全文获取类型
收费全文 | 12140篇 |
免费 | 763篇 |
国内免费 | 60篇 |
学科分类
医药卫生 | 12963篇 |
出版年
2024年 | 8篇 |
2023年 | 57篇 |
2022年 | 117篇 |
2021年 | 228篇 |
2020年 | 171篇 |
2019年 | 242篇 |
2018年 | 279篇 |
2017年 | 236篇 |
2016年 | 301篇 |
2015年 | 360篇 |
2014年 | 462篇 |
2013年 | 606篇 |
2012年 | 983篇 |
2011年 | 952篇 |
2010年 | 647篇 |
2009年 | 551篇 |
2008年 | 889篇 |
2007年 | 956篇 |
2006年 | 901篇 |
2005年 | 869篇 |
2004年 | 741篇 |
2003年 | 648篇 |
2002年 | 664篇 |
2001年 | 117篇 |
2000年 | 73篇 |
1999年 | 116篇 |
1998年 | 103篇 |
1997年 | 106篇 |
1996年 | 71篇 |
1995年 | 66篇 |
1994年 | 42篇 |
1993年 | 60篇 |
1992年 | 21篇 |
1991年 | 34篇 |
1990年 | 18篇 |
1989年 | 24篇 |
1988年 | 16篇 |
1987年 | 20篇 |
1986年 | 19篇 |
1985年 | 15篇 |
1984年 | 17篇 |
1983年 | 14篇 |
1982年 | 18篇 |
1981年 | 15篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1976年 | 7篇 |
1975年 | 7篇 |
1974年 | 6篇 |
1970年 | 8篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
81.
Da Costa CU Wantia N Kirschning CJ Busch DH Rodriguez N Wagner H Miethke T 《European journal of immunology》2004,34(10):2874-2884
Heat shock protein 60 (HSP60) from Chlamydia pneumoniae was described to trigger in vitro inflammatory and cytokine responses including TNF and IL-12p40. Although it can be found in atherosclerotic plaques of patients, the stimulatory potential of chlamydial and other HSP60 in vivo is unclear. We now report that chlamydial HSP60 fails to induce TNF expression in vivo, and significant serum levels of IL-12p40 are only found upon intraperitoneal injection of high doses of HSP60 or after intravenous application. Upon purification of chlamydial HSP60 with polymyxin B-agarose columns, its ability to induce TNF secretion in vitro is much reduced. However, purified chlamydial HSP60 causes increased serum levels of the CXC chemokines KC and MIP2 in vivo, as well as a strong accumulation of polymorphonuclear neutrophils (PMN) in the peritoneal cavity upon intraperitoneal challenge. With respect to PMN accumulation, chlamydial HSP60 is more potent than endotoxin or the CpG oligonucleotide 1668. The responses observed are completely abolished in Toll-like receptor (TLR)2/4-double-deficient mice, while single-deficient mice respond almost normally. Furthermore, KC induction and PMN accumulation are largely dependent on MyD88. In conclusion, HSP60 from C. pneumoniae triggers inflammatory responses in vivo that differ from responses induced by endotoxin or CpG oligonucleotides and are dependent on TLR2 and 4. 相似文献
82.
The probability of synaptic transmitter release determines the spread of excitation and the possible range of computations at unitary connections. To investigate whether synaptic properties between neocortical pyramidal neurons change during the assembly period of cortical circuits, whole-cell voltage recordings were made simultaneously from two layer 5A (L5A) pyramidal neurons within the cortical columns of rat barrel cortex. We found that synaptic transmission between L5A pyramidal neurons is very reliable between 2 and 3 weeks of postnatal development with a mean unitary EPSP amplitude of ∼1.2 mV, but becomes less efficient and fails more frequently in the more mature cortex of ∼4 weeks of age with a mean unitary EPSP amplitude of 0.65 mV. Coefficient of variation and failure rate increase as the unitary EPSP amplitude decreases during development. The paired-pulse ratio (PPR) of synaptic efficacy at 10 Hz changes from 0.7 to 1.04. Despite the overall increase in PPR, short-term plasticity displays a large variability at 4 weeks, ranging from strong depression to strong facilitation (PPR, range 0.6–2.1), suggesting the potential for use-dependent modifications at this intracortical synapse. In conclusion, the transmitter release probability at the L5A–L5A connection is developmentally regulated in such a way that in juvenile animals excitation by single action potentials is efficiently transmitted, whereas in the more mature cortex synapses might be endowed with a diversity of filtering characteristics. 相似文献
83.
Jurjen Schirm Dirk S. Luijt Geke W. Pastoor Johan M. Mandema F. Peter Schrder 《Journal of medical virology》1992,38(2):147-151
Eleven hundred and thirty-three clinical specimens submitted to the laboratory for diagnosis of respiratory virus infections were tested by direct immunofluorescence (DIF) for respiratory syncytial virus (RSV), by shell vial culture, and by conventional cell culture. The shell vial cultures were stained with 8 different monoclonal antibodies both 1 day and 3-7 days after inoculation. In order to limit the cost and the workload, mixtures of monoclonal antibodies were used. Coverslips with HEp-2 cells were incubated with a mixture of FITC-labeled monoclonal antibody to RSV and nonlabeled monoclonal antibody to adenovirus. When no RSV positive IF staining was observed after the first incubation step, the same coverslip was incubated once more with FITC-labeled anti-mouse antibody. A positive reaction at this stage indicated the presence of adenovirus. Similarly, cultures of tertiary monkey kidney cells were investigated with a mixture of two FITC-labeled monoclonals to the influenza viruses A and B and three nonlabeled monoclonals to the parainfluenza viruses 1, 2 and 3. If influenza virus or parainfluenza virus was detected, the exact type was determined by staining different parts of a duplicate coverslip. Shell vial cultures for cytomegalovirus (CMV) were always performed separately on human embryonic lung fibroblasts. Using this approach, we detected RSV (n = 248), CMV (n = 42), parainfluenza virus (n = 31), influenza virus (n = 28), and adenovirus (n = 6), in most cases after only one day of culture. For RSV, the sensitivity of the shell vial method was too low (74%) to allow omission of DIF (sensitivity 95%).(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
84.
Eva-Bettina Brcker Ludwig Suter Josef Brüggen Dirk J. Ruiter Egon Macher Clemens Sorg 《International journal of cancer. Journal international du cancer》1985,36(1):29-35
The phenotypic changes in human melanoma cells during the course of tumor progression were studied with monoclonal antibodies (MAbs) against the melanoma-associated antigens (MAA) M.2.2.4, H.2.8.10, K.1.2, A.1.43, and A.10.33, and HLA-(A,B,C and D). Cryostat sections of 172 primary melanomas of the skin, 157 melanoma metastases and 56 nevi were investigated with an indirect immunoperoxidase method. Phenotypic heterogeneity was observed within lesions at all stages, and also within different tumors of the same patients. Despite this heterogeneity, principles of antigen expression were found. From the reaction pattern of MAbs, the following classifications of antigens were derived: "constitutive" markers of nevomelanocytic cells (M.2.2.4 and H.2.8.10) were found expressed over a wide range of local and systemic tumors. One MAA, K.1.2 (Suter et al., 1985), that declines with progression of melanoma, was classified as an "early" antigen, whereas MAA that appear in primary melanoma in proportion to invasiveness, and which are expressed in metastases of lymph nodes and visceral organs (A.1.43, and A.10.33), were classified as "late" markers of tumor progression. HLA-antigens were classified as "intermediate" markers, HLA-A,B,C, as an "early-intermediate", and HLA-DR as a "late-intermediate" marker. The occurrence of class II HLA, A.1.43-, and A.10.33-positive tumor cells in primary melanoma indicates a high metastatic potential of tumors, independent of tumor thickness. The data show that local and systemic progression of melanoma is associated with qualitative changes in tumor cells which can be recognized by MAbs. 相似文献
85.
Dirk Martens Martin J. Lohse Bernhard Rauch Ulrich Schwabe 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(3):342-348
Summary The aim of the present study was the characterization of adenosine receptors in isolated rat ventricular myocytes. The CAMP-levels of rat ventricular myocytes in the presence of 1 mol/l isoprenaline were reduced by up to 48% by adenosine analogues; the rank order of potency was: R-N6-phenylisopropyladenosine (IC50 60 nmol/1), 5-N-ethylcarboxamidoadenosine (IC50 360 nmol/l) and S-N6-phenylisopropyladenosine (IC50 16 ol/l). The adenosine receptor antagonist XAC (xanthine amine congener) antagonized the effect of R-N6-phenylisopropyladenosine in a concentration-dependent manner with a Ki-value of 20 nmol/l. The A1 receptor-selective radioligand R-N6-125I-p-hydroxyphenylisopropyladenosine bound to membranes prepared from rat ventricular myocytes in a saturable manner with a B
max of 17.7 fmol/mg protein and a K
D-value of 1.1 nmol/l. Adenosine analogues competed for the binding with the same rank order of potency as for the inhibition of the isoprenaline-induced cAMP-increase. GTP inhibited radioligand binding with an IC50-value of 73 ol/l. These results suggest the presence of A1 adenosine receptors on rat ventricular myocytes, which mediate an inhibition of adenylate cyclase. The receptors may be responsible for the effects of adenosine and its analogues on the heart.Abbreviations
125I-HPIA
R-N6-125I-p-hydroxyphenylisopropyladenosine
- PIA
N6-phenylisopropyladenosine
- NECA
5-N-ethyl-carboxamidoadenosine
- XAC
8-4-[([(2-aminoethyl)aminocarbonyl]methyl)oxy]phenyl-1,3-dipropylxanthine (xanthine amine congener)
- Ro 20-1724
4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone
- ScAMPTME
2-O-monosuccinyladenosine-3,5-cyclic monophosphate tyrosyl methyl ester
- HEPES
N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid
- GTP
guanosine-5-tri-phosphate
Send offprint requests to D. Martens 相似文献
86.
The liver is a major site for synthesis and catabolism of plasma proteins. Albumin has various binding sites for anionic drugs,
1acid glycoprotein possesses a single binding site for cationic drugs. In spite of extensive protein binding, the liver can efficiently remove drags from the circulation. Intrahepatic dissociation of the drag-protein complex may involve dissociation-limited debinding under non-equilibrium conditions or surface interaction-facilitated dissociation phenomena. During liver or renal disease and acute-phase conditions plasma protein binding of drugs may be affected. Changes in the unbound drag fraction do not always result in proportional changes in clearance or distribution volume. Potential changes in the unbound concentration in steady-state as well as the fluctuations in total plasma levels depend on the extent of protein binding of a drug, the relative change in the unbound drug fraction, type of clearance, the size of the distribution volume, route of administration as well as concomitant changes in intrinsic (cellular) clearance function. Optimization of dosage regimens for certain drags and interpretation of liver function tests with diagnostic dyes may largely benefit from determination of the unbound rather than the total concentration of the drags involved.Part of this work was supported by Grant 900-521-078 from MEDICON, which is subsidized by The Netherlands' Organization of Pure Research. 相似文献
87.
Carlos R Ferreira Kristina Kintzinger Mary E Hackbarth Ulrike Botschen Yvonne Nitschke M Zulf Mughal Genevieve Baujat Dirk Schnabel Eric Yuen William A Gahl Rachel I Gafni Qing Liu Pedro Huertas Gus Khursigara Frank Rutsch 《Journal of bone and mineral research》2021,36(11):2193-2202
Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA. 相似文献
88.
Rachel Wuerstlein Nadia Harbeck Eva-Maria Grischke Dirk Forstmeyer Raquel von Schumann Petra Krabisch Kerstin Lüdtke-Heckenkamp Andrea Stefek Oliver Stoetzer Andrea Grafe Gabriele Kaltenecker Helmut Forstbauer Doris Augustin Iris Schrader Joke Tio Ulrike Nitz Oleg Gluz Ronald E. Kates Monika Karla Graeser 《Breast care (Basel, Switzerland)》2021,16(1):50
BackgroundProtroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).Patients and MethodsOf the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.ResultsNine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.ConclusionsApplication of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer. 相似文献
89.
Oehler MK Greschik H Fischer DC Tong X Schuele R Kieback DG 《Molecular human reproduction》2004,10(12):853-860
Endometriosis and adenomyosis uteri are chronic, benign diseases caused by the presence of endometrial tissue in ectopic locations, e.g. peritoneal or deep inside the myometrial wall of the uterus and/or in the rectovaginal septum. Although adenomyosis might be considered as a special form of endometriosis, both conditions differ with respect to clinical symptoms and treatment. Induction of a hypo-estrogenic state alone or in combination with surgical removal of the extra-uterine lesion is mostly sufficient for treatment of peritoneal endometriosis. By contrast, adenomyosis uteri rarely responds to hormonal therapy and usually requires a hysterectomy for cure. Consequently, the role of steroid hormone receptors with respect to the aetiology of either condition is still a matter of discussion. Using PCR/single strand conformation polymorphism analysis, we identified somatic estrogen receptor (ER) alpha gene mutations in three out of 55 samples from adenomyosis uteri. Functional characterization revealed that two of the mutant ERalpha proteins display severely impaired DNA-binding and transactivation properties secondary to an altered response to estrogens or changes in epidermal growth factor-mediated ligand-independent activation. Although the exact mechanism remains unknown, we suggest that mutation-related silencing of estrogen responsiveness might render endometriotic cells resistant to hypo-estrogenic conditions thereby accounting for failure of estrogen-ablative therapy in adenomyosis. 相似文献
90.
During preparation of cells for experimentation a considerable amount of bound substance is lost. Our aim was to develop a protocol which retained lectin binding to an extent similar to living cells. This procedure would use fixation procedures suited for fluorescent lectin conjugates and gold-conjugates to be visualized by light- and electron microscopy, respectively. We tested glutaraldehyde and paraformaldehyde in different concentrations before and after lectin binding, different buffers and divalent cations, as additives, to determine the effects on preservation of lectin binding. Lectin binding was visualized and semiquantitatively evaluated by image analysis in the light microscope after silver enhancement of lectin-gold conjugates and by using tetramethyl rhodaminyl isothiocyanate (TRITC)-conjugated lectins. Preservation of lectin binding was best visualized with fluorescent lectin conjugates, whereas during silver enhancement procedures of gold-conjugated lectins, a considerable amount of bound lectins was lost. In general, lectin binding to living cells followed by fixation is superior to fixation before lectin binding. Unfavourable combinations of fixatives and buffers can cause a loss of more than 90% bound lectin. In our experiments with freshly isolated guinea pig cardiomyocytes, lectin binding was best when we used Na-cacodylate buffer with glutaraldehyde fixation (0.1%) after binding of lectins to the living cells. 相似文献