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11.
Baumgartner C; Morell A; Hirt A; Bucher U; Forster HK; Doran JE; Matter L; Brun del Re G; Wagner HP 《Blood》1988,71(5):1211-1217
Elimination of neoplastic B cell populations from autologous bone marrow grafts also removes normal B lymphocytes. This is potentially hazardous for the reconstitution of the immune system in patients undergoing high-dose chemotherapy and total body irradiation followed by autologous marrow rescue. Five pediatric patients with B cell non- Hodgkin's lymphoma in first remission undergoing such a regimen were studied. They received bone marrow pretreated with anti-Y 29/55 monoclonal antibody and complement. B and T lymphocyte subpopulations reached normal levels within 6 months after autologous bone marrow transplantation (ABMT), and serum immunoglobulin levels became normal within 4 to 9 months. Vaccination with diphtheria and tetanus toxoid, trivalent poliomyelitis vaccine of the Salk type, and pneumococcal capsular antigens (38 to 54 months after transplantation) gave rise to specific antibody production. ABO isoagglutinins could be demonstrated in all patients. The response pattern was similar to that of patients who received unmanipulated autologous bone marrow. It is concluded that ex vivo anti-Y 29/55 depletion of the marrow graft does not induce relevant disturbances of humoral immune functions. 相似文献
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Polymicrobial sepsis induces organ changes due to granulocyte adhesion in a murine two hit model of trauma. 总被引:7,自引:0,他引:7
Martijn van Griensven Meryem Kuzu Maike Breddin Frederic B?ttcher Christian Krettek Hans-Christoph Pape Thomas Tschernig 《Experimental and toxicologic pathology》2002,54(3):203-209
INTRODUCTION: Polytrauma patients, who develop organ dysfunction, have often undergone multiple subsequent insults ("hits"). The sequence of organs that show a dysfunction mostly is lung, liver, kidney and heart. The aim of the present study was to investigate whether a second hit after trauma induces organ changes. Furthermore, it was of interest to identify possible pathogenic mediators such as polymorphonuclear granulocytes (PMN) and cytokines. For this purpose, a two hit model of systemic damage in mice was developed. Sepsis was induced by caecal ligation and puncture (CLP), which was preceded 48 hours by a femur fracture, the most common fracture of long bones in trauma patients. This fracture was combined with a haemorrhagic shock. METHODS: In both mouse groups studied, a standardized femur fracture was produced using a blunt guillotine device with a weight of 500 g. This was followed by a haemorrhagic shock with substitution of ringer's lactate after 1 hour. In the study group, CLP was induced by puncturing the caecum using a 21G needle. As a control, sham animals underwent a laparotomy without CLP. Both groups were sacrificed after 48 or 96 hours. Clinical parameters were investigated on a daily basis to evaluate the animals' status. Lung, liver and kidney morphology was studied by light microscopy. PMN adhesion was determined by counting the number of adherent PMN per 100 microm of endothelium. Serum levels of TNF-alpha were measured after 48 and 96 hours. RESULTS: In the group submitted to laparotomy, all animals survived. The induction of polymicrobial sepsis by CLP resulted in an 85% (34/40) mortality within 96 hours after surgery (p < 0.05). The induction of a polymicrobial sepsis resulted in a significantly steady worsening of the clinical situation compared to the sham animals (p < 0.05). Lung morphology demonstrated significant changes at the end of the experimental period after 96 h in the two hit group. The alveolar septa were thickened and in all lungs haemorrhagic foci were observed. The number of PMN adhering to the pulmonary endothelium significantly increased at 96 hours. Some of the liver specimens in the two hit group showed focal hydropic degeneration and PMN infiltration. No kidney pathology was observed. This result coincided with an increase in TNF-alpha serum levels. DISCUSSION: A new rodent model mimicking the situation in the polytraumatized patient was developed. Although the animals showed minimal organ manifestation, a high percentage died probably due to cytokinemia. Furthermore, the increased TNF-alpha levels may lead to increased adhesion of PMN in the lung venules. This adhesion developed four days after the second hit. This might be the initial step for the development of extensive lung lesions in later phases. This model represents the SIRS more than MODS. This is a model for devolopment of posttraumatic disease due to cytokinemia and less for chronic multiple organ dysfunction and failure. 相似文献
14.
Alzheimer’s disease(AD)is a neurodegenerative disease that is characterized by an age-dependent progressive decline of memory,impairment of cognitive functions and changes in personality and behavior.Despite the improvement in understanding of the mechanisms underlying the disease,AD remains an incurable complex disorder with multifaceted pathophysiology to date.Apolipoprotein E(ApoE)is the main cholesterol carrier in the brain that supports lipid transport between brain cells.The individuals carrying the APOE4 allele are known to be at increased risk of developing AD compared with those carrying the more common APOE3 allele. 相似文献
15.
Wegert W Graff J Kaiser D Breddin HK Klinkhardt U Harder S 《International journal of clinical pharmacology and therapeutics》2002,40(4):135-141
OBJECTIVES: The influence of antiplatelet agents on platelet-induced thrombin generation may increase the risk of bleeding. Assessment of the endogenous thrombin potential (ETP), is therefore a parameter deserving attention in early pharmacodynamic studies with antiplatelet drugs. The aim ofthis study was to assess whether an automated ETP-assay can be used to determine possible inhibitory effects of antiplatelet drugs on platelet-associated thrombin generation. METHODS: We first characterized the in vitro dose-response relationship of several platelet agonists (ADP, collagen, U46619, TRAP (amino acid sequence: SFLLRNP) and tissue factor (TF) using the generation of ETP. One submaximal concentration of each agonist was then used to assess the influence of in vivo treatment with aspirin (single oral dose of 500 mg as inhibitor of thromboxane synthesis) and clopidogrel (given orally for 6 days, as an inhibitor of the purinergic P2Y12-receptor on platelets) and in vitro treatment with abciximab (which inhibits the platelet glycoprotein IIb/IIIa-receptor for fibrinogen), on the ETP. RESULTS: The effect of TF and the other platelet inducers on thrombin generation was dose-dependent. Repeat measurements on samples from the same subject, with the same inducer concentration on 2 different occasions showed a variability of approx. 22% (absolute difference between 2 measurements as % of mean). The coefficient on variation of repeat measurements of one sample varied between 7% and 17%, depending on the inducer. After a single dose of aspirin, ETP was reduced by 25-40%, depending on the platelet activating agent used. The reduction in ETP with abciximab in vitro was more pronounced. In contrast, TF-induced ETP was not influenced by aspirin or abciximab. Clopidogrel, administered for 6 days, reduced the ETP by 60% when platelets were stimulated using 20 microM ADP, whereas collagen-induced ETP and TF-induced ETP remained unchanged. CONCLUSIONS: The ETP-method is a sensitive and reproducible method for the detection of drug effects on platelet-induced thrombin generation of high throughput, and can be recommended for studies on the pharmacodynamic profile of drugs interfering with platelet function. 相似文献
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17.
Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643 总被引:7,自引:6,他引:7
Bojes HK; Germolec DR; Simeonova P; Bruccoleri A; Schoonhoven R; Luster MI; Thurman RG 《Carcinogenesis》1997,18(4):669-674
Several structurally dissimilar hypolipidemic drugs, plasticizers and
halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause
hepatocellular adenoma and carcinoma in rats and mice. The mechanism by
which these agents act is unknown, although recent studies have suggested a
link between increased cell proliferation and hepatic cancer caused by
peroxisome proliferators. Here, we demonstrate that neutralizing antibodies
to tumor necrosis factor alpha (TNF alpha) block increases in protein
kinase C and cell proliferation due to [4-
chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a
hypolipidemic drug and potent peroxisome proliferator that causes tumors.
WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF
alpha was detected immunohistochemically exclusively in Kupffer cells.
These results demonstrate that WY-14,643 acts as an indirect mitogen on
hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source
of TNF alpha in the liver, is involved in the mechanism of the mitogenic
effect of WY-14,643.
相似文献
18.
J Komulainen R Lounamaa M Knip EA Kaprio HK Akerblom 《Archives of disease in childhood》1996,75(5):410-415
The determinants of the degree of metabolic decompensation at the diagnosis of type 1 (insulin dependent) diabetes mellitus (IDDM) and the possible role of diabetic ketoacidosis in the preservation and recovery of residual beta cell function were examined in 745 Finnish children and adolescents. Children younger than 2 years or older than 10 years of age were found to be more susceptible to diabetic ketoacidosis than children between 2 and 10 years of age (< 2 years: 53.3%; 2-10 years: 16.9%; > 10 years: 33.3%). Children from families with poor parental educational level had ketoacidosis more often than those from families with high parental educational level (24.4% v 16.9%). A serum C peptide concentration of 0.10 nmol/l or more was associated with a favourable metabolic situation. Low serum C peptide concentrations, high requirement of exogenous insulin, low prevalence of remission, and high glycated haemoglobin concentrations were observed during the follow up in the group of probands having diabetic ketoacidosis at the diagnosis of IDDM. Thus diabetic ketoacidosis at diagnosis is related to a decreased capacity for beta cell recovery after the clinical manifestation of IDDM in children. 相似文献
19.
NC de Bruin KA van Velthoven M de Ridder T Stijnen RE Juttmann HJ Degenhart HK Visser 《Archives of disease in childhood》1996,74(5):386-399
Data on body composition in conjunction with reference centiles are helpful in identifying the severity of growth and nutritional disorders in infancy and for evaluating the adequacy of treatment given during this important period of rapid growth. Total body fat (TBF) and fat-free mass (FFM) were estimated from total body electrical conductivity (TBEC) measurements in 423 healthy term Caucasian infants, aged 14-379 days. Cross sectional age, weight, and length related centile standards are presented for TBF and FFM. Centiles were calculated using Altman's method, based on polynomial regression and modelling of the residual variation. The TBF percentage steeply increased during the first half year of life, and slowly declined beyond this age. Various simple TBEC derived anthropometric prediction equations for TBF and FFM are available to be used in conjunction with these standards. Regression equations for the P50 and the residual SD, depending on age, weight, or length, are provided for constructing centile charts and calculating standard deviation scores. 相似文献
20.
Klinkhardt U Breddin HK Esslinger HU Haas S Kalatzis A Harder S 《British journal of clinical pharmacology》2000,49(4):337-341
AIMS: To investigate potential interactions between reviparin and acetylsalicylic acid (ASA 300 mg o.d. from day 1-5). METHODS: In an open, randomized, three-way-cross over study nine healthy volunteers received reviparin (s.c. injection of 6300 anti-Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300 mg) or placebo from days 1 to 5. Assessments included bleeding time (BT), collagen (1 microg ml-1) induced platelet aggregation (CAG), heptest, plasma antifactor Xa-activity and activated partial thromboplastin time (aPTT). RESULTS: Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of reviparin with ASA were not different from those after ASA alone. aPTT was prolonged to 32 s after reviparin; this effect was not modified if subjects received ASA. Combined treatment with ASA and reviparin had no effect on plasma anti-Xa-activity and heptest compared with reviparin alone. CONCLUSIONS: We could not entirely exclude a small interaction between reviparin and ASA on bleeding time, but the effect is probably without clinical significance. 相似文献