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The activation of the endothelial surface in xenografts is still a poorly understood process and the consequences are unpredictable. The role of Ca2+-messaging during the activation of endothelial cells is well recognized and routinely measured by synthetic Ca2+-sensitive fluorophors. However, these compounds require fresh loading immediately before each experiment and in particular when grown in state-of-the-art 3D cell culture systems, endothelial cells are difficult to access with such sensors. Therefore, we developed transgenic pigs expressing a Ca2+-sensitive protein and examined its principal characteristics. Primary transgenic endothelial cells stimulated by ATP showed a definite and short influx of Ca2+ into the cytosol, whereas exposure to human serum resulted in a more intense and sustained response. Surprisingly, not all endothelial cells reacted identically to a stimulus, rather activation took place in adjacent cells in a timely decelerated way and with distinct intensities. This effect was again more pronounced when cells were stimulated with human serum. Finally, we show clear evidence that antibody binding alone significantly activated endothelial cells, whereas antibody depletion dramatically reduced the stimulatory potential of serum. Transgenic porcine endothelial cells expressing a Ca2+-sensor represent an interesting tool to dissect factors inducing activation of porcine endothelial cells after exposure to human blood or serum.  相似文献   
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Infected bile-induced acute pancreatitis in rabbits   总被引:2,自引:0,他引:2  
Summary Conclusions Bacteria species commonly found in bile of patients with choledocholithiasis render human bile toxic to the pancreas. The severity of infected bile-induced acute pancreatitis depends on the bacterial species. Infected bile-induced acute pancreatitis turns into a sterile inflammation within 10 d. Background Flow of bile into the pancreatic duct was proposed to cause some forms of gallstone pancreatitis. The development of bile-induced acute pancreatitis at physiologic ductal pressure is known to depend on the bacterial infection of bile. In this study, we investigated the effect of a variety of bacteria species commonly found in bile of patients with choledocholithiasis upon the pancreatic toxicity of human bile. The time-course of pancreatic infection in infected bile-induced acute pancreatitis was also analyzed. Methods In rabbits, the pancreatic duct was kept obstructed throughout the experiment. After 24 h, 50 μL of pancreatic juice was obtained from the congested pancreatic duct and replaced with the same quantity of infected human bile. Bile contained bacteria (107 microorganisms/μL) of species frequently found in choledochal secretions of patients with gallstone disease. Effects on pancreatic morphology were studied after 48 h. In another experiment, the number ofEscherichia coli/mg of pancreatic tissue was determined in a time sequence study following exposure of the rabbit pancreatic duct to 50 μLE. coli-infected bile (107 microorganisms/mL) and temporary (12 h) or permanent duct obstruction. Results Sterile bile was not harmful to the pancreas. Infected bile caused an interstitial-edematous pancreatitis with occasional acinar necrosis. The severity of acute pancreatitis depended on the bacterial species. Following pancreatic duct exposure toE. coli-infected bile, there was complete clearance of the bacteria from the gland with a concomitant interstitial leukocyte infiltration within a period of 2–10 d.  相似文献   
46.
Genetically modified animals continue to provide important insights into the molecular basis of health and disease. Research has focused mostly on genetically modified mice, although other species like pigs resemble the human physiology more closely. In addition, cross-species comparisons with phylogenetically distant species such as chickens provide powerful insights into fundamental biological and biomedical processes. One of the most versatile genetic methods applicable across species is CRISPR-Cas9. Here, we report the generation of transgenic chickens and pigs that constitutively express Cas9 in all organs. These animals are healthy and fertile. Functionality of Cas9 was confirmed in both species for a number of different target genes, for a variety of cell types and in vivo by targeted gene disruption in lymphocytes and the developing brain, and by precise excision of a 12.7-kb DNA fragment in the heart. The Cas9 transgenic animals will provide a powerful resource for in vivo genome editing for both agricultural and translational biomedical research, and will facilitate reverse genetics as well as cross-species comparisons.

Chickens and pigs are the most important livestock species worldwide. They are not only important sources of food, but also valuable models for evolutionary biology and biomedical science. Pigs share a high anatomical and physiological similarity with humans and are an important species for translational biomedical research, for example, in the areas of cancer, diabetes, neurodegenerative, and cardiovascular diseases (13). They also resemble the human pathophenotype more closely than rodents. For example, pig models for familial adenomatous polyposis (FAP) develop polyps in the large intestine as observed in human patients (4), whereas mouse FAP models develop them in the small intestine (5). In contrast to mammals, chickens are phylogenetically distant vertebrates from humans, but they were instrumental in the field of developmental biology due to the easy access to the embryonated egg. They are used for studying neurological and cardiovascular functions (68) and provided key findings in B cell development and graft versus host responses (911). Genetically modified livestock species also hold great promise for agriculture by offering new approaches for disease control, such as genome-edited pigs resistant to Porcine Reproductive and Respiratory Syndrome or Avian Leucosis Virus (ALV)-resistant chickens (1215).Due to the lack of fully functional embryonic stem cells, genetic engineering in pigs and chickens has been a laborious, inefficient, and time-consuming procedure (16). The generation of pigs with precise germline modifications required gene targeting in somatic cells followed by somatic cell nuclear transfer. This also is not practical in chickens, where precise alteration of the genome only became possible with recent improvements in the cultivation and manipulation of germline-competent primordial germ cells (PGCs) (1719). These modified PGCs can be injected into the blood vessel system of stage 13 to 15 (Hamburger−Hamilton [HH]) embryos to produce germline chimeras and, by further breeding, genetically modified chickens.With the advent of synthetic endonucleases such as CRISPR-Cas9 efficiency of targeted germline modification has improved in both species (2023). It still requires the generation and breeding of new founder lines, which is time consuming in large animals. To circumvent the need for generating germline-modified animals, attempts have been made to carry out genome editing directly in specific organs or tissues (2427). But this has been hampered by the need to deliver both Cas9 and the required guide RNA (gRNA) and by the limited cargo capacity of viral vectors. To bypass this drawback, Cas9 transgenic mice have been generated, requiring delivery of only the respective gRNAs (28).Here, we describe the generation of both Cas9 transgenic pigs and chickens that ubiquitously express Cas9 endonuclease and provide proof of its function in vitro and in vivo. These animals provide an innovative and efficient model for in vivo genome editing to assess gene function in health and disease.  相似文献   
47.

Purpose

During vibration of the whole unloaded lower leg, effects on capillary blood content and blood oxygenation were measured in the calf muscle. The hypotheses predicted extrusion of venous blood by a tonic reflex contraction and that reactive hyperaemia could be observed after vibration.

Methods

Twelve male subjects sat in front of a vibration platform with their right foot affixed to the platform. In four intervals of 3-min duration vibration was applied with a peak-to-peak displacement of 5 mm at frequencies 15 or 25 Hz, and two foot positions, respectively. Near infrared spectroscopy was used for measuring haemoglobin oxygen saturation (SmO2) and the concentration of total haemoglobin (tHb) in the medial gastrocnemius muscle.

Results

Within 30 s of vibration SmO2 increased from 55 ± 1 to 66 ± 1 % (mean ± SE). Within 1.5 min afterwards SmO2 decreased to a steady state (62 ± 1 %). During the following 3 min of recovery SmO2 slowly decreased back to base line. THb decreased within the first 30 s of vibration, remained almost constant until the end of vibration, and slowly recovered to baseline afterwards. No significant differences were found for the two vibration frequencies and the two foot positions.

Conclusions

The relaxed and unloaded calf muscles did not respond to vibration with a remarkable reflex contraction. The acceleration by vibration apparently ejected capillary venous blood from the muscle. Subsequent recovery did not match with a reactive hyperaemia indicating that the mere mechanical stress did not cause vasodilation.  相似文献   
48.
The co-expression of B7.1 (CD80) and intercellular adhesion molecule (ICAM)-1 (CD54) on tumor cells can induce tumor immunity and immunological memory. We show here that the non-immunogenic tumor lines Lewis lung carcinoma and B16F10 melanoma, co-transfected with B7.1 and ICAM-1, induced cytotoxic levels of membrane tumor necrosis factor (TNF) on naive syngeneic T cells within 24 h. Membrane TNF expression, primarily on CD4 cells, was responsible for tumor cell lysis by naive spleen cells and could be completely abolished by anti-TNF antiserum. It is suggested that the strong induction of TNF cytotoxicity may be important in the establishment of tumor immunity.  相似文献   
49.

Purpose

The aim of this study was to investigate to which degree the peritumoral brain edema in patients with meningiomas depends on aquaporin-4 (AQP4) expression, tumor grade, tumor volume, Ki-67 expression, and cell count.

Procedures

Thirty-three patients (25 women, 8 men; mean age 56.6 ± 16.0 years) with an intracranial meningioma underwent a standardized magnetic resonance (MR) examination prior to surgical resection. Edema indices (EIs) and tumor volumes were measured on the MR images. Tumor grade was classified according to the World Health Organization, and the proliferation index was estimated on Ki-67 antigen-stained specimens. Tumor cell count was evaluated. Eighteen specimens were stained for AQP4 expressioon.

Results

Significant intergroup differences between AQP4 expression grades and EIs were observed (P = 0.03), and a positive correlation was detected between EIs and AQP4 expression grades (r = 0.54; P < 0.05). A ROC analysis with EI as a test variable revealed an AUC of 0.77 (95 % CI 0.55–0.99) for the prediction of a moderate-to-strong AQP4 expression. An EI ≥1.5 predicted a moderate-to-high AQP4 expression with a sensitivity of 77 % and a specificity of 60 %. EI values of 2.2 and 3.5 reached sensitivity/specificity values of 69/80 % and 54/100 %, respectively. The AQP4 expression did not show any significant correlations with tumor grading, tumor volume, Ki-67 expression, or cell count. Moreover, we observed no significant positive or negative correlations between the EI and tumor grading (P = 0.7), tumor volume (P = 0.19), Ki-67 index (P = 0.9), and cell count (P = 0.34).

Conclusion

Peritumoral brain edema in patients with meningiomas may depend on AQP4 expression grades and not on tumor grade, tumor volume, Ki-67 expression, and cell count. The amount of edema predicted AQP4 expressions with moderate-to-good sensitivity and specificity.
  相似文献   
50.
Rabbit antithymocyte globulin-Genzyme™ is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme™ on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme™ during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme™ had almost undetectable levels of recent thymic emigrants (CD45RA+CD31+) of both conventional and regulatory CD4T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4+CD45RA-memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme™. In vitro, rabbit antithymocyte globulin-Genzyme™ induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius™. Rabbit antithymocyte globulin-Genzyme™ in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4+ T cells. The sustained depletion of conventional and regulatory CD4+T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme™ could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative.  相似文献   
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