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91.
Association between gastric cancer mortality and nitrate content of drinking water: Ecological study on small area inequalities 总被引:5,自引:0,他引:5
The carcinogenic feature of N-nitroso compounds has been well established. Similarly, the transformation of ingested nitrate to N-nitroso compounds in the stomach has been thoroughly documented, nevertheless nitrates' carcinogenic effect has not been proved convincingly in human. The present study was aimed to investigate a population of small villages provided by drinking water with high and widely variable nitrate content (72 mg/l median, 290.7 mg/l 95-percentile concentration). Empirical Bayes estimates for settlement-specific age-, sex-, and year-standardised mortality ratios of gastric cancer (GC) were related to the settlement level average nitrate concentrations in drinking water controlling for confounding effects of smoking, ethnicity and education. The log-transformed average nitrate concentration showed significant positive association with stomach cancer mortality in linear regression analysis (p = 0.014). The settlements were aggregated according to the nitrate concentration into 10-percentile groups and the standardised mortality ratios (SMRs) were calculated. Those groups with higher than 88 mg/l average nitrate concentration showed substantial risk elevation and the log-transformed exposure variables proved to be significant predictors of mortality (p equals; 0.032) at this level of aggregation also. The association seemed to be fairly strong (r
2 equals; 0.46). Although this investigation constituting an ecological study has certain limitations, it supports the hypothesis that the high level of nitrate in drinking water is involved in the development of GC. 相似文献
92.
Joanne K. Marcario Mariam Riazi Istvan Adany Himanshu Kenjale Kandace Fleming Janet Marquis Olga Nemon Matthew S. Mayo Thomas Yankee Opendra Narayan Paul D. Cheney 《Journal of neuroimmune pharmacology》2008,3(1):12-25
Morphine is known to prevent the development of cell-mediated immune (CMI) responses and enhance expression of the CCR5 receptor
in monocyte macrophages. We undertook a study to determine the effect of morphine on the neuropathogenesis and immunopathogenesis
of simian immunodeficiency virus (SIV) infection in Indian Rhesus Macaques. Hypothetically, the effect of morphine would be
to prevent the development of CMI responses to SIV and to enhance the infection in macrophages. Sixteen Rhesus Macaques were
divided into three experimental groups: M (morphine only, n = 5), VM (morphine + SIV, n = 6), and V (SIV only, n = 5). Animals in groups M and VM were given 2.5 mg/kg of morphine sulfate, four times daily, for up to 59 weeks. Groups VM
and V were inoculated with SIVmacR71/17E 26 weeks after the beginning of morphine administration. Morphine prevented the development
of enzyme-linked immunosorbent spot-forming cell CMI responses in contrast to virus control animals, all of which developed
CMI. Whereas morphine treatment had no effect on viremia, cerebrospinal fluid viral titers or survival over the time course
of the study, the drug was associated with a tendency for greater build-up of virus in the brains of infected animals. Histopathological
changes in the brains of animals that developed disease were of a demyelinating type in the VM animals compared to an encephalitic
type in the V animals. This difference may have been associated with the immunosuppressive effect of the drug in inhibiting
CMI responses. 相似文献
93.
Role of endogenous cannabinoids in synaptic signaling 总被引:32,自引:0,他引:32
Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns. 相似文献
94.
95.
96.
Kindling-induced epilepsy alters calcium currents in granule cells of rat hippocampal slices 总被引:2,自引:0,他引:2
Istvan Mody James N. Reynolds Michael W. Salter Peter L. Carlen John F. MacDonald 《Brain research》1990,531(1-2):88-94
Single electrode voltage-clamp recordings were obtained from dentate gyrus granule cells (GCs) in hippocampal slices of control and commissurally kindled rats. Two types of calcium currents, a transient and a sustained current, were studied in control and kindled neurons. The threshold of the transient calcium current was lowered in kindled GCs. The sustained calcium current was absent in kindled neurons but it could be restored by the intracellular administration of the calcium chelator EGTA. Our findings are consistent with the hypothesis that the loss of an intraneuronal calcium binding protein (Calbindin-D28K; CaBP) reduces the intraneuronal calcium buffering capacity in kindled neurons and results in the enhanced calcium-dependent inactivation of sustained calcium currents. 相似文献
97.
Dr Prof Bernard Escudier MD Prof Anna Pluzanska MD Piotr Koralewski MD Prof Alain Ravaud MD Prof Sergio Bracarda MD Prof Cezary Szczylik MD Christine Chevreau MD Marek Filipek MD Bohuslav Melichar MD Prof Emilio Bajetta MD Prof Vera Gorbunova MD Jacques-Olivier Bay MD Istvan Bodrogi MD Agnieszka Jagiello-Gruszfeld MD Nicola Moore MSc for the AVOREN Trial investigators 《Lancet》2008,370(9605):2103-2111
98.
99.
Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. 总被引:1,自引:0,他引:1
Mario A Cabrera-Salazar Eric M Roskelley Jie Bu Bradley L Hodges Nelson Yew James C Dodge Lamya S Shihabuddin Istvan Sohar David E Sleat Ronald K Scheule Beverly L Davidson Seng H Cheng Peter Lobel Marco A Passini 《Molecular therapy》2007,15(10):1782-1788
Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients. 相似文献
100.
Pahl A Zhang M Török K Kuss H Friedrich U Magyar Z Szekely J Horvath K Brune K Szelenyi I 《The Journal of pharmacology and experimental therapeutics》2002,301(2):738-746
By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA. 相似文献