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121.
Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the
promutagenic DNA base lesion, O
6-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating
agents such as N-nitroso compounds can produce O
6-methylguanine in cellular DNA. Unrepaired, O
6-methylguanine can lead to the formation of G ? A transition mutations, a known mechanism of human oncogene activation and
tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O
6-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular
carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte
DNA. The paramount importance of O
6-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased
hepatic levels of repair enzyme O
6-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating
agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized
by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O
6-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from
animal models, this suggested a mechanism in which persistence of O
6-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific
gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O
6-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might
be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow
parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of
O
6-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human
MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive
localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively
measure O
6-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular
carcinoma.
Received for publication on July 6, 1998; accepted on Aug. 12, 1998 相似文献
122.
Cutaneous T-cell lymphoma 总被引:1,自引:0,他引:1
123.
Angiotensin-converting enzyme (ACE) gene polymorphism in type II diabetic patients with increased albumin excretion rate 总被引:1,自引:0,他引:1
Sianna Panagiotopoulos Trudy Jeanne Smith G. Peter Aldred Elizabeth Jane Baker Carolyn Jane Jacklin George Jerums 《Journal of diabetes and its complications》1995,9(4):272-276
Approximately one in three patients with diabetes is at risk of developing kidney disease, despite current methods of treatment. It has long been suspected that diabetic kidney disease has a genetic basis, but this has been difficult to prove. Polymorphisms of the angiotensin-converting enzyme (ACE) gene have been shown to be related to the occurrence of nephropathy in type I diabetic patients. This study showed that there was no association in the ACE genotype frequency and increased albumin excretion rate in type II diabetic patients. 相似文献
124.
Spouse Concordance for Alcohol Dependence and Heavy Drinking: Evidence from a Community Sample 总被引:2,自引:0,他引:2
Jane D. McLeod 《Alcoholism, clinical and experimental research》1993,17(6):1146-1155
Using data from a community sample of 586 married couples, levels of spouse concordance for lifetime and current alcohol dependence and heavy drinking were estimated. In addition, marital quality ratings in concordant and discordant couples were compared. Spouse concordance was significant for lifetime alcohol dependence and for both lifetime and current heavy drinking. Marital quality varied as a function of current heavy drinking and alcohol dependence such that members of couples in which neither spouse drank heavily reported better marital quality than other couples. Furthermore, although marital quality did not differ significantly between concordant and discordant couples, couples concordant for current heavy drinking consistently reported poorer marital quality than other couples. 相似文献
125.
Serotonin (5-HT) may be inhibitory to micturition at a spinal level. A potential mechanism of action for serotonergic inhibition of bladder function is a depression of the ascending limb of the supraspinal reflex mediating micturition. Ascending activity evoked by pelvic nerve stimulation was recorded in the thoracic spinal cord of anesthetized cats. For comparison, spinal reflex activity evoked by pelvic nerve stimulation was recorded on the pudendal nerve. The effects of intrathecal administration of serotonergic agents were examined to determine whether spinal and supraspinal responses to bladder afferent activation were modulated by 5-HT. Methysergide (60 nmol), a non-selective serotonergic antagonist, increased ascending activity by 61±7% and depressed spinal reflex activity by 38±6%. Zatosetron (10 nmol), a 5-HT3 antagonist had a similar effect on both activities (increased by 93±24% and decreased by 77±7%, respectively). The effect on ascending activity of blocking 5-HT3 receptors was also confirmed with ICS 205930 and MDL 72222. 2-Methyl-5-HT (800 nmol), a 5-HT3 agonist, depressed ascending activity to 46±9% of control, but enhanced spinal reflex activity by 73±92%. These results demonstrate that stimulation of 5-HT3 and methysergide-sensitive 5-HT receptors can inhibit ascending activity and facilitate spinal reflex activity elicited by activation of bladder afferents. It is suggested that descending serotonergic pathways may participate in the spinal coordination of urinary continence. 相似文献
126.
Head injury mortality in two centers with different emergency medical services and intensive care 总被引:7,自引:0,他引:7
A R Colohan W M Alves C R Gross J C Torner V S Mehta P N Tandon J A Jane 《Journal of neurosurgery》1989,71(2):202-207
The authors report data collected prospectively on 551 cases of head injury in New Delhi, India, and 822 cases in Charlottesville, Virginia. The mortality rate, adjusted for initial severity of injury, was 11.0% in New Delhi versus 7.2% in Charlottesville (p less than 0.02). There was a striking similarity in mortality rates at both centers when comparing patients with the least severe head injuries and those with the most severe injuries according to the motor score of the Glasgow Coma Scale (GCS M). However, in the group with an abnormal but purposeful motor response (GCS M = 5), the mortality rate was 12.5% in New Delhi versus 4.8% in Charlottesville (p less than 0.01). The relative absence of prehospital emergency care and the delay in admission after head injury in New Delhi are cited as two possible causes for the differences in mortality rates in this subgroup of patients with "moderate" head injuries. 相似文献
127.
Willis S Hutchins AM Hammet F Ciciulla J Soo WK White D van der Spek P Henderson MA Gish K Venter DJ Armes JE 《Genes, chromosomes & cancer》2003,36(4):382-392
Chromosome region 17q12-23 commonly shows an increase in DNA copy number in breast cancers, suggesting that several oncogenes are located at this site. We performed a high-resolution expression array and comparative genomic hybridization analysis of genes mapped to the entire 17q12-23 region, to identify novel candidate oncogenes. We identified 24 genes that showed significant overexpression in breast cancers with gain of 17q12-23, compared to cancers without gain. These genes included previously identified oncogenes, together with several novel candidate oncogenes. FISH analysis using specific gene probes hybridized to tissue arrays confirmed the underlying amplification of overexpressed genes. This high-resolution analysis of the 17q12-23 region indicates that several established and novel candidate oncogenes, including a Wnt-signaling pathway member, are amplified and overexpressed within individual primary breast cancer samples. We were also able to confirm the presence of two apparently separate and reciprocally amplified groups of genes within this region. Investigation of these genes and their functional interactions will facilitate our understanding of breast oncogenesis and optimal management of this disease. 相似文献
128.
Edward?J?HolloxEmail author Jane?Davies Uta?Griesenbach Juliana?Burgess Eric?WFW?Alton John?AL?Armour 《Journal of negative results in biomedicine》2005,4(1):9
Human beta-defensin 2 (DEFB4, also known as DEFB2 or hBD-2) is a salt-sensitive antimicrobial protein that is expressed in
lung epithelia. Previous work has shown that it is encoded in a cluster of beta-defensin genes at 8p23.1, which varies in
copy number between 2 and 12 in different individuals. We determined the copy number of this locus in 355 patients with cystic
fibrosis (CF), and tested for correlation between beta-defensin cluster genomic copy number and lung disease associated with
CF. No significant association was found. 相似文献
129.
An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line 总被引:2,自引:0,他引:2
Wang Y Xue H Cutz JC Bayani J Mawji NR Chen WG Goetz LJ Hayward SW Sadar MD Gilks CB Gout PW Squire JA Cunha GR Wang YZ 《Laboratory investigation; a journal of technical methods and pathology》2005,85(11):1392-1404
Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone. 相似文献
130.
Jane M Olson Sompong Vongpunsawad Helena Kuivaniemi Antti Ronkainen Juha Hernesniemi Markku Ryynänen Lee-Lian Kim Gerard Tromp 《BMC medical genetics》2002,3(1):7-7