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951.
952.
Christopher Patterson John W. Feightner Angeles Garcia G.-Y. Robin Hsiung Christopher MacKnight A. Dessa Sadovnick 《CMAJ》2008,178(5):548-556
Background
In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.Methods
We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.Results
Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer''s disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E).Interpretation
Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias and the contribution of other risk factors remains limited. More importantly, there are few data to explain the overall risks and benefits of prevention strategies or their impact of risk modification.Articles to date in this series
- Chertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008;178:316-21.
953.
Mario Pagano J. Dedrick Jordan Susana R. Neves Tracy Nguyen Ravi Iyengar 《Cellular signalling》2008,20(6):1190-1197
The Gs and Gi pathways interact to control the levels of intracellular cAMP. Although coincident signaling through Gs and Gi-coupled receptors can attenuate Gs-stimulated cAMP levels, it is not known if prior activation of the Gi pathway can affect signaling by Gs-coupled receptors. We have found that activated Gαo/i interact with RGS20, a GTPase activating protein for members of the Gαο/i family. Interaction between Gαo/i and RGS20 results in decreased cellular levels of RGS20. This decrease was induced by activated Gαo and Gαi2 but not by Gαq, Gαi1 or Gαi3. The Gαo/i-induced decrease in RGS20 can be blocked by proteasomal inhibitors lactacystin or MG132. Activated Gαo stimulates the ubiquitination of RGS20. The serotonin-1A receptor that couples to Go/i reduces the levels of RGS20 and this effect is blocked by lactacystin, suggesting that Go/i promotes the degradation of RGS20. Expression of RGS20 attenuates the inhibition of β-adrenergic receptor-induced cAMP levels mediated by the serotonin-1A receptor. Prior activation of the serotonin-1A receptor results in loss of the RGS20-mediated attenuation, and the loss of attenuation is blocked when lactacystin is included during the prior treatment. These observations suggest that Go/i-coupled receptors, by stimulating the degradation of RGS20, can regulate how subsequent activation of the Gs and Gi pathways controls cellular cAMP levels, thus allowing for signal integration. 相似文献
954.
WNK protein kinases form a kinase subfamily expressed in multi-cellular organisms and the human genome encodes four distinct WNK genes. Human WNK2 has been recently identified as a cell growth regulator that modulates activation of the ERK1/2 protein kinase and is epigenetically silenced in gliomas. Here we provide mechanistic insight into how WNK2 affects ERK activation. We found that WNK2 depletion decreased RhoA activation and promoted GTP-loading of Rac1, leading to stimulation of the Rac1-effector PAK1, which is the kinase responsible for subsequent phosphorylation of MEK1 at serine 298, thereby increasing MEK affinity towards ERK1/2. We propose that WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation. 相似文献
955.
956.
Testosterone (T) appears to play a role in anxiety and sensorimotor gating in rodents, but whether T acts through the androgen receptor (AR) to influence these behaviors is less clear. We compared adult genetic male mice with the testicular feminization mutation (Tfm), which lack functional ARs, to wild type male littermates (wt males) on an assay of sensorimotor gating (prepulse inhibition of the acoustic startle response; PPI) and several tests thought to reflect anxiety: open field exposure, novel object exposure, elevated plus maze (EPM), and light/dark (LD) box. PPI was similar between groups, but indices of anxiety in the novel object and LD box tests were increased in Tfm males with no significant differences found in the open field or EPM. Since Tfm male mice have decreased circulating T, the same tests were conducted in mice that were gonadectomized (wt males) or sham-operated (Tfm males) as adults and supplemented with T or nothing (B). While T treatment reduced indices of anxiety in the novel object and LD box tests in wt males, it was ineffective in Tfm males. Increased indices of anxiety in Tfm males appear to be related to hyper-activation of the hypothalamic–pituitary–adrenal axis since levels of the stress hormone corticosterone were elevated in Tfm males compared to wt males at baseline and at several time points after exposure to a novel object. These findings demonstrate that ARs influence anxiety and stress responses in mice. 相似文献
957.
Tyburski JB Patterson AD Krausz KW Slavík J Fornace AJ Gonzalez FJ Idle JR 《Radiation research》2008,170(1):1-14
Gamma-radiation exposure has both short- and long-term adverse health effects. The threat of modern terrorism places human populations at risk for radiological exposures, yet current medical countermeasures to radiation exposure are limited. Here we describe metabolomics for gamma-radiation biodosimetry in a mouse model. Mice were gamma-irradiated at doses of 0, 3 and 8 Gy (2.57 Gy/min), and urine samples collected over the first 24 h after exposure were analyzed by ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOFMS). Multivariate data were analyzed by orthogonal partial least squares (OPLS). Both 3- and 8-Gy exposures yielded distinct urine metabolomic phenotypes. The top 22 ions for 3 and 8 Gy were analyzed further, including tandem mass spectrometric comparison with authentic standards, revealing that N-hexanoylglycine and beta-thymidine are urinary biomarkers of exposure to 3 and 8 Gy, 3-hydroxy-2-methylbenzoic acid 3-O-sulfate is elevated in urine of mice exposed to 3 but not 8 Gy, and taurine is elevated after 8 but not 3 Gy. Gene Expression Dynamics Inspector (GEDI) self-organizing maps showed clear dose-response relationships for subsets of the urine metabolome. This approach is useful for identifying mice exposed to gamma radiation and for developing metabolomic strategies for noninvasive radiation biodosimetry in humans. 相似文献
958.
Genomic instability that might occur early during low-dose, fractionated radiation exposures may be traceable in radiogenic compared to spontaneous cancers. Using a human 18K cDNA microarray-based comparative genome hybridization protocol, we measured changes in DNA copy number at over 14,000 loci in nine low-dose (137)Cs gamma-irradiated (acute exposure to 10 cGy/day x 21 days) and nine unirradiated TK6 clones and estimated locus-specific copy-number differences between them. Radiation induced copy-number hypervariability at thousands of loci across all chromosomes, with a sevenfold increase in low-level, randomly positioned DNA gains. Recurrent gains at 40 loci occurred among irradiated clones and were distributed nonrandomly across the genome, with the highest densities in 3q, 13q and 20q at sites that were hypodiploid without irradiation. Another nonrandomly distributed set of 94 loci exhibited relative recurrent gains from a hypodiploid state to a diploid state, suggesting hemizygous-to-homozygous transitions. Frequently recurring losses at 57 loci were concentrated on the single X-chromosome but were sparsely distributed at 0-2 loci per autosome. These results suggest induced mitotic homologous recombination as a possible mechanism of low-dose radiation-induced genomic instability. Genomic instability induced in TK6 cells resembled that seen in radiogenic tumors and suggests a way that radiation could induce genomic instability in preneoplastic cells. 相似文献
959.
Objective To determine the average reduction in blood pressure,
prevalence of adverse effects, and reduction in risk of stroke and ischaemic
heart disease events produced by the five main categories of blood pressure
lowering drugs according to dose, singly and in combination.Design Meta-analysis of 354 randomised double blind placebo
controlled trials of thiazides, β blockers, angiotensin converting enzyme
(ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel
blockers in fixed dose.Subjects 40 000 treated patients and 16 000 patients given
placebo.Main outcome measures Placebo adjusted reductions in systolic and
diastolic blood pressure and prevalence of adverse effects, according to dose
expressed as a multiple of the standard (recommended) doses of the drugs.Results All five categories of drug produced similar reductions in
blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg
diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20%
lower) at half standard dose. The drugs reduced blood pressure from all
pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood
pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater.
The blood pressure lowering effects of different categories of drugs were
additive. Symptoms attributable to thiazides, β blockers, and calcium
channel blockers were strongly dose related; symptoms caused by ACE inhibitors
(mainly cough) were not dose related. Angiotensin II receptor antagonists
caused no excess of symptoms. The prevalence of symptoms with two drugs in
combination was less than additive. Adverse metabolic effects (such as changes
in cholesterol or potassium) were negligible at half standard dose.Conclusions Combination low dose drug treatment increases efficacy
and reduces adverse effects. From the average blood pressure in people who
have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to
lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby
reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at
age 60-69. 相似文献
960.
Cristina Lasheras Sonia Gonzlez Jos M. Huerta Socorro Braga ngeles M. Patterson Serafina Fernndez 《Journal of trace elements in medicine and biology》2003,17(3):171-176
Epidemiological evidence has raised concern that a moderate elevation in body iron stores may increase oxidative stress and risk of heart disease. We examined the cross-sectional association between plasma iron and factors that could affect its levels (antioxidant enzymes, diet), with the concentration of plasma malondialdehyde (MDA) as a marker of lipid peroxidation. Participants were 162 non-smoking institutionalised elderly. Our results show that those in the highest tertile of plasma iron were at least twice as likely to have higher plasma MDA levels. Among the factors affecting plasma iron levels, we found that the upper tertile of erythrocyte-superoxide dismutase (E-SOD) was inversely associated with higher plasma iron, and potato intake explained a sizeable proportion of the variation in plasma iron levels. In addition to potatoes, eggs, wine, fruit in men and green vegetables in women showed a positive association with plasma iron levels. Only potatoes in both sexes, wine in men and eggs in women had an independent effect on plasma MDA. Potatoes, wine, plasma lycopene and plasma iron accounted for 43% of the variability in plasma MDA for males, and E-SOD, potatoes, eggs, plasma lycopene and plasma iron explained 45% for women. A longitudinal study should confirm, whether these MDA levels are related to morbidity and mortality. 相似文献