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1.
The present study was designed to test the hypothesis that the active neurotransmitter processes of release and uptake affect the in vivo microdialysis recovery of dopamine (DA) in the nucleus accumbens (N ACC) of the rat. The in vivo recovery for DA was established for rats which had received either unilateral infusions of the neurotoxin 6-hydroxydopamine (6-OHDA, 8 μg) or vehicle (0.2 μg ascorbate). In the quantitative dialysis method used (point of no net flux method), DA is added to the perfusate at concentrations above and below the expected extracellular concentration (0, 5, 10 and 20 nM) and DA is measured in the dialysate from the brain to generate a series of points. A linear fit is performed, the slope of which is the in vivo recovery of the dialysis probe. The in vivo recovery of the 6-OHDA group was 30 ± 3% which was significantly lower (P < 0.002) than the in vivo recovery of the control group which was 60 ± 3% (mean ± SEM; n = 6/group). The zero intercept of this regression is the point of no net flux, which is the extracellular concentration of DA independent of the probe sampling characteristics. The extracellular DA concentration for the 6-OHDA group was 7.8 ± 1.1nM, which was not significantly different than the control group which was 6.9 ± 0.7nM. The tissue DOPAC/DA ratios of the 6-OHDA lesioned hemispheres were significantly higher than the contralateral hemispheres of the same animals (0.62 ± 0.1vs.0.27 ± 0.1; P < 0.02) while the DOPAC/DA ratios in the control group were not significantly different (0.24 ± 0.1vs.0.27 ± 0.1). The fractional DA efflux from the terminals in the 6-OHDA group was significantly higher than the fractional DA efflux of the control group (0.52 ± 0.08vs.0.03 ± 0.003; P < 0.0001), indicating that the remaining terminals have increased turnover of DA. Despite the increased turnover, however, the number of remaining release and uptake sites are not sufficient to maintain the high in vivo recovery observed in the control group. 相似文献
2.
Michael M. Krausz Richard E. Justice Takayoshi Utsunomiya Herbert B. Hechtman 《Annals of biomedical engineering》1981,9(3):257-262
A simple system has been developed-for the prolonged infusion of an iced solution of prostacyclin (PGI2). In a 24 h period at pH 10, there is a theoretical loss in activity of 6%, while a 5 h infusion leads to a 2% reduction
in activity. The stability of the cooling system was demonstrated in six dog experiments where mean arterial pressure (MAP)
was reduced to 58±3.8 Torr (x±SEM) over a 5 h period of infusing 500 ng/kg/min. In a saline medium, at 3°C, a 5 h PGI2 infusion led to a stable reduction in MAP, whereas, at a temperature of 24°C, a 70 loss of infusate activity was noted.
Supported in part by The National Institute of Health, Grant No. GM24891-04; The U.S. Army Medical Research and Development
Command, Contract No. DAMD17-78-C-8026; The Brigham Surgical Group, Inc., and The Trauma Research Foundation. 相似文献
3.
4.
Adjuvant immunization of HLA-A2-positive melanoma patients with a modified gp100 peptide induces peptide-specific CD8+ T-cell responses. 总被引:3,自引:0,他引:3
John W Smith Edwin B Walker Bernard A Fox Daniel Haley Ketura P Wisner Teri Doran Brenda Fisher Lisa Justice William Wood John Vetto Holden Maecker Annemiek Dols Sybren Meijer Hong-Ming Hu Pedro Romero W Gregory Alvord Walter J Urba 《Journal of clinical oncology》2003,21(8):1562-1573
PURPOSE: To measure the CD8+ T-cell response to a melanoma peptide vaccine and to compare an every-2-weeks with an every-3-weeks vaccination schedule. PATIENTS AND METHODS: Thirty HLA-A2-positive patients with resected stage I to III melanoma were randomly assigned to receive vaccinations every 2 weeks (13 vaccines) or every 3 weeks (nine vaccines) for 6 months. The synthetic, modified gp100 peptide, g209-2M, and a control peptide, HPV16 E7, were mixed in incomplete Freund's adjuvant and injected subcutaneously. Peripheral blood mononuclear cells obtained before and after vaccination by leukapheresis were analyzed using a fluorescence-based HLA/peptide-tetramer binding assay and cytokine flow cytometry. RESULTS: Vaccination induced an increase in peptide-specific T cells in 28 of 29 patients. The median frequency of CD8+ T cells specific for the g209-2M peptide increased markedly from 0.02% before to 0.34% after vaccination (P <.0001). Eight patients (28%) exhibited peptide-specific CD8+ T-cell frequencies greater than 1%, including two patients with frequencies of 4.96% and 8.86%, respectively. Interferon alfa-2b-treated patients also had significant increases in tetramer-binding cells (P <.0001). No difference was observed between the every-2-weeks and the every-3-weeks vaccination schedules (P =.59). CONCLUSION: Flow cytometric analysis of HLA/peptide-tetramer binding cells was a reliable means of quantifying the CD8+ T-cell response to peptide immunization. This assay may be suitable for use in future trials to optimize different vaccination strategies. Concurrent interferon treatment did not inhibit the development of a peptide-specific immune response and vaccination every 2 weeks, and every 3 weeks produced similar results. 相似文献
5.
The effect of structural modification of the human dopamine transporter protein on bi-directional transport was explored using site-directed mutagenesis and rotating disk electrode voltammetry. The substrate-induced DA efflux, as inferred from the K(m) or K(i), was dependent on common structural features for uptake of the substrate inducer: reduced by beta-hydroxylation, stereoselective to alpha-methylation, and relatively insensitive to a switch of a single phenolic hydroxyl group between m- and p-positions. The potencies for substrates to compete with external DA for uptake and to induce DA efflux were similar and highly correlated. Despite these similarities, the efflux of internal DA was substantially slower than the uptake of its inducers. Mutation of serine-528 of the hDAT to alanine (S528A) did not change the structure-activity relationships, maximal uptake rates, and the cation dependence for the uptake of external substrates, although it modestly reduced K(m) or K(i) of most tested substrates. In contrast, it substantially enhanced substrate-induced DA efflux, with maximal efflux rates doubled for all tested inducers. Simultaneous monitoring of tyramine uptake and resulting DA efflux revealed that S528A accelerated the DA efflux relative to tyramine uptake. Saturation analysis suggested that the mutation significantly enhanced the efflux kinetics of internal DA but it exerted little effect on the uptake kinetics of external DA. These findings suggest that Ser-528 may play a role in stabilizing a hDAT conformation unfavorable for outward transport of internal DA, thereby contributing to the efficiency of the transporter. 相似文献
6.
Recent work in this lab which explores the differential behavioral and neurochemical changes following left versus right cerebral damage is reviewed and neural mechanisms which may account for this asymmetry are proposed. Damage to the right frontoparietal cortex in rats, caused by either ischemia or suction, produces hyperactivity for as long as a month after surgery. These lesions also produce decreases in norepinephrine (NE) levels in both ipsilateral and contralateral cortex and in the locus coeruleus. Similar lesions in the left cortex, however, do not produce these behavioral or biochemical changes. Similar lateralized responses have also been produced by intracortical injections of NE neurotoxins, by cortical island lesions, by destroying cortical efferents, and by producing lesions in the nucleus accumbens, which receives a cortical input. These lateralized responses suggest that the neural mechanisms that mediate this phenomenon include both cortical and subcortical components. It is proposed that the neuroanatomical asymmetry is in either accumbal efferents or their postsynaptic connections. 相似文献
7.
Recent preclinical evidence indicates that ovarian hormones, such as estrogen and progesterone, may influence the behavioral effects of psychoactive drugs by interacting directly with neurotransmitter systems in the central nervous system. However, few studies have examined the effects of ovarian hormones on subjective or behavioral responses to psychoactive drugs in humans. In the present study, we assessed the subjective and physiological effects of d-amphetamine during the early and late follicular phases of the menstrual cycle. Nineteen healthy, regularly-cycling women participated in four sessions receiving doses of d-amphetamine (AMPH; 15 mg oral) or placebo during the early and late follicular phases of two menstrual cycles. During the early follicular phase levels of both estrogen and progesterone are low, whereas during the late follicular phase estrogen levels are higher while progesterone remains low. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Most of the subjective and physiological effects of AMPH were not affected by menstrual cycle phase. However, subjects reported greater Unpleasant Stimulation after AMPH, and less Unpleasant Sedation, during the late follicular phase than during the early follicular phase. These results provide limited evidence that higher levels of estrogen during the late follicular phase alter the subjective effects of AMPH in normal, healthy women. 相似文献
8.
Richard O. Phillips Fred S. Sarfo Mohammed K. Abass Justice Abotsi Tuah Wilson Mark Forson Yaw A. Amoako William Thompson Kingsley Asiedu Mark Wansbrough-Jones 《Antimicrobial agents and chemotherapy》2014,58(2):1161-1166
Buruli ulcer, an ulcerating skin disease caused by Mycobacterium ulcerans infection, is common in tropical areas of western Africa. We determined the clinical and microbiological responses to administration of rifampin and streptomycin for 2 weeks followed by administration of rifampin and clarithromycin for 6 weeks in 43 patients with small laboratory-confirmed Buruli lesions and monitored for recurrence-free healing. Bacterial load in tissue samples before and after treatment for 6 and 12 weeks was monitored by semiquantitative culture. The success rate was 93%, and there was no recurrence after a 12-month follow-up. Eight percent had a positive culture 4 weeks after antibiotic treatment, but their lesions went on to heal. The findings indicate that rifampin and clarithromycin can replace rifampin and streptomycin for the continuation phase after rifampin and streptomycin administration for 2 weeks without any apparent loss of efficacy. 相似文献
9.
Prior research has consistently demonstrated that providers often under recognize symptoms. However, this research was limited
by the different ways in which patients and providers were asked about the symptoms patients experience. We sought to (1)
describe the prevalence of patient-reported symptoms in the post-cART era; (2) identify those patient-reported symptoms which
are most strongly associated with health-related quality of life (HRQoL), hospitalization and mortality; and (3) determine
whether primary providers recognize symptoms associated with HRQoL, hospitalization and mortality. We conducted a secondary
analysis using baseline survey data from the Veterans Aging Cohort Study and determined which patient-reported symptoms correlated
with clinical outcomes using regression analyses. Kappa scores were then calculated. HIV-infected patients suffer from a high
burden of symptoms in the post-cART era. Nine out of 20 symptoms correlated with clinical outcomes. Providers universally
under recognized symptoms and demonstrated poor agreement beyond chance when patient-report was used as the gold standard. 相似文献
10.