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81.
We describe a case of pancreatic tumor associated with a giant type IV hiatal hernia that had prolapsed into the posterior mediastinum. Hiatal hernia repair should be performed first because it enables laparoscopic distal pancreatectomy to be performed in the normal anatomical position.  相似文献   
82.
Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights
  • WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.
  • WHAT QUESTION DID THIS STUDY ADDRESS?
This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.
  • WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.
  • HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.  相似文献   
83.
Lysophosphatidic acid (LPA) mediates a wide range of biological responses with G protein-coupled transmembrane receptors (LPA receptors). So far, at least six types of LPA receptors (LPA receptor-1 (LPA1) to LPA6) have been identified. Recently, it has been reported that LPA3 indicates opposite effects on cellular functions of cancer cells. In the present study, to assess a biological role of LPA3 on cell migration ability of colon cancer cells, we generated LPA receptor-3 (LPAR3) knockdown (HCT-sh3-3) cells from HCT116 and measured cell motile and invasion activities. In motility assay with a cell culture insert, HCT-sh3-3 cells showed significantly high cell motile activity, compared with control cells. For invasion assay, the filter was coated with Matrigel. The invasive activity of HCT-sh3-3 cells was significantly higher than that of control cells. Furthermore, we also examined the effects of LPAR3 knockdown on the interaction between colon cancer cells and endothelial F-2 cells. When F-2 cells were cultured with serum-free DMEM containing a supernatant from HCT-sh3-3 cells, the cell growth rate and migration activity of F-2 cells were significantly stimulated, associating with the elevated expressions of vascular endothelial growth factor (VEGF)-A and VEGF-C genes in HCT-sh3-3 cells. These results suggest that LPA3 may act as a negative regulator on cell motile and invasive abilities of colon cancer HCT116 cells.  相似文献   
84.
Introduction The purpose of this study was to examine the normal pituitary gland in male subjects with ultrashort echo time (TE) pulse sequences, describe its appearance and measure its signal intensity before and after contrast enhancement. Methods Eleven male volunteers (mean age 57.1 years; range 36–81 years) were examined with a fat-suppressed ultrashort TE (= 0.08 ms) pulse sequence. The studies were repeated after the administration of intravenous gadodiamide. The MR scans were examined for gland morphology and signal intensity before and after enhancement. Endocrinological evaluation included baseline pituitary function tests and a glucagon stimulatory test to assess pituitary cortisol and growth hormone reserve. Results High signal intensity was observed in the anterior pituitary relative to the brain in nine of the 11 subjects. These regions involved the whole of the anterior pituitary in three subjects, were localised to one side in two examples and were seen inferiorly in three subjects. Signal intensities relative to the brain increased with age, with a peak around the sixth or seventh decade and decreasing thereafter. Overall, the pituitary function tests were considered to be within normal limits and did not correlate with pituitary gland signal intensity. Conclusion The anterior pituitary shows increased signal intensity in normal subjects when examined with T1-weighted ultrashort TE pulse sequences. The cause of this increased intensity is unknown, but fibrosis and iron deposition are possible candidates. The variation in signal intensity with age followed the temporal pattern of iron content observed at post mortem. No relationship with endocrine status was observed.  相似文献   
85.
Objective  Coronary artery bypass grafting (CABG) in patients with left ventricular dysfunction has been considered to be a challenging operation. We assessed the early angiographic and long-term clinical and functional outcomes of patients with poor left ventricular function who underwent isolated CABG. Methods  We retrospectively reviewed the records of 78 patients with a poor left ventricular ejection fraction (35% or less) who underwent isolated CABG between January 1991 and November 2006. The mean age of the patients was 66.1 ± 9.4 years, and their mean New York Heart Association functional class was 3.1 ± 0.8. Their mean end-diastolic left ventricular diameter was 57.4 ± 8.1 mm, and their mean grade of mitral regurgitation was 0.7 ± 1.0. Early postoperative angiograms were performed at 32.5 ± 33.5 days after the operation. Interval echocardiographic data were analyzed, and the long-term survival rate was evaluated. Results  The average number of distal anastomoses per patient was 3.2 ± 1.1. The operative mortality rate was 7.7%. Stroke occurred in 1.3% of patients. The overall patency rates for arterial and venous grafts were 100% and 97.2%, respectively. The left ventricular ejection fraction significantly improved from 28.2% ± 5.1% to 34.4% ± 8.4%. Both the end-diastolic and end-systolic left ventricular dimensions significantly decreased from 57.4 ± 8.1 to 55.1 ± 8.8 mm and from 47.4 ± 8.4 to 45.1 ± 9.7 mm, respectively. The actuarial patient survival rate at 10 years was 73.1%. Conclusion  CABG in patients with left ventricular dysfunction was effective, with favorable early graft patency rates. The long-term outcome was also acceptable, with echocardiographic functional recovery.  相似文献   
86.
Hypothermia is a potential therapy for cerebral hypoxic ischemic injury of not only adults but also neonates. However, the side effects of hypothermia in the developing brain, where a massive amount of neurogenesis occurs, remain unclear. We investigated the proliferation of neural progenitor cells by systemic application of the thymidine analog 5-bromodeoxyuridine (BrdU) in neonatal rats in a severe hypothermic environment. The rat pups were divided into two groups, a hypothermia group (30 degrees C: n=10) and a normothermia group (37 degrees C: n=10). After the pups were placed for 21 h in each environment, 100 mg/kg/day of BrdU was injected intraperitoneally to label dividing cells, and then the pups were sacrificed at 24 h. We examined the number of BrdU-labeled cells in the subventricular zone of the periventricle and the subgranular zone of the dentate gyrus. In the hypothermic environment, BrdU-labeled cells significantly decreased in number in the dentate gyrus, but not in the periventricular region. Thus, the severe hypothermic environment induced a decrease of neurogenesis in the neonatal rat. These observations are noteworthy regarding clinical hypothermia therapy following cerebral hypoxic ischemic injury during the perinatal period.  相似文献   
87.
We studied the incidence of postoperative infection related to CSF leakage and anosmia in basal interhemispheric approach (BIH). Between April, 1990 to March, 2009, 142 cases of anterior communicating (Acom) aneurysm including both unruptured and ruptured have been treated by clipping surgery using BIH. We retrospectively obtained clinical informations from medical records and video records about infectious complications, CSF leakage of cerebrospinal fluid (CSF), olfactory dysfunction and intraoperative findings of damage to the olfactory nerve. In most cases (139 patients, 97%), frontal sinus were opened at craniotomy. Of all, CSF rinorrhea occurred in 4 cases (2.8%), and meningitis in 6 cases. There was only one patient who sufferd from meningitis due to CSF rinorrhea. All that patients recovered completely without deficit. Anosmia occurred in 6 cases (4.2%), and intraoperative injuries in 4 cases (2.8%). There was only one patient in whom anosmia was consistent with nerve injury. In conclusion, BIH is an appropriate procedure for infection risk control in Acom aneurysm surgery. It is difficult to avoid olfactory dysfunction completely, even if olfactory nerves are preserved in form.  相似文献   
88.
C. difficile is the most common infectious cause of healthcare-associated diarrhea but now is increasingly recognized as a cause of diarrhea in outpatients and persons without apparent health care contacts. Emergence and spread of new epidemic clones of C. difficile 027 (PCR-ribotype) and 078/126 (toxinotype) with increase toxin production, an aditional binary toxin and high level resistance to fluoroquinolones and increasing incidence of more rapidly progressive severe disease, require prompt clinical recognition and new tools to predict severity and to prevent recurrences. Although antibiotics are effective at inhibiting C. difficile and treating symptoms, these drugs could not reestablish normal bowel flora and the rate of recurrences is 25%. During the past years we assisted to an impressive search for new and more effective therapy that shoud be save, with low potential for the development of resistance, with low levels of systemic absorbtion and high levels of active drug in the colon and should be associated with a low rate of recurrence after treatment. By consequence, different approaches to the management of recurrent infections have been studied such as new antibiotics (fidaxomicin), human monoclonal antibodies against C. difficile toxins A and B, intravenous human immunoglobulin, active immunization, and probiotic therapy.  相似文献   
89.
Infiltration of natural killer (NK) cells into solid organ allografts is observed in clinical and experimental transplantation. Studies suggest a role for NK cells in acute and chronic rejection of solid organ allografts; however, the effects of immunosuppressive agents on NK cells are not clearly established. Rat NK cell lines were analyzed for proliferation and cytotoxicity in the presence of cyclosporine, FK506, or rapamycin. Lewis recipients of DA liver allografts received immunosuppressive agents after transplantation. NK cells demonstrated robust function both in the absence and presence of cyclosporine and FK506. In contrast, rapamycin significantly inhibited proliferation and cytotoxicity of NK cells. NK cell numbers remained stable in graft recipients treated with cyclosporine and FK506, whereas there was a significant decrease in NK cells in rapamycin-treated recipients. These data indicate that immunosuppressive drugs have differential effects on NK cell function that may impact the immune response of transplant recipients.  相似文献   
90.
Axillary artery perfusion is an attractive alternative to reduce the frequency of atheroembolism in extensive atherosclerotic aorta and aortic aneurysms. This study was conducted to evaluate the flow dynamics of axillary artery perfusion. Transparent glass models of a normal aortic arch and an aortic arch aneurysm were used to evaluate hydrodynamic properties. Streamline analysis and distribution of the shear stress was evaluated using a particle image velocity method. In the normal aortic arch model, rapid flow of 80 cm/s from the right axillary artery ran out from the brachiocephalic artery and grazed the lesser curvature of the aortic arch. There was secondary reversed flow in the ascending aorta. Flow from left axillary perfusion went straight to the descending aorta. In the aortic arch aneurysm model, flow from both axillary arteries hit the lesser curvature of the aortic arch and went into the ascending aorta with vortical flow. Distribution of shear stress was high along the jet from the ostium of the brachiocephalic artery and left subclavian artery. Flow in the aortic arch and the ascending aorta was unexpectedly rapid. Special care must be taken when the patient has frail atheroma around arch vessels or the lesser curvature of the aortic arch during axillary artery perfusion.  相似文献   
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