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951.
952.
The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.  相似文献   
953.
We report a patient with bronchial asthma who presented with pneumomediastinum, pneumopericardium, pneumoretroperitoneum, pneumorrhachis and extensive subcutaneous emphysema, after a period of coughing. Pathogenesis, diagnostic procedures and treatment of pneumomediastinum and its complications are discussed.  相似文献   
954.
A successful primary percutaneous transluminal coronary angioplasty (PTCA) program requires a learning process whereby the efficiency of the cardiac catheterization laboratory to deliver prompt intervention can be refined. The purpose of this study was to (1) quantify this learning process in terms of shortening the time to reperfusion, (2) examine the changes in strategy that allowed for this, and (3) determine if expedited reperfusion by primary PTCA improved patient outcomes. A database of all primary PTCA procedures was established in February 1, 1994. Continuous quality assurance analysis was performed, and program modifications introduced as needed. Patients were separated into early (group A = February 1, 1994 through January 31, 1995) and late (group B1 = February 1, 1995 through June 31, 1995, and group B2 = July 1, 1995 through December 31, 1995) cohorts. Time intervals to certain treatment landmarks were compared among groups. In-hospital outcomes were tabulated. Fifty-two consecutive patients were included (group A = 19, group B1 = 17, group B2 = 16). Time intervals shortened significantly (group A vs group B1 vs group B2) with the time from hospital presentation to first balloon inflation decreasing progressively (from 205 to 119 to 97 minutes; p <0.001). Most of this decrease was obtained by shortening the time from hospital presentation to xylocaine administration (158 to 85 to 72 minutes; p <0.005), although the time from xylocaine to first balloon inflation also decreased (from 47 to 33 to 24 minutes; p <0.005). Parallel decreases for in-hospital mortality (26% vs 0%; p = 0.004), adverse events (47% vs 18%; p = 0.05), and length of hospital stay (13.3 +/- 13.7 vs 8.4 +/- 4.4 days; p = NS) were demonstrated for groups A versus B1 and B2. A learning effect following initiation of a primary PTCA program is demonstrated in which reperfusion was more rapidly achieved as the result of procedural changes directed by quality improvement analysis with a concurrent improvement in in-hospital outcomes.  相似文献   
955.
956.
OBJECTIVE: To assess dynamic Gd-DTPA-enhanced magnetic resonance (MR) imaging in the diagnosis of primary breast pathology, and to test the hypothesis that analysis of contrast agent kinetics increases specificity. METHODS: Forty-seven women underwent breast MR imaging using three-dimensional and dynamic spoiled gradient-recalled sequences. Image interpretation was based on the evaluation of lesion conspicuity, signal intensity, contour and enhancement pattern from the static acquisitions. Assessment of contrast kinetics was based on pixel-by-pixel analysis of the dynamic data. A two-compartment model described by three parameters (amplitude of uptake, exchange rate and washout rate), and a three-compartment model described by two parameters (permeability and exchange rate) were used. Regions of interest were drawn for all lesions found in the dynamic sections. Mean regional pixel values were calculated for each parameter and tested for diagnostic efficacy. RESULTS: Twenty-two malignant and 36 benign lesions were examined. Fibroadenomas accounted for 86% of the benign tumours. Image interpretation had a sensitivity of 0.95 and specificity of 0.86. The fat-suppressed post-contrast images permitted good visualization of the contour and matrix characteristics of fibroadenomas, but all non-fibroadenomatous benign lesions were classified as indeterminate or suspicious. Significant differences were found between benign and malignant lesions in the amplitude of uptake (P = 0.0008) and exchange rate (P < 0.00005) of the two-compartment model, and permeability (P=0.0001) and exchange rate (P < 0.00005) of the three-compartment model. However, image interpretation was superior to the isolated use of quantitative indices (P=0.02). The most discriminating parameters were the exchange rates of both models, with no significant difference between them. CONCLUSION: Assessment of lesion morphology is essential and probably sufficient for the differentiation of fibroadenomas from malignant tumours. However, specificity of conventional MR imaging may be much lower for other types of primary benign breast pathology. Analysis of Gd-DTPA kinetics improves the specificity obtained using simple enhancement measurements and can be used to produce parametric images that provide information about lesion heterogeneity, permeability and vascularity.  相似文献   
957.
Previous studies have indicated that certain members of the cyclin-dependent kinase/mitogen-activated protein kinase superfamily are involved in apoptosis of neuronal cells. Here, we have examined programmed cell death induced by withdrawal of neurotrophic support from CNS (rat retinal) and PNS (chick sympathetic, sensory, and ciliary) neurons. All four neuron types were equally rescued by the purine analogues olomoucine and roscovitine. Olomoucine inhibits multiple cyclin-dependent and mitogen-activated protein kinases with similar potency. Roscovitine is a more selective cyclin-dependent kinase inhibitor; but, so is butyrolactone I, which did not prevent retinal ganglion cell death. The specific p38MAPK inhibitor SB-203580 did not prevent apoptosis in retinal ganglion cells. Death of these cells in the absence of neurotrophic factors was accompanied by morphological changes indicative of apoptosis, including nuclear condensation and fragmentation. Treatment with olomoucine or roscovitine not only prevented these apoptotic changes in retinal ganglion cells but also blocked neurite outgrowth. The survival-promoting activity of olomoucine correlated with its in vitro IC50 for c-Jun N-terminal kinase-1 and its potency to repress c-jun induction in live PC12 cells. Roscovitine was more potent in rescuing neurons than in inhibiting Jun kinase. Thus, the antiapoptotic action of roscovitine might be due to inhibition of additional kinases.  相似文献   
958.
BACKGROUND: Low-income, minority, and inner city women have breast cancer screening rates that are below those of the general population. METHODS: The authors surveyed women who received primary care at Seattle's county hospital about their mammography behaviors in early 1995. Data were analyzed within the context of the PRECEDE framework. RESULTS: Only half (48%) of the women were obtaining regular screening. Breast cancer and mammography beliefs differed by racial group. The following factors differentiated between inner-city women who were and were not regular users: mammography beliefs concerning early detection of disease, pressure from the machine causing breast cancer, and cost (these were less important among white women than members of other racial groups); previous physician discussions, concerns about appointment scheduling, and transportation problems; and social support from physicians, family, and friends. CONCLUSION: Interventions to encourage regular screening among inner-city women should address predisposing, enabling, and reinforcing factors.  相似文献   
959.
960.
OBJECTIVE: The objective of the study was to compare the accuracy of the TDxFLM test (Abbott Laboratories) with the fetal lung maturity cascade (shake, foam stability index, lecithin/sphingomyelin tests) and to determine whether the TDxFLM test could increase the efficiency and reduce the cost without decreasing the reliability of a cascade. STUDY DESIGN: A prospective, single-blinded study was conducted. Uncontaminated amniotic fluid obtained by transabdominal amniocentesis for fetal lung maturity assessment was evaluated with use of the fetal lung maturity cascade and the TDxFLM test. At study completion the results of the TDxFLM test were compared with those of the maturity cascade with regard to hyaline membrane disease, which was defined by strict clinical and radiographic parameters. A power analysis was performed requiring a sample size of 100 infants delivered within 72 hours of amniocentesis with use of the 95% confidence interval. RESULTS: A total of 115 cases had a full maturity cascade performed, of which 40 (35%) had a positive shake or foam stability index and 75 cases required progression to a lecithin/sphingomyelin ratio because of negative results. The TDxFLM test result was > or = 70 mg/gm in 42 (37%) of these 115. One hundred eight newborns were delivered within 72 hours of the amniocentesis; 65% (71) of these were between 30 and 37 weeks of estimated gestational age. There were 7 cases of hyaline membrane disease in the 108 newborns. Of these 108, 87 had a mature original cascade versus 85 mature tests with use of a proposed TDxFLM test-lecithin/sphingomyelin ratio cascade with one case of respiratory distress syndrome and hyaline membrane disease. The sensitivity, specificity, and positive and negative predictive values for the original cascade were 86%, 84%, 27%, and 99%, respectively; for the proposed TDxFLM test-lecithin/sphingomyelin ratio cascade the values were 86%, 83%, 26%, and 99%, respectively. The TDxFLM test-lecithin/sphingomyelin ratio cascade would have resulted in a cost reduction of 24% with no significant delay in turnaround time. CONCLUSION: The TDxFLM test appears to be a reliable and accurate assessment of fetal lung maturity. Furthermore, by replacing the shake and foam stability index portion of the cascade with the TDxFLM test, a cost savings of 24% would occur without a decrease in safety. These results also reveal that it could enhance patient care and be cost efficient for institutions not currently doing fetal pulmonary maturity testing to undertake use of the TDxFLM test and to only send out specimens for a lecithin/sphingomyelin ratio that have an initial immature TDxFLM test result (< 70 mg/gm). Likewise, institutions currently only performing a lecithin/sphingomyelin ratio may consider a TDxFLM test-lecithin sphingomyelin ratio cascade. Although direct costs would increase, they would be counterbalanced by a significant reduction in laboratory technician time.  相似文献   
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