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ABSTRACT

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.

Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.

Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.  相似文献   
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BACKGROUND AND AIM: Determination of the local densities of Helicobacter pylori and its genotypic variations in gastric biopsy specimens by using novel real-time PCR-based methods could support the precise diagnosis and understanding of H. pylori infections. METHODS: Serial dilutions of H. pylori (0.016-16 microg/microl), control, bacterial, and human DNA samples were prepared. Fresh-frozen gastric biopsy specimens were taken from 103 patients, and the DNA was isolated. Quantitative determination of the ureaseA gene using hybridization probes with parallel evaluation of an internal human control gene (beta-globin) was performed by real-time PCR. CagA and VacA s1 genotypic characterizations were also performed. The data were compared with urea breath test (UBT), histology, and serological testing. RESULTS: The presence of H. pylori could be detected by ureaseA-fluorescence energy transfer (53%), UBT (51%), serological testing (48%), and histology (52%) when compared with the gold standard (54%). A significant correlation was found between the quantitative real-time ureaseA/beta-globin ratio-based H. pylori frequency and the UBT results (P<0.01). Significantly increased bacterial density was found in the erosions when compared with the healthy part of the antrum and corpus (P<0.01). Real-time PCR VacA s1 results were in significant correlation (P<0.01) with those of serological tests, but CagA results were not. The genomic profiles (VAC/GAC) were different in 13.7% of the cases, which involved three different locations in the stomach. CONCLUSION: Real-time PCR was the most reliable method for H. pylori diagnosis. Furthermore, quantification and genotyping could also be performed using this technique. The density of H. pylori was significantly increased in macroscopic erosions.  相似文献   
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Pulmonary embolism onset is frequently neglected due to the non-specific character of its symptoms. Pocket-size imaging devices (PSID) present an opportunity to implement imaging diagnostics into conventional physical examination. The aim of this study was to test the hypothesis that supplementation of the initial bedside assessment of patients with suspected pulmonary embolism (PE) with four-point compression venous ultrasonography (CUS) and right ventricular size assessment with the use of PSID equipped with dual probe could positively influence the accuracy of clinical predictions. A single-centre, prospective analysis was conducted on 100 patients (47 men, mean age 68?±?13 years) with suspected PE. Clinical assessment on the basis of Wells and revised Geneva score and physical examination were supplemented with CUS and RV measurements by PSID. The mean time of PSID scanning was 4.9?±?0.8 min and was universally accepted by the patients. Fifteen patients had deep venous thrombosis and RV enlargement was observed in 59 patients. PE was confirmed in 24 patients. If the both CUS was positive and RV enlarged, the specificity was 100% and sensitivity 54%, ROC AUC 0.771 [95% CI 0.68–0.85]. The Wells rule within our study population had the specificity of 86% and sensitivity of 67%, ROC AUC 0.776 (95% CI 0.681–0.853, p?<?0.0001). Similar values calculated for the revised Geneva score were as follows: specificity 58% and sensitivity 63%, ROC AUC 0.664 (95% CI 0.563–0.756, p?=?0.0104). Supplementing the revised Geneva score with additional criteria of CUS result and RV measurement resulted in significant improvement of diagnostic accuracy. The difference between ROC AUCs was 0.199 (95% Cl 0.0893–0.308, p?=?0.0004). Similar modification of Wells score increased ROC AUC by 0.133 (95% CI 0.0443–0.223, p?=?0.0034). Despite the well-acknowledged role of the PE clinical risk assessment scores the diagnostic process may benefit from the addition of basic bedside ultrasonographic techniques.  相似文献   
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Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units. The application of lipoic acid enabled the control of the gold nanoparticle functionalities leading to enhanced solubility and allowing for attachment of both the folic acid and the cytotoxic drug, doxorubicin. More robust attachment of doxorubicin to the nanoparticle through the amide bond resulted in toxicity comparable with that of the drug alone, opening a new perspective for designing more potent, but less toxic nanopharmaceuticals. The increased uptake was accompanied by pronounced nuclear accumulation and observable cytotoxicity. Doxorubicin binding via covalent amide bonds enhanced stability of the whole drug vehicle and provided much better control over doxorubicin release in the cell environment, as compared to physical adsorption or pH sensitive bonding commonly used for anthracycline carriers. Confocal microscopy revealed that the bond was stable in the cytoplasm for 22 h. The ability to slow down the rate of drug release may be crucial for the application in sustained anticancer drug delivery. Biological analyses performed using MTT assay and confocal microscopy confirmed that the ultrasmall AuNPs with the lipoic acid derivative of folic acid exhibit relatively low cytotoxicity, however when loaded with a chemotherapeutic, they cause a significant reduction in the cell viability.

Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units.  相似文献   
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Background and Purpose

Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling.

Experimental Approach

A time-dependent effect of morphine (1 mg·kg−1, i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [35S]-GTPγS binding assay.

Key Results

Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN.

Conclusions and Implications

Our data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β.Tables of Links
TARGETS
GPCRsa1997Enzymesc1997
δ receptorAkt (PKB)
κ receptorClock
μ receptorERK1/2
Nuclear hormone receptorsb1997GSK3β
Rev-Erb-α
Open in a separate window
LIGANDS
Arginine vasopressinGDP
cAMPGTPγS
DADLEMorphine
DAMGONeuropeptide Y
EnkephalinThiopental
GABAU-50488
GastrinUTP
Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,b,cAlexander et al., 2013a, b, c).  相似文献   
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BackgroundThe aim of the study was to check the stability of a diagnosis of major depressive disorder (MDD) in an outpatient setting, as well as to assess the scope of diagnostic conversions into bipolar disorder (BD).Methods: Retrospective chart review of 122 patients with a primary diagnosis of MDD.ResultsDiagnostic conversion from MDD into BD was noticed in 40 subjects (32.8%), 25 patients (20.5%) were treatment-resistant. Mean time to the conversion was 9.27±8.64 years. A negative correlation between the age of illness onset and time to diagnostic conversion was observed (?0.41; p<0.05). Earlier onset of MDD was associated with higher risk of diagnostic conversion (<30vs≥30 years of age at onset: 69% vs 28%, p=0.0001; <35vs≥35 years of age: 50% vs 25%, p=0.0065). Treatment-resistance was more prevalent in the BD conversion group (40% vs 11%; p=0.0002). Diagnostic conversion into BD was also related longer duration of treatment received, higher number of illness episodes, and higher number of hospitalizations.Limitations: Retrospective design of the study.ConclusionsThe problem of diagnosis evolution from MDD to BD was observed in about 1/3 of patients, and was associated with treatment-resistance of depression, earlier onset of depression, longer time of treatment, higher number of depressive episodes and hospitalizations. The variables above may be a useful predictor of bipolar diathesis.  相似文献   
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