Change Detection Memory in Rhesus Monkeys and Humans

Visual short-term memory (VSTM) is the storage of visual information over a brief time period (usually a few seconds or less). Over the past decade, the most popular task for studying VSTM in humans has been the change detection task. In this task, subjects must remember several visual items per trial in order to identify a change following a brief delay interval. Results from change detection tasks have shown that VSTM is limited; humans are only able to accurately hold a few visual items in mind over a brief delay. However, there has been much debate in regard to the structure or cause of these limitations. The two most popular conceptualizations of VSTM limitations in recent years have been the fixed-capacity model and the continuous-resource model. The fixed-capacity model proposes a discrete limit on the total number of visual items that can be stored in VSTM. The continuous-resource model proposes a continuous-resource that can be allocated among many visual items in VSTM, with noise in item memory increasing as the number of items to be remembered increases. While VSTM is far from being completely understood in humans, even less is known about VSTM in non-human animals, including the rhesus monkey (Macaca mulatta). Given that rhesus monkeys are the premier medical model for humans, it is important to understand their VSTM if they are to contribute to understanding human memory. The primary goals of this study were to train and test rhesus monkeys and humans in change detection in order to directly compare VSTM between the two species and explore the possibility that direct species comparison might shed light on the fixed-capacity vs. continuous-resource models of VSTM. The comparative results suggest qualitatively similar VSTM for the two species through converging evidence supporting the continuous-resource model and thereby establish rhesus monkeys as a good system for exploring neurophysiological correlates of VSTM.

Genetic predisposition to prostate cancer

Prostate cancer (PC) is a significant economic and health burden in the U.S. and Europe but its causes are largely unknown. The most significant risk factors (after gender) are age and family history of the disease. A gene with high penetrance but low frequency on chromosome 1q, HPC 1, has been suggested to cause a proportion of the familial aggregation of PC but other more common genes, conferring less risk, are also thought to contribute to disease predisposition. We have pursued a strategy to study both types of genetic risk in PC. To identify high penetrance genes, affected men from thirteen families have been genotyped for genetic linkage analysis at six microsatellite markers spanning 45 cM of 1q24-25. Both LOD score and non-parametric statistics provide no significant support for HPC1 in this genomic region, although 3 of the families did combine to produce a LOD score of 0.9. These families will be included in a genome wide search for other PC predisposition genes as part of a multinational collaboration.^ For study of common genetic factors in PC development, leukocyte DNA samples from an unselected series of 55 patients and 67 controls have been examined for genetic differences in two other candidate genes, the androgen receptor gene, hAR, at Xq11-12, and the vitamin D receptor gene, hVDR, at 12q12-14. hAR was typed for two trinucleotide repeat length polymorphisms, (CAG)$\rm\sb{n}$ and (GGC)$\rm\sb{n},$ encoding polyglutamine and polyglycine tracts, respectively, which have been implicated in PC susceptibility. These data, combined with similarly processed patients and controls from the U.K. show no consistent association of allele length with PC risk. A novel finding, however, has been a significant association between the number of GGC repeats and the length of time between diagnosis and relapse in stage T1-T4 Caucasian patients irrespective of therapy and age of the patient. Of 49 patients who relapsed out of 108 entering the study, those with 16 or fewer GGC repeats had an average relapse-free-period of 101 (+/$-$7.7) months while for those with more than 16 repeats the period averaged 48 (+/$-$2.9) months, a difference of 2.1 fold or 4.4 years.^ The second gene, hVDR, was genotyped at two polymorphisms, a synonymous C/T substitution in exon 9 identified by differential TaqI enzymatic digestion and a variable length polyA tract in the 3$\sp\prime$ UTR. Although these polymorphisms are in strong linkage disequilibrium only the polyA region showed a possible association with PC risk. Men homozygous for alleles with fewer than 18 A's had an increased risk (OR = 3.0, p = 0.0578) compared to controls. This result is opposite to the findings of others and may either indicate off-setting random errors which together balance out to no significant overall effect or reflect more complex genetic and/or environmental associations.^ Overall, this research suggests that single gene familial predisposition may be less prominent in PC than in other cancers and that the characteristics of PC pathology may be useful in identifying the effects of common genetic factors. ^

Relationship of hospital volume to patient mortality, length of stay and total costs in patients receiving brain surgery for cancer: A nationwide analysis

Better morbidity and mortality outcomes associated with increased hospital procedural volume have been demonstrated across a number of different medical procedures. Existence of such a volume-outcome relationship is posited to lead to increased specialization of care, such that patients requiring specific procedures are funneled to physicians and hospitals that achieve a minimum volume of such procedures each year. In this study, the 2009 Nationwide Inpatient Sample is used to examine the relationship between hospital volume and patient outcome among patients undergoing procedures related to malignant brain cancer. Multiple regression models were used to examine the impact of hospital volume on length of inpatient stay and cost of inpatient stay; logistic regression was used to examine the impact of hospital volume on morbidity. Hospital volume was found to be a significant predictor of both length of stay and cost of stay. Hospital volume was associated with a lower length of stay, but was also associated with increased costs. Hospital volume was not found to be a statistically significant predictor of morbidity, though less than three percent of this sample died while in the hospital. Volume is indeed a significant predictor of outcome for procedures related to brain malignancies, though further research regarding the cost of such procedures is recommended.^

Dissecting the Interaction between p53 and TRIM24

Dissecting the Interaction of p53 and TRIM24 Aundrietta DeVan Duncan Supervisory Professor, Michelle Barton, Ph.D. p53, the “guardian of the genome”, plays an important role in multiple biological processes including cell cycle, angiogenesis, DNA repair and apoptosis. Because it is mutated in over 50% of cancers, p53 has been widely studied in established cancer cell lines. However, little is known about the function of p53 in a normal cell. We focused on characterizing p53 in normal cells and during differentiation. Our lab recently identified a novel binding partner of p53, Tripartite Motif 24 protein (TRIM24). TRIM24 is a member of the TRIM family of proteins, defined by their conserved RING, B-box, and coiled coil domains. Specifically, TRIM24 is a member of the TIF1 subfamily, which is characterized by PHD and Bromo domains in the C-terminus. Between the Coiled-coil and PHD domain is a linker region, 437 amino acids in length. This linker region houses important functions of TRIM24 including it’s site of interaction with nuclear receptors. TRIM24 is an E3-ubiquitin ligase, recently discovered to negatively regulate p53 by targeting it for degradation. Though it is known that Trim24 and p53 interact, it is not known if the interaction is direct and what effect this interaction has on the function of TRIM24 and p53. My study aims to elucidate the specific interaction domains of p53 and TRIM24. To determine the specific domains of p53 required for interaction with TRIM24, we performed co-immuoprecipitation (Co-IP) with recombinant full-length Flag-tagged TRIM24 protein and various deletion constructs of in vitro translated GST-p53, as well as the reverse. I found that TRIM24 binds both the carboxy terminus and DNA binding domain of p53. Furthermore, my results show that binding is altered when post-translational modifications of p53 are present, suggesting that the interaction between p53 and TRIM24 may be affected by these post-translational modifications. To determine the specific domains of TRIM24 required for p53 interaction, we performed GST pull-downs with in vitro translated, Flag-TRIM24 protein constructs and recombinant GST-p53 protein purified from E. coli. We found that the Linker region is sufficient for interaction of p53 and TRIM24. Taken together, these data indicate that the interaction between p53 and TRIM24 does occur in vitro and that interaction may be influenced by post-translational modifications of the proteins.

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

A COMPARISON OF COUNTY HOSPITAL UTILIZATION BEFORE AND AFTER INTERVENTION BY THE HOSPITAL'S ALCOHOLISM SERVICES PROGRAM

This study examines the reduction in hospital utilization of 393 public hospital patients who were referred to the hospital's alcoholism screening program for intervention. The 393 patients were the total patient population of the alcoholism screening program for the period of September through December, 1982. Medical records of these patients were investigated to assess the total number of hospital days six months before and six months after intervention. The findings support the hypothesis of decreased utilization. The total number of hospital days for 393 patients before intervention of the alcoholism program was 3,458, with a mean length of stay of 8.80 days. The total number of hospital days after intervention was 458 days, with a mean length of stay of 6.50 days. The average individual difference (decrease) was 7.63 days for one year. From a total of 393 patients counseled by the alcoholism program, 106 (27%) went to treatment for their alcoholism. Other aims were to examine the referral sources (physicians, nurses, social workers and the MAST); study the impact of familial history of alcoholism on referrals, and explore the MAST scores of patients successfully referred. Implications of the study are that it would benefit the public hospital, with their disproportionate numbers of alcoholics, to intervene in the behavioral patterns of alcoholism. Such intervention would be a factor in reducing the overall hospitalization of the alcoholic. ^

THE BACON CHOW STUDY: THE RELATIONSHIP BETWEEN INFECTIOUS ILLNESS AND GROWTH OF INFANTS

Multiple dietary deficiencies and high rates of infectious illness are major health problems leading to malnutrition and limitation of growth of children in developing countries. Longitudinal studies which provide information on illness incidence and growth velocity are needed in order to untangle the complex interrelationship between nutrition, illness and growth. From 1967 to 1973, researchers led by Dr. Bacon Chow of the Johns Hopkins University School of Hygiene undertook a quasi-experimental prospective study in Suilin Township, Taiwan to determine the effects of a nutritional supplement to the diets of pregnant and lactating women on the growth, development and resistance to disease of their offspring. This dissertation presents results from the analysis of infant morbidity and postnatal growth.^ Maternal nutritional supplementation has no apparent effect on the postnatal growth or morbidity of infants. Significant sex differences exist in growth response to illness and in illness susceptibility. Male infants have more diarrhea and upper respiratory illness. Respiratory illness is positively associated with growth rate in weight in the first semester of life. Diarrhea is significantly negatively associated with growth in length in the second semester. Small-for-date infants are more susceptible to illness in general and have a different pattern of growth response than large-for-date infants.^ Principal components analysis of illness data is shown to be an effective technique for making more precise use of ambiguous morbidity data. Multiple regression with component scores is an accurate method for estimating variance in growth rate predicted by indepenent illness variables. A model is advanced in which initial postnatal growth rate determines subsequent susceptibility to nutritional stress and infection. Initial growth rate is a function of prenatal nutrition, but is not significantly affected by maternal supplementation during gestation or lactation. Critical evaluation is made of nutritional supplementation programs which do not afford disease control.^

IL -12 inhibits the metastatic potential of osteosarcoma cells and induces tumor regression via a mechanism involving Fas /Fas ligand pathway

Despite multiple changes in the adjuvant chemotherapy regimens used to treat osteosarcoma (OS), the 2-year metastasis-free survival has remained at 65–70% for the past 10 years. Characterizing the molecular determinants that permit metastatic spread of tumor cells is a crucial element in developing new approaches for the treatment of osteosarcoma. Since OS metastasizes almost exclusively to the lung, an organ with constitutive Fas ligand (FasL) expression, we hypothesized that the expression of Fas (CD95, APO-1) by OS cells may play a role in the ability of these cells to form lung metastases. Fas expression was quantified in human SAOS-2 OS cells and selected variants (LM2, LM4, LM5, LM6, LM7). Using northern blot, FACS and RT-PCR analysis, low Fas expression was found to correlate with higher metastatic potential in these cell lines. The highly metastatic LM7 cell line was transfected with the full-length human Fas gene and injected into athymic nude mice. The median number of metastatic nodules per mouse fell from over 200 to 1.1 and the size of the nodules decreased from a range of 0.5–9.0 mm to less than 0.5 mm in the Fas-transfected cell line compared to the native LM7 cell line. Additionally, the subsequent incidence of lung metastases was lower in the Fas-expressing cell line. IL-12 was seen to upregulate Fas expression in the highly metastatic LM sublines in vitro. To visualize the effects of IL-12 in vivo, nude mice were injected with LM7 cells and treated biweekly for 4 weeks with Ad.mIL-12, saline control or Ad.βgal. Lung sections were analyzed via immunchistochemistry for Fas expression. A higher expression of Fas was found in tumors from mice receiving IL-12. To study the mechanism by which IL-12 upregulates Fas, LM7 cells were transfected with a luciferase reporter gene construct containing the full-length human fas promoter. Treatment with IL-12 increased luciferase activity. We therefore conclude that IL-12 influences the metastatic potential of OS cells by upregulating the fas promoter, resulting in increased cell surface Fas expression and susceptibility to Fas-induced cell death. ^

VISUAL MEMORY PROCESSING BY PRIMATES AND AVIANS IN A RELATIONAL TASK

Three rhesus monkeys (Macaca mulatta) and four pigeons (Columba livia) were trained in a visual serial probe recognition (SPR) task. A list of visual stimuli (slides) was presented sequentially to the subjects. Following the list and after a delay interval, a probe stimulus was presented that could be either from the list (Same) or not from the list (Different). The monkeys readily acquired a variable list length SPR task, while pigeons showed acquisition only under constant list length condition. However, monkeys memorized the responses to the probes (absolute strategy) when overtrained with the same lists and probes, while pigeons compared the probe to the list in memory (relational strategy). Performance of the pigeon on 4-items constant list length was disrupted when blocks of trials of different list lengths were imbedded between the 4-items blocks. Serial position curves for recognition at variable probe delays showed better relative performance on the last items of the list at short delays (0-0.5 seconds) and better relative performance on the initial items of the list at long delays (6-10 seconds for the pigeons and 20-30 seconds for the monkeys and a human adolescent). The serial position curves also showed reliable primacy and recency effects at intermediate probe delays. The monkeys showed evidence of using a relational strategy in the variable probe delay task. The results are the first demonstration of relational serial probe recognition performance in an avian and suggest similar underlying dynamic recognition memory mechanisms in primates and avians. ^