全文获取类型
收费全文 | 963篇 |
免费 | 62篇 |
国内免费 | 5篇 |
专业分类
耳鼻咽喉 | 9篇 |
儿科学 | 31篇 |
妇产科学 | 10篇 |
基础医学 | 128篇 |
口腔科学 | 13篇 |
临床医学 | 74篇 |
内科学 | 229篇 |
皮肤病学 | 19篇 |
神经病学 | 89篇 |
特种医学 | 42篇 |
外科学 | 95篇 |
综合类 | 6篇 |
一般理论 | 1篇 |
预防医学 | 47篇 |
眼科学 | 4篇 |
药学 | 70篇 |
中国医学 | 2篇 |
肿瘤学 | 161篇 |
出版年
2024年 | 2篇 |
2023年 | 5篇 |
2022年 | 13篇 |
2021年 | 19篇 |
2020年 | 16篇 |
2019年 | 13篇 |
2018年 | 18篇 |
2017年 | 18篇 |
2016年 | 16篇 |
2015年 | 26篇 |
2014年 | 30篇 |
2013年 | 52篇 |
2012年 | 81篇 |
2011年 | 67篇 |
2010年 | 45篇 |
2009年 | 38篇 |
2008年 | 66篇 |
2007年 | 64篇 |
2006年 | 64篇 |
2005年 | 71篇 |
2004年 | 70篇 |
2003年 | 49篇 |
2002年 | 55篇 |
2001年 | 10篇 |
2000年 | 10篇 |
1999年 | 9篇 |
1998年 | 11篇 |
1997年 | 10篇 |
1996年 | 14篇 |
1995年 | 2篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 7篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 2篇 |
1988年 | 5篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1970年 | 2篇 |
1969年 | 4篇 |
1968年 | 3篇 |
1967年 | 2篇 |
1959年 | 1篇 |
排序方式: 共有1030条查询结果,搜索用时 15 毫秒
1.
2.
Germ cell tumors of the testes represent a unique paradigm of diseases which can be cured even in extremely advanced phase.
Unfortunately, this makes them unique among adult solid tumors. Seminoma and non seminoma are relatively rare with approximatively
25,000 patients in Europe per year, but numbers are increasing world wide. Different strategies are needed depending on stage
and prognostic scores. Seminoma is extremely sensitive to radiation therapy and chemotherapy, while all germ cell tumors show
a very good response to chemotherapy. Clinical stage I seminoma is currently treated with radiation, single course carboplatin
or surveillance policy. Clinical stage I non seminoma can also be approached with different strategies such as retroperitoneal
lymph node dissection, observation or one-two courses of standard chemotherapy. Stage II seminoma may be treated with either
radiation or chemotherapy, while for all advanced stages chemotherapy is mandatory. Since the mid-eighties PEB (Cisplatin,
Etoposide and Bleomycin) is the regimen of choice and no other schedule has proved superior in terms of efficacy. Surgery
on the residual disease is crucial to the whole strategy and should be performed or attempted in all cases. Consequently,
the correct treatment strategy for these tumors does not depend only on the ability of a single physician, but on a skilled
team specialized in this particular tumor. Second line therapies (VeIP, PEI, TIP) can cure 25%–40% of patients, but improved
strategies for resistant tumors are desperately needed. High-dose chemotherapy has shown very good results in some studies
while being less impressive in others. In any case, it should remain an option for relapsing patients and could be used in
some cases of upfront chemotherapy in patients with slow marker decline, but this should only be considered in referring centers. 相似文献
3.
Dr. Franco Zunino Brunella Barbieri Ornella Bellini Anna Maria Casazza Cristina Geroni Fernando Giuliani Antonio Ciana Giorgio Manzini Franco Quadrifoglio 《Investigational new drugs》1986,4(1):17-23
Summary The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines. 相似文献
4.
5.
Massa O Iafusco D D'Amato E Gloyn AL Hattersley AT Pasquino B Tonini G Dammacco F Zanette G Meschi F Porzio O Bottazzo G Crinó A Lorini R Cerutti F Vanelli M Barbetti F;Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology Diabetology 《Human mutation》2005,25(1):22-27
Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes. 相似文献
6.
Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis 总被引:15,自引:0,他引:15 下载免费PDF全文
Cianchi F Cortesini C Fantappiè O Messerini L Schiavone N Vannacci A Nistri S Sardi I Baroni G Marzocca C Perna F Mazzanti R Bechi P Masini E 《The American journal of pathology》2003,162(3):793-801
To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis. 相似文献
7.
Selected RD1 Peptides for Active Tuberculosis Diagnosis: Comparison of a Gamma Interferon Whole-Blood Enzyme-Linked Immunosorbent Assay and an Enzyme-Linked Immunospot Assay 下载免费PDF全文
Delia Goletti Donatella Vincenti Stefania Carrara Ornella Butera Federica Bizzoni Giuliana Bernardini Massimo Amicosante Enrico Girardi 《Clinical and Vaccine Immunology : CVI》2005,12(11):1311-1316
We recently set up a gamma interferon (IFN-γ) enzyme-linked immunospot assay (ELISPOT), using selected early secreted antigenic target 6 (ESAT-6) peptides, that appears specific for active tuberculosis (A-TB). However, ELISPOT is difficult to automate. Thus, the objective of this study was to determine if the same selected peptides may be used in a technique more suitable for routine work in clinical laboratories, such as whole-blood enzyme-linked immunosorbent assay (WBE). For this purpose, 27 patients with A-TB and 41 control patients were enrolled. Our WBE, using the already described selected peptides from ESAT-6 plus three new ones from culture filtrate protein 10, was performed, and data were compared with those obtained by ELISPOT. Using our selected peptides, IFN-γ production, evaluated by both WBE and ELISPOT, was significantly higher in patients with A-TB than in controls (P < 0.0001). Statistical analysis showed a good correlation between the results obtained by WBE and ELISPOT (r = 0.80, P < 0.001). To substantiate our data, we compared our WBE results with those obtained by QuantiFERON-TB Gold, a whole-blood assay based on region of difference 1 (RD1) overlapping peptides approved for TB infection diagnosis. We observed a slightly higher sensitivity with QuantiFERON-TB Gold than with our WBE (89% versus 81%); however, our test provided a better specificity result (90% versus 68%). In conclusion, results obtained by WBE based on selected RD1 peptides significantly correlate with those generated by ELISPOT. Moreover, our assay appears more specific for A-TB diagnosis than QuantiFERON-TB Gold, and thus it may represent a complementary tool for A-TB diagnosis for routine use in clinical laboratories. 相似文献
8.
Brighina F Piazza A Daniele O Fierro B 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2002,145(2):177-181
Recent studies showed hyperexcitability of the occipital cortex in subjects affected by migraine with aura. It has been shown that 1 Hz repetitive transcranial magnetic stimulation (rTMS) reduces excitability of visual cortex in normal subjects. The aim of the study was to investigate the effects of low frequency (1 Hz) rTMS on visual cortical excitability by measuring changes in phosphene threshold (PT) in subjects with migraine with aura. Thirteen patients with migraine with aura and 15 healthy controls were examined. Using a standardized transcranial magnetic stimulation protocol of the occipital cortex, we assessed the PT (the lowest magnetic stimulation intensity at which subjects just perceived phosphenes) before and after a 1-Hz rTMS train delivered at PT intensity for 15 min. The difference in the proportion of subjects reporting phosphenes in migrainer and control groups was significant (migrainers: 100% vs controls 47%; P<0.05), and 1 Hz rTMS over the occipital cortex led to a significantly increased visual cortex excitability expressed as a decrease in PT in subjects affected by migraine with aura. Conversely, after a 1-Hz TMS train normal subjects showed increased PT values, which suggests a decreased visual cortex excitability. Our findings confirm that the visual cortex is hyperexcitable in migrainers and suggest a failure of inhibitory circuits, which are unable to be upregulated by low frequency rTMS. 相似文献
9.
Analysis of IFN-kappa expression in pathologic skin conditions: downregulation in psoriasis and atopic dermatitis. 总被引:3,自引:0,他引:3
Claudia Scarponi Bernardetta Nardelli David W Lafleur Paul A Moore Stefania Madonna Ornella De Pità Giampiero Girolomoni Cristina Albanesi 《Journal of interferon & cytokine research》2006,26(3):133-140
Interferon-kappa (IFN-kappa) is a type I IFN expressed by keratinocytes, monocytes and dendritic cells (DCs). In human keratinocytes, it is produced in response to double-stranded RNA (dsRNA) and other IFNs and protects from viral infections. In monocytes and DCs, IFN-kappa induces tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) and inhibits lipopolysaccharide (LPS)-induced IL-12. In this study, we evaluated IFN-kappa expression in skin lesions of patients with common immune-mediated inflammatory disorders using immunohistochemical techniques. IFN-kappa was not detectable in healthy skin but was strongly expressed in allergic contact dermatitis and lichen planus-affected skin. IFN-kappa was localized mainly in basal and suprabasal keratinocytes and in some leukocytes infiltrating the dermis. In contrast, IFN-kappa expression in psoriatic or atopic dermatitis (AD) pidermis was weak and detectable in only 2 of 5 patients examined. Consistently, cultured keratinocytes and monocytes obtained from psoriatic and AD patients expressed null or low levels of IFN-kappa in response to IFN-gamma, which strongly upregulates IFN-kappa in normal keratinocytes. IFN-kappa accumulated in keratinocyte cytoplasm and plasma membrane, and only limited amounts were released extracellularly. Soluble IFN-kappa did not influence keratinocyte proliferation or chemokine and membrane molecule expression, and only its membrane-associated form activated IFN-stimulated response element (ISRE) signaling. Given the difference in IFN-kappa expression levels in the skin disorders examined, IFN-kappa presence or deficiency might have different pathogenetic consequences depending also on other disease-specific intrinsic alterations. 相似文献
10.
Nitric oxide donors suppress chemokine production by keratinocytes in vitro and in vivo 总被引:7,自引:0,他引:7 下载免费PDF全文
Giustizieri ML Albanesi C Scarponi C De Pità O Girolomoni G 《The American journal of pathology》2002,161(4):1409-1418
Nitric oxide (NO) is involved in the modulation of inflammatory responses. In psoriatic skin, NO is highly produced by epidermal keratinocytes in response to interferon-gamma and tumor necrosis factor-alpha. In this study, we investigated whether the NO donors, S-nitrosoglutathione (GS-NO) and NOR-1, could regulate chemokine production by human keratinocytes activated with interferon-gamma and tumor necrosis factor-alpha. In addition, we studied the effects of the topical application of a GS-NO ointment on chemokine expression in lesional psoriatic skin. NO donors diminished in a dose-dependent manner and at both mRNA and protein levels the IP-10, RANTES, and MCP-1 expression in keratinocytes cultured from healthy patients and psoriatic patients. In contrast, constitutive and induced interleukin-8 production was unchanged. GS-NO-treated psoriatic skin showed reduction of IP-10, RANTES, and MCP-1, but not interleukin-8 expression by keratinocytes. Moreover, the number of CD14(+) and CD3(+) cells infiltrating the epidermis and papillary dermis diminished significantly. NO donors also down-regulated ICAM-1 protein expression without affecting mRNA accumulation in vitro, and suppressed keratinocyte ICAM-1 in vivo. Finally, NO donors inhibited nuclear factor-kappa B and STAT-1, but not AP-1 activities in transiently transfected keratinocytes. These results define NO donors as negative regulators of chemokine production by keratinocytes. 相似文献