RESUMEN
INTRODUCTION: Male and female never-smokers stratified on parental history of smoking were tested for possible differences in susceptibility to the hedonic effects of nicotine. METHODS: We recruited nicotine-exposed never-smokers with two never-smoking biological parents (PH-) or two ever-smoking biological parents (PH+). After completing a baseline assessment battery focusing on conditions or behaviors associated with smoking, participants were tested for subjective and hedonic effects in response to administration of three different nicotine doses (0.0, 0.5, and 1.0 mg) via nasal spray. Physiological and biochemical reactivity also was monitored. RESULTS: PH+ were significantly more likely to report having experienced a "buzz" upon early smoking experimentation and to have histories of alcohol abuse and alcoholism; they also scored higher on disordered eating. In response to nicotine dosing, PH+ reported an increase in depressed mood, compared with a minimal response in PH-, in keeping with our expectation that nicotine would have more pronounced effects in PH+. Regardless of parental history, women reported experiencing greater anxiety in response to the highest nicotine dose, compared with men. DISCUSSION: Further exploration in larger samples, using more stringent selection criteria, a wider range of measures, and a less aversive dosing method, may provide a full test of the possible utility of the parental history model for illuminating biobehavioral mechanisms underlying response to nicotine. Also important would be broadening the scope of inquiry to include comparisons with ever-smokers to determine what protected PH+ from becoming smokers, despite the presence of factors that might be expected to decrease resilience and increase susceptibility.
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Alcoholismo/psicología , Nicotina/administración & dosificación , Relaciones Padres-Hijo , Padres/psicología , Fumar/psicología , Tabaquismo/psicología , Administración Intranasal , Adulto , Afecto/efectos de los fármacos , Alcoholismo/complicaciones , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agonistas Nicotínicos/administración & dosificación , Distribución por Sexo , Tabaquismo/complicaciones , Adulto JovenRESUMEN
To investigate race differences in retrospectively-reported early smoking experiences, we studied African-American (n=48) and Caucasian (n=155) current smokers who participated in a study designed to identify phenotypic and genotypic factors associated with smoking. Compared with Caucasian smokers, African-American smokers were less educated (mean+/-s.e.m.: 13.3+/-0.25 vs. 14.3 +/- 0.16; p<.01), had higher BMI (28.9+/-1.06 vs. 26.7+/-0.52; p<.05), and smoked significantly fewer cigarettes/day (14.1+/-1.00 vs. 18.4+/-0.74; p<.01). Ninety percent of African-American smokers consumed menthol cigarettes, as opposed to 25% of Caucasian smokers. African-American smokers were significantly older than Caucasian smokers upon initial smoking experimentation (17.4+/-1.1 vs. 14.7+/-0.3; p<.05) and onset of regular smoking (19.7+/-0.9 vs. 17.4+/-0.4; p<.05). African-American smokers were significantly more likely than Caucasian smokers to endorse global pleasurable sensations (48% vs. 30%; p<.05), "pleasurable rush or buzz" (62% vs. 43%; p<.05), and "relaxing" (45% vs. 27%; p<.05) as early experiences with smoking, whereas Caucasian smokers were marginally more likely to report dizziness and difficulty inhaling (61% vs. 45%; p<.10 and 48% vs. 31%; p<.10, respectively). Caucasian smokers were significantly more likely to endorse friends (6.9+/-0.2 vs. 4.8+/-0.4; p<.0001) and "perk me up" (4.2+/-0.3 vs. 3.1+/-0.4; p<.05) and marginally more likely to endorse buzz (4.2+/-0.2 vs. 3.4+/-0.5; p<.10) as reasons for starting to smoke. Further research is needed to determine the relative contributions of genetic, developmental, and socio-cultural factors to these findings.
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Negro o Afroamericano , Fumar/etnología , Población Blanca , Adulto , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Fumar/psicología , Factores SocioeconómicosRESUMEN
From a random digit dialing survey of American women, we assessed current smokers (n=371). Respondents were 33.6+/-7.6 years old, 49.6% married, and 87.6% White, with an FTND score of 3.9+/-2.6. When asked "which cigarette of the day would be the most difficult for you to give up?" 30 women gave uncodable responses and 341 women provided answers subsequently coded into 5 categories: FIRST; 43.7%, MEAL; 29.3%, LAST; 13.8%, ROUTINE; 7.3%, and ENHANCE; 5.9%. Response groups differed significantly on age (p<.01), smoking rate (p<.001), time to first cigarette (p<.001), and self-rated health (p<.05). In post hoc analyses, FIRST were older, smoked more cigarettes/day, and smoked sooner after waking than at least one other group. LAST smoked the fewest cigarettes/day, and ENHANCE rated their health significantly better than did all other groups. The FTND is coded as 1 for "first" and 0 for any other response. Examining more closely the richness contained in that "other" category is a novel approach that may prove useful as a phenotyping tool.
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Actitud , Fumar/psicología , Adulto , Factores de Edad , Estado de Salud , Humanos , Masculino , Psicoterapia de Grupo/métodos , Muestreo , Cese del Hábito de Fumar/métodosRESUMEN
We have demonstrated that folic acid inhibits cell proliferation and epidermal growth factor receptor (EGFR) activation in colon cancer cell lines. We examined the effect of one year supplemental folic acid (5 mg/day) on the rectal mucosal expression of beta-catenin and pGSK3beta, known to be affected by EGF-R, in patients with colorectal adenomas. Folic acid treatment significantly reduced nuclear expression of beta-catenin (P < 0.05) and cellular expression of pGSK3beta (P < 0.01) when compared to placebo. Folic acid may exert its chemopreventive effect, at least in part, through inhibition of nuclear translocation of beta-catenin.
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Adenoma/metabolismo , Núcleo Celular/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas del Citoesqueleto/metabolismo , Ácido Fólico/administración & dosificación , Mucosa Intestinal/efectos de los fármacos , Transactivadores/metabolismo , Adolescente , Adulto , Suplementos Dietéticos , Receptores ErbB/metabolismo , Femenino , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Proyectos Piloto , Placebos , beta CateninaRESUMEN
Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation.
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Adenoma/genética , Adenoma/prevención & control , Proteína de la Poliposis Adenomatosa del Colon/genética , Moléculas de Adhesión Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Ácido Fólico/farmacología , Genes p53/genética , Hematínicos/farmacología , Pérdida de Heterocigocidad , Proteínas Supresoras de Tumor/genética , Adenoma/etiología , Administración Oral , Anciano , División Celular , Neoplasias Colorrectales/etiología , Receptor DCC , ADN de Neoplasias , Método Doble Ciego , Femenino , Humanos , Mucosa Intestinal , Masculino , Persona de Mediana Edad , Placebos , Receptores de Superficie CelularRESUMEN
BACKGROUND: Heparan sulfate proteoglycans are complex cell surface molecules containing polysaccharides called heparan sulfate. Lysosomes, platelet granules, and neutrophils (polymorphonuclear cells) contain heparanases that degrade heparan sulfate. There are at least two groups of heparanases: connective tissue-activating-peptide (CTAP-III) and mammalian heparanase (hpa). The purpose of this study was to quantify the expression of both CTAP-III and hpa in neutrophils and their heparanase activity. MATERIALS AND METHODS: Neutrophils were isolated from whole blood, total RNA collected, and reverse transcriptase--polymerase chain reaction (RT-PCR) performed. Primers were designed for CTAP-III and hpa-1 sequences from GenBank. Neutrophil lysate underwent Western blot analysis (and quantification) with antibodies to the C-terminus of CTAP-III and the 50-kDa subunit of hpa1. Chromatography separated these components of lysate, which were then tested for heparanase activity. RESULTS: Both CTAP-III (281 bp) and hpa-1 (485 bp) messenger RNA (mRNA) were expressed equally by neutrophils with use of quantitative RT-PCR. By Western blot analysis, a CTAP-III-like protein was detected at 80 kDa, and hpa-1 was detected as a 50-kDa protein, with expression not significantly different (P > 0.05). Heparanase activity was significantly different (P < 0.0001) for the 50-kDa hpa-1 protein (1.51 x 10(-6) micromol/min) and the 80-kDa CTAP-III-like protein (0.85 x 10(-6) micromol/min). CONCLUSIONS: Human neutrophils express mRNA and protein for both a CTAP-III-like protein and hpa-1. Although expressed in similar quantity for mRNA and protein, Hpa-1 was more active as heparanase than the CTAP-III-like protein. With more than one class of heparanase in their granules, neutrophils may be able to modify different kinds of heparan sulfate chains.
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Factores de Coagulación Sanguínea/genética , Liasa de Heparina/genética , Neutrófilos/enzimología , Péptidos , Secuencia de Aminoácidos , Anticuerpos , Factores de Coagulación Sanguínea/análisis , Factores de Coagulación Sanguínea/inmunología , Expresión Génica/inmunología , Liasa de Heparina/análisis , Liasa de Heparina/inmunología , Heparitina Sulfato/metabolismo , Humanos , Immunoblotting , Datos de Secuencia Molecular , ARN Mensajero/análisis , Fracciones Subcelulares/enzimologíaRESUMEN
BACKGROUND: Neutrophil (PMN) apoptosis regulates PMN functional longevity and is integral to the resolution of inflammation. We have recently shown that PMN contact with an endothelial monolayer down-regulates spontaneous PMN apoptosis. We sought to explore endothelial-mediated down-regulation of PMN apoptosis following mediator-induced apoptosis. We tested the three known membrane-initiated, receptor-ligand apoptotic pathways: Fas, tumor necrosis factor-alpha (TNF), and TNF-related apoptosis inducing ligand (TRAIL). METHODS: PMNs were isolated from peripheral venous blood of healthy volunteers. PMNs were co-cultured in the absence and presence of a human coronary artery endothelial cell (HCAEC) monolayer for 4 h. PMNs were then stimulated with the pro-apoptotic agonists (agonistic anti-Fas IgM, TNF, and TRAIL) for one hour, followed by an assessment of apoptosis after 5 h. PMN apoptosis was measured using an acridine orange/ethidium bromide in situ fluorescent microscopy assay. Caspase 3 activity was assessed using a spectrophotometric assay. RESULTS: In addition to spontaneous PMN apoptosis, endothelial co-culture resulted in significant increases in the percentages of normal cells and decreased percentages of apoptotic cells after stimulation with agonistic anti-Fas IgM, TNF and TRAIL. Endothelial co-culture did not alter PMN caspase 3 activity. CONCLUSION: Endothelial-mediated down-regulation of PMN apoptosis is conferred after 4 h of co-culture. In addition to spontaneous apoptosis, endothelial contact down-regulated the three known membrane-initiated PMN apoptotic pathways: Fas, TNF, and TRAIL. These data imply that endothelial-mediated down-regulation of PMN apoptosis may involve defects in each apoptotic pathway or a single defect in a distal transduction or effector event common to all three pathways. Alterations in the activity of caspase 3 did not appear to serve as a mechanism for endothelial-mediated down-regulation of PMN apoptosis.