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41.
Background: In the Netherlands, unrestricted access to direct-acting antivirals (DAAs) halved the incidence of acute hepatitis C virus (HCV) infections among HIV-infected men who have sex with men (MSM). To develop strategies that can further reduce the spread of HCV, it is important to understand the transmission dynamics of HCV. We used phylogenetic analysis of a dense sample of MSM to provide insight into the impact of unrestricted access to DAAs on HCV transmission in the Netherlands and in Belgium. Methods: We included 89 MSM that were recently infected with HCV genotype 1a in ten Dutch and one Belgian HIV treatment centers. Sequences were generated using next gene sequencing and Sanger sequencing. Maximum likelihood phylogenetic analysis (general time reversible model) was performed on concatenated NS5A and NS5B sequences and a reference set of 389 highly similar control sequences selected from GenBank. A cluster was based on a minimum bootstrap support of 90% and a 3% genetic distance threshold. Results: We found that 78 (88%) of individuals were part of seven major clusters. All clusters included individuals from across the study region, however, different cities were part of different clusters. In three clusters, HIV-negative MSM clustered with sequences from HIV-positive MSM. All clusters that were observed before the introduction of DAAs persisted after unrestricted access to DAAs became available. Conclusion: Recently acquired HCV infections among MSM in the Netherlands and Belgium are strongly clustered and therefore highly suitable for targeted prevention strategies, such as contact tracing and partner notification. Importantly, despite an HCV incidence reduction after high DAA uptake and continuously monitoring, HCV transmission persisted in the same clusters.  相似文献   
42.
Purpose:In children with cerebral palsy, flexion deformities of the knee can be treated with a distal femoral extension osteotomy combined with either patellar tendon advancement or patellar tendon shortening. The purpose of this study was to establish a consensus through expert orthopedic opinion, using a modified Delphi process to describe the surgical indications for distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening. A literature review was also conducted to summarize the recent literature on distal femoral extension osteotomy and patellar tendon shortening/patellar tendon advancement.Method:A group of 16 pediatric orthopedic surgeons, with more than 10 years of experience in the surgical management of children with cerebral palsy, was established. The group used a 5-level Likert-type scale to record agreement or disagreement with statements regarding distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening. Consensus for the surgical indications for distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening was achieved through a modified Delphi process. The literature review, summarized studies of clinical outcomes of distal femoral extension osteotomy/patellar tendon shortening/patellar tendon advancement, published between 2008 and 2022.Results:There was a high level of agreement with consensus for 31 out of 44 (70%) statements on distal femoral extension osteotomy. Agreement was lower for patellar tendon advancement/patellar tendon shortening with consensus reached for 8 of 21 (38%) of statements. The literature review included 25 studies which revealed variation in operative technique for distal femoral extension osteotomy, patellar tendon advancement, and patellar tendon shortening. Distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening were generally effective in correcting knee flexion deformities and extensor lag, but there was marked variation in outcomes and complication rates.Conclusion:The results from this study will provide guidelines for surgeons who care for children with cerebral palsy and point to unresolved questions for further research.Level of evidence:level V.  相似文献   
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Iridoid monoterpenes, widely distributed in plants and insects, have many ecological functions. While the biosynthesis of iridoids has been extensively studied in plants, little is known about how insects synthesize these natural products. Here, we elucidated the biosynthesis of the iridoids cis-trans-nepetalactol and cis-trans-nepetalactone in the pea aphid Acyrthosiphon pisum (Harris), where they act as sex pheromones. The exclusive production of iridoids in hind legs of sexual female aphids allowed us to identify iridoid genes by searching for genes specifically expressed in this tissue. Biochemical characterization of candidate enzymes revealed that the iridoid pathway in aphids proceeds through the same sequence of intermediates as described for plants. The six identified aphid enzymes are unrelated to their counterparts in plants, conclusively demonstrating an independent evolution of the entire iridoid pathway in plants and insects. In contrast to the plant pathway, at least three of the aphid iridoid enzymes are likely membrane bound. We demonstrated that a lipid environment facilitates the cyclization of a reactive enol intermediate to the iridoid cyclopentanoid-pyran scaffold in vitro, suggesting that membranes are an essential component of the aphid iridoid pathway. Altogether, our discovery of this complex insect metabolic pathway establishes the genetic and biochemical basis for the formation of iridoid sex pheromones in aphids, and this discovery also serves as a foundation for understanding the convergent evolution of complex metabolic pathways between kingdoms.

Iridoids are a class of atypical bicyclic monoterpenoids that are widely distributed in flowering plants, but, notably, are also found in several insect orders, including Coleoptera, Hymenoptera, and Hemiptera (1). Iridoids therefore present an opportunity to compare and contrast the chemical logic of natural product biosynthesis between plants and insects.In plants, iridoids largely act as defensive metabolites or biosynthetic intermediates for other natural products (e.g., monoterpenoid indole alkaloids and isoquinoline alkaloids). The pathway leading to the cyclopentanoid-pyran (iridoid) scaffold was first elucidated in the plant Madagascar periwinkle (Catharanthus roseus) (26) and more recently in the two mint species Nepeta mussinii and Nepeta cataria (79). Iridoid biosynthesis in plants starts with the condensation of the universal terpene precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) to form geranyl diphosphate (GPP), followed by hydrolysis to geraniol (Fig. 1A). Both reactions take place in the plastids and are catalyzed by trans-isoprenyl diphosphate synthase (IDS) and geraniol synthase (GES), respectively. Hydroxylation of geraniol by geraniol-8-hydroxylase (G8H) leads to 8-hydroxygeraniol, which is further oxidized in two consecutive reaction steps by 8-hydroxygeraniol oxidase (HGO) to 8-oxogeranial. This dialdehyde is then converted to the iridoid nepetalactol by a two-step reduction–cyclization sequence that involves the formation of a highly reactive 8-oxocitronellyl enol/enolate intermediate. Initially, reduction and cyclization of 8-oxogeranial were thought to be controlled by a single enzyme, iridoid synthase (ISY) (3), though later studies showed that ISY likely catalyzes only the NADPH-dependent reduction of 8-oxogeranial to the 8-oxocitronellyl enol/enolate intermediate (8). This intermediate can nonenzymatically cyclize, or, alternatively, the stereoselective cyclization of this intermediate to nepetalactol is enzymatically mediated by nepetalactol-related short-chain dehydrogenase (NEPS) or by major latex protein-like (MLPL) enzymes (8, 9). In C. roseus, nepetalactol is further metabolized to secologanin, which serves as a precursor for the formation of monoterpene indole alkaloids in this plant (10). In Nepeta, a NEPS protein oxidizes nepetalactol to nepetalactone (8), with both the alcohol and lactone released as volatiles.Open in a separate windowFig. 1.The formation of iridoids in plants and aphids. (A) Labeling studies suggest that the biosynthesis of iridoids in the pea aphid A. pisum mimics the biosynthetic pathway in iridoid-producing plants. IPP, isopentenyl diphosphate; DMAPP, dimethylallyl diphosphate; GPP, geranyl diphosphate; IDS, isoprenyl diphosphate synthase; GES, geranyl diphosphate synthase; G8H, geraniol 8-hydroxylase; HGO, 8-hydroxygeraniol oxidoreductase; ISY, iridoid synthase; NEPO, nepetalactol oxidase. (B) Relative expression of mevalonate and putative nepetalactone pathway genes in hind legs and front legs of different sexual stages of A. pisum. Relative expression data are based on RPKM values obtained by RNAseq. f-hl, hind legs of sexual females; f-fl, front legs of sexual females; af-hl, hind legs of asexual females; m-hl, hind legs of males.Insects utilize iridoids as both defense compounds and volatile pheromones, but in terms of biosynthesis, comparatively little is understood about insect-derived iridoids. Biosynthetic insights have been obtained from studies on larvae of chrysomelid leaf beetles, which accumulate the iridoid-related monocyclic dialdehydes chrysomelidial and plagiodial (11). Feeding experiments with isotopically labeled precursors and the discovery of some of the enzymes involved in chrysomelidial formation demonstrated that leaf beetles produce these compounds by a series of chemical reactions similar to those that occur in plants (1215). Although the enzymatic basis for this pathway has not been completely established, the fact that the known enzymes are unrelated to their counterparts in plants suggests independent evolution of the pathway occurred (14).Cis-trans-nepetalactol and cis-trans-nepetalactone are the major iridoids produced by catnip (N. mussinii) and catmint (N. cataria) (16). These molecules are responsible for the euphoric effect these plants have on cats, but their ecological function is unclear, though they may play roles in mediating interactions with insects (17). Interestingly, cis-trans-nepetalactol and cis-trans-nepetalactone occur also in aphids, which produce these compounds as volatile sex pheromones (18, 19). The pea aphid Acyrthosiphon pisum, for example, has been reported to biosynthesize (1R,4aS,7S,7aR)-cis-trans-nepetalactol and (4aS,7S,7aR)-cis-trans-nepetalactone in glandular structures on the hind legs of sexual female aphids, from where they are released to attract male conspecifics (18, 20). Recent studies with isotopically labeled iridoid precursors suggest that the iridoid pathway in aphids follows the reaction sequence described for plants (21). However, the underlying enzymatic machinery of this pathway is completely unknown.Here, we report the elucidation of the entire iridoid pathway in the pea aphid A. pisum. By searching for genes expressed exclusively in hind legs of sexual female aphids, the site of iridoid production, we could rapidly identify all six biosynthetic genes/enzymes responsible for the conversion of IPP and DMAPP to cis-trans-nepetalactone. The discovery of the insect nepetalactone pathway in its entirety now allows a comparison of the chemical solutions that have evolved for nepetalactone biosynthesis in plants and animals. Although the chemical steps from GPP to nepetalactone are the same in both Nepeta and pea aphids, the enzymes of these pathways have clearly evolved independently.  相似文献   
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45.
The use of pre-implantation genetic diagnosis (PGD) for hereditary cancer is subject to on-going debate, particularly among professionals. This study evaluates the attitude towards PGD and attitude-associated characteristics of those concerned: family members with a hereditary cancer predisposition. Forty-eight Von Hippel-Lindau and 18 Li–Fraumeni Syndrome families were identified via the 9 family cancer clinics in the Netherlands. In total, 216 high risk family members and partners were approached, of whom 179 (83%) completed a self-report questionnaire. Of the high risk family members, 35% expressed a positive attitude towards PGD. Those with a current desire to have children were significantly more likely to have a positive attitude: 48% would consider the use of PGD. No other sociodemographic, medical or psychosocial variables were associated significantly with a positive attitude. The most frequently reported advantage of PGD is the avoidance of a possible pregnancy termination. Uncertainty about late effects was the most frequently reported disadvantage. These results indicate that approximately half of those contemplating a future pregnancy would consider the use of PGD. The actual uptake, however, is expected to be lower. There is no indication that psychosocial factors affect interest in PGD.  相似文献   
46.
ObjectiveTo demonstrate the safety and efficiency of holmium laser-assisted lithotripsy during sialendoscopy of the submandibular gland using a retrospective, interventional consecutive case series.MethodsWe performed 374 sialendoscopies between 2008 and 2015 and evaluated all patients regarding clinical symptoms, clinical findings, therapy and outcome. We performed 109 procedures of holmium laser-assisted lithotripsy in 64 patients whose sialoliths measured 5 mm or more in diameter. In addition to retrospective case note reviews, we performed telephone interviews of all patients in January 2017.ResultsWe performed 374 consecutive submandibular gland sialendoscopy procedures in 276 patients between 2008 to 2015. Sialolithiasis had either previously been diagnosed, or symptoms highly suggestive of sialolithiasis of the submandibular gland presented in 197 patients.Holmium laser-assisted Laser lithotripsy was performed in 109 cases (64.9%). Smaller mobile concrement was removed directly either by forceps or wire basket, or following marsupialisation of the submandibular duct. This was the case in 88 patients (29.1%). Three patients (0.8%) required surgical removal of the submandibular gland due to early abscess. The majority of patients (n = 374 procedures; 90.1%) remained symptom-free after two or more years following intervention. In the remaining procedures (n = 37 procedures; 9.9%), patients reported discreet postprandial problems but did not seek medical attention. In total, we managed to preserve the submandibular gland and avoid open surgery in 99% of patients through endoscopic management of submandibular concrement and duct stenosis.ConclusionHolmium laser-assisted lithotripsy is a simple, safe, and effective procedure for treating patients with sialolithiasis of the submandibular gland. Removal of the gland is rarely required, and removing the gland without prior sialendoscopy is no longer recommended. It should be offered to all patients with submandibular gland sialolithiasis, or such patients should be referred to the appropriate centre for sialendoscopy before submandibulectomy is considered.  相似文献   
47.
Objective:The purpose of this study was to explore the feasibility to determine regional diagnostic reference levels (RDRLs) for paediatric conventional and CT examinations using the European guidelines and to compare RDRLs derived from weight and age groups, respectively.Methods:Data were collected from 31 hospitals in 4 countries, for 7 examination types for a total of 2978 patients. RDRLs were derived for each weight and age group, respectively, when the total number of patients exceeded 15.Results:It was possible to derive RDRLs for most, but not all, weight-based and age-based groups for the seven examinations. The result using weight-based and age-based groups differed substantially. The RDRLs were lower than or equal to the European and recently published national DRLs.Conclusion:It is feasible to derive RDRLs. However, a thorough review of the clinical indications and methodologies has to be performed previous to data collection. This study does not support the notion that DRLs derived using age and weight groups are exchangeable.Advances in knowledge:Paediatric DRLs should be derived using weight-based groups with access to the actual weight of the patients. DRLs developed using weight differ markedly from those developed with the use of age. There is still a need to harmonize the method to derive solid DRLs for paediatric radiological examinations.  相似文献   
48.
49.
Familial Cancer - In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our...  相似文献   
50.
The Dutch colorectal cancer (CRC) screening program started in 2014, inviting the target population biennially to perform a fecal immunochemical test (FIT). We obtained prospectively collected data from the national screening information-system to present the results of the second round (2016) and evaluate the impact of increasing the FIT cut-off halfway through the first round from 15 to 47 μg Hb/g feces on outcomes in the second round. Second round screening was done with a 47 μg Hb/g feces FIT cut-off. Participants were classified based on first round participation status as either FIT (15,47) or FIT (47,47) participants, and previous nonparticipants. In total, 348,891 (75.9%) out of 459,740 invitees participated in the second round. Participation rates were 93.4% among previous participants and 21.0% among previous non-participants. FIT(47,47) participants had a significantly higher detection rate of AN (15.3 vs. 10.4 per 1,000 participants) compared to FIT(15,47) participants in the second round, while their cumulative detection rate of AN over two rounds was significantly lower (45.6 vs. 52.6 per 1,000 participants). Our results showed that participation in the Dutch CRC screening program was consistently high and that second round detection rates depended on the first round FIT cut-off. The cumulative detection over two rounds was higher among FIT(15,47) participants. These findings suggest that a substantial part of, but not all the missed findings in the first round due to the increased FIT cut-off were detected in the subsequent round.  相似文献   
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