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101.
Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. 总被引:6,自引:0,他引:6
William D Foulkes Kelly Metcalfe Ping Sun Wedad M Hanna Henry T Lynch Parviz Ghadirian Nadine Tung Olufunmilayo I Olopade Barbara L Weber Jane McLennan Ivo A Olivotto Louis R Bégin Steven A Narod 《Clinical cancer research》2004,10(6):2029-2034
PURPOSE: BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied. EXPERIMENTAL DESIGN: ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum. RESULTS: BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P < 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (P(intercept) = 0.0002, P(slope) = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (P(slope) = 0.98). CONCLUSIONS: The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers. 相似文献
102.
103.
Wayne L. Furman John H. Rodman Margaret E. Tonda Xiaolong Luo Bettye Arnold Neyssa Marina Leslie Garrison Roberta Hanna Charles B. Pratt William H. Meyer 《Cancer chemotherapy and pharmacology》1997,41(3):229-236
A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have
great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor
and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited,
and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels.
Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with
myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered
once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic
studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule
only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose
studied (1000 μg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing
doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77–1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase
63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were
<1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent
activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no
demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained
by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase
in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either
extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling
circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the
systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
Received: 29 January 1997 / Accepted: 9 May 1997 相似文献
104.
Liu JM; Chen YM; Chao Y; Liu SM; Tiu CM; Wu HW; Chiou TC; Hsieh RK; Chen LT; Whang-Peng J 《Japanese journal of clinical oncology》1998,28(7):431-435
BACKGROUND: To evaluate the efficacy and toxicity of cisplatin/etoposide
continuous infusion chemotherapy for cancer of unknown primary site in
Taiwan, a region with a high prevalence of endemic viral infections.
METHOD: Between April 1994 and February 1996, 20 patients with a diagnosis
of CUPS were treated, including 15 males and five females, of average age
63.3 years (range 41-83 years). Continuous intravenous infusion of
etoposide 80 mg/m2 and cisplatin 25 mg/m2 was given for 3 days every 3
weeks. Pretreatment tumor marker and viral serology studies were performed
for baseline evaluation. Nearly two-thirds of the patients had poorly
differentiated carcinoma. The average number of metastatic sites was 2.65
(range 1-4), with liver and lymph node involvement predominating. RESULTS:
The overall response rate was 25% (95% CI 17.7-32.3%); 30.7% for poorly
differentiated cancers and 25% for well differentiated cancers. Median
survival was 4 months (range 1-12 months), 4.8 months for patients
attaining partial response. Toxicity was moderate, grade 3 and 4
neutropenia occurred in 55% and grade 3 and 4 thrombocytopenia in 40%;
other toxicities were mild. CA125 and CA199 were elevated in more than 50%
of patients. Viral serology studies were not significantly different from
those of the indigenous population. CONCLUSION: Etoposide and cisplatin
combination chemotherapy has modest activity in patients with extensive
CUPS and, at the schedule and dosage given, it is associated with moderate
toxicity.
相似文献
105.
Wang WS; Hsieh RK; Chiou TJ; Liu JH; Fan FS; Yen CC; Tung SL; Chen PM 《Japanese journal of clinical oncology》1998,28(9):551-554
A 54-year-old man was treated with weekly 24-h infusion of high-dose
5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon
cancer. At first, he tolerated the treatment well and no significant
toxicity was identified. After a total of eight courses of treatment, a
stable disease was observed, but mild shortness of breath was found on
occasion. The patient had no previous history of cardiac disease and the
heart performance assessed by left ventricular ejection fraction before
treatment was normal. Unfortunately, acute pulmonary edema with lethal
cardiogenic shock occurred during the ninth course of treatment, in spite
of intensive medical treatment. The chest X-ray showed extreme
cardiomegaly. Repeated assessment of his heart function by echocardiogram
and ventricular ejection fraction revealed a very poor cardiac performance.
Toxic cardiogenic shock during weekly 24-h infusion of high-dose
5-fluorouracil and leucovorin is extremely rare. To the best of our
knowledge, no case has been reported in the English literature. We report a
case and the relevant literature about the incidence, clinical picture and
possible pathophysiology on 5-fluorouracil-related cardioxicity is
reviewed.
相似文献
106.
Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita 总被引:1,自引:0,他引:1
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Davies NP Eunson LH Gregory RP Mills KR Morrison PJ Hanna MG 《Journal of neurology, neurosurgery, and psychiatry》2000,68(4):504-507
OBJECTIVES: To characterise the clinical and electrophysiological features and to determine the molecular genetic basis of pure paramyotonia congenita in a previously unreported large Irish kindred. METHODS: Clinical and neurophysiological examination was performed on three of the five affected family members. Five unaffected and three affected members of the family were available for genetic testing. Direct sequence analysis of the SCN4A gene on chromosome 17q, was performed on the proband's DNA. Restriction fragment length polymorphism (RFLP) analysis was used to screen other family members and control chromosomes for the SCN4A mutation identified. RESULTS: Each affected member had clinical and examination features consistent with pure paramyotonia congenita. Electrophysiological studies disclosed a 78% drop in compound muscle action potential (CMAP) amplitude on cooling to 20 degrees C. DNA sequence analysis identified a heterozygous point mutation G4367A in exon 24 of the SCN4A gene which segregated with paramyotonia and was absent in 200 control chromosomes. The mutation is predicted to result in a radical amino acid substitution at a highly conserved position within the voltage sensing fourth transmembrane segment of the fourth repeated domain of the sodium channel. CONCLUSIONS: The G4367A mutation is likely to be pathogenic and it associates with a pure paramyotonia phenotype. In keeping with other paramyotonia mutations in this region of the skeletal muscle sodium channel, it is predicted that this mutation will impair voltage sensing or sodium channel fast inactivation in a temperature dependent fashion. This study provides further evidence that exon 24 in SCN4A is a hot spot for paramyotonia mutations and this has implications for a DNA based diagnostic service. 相似文献
107.
Physical activity combined with massage improves bone mineralization in premature infants: a randomized trial. 总被引:5,自引:0,他引:5
Hany Aly Mohamed F Moustafa Sahar M Hassanein An N Massaro Hanna A Amer Kantilal Patel 《Journal of perinatology》2004,24(5):305-309
BACKGROUND: Osteopenia of prematurity is a known source for morbidity in preterm infants. Premature infants have shown favorable outcomes in response to massage and physical activity. Whether such intervention can stimulate bone formation or decrease bone resorption is yet to be determined. OBJECTIVE: To test the hypothesis that massage combined with physical activity can stimulate bone formation and ameliorate bone resorption in premature infants. DESIGN/METHODS: A prospective double-blinded randomized trial was conducted at the Neonatal Intensive Care Unit of Ain Shams University in Cairo, Egypt. Thirty preterm infants (28 to 35 weeks' gestation) were randomly assigned to either control group (Group I, n=15) or intervention group (Group II, n=15). Infants in the intervention group received a daily protocol of combined massage and physical activity. Serum type I collagen C-terminal propeptide (PICP) and urinary pyridinoline crosslinks of collagen (Pyd) were used as indices for bone formation and resorption, respectively. PICP and Pyd were measured at enrollment and at discharge for all subjects. t-Test, ANOVA and linear regression analysis were used for statistical analyses. RESULTS: There was no difference between groups I and II in gestational age (32.1+/-1.8 vs 31.5+/-1.4 weeks) or birth weight (1.429+/-0.148 vs 1.467+/-0.132 g). In the control group, serum PICP decreased over time from 82.3+/-8.5 to 68.78+/-14.6 (p<0.01), while urinary Pyd increased from 447.7+/-282.8 to 744.9+/-373.6 (p<0.01) indicating decreased bone formation and increased bone resorption, respectively. In the intervention group, serum PICP increased over time from 62.5+/-13.8 to 73.84+/-12.9 (p<0.01). Urinary Pyd also increased over time from 445.7+/-266.5 to 716.8+/-301.8 (p<0.01). In a linear regression model including gestational age and intervention, serum PICP increased significantly in the intervention group (regression coefficient 18.8+/-4.6, p=0.0001) while urinary Pyd did not differ between groups (regression coefficient=5.6+/-114.3, p=0.961). CONCLUSIONS: A combined massage and physical activity protocol improved bone formation (PICP) but did not affect bone resorption (Pyd). Pyd increased over time in both groups, possibly due to continuous bone resorption and Ca mobilization. 相似文献
108.
109.
110.
Outi Honkanen Janne Marvola Hanna Kanerva Kai Lindevall Maija Lipponen Tommi Kekki Aapo Ahonen Martti Marvola 《European journal of pharmaceutical sciences》2004,21(5):428-678
The fate (movement and disintegration) of hard novel hydroxypropyl methylcellulose (HPMC) two-piece capsules in the human gastrointestinal tract was investigated using a gamma scintigraphic imaging method. Two different prolonged-release formulations without an active ingredient were used. The capsules contained different viscosity grades of HPMC powder (HPMC K100 and HPMC K4M). The aim was to determine the main reason why the pharmacokinetic profiles of model drugs change when the diluent was changed to a higher viscosity grade. The results were compared with our previous pharmacokinetic studies with corresponding capsules containing metoclopramide hydrochloride or ibuprofen as a model drug. The first observation was that the HPMC capsules had a tendency to attach to the oesophagus. Therefore, it is recommended that the HPMC capsules as well as gelatine capsules be taken with a sufficient amount of water (150–200 ml) in an upright position and maintaining the upright position for several minutes. The viscosity grade of the HPMC did not affect the transit times of the capsules in the GI tract. The major differences between the two formulations were the complete disintegration times of the capsules and the spreading of the capsules to the large intestine. Most of the HPMC K100-based capsules were completely disintegrated during the 8 h study, whereas the HPMC K4M-based capsules still exhibited plug formations in the large intestine. Also the HPMC K100-based capsules spread better to the ascending colon than the HPMC K4M-based capsules. The faster disintegration of the HPMC K100-based capsules explains the differences in the pharmacokinetic profiles of the model drugs between the HPMC K100- and K4M-based capsules in our previous studies. The main absorption site of the drugs from the capsules studied here is probably the large intestine when taken in a fasting state. 相似文献