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991.
Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex 总被引:3,自引:0,他引:3
Chan S Kachilele S McCabe CJ Tannahill LA Boelaert K Gittoes NJ Visser TJ Franklyn JA Kilby MD 《Brain research. Developmental brain research》2002,138(2):109-116
Thyroid hormones are known to be important for optimal development of the human central nervous system. Classically, maternal thyroid hormones have not been thought to have a major role in defining central nervous system development. However, recent epidemiological evidence has indicated that subtle deficiencies in circulating maternal thyroid hormones in the first trimester of pregnancy are associated with adverse neurodevelopment. We have used real time PCR to quantitate the expression of mRNAs encoding the thyroid receptor isoforms (TR alpha1, alpha2, beta1 and beta2) and thyronine deiodinase subtypes (5'-DI, 5'-DII and 5-DIII) in human fetal cerebral cortex from the first and second trimesters of pregnancy. Deiodinase subtype activities have also been determined in these tissues and compared to 'normal' adult human cerebral cortex. Iodothyronine deiodinase mRNAs were expressed in human fetal cerebral cortex from 7 to 8 weeks of gestation. The expression of 5'-DI mRNA was variable in fetal life but increased relative to adult cortex (P<0.05), whereas the activity of this enzyme was below the level of assay detection. 5'-DII mRNA and activity in fetal cerebral cortex was detectable from as early as 7-8 weeks but not significantly different from that in adult life except at 15-16 weeks when mRNA expression increased (P<0.05). Fetal cortex 5-DIII mRNA expression was present from the early first trimester but less abundant than in adult tissue (P<0.01) and 5-DIII activity appeared greater in fetal cortex (P<0.01) as compared to adults. Only TR alpha1 mRNA was more abundantly expressed in fetal cortex than adult tissues (P<0.01). In contrast, the TR isoforms (alpha2 and beta1) were expressed significantly less than in adult tissues (P<0.05). Only 26% of fetal cerebral cortex samples expressed TR beta 1. There is evidence that the developing fetal brain, as early as the first trimester, expresses TRs and exhibits the mechanisms of pre-receptor control of thyroid hormone supply. 相似文献
992.
Chris J. Corrigan 《Treatments in respiratory medicine》2002,1(1):47-54
Asthma is orchestrated by cytokine products of activated T cells. Glucocorticoids are thought to ameliorate asthma at least partly through T cell inhibition. Consequently, other T cell immunomodulatory agents have been assessed for asthma therapy. Since these agents may have serious unwanted effects, attention has been focused on patients with severe asthma refractory to maximal topical, and additional systemic glucocorticoid therapy.Although gold salts show a modest but significant glucocorticoid-sparing effect in severe asthma, lung function is not improved and not all patients respond. The minimum duration of a valid trial of therapy is probably 6 months. Unwanted effects include dermatitis, hepatic dysfunction, proteinuria and interstitial pneumonitis.Meta-analysis of trials of methotrexate in oral glucocorticoid-dependent asthma have confirmed that concomitant weekly methotrexate for a minimum of 3 to 6 months enables significant (approximately 20%) overall reduction in oral glucocorticoid requirements, although only approximately 60% of patients show a significant response. There is little effect on lung function. Blood count and liver function must be monitored. Opportunistic infection is rare but potentially fatal.Cyclosporine, administered for at least 3 months, is effective in only a proportion of patients with oral glucocorticoid-dependent asthma, where it may improve disease severity and/or enable oral glucocorticoid dosage reductions. Regular monitoring of renal function, blood pressure and blood concentrations of cyclosporine is required.The evidence that intravenous immunoglobulin (Ig) is of any benefit in patients with glucocorticoid-dependent asthma is at present equivocal. The therapy is expensive and associated with a high incidence of unwanted effects (fever, aseptic meningitis, urticaria).The macrolides tacrolimus (FK506) and sirolimus (rapamycin) have end effects similar to those of cyclosporine. Brequinar sodium, mycophenolate mofetil and leflunomide are inhibitors of de novo synthesis of pyrimidines and purines, to which T cells are particularly sensitive. Such drugs may in theory be beneficial for therapy of patients with oral glucocorticoid-dependent asthma. Humanized anti-CD4, anti-IgE and anti-interleukin (IL)-5 monoclonal antibodies, and other cytokine inhibitors such as soluble IL-4 receptor have entered early trials.The worth of current immunomodulatory drugs is limited since: (i) not all patients respond, and response cannot be predicted a priori; (ii) the high incidence of unwanted effects makes it difficult to assess overall benefit/risk ratios; (iii) there is increased risk of opportunistic infection and (theoretically) neoplasia; (iv) there are many relative and absolute contraindications to therapy; and (v) there is lack of knowledge about the long-term effects, beneficial or otherwise, of therapy. 相似文献
993.
Wahab PJ Meijer JW Dumitra D Goerres MS Mulder CJ 《Romanian journal of gastroenterology》2002,11(2):121-127
A continuing flow of new scientific developments concerning coeliac disease in the last decade asks for the formulation of a new concept of pathophysiology and clinical approach of the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6. Immunological research has led to the concept of a T-cell driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies, and in addition the understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs and the disease may present with less severe symptoms of malabsorption while screening studies suggest an overall prevalence of up to 1 in 200-300. In the present paper (an update on histopathology) we specifically describe the work of our group in Arnhem, concerning the identification and validation of the spectrum of intestinal histopathology in gluten sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypthyperplasia (Marsh II lesion), and villous atrophy, subdivided in partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of "refractory coeliacs", including the identification of (pre-) malignant aberrant T-cells in the intestinal mucosa of these patients. The new data on immunogenetics, epidemiology, histo-pathology and patient characteristics point to a significant change of views on coeliac disease. 相似文献
994.
Carlier SG de Korte CL Brusseau E Schaar JA Serruys PW van der Steen AF 《Journal of cardiovascular risk》2002,9(5):237-245
Intravascular ultrasound elastography is a method for measuring the local elastic properties of coronary atherosclerotic plaques using intravascular ultrasound (IVUS). Mechanical properties of the different tissues within a plaque are measured through strain. In the last decade, several groups have applied elastography intravascularly with various levels of success. In this paper, the approaches of the different research groups will be discussed and the focus will be on our approach to the application of intravascular elastography. 相似文献
995.
Risha PG Shewiyo D Msami A Masuki G Vergote G Vervaet C Remon JP 《Tropical medicine & international health : TM & IH》2002,7(8):701-707
We evaluated the in vitro availability and its stability under simulated tropical conditions of various formulations of four essential drugs marketed in Tanzania. We obtained 22 formulations (containing paracetamol, acetylsalicylic acid, chloroquine or sulphadoxine/pyrimethamine) from wholesale pharmacies in Dar es Salaam and the Medical Stores Department (Tanzania). The drug content, in vitro availability (dissolution) and its stability under simulated tropical conditions were determined using methods specified in the United States Pharmacopoeia (USP) 24 monograph of the respective drugs. All formulations passed the pharmacopoeia requirements for the drug content. However, seven formulations (three acetylsalicylic acid, two sulphadoxine/pyrimethamine and two paracetamol) failed to meet the USP 24 tolerance limits for dissolution. Another five formulations (three paracetamol and two chloroquine) failed to meet the dissolution tolerance limits after being subjected to an accelerated stability test under simulated tropical conditions (75% RH/40 degrees C) for 6 months. The study has demonstrated the presence on the Tanzanian market of essential drug formulations that met potency requirements and yet had unsatisfactory in vitro availability as they were not robust enough to withstand storage under simulated tropical conditions. 相似文献
996.
Abnormal stimulus-response intensity functions in posttraumatic stress disorder: an electrophysiological investigation 总被引:3,自引:0,他引:3
Lewine JD Thoma RJ Provencal SL Edgar C Miller GA Canive JM 《The American journal of psychiatry》2002,159(10):1689-1695
OBJECTIVE: The purpose of this study was to explore the relationship between combat-related posttraumatic stress disorder (PTSD) and specific augmentation versus reduction patterns for the N100 and P200 components of auditory event-related potentials evoked by tones of increasing intensity. METHOD: Event-related potentials of subjects with PTSD (N=36), subjects with no psychopathology (N=20), subjects with major depression but no PTSD (N=10), and subjects with a history of chronic alcohol abuse but no PTSD (N=8) were recorded. Brain responses were evoked by a 2000-Hz tone presented in intensity blocks of 65, 72.5, 80, 87.5, and 95 dB (SPL). RESULTS: Evoked data from five PTSD subjects were of poor quality and excluded from further analyses. For all but one subject with no psychopathology and for all subjects with a history of alcohol abuse or major depression (but no PTSD), the Cz amplitude of the P200 response component showed augmentation as a nearly linear function of tone intensity. As a group, subjects with PTSD showed no such increase in P200 response magnitude. Examination of the data from individual subjects with PTSD showed that 42% exhibited augmentation patterns similar to those seen for subjects in the comparison groups. However, 58% showed evidence of P200 reduction, with the response to the loudest tone being smaller than responses to tones of intermediate intensity. CONCLUSIONS: The data suggest that there is a significant subgroup of patients with combat-related PTSD who enter into a state of protective inhibition at relatively low stimulus intensities. It is hypothesized that this is an appropriate adaptive mechanism for these subjects rather than an indication of a core neurobiological abnormality. 相似文献
997.
Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke 总被引:8,自引:0,他引:8
Alpha-synuclein is a brain presynaptic protein that is linked to familiar early onset Parkinson's disease and it is also a major component of Lewy bodies in sporadic Parkinson's disease and other neurodegenerative disorders. Alpha-synuclein expression increases in substantia nigra of both MPTP-treated rodents and non-human primates, used as animal models of parkinsonism. Here we describe an increase in alpha-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 microM MPP+, the active metabolite of MPTP, which induces apoptosis in SH-SY5Y cells after a 4-day treatment. We also analysed the activation of the MAPK family, which is involved in several cellular responses to toxins and stressing conditions. Parallel to the increase in alpha-synuclein expression we observed activation of MEK1,2 and ERK/MAPK but not of SAPK/JNK or p38 kinase. The inhibition of the ERK/MAPK pathway with U0126, however, did not affect the increase in alpha-synuclein. The highest increase in alpha-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 microM). Inhibition of ERK/MAPK reduced the damage caused by MPP+. We suggest that alpha-synuclein increase and ERK/MAPK activation have a prominent role in the cell mechanisms of rescue and damage, respectively, after MPP+ -treatment. 相似文献
998.
999.
Amino acids regulate the intracellular trafficking of the general amino acid permease of Saccharomycescerevisiae 下载免费PDF全文
Chen EJ Kaiser CA 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(23):14837-14842
The delivery to the plasma membrane of the general amino acid permease, Gap1p, of Saccharomyces cerevisiae is regulated by the quality of the nitrogen source in the growth medium. In an effort to define how different nitrogen sources control Gap1p sorting, we find that mutations in GDH1 and GLN1 that decrease the flux through the glutamate and glutamine synthesis pathways result in increased Gap1p sorting to the plasma membrane. Conversely, deletion of MKS1, which increases glutamate and glutamine synthesis, decreases Gap1p sorting to the plasma membrane. Glutamate and glutamine are not unusual in their ability to regulate Gap1p sorting, because the addition of all natural amino acids and many amino acid analogs to the growth medium results in increased Gap1p sorting to the vacuole. Importantly, amino acids have the capacity to signal Gap1p sorting to the vacuole regardless of whether they can be used as a source of nitrogen. Finally, we show that rapamycin does not affect Gap1p sorting, indicating that Gap1p sorting is not directly influenced by the TOR pathway. Together, these data show that amino acids are a signal for sorting Gap1p to the vacuole and imply that the nitrogen-regulated Gap1p sorting machinery responds to amino acid-like compounds rather than to the overall nutritional status associated with growth on a particular nitrogen source. 相似文献
1000.
Chiu CH Amemiya C Dewar K Kim CB Ruddle FH Wagner GP 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(8):5492-5497
The duplication of Hox clusters and their maintenance in a lineage has a prominent but little understood role in chordate evolution. Here we examined how Hox cluster duplication may influence changes in cluster architecture and patterns of noncoding sequence evolution. We sequenced the entire duplicated HoxAa and HoxAb clusters of zebrafish (Danio rerio) and extended the 5' (posterior) part of the HoxM (HoxA-like) cluster of horn shark (Heterodontus francisci) containing the hoxa11 and hoxa13 orthologs as well as intergenic and flanking noncoding sequences. The duplicated HoxA clusters in zebrafish each house considerably fewer genes and are dramatically shorter than the single HoxA clusters of human and horn shark. We compared the intergenic sequences of the HoxA clusters of human, horn shark, zebrafish (Aa, Ab), and striped bass and found extensive conservation of noncoding sequence motifs, i.e., phylogenetic footprints, between the human and horn shark, representing two of the three gnathostome lineages. These are putative cis-regulatory elements that may play a role in the regulation of the ancestral HoxA cluster. In contrast, homologous regions of the duplicated HoxAa and HoxAb clusters of zebrafish and the HoxA cluster of striped bass revealed a striking loss of conservation of these putative cis-regulatory sequences in the 3' (anterior) segment of the cluster, where zebrafish only retains single representatives of group 1, 3, 4, and 5 (HoxAa) and group 2 (HoxAb) genes and in the 5' part of the clusters, where zebrafish retains two copies of the group 13, 11, and 9 genes, i.e., AbdB-like genes. In analyzing patterns of cis-sequence evolution in the 5' part of the clusters, we explicitly looked for evidence of complementary loss of conserved noncoding sequences, as predicted by the duplication-degeneration-complementation model in which genetic redundancy after gene duplication is resolved because of the fixation of complementary degenerative mutations. Our data did not yield evidence supporting this prediction. We conclude that changes in the pattern of cis-sequence conservation after Hox cluster duplication are more consistent with being the outcome of adaptive modification rather than passive mechanisms that erode redundancy created by the duplication event. These results support the view that genome duplications may provide a mechanism whereby master control genes undergo radical modifications conducive to major alterations in body plan. Such genomic revolutions may contribute significantly to the evolutionary process. 相似文献