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101.
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E. TANAKA C. NARISAWA H. NAKAMURA Y. SAWA H. ETOH K. TADANO 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(8):795-802
1. The metabolism of 50 μM [3-14C] coumarin has been studied in a panel of 12 human liver microsomal samples of known P450 isoenzyme profile.2. [3-14C] coumarin was metabolized by human liver microsomes to various polar products including 3-, 4- and 7-hydroxycoumarins (3-HC, 4-HC and 7-HC) 6,7-dihydroxycoumarin (6,7-DiHC), o-coumaric acid (o-CA), o-hydroxyphenyl-acetaldehyde (o-HPA), o-hydroxyphenylethanol (o-HPE), o-hydroxyphenylacetic acid (o-HPAA) and o-hydroxyphenylpropionic acid (o-HPPA) and to product(s) that bind covalently to microsomal proteins.3. For all 12 subjects, mean rates of [3-14C] coumarin metabolism to total polar products (metabolism to all products except product(s) covalently bound to microsomal proteins), 7-HC, the 3-hydroxylation pathway (sum of 3-HC, o-HPA, o-HPE and o-HPAA), o-HPPA, 6,7-DiHC and covalent binding were 1420, 1230, 73.8, 52.5, 9.5 and 4.8 pmol/min/mg protein respectively.4. Marked interindividual differences in [3-14C] coumarin metabolism to total polar products (30-fold variation) and 7-HC (2250-fold variation) were observed.5. Good correlations were observed between [3-14C] coumarin metabolism and total polar products, 7-HC, o-HPPA and 6,7-DiHC, but not to 3-hydroxylation pathway products and levels of 2A6 and 2B6 in human liver microsomes.6. [3-14C] coumarin metabolism to any polar products did not correlate with levels of 1A2, 2C8, 2C9, 2E1, 3A3/4 and 4A1 in human liver microsomes. 相似文献
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PREDICTION OF THE THERAPEUTIC DOSE FOR BENZODIAZEPINE ANXIOLYTICS BASED ON RECEPTOR OCCUPANCY THEORY
KIYOMI ITO AKIKO ASAKURA YASUHIKO YAMADA KOUICHI NAKAMURA YASUFUMI SAWADA TATSUJI IGA 《Biopharmaceutics & drug disposition》1997,18(4):293-303
Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (Kd), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the Kd values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r >0·77). In contrast, a good log-linearity (r =0·96) was observed in the correlation between their Kd values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52·3±3·2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory. ©1997 by John Wiley & Sons, Ltd. 相似文献
106.
Involucrin expression in skin appendage tumours 总被引:1,自引:0,他引:1
T. HASHIMOTO N. INAMOTO K. NAKAMURA R. HARADA 《The British journal of dermatology》1987,117(3):325-332
The expression of involucrin was examined in 23 skin tumours of hair follicle origin, 17 tumours of sweat gland origin and three tumours of unknown origin, using an immunoperoxidase technique. All tumours from the hair follicle showed a positive reaction for involucrin. In particular keratoacanthoma and the squamous eddies in various tumours stained strongly. Trichofolliculoma, trichilemmoma and pilomatrixoma exhibited characteristic staining patterns which resembled those in the normal hair follicle. On the other hand the majority of the tumours of sweat gland origin did not stain, with restricted positive reactions in areas showing lumen formation or squamous metaplasia. In contrast to the lack of staining in syringoma, a positive reaction was observed in desmoplastic trichoepithelioma, which is histologically similar to syringoma. Clear cell acanthoma, the origin of which is still controversial, showed a staining pattern which indicated that its origin may not be in the sweat gland. These results suggest that testing for involucrin in skin appendage tumours may be very useful for understanding the kinetics of maturation as well as in determining the origin of the tumours. 相似文献
107.
MASAHIRO MIZOBUCHI M.D. YOSHIHISA ENJOJI M.D. SHIGERU NAKAMURA M.D. HIROMI MURANISHI M.D. MAKOTO UTSUNOMIYA M.D. ATSUSHI FUNATSU M.D. TOMOKO KOBAYASHI M.D. 《Pacing and clinical electrophysiology : PACE》2010,33(3):266-273
Backgrounds: Brugada syndrome can be overlooked due to its dynamic change in its electrocardiogram (ECG) manifestation. We hypothesized that positive ventricular late potential (VLP) in patients with nonspecific ECG would predict the inducible coved ST elevation (type‐1 Brugada ECG) and the patients at high risk. Methods: Thirty‐four patients of nonspecific ECG without structural heart disease were eligible for this study. All patients were referred for evaluation of syncopal episodes and/or cardiac arrest and/or frequent episodes of ventricular premature contractions. We assessed the correlation between baseline VLP and the alteration to a drug‐induced type‐1 Brugada ECG, and also evaluated the diagnostic accuracy of positive VLP in normal ECG subjects for the appearance of a drug‐induced type‐1 Brugada ECG. Results: Twenty‐one patients presented positive VLP and 13 patients showed negative VLP. Parameters of VLP (fQRSd, RMS40, LAS40) presented significant correlation with the alteration to a type‐1 ECG by pilsicainide. VLP demonstrated high sensitivity and negative predictive value for the prediction of type‐1 Brugada ECG. Furthermore, in their follow‐up, at least two cases of ventricular fibrillation were recognized in 21 of positive VLP patients with apparently normal ECGs. Conclusions: VLP in apparently normal ECG can predict the alteration to a drug‐induced type‐1 Brugada ECG and unmask the patients at risk. (PACE 2010; 33:266–273) 相似文献
108.
Different effects of halothane, isoflurane and sevoflurane on sarcoplasmic reticulum of vascular smooth muscle in dog mesenteric artery 总被引:1,自引:0,他引:1
M. YAMAMOTO Y. HATANO M. KAKUYAMA K. NAKAMURA T. TACHIBANA H. MAEDA K. MORI 《Acta anaesthesiologica Scandinavica》1997,41(3):376-380
Background: The direct effect of halothane on vascular smooth muscle is mediated in part via its effects on the sarcoplasmic reticulum (SR). Little information is available concerning the effects of other volatile anesthetics including isoflurane and sevoflurane, whose vascular effects differ from those of halothane. The aim of the present study was to compare the effects of halothane, isoflurane and sevoflurane on the SR by testing the contraction induced by caffeine in vascular smooth muscle. Methods: Rings without endothelium from isolated canine mesenteric artery were mounted in physiological saline solution (PSS) for isometric tension recording. After complete depletion of Ca2+ from the SR by adding 35 mM caffeine, the rings were exposed to normal Ca2+ containing PSS (Ca2+ loading), to Ca2+-free PSS for 10 min, and then to 15 mM caffeine to induce contraction. Anesthetics were administered during Ca2+ loading, the Ca2+-free phase and simultaneously with caffeine administration. Results: Halothane (0.5-2%) attenuated the caffeine-induced contraction of canine mesenteric artery when administered during Ca2+ loading in the SR (P<0.001), whereas isoflurane and sevoflurane (1–4%) failed to affect the contraction. When given simultaneously with caffeine, halothane (1–2%) potentiated the caffeine-induced contraction (P<0.05), but isoflurane and sevoflurane had no effect. When given before caffeine administration, halothane (0.5-2%), isoflurane (24%) and sevoflurane (4%) all potentiated the caffeine-induced contraction (P<0.05). Conclusion: It has been shown that halothane not only potentiates caffeine- induced Ca2+ release from the SR, but also induces contraction by releasing Ca2+ from the SR. We conclude that halothane decreases Ca2+ accumulation in the SR while exerting facilitative and additive effects on caffeine-induced Ca2+ release from the SR when applied before caffeine administration and simultaneously with caffeine, respectively, whereas isoflurane and sevoflurane lack both the ability to decrease Ca2+ accumulation and an additive effect on caffeine-induced Ca2+ release from the SR, but are able to facilitate Ca2+ release by caffeine. 相似文献
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110.
In 1987 Young and Simpson reported a child with hypothyroidism, a congenital heart disease, severe mental retardation and striking facial dysmorphism, including microcephaly, blepharophimosis, bulbous nose, thin lip, low-set ears and micrognathia. This study presents an 8-month-old boy with virtually identical features to those in Young and Simpson's original case. The patient is a sporadic case and his parents are unrelated and phenotypically normal, hence the family data corresponds to any mode of inheritance. This is the first male case reported in the world and the first in Orientals. 相似文献