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71.
Huang Tien L. Székács András Uematsu Tamon Kuwano Eiichi Parkinson Andrew Hammock Bruce D. 《Pharmaceutical research》1993,10(5):639-648
Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K
m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased. 相似文献
72.
Key words dysrhythmia - isorhythmic dissociation - oscillation 相似文献
73.
Great horovement haS been made in the cryopreservation Of inalnlnalian elnbmp since wnttingham['] reported his Pioneering wold about successful cryOPreservationof mouse embryo. It results in the availability of cryOPreserVation of embryos of all stages[']. HOwever, cryopreserved embryos can not avoid the damages by ice crystal,which is a major cause of cen death in the freezing andthawing ProceduresL',']. SO it is necesseq to seareh for anew and more efficient method for embryO cryOPrese… 相似文献
74.
Shuji Kaneko Nobumichi Yada Koichiro Fukuda Masanobu Kikuwaka Akinori Akaike Masamichi Satoh 《British journal of pharmacology》1997,121(4):806-812
- Desensitization of μ- and κ-opioid receptor-mediated inhibition of voltage-dependent Ca2+ channels was studied in a Xenopus oocyte translation system.
- In the oocytes coexpressing κ-opioid receptors with N- or Q-type Ca2+ channel α1 and β subunits, the κ-agonist, U50488H, inhibited both neuronal Ca2+ channel current responses in a pertussis toxin-sensitive manner and the inhibition was reduced by prolonged agonist exposure.
- More than 10 min was required to halve the inhibition of Q-type channels by the κ-agonist. However, the half-life for the inhibition of N-type channels was only 6±1 min. In addition, in the oocytes coexpressing μ-opioid receptors with N-type or Q-type channels, the uncoupling rate of the μ-receptor-mediated inhibition of N-channels was also faster than that of Q-type channels.
- In the oocytes coexpressing both μ- and κ-receptors with N-type channels, stimulation of either receptor resulted in a cross-desensitization of the subsequent response to the other agonist. Treatment of oocytes with either H-8 (100 μM), staurosporine (400 nM), okadaic acid (200 nM), phorbol myristate acetate (5 nM) or forskolin (50 μM) plus phosphodiesterase inhibitor did not affect either the desensitization or the agonist-evoked inhibition of Ca2+ channels.
- These results suggest that the rate of rapid desensitization is dependent on the α1 subtype of the neuronal Ca2+ channel, and that a common phosphorylation-independent mechanism underlies the heterologous desensitization between opioid receptor subtypes.
75.
Marked Suppression of T Cells by a Benzothiophene
Derivative in Patients with Human T-Lymphotropic Virus Type
I-Associated Myelopathy/Tropical Spastic Paraparesis
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Masahiko Makino Miyuki Azuma Shin-Ichi Wakamatsu Yukio Suruga Shuji Izumo Mitchel M. Yokoyama Masanori Baba 《Clinical and Vaccine Immunology : CVI》1999,6(3):316-322
In a search for new anti-autoimmune agents that selectively
suppress activation of autoreactive T cells, one such agent,
5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide
(CI-959-A), was found to be effective. This compound, which is known to
suppress tumor necrosis factor alpha (TNF-α)-induced CD54 expression,
inhibited the primary proliferative response of the T cell to antigen
(Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs),
autologous Epstein-Barr virus-infected B cells, and human T
lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T
cells from patients with HTLV-I-associated myelopathy/tropical spastic
paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their
activation is reported to be associated with CD54 expression. The
spontaneous proliferation of T cells from patients with HAM/TSP was
entirely blocked by CI-959-A. However, in this study, the T-cell
proliferation in 15 patients with HAM/TSP was found to depend more
extensively on major histocompatibility complex (MHC) class II and CD86
than on CD54 Ags. Since most important APCs for the development of
HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on
DC generation and on the expression of surface molecules on activated T
cells is examined. CI-959-A suppressed recombinant
granulocyte-macrophage colony stimulating factor (GM-CSF)- and
recombinant interleukin-4-dependent differentiation of DCs from
monocytes and inhibited the expression of CD54 and, more extensively,
MHC class II and CD86 Ags. CI-959-A showed little toxicity toward
lymphoma or HTLV-I-infected T-cell lines or toward monocytes and
cultured DCs. These results suggest that CI-959-A might be a potent
anti-HAM/TSP agent.Human T lymphotropic virus type I
(HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
is thought to be an autoimmune disease induced by HTLV-I infection
(8, 9, 24). The T lymphocytes obtained from patients with
HAM/TSP patients produce interleukin-2 (IL-2) in vivo and proliferate
spontaneously in vitro without any additional stimuli or cytokines
(35). This spontaneous proliferation of T lymphocytes (SPL)
depends on the interaction of T cells with antigen (Ag)-presenting
cells (APCs) such as dendritic cells (DCs) (17, 25) and
HTLV-I-infected CD4+ T cells (15, 32). The DCs
localized in the blood and nonlymphoid organs are considered to be
functionally immature, in that they are optimized for the uptake and
processing of Ag but not for the initiation of primary T-cell
responses. However, after the uptake of Ag and exposure to inflammatory
agents including tumor necrosis factor alpha (TNF-α) and IL-1, the
DCs undergo a process of maturation and gain the ability to present Ag
to T cells for their priming (22, 26). In addition to DCs,
HTLV-I-infected CD4+ T cells directly stimulate autologous
CD4+ T cells in a major histocompatibility complex (MHC)
class II- and CD86 molecule-dependent fashion (32). Among
the T cells stimulated with these APCs, some might cross-react with
self Ags and closely associate with the development of HAM/TSP.We have been searching for compounds that inhibit the cellular
interaction between APCs and T cells to suppress the activation of
autoreactive and Ag-specific T cells. The molecules associated with the
APC-T cell interaction may provide an effective target for therapy for
autoimmune diseases. Binding of APCs and T cells is initiated by
contact of adhesion molecules, such as CD54 and CD11a/CD18, expressed
on both cells, and induction of sustained proliferation of T cells
requires two independent signals provided by APCs: a T-cell
receptor-mediated Ag-specific signal and a signal mediated by
costimulatory molecules (CSMs) (10, 20) including CD86 and
CD58 Ags (1, 11, 31). Blocking of their tight binding
through adhesion molecules or interaction of the CSMs with CSM ligands
effectively suppressed the abnormal expansion of disease-associated T
cells in vivo and in vitro (19, 30, 32) and sometimes
effectively induced a long-term unresponsiveness of T cells to recall
stimuli.5-Methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carbox-amide
(CI-959-A) is known to inhibit CD54 expression, and its derivative is
reported to inhibit casein kinase II (4). In the present
study, we found that CI-959-A markedly suppressed SPL in patients with
HAM/TSP. Furthermore, the compound suppressed the primary T-cell
proliferative response to stimuli provided by various APCs, the
differentiation of immature DCs from monocytes and their subsequent
maturation, and the induction of expression of MHC class II, CD54, and
CD86 Ags on activated CD4+ T cells. 相似文献
76.
Differential role of components of the fibrinolytic system in the formation and removal of thrombus induced by endothelial injury 总被引:9,自引:0,他引:9
Matsuno H Kozawa O Niwa M Ueshima S Matsuo O Collen D Uematsu T 《Thrombosis and haemostasis》1999,81(4):601-604
The role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4+/-1.3, 9.8+/-1.1 or 9.7+/-1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (1 8.4+/-3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis. 相似文献
77.
Miyaguni T Deguchi S Teruya J Kuniyoshi S Tomita S Soda N Muto Y 《Breast cancer (Tokyo, Japan)》1998,5(2):205-208
A huge phyllodes tumor of the breast that appeared grossly malignant in a 43-year-old woman is described. The patient suffered
from a large breast tumor that suddenly increased in size over 5 months to occupy the entire breast. The tumor was hard, ulcerated
and 20 cm in greatest diameter. Diagnostic imaging (US, CT and MRI) demonstrated a circumscribed mass with a large cystic
cavity. She underwent total mastectomy under a diagnosis of malignant breast tumor. Grossly, the cut surface of the tumor
showed a large cystic cavity surrounding a fleshy, hemorrhagic and necrotic mass with a lobulared or trabeculared appearance.
Unexpectedly, benign phyllodes tumor (PT) without any stromal overgrowth was diagnosed histologically. She has been doing
well since total mastectomy. In our case and in many other reported cases, PT does not show any distinctive correlation between
pathologic findings and tumor behavior. Thus wide local excision is the preferred initial treatment for PT. 相似文献
78.
Kenya Murase Shuji Tanada Takeshi Inoue Yoshifumi Sugawara Ken Hamamoto 《European journal of nuclear medicine and molecular imaging》1993,20(1):32-38
Attenuation coefficient maps (-maps) are a useful way to compensate for non-uniform attenuation when performing single photon emission tomography (SPET). A new method was developed to record single photon transmission data and a-map for the brain was produced using a four-head SPET scanner. Transmission data were acquired by a gamma camera opposite to a flood radioactive source attached to one of four gamma cameras in the four-head SPET scanner. Attenuation correction was performed using the iterative expectation maximization algorithm and the-map. Phantom studies demonstrated that this method could reconstruct the distribution of radioactivity more accurately than conventional methods, even for a severely non-uniform-map, and could improve the quality of SPET images. Clinical application to technetium-99m hexamethylpropylene amine oxime (HMPAO) brain SPET also demonstrated the usefulness of this method. Thus, this method appears to be promising for improvement in the image quality and quantitative accuracy of brain SPET.This work was presented in part at the World Congress on Medical Physics and Biomedical Engineering, 7–12 July 1991, Kyoto, Japan 相似文献
79.
Tohru Ozaki Toshihiko Uematsu Satoru Nagashima Masahiko Nishimoto Mitsuyoshi Nakashima 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(4):478-487
Summary DPI 201-106 (DPI), a novel and potent cardiotonic agent, exhibits its effects by prolonging the open state of Na+ channels, resulting in an increase in action potential duration, and thus, is supposed to share the class III antiarrhythmic activity. The effects of DPI on the hemodynamics, intraventricular conduction and refractoriness of heart, and the incidence of arrhythmias induced by programmed electrical ventricular stimulation (PES) were compared with (±)-dobutamine. Dogs which survived for 5 to 7 days after the induction of myocardial infarction were used as the model. The presence of sub-acute myocardial infarction caused by occluding the left anterior descending coronary artery elicited a mild left ventricular dysfunction represented by a significant decrease in peak LV dp/dt by about 20%.Both i.v. bolus injection of DPI (1, 3 and 5 mg/kg) and i. v. continuous infusion of dobutamine (3, 5 and 10 g/kg/min), which were administered in a cumulative manner, dose-dependently improved the hemodynamic parameters. At the higher doses of both DPI (3 and 5 mg/kg) and dobutamine (5 and 10 g/kg/min) the control values were reached or even exceeded. DPI dose-dependently increased the effective refractory period (ERP) of both non-infarcted and infarcted ventricular myocardia to a similar degree, but the conduction time showed a frequency-dependent increase in the infarcted myocardium to a greater degree than in the non-infarcted myocardium after DPI. In contrast, dobutamine decreased the ERP in both non-infarcted and infarcted myocardia, and slightly increased the difference of refractoriness between the non-infarcted and infarcted zones with no effect on the intraventricular conduction. In the PES study, DPI (3 and 5 mg/kg) produced a significant decrease in the incidence of ventricular tachycardia, whereas dobutamine (5 and 10 g/kg/min) tended to worsen the arrhythmias. These findings suggest that cardiotonic agents with a class III antiarrhythmic property such as DPI may be potentially useful for the management of heart failure accompanied by ischemic heart disease.Abbreviations DPI, DPI 201-106; PES
programmed electrical ventricular stimulation
- LV dp/dt
the rate of rise of left ventricular pressure
- ERP
effective refractory period
- RVOT
right ventricular outflow tract
- VT
ventricular tachycardia
- LAD
left anterior discending coronary artery
Send offprint requests to T. Uematsu at the above address 相似文献
80.
Prof. Mitsuyoshi Nakashima PhD MD J. Yamamoto M. Shihata T. Uematsu H. Shinjo T. Akahori H. Shioya K. Sugiyama Y. Kawahara 《European journal of clinical pharmacology》1992,43(6):657-659
Summary The pharmacokinetics of temocapril hydrochloride, a novel prodrug-type angiotensin-I converting enzyme (ACE) inhibitor, has been studied in patients with mild (Group II) to severe (Group III) renal insufficiency in comparison with subjects with normal renal function (Group I).The pharmacokinetic parameters of the active diacid metabolite, including Cmax, AUC and half-life (t1/2), showed only slight changes between the three groups: AUC (0–) was significantly larger in Group III than Group I, and t1/2 tended to be prolonged in Group III, but the change was not significant.The urinary recovery of the diacid was significantly decreased in Group III. (Group I, 28.1 %, Group II, 21.6 %, Group III, 12.8 %). Compared with other ACE inhibitors, which are mainly excreted through the kidney, the plasma concentration of the active diacid metabolite was hardly influenced by renal function. It was speculated that lowering of the dose of temocapril might be recommended only in patients with severe renal insufficiency. 相似文献