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1.
《Journal of pharmaceutical sciences》2019,108(7):2500-2504
Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field. 相似文献
2.
放射性肝纤维化过程的定量研究 总被引:6,自引:0,他引:6
经^60Coγ线照射大鼠肝区,通过光镜、电镜和图像分析仪、宣研究了照后1年肝脏的病理改变。结果表明,30Gy组在照射后1年内逐渐发生了放射性肝纤维化病变。在肝纤维化发生过程中,肝细胞内糖原颗凿含量进行性减少,间质中胶原纤维含量进行性增加,网状纤维于照射1-3个月呈进行性增加。 相似文献
3.
4.
螺旋CT三期扫描对肝纤维化诊断价值研究 总被引:5,自引:1,他引:4
目的探讨螺旋CT三期扫描对肝纤维化的诊断价值。方法对66例经肝穿刺活检病理证实的慢性乙型肝炎肝纤维化患者组和42例正常对照组进行螺旋CT三期增强扫描。根据纤维化程度分期进行影像资料和相关指标的统计分析。结果肝左叶增大,肝表面形态及肝实质密度的改变,脾脏增大,门静脉增宽和侧枝循环的建立等影像学改变,随着肝纤维化严重程度的加重而有统计学差异。本研究显示57例肝纤维化患者螺旋CT三期扫描诊断肝纤维化52例,敏感性91.2%,特异性77.8%。各期肝纤维化分期准确28例,准确率49.1%;准确判断轻度纤维化(S1、S2)或重度纤维化(S3、S4)44例,准确率77.2%,诊断早期肝硬化16例,准确率84.2%。结论螺旋CT三期扫描能判断肝纤维化的程度,而且是动态观察肝纤维化的病程演进和临床随访的有效手段。 相似文献
5.
Nishida Koyo Mihara Kiyoshi Takino Toichi Nakane Sachi Takakura Yoshinobu Hashida Mitsuru Sezaki Hitoshi 《Pharmaceutical research》1991,8(4):437-444
The effect of electric charge on the hepatic disposition of macromolecules was studied in the rat. Charged derivatives of dextran (T-70) and bovine serum albumin (BSA), mitomycin C–dextran conjugates (MMC-D), and lactosaminated BSA (Lac-BSA) were employed as model macromolecules. After intravenous injection, cationic macromolecules were rapidly eliminated from plasma because of their extensive hepatic uptake, while anionic and neutral macromolecules were slowly eliminated. Cationic macromolecules were recovered from parenchymal and nonparenchymal hepatic cells at a cellular uptake (per unit cell number) ratio of 1.4–3.2, while that of Lac-BSA was 14. During liver perfusion using a single-pass constant infusion mode, cationic macromolecules were continuously extracted by the liver, with extraction ratios at steady-state (E
ss) ranging between 0.03 and 0.54, whereas anionic and neutral macromolecules were almost completely recovered in the outflow at steady state. The E
ss for cationized BSA (Cat-BSA) and cationic MMC-Dcat were concentration dependent and decreased at low temperatures and in the presence of colchicine and cytochalasin B. The possible participation of the internalization process in the uptake of cationic macromolecules by hepatocytes was suggested. 相似文献
6.
J.P. Brouillet B. Hanslick T. Maudelonde M.T. Pivat J. Grenier F. Blanc H. Rochefort 《Clinical biochemistry》1991,24(6):491-496
Using a sandwich enzyme-linked immunoassay, plasma total cathepsin D concentration was assayed in 40 breast cancer patients and 84 patients with various liver diseases and compared to that of 52 normal subjects. There were no significant variations found in breast cancer patients related to tumor size, node invasiveness or metastases. In normal women, cathepsin D levels were slightly but not significantly increased in the luteal phase and in pregnancy. By contrast, plasma cathepsin D concentration was significantly increased in 70-75% of patients with liver disease (cirrhosis, hepatocarcinoma, hepatitis), but not in those with liver steatosis. Cathepsin D was independent of most of the plasma hepatic function tests and was correlated with alpha-fetoprotein in cirrhosis and with alpha-fucosidase in primary hepatocellular carcinoma. We conclude that plasma cathepsin D is not a useful marker in breast cancer. However, since the cellular level of this protease is associated with risk of metastasis in breast cancer, clinical follow-up will be required to test whether high cathepsin D plasma concentration has any prognostic value in liver cirrhosis and primary hepatocarcinoma. 相似文献
7.
Treatment strategy for synchronous metastases of colorectal cancer: is hepatic resection after an observation interval appropriate? 总被引:1,自引:1,他引:0
Yasuhiro Shimizu Kenzo Yasui Tsuyoshi Sano Takashi Hirai Yukihide Kanemitsu Koji Komori Tomoyuki Kato 《Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie》2007,392(5):535-538
Background In cases of synchronous colorectal hepatic metastases, the primary colorectal cancer strongly influences on the metastases.
Our treatment policy has been to conduct hepatic resection for the metastases at an interval of 3 months after colorectal
resection. We examined the appropriateness of interval hepatic resection for synchronous hepatic metastasis.
Materials and methods The subjects were 164 patients who underwent resection of hepatic metastasis of colorectal cancer (synchronous, 70 patients;
metachronous, 94 patients). Background factors for hepatic metastasis and postoperative results were compared for synchronous
and metachronous cases.
Results The cumulative survival rate for 164 patients at 3, 5, and 10 years postoperatively was 71.9%, 51.8%, and 36.6%, and the post-resection
recurrence rate in remnant livers was 26.8%. Interval resection for synchronous hepatic metastases was conducted in 49 cases
after a mean interval of 131 days. No difference was seen in postoperative outcome between synchronous and metachronous cases.
Conclusion The outcome was similarly favorable in cases of synchronous hepatic metastasis and in cases of metachronous metastasis. Delaying
resection allows accurate understanding of the number and location of hepatic metastases, and is beneficial in determining
candidates for surgery and in selecting surgical procedure. 相似文献
8.
血清α—L-岩藻糖苷酶(AFU)对原发性肝癌(PHC)的诊断意义 总被引:1,自引:0,他引:1
目的研究血清α-L-岩藻糖苷酶(AFU)对原发性肝癌的诊断意义。方法分别测定20例正常对照者、45例慢性乙型肝炎、40例肝硬化、50例转移性肝癌及35例原发性肝癌患者的血清AFU。结果原发性肝癌组的血清AFU浓度和阳性率显著高手其他各组。结论血清AFU对原发性肝癌的诊断有重要价值。 相似文献
9.
The effect of the hepatic energy status on the development of posttraumatic jaundice (PTJ) was studied to clarify the mechanism of PTJ. Fifty-four patients with severe torso injury who were expected to develop PTJ on admission with an average Injury Severity Score of 27 were selected for this study. They were retrospectively divided into three groups according to their maximum bilirubin concentration by day 10: group H, 12 patients with marked elevation of serum bilirubin (>8 g/dl); group L, 23 with mild bilirubinemia (2–8 g/dl); and group N, 19 with no bilirubinemia (<2 g/dl). Group H patients, in whom trauma-related shock was severe and prolonged, developed severe hyperbilirubinemia, and their arterial ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state and is closely correlated to its energy production, was significantly lower throughout the first week. In contrast, the AKBR increased to an above normal level, indicating enhanced energy production in groups N and L. The serum direct/total bilirubin was also higher in group H. The abnormal hepatic energy metabolism is considered to have reduced the excretion of conjugated bilirubin from the hepatocytes into the bile canaliculi, which is a process that has to proceed against the bilirubin concentration gradient. The subsequent diffusion of the accumulated water-soluble conjugated bilirubin in hepatocytes into the blood is thus considered to be one of the causes of PTJ. 相似文献
10.
Abstract One hundred eighty-one consecutive patients with fulminant hepatic failure (FHF) presenting in a 2-year period were reviewed. In this cohort we examined the impact of pretransplant renal failure on mortality and morbidity following orthotopic liver transplantation (OLTx). Twenty-seven patients (18 female, 9 male) with a median age of 43.5 years (range 19–65 years) underwent OLTx. FHF was due to idiosyncratic drug reaction ( n = 4), paracetamol overdose ( n = 3), seronegative hepatitis ( n = 17), hepatitis B ( n = 1), veno-occlusive disease ( n = 1), and Wilson's disease ( n = 1). Renal failure was present in 14 patients, 7 of whom died (whereas there was 100 % survival in patients without renal failure). Pretransplant renal failure was associated with prolonged mechanical ventilation (13 days vs 6 days, P = 0.05), prolonged intensive care stay (17 days vs 8 days, P - 0.01) and prolonged hospital stay (27 vs 21 days, P = NS). Pretransplant renal failure did not predict renal dysfunction at 1 year after OLTx. We conclude that the survival of patients transplanted for FHF is inferior to that of patients transplanted for chronic liver disease (67 % vs 88 % 1-year survival in Birmingham). For patients with FHF undergoing transplantation, pretransplant renal failure strongly predicts poor outcome with significantly greater consumption of resources. 相似文献