Bone morphogenetic protein-2 used in spinal fusion with spinal cord injury penetrates intrathecally and elicits a functional signaling cascade
The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and its indications for spinal fusion continue to be expanded with recent reports citing spinal trauma application. However, there are no data establishing the effects of rhBMP-2 on the injured spinal cord.
The purpose of this study was to evaluate the extent of bone morphogenetic protein (BMP)-specific intrathecal signaling after application to the spine at various time points after a spinal cord injury (SCI).
This is an in vivo rat study using a combination of the dorsal hemisection SCI and the posterolateral arthrodesis animal models.
Sixty-five female Sprague-Dawley rats underwent either a T9-T10 dorsal hemisection SCI (n=52) or laminectomy only (n=13). Spinal cord injury animals were further subdivided into four follow-up groups (n=13/group): 30 minutes, 24 hours, 7 days, and 21 days, at which time one of two secondary surgeries were performed: Eight rats per time point received either 43 microg of rhBMP-2 per side or sterile water control over T9-T11 on absorbable collagen sponges (ACSs). Animals were perfused after 24 hours, and spinal cords were immunohistochemically analyzed. Sections of the lesion were stained with BMP-specific pSmad 1, 5, 8 antibody and costained with cell-specific markers. pSmad-positive cells were then counted around the lesion. The remaining five rats (n=5/time point) had luciferase (blood spinal cord barrier [BSCB] permeability marker) injected through the jugular vein. Subsequently, spinal cords were collected and luciferase activity was quantified around the lesion and in the cervical samples (controls) using a luminometer.
After injury, a significant increase in the number of pSmad-positive cells was observed when rhBMP-2 was implanted at the 30-minute, 24-hour, and 7-day time points (p<.05). Costaining revealed BMP-specific signaling activation in neurons, glial cells, macrophages, and fibroblasts. Spinal cord permeability to luciferase was significantly increased at 30 minutes, 24 hours, and 7 days post lesion (p<.05). A significant linear regression was established between the extent of BSCB permeability and pSmad signaling (r(2)=0.66, p=.000).
Our results indicate that rhBMP-2 use around a spinal cord lesion elicits a robust signaling response within the spinal cord parenchyma. All CNS cell types and the invading fibroblasts are activated to the extent dependent on the integrity of the meningeal and BSCB barriers. Therefore, in the presence of a SCI and/or dural tear, rhBMP-2 diffuses intrathecally and activates a signaling cascade in all major CNS cell types, which may increase glial scarring and impact neurologic recovery.
Available from: Zhang Wen
- "Manual palpation is an easy and specific way for assessing rat postero-lateral spinal fusion , , , . 16 weeks after surgery, all rats were killed and the spines were collected and the segments from T12 (Thoracic) to sacrum were preserved. "
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ABSTRACT: Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a critical role in bone regeneration and repair. However, its distribution and side effects are major barriers to its success as therapeutic treatment. The improvement of therapy using collagen delivery matrices has been reported. To investigate a delivery system on postero-lateral spinal fusion, both engineered human BMP-2 with a collagen binding domain (CBD-BMP-2) and collagen scaffolds were developed and their combination was implanted into Sprague-Dawley (SD) rats to study Lumbar 4-5 (L4-L5) posterolateral spine fusion. We divided SD rats into three groups, the sham group (G1, n = 20), the collagen scaffold-treated group (G2, n = 20) and the BMP-2-loaded collagen scaffolds group (G3, n = 20). 16 weeks after surgery, the spines of the rats were evaluated by X-radiographs, high-resolution micro-computed tomography (micro-CT), manual palpation and hematoxylin and eosin (H&E) staining. The results showed that spine L4-L5 fusions occurred in G2(40%) and G3(100%) group, while results from the sham group were inconsistent. Moreover, G3 had better results than G2, including higher fusion efficiency (X score, G2 = 2.4±0.163, G3 = 3.0±0, p<0.05), higher bone mineral density (BMD, G2: 0.3337±0.0025g/cm3, G3: 0.4353±0.0234g/cm3. p<0.05) and more bone trabecular formation. The results demonstrated that with site-specific collagen binding domain, a dose of BMP-2 as low as 0.02mg CBD-BMP-2/cm3 collagen scaffold could enhance the posterolateral intertransverse process fusion in rats. It suggested that combination delivery could be an alternative in spine fusion with dramatically decreased side effects caused by high dose of BMP-2.
PLoS ONE 05/2014; 9(5):e98480. DOI:10.1371/journal.pone.0098480 · 3.23 Impact Factor
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ABSTRACT: This paper analyses the performance of the downlink transmit diversity techniques specified in the standard of the UTRA FDD mode. The Downlink DPCH can use either closed loop or open loop transmit diversity (space time block coding based transmit diversity) or closed loop transmit diversity to improve performance. In order to evaluate how these techniques work, a simulator of the physical layer of UMTS has been implemented in the C language. Simulation results show that the closed loop methods are the best way of getting diversity gain in radio environments with a low Doppler frequency, especially mode 2. Nevertheless, when a correct channel knowledge (high Doppler frequency) does not exist, the open loop transmit diversity mode is the best option.
Spread Spectrum Techniques and Applications, 2002 IEEE Seventh International Symposium on; 10/2002
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ABSTRACT: Summary form only given as follows. Many challenging issues arise under the newly deregulated competitive electric power markets. Instead of centralized decision-making in a vertically integrated environment as in the past, decision-making is now decentralized and driven by market forces. The collapse of the California PX market in early 2001 fostered a lot of debates on the fundamental issues in deregulating electric power markets. Among the most important reasons that cause the collapse of the California market, we focus on our discussion on gaming and price spikes. In fact these phenomena have been observed in almost every electricity market but explicit analysis of them is rare. In this paper, we examine historical bid curves from the original California day-ahead energy market. These curves have the property that slight shifts in either the supply offer or demand bid can cause large changes in the market clearing price. Based on this observation, we formulate a Prisoner's dilemma matrix game to show that suppliers have incentive to withhold capacity from the market. That is, under certain conditions, enough suppliers independently withholding capacity can shift the aggregated supply curve to cause a price spike. We call this phenomenon "opportunistic tacit collusion" to distinguish it from the classical "tacit collusion" that occurs in static repeated Prisoner's dilemma games, where the object is for all players to learn that they can always make excess profits if they withhold a small amount of capacity from the market. Once this is learned suppliers "tacitly collude" to sustain high market prices. We assert, however, that it is not always profitable to withhold capacity from the market, since the opportunity for raising profits does not always exist due to externalities such as the demand bid, network loading, power imports, prices in other markets, etc. In other words, the payoff's in the payoff matrix change with the externalities, making it necessary to recognize when the "opportunity" to drive up profits exists. When enough suppliers recognize the opportunity we get "opportunistic tacit collusion." As we explain, this gaming behavior can take place independently of market power, transmission constraints, or insufficient supply, and is only enhan- ced by those factors. Price spikes from opportunistic tacit collusion can be expected to appear in any single price auction with price insensitive demand, a property that is typical of many electricity markets. Based on the above analysis, possible remedies are proposed. The attention is given to market design and bidding mechanism. The shortcomings of the current instant bidding rule is studied first and a new bidding rule and the associated market scheme are presented.
Power System Technology, 2002. Proceedings. PowerCon 2002. International Conference on; 11/2002
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