transport and dispersion of the radionuclides, levels of contamination of the surrounding area, and the population at risk. VISAC has also been used by the NRC to aid in the development of protective measures for nuclear facilities that may be subjected to attacks by car/truck bombs

Competency to Stand Trial on Trial

This Article considers the legal standards for the determination of competency to stand trial, and whether those standards are understood and applied by psychiatrists and psychologists in the forensic evaluations they perform and in the judgments they make–judgments that are routinely accepted by trial courts as their own judgments. The Article traces the historical development of the competency construct and the development of two competency standards. One standard, used today in eight states that contain 25% of the population of the United States, requires that the defendant be able to assist counsel in the conduct of a defense “in a rational manner.” The second, adopted by the Supreme Court in Dusky v. United States, 362 U.S. 402 (1960) as the Court’s interpretation of the federal competency statute, requires that the defendant have an ability to consult with counsel with a reasonable degree of “rational understanding.” The “rational manner” standard seemingly focuses on the defendant’s behavior; the “rational understanding” standard seemingly focuses on the defendant’s thinking. The Article reports on a survey we conducted of 273 forensic psychiatrists and psychologists who were asked to read two case study vignettes and assess the competency of each criminal defendant using the “rational manner” standard, the “rational understanding” standard, and the federal statutory standard that merely requires that the defendant be able to “assist properly” in his or her defense. In one vignette, the defendant’s thinking was irrational but his behavior was rational. In the other, the defendant’s thinking was rational, but her behavior was irrational. In responding to both vignettes, more than three-fourths of all respondents either found the defendant competent under all three standards or incompetent under all three standards. Surprisingly, in answering the first vignette, the respondents divided almost equally in deciding whether the defendant was competent. The Article analyzes the results of the study and concludes with specific proposals to improve competency to stand trial assessments. Fairness to the defendant requires that the competency standard be clearly defined and applied by those who assess and determine competency

Translocator protein in late stage Alzheimer\u27s disease and Dementia with Lewy bodies brains

OBJECTIVE: Increased translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), in glial cells of the brain has been used as a neuroinflammation marker in the early and middle stages of neurodegenerative diseases, such as Alzheimer\u27s disease (AD) and Dementia with Lewy Bodies (DLB). In this study, we investigated the changes in TSPO density with respect to late stage AD and DLB. METHODS: TSPO density was measured in multiple regions of postmortem human brains in 20 different cases: seven late stage AD cases (Braak amyloid average: C; Braak tangle average: VI; Aged 74-88, mean: 83 ± 5 years), five DLB cases (Braak amyloid average: C; Braak tangle average: V; Aged 79-91, mean: 84 ± 4 years), and eight age-matched normal control cases (3 males, 5 females: aged 77-92 years; mean: 87 ± 6 years). Measurements were taken by quantitative autoradiography using [ RESULTS: No significant changes were found in TSPO density of the frontal cortex, striatum, thalamus, or red nucleus of the AD and DLB brains. A significant reduction in TSPO density was found in the substantia nigra (SN) of the AD and DLB brains compared to that of age-matched healthy controls. INTERPRETATION: This distinct pattern of TSPO density change in late stage AD and DLB cases may imply the occurrence of microglia dystrophy in late stage neurodegeneration. Furthermore, TSPO may not only be a microglia activation marker in early stage AD and DLB, but TSPO may also be used to monitor microglia dysfunction in the late stage of these diseases

Approach to Rectal Cancer Surgery

Rectal cancer is a distinct subset of colorectal cancer where specialized disease-specific management of the primary tumor is required. There have been significant developments in rectal cancer surgery at all stages of disease in particular the introduction of local excision strategies for preinvasive and early cancers, standardized total mesorectal excision for resectable cancers incorporating preoperative short- or long-course chemoradiation to the multimodality sequencing of treatment. Laparoscopic surgery is also increasingly being adopted as the standard rectal cancer surgery approach following expertise of colorectal surgeons in minimally invasive surgery gained from laparoscopic colon resections. In locally advanced and metastatic disease, combining chemoradiation with radical surgery may achieve total eradication of disease and disease control in the pelvis. Evidence for resection of metastases to the liver and lung have been extensively reported in the literature. The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases is showing promise in achieving locoregional control of peritoneal dissemination. This paper summarizes the recent developments in approaches to rectal cancer surgery at all these time points of the disease natural history

Using the A/T/N framework to examine driving in preclinical Alzheimer’s disease

The A/T/N classification system is the foundation of the 2018 NIA-AA Research Framework and is intended to guide the Alzheimer disease (AD) research agenda for the next 5&ndash;10 years. Driving is a widespread functional activity that may be particularly useful in investigation of functional changes in pathological AD before onset of cognitive symptoms. We examined driving in preclinical AD using the A/T/N framework and found that the onset of driving difficulties is most associated with abnormality of both amyloid and tau pathology, rather than amyloid alone. These results have implications for participant selection into clinical trials and for the application time of interventions aimed at prolonging the time of safe driving among older adults with preclinical AD