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981.
Albert JS Ohnmacht C Bernstein PR Rumsey WL Aharony D Alelyunas Y Russell DJ Potts W Sherwood SA Shen L Dedinas RF Palmer WE Russell K 《Journal of medicinal chemistry》2004,47(3):519-529
We have previously described a series of antagonists that showed high potency and selectivity for the NK(1) receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here we show that alteration of the 2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK(1) receptor affinity for the various conformational forms has facilitated the development of a detailed NK(1) pharmacophore model. 相似文献
982.
983.
Phenotypic characterisation of Candida albicans isolated from chronic hyperplastic candidosis 总被引:1,自引:0,他引:1
The phenotypes of 35 Candida albicans isolates from 19 patients with chronic hyperplastic candidosis (CHC) and 35 isolates from 30 patients with non-CHC infections were compared. Typing was based on carbohydrate assimilation, chemical sensitivity and serology. Eight carbohydrate assimilation profiles were evident with the API-20C system and a single profile predominated for isolates from CHC (17 of 19 patients; 89%) and non-CHC (18 of 30 patients; 63%). Chemical sensitivity tests revealed four profiles with no significant difference between CHC and non-CHC isolates. Serotype A predominated for isolates from both CHC (15 of 19 patients; 79%) and non-CHC (25 of 30 patients; 83%) infections. Boric acid resistance was more prevalent in CHC isolates, although a significant difference was not apparent. In summary, there was no overall difference in the phenotypes of isolates from CHC and non-CHC patients, and clonal restriction of CHC isolates was not demonstrated. 相似文献
984.
C L Wilson J A Bodnar B G Brown W T Morgan R J Potts M F Borgerding 《Food and chemical toxicology》2008,46(5):1721-1733
Mainstream cigarette smoke (MSS) from 12 US cigarette brands and two reference cigarettes was evaluated to determine concentrations of dioxins (i.e., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs)). The study included three 'tar' ranges based on Federal Trade Commission (FTC) determination: Low Yield (LY) < or = 5.5, Medium Yield (MY) 9.6-12.2, and High Yield (HY)> or = 14.5 mg/cig. Of the brands studied, the HY cigarettes yielded the greatest mean concentrations of 2005 World Health Organization Toxic Equivalents (WHO-TEQs) on a per cigarette basis. WHO-TEQ levels in LY cigarettes were significantly lower than for HY cigarettes (p=0.039) on a yield per cigarette basis and WHO-TEQ concentrations correlated with 'tar' yield (r=0.73, p=0.007), as did concentration on a WHO-TEQ per body mass per day basis (r=0.73, p=0.007). However, a statistically significant relationship was not observed between 'tar' yield levels and WHO-TEQ concentrations on a per mg Total Particulate Matter (TPM) basis. Concentrations for all brands tested ranged from 0.44 to 3.88 fg WHO-TEQ/mg TPM. Maximum daily exposure estimates calculated from this range (0.004-0.074 pg WHO-TEQ/kg bw/day) are below the current WHO Tolerable Daily Intake range of 1-5 pg/kg bw/day. 相似文献
985.
986.
An automated method for evaluating the image quality of calcified plaques with respect to motion artifacts in noncontrast-enhanced cardiac computed tomography (CT) images is introduced. This method involves using linear regression (LR) and artificial neural network (ANN) regression models for predicting two patient-specific, region-of-interest-specific, reconstruction-specific and temporal phase-specific image quality indices. The first is a plaque motion index, which is derived from the actual trajectory of the calcified plaque and is represented on a continuous scale. The second is an assessability index, which reflects the degree to which a calcified plaque is affected by motion artifacts, and is represented on an ordinal five-point scale. Two sets of assessability indices were provided independently by two radiologists experienced in evaluating cardiac CT images. Inputs for the regression models were selected from 12 features characterizing the dynamic, morphological, and intensity-based properties of the calcified plaques. Whereas LR-velocity (LR-V) used only a single feature (three-dimensional velocity), the LR-multiple (LR-M) and ANN regression models used the same subset of these 12 features selected through stepwise regression. The regression models were parameterized and evaluated using a database of simulated calcified plaque images from the dynamic NCAT phantom involving nine heart rate/multi-sector gating combinations and 40 cardiac phases covering two cardiac cycles. Six calcified plaques were used for the plaque motion indices and three calcified plaques were used for both sets of assessability indices. In one configuration, images from the second cardiac cycle were used for feature selection and regression model parameterization, whereas images from the first cardiac cycle were used for testing. With this configuration, repeated measures concordance correlation coefficients (CCCs) and associated 95% confidence intervals for the LR-V, LR-M, and ANN were 0.817 [0.785, 0.848], 0.894 [0.869, 0.916], and 0.917 [0.892, 0.936] for the plaque motion indices. For the two sets of assess-ability indices, CCC values for the ANN model were 0.843 [0.791, 0.877] and 0.793 [0.747, 0.828]. These two CCC values were statistically greater than the CCC value of 0.689 [0.648, 0.727], which was obtained by comparing the two sets of assessability indices with each other. These preliminary results suggest that the variabilities of assessability indices provided by regression models can lie within the variabilities of the indices assigned by independent observers. Thus, the potential exists for using regression models and assessability indices for determining optimal phases for cardiac CT image interpretation. 相似文献
987.
Neurokinin-1 receptor (NK1-R) expressing neurons are densely distributed throughout the nucleus tractus solitarii (NTS). However, their fundamental role in arterial baroreflex function remains debated. Previously, our group has shown that activation of contraction-sensitive somatic afferents evoke substance P (SP) release in the NTS and resets the arterial baroreflex via activation of a GABAergic NTS circuit. Based on these findings, we hypothesized that modulation of arterial baroreflex function by somatic afferents is mediated by NK1-R dependent inhibition of barosensitive NTS circuits. In the present study, SP-conjugated saporin toxin (SP-SAP) was used to ablate NK1-R expressing NTS neurons. Contraction-sensitive somatic afferents were activated by electrically-evoked muscle contraction and the arterial baroreceptor-heart rate reflex was assessed by constructing reflex curves using a decerebrate, arterially-perfused preparation. Baseline baroreflex sensitivity was significantly attenuated in SP-SAP-treated rats compared with control rats receiving either unconjugated SAP or vehicle. Muscle contraction significantly attenuated baroslope in SAP and vehicle-treated animals and shifted the baroreflex curves to higher systemic pressure. In contrast, somatic afferent stimulation failed to alter baroslope or shift the baroreflex curves in SP-SAP-treated animals. Moreover, when reflex sensitivity was partially restored in SP-SAP animals, somatic stimulation failed to attenuate baroreflex bradycardia. In contrast, SP-SAP and somatic stimulation failed to blunt the reflex bradycardia evoked by the peripheral chemoreflex. Immunohistochemistry revealed that pretreatment with SP-SAP significantly reduced the number of NK1-R expressing neurons in the caudal NTS, while sparing NK1-R expressing neurons rostral to the injection site. This was accompanied by a significant reduction in the number of glutamic acid decarboxylase (GAD67) expressing neurons at equivalent levels of the NTS. These findings indicate that immunolesioning of NK1-R expressing NTS neurons selectively abolishes the depressive effect of somatosensory input on arterial baroreceptor-heart rate reflex function. 相似文献
988.
Objective Clinicians in resource‐poor countries need to identify patients with dengue using readily‐available data. The objective of this systematic review was to identify clinical and laboratory features that differentiate dengue fever (DF) and/or dengue haemorrhagic fever (DHF) from other febrile illnesses (OFI) in dengue–endemic populations. Method Systematic review of the literature from 1990 to 30 October 2007 including English publications comparing dengue and OFI. Results Among 49 studies reviewed, 34 did not meet our criteria for inclusion. Of the 15 studies included, 10 were prospective cohort studies and five were case–control studies. Seven studies assessed all ages, four assessed children only, and four assessed adults only. Patients with dengue had significantly lower platelet, white blood cell (WBC) and neutrophil counts, and a higher frequency of petechiae than OFI patients. Higher frequencies of myalgia, rash, haemorrhagic signs, lethargy/prostration, and arthralgia/joint pain and higher haematocrits were reported in adult patients with dengue but not in children. Most multivariable models included platelet count, WBC, rash, and signs of liver damage; however, none had high statistical validity and none considered changes in clinical features over the course of illness. Conclusions Several individual clinical and laboratory variables distinguish dengue from OFI; however, some variables may be dependent on age. No published multivariable model has been validated. Study design, populations, diagnostic criteria, and data collection methods differed widely across studies, and the majority of studies did not identify specific aetiologies of OFIs. More prospective studies are needed to construct a valid and generalizable algorithm to guide the differential diagnosis of dengue in endemic countries. 相似文献
989.
Frequency and thermal effects on the enhancement of transdermal transport by sonophoresis. 总被引:6,自引:0,他引:6
Gustavo Merino Yogeshvar N Kalia M Bego?a Delgado-Charro Russell O Potts Richard H Guy 《Journal of controlled release》2003,88(1):85-94
The aims of this work were: (i) to examine the role of ultrasound (US) frequency and intensity on the transport of glucose and mannitol across porcine skin in vitro, (ii) to quantify the energy delivered to the skin during application of low-frequency sonophoresis, and (iii) to 'deconvolute' the thermal effect, induced by US application to the skin, to the enhanced permeability of the cutaneous barrier. Low- (20 kHz) and high-frequency (10 MHz) sonophoresis were first compared. Only low frequency US resulted in significantly increased permeation. Low-frequency, US-induced enhancement of mannitol transport was symmetric; that is, mannitol flux was the same when 'delivered' or 'extracted' from a donor solution (in both cases, the US probe was present on the surface side of the skin). Calorimetry was used to quantify the US energy delivered by the sonicator. Subsequently, the US-enhanced transdermal transport of mannitol, during which a significant (and US intensity-dependent) temperature increase occurred, was compared to that provoked, in the absence of sonophoresis, by a comparable thermal effect. Only 25% of this enhancement was attributable to the increased temperature induced by US. It follows that another mechanism, most probably cavitation, is principally responsible for the lowered skin barrier function observed. 相似文献
990.
Douglas W P Hay Giuseppe A M Giardina Don E Griswold David C Underwood Charles J Kotzer Brian Bush William Potts Punam Sandhu Dave Lundberg James J Foley Dulcie B Schmidt Lenox D Martin David Kilian Jeffrey J Legos Frank C Barone Mark A Luttmann Mario Grugni Luca F Raveglia Henry M Sarau 《The Journal of pharmacology and experimental therapeutics》2002,300(1):314-323
In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited (125)I-[MePhe(7)]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K(i) = 2.2 nM and antagonized competitively NKB-induced Ca(2+) mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K(b) = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 209 nM), and was without effect, at 1 microM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED(50) of 0.56 mg/kg). Intraperitoneal SB 235375 (10-30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3-30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system. 相似文献