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121.
122.
Effect of food on pharmacokinetics of an inhaled drug: a case study with a VLA-4 antagonist, HMR1031
HMR1031 is a potent and specific antagonist of the integrin VLA-4 (alpha4beta1) binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. HMR1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler dry-powder inhalation device. A pharmacoscintigraphic study of HMR1031 suggests a lung deposition of approximately 25% and gastrointestinal tract deposition of approximately 75%. Since oral absorption may be contributing to systemic plasma concentrations, the effect of food on HMR1031 was assessed. This was a single-dose (3 mg), open-label, randomized, two-way crossover (fasted vs. fed) study in 8 healthy male subjects. Blood samples were collected at predose and up to 24 hours postdose. Plasma concentrations were determined by the LC/MS/MS method. HMR1031 was rapidly absorbed, with median tmax values of 1.0 and 0.75 hours under fasted and fed conditions, respectively. Under fasted conditions, mean AUCinfinity and Cmax values were 16.4 ng x h/mL and 4.56 ng/mL, respectively. Under fed conditions, mean AUCinfinity and Cmax values decreased to 11.7 ng x h/mL and 2.81 ng/mL, respectively. The mean terminal elimination half-life (t1/2) for both treatment groups was similar (2.7 h). HMR1031 population estimates of the apparent clearance, apparent volume of distribution, and absorption rate were 225 L/h (4.1% coefficient of variation [CV]), 44.5 L (26% CV), and 0.340 h-1 (7.0% CV), respectively. Food is a significant covariate on clearance. These data suggest that food unexpectedly decreases the systemic exposure of inhaled HMR1031 by approximately 30%, probably due to increased liver blood flow and increased biliary excretion. This decrease in systemic exposure is unlikely to affect the topical effect of the drug but may result in increased variability in plasma pharmacokinetics. The disposition and food effect of HMR1031 can be described using mixed-effect modeling. 相似文献
123.
Background: High biliary calcium and trace elements (copper, zinc and iron) in patients with chronic cholelithiasis can be associated with gallstones. Methods: Estimations of calcium, copper, zinc and iron were done in the serum, gall bladder bile and gallstones of 48 patients with chronic cholelithiasis and in 20 age‐ and sex‐matched controls. Biliary levels of calcium and trace elements and bile/serum ratio of calcium and trace elements were compared in the two groups. Results: Serum calcium was significantly less (P= 0.009) than controls, but biliary calcium was higher in the patients with chronic cholecystitis. All trace elements were found to be significantly higher (P≤ 0.036) in the bile of patients with chronic cholelithiasis. The bile/serum ratio of calcium, copper and zinc was significantly greater (P≤ 0.03) in patients of chronic cholelithiasis. Gall bladder bile in patients with chronic cholelithiasis was slightly more alkaline. Pigment stones contained significantly more calcium, copper and iron than cholesterol stones (P≤ 0.001). Conclusion: Higher biliary calcium and trace elements as well as a defective pH of gall bladder bile in patients with chronic cholelithiasis could be the underlying factor in the pathogenesis of gallstones. 相似文献
124.
BACKGROUND: Inhaled corticosteroids (ICSs) reduce local airway inflammation, which is an underlying cause of asthma symptoms. However, potential systemic side effects associated with ICS use are a major concern for asthmatic patients. METHODS: Adult patients (n = 60; > or = 18 years of age) with moderate-to-severe asthma were randomized to receive 4 weeks of treatment with ciclesonide (CIC), 320 microg bid (CIC 640), CIC, 640 microg bid (CIC 1280), fluticasone propionate (FP), 440 microg bid (FP 880), FP 880 microg bid (FP 1760), or placebo (PBO) [all doses expressed as ex-actuator; comparable to ex-valve doses of 800 and 1,600 microg/d for CIC and 1,000 and 2,000 microg/d for FP, respectively]. RESULTS: After 29 days of treatment, CIC 640, CIC 1280, and FP 880 had no significant effect on the mean serum cortisol area under the curve for 0 to 24 h (AUC0-24h). FP 1760 produced a statistically significant suppression in mean serum cortisol AUC0-24h compared to PBO (p = 0.0009; 95% confidence interval [CI] -117.5 [corrected] to -32.1). Results obtained with cosyntropin stimulation revealed no statistically significant differences among the groups. The CIC 640 group demonstrated a significant increase compared to the PBO group in 24-h urinary cortisol levels from baseline at week 4 (p = 0.0224; 95% CI, 0.0023 to 0.0283), while the other treatment groups revealed no change in this parameter. The incidence of treatment-emergent adverse events was similar in all groups, and all adverse events were mild or moderate in severity. CONCLUSION: Treatment with moderate and high doses of CIC does not result in hypothalamic-pituitary-adrenal-axis suppression as compared with PBO. 相似文献
125.
BACKGROUND: Trans-cranial Doppler (TCD) studies after head injury have been done in the first 24 hours after injury and do not specify the exact interval between injury and time of recordings. We have studied cerebral blood flow changes in patients with severe head injury using serial TCD starting within 6 hours after trauma, and present our findings and its correlation with clinical outcome. METHODS: Thirty-two patients with closed severe brain injuries formed the study group. Six-hourly serial TCD studies were done starting within 6 hours after trauma until 48 hours after trauma or death of the patient, whichever was earlier. Flow velocities of the extracranial internal carotid (V(EC-ICA)) and middle cerebral artery (V(MCA)) were recorded to identify vasospasm, hyperemia, or oligemia. Serial changes in flow velocities were correlated with the clinical outcome of the patients at 12 months' follow-up after injury. RESULT: Oligemia (n = 30) and vasospasm (n = 2) were the earliest changes observed within 6 hours of trauma. In the oligemia group, persistent oligemia (n = 14), hyperemia (n = 6), normal flow velocity (n = 5), and vasospasm developing within 24 hours (n = 5) were observed. Eight patients developed vasospasm after 24 hours. All patients with persistent oligemia and vasospasm developing within 24 hours had poor outcome. CONCLUSION: Oligemia is the most common change within 6 hours of head injury. Persistence of oligemia beyond 24 hours is associated with poor outcome. Early (within 24 hours posttrauma) onset of vasospasm is associated with poor outcome; however, delayed (>24 hours after trauma) vasospasm is not associated with poor outcome. 相似文献
126.
127.
Primary cultures of neocortical neurons exhibit spontaneous Ca(2+) oscillations under zero or low extracellular [Mg(2+)] conditions. We find that mature murine neocortical neurons cultured for 9 days also produce spontaneous Ca(2+) oscillations in the presence of physiological [Mg(2+)]. These Ca(2+) oscillations were action potential mediated inasmuch as tetrodotoxin eliminated their occurrence. AMPA receptors were found to regulate the frequency of Ca(2+) oscillations. In contrast, Ca(2+) oscillations were independent of activation of L-type Ca(2+) channels, and NMDA receptors provided only a minor contribution. Release of intracellular Ca(2+) stores was involved in the oscillatory activity since thapsigargin reduced the amplitude and frequency of the oscillations. S-4-carboxyphenylglycine (S)-4CPG), an antagonist of group I metabotropic glutamate receptor (mGluR), also reduced the amplitude of oscillations. In addition, 1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), a group I mGluR agonist, increased the oscillation frequency, suggesting a critical role for mGluR in the generation of Ca(2+) oscillations. The mGluR-mediated release of intracellular Ca(2+) stores appeared to be mediated by phospholipase C (PLC) since the PLC inhibitor U73122 eliminated the Ca(2+) oscillations. These results indicate that Ca(2+) oscillations in neocortical cultures in the presence of physiologic [Mg(2+)] are primarily initiated by excitatory input from AMPA receptors and involve mobilization of intracellular Ca(2+) stores following activation of mGluR. 相似文献
128.
Vikas Sinha Devang Gupta Bela prajapati Yogesh More Priyanka Khandelwal Shashank Nath Singh B. Himanshu 《Indian journal of otolaryngology and head and neck surgery》2008,60(3):207-209
Background The aim of study is to evaluate the Endoscopic dacryocystorhinostomy (DCR) with conventional instruments, its results and
advantage over external dacryocystorhinostomy (DCR).
Methods The study group comprised of 127 patients who underwent consecutive endoscopic dacryocystorhinostomy. The cases operated by
one team were included in the study to make the uniform analysis and its result. There were 48 males and 79 female in this
study and male female ratio was 1:1.6. The mean age of the patient was 37 years (range from 16 years to 58 years). There were
wide variety of cases like epiphora, lacrimal sac abscess, lacrimal sac fistula, acute dacryocystitis and road vehicular accident.
All the patients had undergone non-laser, non-powered conventional instruments surgery under local anesthesia. The lighted
probe was not used in any case for sac identification. The free flow of saline through newly created stoma during sac syringing
was considered as successful criteria. The stent was used in two cases of road vehicular accident and in remaining 125 cases
no stent was used. There were 66 cases of epiphora, 30 cases of lacrimal sac abscess, 26 cases of acute dacryocystitis, 3
cases of lacrimal fistula and 2 case of road traffic accident with multiple fractures. The average follow up period was 17
months (maximum follow up 3 years and minimum 4 months.)
Results The success rate was 96 %.
Conclusion The endoscopic DCR with conventional instruments is safe with very high success rate without any complications. It can be
done in acute cases and very much suited for lacrimal sac abscess and lacrimal sac fistula. 相似文献
129.
Loss of heterozygosity in benign breast epithelium in relation to breast cancer risk 总被引:5,自引:0,他引:5
Euhus DM Cler L Shivapurkar N Milchgrub S Peters GN Leitch AM Heda S Gazdar AF 《Journal of the National Cancer Institute》2002,94(11):858-860
The multistage model of breast carcinogenesis suggests that errors in DNA replication and repair generate diversity in the breast epithelium (the mutator phenotype), resulting in selection and expansion of premalignant clones with an acquired survival advantage. We measured loss of heterozygosity (LOH) in breast epithelial cells obtained by random fine-needle aspiration (FNA) biopsy from 30 asymptomatic women whose risk of breast cancer had been defined by the Gail model. Polymorphic microsatellite markers were selected on the basis of their relevance to breast cancer. Breast epithelium of 11 (37%) of 30 women had normal cytology, and that of 19 (63%) had proliferative cytology (eight with atypia and 11 without atypia). LOH was detected in two women with normal cytology and in 14 women (seven with atypia and seven without atypia) with proliferative cytology (P =.007). The frequency of LOH was associated with the cytological diagnosis, as well. The mean proportion (range) of informative markers demonstrating LOH was 0.02 (0-0.20) for the 11 women with normal cytology, as compared with 0.15 (0-0.50) for the 19 women with proliferative cytology (P =.02). Mean lifetime risk for developing breast cancer, as calculated by the Gail model, was 16.7% for women with no LOH compared with 22.9% for women with any LOH (P =.05). These observations support a multistage model of breast carcinogenesis where the initiating events are those that result in genomic instability. Accurate individualized breast cancer risk assessment may be possible based on molecular analysis of breast epithelial cells obtained by random FNA. 相似文献
130.
Joshi SV 《Pediatrics in review / American Academy of Pediatrics》2002,23(2):67-8; discussion 67-8