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51.
52.
Twenty-one patients with angina pectoris were treated with adrenergic beta-receptor antagonists. Previously the resting heart rate had been used as a guide to treatment, a reduction in the rate to 55-60 beats/min without symptomatic improvement indicating failure of medical treatment. These patients were re-evaluated before coronary arteriography using the peak-exercise heart rate as an index of adrenergic beta-receptor antagonism. The dose of beta-blocking drugs was increased to produce a peak-exercise heart rate of less than 100 beats/min or a consistent rate of 100-125 beats/min which would not lessen in spite of progressive dose increments. The resting heart rate was ignored. On these criteria 15 patients previously considered to have responded inadequately to beta-blockade responded satisfactorily and were therefore removed from the waiting list for coronary arteriography. They all remained well up to two years later. Six patients failed to respond and had coronary arteriography with a view to surgical treatment. Reliance on the resting heart rate as the index of optimum adrenergic beta-receptor antagonism is likely to lead to premature or unnecessary referral for surgery; the failure of beta-blockade in the treatment of angina pectoris can be determined simply and accurately by using peak-exercise heart rate. 相似文献
53.
I. J. Jacobs S. Skates A. P. Davies R. P. Woolas A. Jeyerajah P. Weidemann K. Sibley D. H. Oram 《BMJ (Clinical research ed.)》1996,313(7069):1355-1358
OBJECTIVE: To determine the risk of invasive epithelial ovarian cancer and fallopian tube cancer associated with a raised concentration of the tumour marker CA 125 in asymptomatic postmenopausal women. DESIGN: Serum CA 125 concentration was measured annually in study participants for one to four years. Participants with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. Follow up was by annual postal questionnaire. SETTING: General practice, occupational health departments, ovarian cancer screening unit in a teaching hospital. SUBJECTS: 22,000 volunteers, all postmenopausal women > or = 45 years of age; recruited between 1 June 1986 and 1 May 1990. INTERVENTION: Surgical investigation if the ultrasound examination was abnormal. MAIN OUTCOME MEASURES: Cumulative and relative risk of developing an index cancer (invasive epithelial cancer of the ovary or fallopian tube) after a specified CA 125 result. RESULTS: 49 index cancers developed in the study population during a mean follow up of 6.76 years. The overall cumulative risk of developing an index cancer was 0.0022 for the entire study population and was lower for women with a serum CA 125 concentration < 30 U/ml (cumulative risk 0.0012) but was appreciably increased for women with a concentration > or = 30 U/ml (0.030) and > 100 U/ml (0.149). Compared with the entire study population the relative risk of developing an index cancer within one year and five years was increased 35.9-fold (95% confidence interval 18.3 to 70.4) and 14.3-fold (8.5 to 24.3) respectively after a serum CA 125 concentration > or = 30 U/ml and 204.8-fold (79.0 to 530.7) and 74.5-fold (31.1 to 178.3) respectively after a concentration > or = 100 U/ml. CONCLUSION: CA 125 is a powerful index of risk of ovarian and fallopian tube cancer in asymptomatic postmenopausal women. 相似文献
54.
Shao B Oda MN Bergt C Fu X Green PS Brot N Oram JF Heinecke JW 《The Journal of biological chemistry》2006,281(14):9001-9004
High density lipoprotein (HDL) isolated from human atherosclerotic lesions and the blood of patients with established coronary artery disease contains elevated levels of 3-chlorotyrosine. Myeloperoxidase (MPO) is the only known source of 3-chlorotyrosine in vivo, indicating that MPO oxidizes HDL in humans. We previously reported that Tyr-192 is the major site that is chlorinated in apolipoprotein A-I (apoA-I), the chief protein in HDL, and that chlorinated apoA-I loses its ability to promote cholesterol efflux from cells by the ATP-binding cassette transporter A1 (ABCA1) pathway. However, the pathways that promote the chlorination of specific Tyr residues in apoA-I are controversial, and the mechanism for MPO-mediated loss of ABCA1-dependent cholesterol efflux of apoA-I is unclear. Using site-directed mutagenesis, we now demonstrate that lysine residues direct tyrosine chlorination in apoA-I. Importantly, methionine residues inhibit chlorination, indicating that they can act as local, protein-bound antioxidants. Moreover, we observed near normal cholesterol efflux activity when Tyr-192 of apoA-I was mutated to Phe and the oxidized protein was incubated with methionine sulfoxide reductase. Thus, a combination of Tyr-192 chlorination and methionine oxidation is necessary for depriving apoA-I of its ABCA1-dependent cholesterol transport activity. Our observations suggest that biologically significant oxidative damage of apoA-I involves modification of a limited number of specific amino acids, raising the feasibility of producing oxidation-resistant forms of apoA-I that have enhanced anti-atherogenic activity in vivo. 相似文献
55.
Feuk L Kalervo A Lipsanen-Nyman M Skaug J Nakabayashi K Finucane B Hartung D Innes M Kerem B Nowaczyk MJ Rivlin J Roberts W Senman L Summers A Szatmari P Wong V Vincent JB Zeesman S Osborne LR Cardy JO Kere J Scherer SW Hannula-Jouppi K 《American journal of human genetics》2006,79(5):965-972
Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development. 相似文献
56.
ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL 总被引:4,自引:0,他引:4
Recent developments in lipid metabolism have shown the importance of ATP binding cassette transporters (ABCs) in controlling cellular and total body lipid homeostasis. ABCA1 mediates the transport of cholesterol and phospholipids from cells to lipid-poor apolipoprotein A-I (apoA-I), whereas ABCG1 and ABCG4 mediate the transport of cholesterol from cells to lipidated lipoproteins. ABCA1, ABCG1, and ABCG4 are all expressed in cholesterol-loaded macrophages, and macrophages from ABCA1 and ABCG1 knockout mice accumulate cholesteryl esters. Here, we show that the lipidated particles generated by incubating cells overexpressing ABCA1 with apoA-I are efficient acceptors for cholesterol released from cells overexpressing either ABCG1 or ABCG4. The cholesterol released to the particles was derived from a cholesterol oxidase-accessible plasma membrane pool in both ABCG1 and ABCG4 cells, which is the same pool of cholesterol shown previously to be removed by high density lipoproteins. ABCA1 cells incubated with apoA-I generated two major populations of cholesterol- and phospholipid-rich lipoprotein particles that were converted by ABCG1 or ABCG4 cells to one major particle population that was highly enriched in cholesterol. These results suggest that ABCG1 and ABCG4 act in concert with ABCA1 to maximize the removal of excess cholesterol from cells and to generate cholesterol-rich lipoprotein particles. 相似文献
57.
Cortes JM Marinazzo D Series P Oram MW Sejnowski TJ van Rossum MC 《Journal of computational neuroscience》2012,32(3):387-402
Most neurons in the primary visual cortex initially respond vigorously when a preferred stimulus is presented, but adapt as
stimulation continues. The functional consequences of adaptation are unclear. Typically a reduction of firing rate would reduce
single neuron accuracy as less spikes are available for decoding, but it has been suggested that on the population level,
adaptation increases coding accuracy. This question requires careful analysis as adaptation not only changes the firing rates
of neurons, but also the neural variability and correlations between neurons, which affect coding accuracy as well. We calculate
the coding accuracy using a computational model that implements two forms of adaptation: spike frequency adaptation and synaptic
adaptation in the form of short-term synaptic plasticity. We find that the net effect of adaptation is subtle and heterogeneous.
Depending on adaptation mechanism and test stimulus, adaptation can either increase or decrease coding accuracy. We discuss
the neurophysiological and psychophysical implications of the findings and relate it to published experimental data. 相似文献
58.
Krebs LT Bradley CK Norton CR Xu J Oram KF Starling C Deftos ML Bevan MJ Gridley T 《Genesis (New York, N.Y. : 2000)》2012,50(4):366-374
The Notch-regulated ankyrin repeat protein (Nrarp) is a component of a negative feedback system that attenuates Notch pathway-mediated signaling. In vertebrates, the timing and spacing of formation of the mesodermal somites are controlled by a molecular oscillator termed the segmentation clock. Somites are also patterned along the rostral-caudal axis of the embryo. Here, we demonstrate that Nrarp-deficient embryos and mice exhibit genetic background-dependent defects of the axial skeleton. While progression of the segmentation clock occurred in Nrarp-deficient embryos, they exhibited altered rostrocaudal patterning of the somites. In Nrarp mutant embryos, the posterior somite compartment was expanded. These studies confirm an anticipated, but previously undocumented role for the Nrarp gene in vertebrate somite patterning and provide an example of the strong influence that genetic background plays on the phenotypes exhibited by mutant mice. 相似文献
59.
60.
Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene 总被引:5,自引:0,他引:5
Edwards SM Kote-Jarai Z Meitz J Hamoudi R Hope Q Osin P Jackson R Southgate C Singh R Falconer A Dearnaley DP Ardern-Jones A Murkin A Dowe A Kelly J Williams S Oram R Stevens M Teare DM Ponder BA Gayther SA Easton DF Eeles RA;Cancer Research UK/Bristish Prostate Group UK Familial Prostate Cancer Study Collaborators;British Association of Urological Surgeons Section of Oncology 《American journal of human genetics》2003,72(1):1-12
Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were =55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%-5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer-susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives. 相似文献