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71.
Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B 总被引:6,自引:0,他引:6
Liu G Szczepankiewicz BG Pei Z Janowick DA Xin Z Hajduk PJ Abad-Zapatero C Liang H Hutchins CW Fesik SW Ballaron SJ Stashko MA Lubben T Mika AK Zinker BA Trevillyan JM Jirousek MR 《Journal of medicinal chemistry》2003,46(11):2093-2103
Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice. 相似文献
72.
AIM: To study the experience of, training in, and confidence in the transportation of critically ill neonates amongst paediatric trainees in one UK region. DESIGN: An anonymized questionnaire was sent to all middle grades with paediatrics National Training Numbers from the Trent region. RESULTS: The response rate was 78%. Less than half (45%) of the respondents reported receiving any training in the transportation of neonates, either in the UK or abroad; 45% (30/66) of the trainees reported having performed 10 or fewer neonatal transfers. The self-perceived confidence for transporting neonates was scored on a 10-point scale, to produce a "confidence score", the median score being 7 (IQ range 5, 8). Both as a group and individually, the trainee paediatricians were more confident in transporting neonates than older infants or children (p < 0.0001). Using multiple analysis of covariance, it was found that the most important and significant variables affecting the "confidence scores" for the inter-hospital transportation of critically ill neonates were receipt of any relevant transport training, and the current frequency of transports performed. CONCLUSIONS: Many training-grade paediatricians lack both the experience and training in transporting critically ill neonates, factors that were found to affect their confidence in transferring sick neonates. As the overwhelming majority of neonatal transports in the UK are still arranged by individual units and performed by training-grade paediatricians, concerns regarding both the safety and effectiveness of the current service provision for the inter-hospital transfer of critically ill neonates remain valid. 相似文献
73.
Ventral hernia repair: a study of current practice 总被引:5,自引:5,他引:0
Ventral wall hernias are common; despite this, there are no guidelines on the best surgical management. The aim of this study
was to examine the types of repair in use for abdominal wall hernias in the West of Scotland over a 3-month period. Data were
gathered on 120 patients. There were 60 incisional, 32 umbilical, and 28 epigastric hernias. The main indication for repair
was pain (78%), while 12 patients (10%), presented acutely with incarceration or strangulation. The most common method of
repair was sutured (55%), followed by mesh (29%) and Mayo repair (16%). There was no correlation between use of mesh and hernia
size or whether repair was for a recurrent hernia. Surgical practice varies widely in the repair of ventral wall hernias.
Clinical trials are required to establish the best method of repair for this common condition.
Electronic Publication 相似文献
74.
McCullough JA Evoy D Sweeney KJ Meyers C Ravi N Keeling N Byrne PJ Reynolds JV 《Irish journal of medical science》2003,172(3):132-135
Background Gastric carcinoma is a significant cause of death in Ireland. Surgery offers the best option of cure, but the five-year survival
following resection remains dismal at 10–15%. Experience from Japan and from some Western units suggest that an extended (D2)
lymphadenectomy in association with gastrectomy increases the prospect of cure, but concern about the morbidity and mortality
of this operation and lack of evidence from randomised studies has limited its acceptance.
Aims This study reports the experience of a specialist upper gastrointestinal unit with D2 gastrectomy in a four-year audit.
Methods Sixty-two resections were performed for gastric cancer. Results Nineteen patients were deemed unsuitable for the D2 procedure
and underwent a more limited lymphadenectomy (DO or D1). Forty-three patients underwent D2 resection, 12 with an oesophagogastrectomy,
22 with total gastrectomy and nine with a sub-total distal resection. Eight patients undergoing D2 resection had extended
resections, five with splenectomy and three with a distal pancreatectomy. Post-operative complications occurred in 31% of
patients. Thirty-day and 90-day mortality were zero. Median survival was 822 days in the D2 group (range 120–1,320).
Conclusions These results show that a D2 gastrectomy can be performed with a low morbidity and mortality and a median survival of greater
than two years. 相似文献
75.
Background The contribution of dysmotility to dysphagia in oesophageal cancer is unclear.
Aim To examine oesophageal motility in patients with oesophageal carcinoma and to assess the effect of chemoradiotherapy on motility.
Methods Stationary manometry and 24-hour pH-metry were performed in 12 patients with oesophageal carcinoma and one week following
completion of chemoradiotherapy using 5-fluorouracil (5-FU), cisplatin and 40Gy radiotherapy.
Results All patients had abnormal motility prior to treatment. Peristalsis was impaired in 11 patients with a mean (SD) of 25% (9)
of waves normally propagated. Eight patients had 20% or more simultaneous waves. Following chemoradiotherapy, the percentage
of waves normally propagated increased from 25% (9) to 52% (10) (p < 0.03) and normal peristalsis was restored in four patients.
The percentage of simultaneous waves decreased from 38% (11) to 21.6% (10) (p=0.129) while the percentage of dropped or increased
waves decreased from 20% (11) to 8.3% (4) (p=0.264).
Conclusions Oesophageal motility is disturbed in oesophageal cancer. Dysphagia in oesophageal cancer may be partly explained by oesophageal
dysmotility. This is improved by chemotherapy. 相似文献
76.
Trypanosoma brucei developmentally regulates mitochondrial function during its life cycle. Numerous nuclear encoded mitochondrial proteins undergo posttranslational regulation in a developmental fashion, but exactly how that regulation is achieved is unclear. We are interested in mitochondrial import as a potential regulatory step for nuclear encoded mitochondrial proteins. Previously, an in vitro import system was developed for the procyclic lifestage. We report here the development of an in vitro import system for bloodstream trypanosomes using a crude mitochondrial preparation. NADH dehydrogenase subunit K (NdhK) is a nuclear encoded mitochondrial protein that is constitutively expressed in bloodstream and procyclic trypanosomes. We examined the import of NdhK into procylic and bloodstream mitochondria in vitro. In both lifestages import of NdhK requires a membrane potential across the inner mitochondrial membrane, mitochondrial matrix ATP, and is time dependent. The precursor protein is processed by a matrix associated metalloprotease in a single cleavage step to mature protein. 相似文献
77.
Cuppen JG Van den Brink PJ Camps E Uil KF Brock TC 《Aquatic toxicology (Amsterdam, Netherlands)》2000,48(2-3):233-250
Effects of chronic application of the fungicide Derosal(R) (active ingredient carbendazim) were studied in indoor macrophyte-dominated freshwater microcosms. The concentrations (0, 3.3, 33, 100, 330 and 1000 μg/l) were kept at a constant level for 4 weeks. This paper is the first of a series of two, and describes the fate of carbendazim and its effects on water quality parameters, breakdown of POM, and responses of macroinvertebrates. Carbendazim proved very persistent in the water layer. Values for t(12) varied between 6 and 25 weeks, and decreased with the treatment level. Significant effects on water quality parameters (DO, pH, alkalinity, conductivity) could not be demonstrated. After 4 weeks of incubation, the breakdown of Populus leaves was significantly slower at the two highest carbendazim concentrations. The macroinvertebrate community was seriously affected by carbendazim application, with Oligochaeta, Turbellaria, Hirudinea and some Crustacea as the most sensitive groups. The snail Bithynia decreased in numbers, but other gastropods increased in numbers. Safety factors as proposed by the Uniform Principles (European Union) for the risk assessment of pesticides, to be multiplied with toxicity data of the standard test species (Daphnia, fish, algae), appeared to ensure adequate protection of sensitive populations present in the microcosms. 相似文献
78.
Hajduk PJ Boyd S Nettesheim D Nienaber V Severin J Smith R Davidson D Rockway T Fesik SW 《Journal of medicinal chemistry》2000,43(21):3862-3866
Using an NMR-based screen, a novel class of urokinase inhibitors were identified that contain a 2-aminobenzimidazole moiety. The inhibitory potency of this family of inhibitors is similar to that of inhibitors containing a guanidine or amidine group. However, unlike previously described guanidino- or amidino-based inhibitors which have pK(a) values greater than 9.0, urokinase inhibitors containing a 2-aminobenzimidazole have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved pharmacokinetic properties which could increase the bioavailability of inhibitors which contain this moiety. A crystal structure of one of the lead inhibitors, 2-amino-5-hydroxybenzimidazole, complexed with urokinase reveals the electrostatic and hydrophobic interactions that stabilize complex formation and suggests nearby subsites that may be accessed to increase the potency of this new series of urokinase inhibitors. 相似文献
79.
80.