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111.
Alisan Kahraman Steven F. Bronk Sophie Cazanave Nathan W. Werneburg Justin L. Mott Patricia C. Contreras Gregory J. Gores 《Hepatology research》2009,39(8):805-813
Aim: Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. Thus, our aim was to assess if CTS-1027 is hepato-protective and anti-fibrogenic during cholestatic liver injury.
Methods: C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage.
Results: BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals ( P < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (α-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals ( P < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug ( P < 0.05).
Conclusion: The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury. 相似文献
Methods: C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage.
Results: BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals ( P < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (α-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals ( P < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug ( P < 0.05).
Conclusion: The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury. 相似文献
112.
Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. 总被引:14,自引:11,他引:3 下载免费PDF全文
H Yki-Jrvinen D Mott A A Young K Stone C Bogardus 《The Journal of clinical investigation》1987,80(1):95-100
We examined the insulin dose-response characteristics of human muscle glycogen synthase and phosphorylase activation. We also determined whether increasing the rate of glucose disposal by hyperglycemia at a fixed insulin concentration activates glycogen synthase. Physiological increments in plasma insulin but not glucose increased the fractional activity of glycogen synthase. The ED50: s for insulin stimulation of whole body and forearm glucose disposal were similar and unaffected by glycemia. Glycogen synthase activation was exponentially related to the insulin-mediated component of whole body and forearm glucose disposal at each glucose concentration. Neither insulin nor glucose changed glycogen phosphorylase activity. These results suggest that insulin but not the rate of glucose disposal per se regulates glycogen synthesis by a mechanism that involves dephosphorylation of glycogen synthase but not phosphorylase. This implies that the low glycogen synthase activities found in insulin-resistant states are a consequence of impaired insulin action rather than reduced glucose disposal. 相似文献
113.
114.
Allison M. Mott Eric J. Nunes Lyndsey E. Collins Russell G. Port Kelly S. Sink Jörg Hockemeyer Christa E. Müller John D. Salamone 《Psychopharmacology》2009,204(1):103-112
Rationale Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related
processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental
behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors.
Objective Previous work showed that adenosine A2A antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice.
The present work used a T-maze choice procedure to assess the effects of adenosine A2A and A1 antagonism.
Materials and methods With this task, the two arms of the maze have different reinforcement densities (four vs. two food pellets), and a vertical
44 cm barrier is positioned in the arm with the higher density, presenting the animal with an effort-related challenge. Untreated
rats strongly prefer the arm with the high density of food reward and climb the barrier in order to obtain the food.
Results Haloperidol produced a dose-related (0.05–0.15 mg/kg i.p.) reduction in the number of trials in which the rats chose the high-barrier
arm. Co-administration of the adenosine A2A receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg i.p.), but not the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.75, 1.5, and 3.0 mg/kg i.p.), reversed the effects of haloperidol on effort-related
choice and latency.
Conclusions Adenosine A2A and D2 receptors interact to regulate effort-related decision making, which may have implications for the treatment of psychiatric
symptoms such as psychomotor slowing or anergia that can be observed in depression, parkinsonism, and other disorders. 相似文献
115.
Margaret C.L. Tse Crystal Lane Kevin Mott Nattawat Onlamoon Hui-Mien Hsiao Guey Chuen Perng 《Journal of neuroimmunology》2009,213(1-2):12-19
Chemokines are important in HSE development in the CNS but underlying regulatory events are unknown. Two-hybrid binding assays identified that intercellular adhesion molecule 5 (ICAM-5), an immune modulator in the CNS, interacted with neurovirulence factor, UOL, of HSV-1. Viral load and interleukin levels were similar in UOL deletion virus (ΔUOL), and wild type virus infected mouse brains. However, higher numbers of lymphocytes, but unaltered soluble ICAM-5 and chemokine levels were detected in ΔUOL infected mouse brains. In contrast, lower lymphocyte numbers, reduced soluble ICAM-5, and higher chemokine levels were detected in wild type virus infected brains. Our results suggest that ICAM-5 plays a critical role in modulating chemokine production in the CNS. 相似文献
116.
Abnormal visual evoked potentials (VEPs) have been reported in children treated for acute lymphoblastic leukaemia (ALL), which suggests that VEPs may be useful in screening for toxicity. The authors investigated this by recording flash and pattern VEPs in a control group of 34 siblings of patients, a group of six children studied longitudinally during the early stages of treatment for ALL, and three other follow-up groups. In only three follow-up patients were VEP results outside the normal range and the six ALL patients did not develop new abnormalities during early treatment. Although differences were detected between the groups, there was no evidence of VEPs being a useful means of monitoring the treatment of individual patients. 相似文献
117.
Correlation between muscle glycogen synthase activity and in vivo insulin action in man. 总被引:6,自引:36,他引:6 下载免费PDF全文
We have studied the relationship between in vivo insulin-mediated glucose disposal rates, muscle glycogen content, and muscle glycogen synthase activity in 25 southwest American Indians with normal glucose tolerance and with varying degrees of glucose intolerance. Insulin-mediated glucose disposal (M) was measured by using the hyperinsulinemic euglycemic clamp technique at plasma insulin concentrations of 134 +/- 7 and 1709 +/- 72 microU/ml, with simultaneous indirect calorimetry to assess glucose oxidation and storage rates. Muscle glycogen content and glycogen synthase activity were measured in percutaneous muscle biopsy samples obtained from the vastus lateralis muscle before and after the euglycemic clamp procedure. The results showed that muscle glycogen synthase activity at the end of the euglycemic clamp was well correlated with insulin-mediated glucose storage rates at both low (r = 0.50, P less than 0.02) and high (r = 0.78, P less than 0.0001) insulin concentrations; and also correlated with M (r = 0.66, P less than 0.001 and r = 0.76, P less than 0.0001). Similar correlations were observed between the change in muscle glycogen synthase activity and glucose storage rates and M. The change in muscle glycogen synthase activity correlated with the change in muscle glycogen content (r = 0.46, P less than 0.03) measured before and after the insulin infusions. The change in muscle glycogen content did not correlate with glucose storage rates or M. The data suggest the possible importance of glycogen synthesis in muscle in determining in vivo insulin-mediated glucose disposal rates in man. 相似文献
118.
目的:建立家猪胸腰段脊髓火器贯通伤模型和改良Allen's打击伤后全瘫模型,观察伤后促凋亡基因p53基因的早期表达。方法:实验于2005-05/08在解放军第一七五医院实验室完成。取健康雄性家猪20只,单纯随机分为3组:①火器伤组:9只,在全麻状态下制作胸腰段(L1~L2)脊髓火器伤模型,分为伤后1,3,6h3个时间处死。②打击伤组:9只,L1节段脊髓行改良Allen’s打击,致伤力为500g·cm,处死时间同前。③空白对照组:2只,只麻醉,不造模,伤后6h处死。伤后不同时间点(伤后1,3,6h)和不同节段(伤点、近伤点、中伤点及远伤点)取材,采用SP法进行P53蛋白免疫组化染色,用TJTY-300型全自动图像分析仪测量P53免疫组织化学染色阳性物质吸光度。结果:经补充后20只猪进入结果分析。①脊髓损伤后3h打击伤组伤点,火器伤组近伤段脊髓P53蛋白的表达高于空白对照组(P<0.001),随着时间推移,打击伤组和火器伤组P53蛋白的表达呈升高趋势(P<0.001),且火器伤组要高于打击伤组(P<0.0001)。②在脊髓损伤后6h,打击伤组仅在伤点和近伤段P53蛋白的表达高于空白对照组(5.57±0.82,3.21±0.43,P<0.05),而火器伤组近伤段、中伤段及远段伤均高于空白对照组(6.46±0.66,4.27±0.39,1.16±0.17,P<0.05)。结论:①细胞凋亡基因p53在脊髓损伤中的表达有一定的时空性,在脊髓损伤后3h出现P53蛋白表达量的增加。②脊髓火器伤的波及范围较打击伤更为广泛。 相似文献
119.
120.
Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. 下载免费PDF全文
C Bogardus S Lillioja D Mott G R Reaven A Kashiwagi J E Foley 《The Journal of clinical investigation》1984,73(3):800-805
Previous studies have left unanswered whether human obesity, independent of glucose intolerance, is associated with a "postreceptor" defect in insulin action. We have studied the relationship between the degree of obesity (as estimated by underwater weighing) and the maximal insulin-stimulated glucose disposal rate (M) in vivo in 52 glucose-tolerant Pima Indian males. The relationship was examined independently of differences in age and maximal oxygen uptake (an estimate of "physical fitness"). The maximal insulin-stimulated glucose transport rate (MTR) was also measured in isolated abdominal adipocytes from the same subjects to determine whether differences in M could be explained by differences in glucose transport. The results showed that there was a large variance in M and MTR among these glucose-tolerant subjects. M was better correlated with glucose storage rates than with oxidation rates, as estimated by indirect calorimetry. The most obese subjects had only a 20% lower mean M and 30% lower MTR than the most lean subjects. The lower M in the obese subjects was due to both lower glucose oxidation and storage rates. There was no significant, independent correlation between age or degree of obesity and M or MTR. The maximal oxygen uptake (VO2 max) appeared to independently account for 20% of the variance observed in M. MTR was only weakly correlated with M (r = 0.36, P less than 0.02). We concluded that differences in M in these glucose-tolerant subjects must be explained by factor(s) other than maximal oxygen uptake, age, maximal insulin-stimulated glucose transport in vitro, or degree of adiposity per se. 相似文献