Low monoamine oxidase B in peripheral organs in smokers

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.     

Expression of Tip60, an androgen receptor coactivator,and its role in prostate cancer development

Prostate cancer (CaP) is initially androgen sensitive and responsive to hormone ablation therapy. However, cancer growth recurs despite androgen deprivation in the majority of cases of advanced disease. The molecular basis of this progression still remains unknown. The significance of androgen receptor (AR) coactivator proteins in this androgen-dependent malignancy is only beginning to emerge. In the present study, we examined the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in CaP progression. In hormone refractory CaP biopsies, we observed a nuclear accumulation of Tip60 expression in contrast to a more diffuse distribution pattern observed in benign prostate hyperplasia and primary CaP. Furthermore, in both the prostate xenograft model CWR22 and the LNCaP CaP cell line, we observed that androgen withdrawal promoted upregulation of Tip60 as well as nuclear accumulation. In contrast, androgen exposure resulted in decreased Tip60 expression that was more closely linked to a cytoplasmic presence. Chromatin immunoprecipitation analysis revealed Tip60's recruitment to the PSA gene promoter in both androgen-dependent and -independent cell lines. Thus, in vitro and in vivo data support a possible role for Tip60 in the molecular pathway leading to the development of androgen-independent CaP following long-term androgen deprivation therapy.     

Sextant prostate biopsies predict side and sextant site of extracapsular extension of prostate cancer

PURPOSE: We examined the ability of sextant prostate biopsies in combination with other preoperative data to predict side and sextant site of prostate cancer extracapsular extension in a large cohort of patients. MATERIALS AND METHODS: We examined 223 contemporary cases of prostate cancer managed by radical prostatectomy. Using logistic regression analysis, we determined whether patient age, Gleason score, clinical stage, prostate specific antigen, number of positive sextants, biopsy location or percent of biopsy cores positive for cancer in a sextant site, side and overall gland was predictive of location of pathological extracapsular extension into periprostatic tissue. RESULTS: Of 41 of the 223 (18%) patients with nonorgan confined disease extracapsular extension was localized to 45 sextant sites in 36 (apex 8, mid 22, base 15) while only side of extension was known in 5. In a multivariate analysis the best predictors of the risk of extracapsular extension on a side were average percent biopsy cores positive for cancer overall 15 or greater (odds ratio 8.4, p <0.0001) and average from 3 ipsilateral biopsies 15 or greater (odds ratio 7.4, p <0.0001). When used in combination these 2 factors yielded a model with a positive predictive value of 37% and a negative predictive value of 95%. Sextant specific percent biopsy cores positive for cancer was predictive of risk of extracapsular extension in a sextant (odds ratio 2.5, p = 0.020). CONCLUSIONS: Our data demonstrate that average overall and per side percent biopsy cores positive for cancer is a significant predictor of risk of extracapsular extension on a side. Sextant specific percent biopsy cores positive for cancer is predictive of sextant site of extension. The high negative predictive value of the side specific model identifies patients who are good candidates for nerve sparing surgery.     

Endothelial function in pigs transgenic for human complement regulating factor

BACKGROUND: Expression of human complement regulating factor (hCRF) in porcine organs prevents hyperacute rejection of these organs after xenotransplantation to nonhuman primates. Experiments were designed to characterize endothelial and smooth muscle function of arteries from pigs transgenic for hCD46. METHODS: Arterial blood from outbred pigs transgenic for hCD46 expression and nontransgenic animals of the same lineage was analyzed for angiotensin-converting enzyme (ACE), C-type natriuretic peptide (CNP), and nitric oxide. Aortic endothelial cells were prepared for measurement of mRNA or activity for nitric oxide synthase (NOS). Rings cut from femoral and pulmonary arteries were suspended in organ chambers for measurement of isometric tension. RESULTS: CNP was significantly greater, ACE was similar, and nitric oxide was significantly less in plasma from transgenic compared with nontransgenic pigs. Neither mRNA nor activity of NOS differed between the groups. Endothelium-dependent relaxations to bradykinin and acetylcholine but not the calcium ionophore were shifted significantly to the left in femoral and pulmonary arteries from hCD46 transgenic pigs compared with nontransgenic pigs. The ACE-inhibitor captopril augmented relaxations similarly in both groups, but NG-monomethyl-L-arginine (L-NMMA) did not inhibit relaxations in rings from transgenic pigs. CONCLUSIONS: Data suggest that expression of hCD46 on endothelium of pigs selectively augments endothelium-dependent relaxations to bradykinin by increased release of endothelium-derived factors other than nitric oxide. There does not seem to be any change in activity of ACE or NOS with expression of the human protein. Increased relaxations to bradykinin may be beneficial in lowering vascular resistance when transgenic organs are used for xenotransplantation.     

Development and characterization of anti-Gal B cell receptor transgenic Gal-/- mice

BACKGROUND: The successful clinical application of pig-to-primate xenotransplantation is currently limited by the development of an acute vascular rejection, which is thought to involve an induced humoral immune response to the galactose alpha1,3 galactose (alpha-Gal) antigen. Successful xenotransplantation may require the development of novel methods for removal or neutralization of anti-Gal antibodies and anti-Gal-producing B cells. The large diversity of the B-cell repertoire makes it difficult, however, to isolate and study anti-Gal B-cell development. METHODS: We have established a transgenic mouse model for investigating anti-Gal B cells by introducing a transgene encoding both heavy and light chains for an anti-Gal IgM antibody into an alpha-galactosyltransferase-deficient (Gal-/-) background. We have characterized the frequency, phenotype, and function of transgenic anti-Gal B cells by multiparameter flow cytometric analysis and ELISA. RESULTS: ELISA analysis of serum from animals with the transgene in an alpha-galactosyltransferase-deficient background (Tg Gal-/-), from transgenic animals with a heterozygous alpha-galactosyltransferase background (Tg Gal-/+), and from nontransgenic alpha-galactosyltransferase-deficient littermates (Gal-/-) demonstrated elevated expression of anti-Gal antibodies in Tg Gal-/- mice compared with nontransgenic Gal-/- animals and a lack of transgene expression in the Tg Gal-/+ mice. Anti-Gal antibody expression in Tg Gal-/- mice could be increased by immunization with an ovalbumin-Gal glycoconjugate in vivo and through stimulation with lipopolysaccharide in vitro. Multiparameter flow cytometric analysis indicates that 50% to 80% of splenic and peritoneal B cells expressed the transgene and excluded endogenous immunoglobulin gene rearrangements. The majority of these B cells expressed anti-Gal receptors on the surface, as identified by staining with a fluorescein isothiocyanate-bovine serum albumin-Gal glycoconjugate. FACS analysis of the Tg Gal-/- B cells identified them as a population of CD21highCD23lowIgMhigh marginal zone B cells in the spleen and CD5-CD23low B1 cells in the peritoneal cavity. CONCLUSIONS: These observations suggest that this model can be used to study the regulation of anti-Gal B cells and can establish a reliable source of functional anti-Gal B cells, which could be used to test the effectiveness of alpha-Gal-specific immunosuppressive reagents.     

Depressive symptoms in farm women: effects of health status and farming lifestyle characteristics,behaviors, and beliefs

A multitude of responsibilities, environmental and social influences, and stressors place farm women at high risk for depressive symptoms. This cross sectional survey design study examines demographic, health status, and farm lifestyle characteristics, behaviors and beliefs as risk factors contributing to depressive symptoms among farm women in southeast Louisiana. The study was conducted in a stratified, random sample of 657 women 18 years and older. Factors predictive of depressive symptoms in adjusted logistic regression included those who experience poor health, perceive hazards associated with farming, experience recent farm-related injuries and engage in farming over longer periods of time. These findings help target interventions toward women at risk for depressive symptoms.     

How do Child Development Teams work? Findings from a UK national survey

The area of child disability is the 'Cinderella' of community child health services. It lacks a clear commissioning model, agreed quality standards or guidance on the level of resources required. In this climate of uncertainty, a national survey of Child Development Teams was undertaken in order to describe their basic structure and processes. The paper reports information from 242 multidisciplinary teams providing local services, with statutory funding, to children with neurodevelopmental disability and their families. The picture presented is encouraging in part. For example, 79% of teams operate from a Child Development Centre, which may be expected to enhance team communication. In terms of the initial assessment process for a developmentally delayed child, most teams (91%) report that they would hold a case discussion afterwards, although only 74% would always include parents, and only 70% always give their report(s) to parents. The impression of management practices is weak, with only 62% giving a clear answer about who manages the team, and less than half having a written policy or contract for the team's work. The survey findings provide a sampling framework from which further evaluative research can be generated.