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991.
Yuji Kumagai Tomoe Fujita Machiko Ozaki Shin‐ichi Yokota Mika Maeda Mizue Shida Yoshio Otani Hidetoshi Yamaya Hideo Tsuruta 《Basic & clinical pharmacology & toxicology》2009,104(5):352-359
Abstract: TAS‐108 is a novel steroidal anti‐oestrogen, expected to be useful for the treatment of breast cancer. The present study was conducted to investigate the safety, tolerability and pharmacokinetics of TAS‐108 following the administration at a single oral dose of 40 mg to up to 120 mg in 12 post‐menopausal women and the effect of food on the pharmacokinetics of the drug. All adverse events were mild and involved transient symptoms that resolved without therapeutic intervention. TAS‐108 was readily absorbed and plasma levels of TAS‐108 steadily declined, apparently in a multi‐exponential manner. Cmax and AUC0‐12 were proportionally increased with increasing dose of TAS‐108. The Cmax and AUC0‐t of TAS‐108 and its metabolite, deEt‐TAS‐108, were significantly increased to approximately 150% when TAS‐108 was administered after a meal. Food did not affect the elimination half‐life of TAS‐108 or its metabolites. In this escalating dose‐study of TAS‐108, the drug was well tolerated by healthy post‐menopausal Japanese women. The pharmacokinetics of TAS‐108 indicated dose proportionality, and its bioavailability was significantly increased by food intake. 相似文献
992.
Hiroko Segawa Akemi Onitsuka Masashi Kuwahata Etsuyo Hanabusa Junya Furutani Ichiro Kaneko Yuka Tomoe Fumito Aranami Natsuki Matsumoto Mikiko Ito Mitsuru Matsumoto Minqi Li Norio Amizuka Ken-ichi Miyamoto 《Journal of the American Society of Nephrology : JASN》2009,20(1):104-113
Primary renal inorganic phosphate (Pi) wasting leads to hypophosphatemia, which is associated with skeletal mineralization defects. In humans, mutations in the gene encoding the type IIc sodium–dependent phosphate transporter lead to hereditary hypophophatemic rickets with hypercalciuria, but whether Pi wasting directly causes the bone disorder is unknown. Here, we generated Npt2c-null mice to define the contribution of Npt2c to Pi homeostasis and to bone abnormalities. Homozygous mutants (Npt2c−/−) exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D3 levels, but they did not develop hypophosphatemia, hyperphosphaturia, renal calcification, rickets, or osteomalacia. The increased levels of 1,25-dihydroxyvitamin D3 in Npt2c−/− mice compared with age-matched Npt2c+/+ mice may be the result of reduced catabolism, because we observed significantly reduced expression of renal 25-hydroxyvitamin D–24-hydroxylase mRNA but no change in 1α-hydroxylase mRNA levels. Enhanced intestinal absorption of calcium (Ca) contributed to the hypercalcemia and increased urinary Ca excretion. Furthermore, plasma levels of the phosphaturic protein fibroblast growth factor 23 were significantly decreased in Npt2c−/− mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c+/+, Npt2c+/−, and Npt2c−/− mice. In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis.Inorganic phosphate (Pi) is an essential nutrient in terms of both cellular metabolism and skeletal mineralization. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi needs. Up to 70% of filtered Pi is reabsorbed in the proximal tubule in which sodium (Na)-dependent Pi transport systems in the brush border membrane (BBM) mediated the rate-limiting step in the overall Pi reabsorptive process.1, 2 The type II Na/Pi co-transporter (Npt2a and Npt2c) is expressed in the BBM of the renal proximal tubular cells.2, 3 The type IIa Na/Pi co-transporters (Npt2a) play a major role in reabsorption (70 to 80%) in the kidney. Npt2a-knockout (KO) mice exhibit renal Pi wasting, loss of BBM Na/Pi co-transport, hypophosphatemia, and an appropriate adaptive increase in the serum concentration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] with attendant hypercalcemia, hypercalciuria, and hypoparathyroidism but do not develop rickets.2, 4Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria.5 Npt2a-KO mice display biochemical features similar to patients with HHRH; the bone phenotype is markedly different in the human and mouse disorders.2, 4 Jones et al.6 excluded mutations of the renal Na/Pi transporter NPT2 (human Npt2a) gene in affected members of the family that was originally described by Tieder and colleagues.7 More recently, linkage analyses have suggested that HHRH may arise from mutations in the NPT2c/SLC34A3 gene.8 That HHRH is caused by a loss-of-function mutation is compatible with HHRH phenotype and the prevailing view of renal phosphate regulation. These observations suggest that the Npt2c has an important role in renal Pi reabsorption and bone mineralization and that it may be a key determinant of plasma Pi concentrations in humans; however, it is not clear why loss of function of the less abundant and energetically less favorable electroneutral NaPi-IIc transporter causes rickets and osteomalacia in humans, whereas mutations in the more abundant electrogenic Npt2a elicits a mild skeletal phenotype that lacks the typical features of rickets and osteomalacia in mice. Thus, the goal of this study was to investigate the role of the Npt2c transporter in the overall maintenance of Pi homeostasis and bone mineralization by disrupting the murine Npt2c gene and analyzing the phenotypes. 相似文献
993.
Konishi C Sugama J Sanada H Okuwa M Konya C Nishizawa T Shimamura K 《International wound journal》2008,5(3):470-475
This study aimed to determine the predictive accuracy and factors deteriorating blanchable erythema. A prospective cohort study was conducted in a 832-bed university hospital in Japan. Skin condition, risk factors, care plans and practices were measured everyday for 4 weeks by direct assessments and chart review by research staff. Blanchable erythema developed in 62 (24.9%) and a pressure ulcer in 8 (3.2%) patients. Six of the 62 blanchable erythema patients worsened to pressure ulcer of either stage I or II. Calculating the accuracy of blanchable erythema for predicting pressure ulcer development, sensitivity was 75%, specificity 77% and positive likelihood ratio 3.26. The factors found to deteriorate blanchable erythema were K-scale 'pressure' and inadequate support surface management to a patient whose condition was deteriorating. These results suggested that the value of positive likelihood ratio means small effect to the clinical use. However, if adequate support surface management were implemented to blanchable erythema patients, the incidence of pressure ulcer would probably fall to 0.8%. 相似文献
994.
Diffuse Large B-cell Lymphoma in the Ampulla of Vater Causing Obstructive Jaundice: Report of a Case
We report a case of diffuse large B-cell lymphoma (DLBCL) in the ampulla of Vater, causing painless obstructive jaundice in
a 78-year-old woman. Duodenal endoscopy revealed a mass in the ampulla of Vater and narrowing of the second portion of the
duodenum, although diagnosing DLBCL from an endoscopic biopsy was impossible because there were several kinds of leukocytes
in the infiltrate. We performed pylorus-preserving pancreatoduodenectomy to establish a histological diagnosis, relieve the
obstructive jaundice, and remove the narrowed second portion of the duodenum. Histological and immunohistochemical examination
of the surgically resected specimen confirmed a diagnosis of DLBCL. Chemotherapy is the mainstay of treatment for DLBCL; however,
surgery still plays an important role when the histological diagnosis cannot be established preoperatively and when complications
are not amenable to nonsurgical therapy. 相似文献
995.
Ieta K Tanaka F Haraguchi N Kita Y Sakashita H Mimori K Matsumoto T Inoue H Kuwano H Mori M 《Annals of surgical oncology》2008,15(2):638-648
Background
Human prominin-1 (PROM1, CD133) was used as a marker to detect stem cells (progenitor cells) and cancer stem cells (tumor-initiating cells) in various tissues.
The purpose of this study was to investigate the biological and genetic characteristics of tumor-initiating cells in colon
cancer with both in vitro and in vivo analyses.
Methods The CD133 expression of 12 colon cancer cell lines was evaluated. CD133+ cells were isolated by flow cytometry and examined for in vivo tumor formation, in vitro proliferation, colony formation, and invasion ability. Additionally, we used microarray analysis to compare gene expression
profiles between CD133+ and CD133– isolated cells.
Results CD133+ cells were found in 5 of 12 colon cancer cell lines. Isolated CD133+ cells from the HT29 colon cancer cell line exhibited a higher tumorigenic potential than CD133– cells in the in vivo tumor formation assay. Furthermore, it was shown that CD133+ cells are more proliferative and have higher colony-forming and invasive abilities than CD133– cells in vitro. Microarray analysis found differential gene expression correlating with CD133 expression.
Conclusions It was confirmed that CD133+ cells in colon cancer are useful markers for the detection of tumor-initiating cells. Intimate biological and genetic features
of CD133+ cells in colon cancer cell lines were also revealed. The biological characteristics of CD133+ cells and differentially expressed genes in these cells will help elucidate more details of tumor-initiating cells in colon
cancer.
Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users 相似文献
996.
997.
CD133<Superscript>+</Superscript>CD44<Superscript>+</Superscript> Population Efficiently Enriches Colon Cancer Initiating Cells 总被引:1,自引:0,他引:1
Haraguchi N Ohkuma M Sakashita H Matsuzaki S Tanaka F Mimori K Kamohara Y Inoue H Mori M 《Annals of surgical oncology》2008,15(10):2927-2933
Background Previous reports have demonstrated that CD133+ cells or CD44+ cells might be cancer initiating cells (CIC) of colon cancer. However, the association between the two cell types is unclear.
In this study, we evaluated the tumorigenicity of each population of human colon cancer divided by CD133 and CD44 using non-obese
diabetic/severe combined immunodeficient (NOD/SCID) mice.
Methods Using the colon cancer cell lines HT29 and Caco2 we evaluated the change of expression status of CD133 or CD44 by a treatment
with sodium butyrate (NaBT) that can induce cellular differentiation. Next, we prepared ten clinical samples of colon cancer
and analyzed the expression and tumorigenicity of CD133 and CD44.
Results With NaBT treatment, CD44 expression was greatly downregulated in both HT29 and Caco2 (HT29: nontreatment versus treatment;
77.8% versus 0.6%, Caco2: 14.0% versus 0.4%, respectively), more than CD133 expression (HT29: nontreatment versus treatment;
90.1% versus 67.7%, Caco2: 98.9% versus 76.3%, respectively). In clinical samples, the percentages of CD133+ cells and CD44+ cells varied from 0.3% to 82.0% (mean 35.5%), and from 11.5% to 58.4% (mean 30.0%), respectively. Subcutaneous injection
of CD133+ or CD44+ cells made a tumor in all mice (3/3 and 4/4, respectively). The combined analysis of CD133 and CD44 revealed that only the
CD133+CD44+ population had the ability to produce a tumor (3/3).
Conclusion The findings demonstrate that, at present, the CD133+CD44+ population may be the best to identify tumor initiating cells of human colon cancer.
Naotsugu Haraguchi: Awardee of Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan) for
the 3rd Term Comprehensive 10- Year Strategy for Cancer Control. 相似文献
998.
Various factors are thought to be involved in the pathogenesis of schizophrenia. Recently, biochemical studies using human samples and animal models suggest that oxidative stress and the resulting formation of reactive carbonyl compounds (RCOs) contribute to the pathophysiology of schizophrenia. The accumulation of RCOs, carbonyl stress, results in the modification of proteins and formation of advanced glycation end products (AGEs), such as pentosidine. We previously reported that a certain subtype of schizophrenic patients exhibit idiopathic carbonyl stress with high plasma pentosidine levels and the depletion of vitamin B6, without underlying diabetes or chronic kidney disease, the two major causes of elevated AGEs. Agents able to inhibit AGE formation or entrap carbonyl compounds may also prove to be of therapeutic value. Pyridoxamine, a non-toxic, water-soluble vitamin B6, has potent abilities to entrap toxic carbonyl compounds and prevent toxicity. In particular, the markedly lowered vitamin B6 levels in schizophrenic patients with high pentosidine levels suggest that pyridoxamine may prove to be clinically useful. 相似文献
999.
Minato H Shimizu J Arano Y Saito K Masunaga T Sakashita T Nojima T 《Pathology international》2012,62(4):281-286
Sclerosing mesenteritis is a rare inflammatory and fibrosing disorder of unknown etiology, while IgG4-related disease (IgG4-RD) consists of mass-forming, fibroinflammatory lesions characterized by high serum IgG4 levels and tissue infiltration of many IgG4-positive plasma cells; obliterative phlebitis is common. This report describes a case of sclerosing mesenteritis that was considered a manifestation of IgG4-RD. A 53-year-old man underwent right hemicolectomy because of an ileocecal mass that did not improve with conservative therapy. The ill-defined fibroinflammatory lesion extended in the mesentery with storiform fibrosis, obliterative phlebitis, and infiltration of many IgG4-positive plasma cells. The ratio of IgG4-positive/IgG-positive cells was 64%, and the ratio of forkhead box protein 3 (FOXP3)-positive/CD4-positive cells was elevated (13%). It is likely that at least some cases of sclerosing mesenteritis are a manifestation of IgG4-RD. It is important to investigate this relationship because steroid therapy may benefit such cases. 相似文献
1000.