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121.
Bolognese A Correale G Manfra M Lavecchia A Mazzoni O Novellino E La Colla P Sanna G Loddo R 《Journal of medicinal chemistry》2004,47(4):849-858
New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative. 相似文献
122.
Pretreatment with dexamethasone (Dex) was not toxic for U937 cells but caused a rapid lethal response upon subsequent exposure to otherwise nontoxic concentrations of peroxynitrite. This effect was not associated with enhanced formation of hydrogen peroxide taking place after peroxynitrite and was shown previously to play a pivotal role in the ensuing lethal response. Further analyses revealed that although Dex did not affect cytosolic phospholipase A(2) (cPLA(2)) expression, it markedly reduced the extent of arachidonic acid (AA) release mediated by peroxynitrite-dependent stimulation of cPLA(2). This event, as well as the enhanced toxicity, was abolished by mifepristone, a glucocorticoid receptor antagonist. The outcome of various approaches, using phospholipase A(2) inhibitors, cPLA(2) antisense oligonucleotide-transfected cells, and supplementation with exogenous AA, led to the demonstration that inhibition of cPLA(2) activity is causally linked to the increased susceptibility to peroxynitrite caused by Dex. Finally, the effects of Dex were shown to be mediated by enhanced expression of lipocortin 1 (LC1), a cPLA(2) inhibitory protein. These results indicate that Dex promotes toxicity in U937 cells exposed to otherwise nontoxic concentrations of peroxynitrite and that this event is causally linked to enhanced expression of LC1 leading to inhibition of cPLA(2). Thus, the increased lethal response arises because of LC1-dependent impairment of the AA-induced cytoprotective mechanism triggered by peroxynitrite. 相似文献
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124.
Santonocito AM Consoli U Bagnato S Milone G Palumbo GA Di Raimondo F Stagno F Guglielmo P Giustolisi R 《Leukemia research》2004,28(5):469-477
DNA aneuploidy has been used as a genetic marker of malignancy in multiple myeloma (MM). CD38 and CD138 expression and absence of CD22 and CD19 may define plasmacells (PC). Several authors support evidences of circulating plasmacells, and their role in relapse after autologous stem cell transplantation has been hypothesised. The existence of B-lymphocytes belonging to the myeloma clone is still controversial. If CD19 or CD22 positive B-lymphocytes are part of the myeloma clone, there should be evidence of myeloma-specific genetic markers in this population. Using DNA content measurement in combination with CD19 or CD38 detection in a multiparametric flow cytometry analysis, we studied bone marrow and peripheral blood of 10 aneuploid MM patients. In the bone marrows of all these 10 aneuploid patients (100%), we detected CD38(++) aneuploid plasmacells ( 27 +/- 17%, mean +/- S.D.) and a small number of CD19(+) aneuploid lymphocytes ( 0.11 +/- 0.074%). In 100% of these patients, we also detected CD38(++) aneuploid circulating plasmacells ( 0.6 +/- 0.9 %) and a small number of CD19(+) aneuploid lymphocytes (0.03 +/- 0.04%). In this study, we detected aneuploid CD19(+) lymphocytes and CD38(++) plasmacells in bone marrow and peripheral blood of all MM patients. A crucial role for the detection of aneuploid CD19(+) cells was played by the acquisition of a sufficient number of CD19(+) lymphocytes by using a "live gate" acquisition and "continuous gating" analysis. With the techniques used in this study, it was possible to detect aneuploid B lymphoid cells among normal diploid B cells. The significance of this finding is controversial and opened to different interpretations. 相似文献
125.
126.
Riello R Geroldi C Zanetti O Vergani C Frisoni GB 《International journal of geriatric psychiatry》2004,19(3):209-215
OBJECTIVE: To test the hypothesis that physical symptoms referred to the head might be specifically associated with depression in patients with cognitive impairment. METHODS: Subjects were taken from those enrolled in 'The Mild Project' a prospective study on the natural history of mild dementia (Mini Mental State Examination > or = 18) and with a diagnosis of Alzheimer's disease, vascular dementia, and mild cognitive impairment. A total of 129 subjects were included in the study. Physical symptoms were assessed with a checklist investigating nine different body organs or apparati. Physical symptoms were grouped into those referred to the head (Head Symptoms: ear and hearing; eyes and sight; and head and face) and all the others (Body Symptoms). Depressive symptoms were assessed with the Geriatric Depression Scale (GDS) and physical comorbidity with Greenfield's Index of Disease Severity (IDS). RESULTS: The number of patients reporting one or more Head Symptoms linearly increased with increasing depression severity (Mantel-Haenszel test = 6.497, df = 1, p = 0.011), while the number of patients reporting one or more Body Symptoms linearly increased with increasing physical comorbidity (Mantel-Haenszel test = 4.726, df = 1, p = 0.030). These associations were confirmed in multivariate logistic regression models with adjustment for potential confounders (age, gender, education, cognitive performance, daily function, and diagnosis). CONCLUSIONS: Head Symptoms are specifically associated with depression while Body Symptoms with physical comorbidity, in patients with cognitive impairment. Recognizing these associations in individual patients may help clinicians decide whether to initiate or continue antidepressant therapy or whether to carry out physical instrumental investigations. 相似文献
127.
128.
Sergiacomi G De Nardo D Capria A Manenti G Fabiano S Borzi M De Sanctis G Konda D Sperandio M Schillaci O Masala S Simonetti G Fontana L 《In vivo (Athens, Greece)》2004,18(2):229-235
BACKGROUND: The aim of the present study was to evaluate the role of non-invasive methods in the early detection of pulmonary and cardiac involvement in Systemic sclerosis (SSc) and to identify clinical and/or instrumental patterns of prognostic value. PATIENTS AND METHODS: Twenty female patients affected by SSc (8 with diffuse cutaneous SSc and 12 with limited cutaneous SSc) were enrolled in our study. Cardiac and pulmonary involvement (respiratory function tests and carbon monoxide lung diffusion [DLCO], chest radiography, high resolution computed tomography [HRCT] and lung perfusion magnetic resonance) were evaluated. RESULTS: All 18 patients studied with respiratory function tests showed a significant reduction of DLCO. HRCT was considerably more sensitive than traditional chest radiography (59% versus 28%; p<0.05). Lung perfusion MRI revealed normal findings in 15 patients. Abnormal lung perfusion MRI results were found only in 3 patients. Angina pectoris with electrocardiographic and scintigraphic ischemic changes, severe regional wall motion abnormalities and complex arrhythmias seemed to be associated with poor prognosis. CONCLUSION: Taken together these results indicate that a pulmonary involvement occurs both in limited and in diffuse cutaneous SSc patients and develops, in 83% of the cases, without any regional lung perfusion abnormality. Furthermore, cardiac involvement is detected in 65% of the cases as a consequence of a range of noxious events including myocardial ischemia, fibrosis and pressure overload which may result in ventricular dysfunction and arrhythmias. Lung perfusion MRI should be considered as a complementary diagnostic method for the functional evaluation of these symptoms in systemic sclerosis. 相似文献
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130.
Activity against Plasmodium falciparum of cycloperoxide compounds obtained from the sponge Plakortis simplex 总被引:1,自引:0,他引:1
Fattorusso E Parapini S Campagnuolo C Basilico N Taglialatela-Scafati O Taramelli D 《The Journal of antimicrobial chemotherapy》2002,50(6):883-888
There is an urgent need to discover new antimalarials, due to the spread of chloroquine resistance and the limited number of available drugs. In the last few years, artemisinin, the endoperoxide sesquiterpene lactone derived from Artemisia annua, and its derivatives proved to be very active against Plasmodium falciparum. These compounds are characterized by an endoperoxide pharmacophore that is critical for their antimalarial activity. There are several reports, from our group and others, that marine organisms can be another natural source of stable cyclic peroxides, with selective antifungal or antibacterial activity. With the aim of identifying new bioactive molecules, we evaluated in vitro the antimalarial activity of the major cycloperoxides extracted from the sponge Plakortis simplex. The six-membered endoperoxide compounds plakortin and dihydroplakortin, but not the five-membered cycloperoxide plakortide E, inhibited the growth of cultured P. falciparum parasites, both chloroquine-sensitive D10 strain and chloroquine-resistant W2 strain. The IC50 values were similar for both compounds and in the range of 1263-1117 nM against D10, and 735-760 nM against W2, using the colorimetric parasite lactate dehydrogenase assay. The activity of plakortin and dihydroplakortin was significantly higher against chloroquine-resistant than chloroquine-susceptible parasites, following a pattern similar to that of artemisinin, although they were 50-fold less active. Moreover, plakortin and dihydroplakortin showed an additive effect when used in combination with chloroquine. These results support further studies on cycloperoxides of marine origin to characterize their mechanism of action and identify/synthesize new compounds with stronger antimalarial activity. 相似文献