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981.
Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines. 总被引:2,自引:0,他引:2
Christopher M Lee Christa B Fuhrman Vicente Planelles Morgan R Peltier David K Gaffney Andrew P Soisson Mark K Dodson H Dennis Tolley Christopher L Green Karen A Zempolich 《Clinical cancer research》2006,12(1):250-256
PURPOSE: The phosphatidylinositol 3-kinase (PI3K) catalytic subunit is amplified in cervical cancers, implicating PI3K in cervical carcinogenesis. We evaluated the radiosensitizing effect of PI3K inhibition by LY294002 on clonogenic survival, growth characteristics, and gene expression in cervical cancer cell lines (HeLa and CaSki). EXPERIMENTAL DESIGN: Cervical cancer cells were treated separately and concurrently with the PI3K inhibitor LY294002 (10 micromol/L) and radiation (2 Gy) with serial analysis of cell count, apoptosis, and flow cytometry. PI3K inhibition was assessed by protein analysis of phosphorylated Akt. Clonogenic assays were done with varying doses of radiation and LY294002 and varied time points of administration of LY294002 proximate to the radiation dose. Surviving fractions and dose modification factors (DMF) were calculated. Each experiment was done in triplicate and analyzed using ANOVA regression analysis and Dunnett's t Test. Microarray gene expression analysis was done on the HeLa cell line. RESULTS: PI3K inhibition with LY294002 alone did not decrease cell survival. However, treatment with LY294002 significantly radiosensitized HeLa and CaSki cell lines with DMFs (1 log cell kill) of 1.95 and 1.37, respectively. Compared with post-irradiation, pretreatment produced more radiosensitization (P < 0.0001). DMFs were 2.2, 2.0, 2.0, and 1.2 for LY294002 added at 6, 2, and 0.5 hours before irradiation and 6 hours after irradiation, respectively. LY294002 pretreatment in irradiated HeLa cells led to altered gene expression. CONCLUSIONS: Although LY294002 alone did not produce cytotoxic effects, PI3K inhibition with LY294002 produced significant radiosensitization, showed significant time-dependent effects, increased apoptosis, and altered gene expression. These findings support future investigation of PI3K inhibitors in combination with radiation therapy for carcinoma of the cervix. 相似文献
982.
Endovascular grafting in patients with short proximal necks: an analysis of short-term results 总被引:2,自引:0,他引:2
Greenberg R Fairman R Srivastava S Criado F Green R 《Cardiovascular surgery (London, England)》2000,8(5):350-354
OBJECTIVES: To evaluate the safety of endovascular graft placement in patients with short proximal aneurysm necks, and assess factors contributing to endoleak formation. METHODS: 55 patients were enrolled over a two year period from five centers following the placement of a Talent endograft with a suprarenal stent. Preoperative and 30-day post-implant CT scans were retrospectively analyzed in a blinded fashion by two physicians. Aortic measurements were obtained, the amount of thrombus was subjectively graded, and any extravasation of contrast into the aneurysm sac defined an endoleak. The data were analyzed using a t-test. Analyses compared patients with proximal necks<10mm (SN), n=13) to those with longer necks (LN, n=42), and then contrasted patients with endoleaks (n=12), to those without (n=43). RESULTS: Endoleak rates were identical in the SN and LN groups (21 and 23%). Maximal aneurysm size was larger in the SN group (63 vs 56 mm, P<0.05). Endoleaks were more frequently noted in larger aneurysms (P<0.05), but not related to SN (P=0.6). There was no correlation between endoleaks and the amount of thrombus, aneurysm length, proximal neck diameter or other morphologic characteristics. One of 12 endoleaks resulted from a problem with proximal fixation, nine were due to perfusing vessels, and two were undefined. The proximal neck diameter increased (0.9 mm) over the 30 days (P<0.005). CONCLUSIONS: Short-term proximal fixation can be achieved in proximal necks measuring less than 10mm. The narrow margin of acceptable seal mandates careful follow-up. Larger aneurysms were associated with an increased incidence of endoleaks. SNs were associated with larger aneurysms, but not with an increased incidence of endoleaks. Proximal neck dilation was noted, but likely relates to the placement of an oversized endograft during this brief period of observation. 相似文献
983.
Green J Assady S Nakhoul F Bick T Jakobi P Abassi Z 《Journal of the American Society of Nephrology : JASN》2000,11(7):1188-1198
The clinical features of preeclampsia have been traditionally ascribed to a generalized vascular endothelial cell dysfunction. The present study investigates the effect of sera from preeclamptic women and normal pregnancy on the metabolism of intracellular Ca(2+) concentration ([Ca(2+)](i)) in normal cultured vascular smooth muscle cells (VSMC). Sera were obtained from normotensive pregnant women (NTP) (n = 17), preeclamptic women (PE) (n = 15), pregnant women with chronic (essential) hypertension (pregnant EHT) (n = 8), non-pregnant women with essential hypertension (non-pregnant EHT) (n = 12), and age-matched non-pregnant normotensive women (NNP) (n = 18). Serum (10%) was applied to both primary cultures of rat aortic smooth muscle cells and to the A-10 vascular muscle cell line. Levels of [Ca(2+)](i) were determined fluorometrically. After a 4-h incubation with serum, basal [Ca(2+)](i) was not significantly altered. However, compared with normal pregnant sera, PE sera markedly reduced hormonally induced Ca(2+) transients. Thus, following acute stimulation of rat VSMC (primary cultures) with 10(-8)M angiotensin II, peak [Ca(2+)](i) responses (% increment over baseline) were 443 +/- 22, 184 +/- 18, 259 +/- 12, 274 +/- 23, and 255 +/- 15% in NTP, PE, pregnant EHT, non-pregnant EHT, and NNP, respectively (P <0.01 PE versus NTP, P <0.05 PE versus NNP and pregnant and non-pregnant EHT). These effects of sera on [Ca(2+)](i) were qualitatively reproduced in platelets obtained from healthy volunteers. Also, depolarization-activated Ca(2+) influx in VSMC was affected by the different sera groups in a manner similar to that seen with hormonally induced [Ca(2+)](i) responses. The altered [Ca(2+)](i) changes by PE sera disappeared 5 wk after delivery. The effect of the different sera groups on hormonally triggered Ca(2+) transients in normal VSMC, as well as the normalization of [Ca(2+)](i) responses after delivery, suggest the presence of a circulating serum factor in PE. Inasmuch as [Ca(2+)](i) is the major determinant of VSMC tone, it is possible that consequent to the attenuation of [Ca(2+)](i) responses, this putative circulating factor counterbalances the intense vasoconstriction in PE. 相似文献
984.
985.
Rasmussen DD Mitton DR Green J Puchalski S 《Alcoholism, clinical and experimental research》2001,25(7):999-1005
BACKGROUND: Our previous investigations have suggested that alcohol abuse may induce persistently compromised hypothalamo-pituitary-adrenal (HPA) function, which could increase risk for subsequent alcohol abuse. The apparent similarity of chronic alcohol abuse-induced HPA defects to the compromised HPA functions associated with posttraumatic stress disorder and atypical depression also suggest potential common mechanisms shared with varied neurobehavioral disorders. Accordingly, we have investigated persistent behavioral effects of previous repetitive daily ethanol consumption and withdrawal. METHODS: Male Sprague-Dawley rats received either daily ad libitum chow, ad libitum liquid diet containing ethanol, or pair-fed isocaloric control liquid diet. The ethanol was gradually introduced over 4 weeks, maintained at 5% w/v for four subsequent weeks, and then gradually removed over 1 week. RESULTS: Four weeks after removal of ethanol from the diet, the previously ethanol-consuming rats exhibited greater (p < 0.05) evidence of anxiety in the elevated plus-maze test and in the novel cork-gnawing test, as well as greater (p < 0.05) locomotor response to a novel environment, compared with controls. CONCLUSIONS: These results suggest that repetitive daily alcohol consumption and withdrawal can induce not only persistent defects in HPA function, but also persistent increases in anxiety and behavioral responsiveness to novelty, all consistent with characteristics of abstinent alcoholics as well as with rats that self-administer increased amounts of alcohol and other drugs of abuse. This suggests that alcohol abuse can induce persistent common or interacting changes in neuroendocrine and behavioral responses that may increase risk for subsequent abuse. 相似文献
986.
987.
Therapeutic effects of environmental enrichment on cognitive function and tissue integrity following severe traumatic brain injury in rats 总被引:8,自引:0,他引:8
Postinjury environmental enrichment (EE) has been shown to alter functional and anatomical outcomes in a number of injury paradigms, including traumatic brain injury (TBI). The question of whether EE alters functional outcome following TBI in a model which produces overt histopathological consequences has not been addressed. We investigated this question using the severe, parasagittal fluid percussion injury (FPI) model. Rats (n = 7 per group, enriched and standard for behavior; n = 15 per group for histology) underwent severe (2.2-2.6 atm) FPI, with sham-operated rats (n = 7 per group, enriched and standard for behavior; n = 6 enriched, n = 3 standard for histology) serving as controls. Animals were allowed to recover for 11 days either in standard single housing or together (injured and sham) in an enriched environment consisting of a 92 x 61 x 77-cm ferret cage filled with various stimulatory objects. Consistent with earlier reports, injured animals recovering in the enriched environment showed significantly (P < 0.05) shorter latencies to find the platform in a Morris Water Maze task versus injured/standard animals on day 12 post-TBI. However, both injured groups showed significant deficits versus sham groups (P < 0.05). There were no differences between the sham/enriched and sham/standard groups. No significant group differences in swim speed were observed. At 14 days post-TBI, enriched animals had approximately twofold smaller lesion areas in regions of the cerebral cortex posterior to the injury epicenter (-4.5, -5.8, -6.8 mm relative to bregma; P < 0.05) compared to injured/standard animals. In addition, overall lesion volume for the entire injured cortical hemisphere was significantly smaller in animals recovering in the enriched environment. These results indicate that noninvasive environmental stimulation is beneficial in attenuating cognitive deficits and preserving tissue integrity in a TBI model which causes cerebral contusion and cell death. 相似文献
988.
OBJECTIVE: Psychiatrists are under immense ethical pressure when practicing in circumstances that reasonable, informed colleagues would regard as not "good enough" in that they do not adequately meet the needs of patients and patients' families. This article is an examination of the ethical quandaries that ensue and options for response. METHOD: The authors explore the ways in which mental health systems may become flawed and compare philosophical arguments that deal with the predicament of working in such systems. RESULTS: The principle of fidelity to the patient is compromised in flawed systems, thus threatening professional integrity. Arguments for efficiency or the greater good in the provision of mental health care fail as remedies since they both lead to harms for particular clinical groups, as well as downgrading of a psychiatrist's integrity. CONCLUSIONS: Psychiatrists should submit to the principle of fidelity in working with patients. Since flawed systems undermine fidelity, threatening the patient's interests, psychiatrists are morally responsible for working to improve such systems. 相似文献
989.
OBJECTIVE: To evaluate quality of life (QOL) among treated and never-treated schizophrenic patients. METHOD: QOL ratings were obtained for (a) 112 Moroccan participants with schizophrenia who had never received neuroleptic medications, (b) matched samples of chronically-medicated schizophrenic patients in Morocco and the United States and (c) matched community controls in both countries. RESULTS: QOL ratings were generally higher for US groups, although Moroccan controls obtained higher ratings than US controls for some domains. QOL ratings were higher for controls compared to patients within each country, although US patients' scores were similar to controls on some dimensions. We found no differences between treated and untreated Moroccan patients for any QOL domain, although relationships among predictors were different. CONCLUSION: Within the context of Moroccan culture, benefits of medications alone are not evident in QOL scores. QOL appears to be a complex construct influenced by different factors within each of the groups studied. 相似文献
990.
We investigated in rats the effect N(G)-nitro-L-arginine methyl ester (L-NAME) on retention of a passive avoidance response, and cortical ACh release monitored using the microdialysis technique. Post-training administration of L-NAME impaired 24 h retention of a passive avoidance and decreased cortical ACh release. Both effects of L-NAME were reversed by L-Arg. These results suggest that nitric oxide is involved in retention of the passive avoidance response through the modulation of the forebrain cholinergic system. 相似文献