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11.
Hansen LA; Malarkey DE; Wilkinson JE; Rosenberg M; Woychik RE; Tennant RW 《Carcinogenesis》1998,19(10):1837-1845
We previously reported that papillomas can arise from the follicular
epithelium of v-Ha-ras transgenic TGxAC mice. Since the viable-yellow
mutation (A(vy)) of the mouse agouti gene which regulates coat color
pigmentation by acting within the micro-environment of the hair follicle
has been shown to function as a tumor promoter in the liver, we
hypothesized that it may also play a role in TGxAC skin tumorigenesis.
Endogenous agouti protein product was detected in the outer root sheath of
anagen hair follicles following plucking of the hair shaft, but not in the
interfollicular epithelium, in TGxAC mice on an FVB/N genetic background.
It was also detected in papillomas from these mice produced by
12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking.
Expression of the A(vy) allele in the v-Ha-ras transgenic TGxAC mouse line
results in an approximately 2-fold increase in papilloma development
compared with controls which did not carry the A(vy) allele following
twice-weekly treatment with 1.25, 2.5 or 5.0 microg TPA. In addition,
TPA-treated, papilloma-bearing F1 mice which carried the A(vy) allele, but
not F1 mice which did not carry the A(vy) allele, exhibited a syndrome of
humoral hypercalcemia mediated by parathyroid hormone-related protein
(PTHrP) that led to weight loss, hypercalcemia and hypophosphatemia. Thus,
we conclude that the A(vy) allele can influence the development of skin
tumors and PTHrP-mediated humoral hypercalcemia in v-Ha-ras transgenic
TGxAC mice.
相似文献
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Ortiz-Alvarez O; Cabral D; Prendiville JS; Stringer D; Petty RE; Malleson PN 《Rheumatology (Oxford, England)》1997,36(2):280-284
Two children are reported in whom intestinal pseudo-obstruction was the
initial manifestation of systemic sclerosis. Gastrointestinal symptoms and
skin changes resolved or improved in both children following treatment with
prednisone and penicillamine (case 1) or methotrexate (case 2), although
radiological changes of the gastrointestinal tract persisted at 3 and 2 yr
of follow-up, respectively.
相似文献
14.
Jacqueline AM Smith DL Patil OT Daniels Y-S Ding J-D Gallezot S Henry KHS Kim S Kshirsagar WJ Martin GP Obedencio E Stangeland PR Tsuruda W Williams RE Carson ST Patil 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(2)
Background:
Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.Methods:
We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.Results:
TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [11C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [11C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.Conclusions:
These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation. 相似文献15.
Jolien Suurmond Jurgen van Heemst Jacqueline van Heiningen Annemarie L. Dorjée Marco W. Schilham Feddo B. van der Beek Tom W.J. Huizinga Annemie J.M. Schuerwegh René E.M. Toes 《European journal of immunology》2013,43(7):1758-1768
Mast cells (MCs) are immune cells residing in tissues where pathogens are first encountered. It has been indicated that MCs might also be involved in setting the outcome of T‐cell responses. However, little is known about the capacity of human MCs to express MHC class II and/or to capture and present antigens to CD4+ T cells. To study the T‐cell stimulatory potential of human MCs, CD34+ stem cell derived MCs were generated. These cells expressed HLA‐DR when stimulated with IFN‐γ, and, importantly, presented peptide and protein for activation of antigen‐specific CD4+ T cells. The interplay between MC and T cell led to increased HLA‐DR expression on MCs. MCs were present in close proximity to T cells in tonsil and expressed HLA‐DR and CD80, indicating their ability to present antigens to CD4+ T cells in T‐cell areas of human LNs. Our data show that MCs can present native antigens to human CD4+ T cells and that HLA‐DR expressing MCs are present in tonsil tissue, indicating that human MCs can directly activate T cells and provide a rationale to study the potential of MCs to prime and/or skew human T‐cell responses. 相似文献
16.
Control of systemic B cell-mediated autoimmune disease by nonmyeloablative conditioning and major histocompatibility complex-mismatched allogeneic bone marrow transplantation 下载免费PDF全文
Flierman R Witteveen HJ van der Voort EI Huizinga TW de Vries RR Fibbe WE Toes RE van Laar JM 《Blood》2005,105(7):2991-2994
Systemic autoimmune disease (AID) can be controlled with conventional therapies in most patients. However, relapses are common, leading to progressive disability and premature death. Nonmyeloablative conditioning and allogeneic bone marrow transplantation (BMT) could be an effective treatment for severe AID, because of mild toxicity of the conditioning and the potential benefits of donor chimerism. We examined the effects of this treatment in experimental autoimmune arthritis. Our results demonstrate the induction of complete donor chimerism and significant suppression of disease activity. No clinical graft-versus-host disease (GVHD) was observed. The beneficial effects were most likely caused by the elimination of plasma cells producing pathogenic autoantibodies, because these antibodies disappeared rapidly after BMT. Although this type of treatment was effective in organ-specific T-cell-mediated AID, the present study provides convincing evidence that nonmyeloablative conditioning and allogeneic BMT can effectively treat severe B-cell-mediated AID with a systemic inflammatory component. 相似文献
17.
Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10 总被引:8,自引:0,他引:8
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