全文获取类型
收费全文 | 331篇 |
免费 | 17篇 |
国内免费 | 6篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 13篇 |
妇产科学 | 2篇 |
基础医学 | 58篇 |
口腔科学 | 2篇 |
临床医学 | 27篇 |
内科学 | 60篇 |
皮肤病学 | 26篇 |
神经病学 | 10篇 |
特种医学 | 34篇 |
外科学 | 26篇 |
综合类 | 7篇 |
预防医学 | 20篇 |
眼科学 | 1篇 |
药学 | 20篇 |
中国医学 | 3篇 |
肿瘤学 | 43篇 |
出版年
2022年 | 2篇 |
2019年 | 4篇 |
2017年 | 2篇 |
2016年 | 5篇 |
2015年 | 3篇 |
2014年 | 4篇 |
2013年 | 10篇 |
2012年 | 11篇 |
2011年 | 19篇 |
2010年 | 14篇 |
2009年 | 8篇 |
2008年 | 15篇 |
2007年 | 10篇 |
2006年 | 10篇 |
2005年 | 14篇 |
2004年 | 16篇 |
2003年 | 12篇 |
2002年 | 12篇 |
2001年 | 6篇 |
2000年 | 8篇 |
1999年 | 15篇 |
1998年 | 16篇 |
1997年 | 19篇 |
1996年 | 3篇 |
1995年 | 9篇 |
1994年 | 2篇 |
1993年 | 7篇 |
1992年 | 2篇 |
1991年 | 6篇 |
1990年 | 13篇 |
1989年 | 10篇 |
1988年 | 5篇 |
1987年 | 7篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1969年 | 4篇 |
1968年 | 4篇 |
1965年 | 2篇 |
1936年 | 2篇 |
1932年 | 3篇 |
1925年 | 2篇 |
1921年 | 2篇 |
1919年 | 2篇 |
1909年 | 3篇 |
1905年 | 1篇 |
排序方式: 共有354条查询结果,搜索用时 15 毫秒
91.
Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A (PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers. 相似文献
92.
Dozent Dr. Otto Kren 《Archives of dermatological research》1919,125(5):561-586
Ohne ZusammenfassungPrimararztReferat, erstattet in der Sitzung der Wiener dermatologischen Gesellschaft vom 11./VII. 1918. 相似文献
93.
L. Kemény Z. Csoma E. Bagdi A.H. Banham L. Krenács A. Koreck 《The British journal of dermatology》2010,163(1):167-173
Background One of the major technological breakthroughs in the last decade is represented by the diversified medical applications of light‐emitting diodes (LEDs). LEDs emitting in the ultraviolet (UV) B spectrum might serve as a more convenient alternative for targeted delivery of phototherapy in inflammatory skin diseases such as psoriasis. Objectives We investigated the efficacy and safety of a new UVB‐LED phototherapeutic device in chronic plaque‐type psoriasis. Methods Twenty patients with stable plaque‐type psoriasis were enrolled into a prospective, right‐left comparative, open study. Symmetrical lesions located on extremities or trunk were chosen; one lesion was treated with the study device, whereas the other lesion served as an untreated control. Two treatment regimens were used in the study, one with an aggressive dose escalation similar to those used for outpatient treatment and one with slow increase in dose, similar to those used for treatment at home. Results Patients in both groups responded rapidly to the UVB‐LED therapy. Early disease resolution was observed in 11 patients (seven in the first group and four in the second group). Overall improvement at end of therapy was 93% in the high‐dose group and 84% in the low‐dose group. Four patients from the high‐dose group and five from the low‐dose group were still in remission at the 6‐month follow‐up visit. Conclusions These results suggest that this innovative UVB‐LED device is effective in the treatment of localized psoriasis and may be useful in other UV‐responsive skin diseases. 相似文献
94.
Blood formation by pluripotent stem cells and their progeny is thought to be regulated by receptor-ligand interactions between cell-substrate, cell-cell and cell-matrix in the bone marrow. Primitive stem cells form progenitors and, in their turn, these give rise to haemopoietic progeny which are more specifically committed in that they can form progressively fewer types of blood cells. Recently we have established that direct cell-cell communication via gap junctions may be part of this regulatory system. Connexin43 gap junctions metabolically couple the three dimensional meshwork of bone marrow stromal cells to form a functional syncytium in which some blood-forming cells are also coupled. The expression of gap junctions in the bone marrow is markedly upregulated when there is an urgent and substantial demand for blood-formation; for example, following cytotoxic injury after 5-fluorouracil or irradiation; or during neonatal blood-formation and in the epiphysis of growing bones. Chemical blockade of gap junctions blocks blood-formation in long-term cultures but is reversible after the blockade has been relieved. This short review highlights briefly the known regulatory mechanisms of blood-formation with especial attention to gap junctional communication. 相似文献
95.
Mouse model of X-linked Alport syndrome 总被引:3,自引:0,他引:3
Rheault MN Kren SM Thielen BK Mesa HA Crosson JT Thomas W Sado Y Kashtan CE Segal Y 《Journal of the American Society of Nephrology : JASN》2004,15(6):1466-1474
X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for alpha5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With alpha5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state. 相似文献
96.
Vannucci L Fiserová A Sadalapure K Lindhorst TK Kuldová M Rossmann P Horváth O Kren V Krist P Bezouska K Luptovcová M Mosca F Pospísil M 《International journal of oncology》2003,23(2):285-296
Glyco-coat changes on cancer cells due to aberrant glycosylation are potential targets for immune recognition through lectin-like receptors on immune cells. These cells include natural killer (NK), CD8+ and CD4+ lymphocytes, all reported to have, together with cytokines, important functions in antitumor immunity. The aim of this study was to evaluate a possible role of synthetic monodisperse multivalent neo-glycoconjugates, namely glycodendrimers, as a new approach to anticancer immune modulation through carbohydrate-mediated immune recognition. Octavalent polyamidoamine dendrimers functionalized with N-acetyl-glucosamine residues (PAMAM-GlcNAc8), with in vitro high affinity for the recombinant lymphocyte receptor NKR-P1A, were employed. To follow the fate of the compound, a fluorescent marker was conjugated to the tetra-branched semi-component of the dendrimer. Tumor development and immunity were evaluated in C57BL/6 mice. Animals were inoculated with B16F10 melanoma cells and underwent different protocols of PAMAM-GlcNAc8 administration. Advantages on survival and reduction of tumor growth were obtained in dose-dependent manner, by IP route. Increase of CD69+ cells in the spleen and their appearance inside the tumors, early progressive release of IL-1beta, a later production of INFgamma and IL-2 concomitant to an increment of CD4+ cells were observed. Cytotoxicity assays, performed ex vivo, showed an enhanced NK cell activity proportioned to the percentage of activated NK cells. Our data suggest that well-defined multivalent neo-glycoconjugates can stimulate an antitumor immune response engaging both innate and acquired immunity. 相似文献
97.
98.
Huang MT; Lou YR; Xie JG; Ma W; Lu YP; Yen P; Zhu BT; Newmark H; Ho CT 《Carcinogenesis》1998,19(9):1697-1700
Female Sencar mice (6 weeks old) were administered 1 mg of 7,12-
dimethylbenz[a]anthracene (DMBA) by oral gavage once a week for 5 weeks. At
20 weeks after the first dose of DMBA, 68% of mice developed mammary tumors
(the average 1.08 tumors per mouse) and 45% had lymphomas/leukemias.
Feeding 1% dibenzoylmethane (DBM) in AIN 76A diet, starting at 2 weeks
before the first dose of DMBA and continuing until the end of the
experiment, inhibited both the multiplicity and incidence of DMBA-induced
mammary tumor by 97%. The incidence of lymphomas/leukemias was completely
inhibited by 1% DBM diet. In contrast, feeding 2% curcumin diet had little
or no effect on the incidence of mammary tumors, and the incidence of
lymphomas/leukemias was reduced by 53%.
相似文献
99.
Co-downregulation of PTEN, KAI-1, and nm23-H1 tumor/metastasis suppressor proteins in non-small cell lung cancer 总被引:11,自引:0,他引:11
Goncharuk VN del-Rosario A Kren L Anwar S Sheehan CE Carlson JA Ross JS 《Annals of diagnostic pathology》2004,8(1):6-16
The multistep process of carcinogenesis implies the accumulation of multiple molecular defects. Alteration of tumor suppressor and metastasis suppressor genes are the important steps. Increasing experimental evidence indicates that decreased expression of tumor-metastasis/suppressor genes and gene products are involved in the progression of a variety of human malignancies. In the present study, we have extended this analysis to non-small cell lung carcinomas (NSCLC). The expression and prognostic significance of the tumor suppressor gene PTEN and metastasis suppressor genes nm23-H1 and KAI-1 was evaluated in NSCLCs. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissues from 53 bronchogenic adenocarcinomas and 51 squamous cell carcinomas using monoclonal antibodies against PTEN, nm23H-1, and KAI-1 proteins. Immunohistochemical results were correlated with tumor stage, grade, lymph nodes positivity, metastasis, and patient survival. Significant co-expression of PTEN, nm23-H1 and KAI-1 was observed in NSCLC (P<.001 to .002). The immunohistochemical expression of these proteins was significantly higher in stages 1 and 2 compared with stages 3 and 4 (P=.04 for PTEN and KAI-1, P=.039 for nm23-H1). When all stages were considered together, loss of immunoreactivity for PTEN, nm23-H1 and KAI-1 was found in advanced NCSCLs (P=.015 for PTEN, P=.001 for KAI-1, P=.004 for nm23-H1), which is suggestive of co-downregulation of these proteins in the process of tumor progression. On multivariate analysis, negative staining for PTEN (P=.014), KAI-1 (P=.034), and nm23-H1 (a trend toward association for nm23-H1 reached near significance P=.08) correlated with disease-related death. Positive lymph node status was associated with negative immunostaining for PTEN (P=.007) but no correlation was observed for nm23-H1 and KAI-1. Loss of expression was linked to distant metastasis (P=.006 for PTEN, P=.002 for nm23H1, P=.001 for KAI-1). On multivariate analysis, co-downregulation of PTEN (P=.009), KAI-1 (P=.02), and nm23-H1 (P=.011) independently predicted shortened survival in NSCLC. Although NSCLC exhibits strong co-expression of PTEN, nm23-H1 and KAI-1, there is a loss of these proteins in high-stage tumors. Co-downregulation of PTEN, KAI-1, and nm23-H1 significantly correlates with distant metastasis and predicts shortened survival. Our study supports a role of these tumor suppressor and metastasis suppressor genes in the evolution and progression of NSCLC. 相似文献
100.
Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice 总被引:4,自引:3,他引:4
Lamb BT; Call LM; Slunt HH; Bardel KA; Lawler AM; Eckman CB; Younkin SG; Holtz G; Wagner SL; Price DL; Sisodia SS; Gearhart JD 《Human molecular genetics》1997,6(9):1535-1541
Missense mutations in the beta-amyloid precursor protein gene (APP) co-
segregate with a small subset of autosomal dominant familial Alzheimer's
disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid
(A beta) peptide and neurodegeneration are principal neuropathological
hallmarks. To accurately examine the effect of missense mutations on APP
metabolism and A beta production in vivo, we have introduced yeast
artificial chromosomes (YACs) containing the entire approximately 400 kbp
human APP gene encoding APP harboring either the asparagine for lysine and
leucine for methionine FAD substitution at codons 670 and 671
(APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717
(APP(V7171)) or a combination of both substitutions into transgenic mice.
We demonstrate that, relative to YAC transgenic mice expressing wild-type
APP, high levels of A beta peptides are detected in the brains of YAC
transgenic mice expressing human APP(K670N/M671L) that is associated with a
concomitant diminution in the levels of apha-secretase-generated soluble
APP derivatives. Moreover, the levels of longer A beta peptides (species
terminating at amino acids 42/43) are elevated in YAC transgenic mice
expressing human APP(V7171). These mice should prove valuable for detailed
analysis of the in vivo effects of the APP FAD mutations in a variety of
tissues and throughout aging and for testing therapeutic agents that
specifically alter APP metabolism and A beta production.
相似文献