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81.
Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease 总被引:4,自引:4,他引:0
To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer’s disease (AD), six
otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic
channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design.
Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively
similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition.
No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central
nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential
therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson’s disease
are warranted.
Received: 27 February 1998/Final version: 9 September 1998 相似文献
82.
Jinee Rizzo Alexandra M. Levine Geoff R. Weiss Tillman Pearce Maura Kraynak Robert Mueck Susan Smith Daniel D. Von Hoff John G. Kuhn 《Investigational new drugs》1996,14(2):227-234
Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain. 相似文献
83.
Although Hodgkin's disease (HD) is not usually associated
withcongenital or acquired immunodeficiency disorders, recent
evidencewould suggest a statistically significant increase in HD
amongindividuals infected with human immunodeficiency virus
(HIV).In the setting of underlying HIV infection, clinical and
pathologiccharacteristics of HD may differ from usual
expectations. Thus,70%-100% of HIV-infected
patients with HD present with systemic"B" symptoms.
Likewise, disseminated, stage III or IV diseaseis reported in
approximately 75%-90%. Bone marrow is a commonsite
of extranodal HD, occurring in 40%-50%. Complete
responserates after multiagent chemotherapy range from
approximately45% to 70%, although median survival
has been only in the rangeof approximately 18 months.
Hematologic toxicity from multiagentchemotherapy may be
substantial, even with the use of hematopoieticgrowth factor
support. It is apparent that new strategies oftherapeutic
intervention must be explored. 相似文献
84.
The effect of dimethylnitrosamine on the nucleosomal structure of mouse liver chromatin was studied. After a single oral dose of dimethylnitrosamine (2–75 mg/kg body weight 45 min before sacrifice) liver nuclei were isolated and incubated with micrococcus nuclease. Nucleosomes were separated on sucrose density gradients. There were no differences in nucleosomal sedimentation velocities between preparations from control and dimethylnitrosamine treated animals. The supernatant obtained after centrifugation of the lysed nuclei (2 min at 4,000 g
av) and nucleosomal peak fractions were used for isolation of DNA. DNA was heat denatured in 7 M urea or formamide. After electrophoresis on polyacrylamide gels areas under mononucleosomal DNA and smaller fragments were measured and compared with the total DNA area. The increase in DNA fragmentation was dimethylnitrosamine dose response dependent. When expressed as per cent of controls it amounted to 106% for 2 mg; 115% for 10 mg; 127% for 25 mg; 164% for 75 mg dimethylnitrosamine/kg body weight. A good correlation between mobility and log of chain length of
174 RF DNA-Hae III digest was obtained in nondenaturing 5% polyacrylamide gels and denaturing non-aqueous formamide polyacrylamide gels but not in 12% polyacrylamide gels containing 7 M urea. DNA of mononucleosomal peak fractions contained 200 and that of dinucleosomal peak fractions 400 nucleotides. Fragmentation of DNA was closely related to in vivo dimethylnitrosamine treatment but was not detected in measurements of protein-DNA complexes in the chromatin. It was disclosed on denaturation of DNA followed by polyacrylamide gel electrophoresis.Abbreviations DMN
dimethylnitrosamine
- SDS
sodium dodecyl sulfate
The work was supported by Grant Number 1 R0 1 CA26642-01, awarded to A.v.d.D. by the National Cancer Institute, DHEW 相似文献
85.
Effect of aluminum adjuvants on safety and immunogenicity of Haemophilus influenzae type b-CRM197 conjugate vaccine 总被引:1,自引:0,他引:1
güler Kanra Simonetta Viviani Kadriye Yurdakök Elif Özmert Alessandra Anemona SongüL Yalçn Okan Demiralp Nihan Bilgili Ates Kara Ali BüLent Cengiz Belgin Mutlu Alexandra Baldini Elisa Marchetti Audino Podda 《Pediatrics international》2003,45(3):314-318
OBJECTIVE: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM197 (Hib-CRM197) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO4). METHODS: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Gülveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days. RESULTS: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO4 vaccine (19, 10, 11% in Chiron Hib/AlPO4, VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 micro g/mL, respectively (P < 0.05). CONCLUSIONS: The use of aluminum compounds adjuvants in Hib-CRM197 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers. 相似文献
86.
Daniela S Pontes Fernanda A Dorella Luciana A Ribeiro Anderson Miyoshi Yves Le Loir Alexandra Gruss Sérgio C Oliveira Philippe Langella Vasco Azevedo 《Journal of drug targeting》2003,11(8-10):489-493
The Brucella abortus ribosomal protein L7/L12 is an immunodominant antigen and an interesting candidate for the development of oral live vaccines against brucellosis. Here, a recombinant Lactococcus lactis strain producing L7/L12 under the control of nisin inducible promoter was orally administered to BALB/c mice. Significant levels of anti-L7/L12 specific IgA detected in feces revealed an induced local humoral immune response. However, serum analysis did not reveal any anti-L7/L12 antibodies suggesting the absence of a systemic response. Nevertheless, the vaccinated mice showed a partial protective immunity against B. abortus virulent strain (S2308) challenged by intraperitoneal inoculation. 相似文献
87.
Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. 总被引:5,自引:0,他引:5
Satu M?nnist? Stephanie A Smith-Warner Donna Spiegelman Demetrius Albanes Kristin Anderson Piet A van den Brandt James R Cerhan Graham Colditz Diane Feskanich Jo L Freudenheim Edward Giovannucci R Alexandra Goldbohm Saxon Graham Anthony B Miller Thomas E Rohan Jarmo Virtamo Walter C Willett David J Hunter 《Cancer epidemiology, biomarkers & prevention》2004,13(1):40-48
Intervention trials with supplemental beta-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7-16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. beta-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87-1.11; highest versus lowest quintile). The RRs for alpha-carotene, lutein/zeaxanthin, and lycopene were also close to unity. beta-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67-0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in beta-cryptoxanthin, such as citrus fruit, may modestly lower the risk. 相似文献
88.
c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. 总被引:4,自引:0,他引:4
Alexandra Giatromanolaki Michael I Koukourakis Costantinos Simopoulos Alexandros Polychronidis Kevin C Gatter Adrian L Harris Efthimios Sivridis 《Clinical cancer research》2004,10(23):7972-7977
c-erbB-2-positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1alpha (HIF1alpha) production (Laughner et al., Mol Cell Biol 2001;21:3995-4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1alpha expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2-positive and 90 c-erbB-2-negative carcinomas) were stained immunohistochemically for HIF1alpha and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1alpha protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1alpha expression. If activation of c-erbB-2 in humans results in overexpression of HIF1alpha independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2-positive breast tumors. 相似文献
89.
Alexandra E Connelly Jessie Satia-Abouta Christopher F Martin Temitope O Keku John T Woosley P Kay Lund Robert S Sandler 《Cancer epidemiology, biomarkers & prevention》2003,12(6):559-565
Apoptosis, or programmed cell death, may lower the risk of neoplasia by removing genetically damaged or mutated cells. A high rate of apoptosis has been linked to a reduced risk of colorectal adenomas; therefore, it is important to understand factors that impact apoptosis. Antioxidants (e.g., vitamin C) protect cells from harmful oxidation processes but may interfere with apoptosis by protecting genetically damaged cells from reactive oxygen species-dependent cell death. The objective of this study was to evaluate the association between vitamin C intake and apoptosis in normal rectal mucosa. Study participants were part of a large, cross-sectional study, the Diet and Health Study III. Participants were recruited from consecutive, consenting patients who underwent colonoscopy at University of North Carolina Hospitals between August 1, 1998 and March 4, 2000. Vitamin C intake, obtained from a food frequency questionnaire, included both dietary sources and vitamin supplements. Apoptosis was measured by morphological evaluation of H&E-stained sections obtained from pinch biopsy samples of normal rectal mucosa in consenting participants (n = 503). The relationship between vitamin C and apoptosis varied by adenoma status. Among individuals with adenomas, there was an inverse linear association between apoptosis and total vitamin C intake. Similarly, individuals with adenomas in the highest quintile of total vitamin C intake were substantially less likely than those in the lowest quintile to have increased colonic apoptosis (odds ratio, 0.05; 95% confidence interval, 0.01-0.46). Vitamin C was not significantly associated with apoptosis in adenoma-free patients. High vitamin C intake was associated with reduced colorectal apoptosis among individuals with adenomas in this study population. Given that high apoptosis may lower colorectal cancer risk, vitamin C supplements may be contraindicated for patients with a history of adenomas. 相似文献
90.
Paul J Hesketh Steven M Grunberg Richard J Gralla David G Warr Fausto Roila Ronald de Wit Sant P Chawla Alexandra D Carides Juliana Ianus Mary E Elmer Judith K Evans Klaus Beck Scott Reines Kevin J Horgan 《Journal of clinical oncology》2003,21(22):4112-4119
PURPOSE: In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS: The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy. 相似文献