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71.
72.
TR Miller I Milicic J Bauch J Du B Surber KE Browman K Marsh M Cowart JD Brioni TA Esbenshade 《British journal of pharmacology》2009,157(1):139-149
Background and purpose:
The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models.Experimental approach:
In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups.Key results:
In adult rats, [3H]-A-349821, 1.5 µg·kg−1, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response.Conclusions and implications:
When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists. 相似文献73.
A. W. G. Waugh S. Garg K. Matic L. Gramlich C. Wong D. C. Sadowski M. Millan R. Bailey D. Todoruk R. Cherry C. W. Teshima L. Dieleman R. N. Fedorak 《Alimentary pharmacology & therapeutics》2010,32(9):1129-1134
Aliment Pharmacol Ther 2010; 32: 1129–1134
Summary
Background Tumour necrosis factor‐blockade with infliximab has advanced the treatment of Crohn’s disease. While infliximab is efficacious, it remains to be determined whether patients who enter clinical remission with an anti‐tumour necrosis factor therapy can have their treatment stopped and retain the state of remission. Aim To assess in patients with Crohn’s disease who obtained infliximab‐induced remission, the proportion who relapsed after infliximab discontinuation. Methods This longitudinal cohort study examined patients from a University‐based IBD referral centre. Forty eight patients with Crohn’s disease in full clinical remission and who then discontinued infliximab were followed up for up to 7 years. Crohn’s disease relapse was defined as an intervention with Crohn’s disease medication or surgery. Results Kaplan–Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7‐year follow‐up. Conclusions In patients with Crohn’s disease with an infliximab‐induced remission, stopping infliximab results in a predictable relapse in a majority of patients. Nevertheless, a small percentage of patients sustain a long‐term remission. 相似文献74.
V Thulasiraman TR Ramesh Pandian S Cheralathan S Ashok 《Indian Journal of Orthopaedics》2010,44(4):471-473
Idiopathic internal jugular phlebectasia, occurs either unilaterally or bilaterally affecting the internal jugular vein is a rare congenital variation often diagnosed during childhood. It usually presents with a benign swelling over the lateral side of neck on the affected side, seen on exertion. A-30-year old male was operated for anterior cervical dissectomy from right lateral approach and was diagnosed per-operatively as internal jugular phlebectasia. The surgery was abandoned at this stage on the advice of cardiothoracic surgeon to investigate the patient for the secondary etiological factors for internal jugular vein dilatation. The patient was reassured without any active intervention for the phlebectasia and cervical dissectomy was performed in the second surgery through the lateral approach from left side. This case is presented in view of rarity and suggested that during preoperative workup the nearby structures like carotid sheath should be evaluated by magnetic resonance imaging to avoid such per-operative surprises. 相似文献
75.
TR Villa AR Correa Moutran LA Sobirai Diaz MM Pereira Pinto FA Carvalho AA Gabbai & D de Souza Carvalho 《Cephalalgia : an international journal of headache》2009,29(6):631-634
The aim of this study was to evaluate the visual attention of children with migraine and compare it with a control group. Thirty migrainous children and 30 controls without headache were subjected to a visual attention assessment with Trail Making Tests (TMT) A/B, Letter Cancellation Test, and the Brazilian computerized test Visual Attention Test, third edition. The migraine group was evaluated after 2 days without headache. The migraine group had an inferior performance compared with the control group on TMT A ( P = 0.03) and B ( P = 0.001), and more errors on tasks 1 ( P = 0.032) and 2 ( P = 0.015) of the Visual Attention Test, presenting difficulty with selective and alternate attention. Attention is a neurological function that depends on structures such as the brainstem, cerebral cortex and the limbic system and on neurotransmitters such as dopamine and noradrenaline. The neurochemical aspects involved in the physiopathology of migraine and attention mechanisms probably predispose these children to visual attention deficits. 相似文献
76.
77.
Comparison of pulmonary and pleural responses of rats and hamsters to inhaled refractory ceramic fibers 总被引:1,自引:1,他引:0
Gelzleichter TR; Bermudez E; Mangum JB; Wong BA; Janszen DB; Moss OR; Everitt JI 《Toxicological sciences》1999,49(1):93-101
The present study was designed to determine whether pleural fiber burdens
or subchronic pleural fibroproliferative and inflammatory changes can help
explain the marked interspecies differences in pleural fibrosis and
mesothelioma that are observed following long-term inhalation of RCF-1
ceramic fibers by rats and hamsters. Fischer 344 rats and Syrian golden
hamsters were exposed to RCF-1 for 4 h per day, 5 days per week, for 12
consecutive weeks. Lung and pleural fiber burdens were characterized during
and after exposure. For all time points, approximately 67% of fibers
associated with lung tissues from both rats and hamsters were longer than 5
microns in length. In comparison, fibers longer than 5 microns recovered
from the pleural compartment, following a 12-week exposure and 12 weeks of
recovery, accounted for 13% (hamsters) and 4% (rats) of the distribution.
In the 12 weeks after the cessation of exposure, the number of fibers
longer than 5 microns in length remained constant in the hamster at
approximately 150 fibers per cm2 pleura. This was 2 to 3 times the
corresponding fiber surface density in the rat. Significant pulmonary and
pleural inflammation was detected at all time points and for both species.
DNA synthesis by pleural mesothelial cells was quantified by
bromodeoxyuridine uptake following 3 days of labeling. Labeling indices
were higher in hamsters than in rats, both for RCF-1-exposed and filtered
air-control animals and was highest for the parietal surface of the pleura.
Significantly greater collagen deposition was measured in the visceral
pleura of hamsters 12 weeks post-exposure but was not significantly
elevated in rats. These findings demonstrate that subchronic inhalation
exposure to RCF-1 induces pleural inflammation, mesothelial-cell turnover,
pleural fibrosis, and an accumulation of fibers with a length greater than
5 microns in the hamster. The accumulation of long fibers in the pleural
space may contribute to the pathology observed in the hamster following
chronic inhalation of RCF- 1, whereas the presence of short, thin fibers
may play a role in the acute-phase biological response seen in both
species.
相似文献
78.
Hong HL; Devereux TR; Melnick RL; Eldridge SR; Greenwell A; Haseman J; Boorman GA; Sills RC 《Carcinogenesis》1997,18(4):783-789
Isoprene is the 2-methyl analog of 1,3-butadiene, a genotoxic and
carcinogenic compound in rats and mice. Male B6C3F1 mice were exposed to 0,
2200 or 7000 ppm isoprene by inhalation (6 h/day; 5 days/week) for 26
weeks. Following a 26-week recovery period, an increased incidence of
Harderian gland (HG) neoplasms was observed at both concentrations. The
present study was designed to characterize genetic alterations in the K-ras
and H-ras protooncogenes in HG neoplasms. Mutations in K-ras and H-ras were
identified by single-strand conformational analysis and direct sequencing
of polymerase chain reaction (PCR) amplified DNA, isolated from
paraffin-embedded sections of HG neoplasms. A higher frequency of ras
mutations, in particular K- ras mutations, was detected in isoprene-induced
neoplasms than in 1,3- butadiene-induced or control HG neoplasms. All of
the isoprene-induced HG neoplasms exhibited activated K-ras (60%) or H-ras
(40%) mutations. In contrast, ras mutations were detected in 69% of HG
neoplasms from 1,3-butadiene exposed mice (14% K-ras and 55% H-ras) and in
56% of HG neoplasms obtained from control B6C3F1 mice (8% K-ras and 48%
H-ras). The predominant mutations in isoprene-induced HG neoplasms, but not
in previously or newly analysed 1,3-butadiene-induced HG neoplasms,
consisted of A-->T transversions (CAA-->CTA) at K-ras codon 61
(15/30) and C-->A transversions (CAA-->AAA) at H-ras codon 61 (8/30).
Two- thirds of the K-ras CTA mutations were detected in HG neoplasms from
the 2200 ppm exposure group while one-third was present in the 7000 ppm
group. Isoprene-induced HG neoplasms with K-ras or H-ras mutations had an
elevated proliferating cell nuclear antigen (PCNA) index, compared to
spontaneous HG neoplasms without ras mutations. The high frequency and
specificity of the ras mutation profile suggest that ras protooncogene
activation contributes to isoprene-induced HG tumorigenesis.
相似文献
79.
Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human cytochrome P4501B1 总被引:1,自引:1,他引:1
Cytochrome P4501B1 (CYP1B1) is the most recently identified member of the
dioxin-inducible CYP1 family. CYP1B1 is constitutively expressed in most
human tissues, including colon and breast, and can activate numerous
chemically diverse carcinogens. We evaluated the metabolism of the dietary
heterocyclic amine carcinogen 2-amino-1-methyl-6-
phenylimidazo[4,5-b]pyridine (PhIP) by microsomes from yeast expressing the
human CYP1B1 protein. PhIP metabolites were analysed by HPLC with
fluorescence and absorbance detection. We found that human CYP1B1
metabolizes PhIP to three products: N2-OH-PhIP, a mutagenic activation
product; 4'-OH-PhIP, a detoxification product; and 2-OH-PhIP, the mutagenic
potential of which is unknown. Metabolite identity was confirmed by
co-elution with authentic standards and synchronous fluorescence
spectroscopy. The identity of the 2-OH-PhIP standard was additionally
confirmed by mass spectrometry. Kinetic studies of the formation of
N2-OH-PhIP, 4'-OH-PhIP and 2-OH-PhIP by CYP1B1 indicated apparent Km values
of 5.7 +/- 1.3, 2.2 +/- 0.5 and 1.3 +/- 0.2 microM, respectively. Apparent
turnover rates were 0.40 +/- 0.03, 0.93 +/- 0.02 and 0.04 +/- 0.00 nmol
product/min nmol P450, respectively. At saturating levels of substrate,
CYP1B1-mediated formation of the non- mutagenic metabolite 4'-OH-PhIP was
favored two-fold over that of the mutagenic metabolite, N2-OH-PhIP and
>10-fold over that of 2-OH-PhIP. The formation of N2-OH-PhIP, a potent
mutagen implicated in the etiology of human colon and breast cancer,
indicates that CYP1B1 may play an important role in PhIP-mediated
carcinogenesis.
相似文献
80.