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51.
Intra- and extracellular amyloid fibrils are formed in cultured pancreatic islets of transgenic mice expressing human islet amyloid polypeptide. 总被引:4,自引:1,他引:4 下载免费PDF全文
E J de Koning E R Morris F M Hofhuis G Posthuma J W H?ppener J F Morris P J Capel A Clark J S Verbeek 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(18):8467-8471
Islet amyloid polypeptide (IAPP) is the constituent peptide of amyloid deposits found in the islets of non-insulin-dependent diabetic patients. Formation of islet amyloid is associated with a progressive destruction of insulin-producing beta cells. Factors responsible for the conversion of IAPP into insoluble amyloid fibrils are unknown. Both the amino acid sequence of human IAPP (hIAPP) and hypersecretion of hIAPP have been implicated as factors for amyloid fibril formation in man. We have generated transgenic mice using rat insulin promoter-hIAPP or rat IAPP (rIAPP) gene constructs. No fibrillar islet amyloid was detectable in vivo in these normoglycemic mice, although small amorphous perivascular accumulations of IAPP were observed in hIAPP mice only. To determine the effects of glucose on IAPP secretion and fibrillogenesis, pancreatic islets from transgenic and control mice were examined in vitro. Islet IAPP secretion and content were increased in transgenic islets compared with control islets. IAPP-immunoreactive fibrils were formed at both intra- and extracellular sites in isolated hIAPP islets cultured with glucose at 11.1 and 28 mM for only 7 days. At 28 mM glucose, fibrils were present in deep invaginations of beta cells as observed in non-insulin-dependent diabetic patients. No fibrils were present at low glucose concentrations in hIAPP islets or at any glucose concentration in rIAPP or control islets. Thus, glucose-induced expression and secretion of hIAPP in transgenic mouse islets can lead to formation of amyloid fibrils similar to that found in non-insulin-dependent diabetes mellitus. 相似文献
52.
Serruys PW García-García HM Buszman P Erne P Verheye S Aschermann M Duckers H Bleie O Dudek D Bøtker HE von Birgelen C D'Amico D Hutchinson T Zambanini A Mastik F van Es GA van der Steen AF Vince DG Ganz P Hamm CW Wijns W Zalewski A;Integrated Biomarker Imaging Study- Investigators 《Circulation》2008,118(11):1172-1182
53.
Koning FA Jansen CA Dekker J Kaslow RA Dukers N van Baarle D Prins M Schuitemaker H 《AIDS (London, England)》2004,18(8):1117-1126
OBJECTIVE: To investigate possible correlates of HIV resistance in participants from the Amsterdam Cohort of Homosexual men who have remained HIV seronegative despite high-risk sexual behaviour. DESIGN/METHODS: We studied in vitro HIV-1 susceptibility and adaptive and innate immunity in 29 high-risk seronegative (HRSN) and 15 HIV-negative pre-seroconversion (pre-SC) homosexual men from the same Amsterdam Cohort Study (ACS) who seroconverted to HIV-1 positive during active follow-up. Host genetics were compared between HRSN and HIV-positive ACS participants. RESULTS: We found lower in vitro susceptibility for a CCR5-using (R5) HIV-1 variant, higher RANTES production levels, but no difference in coreceptor expression in HRSN as compared with pre-SC controls. Reduced R5 in vitro susceptibility of two HRSN tested was restored to normal levels by addition of antibodies against beta-chemokines. A higher proportion of HRSN carried the SDF-1 3'A variant and HLA-A*11, A*31 and Cw*15 alleles. ELIspot analysis with HIV-1 peptide stimulation revealed low frequencies of HIV-1-specific CD8 interferon-gamma producing cytotoxic T cells in both HRSN and pre-SC controls. CONCLUSIONS: Low in vitro R5 susceptibility of cells from the HRSN men was due to beta-chemokine mediated inhibition of virus replication. The presence of HIV-1 specific cytotoxic T cells in both HRSN and pre-SC participants may signify exposure to the virus rather than protection from infection. Host genetic characteristics and other factors affecting innate immunity may contribute to differential resistance to HIV-1 infection among exposed seronegative individuals. 相似文献
54.
Zeba N. Singh Yogesh Jethava Ginell R. Post Daisy Alapat Jeffrey Sawyer Sarah Waheed Bijay Nair Saad Z. Usmani Clyde Bailey Nathan Petty Frits Van Rhee Bart Barlogie 《Clinical Case Reports》2015,3(3):183-192
Assiduous surveillance for genetic aberrations is necessary in patients on cytotoxic therapies to detect therapy‐related myeloid neoplasms (t‐MN). Current modalities include metaphase cytogenetics and FISH. Since t‐MN may develop abruptly in cytogenetically normal patients, a discussion exploring additional methods such as SNP‐array and targeted‐deep‐sequencing to detect subchromosomal abnormalities is needed. 相似文献
55.
Gijs Kooij Kathrin Kopplin Rosel Blasig Marchel Stuiver Nathalie Koning Gera Goverse Susanne M. A. van der Pol Bert van het Hof Maik Gollasch Joost A. R. Drexhage Arie Reijerkerk Iwan C. Meij Reina Mebius Thomas E. Willnow Dominik Müller Ingolf E. Blasig Helga E. de Vries 《Acta neuropathologica》2014,128(2):267-277
Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood–cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity. 相似文献
56.
Vrieze A Van Nood E Holleman F Salojärvi J Kootte RS Bartelsman JF Dallinga-Thie GM Ackermans MT Serlie MJ Oozeer R Derrien M Druesne A Van Hylckama Vlieg JE Bloks VW Groen AK Heilig HG Zoetendal EG Stroes ES de Vos WM Hoekstra JB Nieuwdorp M 《Gastroenterology》2012,143(4):913-916.e7
Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 μmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776). 相似文献
57.
BackgroundFamily history may help in risk stratification, especially in the young. This study assesses the predictive value of a positive family history of cardiovascular disease for myocardial infarction (MI) and ischemic stroke (IS).Methods/ResultsThe RATIO study case–control study includes women with MI (N = 248), IS (N = 203) and 925 healthy matched controls. Odds ratios (ORs) and 95% confidence intervals (95%CI) were calculated with logistic regression. The risk of MI was almost fourfold increased in women with a family history positive for MI (OR 3.70, 95%CI 2.68–5.10), whereas the risk of IS was, if anything, only slightly elevated (1.25, 0.83–1.87). A family history of stroke (ischemic and hemorrhagic) was associated with a twofold increase in MI risk (2.00, 1.29–3.12), whereas the IS risk was again not clearly associated (1.37, 0.79–2.40).ConclusionsThe predictive value of a family history for cardiovascular disease differs between MI and IS. 相似文献
58.
C Beyrer SD Baral F van Griensven SM Goodreau S Chariyalertsak AL Wirtz R Brookmeyer 《Lancet》2012,380(9839):367-377
Epidemics of HIV in men who have sex with men (MSM) continue to expand in most countries. We sought to understand the epidemiological drivers of the global epidemic in MSM and why it continues unabated. We did a comprehensive review of available data for HIV prevalence, incidence, risk factors, and the molecular epidemiology of HIV in MSM from 2007 to 2011, and modelled the dynamics of HIV transmission with an agent-based simulation. Our findings show that the high probability of transmission per act through receptive anal intercourse has a central role in explaining the disproportionate disease burden in MSM. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiological data show substantial clustering of HIV infections in MSM networks, and higher rates of dual-variant and multiple-variant HIV infection in MSM than in heterosexual people in the same populations. Prevention strategies that lower biological transmission and acquisition risks, such as approaches based on antiretrovirals, offer promise for controlling the expanding epidemic in MSM, but their potential effectiveness is limited by structural factors that contribute to low health-seeking behaviours in populations of MSM in many parts of the world. 相似文献
59.
Visser G de Jager W Verhagen LP Smit GP Wijburg FA Prakken BJ Coffer PJ Buitenhuis M 《Journal of inherited metabolic disease》2012,35(2):287-300
Glycogen storage disease type 1b (GSD 1b) is caused by mutations in the Glucose-6-phosphate transporter and is characterized
by impaired glucose homeostasis. In addition, GSD-1b is associated with chronic neutropenia resulting in recurrent infections
and inflammatory bowel disease. It is unclear whether the neutropenia is solely due to enhanced apoptosis of mature neutrophils
or whether aberrant neutrophil development may also contribute. Here we demonstrate that hematopoietic progenitors from GSD-1b
patients are not impaired in their capacity to develop into mature neutrophils. However, optimal survival of neutrophil progenitors
from GSD-1b patients requires high glucose levels (> 200 mg dl−1), suggesting that even under normoglycemic conditions these cells are more prone to apoptosis. Furthermore, analysis of cytokine
levels in peripheral blood suggests an inflammatory state with an inverse correlation between the level of inflammation and
the number of neutrophils. Finally, in some patients, with low numbers of peripheral blood neutrophils, high numbers of neutrophils
were observed in the intestine. Together, these results suggest that the neutropenia observed in GSD-1b patients is not caused
by impaired maturation, but may be caused by both increased levels of apoptosis and egress of neutrophils from the blood to
the inflamed tissues. 相似文献
60.
Andersson HM Siegerink B Luken BM Crawley JT Algra A Lane DA Rosendaal FR 《Blood》2012,119(6):1555-1560
VWF and ADAMTS13 are major determinants of platelet adhesion after vessel injury. In the present study, we aimed to determine whether VWF or ADAMTS13 plasma antigen levels influence the risks of ischemic stroke (IS) or myocardial infarction (MI) in young women and how these risks are affected by oral contraceptive (OC) use. VWF and ADAMTS13 plasma antigen levels were measured in a frequency-matched case-control study of 1018 young (18-49 years) women including 175 IS patients and 205 MI patients. Increasing levels of VWF and decreasing levels of ADAMTS13 were associated with the risk of IS and MI in a dose-dependent manner. Having both high VWF and low ADAMTS13 resulted in an odds ratio (OR) of 6.9 (95% confidence interval [95% CI], 2.0-23.0) for IS and 11.3 (95% CI, 3.6-35.2) for MI. Use of OCs increased the risk of IS and MI associated with high VWF (OR = 12; 95% CI, 5.5-26.2 and OR = 7.5, 95% CI, 3.6-15.7, respectively) and the risk of IS associated with low ADAMTS13 (OR = 5.8, 95% CI, 2.7-12.4). We conclude that high VWF and low ADAMTS13 plasma levels both increase the risk of IS and MI. The risks associated with high VWF or low ADAMTS13 levels are further increased by the use of OCs. 相似文献