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71.
Viviane Hess Roger A'Hern Nazar Nasiri D Michael King Peter R Blake Desmond P J Barton John H Shepherd T Ind J Bridges K Harrington Stanley B Kaye Martin E Gore 《Journal of clinical oncology》2004,22(6):1040-1044
PURPOSE: Invasive mucinous carcinoma of the ovary (mucinous epithelial ovarian cancer [mEOC]) is a histologic subgroup of epithelial ovarian cancer (EOC). Chemotherapy for mEOC is chosen according to guidelines established for EOC. The purpose of this study is to determine whether this is appropriate. PATIENTS AND METHODS: Women with advanced mEOC (International Federation of Gynecology and Obstetrics stage III or IV) who underwent first-line platinum-based chemotherapy were compared with women with other histologic subtypes of EOC in a case-controlled study. RESULTS: Eighty-one patients (27 cases, 54 controls) treated with platinum-based regimens were analyzed. The response rates for cases and controls were 26.3% (95% CI, 9.2% to 51.2%) and 64.9% (95% CI, 47.5% to 79.8%), respectively (P=.01). The odds ratio for complete or partial response to chemotherapy for mEOC was 0.19 (95% CI, 0.06 to 0.66; P=.009) compared with other histologic subtypes of EOC. Median progression-free survival was 5.7 months (95% CI, 1.9 to 9.6 months) versus 14.1 months (95% CI, 12.0 to 16.2 months; P<.001) and overall survival was 12.0 months (95% CI, 8.0 to 15.6 months) versus 36.7 months (95% CI, 25.2 to 48.2 months; P<.001) for cases and controls, respectively. The hazard ratio for progression and death was 2.94 (95% CI, 1.71 to 5.07; P<.001) and 3.08 (95% CI, 1.69 to 5.6; P<.001), respectively, for mEOC patients as compared with controls. CONCLUSION: Patients with advanced mEOC have a poorer response to platinum-based first-line chemotherapy compared with patients with other histologic subtypes of EOC, and their survival is worse. Specific alternative therapeutic approaches should be sought for this group of patients, perhaps involving fluorouracil-based chemotherapy. 相似文献
72.
73.
Steinar Aamdal Uta Bruntsch Jean Kerger Jaap Verweij Wim Bokkel Huinink Jantien Wanders Ram Rastogi Hillary R. Franklin Stan B. Kaye 《Cancer chemotherapy and pharmacology》1997,40(5):439-443
The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical
antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma
and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy,
were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade ≥ 3) and the main nonhematological
toxicity was nausea and vomiting (21/30 patients, WHO grade ≥ 2). Serious nephrotoxicity was observed early in the renal cancer
study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped
after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in
3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted
5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months].
In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin
has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity
of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting.
Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number
of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion
can yet be drawn.
Received: 16 March 1996 / Accepted: 25 March 1997 相似文献
74.
Martin A. Graham Suresh Senan Hernani Robin Jr. Nils Eckhardt Dennis Lendrem Jeffery Hincks Dennis Greenslade Roy Rampling Stanley B. Kaye Reinhard von Roemeling Paul Workman 《Cancer chemotherapy and pharmacology》1997,40(1):1-10
Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug
free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination
with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were
investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold;
firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine,
and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic
studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD10 to the LD50. The AUC at the LD10 (2932 μg ml-1min) was used to determine a target AUC value of 1173 μg ml-1min (equivalent to 40% of the mouse LD10 AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every
3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m2) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration
of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a
PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD10 294 mg/m2, LD50 303 mg/m2). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic
ptosis and conjunctivitis were observed at doses of >300 mg/m2. The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t
1/2=36±0.65 min) occuring at the LD10 dose of 294 mg/m2. A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of
36–450 mg/m2. Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m2 and the MTD was 390 mg/m2 for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally
bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold
increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the
two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m2 (range 1035–1611 μg ml-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose
enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism
observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between
species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have
been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at
tolerable doses.
Received: 27 May 1996 / Accepted: 30 September 1996 相似文献
75.
S. S. Sane Alexander Towbin Elizabeth A. Bergey Robin D. Kaye Charles R. Fitz Leland Albright Richard B. Towbin 《Pediatric radiology》1998,28(7):521-523
Objective. The purpose of this study is to determine the risk of CNS and/or peritoneal infection in children with ventriculoperitoneal
shunts in whom a percutaneous gastrostomy tube is placed. Materials and methods. We placed 205 gastrostomy or gastrojejunostomy tubes from January of 1991 to December 1996. Twenty-three patients (10 boys,
13 girls) had ventriculoperitoneal shunts at the time of placement. All shunts were placed at least 1 month prior to placement
of the gastrostomy tube. The patients ranged in age from 8 months to 16 years with a mean age of 6 years, 9 months. Patient
weight ranged from 2 kg to 60 kg. All 23 children required long-term nutritional support due to severe neurologic impairment.
No prophylactic antibiotics were given prior to the procedure. Of the patients, 21/23 had a 14-F Sacks-Vine gastrostomy tube
with a fixed terminal retention device inserted, using percutaneous fluoroscopic antegrade technique. Two of the 23 patients
had a Ross 14-F Flexi-flo gastrostomy tube which required a retrograde technique due to a small caliber esophagus in these
children. Results. All 23 children had technically successful placements of percutaneous gastrostomy (7) or gastrojejunostomy (16) tubes. Of
the children, 21/23 (91 %) had no complications from the procedure. Two of 23 (9 %) patients demonstrated signs of peritonitis
after placement of their gastrostomy tubes and subsequently had shunt infections. In both, children CSF culture grew gram-positive
cocci. The antegrade technique was used in both children who developed peritonitis. Conclusion. Our study indicates children with ventriculoperitoneal shunts who undergo percutaneous gastrostomy are at greater risk for
infection and subsequent shunt malfunction. Therefore, we recommend prophylactic antibiotic therapy to cover for skin and
oral flora.
Received: 5 August 1997 Accepted: 26 December 1997 相似文献
76.
This study analysed a sample of food advertisements shown during 63 hours of children's programming to investigate compliance and non‐compliance with one of the Australian Children's Television Standards (CTS): CTS 20.2a. This standard regulates the way premium offers may, and may not, be used to sell products to children. Of the 1721 advertisements contained in the sample, 544 (32%) were for food. A significantly higher number of food advertisements (41%) were shown during ‘C’ programs (which are specifically regulated and produced for children six to 13 years of age and suitable for viewing without adult supervision), compared with 30% during the less regulated ‘G’ programs (P= < 0.001) (suitable for children to view without adult supervision but not produced specifically for a child audience). Over one‐third of food advertisements (36%) in ‘C’ time contained a premium offer compared with 17% in ‘G’ time (P= < 0.0001). Using a precisely defined interpretation of CTS 20.2a, this study found 30 (31%) of food advertisements breached the standard during ‘C’ programs. This was a significantly higher proportion than the 54 (12%) of breaches in ‘G’ time (P= < 0.0001). From this study, the current regulatory system has not resulted in more responsible food advertising during ‘C’ programs, and the widespread breaches of CTS 20.2a indicate this standard is ineffective as a means of regulating food advertising. The Australian Broadcasting Authority has recognised that children need protection from unfair marketing practices and the improper use of premium offers to promote a food product, therefore CTS 20.2a needs urgent review to make it more effective. 相似文献
77.
Anthony D Harris Yehuda Carmeli Matthew H Samore Keith S Kaye Eli Perencevich 《Infection control and hospital epidemiology》2005,26(4):342-345
BACKGROUND: Case-control studies often analyze risk factors for antibiotic resistance. Recently published articles have illustrated that randomly selected control-patients may be preferable to those with the susceptible phenotype of the organism. A possible methodologic problem with randomly selected control-patients is potential bias due to control group misclassification. This occurs if some control-patients did not have clinical cultures performed and thus might have been unidentified case-patients. If this bias exists, these studies might be expected to report lower odds ratios (ORs) because control-patients would be more like case-patients. OBJECTIVE: To analyze potential biases that might arise due to control group misclassification and potentially larger selection biases that may be introduced if control-patients are required to have at least one clinical culture. PATIENTS: One hundred twenty case-patients, 770 control-patients in group 1, and 510 control-patients in group 2. METHODS: Two case-control studies. Case-patients had clinical cultures positive for imipenem-resistant Pseudomonas aeruginosa. The first group of control-patients were random. The second group of control-patients were identical to those in group 1 except being required to have at least one clinical culture. RESULTS: Univariate analyses showed higher ORs for case-patients versus control-patients in group 1 (imipenem [OR, 12.5], piperacillin-tazobactam [OR, 3.7], and vancomycin [OR, 4.7]) as compared with case-patients versus control-patients in group 2 (imipenem [OR, 8.0], piperacillin-tazobactam [OR, 2.5], and vancomycin [OR, 3.0]). CONCLUSION: Requiring control-patients to have at least one clinical culture introduces a selection bias likely because it eliminates patients with less severe illness. 相似文献
78.
Keith S Kaye Anthony D Harris Matthew Samore Yehuda Carmeli 《Infection control and hospital epidemiology》2005,26(4):346-351
OBJECTIVE: There are significant limitations of the standard case-control study design for identifying risk factors for resistant organisms. The objective of this study was to develop a study design to overcome these limitations. DESIGN: Theoretical analysis of different types of study designs that can be used in risk factor studies for resistant organisms. RESULTS: We developed the case-case-control study design, which uses two separate case-control analyses within a single study. The first analysis compares patients infected with resistant bacteria (resistant cases) with control-patients without infection caused by the target organism, who are therefore representative of the source population; and the second analysis compares patients infected with the susceptible phenotype of the target organism (susceptible cases) with the same control-patients without infection caused by the target organism. These two analyses provide risk models for (1) isolation of the resistant phenotype of the target organism as compared with the source population and (2) isolation of the susceptible phenotype of the organism as compared with the source population. When these two risk models are compared and contrasted, risk factors specifically associated with isolation of the resistant phenotype can be identified. CONCLUSIONS: The case-case-control study design is an effective method for identifying risk factors for antimicrobial-resistant pathogens. Although the case-case-control study design has limitations, it is, in our opinion, more informative and less flawed than the standard case-control study design. 相似文献
79.
Effects of remifentanil on neutrophil adhesion, transmigration, and intercellular adhesion molecule expression 总被引:2,自引:0,他引:2
Hofbauer R Frass M Gmeiner B Sandor N Schumann R Wagner O Kaye AD 《Acta anaesthesiologica Scandinavica》2000,44(10):1232-1237
BACKGROUND: Anaesthetic drugs are used for pain therapy and anaesthesia. Neutrophils play a significant role during the process of inflammation. The aim of the current study was to investigate the effects of remifentanil and fentanyl on neutrophil migration through endothelial cell monolayers, and on adhesion molecule expression. METHODS: After isolation of polymorphonuclear neutrophils (PMNL) we used a currently described migration assay. PMNL and/or endothelial cell monolayers (ECM) were pre-treated with remifentanil using clinically relevant, as well as higher and lower concentrations or relevant concentrations of fentanyl. RESULTS: Concentrations of remifentanil (50 ng/mL) similar to the relevant plasma concentration were able to inhibit PMNL migration through ECM significantly (migration compared to the control 82+/-7% SD; P<0.05), when both cell types were treated with the synthetic narcotic remifentanil. Fentanyl (30 ng/mL) showed a stronger inhibitory effect (migration compared to the control 67+/-9.2%; P<0.05). Endothelial cell adhesion molecule expression was reduced after either remifentanil or fentanyl. CONCLUSION: The results of the present investigation indicate that remifentanil influences interaction of ECM against human neutrophils. Compared to fentanyl, remifentanil seems to exhibit minor inhibitory effects on neutrophil migration. 相似文献
80.
Study OBJECTIVE: To estimate the incidence of lower limb fractures in the United Kingdom and assess the relative importance of various risk factors for lower limb fractures. DESIGN: Cohort analysis and matched case-control study. SETTING: General practices contributing information to the General Practice Research Database. SUBJECTS: Individuals registered with these general practices who were at risk for a first time lower limb fracture from 1 January 1990 to 31 December 2001. MAIN OUTCOME MEASURES: Age, sex, and fracture site specific incidence rates; relative risks and population attributable risks for various medical risk factors. RESULTS: Overall, the risk of lower limb fracture was 17% higher in women then in men. Within age groups, men and women had generally similar proportions of fractures at specific sites in the lower limb. Among the risk factors evaluated, road collisions were associated with the highest relative risk for lower limb fracture, but only accounted for 3.1% or less of the population attributable risk for specific fracture types in any age group. The relative risk for lower limb fracture associated with a diagnosis of dementia was 2.3 (95% confidence interval 2.0 to 2.6), while relative risk estimates for other medical diagnoses were less than 2. Fracture risk was increased among current users of corticosteroids, antipsychotics, antidepressants, and hypnotic/sedatives, but the population attributable risks for each of these drug classes within fracture and age specific strata were only 3.0% or less. CONCLUSIONS: Many risk factors for lower limb fracture have been identified, but population attributable risk estimates for various risk factors are small. These findings suggest that multifactorial prevention programs are needed to decrease the incidence of lower limb fractures in the general population. 相似文献