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101.
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
102.
Yamamoto H Okada M Kanehira A Yamada A Kawamura M 《The Annals of thoracic surgery》1999,68(6):2361-2363
A new technique of video-assisted thoracic sympathectomy through retrosternal pulmonary junction can be done safely using a scope guide and a flexible scope. Bilateral thoracic sympathectomy was performed, employing a single skin incision, in 18 patients with palmar hyperhidrosis. The advantages include minimal neuralgia and superior cosmesis. 相似文献
103.
T. Goto Masahiko Shimura Mitsuru Nakazawa 《Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie》1999,237(9):787-789
· Background: To investigate the usefulness of indocyanine green (ICG) iris angiography for monitoring vascular abnormalities
and the clinical course of metastatic iris tumor during chemotherapy. · Methods: We performed ICG iris angiography at several
points during systemic chemotherapy for a 67-year-old man who had been diagnosed as having small-cell carcinoma of the lung
with metastatic iris tumors. · Results: ICG iris angiography clearly demonstrated hyperfluorescent tumor vessels, rubeosis
iridis, and dilated iris stromal vessels. After chemotherapy, these hyperfluorescent vessels and rubeosis regressed. · Conclusion:
ICG iris angiography appears to be an effective and useful method for observing abnormal vessels associated with metastatic
iris tumors.
Received: 11 May 1998 Revised version received: 30 July 1998 Accepted: 13 August 1998 相似文献
104.
Shiraishi M Suzuki K Abe T Kikuchi T Satoh H Nakaji S Sugawara K 《Environmental health and preventive medicine》1996,1(2):65-70
Neutrophil functions, including chemotaxis, reactive oxygen species (ROS)-producing capacity of neutrophils, and serum opsonic activity were investigated in 9 young healthy male volunteers. Venous blood of these volunteers was obtained under standardized conditions at 4-h intervals over a 24-h span. Neutrophil chemotaxis was evaluated by a modified Boyden technique, ROS-producing capacity of neutrophils and serum opsonic activity were measured by a simultaneous multiple measurement system based on luminol-dependent chemiluminescence and indicated by peak height and peak time. ROS-producing capacity of neutrophils and serum opsonic activity were activated in the daytime, and decreased from night to morning. There were negative correlations between the peak time of the luminol-dependent chemiluminescent response, neutrophil number (p<0.01) and segmented neutrophil number (p>0.01). On the other hand, no significant correlations were noted between serum opsonic activity and IgG, IgA, IgM, C3 or C4. In contrast, the peaks of neutrophil chemotaxis were at the wake-up time (6:00a.m.) and in the evening (6:00p.m.). This study indicates that diurnal variation of neutrophil function exists. 相似文献
105.
Naohiro Kajiwara Masahiko Taguchi Hiroshi Saito Shin Nakajima Aeru Hayashi Norihiko Kawate Chimori Konaka Hiromi Wada Harubumi Kato 《Transplant international》1996,9(3):194-200
We examined the efficacy of two new preservation solutions containing trehalose-an extracellular type (ET-K) of solution and an intracellular type (IT-K) of solution — in relation to that of Euro-Collins (EC) solution in 20-h canine lung preservation. Canine lungs were flushed with one of the three solutions (n=5 for each solution) after pretreatment with PGE1 (20 g/kg) and were stored for 20 h at 4°C. The left lungs were transplanted and evaluated to 6 h post transplant. In the ET-K group, the arterial oxygen tension after reperfusion was significantly higher than in the IT-K and EC groups. The pulmonary vascular resistance, wet/dry weight ratio, and histological evaluation of each transplanted lung in the ET-K group were also better than in the IT-K and EC groups. This indicates that ET-K solution is useful for 20-h preservation of canine lung grafts. 相似文献
106.
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
107.
Masahiko Fujita Eigo Takabatake Keiko Tsuchiya 《Archives of environmental contamination and toxicology》1982,11(5):645-649
Experiments were made to observe the effects of the maternal administration of cadmium and zinc and their influence on the metal-binding capacity of metallothionein in the rat fetus. Metallothionein was detected in the fetal liver as early as day 16 of gestation and may have appeared earlier. The zinc concentration in the metallothionein fraction was low on day 16 but increased as gestation progressed. The metal-binding capacity was fairly high on day 16 but increased at a slower rate than the zinc concentration. Following the intraperitoneal administration of zinc (100 moles Zn/kg) or cadmium (5 moles Cd/kg) once a day on days 14, 15 and 16 of gestation to the dam, the concentration of zinc in the metallothionein fraction of the maternal liver was far greater than that in the fetal liver. In contrast, cadmium was found only in the metallothionein fraction of the maternal liver; it was not found in the fetal liver, which suggests an effective placental barrier to cadmium. The metalbinding capacity in the fetal liver was induced by the maternal administration of zinc, but not cadmium. 相似文献
108.
In order to obtain basic data on the effect of broad-spectrum protease inhibitor against local symptoms of Viperidae snake envenomation, inhibitory capacity of rat murinoglobulin on local hemorrhagic and edematogenic activities of venoms from Crotalus atrox, Bothrops jararaca, Lachesis muta muta, Trimeresurus flavoviridis and Echis carinatus sochureki were examined. Murinoglobulin, pre-incubated with the crude venoms at 37 degrees C for 15 min, inhibited hemorrhagic activity of all five venoms to various extents. The activity of C. atrox was almost completely inhibited at the murinoglobulin/venom ratio (w/w) of 20. The activity of B. jararaca, Lachesis muta muta and T. flavoviridis venoms was considerably inhibited at the ratio of 20 (77.2, 80.0 and 86.2% inhibition, respectively), however some of the activity still remained even at the ratio of 40 (84.2, 79.8 and 86.2% inhibition, respectively). Among the five venoms, E. c. sochureki venom is quite resistant to murinoglobulin treatment and statistically significant inhibition was only found at the ratio of 40 (64.1% inhibition). Fibrinolytic and gelatinase activities were more susceptible to murinoglobulin inhibition. The treatment at the ratios of 10 and 20 almost completely inhibited respectively the fibrinolytic and the gelatinase activities of all the venoms. Murinoglobulin treatment also significantly inhibited the edematogenic activity of L. muta muta, T. flavoviridis and Echis carinatus sochureki. The treatment of murinoglobulin at the ratio of 40 considerably suppressed the swelling up to 60 min after subcutaneous injection of L. muta muta and E. c. sochureki venoms, and up to 30 min after T. flavoviridis venom injection. Murinoglobulin is a potent inhibitor against local effects of multiple snake venoms in Viperidae family. 相似文献
109.
Kentaroh Kamata Masato Inazu Hiroshi Takeda Hiroshi Goto Teruhiko Matsumiya Masahiko Usui 《Pharmacological research》2003,47(6):485-491
Inducible nitric oxide (NO) synthase (iNOS) is believed to contribute to the pathogenesis of endotoxin-induced uveitis (EIU). In the present study, we investigated the inhibitory effects of N(G)-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, and S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBITU), a potent and selective iNOS inhibitor, on intraocular NO production in EIU rabbits using an in vivo intraocular microdialysis technique. The flare level in the anterior chamber increased from 1h after the injection of 100 micro g/kg lipopolysaccharide (LPS), and continued to increase for 24h. Aqueous humor protein concentrations were significantly increased at 24h after LPS-injection. These changes were significantly reduced by L-NAME (10mg/kg) and PBITU (1mg/kg), but not by D-NAME (10mg/kg). The increase in NO(2)(-) and NO(3)(-) levels in the dialysate induced by LPS was significantly inhibited by L-NAME (10mg/kg) and PBITU (1mg/kg), but not by D-NAME (10mg/kg). These results suggest that activation of iNOS may play a key role in the development of EIU, and selective inhibitors of iNOS may have therapeutic applications in the treatment of EIU. 相似文献
110.
Expression level of valosin-containing protein is strongly associated with progression and prognosis of gastric carcinoma. 总被引:9,自引:0,他引:9
Shinji Yamamoto Yasuhiko Tomita Yoshihiko Hoshida Shuji Takiguchi Yoshiyuki Fujiwara Takushi Yasuda Masahiko Yano Shoji Nakamori Masato Sakon Morito Monden Katsuyuki Aozasa 《Journal of clinical oncology》2003,21(13):2537-2544
PURPOSE: Valosin-containing protein (VCP; also known as p97) was shown to be associated with antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. In this study, association of VCP expression with recurrence of gastric carcinoma (GC), in which lymphatic vessels are the main route of spread, was examined. PATIENTS AND METHODS: VCP expression in 330 patients with GC (242 males and 88 females) with ages ranging from 26 to 81 years (median, 60 years) was analyzed by immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. RESULTS: Ninety-four (28.7%) patient cases showed level 1 and 233 patient cases (71.3%) showed level 2 VCP expression. Patients with level 2 expression showed higher rates of large tumor size (P <.0001), undifferentiated histologic subtype (P <.05), presence of vascular and lymphatic invasion (P <.0001 for both), presence of lymph node metastasis (P <.0001), deep tumor invasion (P <.0001), and poorer disease-free and overall survivals (P <.0001 for both) compared with those with level 1 VCP expression. Multivariate analysis revealed VCP expression level as an independent prognosticator for disease-free and overall survival. VCP level was an indicator for disease-free and overall survival in the early (pT1; P <.01 and P <.05, respectively) and advanced (pT2-4; P <.05 for both) group of pathologic tumor-node-metastasis system classification. CONCLUSION: The prognostic significance of VCP expression level in GC was demonstrated. 相似文献