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排序方式: 共有69条查询结果,搜索用时 718 毫秒
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DJ Behm NV Aiyar AR Olzinski JJ McAtee MA Hilfiker JW Dodson SE Dowdell GZ Wang KB Goodman CA Sehon MR Harpel RN Willette MJ Neeb CA Leach SA Douglas 《British journal of pharmacology》2010,161(1):207-228
BACKGROUND AND PURPOSE
Recently identified antagonists of the urotensin–II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.EXPERIMENTAL APPROACH
The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.KEY RESULTS
GSK1440115 (pKi= 7.34–8.64 across species) and GSK1562590 (pKi= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA2= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pKb= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pKb= 8.87–8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.CONCLUSIONS AND IMPLICATIONS
Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo. 相似文献23.
24.
SA Pungavkar MA Lawande DP Patkar NV Agrawal S Gadani 《Journal of Medical Imaging and Radiation Oncology》2005,49(6):489-492
Optic nerve glioma is the most common primary neoplasm of the optic nerve in childhood. It can extend intracranially along the optic pathway (optic pathway glioma). The lesion tends to present with decreased visual acuity in the affected eye, but can cause additional symptoms when it is large. Local involvement within the orbit can be characterized using CT, but MRI is superior in showing the intracranial extent of the lesion. Intracranial calcification in optic pathway glioma is rare. We present a rare case of optic pathway glioma with calcification in the intracranial component. Also, we describe MR spectroscopy (MRS) findings in this case. 相似文献
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Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR 总被引:12,自引:2,他引:12
Cremers FP; van de Pol DJ; van Driel M; den Hollander AI; van Haren FJ; Knoers NV; Tijmes N; Bergen AA; Rohrschneider K; Blankenagel A; Pinckers AJ; Deutman AF; Hoyng CB 《Human molecular genetics》1998,7(3):355-362
Ophthalmological and molecular genetic studies were performed in a
consanguineous family with individuals showing either retinitis pigmentosa
(RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive)
inheritance of allelic defects, linkage analysis positioned the causal gene
at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR
gene involved in Stargardt's disease (STGD) and age- related macular
degeneration (AMD). We completed the exon-intron structure of the ABCR gene
and detected a severe homozygous 5[prime] splice site mutation,
IVS30+1G->T, in the four RP patients. The five CRD patients in this
family are compound heterozygotes for the IVS30+1G- >T mutation and a
5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice
site mutations were found heterozygously in two unrelated STGD patients,
but not in 100 control individuals. In these patients the second mutation
was either a missense mutation or unknown. Since thus far no STGD patients
have been reported to carry two ABCR null alleles and taking into account
that the RP phenotype is more severe than the STGD phenotype, we
hypothesize that the intron 30 splice site mutation represents a true null
allele. Since the intron 30 mutation is found heterozygously in the CRD
patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime]
splice site partially functional. These results show that mutations in the
ABCR gene not only result in STGD and AMD, but can also cause autosomal
recessive RP and CRD. Since the heterozygote frequency for ABCR mutations
is estimated at 0.02, mutations in ABCR might be an important cause of
autosomal recessive and sporadic forms of RP and CRD.
相似文献
27.
Organization, expression and polymorphism of the human persyn gene 总被引:13,自引:0,他引:13
Ninkina NN; Alimova-Kost MV; Paterson JW; Delaney L; Cohen BB; Imreh S; Gnuchev NV; Davies AM; Buchman VL 《Human molecular genetics》1998,7(9):1417-1424
Persyn is a recently identified member of the synuclein family with a
distinct pattern of expression during pre- and postnatal development of the
mouse peripheral and central nervous systems. As with other synucleins,
persyn is believed to be involved in the pathogenesis of human
neurodegenerative diseases. However, in contrast to other synucleins, high
levels of persyn mRNA expression were also found in advanced breast
carcinomas, suggesting an involvement of the encoded protein in breast
tumour progression. Here we have used an antibody specific to human persyn
to demonstrate that the level of this protein is increased in ageing
cerebral cortex and in breast tumours. We cloned, characterized and
sequenced the human persyn genomic locus and localized it to the long arm
of chromosome 10 in the q23.2-q23.3 region. Sequence information was used
to search for specific mutations in the protein coding regions of persyn
mRNA and the persyn gene in breast tumours and tumour cell lines. No
tumour-specific mutations were found, but two linked polymorphisms in the
coding region were detected, both in mRNA and exons III and IV of the gene.
These results suggest that development of breast tumours correlates with
overexpression of the wild-type persyn protein. Detailed characterization
of the human persyn locus is important for further studies of the
involvement of persyn in neurodegeneration and malignancy.
相似文献
28.
Objectives To test the feasibility of the use of high thoracic epidural anesthesia as a sole anesthetic in patients undergoing off pump coronary artery bypass surgery, avoiding general anesthesia. Methods Between October 2002 to April 2003, twenty five cases underwent beating heart coronary artery revascularization without endotracheal general anesthesia, using high thoracic epidural anesthesia and analgesia. All the patients underwent epidural catheterization on the evening before the surgery. Resuits The patients in all received 71 grafts (single n= 11, double n = 5, triple n = 6, quadruple n =3). Six patients underwent repeat coronary artery bypass. Except one was converted to general anesthesia and cardiopulmonary bypass, the other patients underwent off- pump coronary artery bypass graft surgery, 2 patients underwent grafting via left thoracotomy (MIDCAB) and the rest through mid sternotomy. There was no mortality. Mean length of stay in the intensive care unit was 16 . 2 ( 4.2 hours and hospital was 3.0(1.2 days. Conclusions Our experience confirms the feasibility of performing muhiple coronary artery bypasses in conscious patients without endotracheal general anesthesia. 相似文献
29.
Abstract: Background/aims: In contrast to the normal adult liver, the fetal human and rat livers, and the liver of rats with cholestasis secondary to bile duct resection (BDR) express the preproenkephalin (ppENK) mRNA, which codes for the endogenous opioid peptide Met‐enkephalin. In addition, Met‐enkephalin immunoreactivity (MEIR) is detected in hepatocytes and in proliferating bile ductules in the cholestatic rat liver. These data suggest that cholestasis is associated with the resurgence of cells that produce Met‐enkephalin. To explore further the status of opioids in cholestasis, we studied the expression of MEIR in liver tissue. Methods: The MEIR was sought in paraffin‐preserved liver tissues from patients with primary biliary cirrhosis (PBC) (n = 10). Results: The MEIR was detected in all the PBC livers. Its intensity varied from weak to strong on hepatocytes and bile ducts and the strongest expression appeared as coarse granules. The MEIR was either absent or only faintly expressed by some hepatocytes from disease and nondisease control biopsies, but absent from bile ducts. Conclusion: These results suggest that the human liver in cholestasis may be a source of endogenous opioids. 相似文献
30.