全文获取类型
收费全文 | 186篇 |
免费 | 18篇 |
专业分类
204篇 |
出版年
2018年 | 2篇 |
2017年 | 2篇 |
2015年 | 13篇 |
2014年 | 9篇 |
2013年 | 4篇 |
2012年 | 7篇 |
2011年 | 8篇 |
2010年 | 14篇 |
2009年 | 3篇 |
2008年 | 7篇 |
2007年 | 6篇 |
2006年 | 7篇 |
2005年 | 5篇 |
2004年 | 5篇 |
2003年 | 3篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 4篇 |
1998年 | 7篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1970年 | 1篇 |
1969年 | 3篇 |
1967年 | 1篇 |
1965年 | 1篇 |
1961年 | 1篇 |
1959年 | 1篇 |
1949年 | 1篇 |
1932年 | 1篇 |
1931年 | 1篇 |
1910年 | 1篇 |
排序方式: 共有204条查询结果,搜索用时 15 毫秒
21.
22.
Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration. 相似文献
23.
Stefan TG Bruijnen Mignon AC van der Weijden Joannes P Klein Otto S Hoekstra Ronald Boellaard J Christiaan van Denderen Ben AC Dijkmans Alexandre E Voskuyl Irene E van der Horst-Bruinsma Conny J van der Laken 《Arthritis research & therapy》2012,14(2):R71
Introduction
Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference.Methods
In a stepwise approach different PET tracers were investigated. First, whole body [18F]FDG and [11C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [18F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data.Results
No increased [18F]FDG and [11C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]Fluoride PET positive lesions.Conclusions
Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging. 相似文献24.
Inspiratory muscle weakness in patients with COPD is of major clinical relevance. For instance, maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered pathologic of nature. Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single fiber level is associated with loss of myosin content in these fibers. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. This review postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities. Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings indicate the ubiquitin-proteasome pathway as a prime target to attenuate diaphragm wasting in COPD. 相似文献
25.
Wilson MT Steyn-Ross DA Sleigh JW Steyn-Ross ML Wilcocks LC Gillies IP 《Journal of computational neuroscience》2006,21(3):243-257
We use a mean-field macrocolumn model of the cerebral cortex to offer an interpretation of the K-complex of the electroencephalogram
to complement those of more detailed neuron-by-neuron models. We interpret the K-complex as a momentary excursion of the cortex
from a stable low-firing state to an unstable high-firing state, and hypothesize that the related slow oscillation can be
considered as the periodic oscillation between two meta-stable solutions of the mean-field model. By incorporating a Hebbian-style
learning rule that links the growth in synapse strength to fluctuations in soma potential, we demonstrate a self-organization
behaviour that draws the modelled cortex close to the edge of stability of the low-firing state. Furthermore, a very slow
oscillation can occur in the excitability of the cortex that has similarities with the infra-slow oscillation of sleep.
Action Editor: Nicolas Brunel 相似文献
26.
van Gool CJ van Houwelingen AC Hornstra G 《The Journal of nutritional biochemistry》2000,11(11-12):543-547
Phenylketonuric patients are on a special diet that lacks certain essential fatty acids. This study evaluates the essential fatty acid status of a group of phenylketonuric patients in the Netherlands undergoing dietary treatment. To this end, the essential fatty acid status of nine phenylketonuria patients was studied. On the basis of age and gender, two control subjects were selected for each patient. The essential fatty acid composition of duplicate food portions and the essential fatty acid status of plasma and erythrocytes were analyzed. Phenylketonuria subjects had a different essential fatty acid profile from their peers, especially concerning the n-3 fatty acids. N-6 and n-3 fatty long-chain polyenes were hardly consumed by phenylketonuria subjects, in contrast to the control subjects. Linoleic acid, on the other hand, was consumed in significantly higher amounts by phenylketonuria subjects and made up about 40% of their daily fat consumption. The essential fatty acid consumption pattern of the phenylketonuria subjects is mirrored by the essential fatty acid concentrations in blood. The essential fatty acid status of the phenylketonuric diet should be improved in order to prevent deficiency in n-3 fatty acids. 相似文献
27.
Moira L. Steyn-Ross D. Alistair Steyn-Ross Jamie W. Sleigh 《Cognitive neurodynamics》2012,6(3):215-225
During slow-wave sleep, general anesthesia, and generalized seizures, there is an absence of consciousness. These states are
characterized by low-frequency large-amplitude traveling waves in scalp electroencephalogram. Therefore the oscillatory state
might be an indication of failure to form coherent neuronal assemblies necessary for consciousness. A generalized seizure
event is a pathological brain state that is the clearest manifestation of waves of synchronized neuronal activity. Since gap
junctions provide a direct electrical connection between adjoining neurons, thus enhancing synchronous behavior, reducing
gap-junction conductance should suppress seizures; however there is no clear experimental evidence for this. Here we report
theoretical predictions for a physiologically-based cortical model that describes the general anesthetic phase transition
from consciousness to coma, and includes both chemical synaptic and direct electrotonic synapses. The model dynamics exhibits
both Hopf (temporal) and Turing (spatial) instabilities; the Hopf instability corresponds to the slow (≲8 Hz) oscillatory
states similar to those seen in slow-wave sleep, general anesthesia, and seizures. We argue that a delicately balanced interplay
between Hopf and Turing modes provides a canonical mechanism for the default non-cognitive rest state of the brain. We show
that the Turing mode, set by gap-junction diffusion, is generally protective against entering oscillatory modes; and that
weakening the Turing mode by reducing gap conduction can release an uncontrolled Hopf oscillation and hence an increased propensity
for seizure and simultaneously an increased sensitivity to GABAergic anesthesia. 相似文献
28.
G De Serres MC Gariépy B Coleman I Rouleau S McNeil M Benoît A McGeer A Ambrose J Needham C Bergeron C Grenier K Sleigh A Kallos M Ouakki N Ouhoummane G Stiver L Valiquette A McCarthy J Bettinger;PHAC-CIHR influenza Research Network 《PloS one》2012,7(7):e38563
Background
This study assessed the short and the long term safety of the 2009 AS03 adjuvanted monovalent pandemic vaccine through an active web-based electronic surveillance. We compared its safety profile to that of the seasonal trivalent inactivated influenza vaccine (TIV) for 2010–2011.Methodology/Principal Findings
Health care workers (HCW) vaccinated in 2009 with the pandemic vaccine (Arepanrix ® from GSK) or HCW vaccinated in 2010 with the 2010–2011 TIV were invited to participate in a web-based active surveillance of vaccine safety. They completed two surveys the day-8 survey covered the first 7 days post-vaccination and the day-29 survey covered events occurring 8 to 28 days after vaccination. Those who reported a problem were called by a nurse to obtain details. The main outcome was the occurrence of a new health problem or the worsening of an existing health condition that resulted in a medical consultation or work absenteeism. For the pandemic vaccine, a six-month follow-up for the occurrence of serious adverse events (SAE) was conducted. Among the 6242 HCW who received the pandemic vaccine, 440 (7%) reported 468 events compared to 328 of the 7645 HCW (4.3%) who reported 339 events after the seasonal vaccine. The 2009 pandemic vaccine was associated with significantly more local reactions than the 2010–2011 seasonal vaccine (1% vs. 0.03%, p<0.001). Paresthesia was reported by 7 HCW (0.1%) after the pandemic vaccine but by none after the seasonal vaccine. For the pandemic vaccine, no clustering of SAE was found in the 6 month follow-up.Conclusion
The 2009 pandemic vaccine seems to have a good safety profile, similar to the 2010–2011 TIV, with the exception of local reactions. This surveillance was adequately powered to identify AE associated with an excess risk ≥1 per 1000 vaccinations but is insufficient to detect rare AE.Trial Registration
ClinicalTrials.gov , NCT01289418 NCT01318876相似文献29.
Humans create ecologically simplified landscapes that favour some wildlife species, but not others. Here, we explore the possibility that those species that tolerate or do well in human-modified environments, or 'synanthropic' species, are predominantly the hosts of zoonotic emerging and re-emerging infectious diseases (EIDs). We do this using global wildlife conservation data and wildlife host information extracted from systematically reviewed emerging infectious disease literature. The evidence for this relationship is examined with special emphasis on the Australasian, South East Asian and East Asian regions. We find that synanthropic wildlife hosts are approximately 15 times more likely than other wildlife in this region to be the source of emerging infectious diseases, and this association is essentially independent of the taxonomy of the species. A significant positive association with EIDs is also evident for those wildlife species of low conservation risk. Since the increase and spread of native and introduced species able to adapt to human-induced landscape change is at the expense of those species most vulnerable to habitat loss, our findings suggest a mechanism linking land conversion, global decline in biodiversity and a rise in EIDs of wildlife origin. 相似文献