全文获取类型
收费全文 | 1130篇 |
免费 | 65篇 |
国内免费 | 20篇 |
专业分类
耳鼻咽喉 | 6篇 |
儿科学 | 32篇 |
妇产科学 | 17篇 |
基础医学 | 142篇 |
口腔科学 | 34篇 |
临床医学 | 141篇 |
内科学 | 263篇 |
皮肤病学 | 11篇 |
神经病学 | 108篇 |
特种医学 | 117篇 |
外科学 | 100篇 |
综合类 | 12篇 |
预防医学 | 58篇 |
眼科学 | 15篇 |
药学 | 89篇 |
中国医学 | 2篇 |
肿瘤学 | 68篇 |
出版年
2019年 | 15篇 |
2018年 | 12篇 |
2017年 | 13篇 |
2016年 | 16篇 |
2015年 | 13篇 |
2014年 | 15篇 |
2013年 | 48篇 |
2012年 | 35篇 |
2011年 | 38篇 |
2010年 | 36篇 |
2009年 | 43篇 |
2008年 | 40篇 |
2007年 | 32篇 |
2006年 | 32篇 |
2005年 | 29篇 |
2004年 | 39篇 |
2003年 | 23篇 |
2002年 | 31篇 |
2001年 | 18篇 |
2000年 | 24篇 |
1999年 | 31篇 |
1998年 | 39篇 |
1997年 | 41篇 |
1996年 | 32篇 |
1995年 | 30篇 |
1994年 | 32篇 |
1993年 | 21篇 |
1992年 | 25篇 |
1991年 | 25篇 |
1990年 | 31篇 |
1989年 | 30篇 |
1988年 | 26篇 |
1987年 | 23篇 |
1986年 | 32篇 |
1985年 | 19篇 |
1984年 | 13篇 |
1983年 | 17篇 |
1982年 | 16篇 |
1981年 | 15篇 |
1980年 | 10篇 |
1979年 | 10篇 |
1978年 | 9篇 |
1977年 | 14篇 |
1976年 | 19篇 |
1975年 | 14篇 |
1972年 | 10篇 |
1970年 | 13篇 |
1969年 | 7篇 |
1968年 | 6篇 |
1967年 | 8篇 |
排序方式: 共有1215条查询结果,搜索用时 31 毫秒
111.
112.
Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation
下载免费PDF全文
![点击此处可从《The Journal of pathology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Hyun Young Koo Lamis MF El‐Baz StaceyL House Sarah N Cilvik Samuel J Dorry Nahla M Shoukry Mohamed L Salem Hani S Hafez Nickolai O Dulin David M Ornitz Robert D Guzy 《The Journal of pathology》2018,246(1):54-66
Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
113.
Gatherings of large numbers of people at concerts, sporting events, and other occasions lead to an assembled population with a potential for a wide variety of illnesses and injuries. The collection of large numbers of people in a single location has led some authors to recommend the placement of resuscitation equipment or other medical services in close proximity to these activities. These recommendations not withstanding, data on the frequency of critical illness at mass gatherings (a group exceeding 1000 persons) are difficult to ascertain. Therefore, it was the purpose of this study to describe the incidence of critical illnesses among assembled populations at mass gatherings. An observational prospective study was conducted involving patient encounters at a large, multipurpose, indoor mass-gathering complex in Houston, Texas occurring between Septemver 1, 1996 and June 30, 1997. Demographic, treatment, disposition and diagnostic data were analyzed in a computerized database. Of the 3.3 million attendants to the 253 events analyzed during the 10-month study period, there were 2762 (0.08%) patient encounters. Fifty-two percent were women. Mean age was 32 ± 15.6 years. Of these patients, 51.1% were patrons and the remaining patients were employees or contractors of the facility. A wide variety of illness was seen with trauma (39.5%), headache (31%), and other medical complaints (29.5%) being most frequent. Disposition of the patients included 95.3% being discharged to go back to the event and 2.2% being counseled to seek other medical attention. One hundred twenty-nine patients (4.7%) were referred to the Emergency Department (ED); of these, 70 were transferred for abrasions, lacerations, or skeletal injuries and 13 for chest pain. Of those referred to the ED, 50 (38.7%) patients were transported by ambulance and only 17.4% were admitted to telemetry, with none admitted to an ICU. It is concluded that critical illness at mass gatherings is infrequent, as seen in this study, with very few being admitted to telemetry and none to an ICU. Careful consideration of cost-benefit should occur when determining allocation of resources for these activities. 相似文献
114.
115.
Piperine,a major constituent of black pepper,inhibits human P-glycoprotein and CYP3A4 总被引:7,自引:0,他引:7
Bhardwaj RK Glaeser H Becquemont L Klotz U Gupta SK Fromm MF 《The Journal of pharmacology and experimental therapeutics》2002,302(2):645-650
Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC(50) values of 15.5 and 74.1 microM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K(i) values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 microM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally. 相似文献
116.
117.
Richard Kuehl Priscilla S. Brunetto Anne-Kathrin Woischnig Massimo Varisco Zarko Rajacic Juerg Vosbeck Luigi Terracciano Katharina M. Fromm Nina Khanna 《Antimicrobial agents and chemotherapy》2016,60(4):2467-2475
Implant-associated infections (IAIs) are a dreaded complication mainly caused by biofilm-forming staphylococci. Implant surfaces preventing microbial colonization would be desirable. We examined the preventive effect of a silver-coated titanium-aluminum-niobium (TiAlNb) alloy. The surface elicited a strong, inoculum-dependent activity against Staphylococcus epidermidis and Staphylococcus aureus in an agar inhibition assay. Gamma sterilization and alcohol disinfection did not alter the effect. In a tissue cage mouse model, silver coating of TiAlNb cages prevented perioperative infections in an inoculum-dependent manner and led to a 100% prevention rate after challenge with 2 × 106 CFU of S. epidermidis per cage. In S. aureus infections, silver coating had only limited effect. Similarly, daptomycin or vancomycin prophylaxis alone did not prevent S. aureus infections. However, silver coating combined with daptomycin or vancomycin prophylaxis thwarted methicillin-resistant S. aureus infections at a prevention rate of 100% or 33%, respectively. Moreover, silver release from the surface was independent of infection and occurred rapidly after implantation. On day 2, a peak of 82 μg Ag/ml was reached in the cage fluid, corresponding to almost 6× the MIC of the staphylococci. Cytotoxicity toward leukocytes in the cage was low and temporary. Surrounding tissue did not reveal histological signs of silver toxicity. In vitro, no emergence of silver resistance was observed in several clinical strains of staphylococci upon serial subinhibitory silver exposures. In conclusion, our data demonstrate that silver-coated TiAlNb is potent for prevention of IAIs and thus can be considered for clinical application. 相似文献
118.
Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) is currently tested in clinical trials for future treatment of primary sclerosing cholangitis because of beneficial effects in cholestatic Mdr2 knock‐out mice. Uptake of UDCA and norUDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and norUDCA are poorly understood. We therefore investigated whether UDCA and norUDCA are substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and Na+‐taurocholate co‐transporting polypeptide (NTCP), which are localized in the basolateral membrane of hepatocytes. Uptake of [3H]UDCA and [14C]norUDCA into Human embryonic kidney (HEK) cells stably expressing OATP1B1, OATP1B3, OATP2B1 or NTCP was investigated and compared with uptake into vector control cells. Uptake ratios were calculated by dividing uptake into transporter‐transfected cells by uptake into respective control cells. Uptake ratios of OATP1B1‐, OATP1B3‐ and OATP2B1‐mediated UDCA and norUDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was significantly higher into HEK‐NTCP cells only at the lowest tested concentration (1 μM, p < 0.001) compared with the control cells with an uptake ratio of 1.34‐fold. NorUDCA was not significantly transported by NTCP. The low uptake rates suggest that OATP1B1, OATP1B3, OATP2B1 and NTCP are not relevant for hepatocellular uptake and effects of UDCA and norUDCA in human beings. 相似文献
119.
120.
Troeger H Epple HJ Schneider T Wahnschaffe U Ullrich R Burchard GD Jelinek T Zeitz M Fromm M Schulzke JD 《Gut》2007,56(3):328-335
BACKGROUND: Giardia lamblia causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. AIM: To characterise the inherent pathomechanisms of G lamblia infection. METHODS: Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I(SC)) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. RESULTS: In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) Omega cm(2); p<0.05) whereas mannitol flux was not significantly altered (140 (27) vs 105 (16) nmol/h/cm(2)). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I(SC) increased from 191 (20) in control to 261 (12) microA/h/cm(2) in giardiasis. The bumetanide-sensitive portion of I(SC) in giardiasis was also increased (51 (5) vs 20 (9) microA/h/cm(2) in control; p<0.05). Finally, phlorizin-sensitive Na(+)-glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) microA/h/cm(2)). CONCLUSIONS: G lamblia infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na(+)-dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components. 相似文献