74 research outputs found
Cardiovascular Damage in Alzheimer Disease: Autopsy Findings From the Bryan ADRC
Autopsy information on cardiovascular damage was investigated for pathologically confirmed Alzheimer disease (AD) patients (n = 84) and non-AD control patients (n = 60). The 51 relevant items were entered into a grade-of-membership model to describe vascular damage in AD. Five latent groups were identified āI: early-onset AD,ā āII: controls, cancer,ā āIII: controls, extensive atherosclerosis,ā āIV: late-onset AD, male,ā and āV: late-onset AD, female.ā Expectedly, Groups IV and V had elevated APOE Ļµ4 frequency. Unexpectedly, there was limited atherosclerosis and frequent myocardial valve and ventricular damage. The findings do not indicate a strong relationship between atherosclerosis and AD, although both are associated with the APOE Ļµ4. Instead, autopsy findings of extensive atherosclerosis were associated with possible, not probable or definite AD, and premature death. They are consistent with the hypothesis that brain hypoperfusion contributes to dementia, possibly to AD pathogenesis, and raise the possibility that the APOE allele Ļµ4 contributes directly to heart valve and myocardial damage
CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy
Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppcā/ā;Ptenpc+/ā mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbpā/ā;Pten+/ā and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppcā/ā;Ptenpc+/ā mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients
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Neuropsychological Assessment, Neuroimaging, and Neuropsychiatric Evaluation in Pediatric and Adult Patients with Sickle Cell Disease (SCD)
Traditionally, neuropsychological deficits due to Sickle Cell Disease (SCD) have been understudied in adults. We have begun to suspect, however, that symptomatic and asymptomatic Cerebrovascular Events (CVE) may account for an alarming number of deficits in this population. In the current brief review, we critically evaluated the pediatric and adult literatures on the neurocognitive effects of SCD. We highlighted the studies that have been published on this topic and posit that early detection of CVE via neurocognitive testing, neuropsychiatric evaluations, and neuroimaging may significantly reduce adult cognitive and functional morbidities
A comparative analysis of the information content in long and short SAGE libraries
BACKGROUND: Serial Analysis of Gene Expression (SAGE) is a powerful tool to determine gene expression profiles. Two types of SAGE libraries, ShortSAGE and LongSAGE, are classified based on the length of the SAGE tag (10 vs. 17 basepairs). LongSAGE libraries are thought to be more useful than ShortSAGE libraries, but their information content has not been widely compared. To dissect the differences between these two types of libraries, we utilized four libraries (two LongSAGE and two ShortSAGE libraries) generated from the hippocampus of Alzheimer and control samples. In addition, we generated two additional short SAGE libraries, the truncated long SAGE libraries (tSAGE), from LongSAGE libraries by deleting seven 5' basepairs from each LongSAGE tag. RESULTS: One problem that occurred in the SAGE study is that individual tags may have matched to multiple different genes ā due to the short length of a tag. We found that the LongSAGE tag maps up to 15 UniGene clusters, while the ShortSAGE and tSAGE tags map up to 279 UniGene clusters. Both long and short SAGE libraries exhibit a large number of orphan tags (no gene information in UniGene), implying the limitation of the UniGene database. Among 100 orphan LongSAGE tags, the complete sequences (17 basepairs) of nine orphan tags match to 17 genomic sequences; four of the orphan tags match to a single genomic sequence. Our data show the potential to resolve 4ā9% of orphan LongSAGE tags. Finally, among 400 tSAGE tags showing significant differential expression between AD and control, 79 tags (19.8%) were derived from multiple non-significant LongSAGE tags, implying the false positive results. CONCLUSION: Our data show that LongSAGE tags have high specificity in gene mapping compared to ShortSAGE tags. LongSAGE tags show an advantage over ShortSAGE in identifying novel genes by BLAST analysis. Most importantly, the chances of obtaining false positive results are higher for ShortSAGE than LongSAGE libraries due to their specificity in gene mapping. Therefore, it is recommended that the number of corresponding UniGene clusters (gene or ESTs) of a tag for prioritizing the significant results be considered
Emotional Reactions to Pain Predict Psychological Distress in Adult Patients with Sickle Cell Disease (SCD)
Differentiating somatic from emotional influences on the experience of chronic pain has been of interest to clinicians and researchers for many years. Although prior research has not well specified these pathways at the anatomical level, some evidence, both theoretical and empirical, suggest that emotional reactions influence the experience of disease and non-disease-related pains. Other studies suggest that treatments directed at negative emotional responses reduce suffering associated with pain. The current study was conducted to explore the influence of emotional reactions to pain as a predictor of psychological distress in a sample of adult Blacks with Sickle Cell Disease (SCD). Using cross-sectional survey data, we evaluated whether negative emotional reactions to the experience of pain were predictive of psychological distress after controlling for the somatic dimension of pain and age in n = 67 Black patients with Sickle Cell Disease (SCD). Results showed that greater negative emotion associated with pain predicted Somatization (p < .01), Anxiety (p < .05), Phobic Anxiety (p < .05), and Psychoticism (p < .05). Increased negative emotion associated with pain was also predictive of the General Symptoms Index (p < .05) and the Positive Symptoms Total from the SCL-90-R (p < .01). We believe the current study demonstrates that negative emotional reactions to the experience of pain in adults with SCD are predictive of psychological distress above and beyond the influences of age and the direct nociceptive experience. We also believe these data to be valuable in conceptualizing the allocation of treatment resources toward a proactive approach with early identification of patients who are responding poorly for the purpose of potentially reducing later psychopathology. A deeper understanding of the ways that subpopulations cope with chronic disease-related pain may produce models that can be ultimately generalized to the consumers of the majority of healthcare resources
Age-Dependent Cytokine Responses: Trimethyltin Hippocampal Injury in Wild-Type, APOE Knockout, and APOE4 Mice
International audienceIn this study, the hippocampal neurotoxicant trimethyltin (TMT) was used to examine possible differential susceptibility associated with the apolipoprotein E genotype. Miceāwild type (C57BL6J), APOE knockout, and APOE4 transgenicāreceived either saline or TMT (2 mg/kg, ip) at either 21 days or 8 months of age. At both ages, similar mRNA levels were seen in the hippocampus across genotypes for ICAM-1, A20, and MAC-1. GFAP mRNA was higher in the APOE knockouts and APOE4 as compared to wild-type mice. Within 24 h, TMT produced cell death of hippocampal dentate granule neurons and mild astrogliosis in all animals. In 21-day-old mice, TMT exposure significantly increased mRNA levels for ICAM-1 and MIP-1Ī± in all genotypes. EB-22, GFAP, TNFĪ±, and TGF-Ī²1 levels were significantly elevated in both wild-type and APOE knockout mice following TMT. At 8 months of age, genotype specific differences were observed. mRNA levels for GFAP, TNFĪ², TNFĪ±, and MIP-1Ī± were increased in both APOE knockout and APOE4 mice compared to wild-type mice. TMT exposure significantly increased mRNA levels for GFAP and MIP-1Ī± in all animals. TNFĪ± mRNA levels were increased in wild-type and APOE4 mice while EB22 mRNA levels were increased in both the APOE knockout and APOE4 mice but not wild-type mice. These data suggest an age-dependent effect on both microglia early inflammatory responses to injury associated with the APOE genotype
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Model of Genetic Susceptibility to Late-Onset Alzheimerās Disease: Mice Transgenic for Human Apolipoprotein E Alleles
Alzheimerās disease (AD) is a common neurodegenerative disorder in late life, affecting eventually up to 30% or more of individuals with a devastating and progressive syndrome of impairment of memory, cognition, and language. The clinical diagnosis of AD is based on identification of adequate clinical evidence for dementia syndrome; exclusion of other etiologies of dementia, particularly reversible causes; and observation of progression over time. The pathological confirmation of AD is based on examination of vulnerable areas of cerebral cortex and identification of features such as neurofibrillary tangles and amyloid plaques in quantities in excess for age. These āclassicā neuropathological features are accompanied by brain atrophy, neuronal loss, and abundant reactive astrogliosis and microgliosis. The profile of cortical vulnerability has been well defined for AD and prominently includes hippocampus, entorhinal cortex, and other association cortices. These common clinical and pathological features serve to group together what is now clearly a family of Alzheimer diseases. One part of this family can be defined by allelic effects of the AD susceptibility gene, apolipoprotein E (APOE)
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Complex Genetic Disease: Can Genetic Strategies in Alzheimer's Disease and New Genetic Mechanisms Be Applied to Epilepsy?
Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using āreverseā or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in CreutzfeldtāJakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in CharcotāMarieāTooth disease (type 1 A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues. There is growing recognition that neurologic diseases are often complex genetic diseases with multifactorial rather than simple modes of inheritance. For example, genetic association/linkage strategies have interacted with biochemistry and immunopathology studies to produce new insights into the disease mechanism of lateāonset Alzheimer's disease. The role of apolipoprotein E in lateāonset Alzheimer's disease is an example of how new analytical techniques of genetic disease can be applied to dissect multiple genes. Similar research strategies are suggested for the study of epilepsy as a complex disease
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