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91.
Role of ADP-ribosyl transferase in differentiation of human granulocyte- macrophage progenitors to the macrophage lineage 总被引:6,自引:0,他引:6
Nuclear adenosine diphosphate-ribosyl (ADP-ribosyl) transferase is a chromatin-bound enzyme catalyzing the transfer of ADP-ribose from NAD+ to chromatin proteins. The physiologic function of this covalent modification of chromatin has not been fully established, but roles in both DNA repair and in differentiation have been proposed. We demonstrate that three specific inhibitors of ADP-ribosyl transferase (5-methylnicotinamide, 3-methoxybenzamide, 3-aminobenzamide) inhibit differentiation of human granulocyte-macrophage progenitor cells to the macrophage lineage. Differentiation to the neutrophil-granulocyte lineage is much less affected. The inhibition of macrophage differentiation seems to relate to the ability of these compounds to inhibit ADP-ribosyl transferase. A structural analogue (3- methoxybenzoic acid), which is not inhibitory for the enzyme, did not inhibit macrophage differentiation. Additional evidence for a role of ADP-ribosyl transferase in the differentiation of granulocyte- macrophage progenitors was obtained from experiments in which enzyme activity levels were measured in permeabilized marrow cells. Marrow cell ADP-ribosyl transferase activity increased after 3-hr stimulation by the differentiation/proliferation stimulus--granulocyte-macrophage colony-stimulating activity (GM-CSA). Unstimulated marrow cells showed low or undetectable levels of enzyme activity. 相似文献
92.
Estrogen-induced microsatellite DNA alterations are associated with Syrian hamster kidney tumorigenesis 总被引:4,自引:0,他引:4
Exposure to estrogens is associated with an increase in cancers, including
malignancies of the breast and uterus in humans, and of the kidney in
hamsters. DNA damage induced by metabolic activation of estrogen has been
postulated to result in gene mutations critical for the development of
estrogen-induced kidney tumors in hamsters. As part of our examination of
the genetic consequences of estrogen-induced DNA damage, we searched for
estrogen-induced alterations in microsatellite DNA, a frequent site of
mutation in tumors. Genomic DNA isolated from kidney of hamsters treated
with estradiol, from estrogen-induced kidney tumors and from untreated
age-matched controls, was examined by Southern blot analysis with three
multi-locus oligonucleotide probes: (GACA)4, (CAC)6 and (CAG)6. Alterations
in DNA fragments containing GACA and CAC tandem repeats were detected in
kidney DNA of hamsters treated with hormone for 3 and 4 months, whereas no
such effects were seen in control animals. In estrogen-induced tumors,
microsatellite alterations were observed in fragments that contain these
same two repeat sequences and also CAG repeat sequences. The induction of
microsatellite alterations by estradiol in kidney DNA preceding
estrogen-induced renal malignancy may play a role in hormone-induced
tumorigenesis.
相似文献
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CZ Zhu JP Mikusa Y Fan PR Hollingsworth M Pai P Chandran AV Daza BB Yao MJ Dart MD Meyer MW Decker GC Hsieh P Honore 《British journal of pharmacology》2009,157(4):645-655
Background and purpose:
Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain.Experimental approach:
WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB1 and CB2 receptor antagonists.Key results:
WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB1 versus CB2 receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB1 receptor antagonist, but not with a CB2 receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB1 and CB2 antagonists blocked systemic WIN-induced analgesic activity.Conclusions and implications:
Both CB1 and CB2 receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB1 but not CB2 receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB1 receptors in the brain.British Journal of Pharmacology (2009) 157, 645–655; doi:10.1111/j.1476-5381.2009.00184.x; published online 3 April 2009 相似文献96.
Ho AD; Ganeshaguru K; Knauf WU; Dietz G; Trede I; Hunstein W; Hoffbrand AV 《Blood》1988,72(6):1884-1890
Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S- adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response. 相似文献
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DG Schroeder B. Torún AV Bartlett H. Miracle-McMahill 《Acta paediatrica (Oslo, Norway : 1992)》1997,86(11):1155-1161
A community-based, randomized trial was conducted to evaluate a locally available diet for the management of acute diarrhea ( n = 99 episodes) in 90 Guatemalan children, 4–42 months of age. The Test Diet (TD), a combination of a semi-solid pap (maize flour, black beans, oil) and a liquid gruel, Incaparina (maize flour, cotton seed flour, sugar), in addition to breast-milk and other home foods (group TD, n = 45 episodes) was offered for 14 d and compared to usual home feeding (group HF, n = 54 episodes). Diarrhea episodes after admission were significantly shorter for group TD (median 2. 0 d) than group HF (median 4. 4 d, p = 0. 003) after adjusting for potential confounders. Weight gains did not differ significantly between groups. We conclude that community-based dietary management of acute childhood diarrhea using energy-dense, locally available foods is feasible and may shorten diarrhea duration. This may encourage mothers to follow recommendations for continued feeding during diarrhea in developing country environments. 相似文献
100.
Age-related differences in distractibility and response to methylphenidate in monkeys 总被引:2,自引:0,他引:2
Prendergast MA; Jackson WJ; Terry AV Jr; Kille NJ; Arneric SP; Decker MW; Buccafusco JJ 《Cerebral cortex (New York, N.Y. : 1991)》1998,8(2):164-172
Increased susceptibility to distraction is a symptom of normal aging and
several clinical syndromes, including Alzheimer's disease and attention
deficit disorders. In the present study, aged and young adult macaques were
well-trained to perform an automated delayed matching-to- sample (DMTS)
task which assesses both attention and short-term memory. On 19% of all
trials, a task-relevant distracting stimulus was presented during either
the initial 1 or 3 s of delay intervals (early onset) or the final 1 or 3 s
of delay intervals (late onset). In aged monkeys, both early and late onset
distractors lasting 1 or 3 s impaired delayed recall on trials with the
shortest delay intervals, but did not affect accuracy on trials with long
delay intervals. In contrast, young adult monkeys were impaired only by the
presence of an early onset distractor lasting 3 s. Impairment was selective
for only those trials with the shortest delay intervals. Late onset
distractors were relatively ineffective in producing distractibility in
young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to
reduce distractibility in aged monkeys, producing locomotor abnormalities
and hypophagia at doses ranging from 0.25 to 1.0 mg/kg. In young adult
monkeys, however, distractibility was significantly attenuated by
administration of the 0.125 mg/kg dose. Habituation to the distracting
stimulus (under saline conditions) was assessed throughout the study and
was not evident at any time point of testing. These data indicate that
attention and recall after brief delays are impaired following exposure to
a task-relevant distracting stimulus in both aged and young adult monkeys,
but that aged monkeys are more susceptible to distraction and do not
receive significant benefit from MPH administration.
相似文献