Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Mar 2006
Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population.
Inherited mutations in BRCA1 and BRCA2 lead to significantly increased risks of breast and ovarian cancer. We used epidemiologic methods to evaluate the relative risks of breast cancer vs. ovarian cancer among women of Ashkenazi Jewish ancestry with inherited mutations in BRCA1 or BRCA2. The cancer of a family's index case (i.e., breast cancer vs. ovarian cancer) was significantly associated with site-specific risks of cancer in relatives known to carry mutations in BRCA1 or BRCA2. ⋯ For each later decade of birth, risk increased 1.2-fold (P = 0.03). Effects of cancer site of the index case and of birth cohort were independent. These results suggest that both genetic and nongenetic factors modify cancer risks among BRCA1 and BRCA2 mutation carriers, and that genetic modifiers and other familial factors may influence risk specifically for either breast or ovarian cancer.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2006
Differential effects of aging on fluid intake in response to hypovolemia, hypertonicity, and hormonal stimuli in Munich Wistar rats.
A significant proportion of aged humans may have impaired thirst and inadequate fluid intake after a period of fluid deprivation. We have studied the water drinking responses, relative to body weight, of Munich Wistar (MW) rats in response to osmotic, hypovolemic, dehydrational, and angiotensin (Ang)-related stimuli as they aged from 3 to 24 months. Young 3-months-old (m.o.) rats had the largest daily fluid intakes and drinking responses to hypertonic and dehydrational stimuli, suggesting that they have accentuated thirst in comparison with older age groups. ⋯ Ang II or s.c. isoproterenol were not reduced in 24-m.o. rats, nor was the drinking associated with feeding. Therefore, there are specific impairments of water intake in response to hypertonicity and hypovolemia in aged MW rats, but Ang-related drinking is not reduced. Like aged humans, aged MW rats exhibit high plasma atrial natriuretic peptide levels and impaired cardiovascular reflexes that could contribute to the impairment of thirst with age.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2006
Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex.
Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. ⋯ Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2006
Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody.
Hutchinson-Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC-->GGT) mutation within exon 11 of LMNA, which elicits a deletion of 50 aa near the C terminus of prelamin A. ⋯ Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2006
Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function.
In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-cell-deficient mice. ⋯ Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.