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1.
The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanations for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice. 相似文献
2.
K. Hamano Hiroshi Ito Andrew Bushell Kathryn J. Wood Kensuke Esato 《Transplant international》1997,10(4):293-298
In this study, the effect of combining anti-CD4 monoclonal antibody (mAb) and cyclosporin (CyA) therapy at the time of transplantation
was examined. A mouse cardiac allograft model was used. Anti-CD4 mAb administered perioperatively induces long-term survival.
The addition of a short course of CyA given subcutaneously in a regimen of either a high-dose treatment or a standard dose
treatment to the anti-CD4 mAb treatment protocol did not have a detrimental effect on graft survival. Despite having no significant
effect on graft survival, the addition of CyA to the treatment protocol did result in a significant decrease in the level
of IL-2 present in the hearts 7 days after transplantation. The decrease in IL-2 production was directly related to the presence
of CyA in vivo. When CyA treatment was continued throughout the period during which unresponsiveness to the graft is induced
by anti-CD4 mAb therapy, 50 % of the grafted hearts were rejected once the CyA was discontinued. In conclusion, the combined
use of anti-CD4 mAb therapy and CyA did not have a negative effect on graft survival in this model when the two agents were
used concurrently at the time of transplantation.
Received: 2 October 1996 Received after revision: 31 January 1997 Accepted: 5 February 1997 相似文献
3.
Nicotine discrimination and self-administration in humans as a function of smoking status 总被引:2,自引:2,他引:0
Nicotine’s discriminative stimulus effects may be critical to understanding reinforcement of tobacco smoking. It is not known
whether regular nicotine exposure produces tolerance or sensitivity to these effects. In this study, male and female smokers
(n = 11) and never-smokers (n = 10) were trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) on day 1. On day 2, both groups were
tested on generalization of this discrimination across intermittent presentations of 0, 3, 6, 12, and 20 μg/kg nicotine in
random order. Quantitative and quantal behavioral discrimination tasks, used in previous research, were employed. On day 3,
subjects were instructed to self-administer sprays from the 20 μg/kg nicotine versus 0 bottles in a concurrent-choice procedure.
All but one subject (female smoker) learned reliably to discriminate 20 μg/kg nicotine from placebo (≥ 80% correct) on day 1. Nicotine-appropriate responding on day 2 was attenuated in smokers versus never-smokers at 20 μg/kg
on the quantitative task and at 12 μg/kg on the quantal task, suggesting tolerance. There was no difference in responding
at other doses. Smokers also showed attenuated responses on the subjective measure of “head rush”, which was associated with
discrimination responding in both groups. Nicotine self-administration was significantly greater in smokers versus never-smokers,
who self-administered nicotine below chance levels, and was inversely related to discrimination behavior in never-smokers
but unrelated in smokers. Women smokers showed less change in nicotine-appropriate responding across generalization doses,
reported less confidence in discriminating training doses during acquisition on day 1, and tended to self-administer less
nicotine on day 3. These results indicate that smokers may become tolerant to the discriminative stimulus effects of nicotine,
perhaps promoting increased use.
Received: 1 October 1996/Final version: 28 January 1997 相似文献
4.
Ch. Baron Ph. Lang V. Bierre G. Rostoker B. Weil Ch. Baron V. Bierre G. Rostoker B. Weil 《Transplant international》1994,7(S1):606-610
Abstract The i.v. inoculation of parental spleen cells into unirradiated adult F1 hybrid mice results in a graft-versus-host reaction (GVHR). In the strain combination B10D2±(B10.BRx B10.D2) F1, this reaction is associated with thymic injury and transient but profound cellular immune deficiency. We further analysed the immune status of these mice 60 days after GVHR induction. Phenotypic studies of spleen cells showed that these mice were re-populated with parental lymphocytes resulting in a high degree of chimerism (85%). At this time, the mice looked healthy and recovered a normal cytotoxic T cell response (CTL) against allogeneic cells. GVH chimeric splenocytes were unresponsive against F 1 hybrid cells in mixed lymphocyte culture (MLC), but exhibited anti-F1 CTL reactivity. We also analysed the anti-F 1 reactivity of these mice in vivo. GVH chimeric splenocytes were unable to induce GVHR after injection into a new F1 hybrid and F1 GVH mice specifically rejected F1 bone marrow (BM) cells after lethal irradiation. Grafting a neonatal parental thymus prevented the rejection of F1 BM cells and restored CTL alloreactivity. It is concluded that the chimeric state induced by GVHR is associated with a split tolerance and that a radiosensitive thymic-dependent mechanism is involved in maintaining self-tolerance in these mice. 相似文献
5.
Rüdiger Schulz 《Naunyn-Schmiedeberg's archives of pharmacology》1988,338(6):644-648
Summary Chronic activation of opioid receptors results in the development of tolerance and dependence. Tolerance may be confined to a single receptor type and thus has been termed selective tolerance. The present investigation reveals that prolonged activation of an inhibitory acting receptor type not only results in dependence associated with this receptor but also brings about cross-dependence. Cross-dependence involves both opioid receptors as well as non-opioid receptors, e. g. adrenoceptors. The experimental design employed did not permit conclusions to be drawn about whether those receptors exhibiting cross-dependence also developed tolerance. Regardless of the receptors and their specific subsequent transduction systems, all the receptors which showed dependence and cross-dependence proved sensitive to pertussis toxin, suggesting a critical function of GTP-binding proteins for the development of not only opioid dependence but also for drug dependence in general. Since multiple transmitter receptors may converge on the same ion channel, the concept of convergent dependences may be linked to GTP-binding proteins. However, no conclusions can be drawn with regard to the precise biochemical mechanisms underlying dependence.
Send offprint requests to R. Schulz at the above address 相似文献
6.
Dr. David Lo Christina R. Reilly Linda C. Burkly Jenefer DeKoning Terri M. Laufer Laurie H. Glimcher 《Immunologic research》1997,16(1):3-14
Ten years ago, we proposed a model for thymus function in which thymic epithelial cells are primarily responsible for imprinting
major histocompatibility complex (MHC)-restricted specificity, and bone marrow-derived macrophages or dendritic cells are
responsible for the induction of self-tolerance. Since then, transgenic and knockout models have allowed for a dissection
of thymic stromal components in vivo, leading to a new understanding of their specialized functions. We have determined that
with regard to class II-restricted CD4 T-cell development, two distinct subsets of thymic epithelium help shape the repertoire:
Cortical epithelium appears solely responsible for positive selection, whereas a fucose-bearing subset of medullary epithelium
is specialized for negative selection. This absolute separation of positive and negative selection into two distinct spatial
and temporal compartments leads to a much simpler view of the process of repertoire selection. Finally, a novel view of the
function of the thymic medulla is discussed. 相似文献
7.
Clio Mamalaki Marianna Murdjeva Mauro Tolaini Trisha Norton Phillip Chandler Alain Townsend Elizabeth Simpson Dimitris Kioussis 《Clinical & developmental immunology》1995,4(4):299-315
Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed
with transgenic mice expressing the cognate antigenic protein under the control of the H-
2Kb promoter. Double-transgenic mice show negative selection of thymocytes at the
CD4+8+TCR10 to CD4+8+TCRhi transition stage. A few CD8 T cells, however, escape clonal
deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of
the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do
not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can
develop low but detectable levels of antigen-specific cytotoxic function after stimulation
in vitro in the presence of IL-2. 相似文献
8.
We measured body temperature and serum iron concentration after five daily consecutive injections of febrile doses of Salmonella typhosa lipopolysaccharide (0.1 g/kg) and two doses of Staphylococcus aureus cell walls (1×107 and 5×107 cells) in rabbits. Tolerance to endotoxin injection, as manifest by a significant attenuation in the body temperature elevation, developed after the first injection of endotoxin. The endotoxin-induced fall in serum iron concentration was attenuated significantly by the 5th day of endotoxin injection. In contrast, no tolerance developed in either the body temperature or serum iron response following repeated daily injections of S. aureus. Rabbits rendered tolerant to endotoxin showed normal febrile and serum iron responses to subsequent S. aureus injection. Rabbits given serial injections of S. aureus, although not tolerant to S. aureus itself, exhibited attenuated body temperature responses but not serum iron responses to endotoxin injection. We suggest that repeated injection of endotoxin diminishes the ability of endotoxin to stimulate endogenous pyrogen (EP) synthesis and/or release, a property not shared by the gram-positive pyrogen S. aureus. However, repeated injection of S. aureus weakens the central endotoxin-EP pathway. 相似文献
9.
Effective induction of immune tolerance by portal venous infusion with IL-10 gene-modified immature dendritic cells leading to prolongation of allograft survival 总被引:14,自引:0,他引:14
Zhang M Wang Q Liu Y Sun Y Ding G Fu Z Min Z Zhu Y Cao X 《Journal of molecular medicine (Berlin, Germany)》2004,82(4):240-249
Dendritic cells (DC) not only initiate T cell responses, but are also involved in the induction of tolerance. The functional properties of DC are strictly dependent on their state of maturation. It has been shown that immature DC can induce immune tolerance and prolong allograft survival. Interleukin-10 (IL-10) is an important immunosuppressive cytokine which inhibits maturation and function of DC. In order to improve the tolerogenicity of DC, we and others showed that adenovirus vectors can effectively mediate IL-10 genetic modification of DC, and IL-10 genetic modification can inhibit MHC II, B7.2, and CD40 expression, IL-12 secretion and the T cell stimulatory capacity of DC. The primary aim of this study is to examine the in vivo effects of this approach on allograft survival in a murine cardiac allograft transplantation model. To our surprise, we observed that infusion of immature DC genetically modified to express IL-10 (DC-IL-10) via the tail vein could not prolong allograft survival in the recipients, but shortened their survival. More interestingly, portal venous infusion of DC-IL-10 markedly prolonged allograft survival. The diverse effects of DC-IL-10 infusion through different routes may be due to the different immune responses to alloantigens in recipients that received DC-IL-10 via either the portal or the tail vein. Decreased cytotoxicity, polarization of Th2 response, poor T cell stimulating activity of liver DC and enhanced incidence of donor DC in the recipients may contribute to the more efficient prolongation of allograft survival observed after portal venous infusion of DC-IL-10. These results suggest that portal venous infusion may be an effective approach for immature DC to induce immune tolerance or hyporesponsiveness against donor antigens, and prolong allograft survival.Abbreviations
APC
Antigen-presenting cells
-
CTL
Cytotoxic T lymphocytes
-
DC
Dendritic cells
-
DC-IL-10
IL-10 gene-modified immature dendritic cells
-
iDC
Immature dendritic cells
-
IL-10
Interleukin-10
-
MLR
Mixed leukocyte reaction
-
MOI
Multiplicity of infection 相似文献
10.
Cohn M 《Immunologic research》2005,31(2):133-150
An effective immune response to an antigen requires two sets of decisions: Decision 1, the sorting of the repertoire, and
Decision 2, the regulation of effector class. The repertoire, because it is somatically generated, large, and random, must
be sorted by a somatic mechanism that subtracts those specificities (anti-self) that, if expressed, would debilitate the host,
leaving a residue (anti-nonself) that, if not expressed, would result in the death of the host by infection. The self-nonself
discrimination is the metaphor used to describe Decision 1, the sorting of the repertoire. In order to be functional, the
sorted repertoire must be coupled to a set of biodestructive and ridding effector functions, such that the response to each
antigen is treated in a coherent and independent manner. Although a reasonably complete framework for Decision 1 exists, Decision
2 lacks conceptualization. The questions that must be considered to arrive at a proper framework are posed. It should be emphasized
that manipulation at the level of Decision 2 is where clinical applications are likely to be found. 相似文献