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971.
T cells may interact with a number of bacterial surface antigens, an encounter which has the potential to downmodulate host immune responses. Neisseria meningitidis, a human colonizer and an agent of septicemia and meningitis, expresses Opa proteins which interact with the CEACAM1 receptor expressed on activated T cells. Since CEACAM1 can act as an inhibitory receptor and T cells in subepithelial tissues may encounter whole bacteria, which often express Opa proteins in vivo, this study assessed primarily if Opa proteins expressed on meningococci affect T-cell functions. In addition, Opa-containing outer membrane vesicles (OMV) have been used as vaccine antigens, and therefore Opa+ and Opa OMV were also studied. While Opa+ bacteria adhered to CEACAM-expressing T cells, both the Opa+ and Opa phenotypes induced no to a small transient depression, followed by a prolonged increase in proliferation as well as cytokine production. Such responses were also observed with heat-killed bacteria or OMV. In addition, while anti-CEACAM antibodies alone inhibited proliferation, on coincubation of T cells with bacteria and the antibodies, bacterial effects predominated and were Opa independent. Thus, while Opa proteins of N. meningitidis can bind to T-cell-expressed CEACAM1, this is not sufficient to overcome the T-cell recognition of bacterial factors, which results in a proliferative and cytokine response, an observation consistent with the ability of the host to establish lasting immunity to Opa-expressing meningococci that it frequently encounters. The data also imply that Opa-proficient vaccine preparations may not necessarily inhibit T-cell functions via CEACAM1 binding.Neisseria meningitidis (meningococci) and Neisseria gonorrhoeae (gonococci), which are highly related at the genetic and antigenic levels, are human-specific mucosal bacteria capable of causing localized or systemic infection. N. meningitidis may colonize the human respiratory mucosal tissue of 3 to 30% of healthy individuals asymptomatically but, in some situations, may penetrate into deeper tissues to cause invasive diseases, such as septicemia and meningitis (5). N. gonorrhoeae may also be carried asymptomatically in a few individuals (13), but in most cases it causes localized infections of urogenital mucosa, and in a few untreated gonorrhea patients, disseminated infection may develop (20).Immune responses to mucosal bacteria are initiated at mucosa-associated lymphoid tissue, where CD4+ T-cell priming occurs and results in the generation of effector and memory T cells (12). Bacterial colonization, and the subsequent disease process in susceptible individuals, begins with adhesion to specific receptors on human mucosal epithelial cells. N. meningitidis and N. gonorrhoeae express colony opacity-associated (Opa) proteins in vitro and in vivo that enable them to attach to human cells. It is now well established that the major receptors targeted by the Opa proteins belong to the CEACAM (carcinoembryonic antigen-related cell adhesion molecule) family of receptors (6, 44, 45). CEACAM1 is one of several related molecules expressed on human epithelial cells, endothelial cells, and leukocytes, but CEACAM1 is the only member of the family expressed on T cells (19, 28). CEACAM1 is a transmembrane molecule with either a long (L) or a short (S) cytoplasmic tail. CEACAM1-L, with a long cytoplasmic tail, contains two tyrosine residues which form part of modified immunoreceptor tyrosine-based activation/inhibition motifs (ITAM/ITIM motifs) (16). The relative abundance of the isoforms, which may be present simultaneously in CEACAM1-expressing tissues, may dictate the signaling outcomes of CEACAM1 ligation (35).In addition, Opa structural variations may also affect bacterial specificity and affinity for distinct CEACAMs (10, 40, 44). N. meningitidis and N. gonorrhoeae possess multiple complete copies of opa genes (up to 4 and 11 genes, respectively), with the consequence that distinct isolates may express structurally variant Opa proteins. Variations within the Opa family of transmembrane proteins occur in three of the four surface-exposed loops. It has been shown for strains of distinct serogroups of N. meningitidis that these variations influence the specificity of Opa proteins for different members of the CEACAM family (10, 40). Different meningococcal isolates further possess a wide range of opa alleles, variable regions, and repertoires. Particular Opa repertoires appear to correlate with hyperinvasiveness and disease but not with the severity of meningococcal disease (4). The host cell interface where Opa proteins exert such an influence remains to be defined, and while several studies have assessed the potential of Opa proteins to influence meningococcal interactions with human epithelial cells (15, 44), a limited number of studies have examined their effect on T cells (23), and none have studied the potential of live Opa-expressing meningococci to influence T-cell functions.Previous studies have shown that a number of neisserial outer membrane proteins can modulate T-cell function. Of these, TspA (T-cell-stimulating protein A), IgA1 protease, pili, and porins can induce a proliferative response in T cells (27, 31, 34, 38). In contrast, an interaction of Opa+ N. gonorrhoeae with CEACAM1 inhibited immune responses of CD4+ T cells (2) and B cells (26). In the case of T cells, the inhibitory signal delivered by the N. gonorrhoeae Opa-CEACAM1 interaction was reported to involve the phosphotyrosine phosphatases 1 and 2 (SHP-1 and SHP-2) that interact with ITIM (2, 24). Interestingly, engagement of Opa+ N. gonorrhoeae with CEACAM1 on B cells occurred independently of ITIM involvement (26). Overall, the above reports highlight the following two important points: (i) with respect to cellular activation, the end product of neisseria-target cell interactions may be determined by a number of distinct bacterial and host cell characteristics; and (ii) in the context of the consequences of bacterial engagement with CEACAM1, such an interaction may not always bring into play the expected consequences of its ITIM-like motifs. Other notable observations include the following. Outer membrane vesicles (OMV) of some Opa-expressing N. meningitidis strains have been reported to inhibit CD4+ T-cell function (23), which is in line with CD4+ T-cell-inhibiting effects of Opa+ N. gonorrhoeae (2). However, N. meningitidis carriage is regarded as an immunizing event and has been shown to induce lasting T-cell memory (7, 8).Collectively, these previous reports highlight the need for comprehensive studies to define the consequences of meningococcal interactions with cells of the human immune system, particularly as mucosal bacteria are increasingly being shown to reside in subepithelial tissues, where they may encounter T cells. This may occur, and since no comprehensive studies are yet available on T-cell responses that may ensue upon encountering live N. meningitidis, and particularly on the influence of Opa proteins in general when presented in whole bacteria, the focus of this study was to assess the immune responses of CD4+ T cells to well-characterized phenotypes of live N. meningitidis and to compare these with responses to Escherichia coli cells either expressing or lacking meningococcal Opa proteins. In addition, we compared the effects of heat-killed N. meningitidis and OMV derived from a meningococcal serogroup B strain on T-cell proliferation. The latter preparations are likely to be used as vaccine preparations and therefore, in our view, warranted such studies. In order to assess the T-cell responses to other CEACAM-binding agents and to study the effects of bacterial presence when Opa-CEACAM interactions are inhibited, the studies included cross-linking antireceptor antibodies as well as a recombinant molecule, rD-7, which carries the CEACAM-binding motif of Moraxella catarrhalis UspA1 adhesin (17) and has the potential to block bacterial binding without inducing a signaling cascade in T cells because the recombinant peptide may not cross-link CEACAM1 on T cells.In our studies, frequently, but not invariably, an early Opa-independent transient decrease in T-cell proliferation was observed. This phase was followed by a profound stimulatory effect on T-cell immune functions, as assessed by proliferation assays and cytokine responses. In contrast, using anti-CEACAM1 antibodies in analogous assays, a significant inhibition of T-cell proliferation was observed. Overall, these data show that a certain surface component(s) of pathogenic Neisseria, whose precise identity remains to be determined, can exert either mild inhibitory or strong stimulatory effects on CD4+ T cells and that, most importantly, the latter predominate. Thus, it appears that human CD4+ T cells respond positively to one or more bacterial antigens to overcome any inhibition that may be induced via the engagement of CEACAM1, perhaps representing an advanced counterstrategy of the host.  相似文献   
972.

AIMS

An integrated population pharmacokinetic–pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic–pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time.

METHODS

Data (n = 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects.

RESULTS

Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg−1 3 min after rocuronium, sugammadex 4 mg kg−1 during deep neuromuscular blockade and sugammadex 2 mg kg−1 during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time.

CONCLUSIONS

Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min.  相似文献   
973.
We evaluated massive parallel sequencing and long-range PCR (LRP) for rare variant detection and allele frequency estimation in pooled DNA samples. Exons 2 to 16 of the MUTYH gene were analyzed in breast cancer patients with Illumina's (Solexa) technology. From a pool of 287 genomic DNA samples we generated a single LRP product, while the same LRP was performed on 88 individual samples and the resulting products then pooled. Concentrations of constituent samples were measured with fluorimetry for genomic DNA and high-resolution melting curve analysis (HR-MCA) for LRP products. Illumina sequencing results were compared to Sanger sequencing data of individual samples. Correlation between allele frequencies detected by both methods was poor in the first pool, presumably because the genomic samples amplified unequally in the LRP, due to DNA quality variability. In contrast, allele frequencies correlated well in the second pool, in which all expected alleles at a frequency of 1% and higher were reliably detected, plus the majority of singletons (0.6% allele frequency). We describe custom bioinformatics and statistics to optimize detection of rare variants and to estimate required sequencing depth. Our results provide directions for designing high-throughput analyses of candidate genes. Hum Mutat 30:1–10, 2009. © 2009 Wiley-Liss, Inc.  相似文献   
974.
ObjectiveTo assess what portion size labeling format is most promising in helping consumers selecting appropriate soft drink sizes, and whether labeling impact depends on the size portfolio.MethodsAn experimental study was conducted in fast-food restaurants in which 2 labeling formats (ie, reference portion size and small/medium/large labels) were compared to a control condition, and 2 size ranges were assessed. The main outcome variable was participants' intended soft drink size choice. Stimulus material was presented through photographs.ResultsThere was a statistical trend for reference portion size labeling increasing the likelihood to choose small sizes (n = 158, odds ratio = 2.55, P = .06, confidence interval: 0.84-7.70).Conclusions and ImplicationsReference portion size labeling is potentially most promising in reducing large portion size preferences. More research assessing the effectiveness of reference portion size labeling (combined with pricing strategies) on actual choices and consumption behavior in a realistic setting is recommended.  相似文献   
975.
Kawasaki Disease (KD) is an acute, self-limiting, vasculitis typically occurring in children under the age of five. Less than 5% of children with KD develop coronary aneurysms and require follow-up by a (paediatric) cardiologist. The majority of patients do not receive follow-up care. However, recent data suggest that the inflammation associated with KD has the potential to affect the entire cardiovascular system. Patients with a history of KD may have an increased risk of long-term cardiovascular sequelae. Therefore KD should be considered a cardiovascular risk factor.  相似文献   
976.
de Krom MP  Mol AP 《Appetite》2010,55(3):671-678
Irrespective of major food crises in the 2000s consumer trust in food seems to remain high in Western Europe. Transparent information provision to consumers on food risks is a central strategy of the EU, its Member States and private food providers to build food trust among consumers. But can the interpretation of such information by consumers explain high levels of trust in food safety? Following recent outbreaks of avian influenza in the UK, this paper investigates the constitution of food trust among UK poultry consumers by focusing on the place where consumer decisions are made: the shopping floor. In-store qualitative interviews with consumers of a variety of poultry products at different shops are used to reveal the use of information in constructing trust. Besides on knowledge inducted from information provision, trust depends as much on consumer strategies to handle non-knowing of food risks. Three main forms of trust relations are distinguished, which together at a system level result in high levels of consumer trust in food.  相似文献   
977.
Liver disease develops in one‐third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.  相似文献   
978.
The prothrombin 20210A mutation has been associated with an increased risk for venous thromboembolism (VTE) and arterial cardiovascular disease. The risks for asymptomatic carriers of this mutation have thus far been studied only in case-control and retrospective cohort studies. Here we present the results of the first prospective observational study in asymptomatic first-degree family members of patients with either VTE or premature atherosclerosis and the prothrombin 20210A mutation. We included 464 individuals (236 carriers) with a total follow-up duration of 1816 years (943 years for the carriers). The annual incidence of a first VTE was 0.37% (95% CI, 0.08-1.08) for carriers and 0.12% (95% CI, 0.00-0.69) for noncarriers (HR, 3.1; 95% CI, 0.3-29.6). The annual incidence of a first arterial cardiovascular event was 0.56% (95% CI, 0.18-1.31) for carriers and 0.73% (95% CI, 0.27-1.58) for noncarriers (adjusted HR, 0.7; 95% CI, 0.2-2.5). We conclude that the absolute incidence of a first VTE or arterial cardiovascular event is low; therefore, the clinical implications of carriership of the prothrombin 20210A mutation are limited, and routinely testing all first-degree relatives of probands with this mutation does not appear to be justified.  相似文献   
979.
Somers P  Knaapen M 《Angiology》2006,57(5):546-555
Varicosity is a complex venous pathology affecting the lower extremities. The exact etiology and physiopathology of varicose vein disease remain, however, unclear. Several theories exist from incompetence of the valves to a disturbance of the smooth muscle cells (SMC) and extra-cellular matrix (ECM) organization providing a weakness of the venous wall. Multiple studies have been performed to explain the underlying mechanisms of varicosity inducing alterations in the expression patterns of the endothelium, SMC, and ECM. In that respect, most attention has been focused on the alteration of the endothelium due to blood stasis and hypoxia inducing migration/proliferation of the medial SMC into the intima. Also, studies in the deformation of the ECM induced by alterations of the expression patterns of the metalloproteinases (MMP) and their inhibitors (TIMPs) have been put forward to explain the etiology of varicosity. However, less attention has been paid to the hormonal changes that occur during pregnancy and menopause, crucial factors to be involved in the etiology of varicosity. Since alteration of the estrogen receptor-b (ERb) expression could enhance directly the cellular volume of SMC and thus the disorganization of the contractile-elastic units, hypertrophy of SMC must be accounted a pivotal role that could induce the weakness of the venous wall. Altogether, this review summarizes an overview of the latest findings of varicosity with respect to the histopathological changes of the different cellular components of the varicose vein wall related to functional and morphologic alterations.  相似文献   
980.
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder. Genetics has an important role in the aetiology of this disease. In this study, we describe the clinical findings in a Dutch family with eight patients suffering from ADHD, in whom five had at least one other psychiatric disorder. We performed a genome-wide (parametric and nonparametric) affected-only linkage analysis. Two genomic regions on chromosomes 7 and 14 showed an excess of allele sharing among the definitely affected members of the family with suggestive LOD scores (2.1 and 2.08). Nonparametric linkage analyses (NPL) yielded a maxNPL of 2.92 (P=0.001) for marker D7S502 and a maxNPL score of 2.56 (P=0.003) for marker D14S275. We confirmed that all patients share the same haplotype in each region of 7p15.1–q31.33 and 14q11.2–q22.3. Interestingly, both loci have been reported before in Dutch (affected sib pairs) and German (extended families) ADHD linkage studies. Hopefully, the genome-wide association studies in ADHD will help to highlight specific polymorphisms and genes within the broad areas detected by our, as well as other, linkage studies.  相似文献   
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