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51.
Keiko Goto Yutaka Fujiwara Takeshi Isobe Naoko Chayahara Naomi Kiyota Toru Mukohara Yukari Tsubata Takamasa Hotta Kenji Tamura Noboru Yamamoto Hironobu Minami 《Cancer science》2019,110(6):1987-1994
Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m2), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m2), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m2), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m2). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe. 相似文献
52.
Eo Toriyama Tomoko Hata Kenichi Yokota Masahiko Chiwata Rena Kamijo Miki Hashimoto Masataka Taguchi Makiko Horai Masatoshi Matsuo Emi Matsuo Yumi Takasaki Yasuhisa Kawaguchi Hidehiro Itonaga Shinya Sato Koji Ando Yasushi Sawayama Jun Taguchi Yoshitaka Imaizumi Hideki Tsushima Tatsuro Jo Shinichiro Yoshida Yukiyoshi Moriuchi Yasushi Miyazaki 《Cancer science》2020,111(12):4490
The efficacy of azacitidine (AZA) on survival of lower risk (LR) ‐ myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long‐term survival benefit of AZA for patients with LR‐MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR‐MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis‐stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection‐related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR‐MDS patients. 相似文献
53.
Mitsutoshi Yamada Suguru Sato Reina Ooka Kazuhiro Akashi Akihiro Nakamura Kenji Miyado Hidenori Akutsu Mamoru Tanaka 《Reproductive Medicine and Biology》2021,20(1):53-61
BackgroundPathogenic mitochondrial (mt)DNA mutations, which often cause life‐threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second‐generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins.MethodsBased on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT.Main findingsMRT does not compromise pre‐implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation.ConclusionThe maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT. 相似文献
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56.
Toshito Nakagawa Stephen Fowler Kenji Takanashi Kuresh Youdim Tsuyoshi Yamauchi Kosuke Kawashima 《Xenobiotica; the fate of foreign compounds in biological systems》2018,48(6):546-554
1.?The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated.2.?The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b.3.?M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major.4.?In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug–drug interactions. 相似文献
57.
Hille T. de Vries Takashi Nakamae Kenji Fukui Damiaan Denys Jin Narumoto 《European neuropsychopharmacology》2018,28(6):780-781
Background
A large number of studies have reported the high prevalence of problematic internet use (PIU) among adolescents and students (13-50%)1, and PIU has been associated with many psychiatric symptoms2. In contrast, only a few studies have investigated its prevalence among the adult population. To the best of our knowledge, there have been no studies investigating the prevalence and comorbidity of PIU in a psychiatric population although psychiatric symptoms might either induce PIU in patients with psychiatric illnesses, or PIU might induce or aggravate psychiatric symptoms. The aims of this study are to investigate the prevalence of PIU and psychiatric co-morbidity among adult psychiatric patients.Methods
Three hundred thirty-three adult psychiatric patients with internet access were recruited at the outpatient clinic of psychiatry at the University Hospital, Kyoto Prefectural University of Medicine over a three-month period. Two hundred thirty-one of them completed the survey (response rate: 69.4%; Male/Female/Transgender: 90/139/2; mean age = 42.2). We divided participants into “normal internet users” and “problematic internet users” using a combination of Young’s Internet Addiction Test (IAT) and the Compulsive Internet Use Scale (CIUS), using established cut-off values. Demographic data and comorbid psychiatric symptoms were compared between the two groups, using self-rating scales measuring insomnia (Athens Insomnia Scale, AIS), depression (Beck Depression Inventory, BDI), anxiety (State-trait Anxiety Inventory, STAI), attention deficit hyperactivity disorder (ADHD) (Adult ADHD Self-report Scale, ASRS), autism (Autism Spectrum Quotient, AQ), obsessive-compulsive disorder (OCD) (Obsessive-Compulsive Inventory, OCI), social anxiety disorder (SAD) (Liebowitz Social Anxiety Scale, LSAS), alcohol abuse, and impulsivity (Barratt Impulsive Scale, BIS).Results
Of our 231 respondents, 58 (25.1%) were defined as problematic internet users, as they scored high on either the IAT (40 or more) or CIUS (21 or more). The age of problematic internet users was significantly lower than that of normal internet users (35.9 vs 43.6, p<0.001, Mann-Whitney U test). The problematic internet users scored significantly higher on scales measuring sleep problems (AIS, 8.8 for problematic internet users vs 6.3 for normal internet users, p<0.001), depression (BDI, 27.4 vs 18.3, p<0.001), trait anxiety (STAI, 61.8 vs 53.9, p<0.001), ADHD (ASRS, part A 3.1 vs 1.8 and part B 3.5 vs 1.8, p<0.001), autism (AQ, 25.9 vs 21.6, p<0.001), OCD (OCI, 63.2 vs 36.3, p<0.001), SAD (LSAS, 71.4 vs 54.0, p<0.001), and impulsivity (BIS, 67.4 vs 63.5, p=0.004).Conclusions
The prevalence of PIU among adult psychiatric patients is relatively high (25%). As previous studies reported in the general population, PIU among adult psychiatric patients was associated with lower age and higher psychiatric comorbidity. Longitudinal research is needed to determine any causal relations between problematic internet use and psychopathological illnesses. 相似文献58.
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60.
Shin-ichiro Nitta Mari Hashimoto Yasuhiro Kazuki Shoko Takehara Hiraku Suzuki Mitsuo Oshimura Hidetaka Akita Kan Chiba Kaoru Kobayashi 《The AAPS journal》2018,20(3):61
Cytochrome P450 3A (CYP3A) enzymes metabolize approximately half of all drugs on the market. Since the endogenous compounds 4β-hydroxycholesterol (4β-HC) and 25-hydroxycholesterol (25-HC) are generated from cholesterol via CYP3A enzymes, we examined whether the plasma levels of 4β-HC and 25-HC reflect hepatic CYP3A4 activity by using a CYP3A-humanized mouse model, in which the function of endogenous Cyp3a was genetically replaced by human CYP3A. CYP3A-humanized mice have great advantages for evaluation of the relationship between hepatic CYP3A protein levels and plasma and hepatic levels of 4β-HC and 25-HC. Levels of CYP3A4 protein in the liver microsomes of CYP3A-humanized mice were increased by treatment with pregnenolone-16α-carbonitrile, a CYP3A inducer. Hepatic and plasma levels of 4β-HC and 25-HC normalized by cholesterol were significantly correlated with hepatic CYP3A4 protein levels. In addition, in vitro studies using human liver microsomes showed that the formation of 4β-HC was strongly inhibited by a CYP3A inhibitor, while the inhibitory effect of the CYP3A inhibition on the formation of 25-HC was weak. These results suggested that CYP3A mainly contributed to the formation of 4β-HC in human liver microsomes, whereas other factors may be involved in the formation of 25-HC. In conclusion, the in vivo studies using CYP3A-humanized mice suggest that plasma 4β-HC and 25-HC levels reflect hepatic CYP3A4 activity. Furthermore, taking the results of in vitro studies using human liver microsomes into consideration, 4β-HC is a more reliable biomarker of hepatic CYP3A activity. 相似文献