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51.
Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. 总被引:28,自引:0,他引:28
Placental and endometrial partial pressures of oxygen (PO2) were measured using a polarographic oxygen electrode during the first trimester of pregnancy. Between 8-10 weeks' gestation, placental PO2 levels were significantly lower (P less than .001) than endometrial levels. A significant (P less than .001) increase was observed for placental PO2 values measured at 12-13 weeks compared with those obtained at 8-10 weeks. We suggest that the increase of placental PO2 at the end of the first trimester is related to the establishment of continuous maternal blood flow in the intervillous space. 相似文献
52.
53.
The entire gastroesophageal junction of 36 patients who had been operated for squamous cell carcinoma of the upper or middle esophagus was examined. Hematoxylin and eosin-stained slides were evaluated by two pathologists for the following histologic details: minimal and maximal length of cardiac mucosa (CM) and oxyntocardiac mucosa (OCM, mixture of cardiac and fundic glands), degree of inflammation in CM and OCM, and presence of intestinal metaplasia or pancreatic metaplasia. Sections of gastric corpus mucosa were evaluated for the presence of gastritis and infection; sections of esophageal squamous epithelium were evaluated for the presence of reflux esophagitis. CM was present in the entire circumference of the gastroesophageal junction in 20 cases, in parts of the circumference in 15 cases, and entirely absent in one case. The maximal length per case ranged between 1 and 15 mm (median 5 mm). OCM was circumferentially present in 22 cases and partially present in 14 cases. The maximal length ranged between 2 and 24 mm (median 7 mm). Locations of CM/OCM over submucosal esophageal glands or squamous epithelium-lined ducts, both indicating a location in the esophagus, were found in eight cases (22%) and in four cases (11%), respectively. In 18 cases (50%) intestinal metaplasia was present in CM/OCM; pancreatic metaplasia was found in 22 cases (61%). A statistically not significant trend for increase of minimal length of CM, OCM, and the sum of both was found in the presence of gastroesophageal reflux disease. Neither the presence of intestinal metaplasia nor of pancreatic metaplasia in CM/OCM was correlated with gastroesophageal reflux disease. In conclusion, the high variability in length, the frequent occurrence of intestinal metaplasia and pancreatic metaplasia, and the frequent extension into the esophagus suggest that CM/OCM is a dynamic structure that probably mirrors the influence of underlying gastroesophageal diseases. Because of the short length and incomplete circumferential extension of CM/OCM, future endoscopic-bioptic investigations will probably have to be based on more extensive sampling of the gastroesophageal junction. 相似文献
54.
Kukkonen H Rovamo J Donner K Tammikallio M Raninen A 《Investigative ophthalmology & visual science》2002,43(9):3131-3135
PURPOSE: Because of the limited contrast range, increasing the duration of the noise frame is often the only option for increasing the masking potency of external, white temporal noise. This, however, reduces the high-frequency cutoff beyond which noise is no longer white. This study was conducted to determine the longest noise frame duration that produces the strongest masking effect and still mimics white noise on the detection of sinusoidal flicker. METHODS: Contrast energy thresholds (E(th)) were measured for flicker at 1.25 to 20 Hz in strong, purely temporal (spatially uniform), additive, external noise. The masking power of white external noise, characterized by its spectral density at zero frequency N0, increases with the duration of the noise frame. RESULTS: For short noise frame durations, E(th) increased in direct proportion to N0, keeping the nominal signal-to-noise ratio [SNR = (E(th)/N0)(0.5)] constant at threshold. The masking effect thus increased with the duration of the noise frame and the noise mimicked white noise. When noise frame duration and N0 increased further, the nominal SNR at threshold started to decrease, indicating that noise no longer mimicked white noise. The minimum number of noise frames per flicker cycle needed to mimic white noise decreased with increasing flicker frequency from 8.3 at 1.25 Hz to 1.6 at 20 Hz. CONCLUSIONS: The critical high-frequency cutoff of detection-limiting temporal noise in terms of noise frames per signal cycle depends on the temporal frequency of the signal. This is opposite to the situation in the spatial domain and must be taken into consideration when temporal signals are masked with temporal noise. 相似文献
55.
Hyperbilirubinemia is a frequent side effect induced by long-term therapy with the antibiotic fusidate. The aim of this study was to elucidate the molecular mechanisms of fusidate-induced hyperbilirubinemia by investigating its influence on hepatic transport systems in the canalicular membrane. Using canalicular membrane vesicles from rat liver, we determined the effect of fusidate on the adenosine 5'-triphosphate (ATP)-dependent transport of substrates of the apical conjugate export pump, multi-drug resistance protein 2 (Mrp2, symbol Abcc2) and the bile salt export pump (Bsep, symbol Abcb11). Fusidate inhibited the ATP-dependent transport of the Mrp2 substrates 17beta-glucuronosyl estradiol and leukotriene C4, and the transport of cholyltaurine by Bsep with Ki values of 2.2+/-0.3, 7.6+/-1.3, and 5.5+/-0.8 microM, respectively. To elucidate the in vivo implication of these findings, the effect of fusidate treatment on the elimination of intravenously administered tracer doses of 17beta-glucuronosyl estradiol and cholyltaurine into bile was studied in rats. Treatment with fusidate (100 micromol/kg body weight) reduced the biliary excretion rate of 17beta-glucuronosyl [3H]estradiol and [3H]cholyltaurine by 75 and 80%, respectively. Extended treatment of rats with fusidate (100 micromol/kg body weight, three times daily i.p. for 3 days) reduced hepatic Mrp2 protein levels by 61% (P<0.001). Our data suggest that there are at least two different mechanisms involved in the impairment of transport processes and hepatobiliary elimination by fusidate, direct inhibition of transport of Mrp2 and Bsep substrates by competitive interaction and impairment by a decreased level of hepatic Mrp2. 相似文献
56.
Matias PM Carrondo MA Coelho R Thomaz M Zhao XY Wegg A Crusius K Egner U Donner P 《Journal of medicinal chemistry》2002,45(7):1439-1446
The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been determined at 1.95 A resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (AR(ccr)) isolated from the androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure of the AR(ccr) LBD complexed with 9alpha-fluorocortisol shows the typical conformation of an agonist-bound nuclear receptor in which helix 12 is precisely positioned as a "lid" for the ligand-binding pocket. Binding of 9alpha-fluorocortisol to the AR(ccr) involves favorable hydrogen bond patterns on the C17 and C21 substituents of the ligand due to the mutations at 701 and 877 in the AR(ccr). Our studies provide the first structural explanation for the glucocorticoid activation of AR(ccr), which is important for the development of new therapeutic treatments for androgen-independent prostate cancer. 相似文献
57.
Anjaiah Srirangam Ranjana Mitra Mu Wang J Christopher Gorski Sunil Badve LeeAnn Baldridge Justin Hamilton Hiromitsu Kishimoto John Hawes Lang Li Christie M Orschell Edward F Srour Janice S Blum David Donner George W Sledge Harikrishna Nakshatri David A Potter 《Clinical cancer research》2006,12(6):1883-1896
PURPOSE: These studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vivo and, if so, how. EXPERIMENTAL DESIGN: Ritonavir effects on breast cancer cell growth were studied in the estrogen receptor (ER)-positive lines MCF7 and T47D and in the ER-negative lines MDA-MB-436 and MDA-MB-231. Effects of ritonavir on Rb-regulated and Akt-mediated cell proliferation were studied. Ritonavir was tested for inhibition of a mammary carcinoma xenograft. RESULTS: ER-positive estradiol-dependent lines (IC50, 12-24 micromol/L) and ER-negative (IC50, 45 micromol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-alpha levels notably in ER-positive lines. Ritonavir causes G1 arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D1 but not cyclin E, and depletes phosphorylated Rb and Ser473 Akt. Ritonavir induces apoptosis independent of G1 arrest, inhibiting growth of cells that have passed the G1 checkpoint. Myristoyl-Akt, but not activated K-Ras, rescues ritonavir inhibition. Ritonavir inhibited a MDA-MB-231 xenograft and intratumoral Akt activity at a clinically attainable serum Cmax of 22 +/- 8 micromol/L. Because heat shock protein 90 (Hsp90) substrates are depleted by ritonavir, ritonavir effects on Hsp90 were tested. Ritonavir binds Hsp90 (K(D), 7.8 micromol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90alpha short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations. CONCLUSIONS: Ritonavir inhibits breast cancer growth in part by inhibiting Hsp90 substrates, including Akt. Ritonavir may be of interest for breast cancer therapeutics and its efficacy may be increased by sustained exposure or Hsp90 RNA interference. 相似文献
58.
Sudden unexplained death in children with epilepsy 总被引:9,自引:0,他引:9
BACKGROUND: Sudden unexplained death is a significant cause of mortality in people with epilepsy. Risk factors that have been identified include male sex, poor compliance with medications, and antiepileptic drug (AED) polypharmacy. However, these may not apply to the pediatric population in which the causes of epilepsy differ from the adult population. Therefore, risk factors for sudden unexplained death in epilepsy (SUDEP) in children must be evaluated independently from those in the adult population. METHODS: Cases of SUDEP in children less than 18 years of age occurring over a 10-year period in the province of Ontario, Canada, were identified. Records were reviewed for demographic and clinical features and neuropathology findings. RESULTS: Twenty-seven cases of SUDEP in children were identified. Sixty-three percent were male. Age at death ranged from 8 months to 15 years. Fourteen children had symptomatic epilepsy (52%), five had cryptogenic epilepsy (18%), and eight had idiopathic epilepsy (30%). Twelve children were treated with one AED (46%), 10 were on two AED (38%), and three were on three AED (12%). At the time of death, seven children had one serum AED concentration below the therapeutic range (35%) and 12 children had AED levels within the therapeutic range (60%). CONCLUSIONS: This case series represents the largest series of sudden unexplained death in children with epilepsy. At least two previously described risk factors for SUDEP in adults, low serum AED levels at time of death and AED polytherapy, do not appear to be significant in children. 相似文献
59.
A DNA endonuclease, isolated from the nuclei of normal human and xeroderma
pigmentosum complementation group A (XPA) cells, which recognizes
predominately pyrimidine dimers, was examined for the mechanism by which it
locates sites of damage on UVC-irradiated DNA. In reaction mixtures with
low ionic strengths (i.e. lacking KCl), the normal and XPA endonuclease
locate sites of UV damage on both naked and reconstituted nucleosomal DNA
by different mechanisms. On both of these substrates, the normal
endonuclease acts by a processive mechanism, meaning that it binds
non-specifically to DNA and scans the DNA for sites of damage, whereas the
XPA endonuclease acts by a distributive one, meaning that it randomly
locates sites of damage on DNA. However, while both the normal and XPA
endonucleases can incise UVC irradiated naked DNA, they differ in ability
to incise damaged nucleosomal DNA. The normal endonuclease showed increased
activity on UVC treated nucleosomal DNA compared with naked DNA, whereas
the XPA endonuclease showed decreased activity on the damaged nucleosomal
substrate. Since a processive mechanism of action is sensitive to the ionic
strength of the micro-environment, the KCl concentration of the reaction
was increased. At 70 mM KCI, the normal endonuclease switched to a
distributive mechanism of action and its ability to incise damaged
nucleosomal DNA also decreased. These studies show that there is a
correlation between the ability of these endonucleases to act by a
processive mechanism and their ability to incise damaged nucleosomal DNA;
the normal endonuclease, which acts processively, can incise damaged
nucleosomal DNA, whereas the XPA endonuclease, which acts distributively,
is defective in ability to incise this substrate.
相似文献
60.
Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is
associated with an increased risk of hepatocellular carcinoma (HCC). The
hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular
DNA. To determine whether nutritional factors and hormonal status may
influence the binding of AFB1 to hepatic DNA, a cross- sectional study was
performed on a total of 42 male asymptomatic hepatitis B surface antigen
(HBsAg) carriers and 43 male non-carriers in a cohort study on the
multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo,
AFB1-N7-guanine, was measured by high- performance liquid chromatography in
urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg
carriers had a higher detection rate of urinary AFB1-DNA adducts than
non-carriers and the difference was statistically significant after
multivariate adjustment. After taking into account the total AFB1 urinary
metabolite level, chronic HBsAg carrier status, and other potential
confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and
beta-carotene were positively associated with the detection rate of the
AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level
was inversely related to the presence of the adducts in urine. The
association of urinary AFB1-DNA adducts with the plasma levels of
cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was
observed at both low and high exposure levels of AFB1. There was a
synergistic interaction of plasma alpha-tocopherol with alpha- and beta-
carotene on the adduct levels. No association with the adducts was found
for plasma levels of retinol and testosterone. This study demonstrated
different associations of antioxidant vitamins with AFB1- DNA adduct
formation. The data consistent with our previous finding in cultured
woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced
AFB1-DNA adduct formation suggest that prospective investigation of the
relationship between plasma micronutrients and risk of AFB1-related HCC is
warranted.
相似文献