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991.
M J Econs D F Barker M C Speer M A Pericak-Vance P R Fain M K Drezner 《The Journal of clinical endocrinology and metabolism》1992,75(1):201-206
X-linked hypophosphatemic rickets (HYP), the most common form of familial hypophosphatemic (vitamin D-resistant) rickets, is an X-linked dominant disorder characterized by decreased renal tubular phosphate reabsorption and consequent hypophosphatemia. Despite the application of a wide variety of biochemical and cell biology techniques, controversy exists regarding whether a primary renal abnormality underlies the abnormal phosphate transport or if this defect is secondary to the effects of a hormonal/metabolic factor. Thus localization of the HYP gene and its ultimate cloning may be necessary to elucidate the pathophysiology of the disorder. In order to map the human HYP gene we investigated several new polymorphic probes for linkage to HYP and constructed a map of markers around the gene. The database used to ascertain linkage and perform mapping included 5 large HYP kindreds, 40 Centre d'Etudie Polymorphisms Humain reference pedigrees, and 19 kindreds which had been obtained for other disease linkage studies. Two point LOD scores (odds of linkage, log10) indicate that the probes DXS365, DXS257, DXS451, and DXS41 are tightly linked to the HYP locus. Indeed, there were no cross-overs between DXS365 and HYP with a peak LOD score of 13.98 [recombination fraction (theta) = 0.00]. Moreover, multipoint analysis reveals a probable locus order of: Xtel-DXS315-DXS43-DXS257-HYP-DXS41-DXS4 51-Xcen. The likelihood of HYP occurring between DXS257 and DXS41 is 407:1 over the next most likely position. DXS365 is located between DXS41 and DXS43 but could not be located with respect to HYP and DXS257. Regardless, we have located the HYP gene between the flanking markers DXS257 (telomeric) and DXS41 (centromeric) which are 3.5 centiMorgans apart. Thus, the results of this study will facilitate attempts to further localize and eventually clone the gene. 相似文献
992.
Malarial ookinetes express an immunodominant surface protein (P28) that is a priority candidate for the development of transmission-blocking vaccines. The full length P28 gene from Plasmodium berghei [Pbs21(1-213)] and a deletion construct [Pbs21(1-188)] encoding a protein that lacks the 25 C-terminal amino acids, including the glycosylphosphatidylinositol (GPI) anchor signal, were expressed in insect cells using baculovirus vectors. Pbs21(1-213) protein is strongly hydrophobic, found in the cytoplasm and on the surface of Spodoptera Sf21 cells, and in the culture medium. Pbs21(1-188) protein was largely found in the aqueous phase of the medium and in the cytoplasm of Sf21 cells, but was not detected on the cell surface. The presence of 25 C-terminal amino acids is therefore critical to the attachment of recombinant Pbs21 to the parasite plasma membrane. Mice were immunized subcutaneously or intramuscularly with affinity purified recombinant Pbs21(1-213), Pbs21(1-188) or native Pbs21 proteins. Following two immunizations, native Pbs21 induces higher titres when administered by either route, than the recombinant protein bearing an insect GPI anchor, which in turn is markedly more immunogenic than the recombinant polypeptide lacking a GPI anchor. When specific anti Pbs21 antibody titres exceeded 1 mg/ml all three antigens were capable of inducing transmission blockade > or = 90%, below 1 mg/ml blockade did not correlate with antibody concentration. 相似文献
993.
Barker JE Schuldt AJ Lessard ML Jude CD Vogler CA Soper BW 《Experimental hematology》2003,31(11):1112-1118
To block development of progressive childhood diseases, in utero transplantation (IUTx) requires immediate and significant donor peripheral blood (PB) cell amplification. To date, negligible and nontherapeutic donor PB cell levels have been observed postnatally, except in patients with immunodeficiency diseases. Donor cell fate in utero still is not clear. Ease of identifying and quantifying beta-glucuronidase (GUSB)-expressing donor cells in GUSB-null mucopolysaccharidosis type VII (MPSVII) mouse recipients allowed us to evaluate temporal donor cell engraftment and amplification post-IUTx. Like humans, MPSVII mice are unable to catabolize lysosomal glycosaminoglycans and progressively develop severe storage disease unless they are treated early in life.IUTx recipients were nonablated MPSVII fetuses and genetically stem cell-deficient, and hence myeloablated, W(41)/W(41) MPSVII fetuses. Donor GUSB+ cells were identified and counted in histochemical tissue sections. Quantitative results were confirmed by flow cytometry, enzyme analysis, and histopathology.Whereas GUSB+ cells engraft in most tissues in utero, significant amplification does not occur until the first postnatal week in the nonablated MPSVII hosts. In contrast, genetically myeloablated MPSVII recipients display widely distributed donor cell replacement accompanied by extensive amplification in utero. In both models, storage is alleviated in adult tissues with significant donor cell repopulation.To become therapeutic, IUTx must overcome the limitations of donor cell expansion in the highly competitive fetal environment. Fortunately, nonablative mechanisms to amplify cells in utero are coming on line. 相似文献
994.
Late life metabolic syndrome, early growth, and common polymorphism in the growth hormone and placental lactogen gene cluster 总被引:3,自引:0,他引:3
Day IN Chen XH Gaunt TR King TH Voropanov A Ye S Rodriguez S Syddall HE Sayer AA Dennison EM Tabassum F Barker DJ Cooper C Phillips DI 《The Journal of clinical endocrinology and metabolism》2004,89(11):5569-5576
Low rates of fetal and infant growth are associated with the metabolic syndrome and cardiovascular disease in later life. We investigated common genetic variation in the GH-CSH gene cluster on chromosome 17q23 encoding GH, placental lactogens [chorionic somatomammotropins (CSH)], and placental GH variant in relation to fetal and infant growth and phenotypic features of the metabolic syndrome in subjects aged 59-72 yr from Hertfordshire, UK. Allele groups T, D1, and D2 of a locus herein designated CSH1.01 were examined in relation to GH-CSH single nucleotide polymorphisms and to specific phenotypes. Average birth weights were similar for all genotype groups. Men with T alleles were significantly lighter at 1 yr of age, shorter as adults, and had higher blood pressures, fasting insulin (T/T 66% higher than D2/D2) and triglyceride concentrations, and insulin and glucose concentrations during a glucose tolerance test. Birth weight and 1-yr weight associations with metabolic syndrome traits were independent of the CSH1.01 effects. Common diversity in GH-CSH correlates with low 1-yr weight and with features of the metabolic syndrome in later life. GH-CSH genotype adds substantially to, but does not account for, the associations between low body weight, at birth and in infancy, and the metabolic syndrome. 相似文献
995.
Mucinous Cystadenoma: Pitfalls of Differential Diagnosis 总被引:1,自引:0,他引:1
Jonathan R. Sachs M.D. Julius J. Deren M.D. Min Sohn M.D. Moreye Nusbaum M.D. 《The American journal of gastroenterology》1989,84(7):811-816
Cystic neoplasms of the pancreas often are difficult to differentiate from pseudocysts. It has been proposed that a history of clinical pancreatitis, elevated serum pancreatic enzymes, elevated cyst fluid amylase, and a communication with the pancreatic duct suggest the diagnosis of a pseudocyst. We report the case of a young woman who presented with a cystic mass in the pancreas and was thought to have a pseudocyst because of the above; at surgery, a mucinous cystadenoma was documented. The pitfalls of differentiating neoplastic cysts of the pancreas from pseudocysts are discussed. 相似文献
996.
Hsu LC Ali SR McGillivray S Tseng PH Mariathasan S Humke EW Eckmann L Powell JJ Nizet V Dixit VM Karin M 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(22):7803-7808
NOD2, a NOD-like receptor (NLR), is an intracellular sensor of bacterial muramyl dipeptide (MDP) that was suggested to promote secretion of the proinflammatory cytokine IL-1beta. Yet, the molecular mechanism by which NOD2 can stimulate IL-1beta secretion, and its biological significance were heretofore unknown. We found that NOD2 through its N-terminal caspase recruitment domain directly binds and activates caspase-1 to trigger IL-1beta processing and secretion in MDP-stimulated macrophages, whereas the C-terminal leucine-rich repeats of NOD2 prevent caspase-1 activation in nonstimulated cells. MDP challenge induces the association of NOD2 with another NLR protein, NALP1, and gel filtration analysis revealed the formation of a complex consisting of NOD2, NALP1, and caspase-1. Importantly, Bacillus anthracis infection induces IL-1beta secretion in a manner that depended on caspase-1 and NOD2. In vitro, Anthrax lethal toxin strongly potentiated IL-1beta secretion, and that response was NOD2 and caspase-1-dependent. Thus, NOD2 plays a key role in the B. anthracis-induced inflammatory response by being a critical mediator of IL-1beta secretion. 相似文献
997.
J C Cawley G F Burns C P Worman R J Flemans R Sibbald C R Barker B E Roberts 《Scandinavian journal of haematology》1978,21(3):233-242
Morphological and immunological marker data on a patient with 'pure' monocytic leukaemia are presented and compared with those of 6 cases of clearly mixed myelomonocytic leukaemia with a variable monocytic component. In all patients studied, the leukaemic monocytes expressed a receptor for the Fc of IgG, and IgG sensitization markedly enhanced phagocytosis of ox erythrocytes. A variable, but lower, percentage of the leukaemic monocytes had a receptor for mouse C3, but the cells uniformly lacked surface immunoglobulin and receptors for the Fc of IgM and for unsensitised mouse erythrocytes. Cytochemical and ultrastructural study also showed no clear difference between the monocytes of the 'pure' and mixed monocytic leukaemias. This report therefore lends no support to the concept of distinct types of monocytic leukaemia. 相似文献
998.
Tumor trapping of 5-fluorouracil: in vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits. 总被引:1,自引:0,他引:1 下载免费PDF全文
W Wolf C A Presant K L Servis A el-Tahtawy M J Albright P B Barker R Ring rd D Atkinson R Ong M King et al. 《Proceedings of the National Academy of Sciences of the United States of America》1990,87(1):492-496
The pharmacokinetics of 5-fluorouracil (5FU) were studied in vivo in patients with discrete tumors and in rabbits bearing VX2 tumors by using 19F NMR spectroscopy. The human studies were conducted in a 1.5-T Magnetom magnetic resonance imager (Siemens), and the rabbit studies were conducted in a 4.7-T GE/Nicolet 33-cm bore magnet. Free 5FU was detected in the tumors of four of the six patients and in all VX2 tumors but not in normal rabbit tissues. No other metabolites were seen in these tumors, contrary to the extensive catabolism we had previously documented using 19F NMR spectroscopy in both human and animal livers. The tumor pool of free 5FU in those human tumors that trapped 5FU was determined to have a half-life of 0.4-2.1 hr, much longer than expected and significantly longer than the half-life of 5FU in blood (5-15 min), whereas the half-life of trapped 5FU in the VX2 tumors ranged from 1.05 to 1.22 hr. In this initial experience, patient response to chemotherapy may correlate with extent of trapping free 5FU in the human tumors. These studies document that NMR spectroscopy is clinically feasible in vivo, allows noninvasive pharmacokinetic analyses at a drug-target tissue in real time, and may produce therapeutically important information at the time of drug administration. Demonstration of the trapping of 5FU in tumors provides both a model for studying metabolic modulation in experimental tumors (in animals) and a method for testing modulation strategies clinically (in patients). 相似文献
999.
Pam R. Taub Adena Zadourian Hannah C. Lo Cameron K. Ormiston Shahrokh Golshan Jonathan C. Hsu 《Journal of the American College of Cardiology》2021,77(7):861-871
BackgroundPostural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited.ObjectivesThis study investigated the effect of ivabradine (selective blocker of the Ifunny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test.MethodsIn total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month.ResultsThe average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.ConclusionIvabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype. 相似文献
1000.
Robert Clarke Jonathan R Emberson Elizabeth Breeze Juan P Casas Sarah Parish Aroon D Hingorani Astrid Fletcher Rory Collins Liam Smeeth 《European heart journal》2008,29(6):800-809
AIMS: To compare the predictive value of inflammatory biomarkers and lipids for vascular and non-vascular mortality in older men. METHODS AND RESULTS: The relevance of inflammatory biomarkers and lipids for vascular and non-vascular mortality was assessed in a prospective study of 5360 men (mean age 77 years) followed for 7 years. Vascular mortality was positively associated with log C-reactive protein (lnCRP), fibrinogen and total/HDL-C (high-density lipoprotein cholesterol), and inversely associated with albumin [age adjusted hazard ratio (HR) per 2-SD higher usual level (approximately the difference between the top and the bottom thirds of the distribution): 2.09 for lnCRP; 1.70 for fibrinogen; 0.50 for albumin and 1.45 for total/HDL-C]. The associations with the inflammatory markers were attenuated after adjustment for established risk factors, including lipids [adjusted HRs: 1.86 (lnCRP); 1.44 (fibrinogen); 0.51 (albumin)], and further attenuated (and, for fibrinogen, no longer predictive) after adjustment for each other [fully adjusted HRs: 1.60 (lnCRP); 1.01 (fibrinogen); 0.61 (albumin)]. Higher CRP and lower albumin levels were also associated with significantly raised non-vascular mortality independently of other characteristics [fully adjusted HRs: 1.62 (lnCRP); 0.65 (albumin)]. CONCLUSION: In this cohort of older men, higher CRP and lower albumin levels strongly predicted both vascular and non-vascular mortality, independently of other characteristics. 相似文献