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排序方式: 共有479条查询结果,搜索用时 15 毫秒
31.
Cohen LH Pieterman E van Leeuwen RE Overhand M Burm BE van der Marel GA van Boom JH 《Biochemical pharmacology》2000,60(8):1061-1068
Anchoring of small G-proteins to cellular membranes via a covalently bound lipophylic prenyl group is essential for the functioning of these proteins. For example, the farnesylation of Ras by the action of the enzyme protein:farnesyl transferase (PFT) is pivotal for its signalling function in cell growth and differentiation. The development of inhibitors of PFT was triggered by the role of mutated Ras in certain types of cancer and by the observation that non-farnesylated Ras is inactive. Besides the screening of existing compounds for PFT inhibition, rational drug design has also led to new inhibitors. Our research is in the field of atherosclerosis and concerns the development of inhibitors of the growth of vascular smooth muscle cells. The latter process gives rise to reocclusion of the coronary artery (restenosis) after balloon angioplasty. We and others have developed several analogues of the two substrates of PFT, i.e. farnesyl pyrophosphate (FPP) and the so-called CAAX peptide consensus sequence, which were tested in vitro for the inhibition of PFT and of other enzymes involved in protein prenylation, such as protein:geranylgeranyl transferase-1 (PGGT-1). The FPP analogue TR006, a strong inhibitor of PFT (IC(50) of 67 nM), blocked the proliferation of cultured human smooth muscle cells and inhibited platelet-derived growth factor- and basic fibroblast growth factor-induced DNA synthesis. Similar but more highly charged compounds failed in this respect, probably because of an impaired uptake in the cells. Less charged derivatives were designed to circumvent this problem. The effect on the GF-induced activation of intermediates in signal transduction pathways was investigated in order to gain insight into the mechanism of action within the cells. TR006 decreased the bFGF activation of extracellular signal-regulated kinase 1 (ERK1), suggesting its involvement in inhibiting Ras activity. Although other analogues inhibited DNA synthesis, they affected neither ERK1 activation nor p38/stress-activated protein kinase 2 or Jun N-terminal kinase 1 activation. Since some of these compounds were also shown to be inhibitors of in vitro PGGT-1 activity, the geranylgeranylation of other G-proteins may be decreased by these compounds. Rho seems to be a good candidate as a target for inhibitors of PGGT-1. This uncertainty as to the mechanism of action within non-transformed as well as transformed cells applies to all prenylation inhibitors, but is not holding back their further development as drugs. Their current and possible future application as therapeutics in cancer, restenosis, angiogenesis, and osteoporosis is briefly discussed. 相似文献
32.
Incipient CADASIL 总被引:1,自引:0,他引:1
Lesnik Oberstein SA van den Boom R Middelkoop HA Ferrari MD Knaap YM van Houwelingen HC Breuning MH van Buchem MA Haan J 《Archives of neurology》2003,60(5):707-712
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited. OBJECTIVE: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years. DESIGN: Clinical characterization and blinded survey comparing MCs with non-MCs. SETTING: Referral center. PARTICIPANTS: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria. METHODS: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale. RESULTS: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps. CONCLUSIONS: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL. 相似文献
33.
Cerebral microbleeds in CADASIL 总被引:16,自引:0,他引:16
Lesnik Oberstein SA van den Boom R van Buchem MA van Houwelingen HC Bakker E Vollebregt E Ferrari MD Breuning MH Haan J;Dutch CADASIL Research Group 《Neurology》2001,57(6):1066-1070
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy leading to recurrent cerebral infarcts and dementia. Intracerebral hemorrhage (ICH) has been described sporadically in patients with CADASIL, suggesting that the affected arteries in CADASIL are not bleed-prone. However, the presence of cerebral microbleeds, which often remain undetected on conventional MRI, has not been determined in CADASIL. OBJECTIVE: To determine whether cerebral vessels in patients with CADASIL are prone to microbleeding. METHODS: T2*-weighted gradient echo MRI, which is highly sensitive for visualizing microbleeds, was performed in patients with CADASIL and their family members (n = 63). Known risk factors for ICH were determined for all individuals. On an exploratory basis, the presence of cerebral microbleeds was correlated with demographic variables, vascular risk factors, disease progression, ischemic MR lesions, and genotype. RESULTS: Cerebral microbleeds were present in 31% of symptomatic CADASIL mutation carriers, predominantly in the thalamus. Vascular risk factors such as hypertension did not account for the microbleeds in these patients. Factors associated with microbleeds were age (p = 0.008), Rankin disability score (p = 0.017), antiplatelet use (p = 0.025), number of lacunae on MRI (p = 0.009), and the Arg153Cys Notch3 mutation (p = 0.017). After correction for age, only the Arg153Cys mutation remained significantly associated with the presence of microbleeds. CONCLUSION: Patients with CADASIL have an age-related increased risk of intracerebral microbleeds. This implies that they may have an increased risk for ICH, which should be taken into account in CADASIL diagnosis and patient management. 相似文献
34.
35.
Delsing DJ Post SM Groenendijk M Solaas K van der Boom H van Duyvenvoorde W de Wit EC Bloks VW Kuipers F Havekes LM Princen HM 《Journal of cardiovascular pharmacology》2005,45(1):53-60
The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (0 [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w) lovastatin. The highest dose of rosuvastatin reduced plasma cholesterol and triglyceride levels by 39% and 42%, respectively, compared with the HFC control. Lovastatin had no effect on plasma cholesterol and triglyceride levels. In ApoE*3-Leiden mice on a chow diet, rosuvastatin (0.005% [w/w]) decreased plasma cholesterol levels by 35% without having an effect on triglyceride levels. On a chow diet, expression of genes involved in cholesterol biosynthesis and uptake in the liver was increased by rosuvastatin. Further mechanistic studies in HFC-fed mice showed that rosuvastatin treatment resulted in decreased hepatic VLDL-triglyceride and VLDL-apolipoprotein B production. VLDL lipid composition remained unchanged, indicating a reduction in the number of VLDL particles secreted. Lipolytic activity and expression of genes involved in cholesterol and triglyceride synthesis and beta-oxidation of fatty acids in the liver were not affected by rosuvastatin treatment, and hepatic lipid content did not change. However, activity of hepatic diacylglycerol acyltransferase was significantly decreased by 25% after rosuvastatin treatment. Moreover, biliary excretion of cholesterol, phospholipids, and bile acids was increased during treatment. The results indicate that rosuvastatin treatment in ApoE*3-Leiden mice on a HFC diet leads to redistribution of cholesterol and triglycerides in the body, both by reduced hepatic VLDL production and triglyceride synthesis and by enhanced hepatobiliary removal of cholesterol, bile acids, and phospholipids, resulting in substantial reductions in plasma cholesterol and triglyceride levels. 相似文献
36.
Krombach GA van den Boom M Di Martino E Schmitz-Rode T Westhofen M Prescher A Günther RW Wildberger JE 《European radiology》2005,15(8):1505-1513
The purpose of the study was to obtain reference values for the sizes of anatomical structures of the inner ear on computed tomography (CT) images and to compare these values with those obtained from patients with Menières disease. CT images of the temporal bone of 67 patients without inner ear pathology and 53 patients with Menières disease have been evaluated. CT was performed in the sequential mode (1-mm slice thickness, 120 kV, 125 mA). Anatomical structures, such as the length and the width of the cochlea and of the vestibule, the height of the basal turn, the length and the width of the cochlear, the vestibular and the singular aqueduct and the internal auditory meatus and the diameter of the semicircular canals, were measured, using a dedicated postprocessing workstation. Reference values from the control group could be obtained. In the patients with Menières disease, the length and the width of the vestibular aqueduct were smaller, compared with the values from the control group. The values obtained from the control group can serve as reference values for adult patients. The different sizes of anatomical structures of the control group and of patients suffering from Menières disease suggest that functional impairment might be related to subtle morphological changes. 相似文献
37.
van den Boom J Kristiansen JB Voss LM Stott NS 《Journal of paediatrics and child health》2005,41(1-2):48-51
OBJECTIVE: This report describes episodes of acute neutropenia associated with flucloxacillin use in children treated for bone and joint infections. METHODS: A retrospective chart audit was performed on eight children who developed neutropenia when treated with flucloxacillin. RESULTS: Eight children (aged 1 month to 13 years) had a diagnosis of neutropenia attributed to treatment with flucloxacillin, seven of whom received parenteral therapy. The time to onset of neutropenia averaged 27 days, with neutrophil counts returning to normal limits in all patients after 2 to 9 days. Two children were asymptomatic when the neutropenia was detected. The average flucloxacillin dose used was 65% (range 20-100%) of the recommended maximum dose. CONCLUSIONS: These cases suggest that flucloxacillin should be used with greater caution and guidelines for dosing and clinical monitoring (regular neutrophil counts) need to be reassessed, despite none of these patients experiencing serious sequelae. 相似文献
38.
van den Boom R Bornebroek M Behloul F van den Berg-Huysmans AA Haan J van Buchem MA 《Neurology》2005,64(7):1288-1289
In a hereditary variant of cerebral amyloid angiopathy (CAA), cerebral hemorrhage with amyloidosis-Dutch type, supratentorial microbleeds were found to occur independently of the presence of hypertension, whereas hypertension probably contributed to the development of cerebellar microbleeds. This predictable hereditary variant of CAA may be a useful model to study microbleeds in relation to CAA. 相似文献
39.
Experience of parenthood, couple relationship, social support, and child-rearing goals in planned lesbian mother families 总被引:1,自引:0,他引:1
Bos HM van Balen F van Den Boom DC 《Journal of child psychology and psychiatry, and allied disciplines》2004,45(4):755-764
BACKGROUND: The phenomenon of planned lesbian families (i.e., two-mother families in which the child was born to the lesbian relationship) is relatively new and very little research has been conducted among those families. The overall aim of this research was to examine whether planned lesbian mother families differ from heterosexual families on factors that are assumed to influence the parent-child relationship, such as experience of parenthood, child-rearing goals, couple relationship, and social support. METHOD: A hundred lesbian two-mother families were compared with 100 heterosexual families having naturally conceived children. A variety of measures were used to collect the data, including questionnaires and a diary of activities kept by the parents. RESULTS: Lesbian parents are no less competent or more burdened than heterosexual parents. Both lesbian and heterosexual parents consider it important to develop qualities of independence in their child. However, 'conformity' as a child-rearing goal is less important to lesbian mothers. Furthermore, lesbian social mothers feel more often than fathers in heterosexual families that they must justify the quality of their parenthood. CONCLUSION: There are few differences between lesbian couples and heterosexual couples, except that lesbian mothers appear less attuned to traditional child-rearing goals and lesbian social mothers appear more to defend their position as mother. 相似文献
40.
Welters MJ Filippov DV van den Eeden SJ Franken KL Nouta J Valentijn AR van der Marel GA Overkleeft HS Lipford G Offringa R Melief CJ van Boom JH van der Burg SH Drijfhout JW 《Vaccine》2004,23(3):305-311
Many successful candidate vaccines capable of combating tumours in animal models come to an untimely end because of the costs associated with the approval and production of the GMP-grade materials, which are usually of biological origin, for use in humans. We have used a GMP-compatible method to chemically synthesize a pure synthetic E7 protein of the human papillomavirus type 16 (HPV16-E7). This oncogen-derived protein is constitutively expressed in cervical cancer and its precursors and is thus considered as an excellent target for tumour-specific immunity. Injection of a mixture of the synthetic HPV16-E7 protein and the synthetic adjuvant CpG in mice resulted in strong functional HPV16-specific cytotoxic T-lymphocyte responses as measured by CD8+ MHC class I-tetramer staining, the detection of antigen-specific intracellular IFNgamma production and the ability to protect mice against a challenge with HPV16-E7+ TC-1 tumour cells in both prophylactic and therapeutic vaccination regimens. Our results demonstrate the potential use of pure synthetic vaccines that can be efficiently produced under GMP at low cost, which will stimulate the translation of new vaccination strategies into phase I/II clinical trials. 相似文献