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51.
Moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischemia; however, its mechanisms remain poorly defined. Using a model of complete umbilical cord occlusion for 25 min in 0.7 gestation fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.5 +/- 0.2 degrees C to <34 degrees C; mean +/- SD), from 90 min to 70 h after the end of the insult, on postocclusion epileptiform activity. In the first 6 h after the end of occlusion, fetal electroencephalographic (EEG) activity was abnormal with a mixture of fast and slow epileptiform transients superimposed on a suppressed background; seizures started a mean of 8 h after occlusion. There was a close correlation between numbers of these EEG transients and subsequent neuronal loss in the striatum after 3 days recovery (r(2) = 0.65, P = 0.008). Hypothermia was associated with a marked reduction in numbers of epileptiform transients in the first 6 h, reduced amplitude of seizures, and reduced striatal neuronal loss. In conclusion, neuroprotection with delayed, prolonged head cooling after a severe asphyxial insult in the preterm fetus was associated with potent, specific suppression of epileptiform transients in the early recovery phase but not of numbers of delayed seizures. 相似文献
52.
William V. Lechner Rachel L. Gunn Alexia Minto Noah S. Philip Richard A. Brown Lisa A. Uebelacker 《Substance use & misuse》2018,53(7):1177-1183
Background: Three key domains including negative emotionality, incentive salience, and executive function form the core functional elements of addictive behaviors. Variables related to these broader domains have been studied extensively in relation to one another; however, no studies to date, have examined models including variables from all three domains, in relation to nicotine dependence. Method: Smokers (N = 117), 65.8% female, 78% white, mean age of 44.4 (SD = 10.8), enrolled in a smoking cessation program completed measures of negative affect (a component of negative emotionality), urge to smoke (incentive salience), and working memory (WM; a core executive function), during a baseline assessment period prior to initiating treatment. Results: Negative affect was associated with greater urge to smoke, and this elevated urge to smoke was associated with higher levels of nicotine dependence. Further, a significant moderated mediation indicated that WM moderated the relationship between increased urge to smoke and nicotine dependence. For those with low to average WM, urge to smoke was significantly related to nicotine dependence; however, for those with higher WM (+1 SD), urge to smoke stemming from negative affect was not associated with nicotine dependence. Conclusions: To our knowledge, this is the first reported relationship between negative affect, urge to smoke, WM, and nicotine dependence. Although preliminary, results indicate that WM may moderate the relationship between urge to smoke associated with negative affect and nicotine dependence. Treatments targeting WM may be particularly useful for individuals with average to low WM who experience urge to smoke related to negative affect. 相似文献
53.
Karen Liao Stacy Derbyshire Kai-fen Wang Cherilyn Caucci Shuo Tang Claire Holland Amy Loercher George R. Gunn 《The AAPS journal》2018,20(3):51
Bridging immunoassays commonly used to detect and characterize immunogenicity during biologic development do not provide direct information on the presence or development of a memory anti-drug antibody (ADA) response. In this study, a B cell ELISPOT assay method was used to evaluate pre-existing ADA for anti-TNFR1 domain antibody, GSK1995057, an experimental biologic in treatment naive subjects. This assay utilized a 7-day activation of PBMCs by a combination of GSK1995057 (antigen) and polyclonal stimulator followed by GSK1995057-specific ELISPOT for the enumeration of memory B cells that have differentiated into antibody secreting cells (ASC) in vitro. We demonstrated that GSK1995057-specific ASC were detectable in treatment-naïve subjects with pre-existing ADA; the frequency of drug-specific ASC was low and ranged from 1 to 10 spot forming units (SFU) per million cells. Interestingly, the frequency of drug-specific ASC correlated with the ADA level measured using an in vitro ADA assay. We further confirmed that the ASC originated from CD27+ memory B cells, not from CD27?-naïve B cells. Our data demonstrated the utility of the B cell ELISPOT method in therapeutic protein immunogenicity evaluation, providing a novel way to confirm and characterize the cell population producing pre-existing ADA. This novel application of a B cell ELISPOT assay informs and characterizes immune memory activity regarding incidence and magnitude associated with a pre-existing ADA response. 相似文献
54.
Basis pursuit denoising is a new approach for data-driven estimation of parametric images from dynamic positron emission tomography (PET) data. At present, this kinetic modeling technique does not allow for the estimation of the errors on the parameters. These estimates are useful when performing subsequent statistical analysis, such as, inference across a group of subjects or when applying partial volume correction algorithms. The difficulty with calculating the error estimates is a consequence of using an overcomplete dictionary of kinetic basis functions. In this paper, a bootstrap approach for the estimation of parameter errors from dynamic PET data is presented. This paper shows that the bootstrap can be used successfully to compute parameter errors on a region of interest or parametric image basis. Validation studies evaluate the methods performance on simulated and measured PET data ([(11)C]Diprenorphine-opiate receptor and [(11)C]Raclopride-dopamine D(2) receptor). The method is presented in the context of PET neuroreceptor binding studies, however, it has general applicability to a wide range of PET/SPET radiotracers in neurology, oncology and cardiology. 相似文献
55.
S Ashworth A Berges E A Rabiner A A Wilson R A Comley R Y K Lai R Boardley G Searle R N Gunn M Laruelle V J Cunningham 《British journal of pharmacology》2014,171(5):1241-1249
BACKGROUND AND PURPOSE
This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers.EXPERIMENTAL APPROACH
PET scans were obtained after i.v. administration of the H3-specific radioligand [11C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan.KEY RESULTS
Following administration of GSK239512, there was a reduction in the brain uptake of [11C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL−1. This corresponds to a free concentration of 4.50 × 10−12 M (pK = 11.3).CONCLUSIONS AND IMPLICATIONS
The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose. 相似文献56.
David Erritzoe Andri Tziortzi David Bargiela Alessandro Colasanti Graham E Searle Roger N Gunn John D Beaver Adam Waldman David J Nutt Massimo Bani Emilio Merlo-Pich Eugenii A Rabiner Anne Lingford-Hughes 《Neuropsychopharmacology》2014,39(7):1703-1712
Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [11C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [11C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [11C]PHNO binding between the groups at baseline. However, baseline [11C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (VT: 16.5±4 vs 13.7±2.9, p=0.040), a region in which the [11C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (VT) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in VT following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [11C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse. 相似文献
57.
Colonic crypt cell proliferation state assessed by whole crypt microdissection in sporadic neoplasia and familial adenomatous polyposis 总被引:4,自引:0,他引:4 下载免费PDF全文
BACKGROUND: It has yet to be established whether proliferative activity in the macroscopically normal colonic mucosa is causally correlated with neoplastic risk. Measurement of proliferative activity in human subjects is of necessity usually undertaken using indirect methods with inherent limitations, and relatively little has been published on the effect of normal biological variables on such indices. AIMS: To establish the validity of mitosis counts following whole crypt microdissection as an index of the crypt cell proliferative state (CCPS) and to examine the effect of normal biological variables (age, sex, and colonic site) and colonic neoplasia on the mitotic index in macroscopically normal human colon. SUBJECTS: Mucosal samples were obtained at colectomy or colonoscopy from 107 individuals (24 controls, 23 sporadic adenoma patients, 31 sporadic carcinoma patients, and 29 patients with familial adenomatous polyposis (FAP)). METHODS: Mucosal specimens were hydrated, hydrolysed, and small groups of crypts separated from the main specimen under a dissecting microscope. The total number of mitoses/crypt were counted by one observer for each of 10 complete crypts. RESULTS: Validation work established that whole crypt mitoses counts were reliable and reproducible. There was no relation between age and mean mitoses/crypt (Pearson correlation coefficient -0.1). The CCPS count was higher for males than for females (difference in means 2.8 (95% confidence interval 0.80-4.66)) among controls but there was no gender difference in the three disease groups. For all disease groups and controls, the crypt mitotic count showed a significant linear increase (p=0.004) from the rectum to the caecum. Biopsies from within 5 cm of the macroscopic margin of a carcinoma (near) gave a mean mitosis count of 12.6 while those from more than 10 cm (far) were lower but not significantly so (p=0.12) with a count of 9.0. The mean mitoses/crypt were similar for the controls and adenomas (5.6 and 4.7, respectively) but greater for the cancers and especially for FAP (8.3 and 14.2, respectively). Statistical analysis confirmed that there were significant differences (p<0.05) between controls and all disease groups together, between sporadic disease and FAP, and between adenoma and carcinoma subjects at each of the four colonic sites. Post hoc comparison by t test showed significantly greater CCPS for FAP compared with controls (p<0.001) and for sporadic cancer versus controls (p=0.04). CONCLUSIONS: Whole crypt microdissection and mitosis counting is a reliable, reproducible, and robust technique for assessing CCPS in the human colon. CCPS is unaffected by age but increases from the distal to the proximal colon. CCPS is increased if a sporadic cancer is present and markedly increased in FAP. However, the precise relation of an increased CCPS to the neoplastic process remains uncertain. 相似文献
58.
S Natesan S Ashworth J Nielsen S-P Tang C Salinas S Kealey J B Lauridsen T B Stensb?l R N Gunn E A Rabiner S Kapur 《Translational psychiatry》2014,4(4):e376
A number of phosphodiesterase 10A (PDE10) inhibitors are about to undergo clinical evaluation for their efficacy in treating schizophrenia. As phosphodiesterases are in the same signalling pathway as dopamine D2 receptors, it is possible that prior antipsychotic treatment could influence these enzyme systems in patients. Chronic, in contrast to acute, antipsychotic treatment has been reported to increase brain PDE10A levels in rodents. The aim of this study was to confirm these findings in a manner that can be translated to human imaging studies to understand its consequences. Positron emission tomography (PET) scanning was used to evaluate PDE10A enzyme availability, after chronic haloperidol administration, using a specific PDE10A ligand ([11C]MP-10). The binding of [11C]MP-10 in the striatum and the cerebellum was measured in rodents and a simplified reference tissue model (SRTM) with cerebellum as the reference region was used to determine the binding potential (BPND). In rats treated chronically with haloperidol (2 mg kg−1 per day), there was no significant difference in PDE10A levels compared with the vehicle-treated group (BPND±s.d.: 3.57±0.64 versus 2.86±0.71). Following PET scans, ex vivo analysis of striatal brain tissue for PDE10A mRNA (Pde10a) and PDE10A enzyme activity showed no significant difference. Similarly, the PDE10A protein content determined by western blot analysis was similar between the two groups, contrary to an earlier finding. The results of the study indicate that prior exposure to antipsychotic medication in rodents does not alter PDE10A levels. 相似文献
59.
G. Lennon N. Reidy P. J. Collins L. Gunn P. V. Coyle B. Cryan S. Fanning H. O’Shea 《Archives of virology》2014,159(7):1697-1705
Norovirus (NoV) gastroenteritis occurs in all age groups and is the most common cause of gastroenteritis in the community. However, detection methods and rates vary widely, and few data are available to compare these, particularly in Ireland. Detection of noroviruses through antigen and molecular-based strategies was carried out on 135 suspected NoV-positive samples, collected over the course of three NoV outbreaks, from 2002 to 2006, in the southern region of Ireland. A commercially available ELISA and a panel of six primer sets were evaluated to determine their suitability for NoV detection in Irish clinical samples. The key findings of this study were the detection of both GGI and GGII noroviruses by ELISA, but the detection of only GGII noroviruses by RT-PCR. In addition to this, a variation in the levels of detection from 9.4 % to 17.3 % was observed for conventional PCR assays, while a detection rate of 46.3 % was observed for the real-time PCR assay. A proportion (17.8 %) of samples were found to be negative by all detection strategies, suggesting the possibility of reporting false positives for these samples or low-copy positives that do not often repeat. Sequencing information from selected samples also revealed nucleotide polymorphisms, compromising efficient primer binding in the case of one primer pairing. Phylogenetic analysis of the partial polymerase gene identified NoV GII.4 as the dominant genotype, in accordance with previous NoV studies in Ireland. Investigating the NoV diversity of the circulating strains and the dynamics of strain replacement is important to better assess the efficacy of future NoV vaccines and to facilitate the early detection of changes in circulating NoV strains. 相似文献
60.
The present study compared the short-term and long-term neuroprotective and neurobehavioral effects of transforming growth factor beta-1 (TGF beta-1) after hypoxic-ischemic injury in adult rats. TGF beta-1 (10 ng) or vehicle were administered intracerebroventricularly (i.c.v.) 2 h after hypoxia-ischemia. Adhesive removal test was assessed after 10 or 40 days, and the neuronal outcome then determined. TGF beta-1 significantly increased the area of intact cortex compared with vehicle 10 days after the injury, with a significant improvement in neurological function. In contrast, after 40 days recovery TGFbeta-1 neither improved neuronal outcome nor neurological function, suggesting TGFbeta-1 can transiently improve functional and histological recovery from hypoxia-ischemia. 相似文献