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11.
Several studies have shown that pituitary adenylate cyclase activating polypeptide (PACAP) stimulates at very low concentration insulin release from pancreatic beta cells. In addition, PACAP has been evidenced in pancreatic nervous fibers surrounding the islets, the core of the islet, and the capillaries. The aim of the present study was to demonstrate internalization of PACAP in pancreatic islet cells. Pancreatic islets were obtained from Wistar rat pancreata by modified Lacy's isolation method. The isolated islets were incubated in the presence of Fluo-PACAP 27, a fluorescent ligand specific for PACAP receptors. At the end of incubation the islets were fixed in paraformaldehyde and then observed by confocal microscope. Fluo-PACAP 27 was internalized into pancreatic islet cells, and this process was time- and temperature-dependent (37 degrees C). The fluorescent molecules converged toward the nucleus where an intense fluorescence was evidenced after 60 minutes. Incubation with phenyl arsine oxide as well as with PACAP 6-38, a receptor antagonist, prevented the internalization process. Further studies are required to explain the internalization process of PACAP 27 into the nucleus of pancreatic islet cells. 相似文献
12.
Fodero-Tavoletti MT Cappai R McLean CA Pike KE Adlard PA Cowie T Connor AR Masters CL Rowe CC Villemagne VL 《Brain imaging and behavior》2009,3(3):246-261
With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent
or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment
of Aβ burden in vivo. Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in
plasma and cerebrospinal fluid, are proving valuable in the early and differential diagnosis of Alzheimer’s disease (AD).
11C-PiB PET has proven useful in the discrimination of dementias, showing significantly higher PiB retention in grey matter
of AD patients when compared with healthy controls or patients with frontotemporal dementia. 11C-PiB PET also appears to be more accurate than FDG for the diagnosis of AD. Despite apparently underestimating the Aβ burden
in the brain, 11C-PiB PET is an optimal method to differentiate healthy controls from AD, matching histopathological reports in aging and
dementia and reflecting the true regional density of Aβ plaques in cortical areas. High striatal Aβ deposition seems to be
typical for carriers of familial forms of AD, whilst ApoE ε4 carriers, independent of diagnosis or disease severity, present
with higher Aβ burden than non- ε4 carriers. Characterization of the binding properties of PiB has shown that despite binding
to other misfolded proteins in vitro, PiB is extremely selective for Aβ at the concentrations achieved during a PET scan. Aβ burden as assessed by PET does not
correlate with measures of cognition or cognitive decline in AD. Approximately 30% of apparently healthy older people, and
50–60% of people with mild cognitive impairment, present with cortical 11C-PiB retention. In these groups, Aβ burden does correlate with episodic memory and rate of memory decline. These observations
suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Αβ deposition occurs well before the
onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations, coupled with different disease-specific
tracers and biomarkers are required not only to confirm this hypothesis, but also to better elucidate the role of Αβ deposition
in the course of Alzheimer’s disease. 相似文献
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14.
Lawson VA Klemm HM Welton JM Masters CL Crouch P Cappai R Ciccotosto GD 《Journal of neuropathology and experimental neurology》2011,70(11):1036-1045
Prion diseases or transmissible spongiform encephalopathies are a group of fatal and transmissible disorders affecting the central nervous system of humans and animals. The principal agent of prion disease transmission and pathogenesis is proposed to be an abnormal protease-resistant isoform of the normal cellular prion protein. The microtubule-associated protein tau is elevated in patients with Creutzfeldt-Jakob disease. To determine whether tau expression contributes to prion disease pathogenesis, tau knockout and control wild-type mice were infected with the M1000 strain of mouse-adapted human prions. Immunohistochemical analysis for total tau expression in prion-infected wild-type mice indicated tau aggregation in the cytoplasm of a subpopulation of neurons in regions associated with spongiform change. Western immunoblot analysis of brain homogenates revealed a decrease in total tau immunoreactivity and epitope-specific changes in tau phosphorylation. No significant difference in incubation period or other disease features were observed between tau knockout and wild-type mice with clinical prion disease. These results demonstrate that, in this model of prion disease, tau does not contribute to the pathogenesis of prion disease and that changes in the tau protein profile observed in mice with clinical prion disease occurs as a consequence of the prion-induced pathogenesis. 相似文献
15.
George AJ Holsinger RM McLean CA Tan SS Scott HS Cardamone T Cappai R Masters CL Li QX 《Neurobiology of aging》2006,27(4):614-623
Phosphatidylethanolamine binding protein (PEBP) is a multifunctional protein, with proposed roles as the precursor protein of hippocampal cholinergic neurostimulating peptide (HCNP), and as the Raf kinase inhibitor protein (RKIP). Previous studies have demonstrated a decrease in PEBP mRNA in CA1 region of AD hippocampus. The current study demonstrates that PEBP is decreased in the hippocampus of 11 month Tg2576 mice, in the absence of change in mRNA levels compared to non-transgenic littermates. The level of PEBP in transgenic mouse hippocampus significantly decreases at 11 months (a time point when Abeta begins accumulating) and 15 months (when Abeta plaques have formed). There was a significant correlation between decreased PEBP expression and accumulation of Abeta. Immunohistochemical studies on Tg2576 and AD brain sections demonstrate that PEBP immunoreactivities are present at the periphery of dense multicore Abeta plaques, and in selective astrocytes, primarily surrounding plaques. These findings suggest that PEBP expression may be influenced by accumulation of Abeta. Down-regulation of PEBP may result in lower levels of HCNP or altered coordination of signal transduction pathways that may contribute to neuronal dysfunction and pathogenesis in AD. 相似文献
16.
Frances Corrigan Robert Vink Peter C. Blumbergs Colin L. Masters Roberto Cappai Corinna van den Heuvel 《Neuroscience letters》2012
Treatment with sAPPα, the product of non-amyloidogenic processing of the amyloid precursor protein (APP) has been shown to be protective following diffuse traumatic brain injury (TBI), by improving motor outcome and reducing axonal injury. However the effects of treatment with sAPPα following a focal TBI have yet to be determined. To investigate this, mice were subjected to a controlled cortical impact injury and treated with either sAPPα or its vehicle at 30 min post-injury. Following treatment with sAPPα the mice showed a significant improvement in motor and cognitive function early following injury, as determined on the ledged beam and Barnes Maze, respectively, relating to a more rapid rate of recovery. However the effect of treatment with sAPPα was not as dramatic as that seen previously following a diffuse injury. Nonetheless, these improvements in functional outcome were acompanied by a small but significant improvement in the amount of cortical and hippocampal at 7 days post-injury, and provide further support for the efficacy of sAPPα as a potential neuroprotective agent following TBI. 相似文献
17.
Janetta G. Culvenor Fran Maher Genevive Evin Fiorella Malchiodi-Albedi Roberto Cappai John R. Underwood John B. Davis Eric H. Karran Gareth W. Roberts Konrad Beyreuther Colin L. Masters 《Journal of neuroscience research》1997,49(6):719-731
The recently identified Alzheimer's disease-associated presenilin 1 and 2 (PS1 and PS2) genes encode two homologous multi membrane-spanning proteins. Rabbit antibodies to the N-terminal domain of PS1 detected PS1 in human neuroblastoma SH-SY5Y wild type and PS1 transfectants (SY5Y-PS1) as well as in mouse P19, in CHO-K1 and CHO-APP770 transfected cells, in rat cerebellar granule and hippocampal neurons, and astrocytes. Immunoblotting detected full-length protein of 50 kDa, and a major presumptive cleavage product of 30 kDa. The immunofluorescence pattern resembled labeling of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) marker protein ERGIC-53. PS1 distribution showed slight condensation after brefeldin A and more marked condensation after incubation of cells at 16°C, characteristic of the ERGIC compartment. Double labeling showed colocalization of ERGIC-53 with PS1 in the SY5Y-PS1 cells. PS1 labeling of SY5Y-PS1 and P19 cells showed overlap of the cis-Golgi marker p210 and colocalization with p210 after brefeldin A which causes redistribution of p210 to the ERGIC. Expression of PS1 did not change in level or cellular distribution during development of neurons in culture. Double labeling for the amyloid precursor protein (APP) and PS1 on SY5Y-PS1 cells and CHO-APP770 cells showed some overlap under control conditions. These results indicate that PS1 is a resident protein of the ERGIC and could be involved in trafficking of proteins, including APP, between the ER and Golgi compartments. J. Neurosci. Res. 49:719–731, 1997. © 1997 Wiley-Liss, Inc. 相似文献
18.
Dana Bliuc Thach Tran Jonathan D. Adachi Gerald J. Atkins Claudie Berger Joop van den Bergh Roberto Cappai John A. Eisman Tineke van Geel Piet Geusens David Goltzman David A. Hanley Robert Josse Stephanie Kaiser Christopher S. Kovacs Lisa Langsetmo Jerilynn C. Prior Tuan V. Nguyen Lucian B. Solomon Catherine Stapledon Jacqueline R. Center For the Canadian Multicentre Osteoporosis Study Research Group 《Journal of bone and mineral research》2021,36(11):2106-2115
Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (≥3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE ≥ 24). The annual % change in MMSE was similar for both genders (women −0.33, interquartile range [IQR] −0.70 to +0.00; and men −0.34, IQR: −0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. © 2021 American Society for Bone and Mineral Research (ASBMR). 相似文献
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20.
Marco Agrifoglio Fabio Barili Luca Dainese Antioco Cappai Faisal H Cheema Paolo Biglioli 《Journal of cardiothoracic surgery》2009,4(1):55-3