全文获取类型
收费全文 | 167篇 |
免费 | 10篇 |
国内免费 | 3篇 |
专业分类
儿科学 | 5篇 |
妇产科学 | 6篇 |
基础医学 | 7篇 |
口腔科学 | 1篇 |
临床医学 | 11篇 |
内科学 | 85篇 |
皮肤病学 | 5篇 |
神经病学 | 9篇 |
外科学 | 34篇 |
综合类 | 5篇 |
预防医学 | 1篇 |
药学 | 7篇 |
肿瘤学 | 4篇 |
出版年
2021年 | 3篇 |
2019年 | 1篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 1篇 |
2014年 | 2篇 |
2012年 | 2篇 |
2011年 | 1篇 |
2010年 | 2篇 |
2009年 | 3篇 |
2008年 | 6篇 |
2007年 | 3篇 |
2006年 | 8篇 |
2005年 | 7篇 |
2004年 | 11篇 |
2003年 | 20篇 |
2002年 | 19篇 |
2001年 | 6篇 |
2000年 | 6篇 |
1999年 | 8篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1996年 | 2篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 2篇 |
1975年 | 5篇 |
1974年 | 9篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1971年 | 2篇 |
1970年 | 6篇 |
1969年 | 3篇 |
1968年 | 5篇 |
1966年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有180条查询结果,搜索用时 203 毫秒
91.
Parlow JJ Case BL Dice TA Fenton RL Hayes MJ Jones DE Neumann WL Wood RS Lachance RM Girard TJ Nicholson NS Clare M Stegeman RA Stevens AM Stallings WC Kurumbail RG South MS 《Journal of medicinal chemistry》2003,46(19):4050-4062
Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250 x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis. 相似文献
92.
Martín J Hunt SL Dubus P Sotillo R Néhmé-Pélluard F Magnuson MA Parlow AF Malumbres M Ortega S Barbacid M 《Oncogene》2003,22(34):5261-5269
Lack of Cdk4 expression in mice leads to insulin-deficient diabetes and female infertility owing to a reduced number of pancreatic beta cells and prolactin-producing pituitary lactotrophs, respectively. Cdk4 null mice display also reduced body and organ size. Here, we show that Cdk4 is essential for the postnatal proliferation of pancreatic beta cells but not for embryonic neogenesis from ductal epithelial cells. Re-expression of endogenous Cdk4 in beta cells and in the pituitary gland of Cdk4 null mice restores cell proliferation and results in fertile and normoglycemic animals, thus, demonstrating that the proliferation defects in these cellular populations are cell autonomous because of the lack of Cdk4 expression. However, these mice remain small in size, indicating that this phenotype is not because of pancreatic- or pituitary-mediated endocrine defects. This phenotype is a consequence of reduced cell numbers rather than reduced cell size. Thus, mammalian Cdk4 is not only involved in controlling proliferation of specific cell types but may play a wider role in establishing homeostatic cell numbers. 相似文献
93.
We hypothesize that the endogenously present lipoidal estrogen fatty acid esters may have a stronger mitogenic action in the fat-rich mammary tissues than in the uterus. To test this hypothesis, we compared the activity of estradiol-17beta-stearate (E(2)-17beta-S) with that of estradiol-17beta (E(2)) in stimulating the growth of mammary glandular cells versus the growth of uterine endometrial cells in ovariectomized female Sprague Dawley rats. Experimentally, an estimated 0.5 or 5 nmol of E(2)-17beta-S or E(2) was released daily to ovariectomized female rats through an Alzet pump implanted under the back skin of the animal for 10 or 23 days. The growth-stimulatory effect of E(2)-17beta-S and E(2) on mammary glandular cells was determined according to 5-bromo-2'-deoxyuridine labeling indices, and their effect on the uterus was determined by measuring both the 5-bromo-2'-deoxyuridine labeling index and the uterine wet weight. Our results showed that chronic treatment of ovariectomized female rats with 0.5 or 5 nmol/day E(2)-17beta-S for 10 or 23 days had a stronger stimulatory effect on mammary glandular cell proliferation than treatment with equimolar doses of E(2). In the uterus, however, E(2) was more active in stimulating the proliferation of uterine endometrial cells than E(2)-17beta-S at equimolar doses. Our results demonstrated, for the first time, that a naturally occurring estradiol-17beta-fatty acid ester has a differential, strong mitogenic effect in the fat-rich mammary tissues, and this effect was not observed with E(2). It is tempting to suggest that the fatty acid esters of the endogenous estrogens and their bioactive metabolites (e.g., 4-hydroxyestradiol and 16alpha-hydroxyestrone) may be of unique importance for stimulating cell growth and possibly also for inducing tumor formation in the fat-rich mammary tissues as compared with the uterus. More studies are warranted to test these ideas. 相似文献
94.
Khala Albert BSc Janet van Vlymen MD Paula James MD Joel Parlow MD 《Journal canadien d'anesthésie》2009,56(5):352-356
Purpose
Ringer’s lactate (RL) may be preferable to normal saline (NS) for large volume resuscitation. Authorities recommend against its mixture with packed red blood cells (PRBC) due to a theoretical risk of clotting. The purpose of this study was to test whether RL, as compared with NS, leads to a risk of clotting when used to dilute AS-3 preserved PRBC in a clinically relevant model.Methods
Following Ethics Board approval, eight units of unused, unexpired AS-3 preserved PRBC were obtained. Four sets of two parallel studies were performed, comparing RL with NS as the diluent for PRBC. The mixtures were infused using gravity flow through standard blood filter tubing and fluid warmer, to simulate an intraoperative blood transfusion. A series of progressively more dilute samples was collected. These were filtered and analyzed macroscopically, then using enzyme-linked immunosorbent assay to quantify the amount of F1+2 (the breakdown products of thrombin generation).Results
No filters in any of the NS and RL mixtures contained evidence of clot or debris. In the NS group, the F1+2 levels ranged from 2.7 to 38.0 pmol · L?1. In the RL group, the F1+2 levels ranged from 3.2 to 289.7 pmol · L?1. All of these values were below the physiologic levels determined in previous studies.Conclusion
In this simulation of intraoperative blood transfusion, RL did not lead to visible or molecular evidence of activation of the clotting cascade. The current study challenges recommendations that AS-3 PRBC should not be mixed with RL for rapid transfusion. 相似文献95.
George AP Kuehn SM Vassilyadi M Richards PM Parlow SE Keene DL Ventureyra EC 《Pediatric neurology》2003,28(1):42-47
Late effects of radiotherapy on intellectual functioning have been well documented in children treated for posterior fossa tumors. Other aspects of cognitive functioning, such as memory, have not been adequately assessed in this population. This retrospective review reports on 15 children diagnosed with medulloblastoma or cerebellar astrocytoma who were administered a norm-referenced standardized test of memory functioning (i.e., Wide Range Assessment of Memory and Learning) an average of 3.5 years after treatment. Analyses revealed that sample means of IQ and memory were significantly lower than those of the normative population. No significant differences were found between the verbal and nonverbal IQ, or verbal and visual memory. Age at diagnosis accounted for a significant proportion of variability in the intelligence ratings but not in the memory indexes. The IQ scores of children less than 6 years of age at diagnosis were significantly lower than those of children diagnosed when over 6 years of age. Given the substantial variability within the older age group, there was insufficient power to detect true differences between memory index means for children by age at diagnosis. Follow-up assessments over 5 years may better identify the long-term effects of radiotherapy on memory functioning. 相似文献
96.
Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis 总被引:1,自引:0,他引:1
Ramsey MM Ingram RL Cashion AB Ng AH Cline JM Parlow AF Sonntag WE 《Endocrinology》2002,143(10):4139-4142
Increased plasma IGF-1 has consistently been associated with a variety of human cancers, whereas reduced levels of IGF-1 are associated with increased lifespan in other species. However, the aforementioned relationships are correlational or are derived from animal models that are not specific for growth hormone/IGF-1 excess or deficiency. This study was designed to assess the effects of physiological changes in growth hormone and IGF-1 expression on dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. At 50 days of age, female heterozygous (dw/+) and growth hormone deficient dwarf (dw/dw) rats of the Lewis strain received a single dose of DMBA (80 micro g/g of body weight) via oral gavage. Animals were assigned to one of four experimental groups: a) heterozygous animals (normal size), b) dwarf animals administered vehicle, c) dwarf animals administered low levels of porcine growth hormone (50 micro g twice daily), and d) dwarf animals administered high levels of porcine growth hormone (200 micro g twice daily). At study termination, heterozygous animals exhibited a 70% incidence of mammary tumors, whereas no tumors were observed in saline-treated dwarf animals. Administration of either 100 micro g or 400 micro g growth hormone/day resulted in a dose dependent increase in incidence of mammary tumors (83 and 100%, respectively). Furthermore, heterozygous animals exhibited 1.5 +/- 0.25 tumors per tumor-bearing animal, whereas dwarf animals administered 100 micro g and 400 micro g growth hormone per day had 1.9 +/- 0.63 and 3.4 +/- 0.83 tumors per animal, respectively. The present study demonstrates that DMBA-induced carcinogenesis is dependent on critical plasma levels of growth hormone and IGF-1, and that growth hormone/IGF-1 deficient animals are resistant to DMBA-induced carcinogenesis. 相似文献
97.
Richard G. Jung Trevor Simard Christopher Kovach Kelsey Flint Creighton Don Pietro Di Santo Marianna Adamo Luca Branca Francesca Valentini Tomás Benito-González Felipe Fernández-Vázquez Rodrigo Estévez-Loureiro Alessandra Berardini Nicolina Conti Claudio Rapezzi Elena Biagini Simon Parlow Risa Shorr Benjamin Hibbert 《JACC: Cardiovascular Interventions》2021,14(1):1-11
ObjectivesThe aim of this study was to evaluate the outcome of transcatheter mitral valve repair (TMVr) in patients with cardiogenic shock and significant mitral regurgitation (MR).BackgroundPatients in cardiogenic shock with severe MR have a poor prognosis in the setting of conventional medical therapy. Because of its favorable safety profile, TMVr is being increasingly used as an acute therapy in this population, though its efficacy remains unknown.MethodsA multicenter, collaborative, patient-level analysis was conducted. Patients with cardiogenic shock and moderate to severe (3+) or severe (4+) MR who were not surgical candidates were treated with TMVr. The primary outcome was in-hospital mortality. Secondary outcomes included 90-day mortality, heart failure (HF) hospitalization, and the combined event rate of 90-day mortality and HF hospitalization following dichotomization by TMVr device success.ResultsBetween January 2011 and February 2019, 141 patients across 14 institutions met the inclusion criteria. In-hospital mortality occurred in 22 patients (15.6%), at 90 days in 38 patients (29.5%), and at one year in 55 patients (42.6%). Median length of hospital stay following TMVr was 10 days (interquartile range: 6 to 20 days). HF hospitalization occurred in 26 patients (18.4%) at a median of 73 days (interquartile range: 26 to 546 days). When stratified by TMVr procedural results, successful TMVr reduced rates of in-hospital mortality (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.13 to 0.98; p = 0.04), 90-day mortality (HR: 0.36; 95% CI: 0.16 to 0.78; p = 0.01), and the composite of 90-day mortality and HF hospitalization (HR: 0.41; 95% CI: 0.19 to 0.90; p = 0.03).ConclusionsTMVr may improve short- and intermediate-term mortality in high-risk patients with cardiogenic shock and moderate to severe MR. Randomized studies are needed to definitively establish MR as a therapeutic target in patients with cardiogenic shock. 相似文献
98.
Gao W Kearbey JD Nair VA Chung K Parlow AF Miller DD Dalton JT 《Endocrinology》2004,145(12):5420-5428
Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5alpha-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5alpha-reductase (Ki, >20 microm) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5alpha-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH. 相似文献
99.
GH, prolactin (PRL), and IGF-I stimulate lactation-related metabolic processes in mammary epithelial cells. However, the ability of these factors to stimulate milk production in animals varies depending on species and experimental variables. Previous work in our laboratory demonstrated that transgenic overexpression of des(1-3)IGF-I within the mammary glands of lactating mouse dams increased lactation capacity during prolonged lactation. This work also suggested that some of the effects of the overexpressed IGF-I may have been mediated through elevated concentrations of IGF-I or PRL in the systemic circulation. In the present study, murine GH and PRL, and a human IGF-I analog, long-R3-IGF-I (LR3), were administered as s.c. injections to compare their ability to enhance milk production, and alter mammary gland signaling and gene expression. Lactation capacity, as measured by litter gain, was increased (P<0.05) by GH, but not by PRL. LR3 increased (P<0.05) mammary phospho-Akt and suppressors of cytokines signaling 3 (SOCS3) gene expression, and had a modest ability to increase (P<0.05) lactation capacity. GH both increased (P<0.05) mammary SOCS1 expression and decreased (P<0.05) mammary expression of tryptophan hydroxylase 1, the rate-limiting enzyme in the synthesis of serotonin and a potential feedback inhibitor of lactation. These results suggest that while both GH and IGF-I stimulate milk production in the lactating mouse, the effect of GH may be additionally mediated through IGF-I-independent effects associated with repression of mammary serotonin synthesis. 相似文献
100.