Serotonin Transporter Promoter Polymorphism Genotype Is Associated With Behavioral Disinhibition and Negative Affect in Children of Alcoholics

Serotonergic (5-HT) dysfunction has been implicated in the etiology of both behavioral disinhibition (BD) and negative affect (NA). This work extends our previous finding of relationships between whole blood 5-HT and both BD and NA in pubescent, but not prepubescent, children of alcoholics and continues examination of a hypothesized role of 5-HT dysfunction in alcoholism risk. The long and short (L and S) variants of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) are responsible for differing transcriptional efficiencies in 5-HT uptake. Although associations have been found between the SS 5-HTTLPR genotype and severe alcoholism and neuroticism, recent reports describe relationships between the LL genotype and both low level of response to alcohol and alcoholism diagnosis and a predominance of the LL genotype in early-onset alcoholics. Methods : This report is from an ongoing prospective study of the development of risk for alcoholism and other problematic outcomes in a sample of families classified by father's alcoholism subtype. This study examines relationships between 5-HTTLPR genotype and both child BD (Child Behavior Checklist Aggressive Behavior) and NA (Child Behavior Checklist Anxious/Depressed) in offspring from 47 families. Results : Results showed significantly higher levels of BD and NA in the 16 children with the LL genotype than the 46 SS or SL children. Conclusions : Behaviors of undercontrol, which occur at increased rates in children of alcoholics, may be genetically influenced through the regulation of the 5-HT transporter. Due to the small sample size and the preliminary nature of our findings, replication is necessary.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65855/1/j.1530-0277.2001.tb02302.x.pd

Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system

INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), α-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin. METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver. RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells. CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast

Neurocognitive Consequences of HIV Infection in Older Adults: An Evaluation of the “Cortical” Hypothesis

The incidence and prevalence of older adults living with HIV infection is increasing. Recent reports of increased neuropathologic and metabolic alterations in older HIV+ samples, including increased cortical beta-amyloid, have led some researchers to suggest that aging with HIV may produce a neuropsychological profile akin to that which is observed in “cortical” dementias (e.g., impairment in memory consolidation). To evaluate this possibility, we examined four groups classified by HIV serostatus and age (i.e., younger ≤40 years and older ≥50 years): (1) Younger HIV− (n = 24); (2) Younger HIV+ (n = 24); (3) Older HIV− (n = 20); and (4) Older HIV+ (n = 48). Main effects of aging were observed on episodic learning and memory, executive functions, and visuoconstruction, and main effects of HIV were observed on measures of verbal learning and memory. The interaction of age and HIV was observed on a measure of verbal recognition memory, which post hoc analyses showed to be exclusively attributed to the superior performance of the younger HIV seronegative group. Thus, in this sample of older HIV-infected individuals, the combined effects of HIV and aging do not appear to result in a “cortical” pattern of cognitive deficits

Serotonergic Contribution to Boys' Behavioral Regulation

Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure.Participants were 23 boys (age 10 years) with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered.Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter.The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors

Adenovirus Gene Transfer to Amelogenesis Imperfecta Ameloblast-Like Cells

To explore gene therapy strategies for amelogenesis imperfecta (AI), a human ameloblast-like cell population was established from third molars of an AI-affected patient. These cells were characterized by expression of cytokeratin 14, major enamel proteins and alkaline phosphatase staining. Suboptimal transduction of the ameloblast-like cells by an adenovirus type 5 (Ad5) vector was consistent with lower levels of the coxsackie-and-adenovirus receptor (CAR) on those cells relative to CAR-positive A549 cells. To overcome CAR -deficiency, we evaluated capsid-modified Ad5 vectors with various genetic capsid modifications including “pK7” and/or “RGD” motif-containing short peptides incorporated in the capsid protein fiber as well as fiber chimera with the Ad serotype 3 (Ad3) fiber “knob” domain. All fiber modifications provided an augmented transduction of AI-ameloblasts, revealed following vector dose normalization in A549 cells with a superior effect (up to 404-fold) of pK7/RGD double modification. This robust infectivity enhancement occurred through vector binding to both αvβ3/αvβ5 integrins and heparan sulfate proteoglycans (HSPGs) highly expressed by AI-ameloblasts as revealed by gene transfer blocking experiments. This work thus not only pioneers establishment of human AI ameloblast-like cell population as a model for in vitro studies but also reveals an optimal infectivity-enhancement strategy for a potential Ad5 vector-mediated gene therapy for AI

Interaction of synthetic opioid metenkephalin peptide analogs, lilly 127623 and FK 33-824 with indole hallucinogens: Antagonism of N,N-dimethyltryptamine- and LSD-induced disruption of food-rewarded bar pressing behavior in the rat

The selected opioid metenkephalin synthetic peptide analogs Lilly (LY) 127623 and FK 33-824 were tested for behavioral dose effects and potential interaction with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained on a positive reinforcement fixed-ratio 4 (FR-4) behavioral bar pressing schedule, i.e., a reward of 0.01 ml sugar-sweetened evaporated milk was earned on every fourth bar press. DMT (3.2 mg/kg) and LSD (0.1 mg/kg), administered IP following a 0.9% NaCl 15–20-min control pretreatment, disrupted established food-rewarded FR-4 bar pressing in a consistent and reproducible manner. Animals pretreated IP with predetermined behaviorally noneffective doses of LY 127623 (0.01–0.32 mg/kg) and FK 33-824 (0.001–0.01 mg/kg) 15–20 min prior to receiving DMT demonstrated significant antagonism to DMT-induced disruption of FR-4 bar pressing, while doses of 0.10–0.32 mg/kg LY 127623 and 0.00032–0.0032 mg/kg FK 33-824 significantly antagonized LSD-induced behavioral effects.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46430/1/213_2004_Article_BF00432112.pd

Idosos portadores de HIV e vivendo com AIDS no contexto da capacidade funcional Ancianos portadores de VIH y viviendo con SIDA en el contexto de la capacidad funcional Elderly people with HIV living with AIDS in the context of functional capacity

A Síndrome da Imunodeficiência Adquirida (Aids) na velhice é mais uma doença crônica que pode comprometer a autonomia e a independência e afetar a capacidade funcional dos portadores idosos. Nesta perspectiva, este estudo visou a discutir sobre a capacidade funcional dos portadores do Vírus da Imunodeficiência Humana - HIV/Aids com 60 anos ou mais, baseado na incursão da bibliografia brasileira, com a finalidade de estimular novas produções, diminuir a lacuna na literatura e fornecer conhecimento aos profissionais e gestores de serviços e políticas de saúde do idoso.<br>El Síndrome de la Imunodeficiencia Adquirida (SIDA) en la vejez es una enfermedad crónica más que puede comprometer a la autonomía y la independencia y afectar la capacidad funcional de los portadores ancianos. En esta perspectiva, este estudio tuvo como objetivo discutir sobre la capacidad funcional de los portadores del Virus de la Imunodeficiencia Humana - VIH/SIDA con 60 años o más, fundamentado en la incursión de la bibliografía brasileña, con la finalidad de estimular nuevas producciones, disminuir la laguna en la literatura y ofrecer conocimiento a los profesionales y gestores de servicios y políticas de salud del anciano.<br>The Acquired Immunodeficiency Syndrome (AIDS) in old age is more of a chronic disease that can compromise autonomy and independence, and affect functional capacity of the elderly carriers. From this perspective, this study aimed to discuss the functional capacity of carriers of the Human Immunodeficiency Virus - HIV / AIDS - aged 60 years or more, based on a foray into the the Brazilian bibliography, with the purpose of stimulating new production, diminishing the shortage in the literature and to provide knowledge for professionals and service managers and health policies for the elderly