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31.
It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits.  相似文献   
32.
Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090)  相似文献   
33.
A key challenge in the analytical assessment of therapeutic proteins is the comprehensive characterization of their higher-order structure (HOS). To directly assess HOS, a new type of assay is warranted. The most sensitive and detailed method for characterizing HOS is unquestionably nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopy provides direct information about the HOS at an atomic level, and with modern NMR spectrometers and improved pulse sequences, this has become feasible even on unlabeled proteins. Hence, NMR spectroscopy could be a very powerful tool for control of HOS following, for example, process changes resulting in structural changes, oxidation, degradation, or chemical modifications. We present a method for characterizing the HOS of therapeutic proteins by monitoring their methyl groups using 2D H, C-correlated NMR. We use a statistical model that compares the NMR spectrum of a given sample to a reference and results in one output value describing how similar the HOS of the samples are. This makes the overall result easy to interpret even for non-NMR experts. We show that the method is applicable to proteins of varying size and complexity (here up to ~30 kDa) and that it is sufficiently sensitive for the detection of small changes in both primary and HOS.  相似文献   
34.
So far, no suitable 5‐HT7R radioligand exists for clinical positron emission tomography (PET) imaging. [18F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non‐human primates (NHPs). Furthermore, we investigate species differences in 5‐HT7R binding with [3H]SB‐269970 autoradiography in post‐mortem pig, NHP, and human brain tissue. Specific binding of [18F]2FP3 was investigated by intravenous administration of the 5‐HT7R specific antagonist SB‐269970. [3H]SB‐269970 autoradiography was performed as previously described. [18F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB‐269970 only resulted in decreased binding of 20% in the thalamus, a 5‐HT7R–rich region. Autoradiography on post‐mortem pig, NHP, and human tissues revealed that specific binding of [3H]SB‐269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5‐HT7R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5‐HT7Rs in vivo and that part of the PET signal arises from targets other than the 5‐HT7R.  相似文献   
35.
Smoking Is a Risk Factor for Recurrence of Groin Hernia   总被引:15,自引:0,他引:15  
Studies of connective tissue from patients with inguinal hernia have shown that smoking may be associated with hernia formation due to a defective connective tissue metabolism. Whether smoking is a risk factor for recurrence, too, was examined in this study. From December 1990 through December 1995, 649 patients underwent hernia repair as open sutured repair (Cooper ligament or abdominal ring repair) or as open mesh repair. Five hundred forty-four eligible patients were evaluated for recurrence 2 years postoperatively. Association between recurrence and 17 patient-, disease-, and intraoperative variables were analyzed by multiple logistic regression. The results showed that smoking was significantly and independently associated with recurrence compared to nonsmoking [odds ratio (OR = 2.22; 95% confidence interval (95% CI) = 1.19–4.15)]. Open sutured repair compared to open mesh repair was the most significant predictor for recurrence (OR = 7.23; 95% CI = 3.01–17.37). Surprisingly, local anesthesia was associated with a higher risk of recurrence compared to general anesthesia (OR = 2.44; 95% CI = 1.19–5.09). Potential confounders and other risk factors for hernia recurrence such as age, alcohol consumption, previous surgery, and anatomical characteristics of the hernia were adjusted for in the analysis. In conclusion, smoking is an important risk factor for recurrence of groin hernia, presumably due to an abnormal connective tissue metabolism in smokers.  相似文献   
36.
Systemic administration of recombinant erythropoietin (EPO) has been demonstrated to mediate neuroprotection. This effect of EPO may in part rely on a beneficial effect on cerebrovascular dysfunction leading to ischaemic neuronal damage. We investigated the in vivo effects of subcutaneously administered recombinant EPO on impaired cerebral blood flow (CBF) autoregulation after experimental subarachnoid haemorrhage (SAH). Four groups of male Sprague-Dawley rats were studied: group A, sham operation plus vehicle; group B, sham operation plus EPO; group C, SAH plus vehicle; group D, SAH plus EPO. SAH was induced by injection of 0.07 ml of autologous blood into the cisterna magna. EPO (400 iu kg(-1) s.c.) or vehicle was given immediately after the subarachnoid injection of blood or saline. Forty-eight hours after the induction of SAH, CBF autoregulatory function was evaluated using the intracarotid (133)Xe method. CBF autoregulation was preserved in both sham-operated groups (lower limits of mean arterial blood pressure: 91+/-3 and 98+/-3 mmHg in groups A and B, respectively). In the vehicle treated SAH-group, autoregulation was abolished and the relationship between CBF and blood pressure was best described by a single linear regression line. A subcutaneous injection of EPO given immediately after the induction of SAH normalized autoregulation of CBF (lower limit in group D: 93+/-4 mmHg, NS compared with groups A and B). Early activation of endothelial EPO receptors may represent a potential therapeutic strategy in the treatment of cerebrovascular perturbations after SAH.  相似文献   
37.
The 5-HT(1A) receptor is a well-characterized serotonin receptor playing a role in many central nervous functions and known to be involved in depression and other mental disorders. In situ hybridization, immunocytochemical, and binding studies have shown that the 5-HT(1A) receptor is widely distributed in the rat brain, with a particularly high density in the limbic system. The receptor's localization in the different neuronal subtypes, which may be of importance for understanding its role in neuronal circuitries, is, however, unknown. In this study we show by immunocytochemical double-labeling techniques, that the 5-HT(1A) receptor is present on both pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define two different subtypes of interneurons. Moreover, semiquantitative analysis showed that the receptor's distribution in the different neuronal types varies between brain areas. In cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both principal cells and calbindin- and parvalbumin-containing neurons. In septum and thalamus, the receptor was mostly present on calbindin- and parvalbumin-containing cells. Especially in the medial septum and thalamic reticular nucleus, the receptor highly colocalized with parvalbumin-positive neurons. These results suggest a diverse function of the 5-HT(1A) receptor in modulating neuronal circuitry in different brain areas, that may depend on the type of neuron the receptor is predominantly located on.  相似文献   
38.
The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with single-photon emission tomography (SPET). The aim of the present study was to describe a method for accurate quantification of binding data following a bolus injection of [(123)I]PE2I. Six healthy subjects (age 51+/-24 years) underwent xenon-133 SPET for quantification of regional CBF and [(123)I]PE2I SPET for quantification of DAT binding. rCBFs were within normal limits in all subjects. Fitting data to a two-tissue compartment model resulted in striatal K(1) values of 0.39+/-0.08 ml ml(-1) min(-1), equal to a first-pass extraction fraction of 0.72+/-0.13. Distribution volumes (DVs) were calculated using compartment analysis, area under the curve analysis and Logan analysis. Logan analysis is preferred since stable DV values were already obtained 120 min after [(123)I]PE2I injection. Mean striatal DV was 37.9+/-9.6 ml ml(-1) and mean occipital cortex DV was 5.5+/-0.7 ml ml(-1). In the absence of local pathology in a reference tissue, Logan analysis without blood sampling is an attractive method for accurate quantification of striatal [(123)I]PE2I binding. The distribution volume ratio (DVR) (6.6+/-1.4) was in good agreement with the DVR calculated with blood (6.7+/-1.4).  相似文献   
39.
The ultimate solution in prevention of occupational cancer risks would be to remove carcinogens from the working environment. Elimination of carcinogenic substances can be achieved by replacement of the carcinogen with non-carcinogen(s) having the same functionality, or by using a different process that produces adequate results without the use of carcinogenic agents. This paper presents selected methods and tools, which have been used for substitution purposes in practice. These are: 1. a strategy for substitution, 2. a tool for creating ideas on how to substitute, 3. a software package, SUBTEC, for solving some technical and industrial hygiene problems, and 4. a proposal for a strategy to deal with organizational and psychological barriers encountered when changes are to be introduced.  相似文献   
40.
Ptaquiloside (PTA) is a natural toxin produced by bracken (Pteridium aquilinum [L.] Kuhn). Assessment of PTA toxicity is needed because PTA deposited from bracken to soil may leach to surface and groundwater. Inhibition of soil respiration and genotoxic activity of PTA was determined by a soil microbial carbon transformation test and an umu test, respectively. In the carbon transformation test, sandy loam soil was incubated at five different initial concentrations of PTA for a period of 28 d, after which glucose was added and respiration measured for 12 consecutive hours. The tests were performed at 20 degrees C and soil moisture content of approximately 15%. For soil material sampled in the autumn, initial PTA concentrations ranging from 0.008 to 40.6 microg PTA/g dry soil were tested. From fitting of data by a sigmoidal function, a 10% effect dose (ED10) was estimated to 13 microg PTA/ g dry soil, with an upper 95% confidence limit of 43 microg PTA/g dry soil and a 95% lower confidence limit of -infinity microg PTA/g dry soil. For soil material sampled in late winter, initial PTA concentrations ranging from 1.56 to 212 microg PTA/g dry soil were tested, resulting in an ED10 value of 55 microg PTA/g dry soil, with an upper 95% confidence limit of 70 microg PTA/g dry soil and a 95% lower confidence limit of 40 microg PTA/g dry soil. The genotoxic activity of PTA was determined using the umu test without and with metabolic activation (addition of S9 rat liver homogenate). In tests with addition of S9, the induction ratio exceeded the critical ratio of 1.5 at a PTA concentration of 46 +/- 16 microg/ml and, in tests without S9, the critical ratio was exceeded at a PTA concentration of 279 +/- 22 microg/ml. The genotoxicity of PTA is comparable to that of quercetin, another bracken constituent. The toxicity of PTA toward microorganisms prolongs the persistence of PTA in terrestrial environments, increasing the risk of PTA leaching to drainage and groundwater.  相似文献   
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