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11.
Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the protumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not only rely on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2-dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the protumorigenic role of EV in MM as well as other tumors.  相似文献   
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Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are well-established tools for investigating the human motor system in-vivo. We here studied the relationship between movement-related fMRI signal changes in the primary motor cortex (M1) and electrophysiological properties of the hand motor area assessed with neuronavigated TMS in 17 healthy subjects. The voxel showing the highest task-related BOLD response in the left hand motor area during right hand movements was identified for each individual subject. This fMRI peak voxel in M1 served as spatial target for coil positioning during neuronavigated TMS. We performed correlation analyses between TMS parameters, BOLD signal estimates and effective connectivity parameters of M1 assessed with dynamic causal modeling (DCM). The results showed a negative correlation between the movement-related BOLD signal in left M1 and resting as well as active motor threshold (MT) obtained for left M1. The DCM analysis revealed that higher excitability of left M1 was associated with a stronger coupling between left supplementary motor area (SMA) and M1. Furthermore, BOLD activity in left M1 correlated with ipsilateral silent period (ISP), i.e. the stronger the task-related BOLD response in left M1, the higher interhemispheric inhibition effects targeting right M1. DCM analyses revealed a positive correlation between the coupling of left SMA with left M1 and the duration of ISP. The data show that TMS parameters assessed for the hand area of M1 do not only reflect the intrinsic properties at the stimulation site but also interactions with remote areas in the human motor system.  相似文献   
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To quantify the advantages of a 6 degrees of freedom (dof) versus the conventional 3- or 4-dof correction modality for stereotactic body radiation therapy (SBRT) treatments. Eighty-five patients were fitted with 5-7 infra-red passive markers for optical localization. Data, acquired during the treatment, were analyzed retrospectively to simulate and evaluate the best approach for correcting patient misalignments. After the implementation of each correction, the new position of the target (tumor's center of mass) was estimated by means of a dedicated stereotactic algorithm. The Euclidean distance between the corrected and the planned location of target point was calculated and compared to the initial mismatching. Initial and after correction median+/-quartile displacements affecting external control points were 3.74+/-2.55 mm (initial), 2.45+/-0.91 mm (3-dof), 2.37+/-0.95 mm (4-dof), and 2.03+/-1.47 mm (6-dof). The benefit of a six-parameter adjustment was particularly evident when evaluating the results relative to the target position before and after the re-alignment. In this context, the Euclidean distance between the planned and the current target point turned to 0.82+/-1.12 mm (median+/-quartile values) after the roto-translation versus the initial displacement of 2.98+/-2.32 mm. No statistical improvements were found after 3- and 4-dof correction (2.73+/-1.22 mm and 2.60+/-1.31 mm, respectively). Angular errors were 0.09+/-0.93 degrees (mean+/-std). Pitch rotation in abdomen site showed the most relevant deviation, being -0.46+/-1.27 degrees with a peak value of 5.46 degrees . Translational misalignments were -0.68+/-2.60 mm (mean+/-std) with the maximum value of 12 mm along the cranio-caudal direction. We conclude that positioning system platforms featuring 6-dof are preferred for high precision radiation therapy. Data are in line with previous results relative to other sites and represent a relevant record in the framework of SBRT.  相似文献   
16.
The effect of glucagon was studied on the isolated gastric fundus from immature rats in comparison with histamine. Glucagon (10–7–3×10–6 M) caused a concentration-dependent increase in acid output, being approximately 25 fold more potent than histamine (ED50 values were 6.38×10–7 M and 2.42×10–5 M for glucagon and histamine, respectively). These compounds, however, did not differ in regard to the maximum response. The stimulatory effect of glucagon was not enhanced by pretreatment with 3×10–8 M forskolin or 10–7 M ICI 63197, a phosphodiesterase (PD) inhibitor. Conversely, both forskolin and ICI 63197 shifted to the left the concentration-response curve to histamine. The increase in acid secretion by glucagon was reduced by PGE1 (10–5 M) and PGE2 (10–5 M) but only PGE2 inhibited the response to histamine. From these data it can be concluded that glucagon stimulated acid production in the stomach from immature rats, and this effect does not seem to involve the same adenylate cyclase activated by histamine.  相似文献   
17.
ObjectivesTo investigate the association between choice of treatment and patients' income after cruciate ligament (CL) injury and assess the effect of different covariates such as sex, age, comorbidities and type of work.MethodsThis entire-population cohort study in Sweden included working patients with a diagnosed CL injury between 2002 and 2005, identified in The National Swedish Patient Register (n = 13,662). The exposure was the treatment choice (operative or non-operative treatment). The main outcome measure was average yearly income five years after CL diagnosis, adjusted for the following covariates: sex, age, comorbidities, type of work, region, calendar year, education and income.ResultsRelative to non-operative treatment, operative treatment was associated with greater average yearly incomes (nine to 15%) after injury among patients between 20 and 50 years, patients with partial university education, patients living in large cities and patients with one comorbidity, despite no overall significant association in the national cohort. Delayed operative treatment (> 1 year) had no significant association with income change, whereas early operative treatment (< 1 year) was associated with higher average yearly incomes (11 to 16%) among females, patients between 20 and 50 years, patients living in large cities and patients with one comorbidity.ConclusionsIn a broad sense, treatment choice was not associated with changes in income five years after CL injuries among patients in the workforce, however earlier operative treatment was associated with higher average incomes among patients with ages between 20 and 50, females, living in large cities, with one comorbidity and with a high level of education.  相似文献   
18.
Alpha-synuclein is a brain presynaptic protein that is linked to familiar early onset Parkinson's disease and it is also a major component of Lewy bodies in sporadic Parkinson's disease and other neurodegenerative disorders. Alpha-synuclein expression increases in substantia nigra of both MPTP-treated rodents and non-human primates, used as animal models of parkinsonism. Here we describe an increase in alpha-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 microM MPP+, the active metabolite of MPTP, which induces apoptosis in SH-SY5Y cells after a 4-day treatment. We also analysed the activation of the MAPK family, which is involved in several cellular responses to toxins and stressing conditions. Parallel to the increase in alpha-synuclein expression we observed activation of MEK1,2 and ERK/MAPK but not of SAPK/JNK or p38 kinase. The inhibition of the ERK/MAPK pathway with U0126, however, did not affect the increase in alpha-synuclein. The highest increase in alpha-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 microM). Inhibition of ERK/MAPK reduced the damage caused by MPP+. We suggest that alpha-synuclein increase and ERK/MAPK activation have a prominent role in the cell mechanisms of rescue and damage, respectively, after MPP+ -treatment.  相似文献   
19.
We report a female child with tetrasomy of the 15q11-q13 chromosomal region, and autistic disorder associated with mental retardation, developmental problems and behavioral disorders. Combining classical and molecular cytogenetic approaches by fluorescence in situ hybridization technique, the karyotype was demonstrated as 47,XX,+mar.ish der(15)(D15Z1++,D15S11++,GABRB3++,PML-). Duplication of the 15q proximal segment represents the most consistent chromosomal abnormality reported in association with autism. The contribution of the GABA receptor subunit genes, and other genes mapped to this region, to the clinical symptoms of the disease is discussed.  相似文献   
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