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21.
MR Dweck NV Joshi W Jenkins C Jones MWL Chow Alison Fletcher EJR van Beek NA Boon JHF Rudd DE Newby 《Lancet》2013
BackgroundCalcification and inflammation are key pathological processes in aortic stenosis and atherosclerosis. Using combined positron emission tomography and computed tomography (PET/CT), we sought to investigate their contribution to disease progression in aortic stenosis and to help identify vulnerable atherosclerotic plaque.MethodsIn the first part of the study patients with calcific aortic valve disease stenosis were prospectively compared with age-matched and sex-matched controls with normal valves. Aortic valve severity was determined at baseline and 1 year by echocardiography and CT calcium scoring. Calcification and inflammation in the valve were assessed by sodium 18-fluoride (NaF) and 18-fluorodeoxyglucose (FDG) uptake with PET. In the second part of the study NaF and FDG activity was assessed in the coronary arteries both in patients with stable coronary disease and in patients after myocardial infarction.Findings101 patients with aortic stenosis were compared with 20 controls. Tracer activity (target to background ratio [TBR]) was higher in patients with aortic stenosis than in controls (mean NaF 2·87 [SD 0·82] vs 1·55 [0·17], FDG 1·58 [0·21] vs 1·30 [0·13]; both p<0·01). NaF uptake displayed a progressive rise with valve severity (r2=0·540) with a more modest increase observed for FDG (r2=0·218). Baseline NaF correlated closely with alkaline phosphatase staining on immunohistochemistry (r2=0·79) and was a better predictor of disease progression at 1 year (r2=0·44, n=20) than was FDG (r2=0·02) or baseline calcium score (r2=0·36, current best predictor). Increased NaF activity was observed in 45 (42%) of 106 patients with stable coronary atherosclerosis and was localised to individual coronary plaques. These patients had higher rates of previous major adverse cardiovascular events (p=0·016) and higher Framingham risk scores (p=0·011) than did patients without increased uptake. In patients after myocardial infarction (n=15) intense NaF activity was observed at the site of the culprit lesion, with increased uptake compared with the maximum uptake elsewhere in the coronary arteries (TBR median 1·56 [IQR 1·49–1·82] vs 1·23 [1·15–1·48], p=0·02).InterpretationIn the valve, NaF holds promise in predicting aortic stenosis progression. In the coronary arteries it identifies culprit plaque post myocardial infarction and stable patients at elevated cardiac risk.FundingBritish Heart Foundation. 相似文献
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DJ Behm NV Aiyar AR Olzinski JJ McAtee MA Hilfiker JW Dodson SE Dowdell GZ Wang KB Goodman CA Sehon MR Harpel RN Willette MJ Neeb CA Leach SA Douglas 《British journal of pharmacology》2010,161(1):207-228
BACKGROUND AND PURPOSE
Recently identified antagonists of the urotensin–II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.EXPERIMENTAL APPROACH
The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.KEY RESULTS
GSK1440115 (pKi= 7.34–8.64 across species) and GSK1562590 (pKi= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA2= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pKb= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pKb= 8.87–8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.CONCLUSIONS AND IMPLICATIONS
Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo. 相似文献25.
Organization, expression and polymorphism of the human persyn gene 总被引:13,自引:0,他引:13
Ninkina NN; Alimova-Kost MV; Paterson JW; Delaney L; Cohen BB; Imreh S; Gnuchev NV; Davies AM; Buchman VL 《Human molecular genetics》1998,7(9):1417-1424
Persyn is a recently identified member of the synuclein family with a
distinct pattern of expression during pre- and postnatal development of the
mouse peripheral and central nervous systems. As with other synucleins,
persyn is believed to be involved in the pathogenesis of human
neurodegenerative diseases. However, in contrast to other synucleins, high
levels of persyn mRNA expression were also found in advanced breast
carcinomas, suggesting an involvement of the encoded protein in breast
tumour progression. Here we have used an antibody specific to human persyn
to demonstrate that the level of this protein is increased in ageing
cerebral cortex and in breast tumours. We cloned, characterized and
sequenced the human persyn genomic locus and localized it to the long arm
of chromosome 10 in the q23.2-q23.3 region. Sequence information was used
to search for specific mutations in the protein coding regions of persyn
mRNA and the persyn gene in breast tumours and tumour cell lines. No
tumour-specific mutations were found, but two linked polymorphisms in the
coding region were detected, both in mRNA and exons III and IV of the gene.
These results suggest that development of breast tumours correlates with
overexpression of the wild-type persyn protein. Detailed characterization
of the human persyn locus is important for further studies of the
involvement of persyn in neurodegeneration and malignancy.
相似文献
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SA Pungavkar MA Lawande DP Patkar NV Agrawal S Gadani 《Journal of Medical Imaging and Radiation Oncology》2005,49(6):489-492
Optic nerve glioma is the most common primary neoplasm of the optic nerve in childhood. It can extend intracranially along the optic pathway (optic pathway glioma). The lesion tends to present with decreased visual acuity in the affected eye, but can cause additional symptoms when it is large. Local involvement within the orbit can be characterized using CT, but MRI is superior in showing the intracranial extent of the lesion. Intracranial calcification in optic pathway glioma is rare. We present a rare case of optic pathway glioma with calcification in the intracranial component. Also, we describe MR spectroscopy (MRS) findings in this case. 相似文献
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R F Averkina 《Arkhiv patologii》1975,37(7):56-61
Intravenous administration of anti-renal serum in a dose 1--1.6 ml to mice line CBA brought about drastic changes in the kidney ranging from severe dystrophy of the tubule cells to necrosis of the epithelium of the proximal and straight tubules. A smaller dose (0.5 ml) produced initially degenerative changes in individual cells of the proximal convoluted and straight tubules, and 2--6 months later degenerative changes were noted almost in all cells of the tubules referred to above. The glomerular apparatus was affected in a lesser degree. The relative weight of the kidneys of the mice treated with anti-renal serum at the end of the 3rd month was less than that in control animals. The urine contained granular and hyaline cylinders and a considerable amount of protein. Concentration of urea in the blood serum of the experimental animals was found to be elevated. 相似文献
30.
R. F. Averkina 《Bulletin of experimental biology and medicine》1957,43(6):720-723
Summary Antigenic properties of the heart tissues of chicken embryo of 5, 6, 12, 14, 18 days, of mature chickens, reptiles (Naotrix natrix) and amphibia (Rana ridibunda) were comparatively studied by the complement fixation test. With the development of the chicken embryo antigenic properties of the heart tissues approach more and more those of the mature chicken. In the more early embryonic periods they resemble those of the grass snake and frog. With the development of the chicken embryo this similarity becomes less and less pronounced.Presented by N. N. Zhukov-Verezhnikov, Active Member of the USSR Academy of Medical Sciences 相似文献