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11.
Burger AM 《BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy》1999,12(6):413-422
Curing cancers is one of the most challenging tasks of modern medicine. The major problem is the heterogeneity of human tumours and thus finding a 'universal' target for cancer treatment. The discovery that the expression of the enzyme telomerase is a hallmark of immortality and cancer, and that it is found in the majority (>85%) of human tumours but is repressed in most normal cells, has therefore caused considerable excitement. These observations led to the design of potential telomerase inhibitors and ideas about targeting telomerase in the clinic. To date, several classes of telomerase inhibitory agents have been identified and are in preclinical development. However, the approach has not yet been tested clinically. Because of the proposed function of telomerase, and the understanding that replicative cell senescence or cell death result from progressive telomere shortening during successive cell divisions, even complete enzyme inhibition will not produce immediate cell death. Designing clinical trials for promising telomerase inhibitors requires consideration of the novel mechanism of action of these drugs. A lag period between initiation of treatment and occurrence of effects is likely, and thus anti-telomerase therapy might best be given in adjuvant treatment protocols after initial tumour debulking therapy and in combination with other cytostatic agents. The available knowledge of telomerase biology and its association with human tumours suggests that telomerase inhibition might prove a valuable addition to current cancer treatment regimens. 相似文献
12.
We investigated the surface phenotype of CD3+CD4+ T cell receptor (TCR) αβ+ T cells repopulating the intestinal lymphoid tissues of C.B-17 scidlscid (severe-combined immunodeficient; scid) (H-2d, Ld+) mice. CD4+ CD8? T cells were cell sorter-purified from various secondary and tertiary lymphoid organs of congenic C.B-17 +/+ (H-2d, Ld+) or semi-syngeneic dm2 (H-2d, Ld?) immunocompetent donor mice. After transfer of 105 cells into young scid mice, a mucosa-homing, memory CD44hi CD45RBlo CD4+ T cell population was selectively engrafted. Large numbers of single-positive (SP) CD3+ CD2+ CD28+ CD4+ CD8? T cells that expressed the α4 integrin chain CD49d were found in the spleen, the mesenteric lymph nodes, the peritoneal cavity and the gut lamina propria of transplanted scid mice. Unexpectedly, large populations of donor-type doublepositive (DP) CD4+ CD8α+ CD8β? T cells with high expression of the CD3/TCR complex appeared in the epithelial layer of the small intestine of transplanted scid mice. In contrast to SP CD4+ T cells, the intraepithelial DP T cells showed low expression of the CD2 and the CD28 co-stimulator molecules, and of the α4 integrin chain CD49d, but expressed high levels of the αIEL integrin chain CD103. The TCR-Vβ repertoire of DP but not SP intraepithelial CD4+ T cells was biased towards usage of the Vβ6 and Vβ8 viable domains. Highly purified populations of SP and DP CD4+ T cell populations from the small intestine epithelial layer of transplanted scid mice had different abilities to repopulate secondary scid recipient mice: SP CD4+ T cells repopulated various lymphoid tissues of the immunodeficient host, while intraepithelial DP CD4+ T cells did not. Hence, a subset of CD3+ CD4+ TCRαβ+ T cells apparently undergoes striking phenotypic changes when it enters the microenvironment of the small intestine epithelial layer. 相似文献
13.
Dialysable transfer factor (TF) was given in 10 paediatric patients with severe atopic dermatitis (AD). Ten patients with AD, matched for age and severity of disease, served as controls.
Prior to the therapy with TF and at weekly intervals thereafter, T- and B-cells in the blood, PHA-stimulation, total IgE and specific IgE antibodies to inhalant and food antigens were determined. Therapy with TF was followed by IgE depression in 8/10 patients and was most pronounced in three patients with initially high levels. Some decrease of IgE levels was seen in four controls also, none of them, however, fell to normal levels as was seen in two of the treated patients.
Specific IgE levels decreased slightly, but always remained within the pathological range. T-cell counts in the blood increased in 2/10 cases as well as PHA-stimulation. B-cell counts remained within normal limits. Clinical improvement was seen in one patient, five improved slightly and four remained unchanged.
Our results indicate, that transfer factor can lower total IgE levels in cases with atopic dermatis. The effect is most marked in patients with high total IgE levels. Skin involvement, however, does not closely follow in vitro findings. 相似文献
Prior to the therapy with TF and at weekly intervals thereafter, T- and B-cells in the blood, PHA-stimulation, total IgE and specific IgE antibodies to inhalant and food antigens were determined. Therapy with TF was followed by IgE depression in 8/10 patients and was most pronounced in three patients with initially high levels. Some decrease of IgE levels was seen in four controls also, none of them, however, fell to normal levels as was seen in two of the treated patients.
Specific IgE levels decreased slightly, but always remained within the pathological range. T-cell counts in the blood increased in 2/10 cases as well as PHA-stimulation. B-cell counts remained within normal limits. Clinical improvement was seen in one patient, five improved slightly and four remained unchanged.
Our results indicate, that transfer factor can lower total IgE levels in cases with atopic dermatis. The effect is most marked in patients with high total IgE levels. Skin involvement, however, does not closely follow in vitro findings. 相似文献
14.
15.
Amadou Kane Edmond Ekué Creppy Angelika Roth Robert Röschenthaler Guy Dirheimer 《Archives of toxicology》1986,58(4):219-224
The distribution of a single low dose of [3H]ochratoxin A (OTA) in different tissues of male Wistar rats, after administration by intubation, was investigated after 5 h, 24 h and 48 h. This dose corresponds to concentrations encountered in naturally contaminated feed (4 ppm). The distribution of [3H]-label varied with the time elapsed after administration; at 5 h the highest specific label was found in the stomach contents and in decreasing order in: intestinal contents, lung, liver, kidney, heart, fat, intestine, testes, and the lowest in muscles, spleen and brain. With exception of brain, fat, stomach and lung, all tissues showed maximum levels at 24 h, after which time the label decreased steadily, whereas in fat it increased.After a 12-week feeding experiment, with doses of 288.8 g/kg corresponding to an intake of 4 ppm in feed each 48 h, the DNA in liver and kidneys was investigated for damage. By the alkaline elution method combined with micro-spectrofluorimetric determinations of DNA, evidence for DNA single-strand breaks was obtained. These findings support reports on the carcinogenic action of OTA. 相似文献
16.
Wong Jasin Ezeife Nnaemezie Kudla Angelika Crown Deborah Trierweiler Robert Capraro Pamela Tomazin Stephanie Su Han Pham Tri Heinemann Allen W. 《Journal of occupational rehabilitation》2022,32(3):464-472
Journal of Occupational Rehabilitation - Purpose The COVID-19 pandemic has disproportionately affected the lives of people with disabilities (PWD). How the pandemic affects the employment of PWD... 相似文献
17.
Erkens Christiane Scharmanski Sara Heßling Angelika 《Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz》2021,64(11):1382-1390
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Seit 1998 erhebt die Bundeszentrale für gesundheitliche Aufklärung (BZgA) im Rahmen ihrer Repräsentativbefragung... 相似文献
18.
Angelika Krämer Wolfgang Saeger Gesche Tallen Dieter K. Lüdecke 《Endocrine pathology》1994,5(4):198-211
To assess the proliferative activity of pituitary adenomas, 36 surgically removed adenomas were studied by light microscopical parameters; mitotic count; expression of PCNA, Ki-67, cathepsin D, and EGF; and image cytometry. Three adenomas (9%) showed high, 11 (34%) medium, 17 (53%) moderate, and 1 (3%) low structural differentiation. In 10 adenomas (31%), no mitosis was observed. The average was 2.4 mitoses/100 HPF; the highest count was 7.1 mitoses/100 HPF. Eleven adenomas (33.3%) were PCNA-negative; in 20 adenomas (60.6%), between 0.05 and 3.9, and in 2 adenomas (6.0%), between 10.5 and 16.4 PCNA-positive nuclei were observed. Only a recurrent null-cell adenoma (9%) was Ki-67-negative. Three adenomas (9.1%) were EGF-negative, 28 (84.8%) showed up to 10% positive cells, and 2 (6.1 %) showed between 10 and 30% positive cells; 19 adenomas (68%) were cathepsin D-negative, including all endocrine-inactive adenomas. Half the adenomas had an euploid DMA stem line. Endocrine-inactive adenomas displayed a higher rate of euploid DNA stem lines than endocrine-active adenomas. The S-phase fraction varied between 2.97 and 28%, with a mean value of 14.4%. Half the adenomas showed an S-phase fraction of 11.65% or lower. 相似文献
19.
Modulation of electrically evoked [3H]-noradrenaline release from cultured chick sympathetic neurons
Clemens Allgaier Angelika Schobert Manuela Belledin Rolf Jackisch Georg Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1994,350(3):258-266
In the present study we attempted a comprehensive characterization of modulation of noradrenaline release from chick sympathetic neurons. To this purpose sympathetic neurons derived from chick lumbosacral paravertebral ganglia and kept in culture for 7 days were loaded with 0.05 mol/l [3H]-noradrenaline and subjected to electrical field stimulation (36 pulses/3 Hz). Since the released transmitter was partially recaptured, superfusion was usually performed in the presence of (+)-oxaprotiline, an inhibitor of noradrenaline re-uptake. [3H]-Noradrenaline was released in a manner which was dependent on extracellular Ca2+ and sensitive to tetrodotoxin (TTX). -Conotoxin (-CTX; 100 nmol/l) abolished [3H]-noradrenaline release indicating that influx through -CTX-sensitive Ca2+-channels was essential for transmitter release. 1,4-dihydro-2,6-dimethyl-5-nitro4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester ((±)Bay K 8644) and 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridinecarboxylic acid isopropyl ester ((±)-202-791), agonists at L-type voltage sensitive Ca2+-channels (VSCCs), increased noradrenaline release and induced, in addition, an overflow of tritium which was Ca2+-dependent and prevented by the presence of TTX. The L-type VSCC antagonists (–)-202-791 and (+)-4-(4-benzofurazanyl)-1,4-dihydro2,6-dimethyl-3,5-pyridinedicar boxylic acid methyl, isopropyl ester ((+)-PN 200–110) diminished [3H]-noradrenaline release. These data suggest that L-type VSCCs, probably located on the cell body of the neuron, play an additional role in modulation of release. The full 2-adrenoceptor agonists 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline ( UK-14,304) and noradrenaline significantly inhibited noradrenaline release, whereas clonidine, a partial a2-agonist, produced only a slight inhibition even at 10 mol/l. The facilitation of noradrenaline release observed in the presence of the 2-adrenoceptor antagonist rauwolscine was very low in comparison to that obtained with brain slices and isolated smooth muscle tissues. These results corroborate the observation that noradrenaline release from chick sympathetic neurons is regulated by an 2-adrenoceptor which needs further subtype characterization. The experiments were mostly performed at 25°C, since a rise in temperature to 37°C increased the resting outflow, but not the evoked overflow of tritium, approximately 4-fold. In the presence of pargyline to block monoamine oxidase, however, the temperature-dependent enhancement was diminshed and the release showed properties comparable to those observed at 25°C (with respect to TTX-sensitivity, Ca2+ dependence and modulation via 2-adrenoceptors). In addition to the 2-adrenoceptors, we detected inhibitory -adrenoceptors, opioid and receptors, and P2 purinoceptors as well as facilitatory prostaglandin (PG) E receptors. No indication was found for a functional relevance of 5-hydroxytryptamine (5-HT), opioid , PGD, adenosine A1 or glutamate receptors. In conclusion, electrically evoked noradrenaline release from cultured chick sympathetic neurons shows the properties of action-potential-induced transmitter release and is bidirectionally regulated by various substances. Therefore, sympathetic neurons in culture offer the possibility to investigate directly the mechanisms bringing about receptor-coupled modulation of transmitter release.Abbreviations ATP
adenosine 5-triphosphate
- Bay K 8644
1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester
- DAGO
(d-Ala2,N-methyl-Phe4,Gly-ol5)-enkephalin
- DPDPE
(d-Pen 2,5)-enkephalin
- 5-HT
5-hydroxytryptamine
- -CTX
-conotoxin
- KRBB
modified Krebs-Ringer bicarbonate buffer
- NMDA
N-methyl-d-aspartic acid
- PG
prostaglandin
- PN 200-110
4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxy lic acid methyl, isopropyl ester
- R-PIA
R(–)-N6-(2-phenyl-isopropyl)-adenosine
- TTX
tetrodotoxin
- U-50,488H
trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide
- UK-14,304
5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline
- VSCC
voltage sensitive Ca2+-channel
- 202-791
4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridinecarboxylic acid isopropyl ester
Correspondence to: C. Allgaier at the above address 相似文献
20.
Clemens Allgaier Henning Wellmann Angelika Schobert Gerhart Kurz Ivar von Kügelgen 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(1):25-30
The ATP-induced increase in tritium outflow from cultured chick sympathetic neurons prelabelled with [3H]-noradrenaline was investigated.Seven days-old dissociated cell cultures of embryonic paravertebral ganglia, loaded with [3H]-noradrenaline (0.05 M), were superfused in the presence of (+)-oxaprotiline and exposed to ATP, ATP-analogues, or 1,1-dimethyl-4-piperazinium (DMPP) for 2 min. ATP (3 LM-3 mM), 2-methylthio-ATP (3–100 M), as well as DMPP (10 and 100 M) induced a significant overflow of tritium. The EC50-value of ATP was 20 M. Both the ATP-induced and the DMPP-induced tritium overflow was Ca2+-dependent and sensitive to tetrodotoxin (0.3 M) and -conotoxin (0.1 M); in addition, it was inhibited by the 2-adrenoceptor agonist 5-bromo-6-(2-imidazoline-2-ylamino)-quinoxaline (UK-14,304; 1 M). The effects of ATP and DMPP were not additive. The ATP-induced as well as the DMPP-induced overflow of tritium was diminished by the P2-purinoceptor antagonists suramin (300 M) and reactive blue 2 (3 M); in all 4 cases, the inhibition amouted to approximately 40%. The tritium overflow induced by ATP or DMPP was almost abolished by the nicotinic receptor antagonist mecamylamine (10 M) and markedly inhibited by hexamethonium (100 M). Neither ATP nor electrical stimulation caused an overflow of tritium from cultures loaded with [3H]-choline.The results suggest that ATP at molar concentrations induces noradrenaline release from cultured chick sympathetic neurons via an action on a subclass of the nicotinic cholinoceptor. 相似文献