Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

Endogenous angiotensinergic system in neurons of rat and human trigeminal ganglia

To clarify the role of Angiotensin II (Ang II) in the sensory system and especially in the trigeminal ganglia, we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of Ang II and substance P in the rat and human trigeminal ganglia. The rat trigeminal ganglia expressed substantial amounts of Ang-N- and ACE mRNA as determined by quantitative real time PCR. Renin mRNA was untraceable in rat samples. Cathepsin D was detected in the rat trigeminal ganglia indicating the possibility of existence of pathways alternative to renin for Ang I formation. In situ hybridization in rat trigeminal ganglia revealed expression of Ang-N mRNA in the cytoplasm of numerous neurons. By using immunocytochemistry, a number of neurons and their processes in both the rat and human trigeminal ganglia were stained for Ang II. Post in situ hybridization immunocytochemistry reveals that in the rat trigeminal ganglia some, but not all Ang-N mRNA-positive neurons marked for Ang II. In some neurons Substance P was found colocalized with Ang II. Angiotensins from rat trigeminal ganglia were quantitated by radioimmunoassay with and without prior separation by high performance liquid chromatography. Immunoreactive angiotensin II (ir-Ang II) was consistently present and the sum of true Ang II (1-8) octapeptide and its specifically measured metabolites were found to account for it. Radioimmunological and immunocytochemical evidence of ir-Ang II in neuronal tissue is compatible with Ang II as a neurotransmitter. In conclusion, these results suggest that Ang II could be produced locally in the neurons of rat trigeminal ganglia. The localization and colocalization of neuronal Ang II with Substance P in the trigeminal ganglia neurons may be the basis for a participation and function of Ang II in the regulation of nociception and migraine pathology.

Economic efficiency analysis of different strategies to control post-weaning multi-systemic wasting syndrome and porcine circovirus type 2 subclinical infection in 3-weekly batch system farms.

The study assessed the economic efficiency of different strategies for the control of post-weaning multi-systemic wasting syndrome (PMWS) and porcine circovirus type 2 subclinical infection (PCV2SI), which have a major economic impact on the pig farming industry worldwide. The control strategies investigated consisted on the combination of up to 5 different control measures. The control measures considered were: (1) PCV2 vaccination of piglets (vac); (2) ensuring age adjusted diet for growers (diets); (3) reduction of stocking density (stock); (4) improvement of biosecurity measures (bios); and (5) total depopulation and repopulation of the farm for the elimination of other major pathogens (DPRP). A model was developed to simulate 5 years production of a pig farm with a 3-weekly batch system and with 100 sows. A PMWS/PCV2SI disease and economic model, based on PMWS severity scores, was linked to the production model in order to assess disease losses. This PMWS severity scores depends on the combination post-weaning mortality, PMWS morbidity in younger pigs and proportion of PCV2 infected pigs observed on farms. The economic analysis investigated eleven different farm scenarios, depending on the number of risk factors present before the intervention. For each strategy, an investment appraisal assessed the extra costs and benefits of reducing a given PMWS severity score to the average score of a slightly affected farm. The net present value obtained for each strategy was then multiplied by the corresponding probability of success to obtain an expected value. A stochastic simulation was performed to account for uncertainty and variability. For moderately affected farms PCV2 vaccination alone was the most cost-efficient strategy, but for highly affected farms it was either PCV2 vaccination alone or in combination with biosecurity measures, with the marginal profitability between 'vac' and 'vac+bios' being small. Other strategies such as 'diets', 'vac+diets' and 'bios+diets' were frequently identified as the second or third best strategy. The mean expected values of the best strategy for a moderately and a highly affected farm were £14,739 and £57,648 after 5 years, respectively. This is the first study to compare economic efficiency of control strategies for PMWS and PCV2SI. The results demonstrate the economic value of PCV2 vaccination, and highlight that on highly affected farms biosecurity measures are required to achieve optimal profitability. The model developed has potential as a farm-level decision support tool for the control of this economically important syndrome.

A Near-Real-Time Automatic Orbit Determination System for COSMIC and Its Follow-On Satellite Mission: Analysis of Orbit and Clock Errors on Radio Occultation

The COSMIC-2 mission is a follow-on mission of the Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) with an upgraded payload for improved radio occultation (RO) applications. The objective of this paper is to develop a near-real-time (NRT) orbit determination system, called NRT National Chiao Tung University (NCTU) system, to support COSMIC-2 in atmospheric applications and verify the orbit product of COSMIC. The system is capable of automatic determinations of the NRT GPS clocks and LEO orbit and clock. To assess the NRT (NCTU) system, we use eight days of COSMIC data (March 24-31, 2011), which contain a total of 331 GPS observation sessions and 12 393 RO observable files. The parallel scheduling for independent GPS and LEO estimations and automatic time matching improves the computational efficiency by 64% compared to the sequential scheduling. Orbit difference analyses suggest a 10-cm accuracy for the COSMIC orbits from the NRT (NCTU) system, and it is consistent as the NRT University Corporation for Atmospheric Research (URCA) system. The mean velocity accuracy from the NRT orbits of COSMIC is 0.168 mm/s, corresponding to an error of about 0.051 μrad in the bending angle. The rms differences in the NRT COSMIC clock and in GPS clocks between the NRT (NCTU) and the postprocessing products are 3.742 and 1.427 ns. The GPS clocks determined from a partial ground GPS network [from NRT (NCTU)] and a full one [from NRT (UCAR)] result in mean rms frequency stabilities of 6.1E-12 and 2.7E-12, respectively, corresponding to range fluctuations of 5.5 and 2.4 cm and bending angle errors of 3.75 and 1.66 μrad .

Good just isn't Good enough. Best System Probabilities and the Foundations of Statistical Mechanics

Statistical physicists assume a probability distribution over micro-states to explain thermodynamic behavior. The question of this paper is whether these probabilities are part of a best system and can thus be interpreted as Humean chances. I consider two strategies, viz. a globalist as suggested by Loewer, and a localist as advocated by Frigg and Hoefer. Both strategies fail because the system they are part of have rivals that are roughly equally good, while ontic probabilities should be part of a clearly winning system. I conclude with the diagnosis that well-defined micro-probabilities under-estimate the robust character of explanations in statistical physics.

Microbial-immune cross-talk and regulation of the immune system

We are all born germ-free. Following birth we enter into a lifelong relationship with microbes residing on our body's surfaces. The lower intestine is home to the highest microbial density in our body, which is also the highest microbial density known on Earth (up to 10(12) /g of luminal contents). With our indigenous microbial cells outnumbering our human cells by an order of magnitude our body is more microbial than human. Numerous immune adaptations confine these microbes within the mucosa, enabling most of us to live in peaceful homeostasis with our intestinal symbionts. Intestinal epithelial cells not only form a physical barrier between the bacteria-laden lumen and the rest of the body but also function as multi-tasking immune cells that sense the prevailing microbial (apical) and immune (basolateral) milieus, instruct the underlying immune cells, and adapt functionally. In the constant effort to ensure intestinal homeostasis, the immune system becomes educated to respond appropriately and in turn immune status can shape the microbial consortia. Here we review how the dynamic immune-microbial dialogue underlies maturation and regulation of the immune system and discuss recent findings on the impact of diet on both microbial ecology and immune function.

The ovine cerebral venous system: comparative anatomy, visualization, and implications for translational research.

Cerebrovascular diseases are significant causes of death and disability in humans. Improvements in diagnostic and therapeutic approaches strongly rely on adequate gyrencephalic, large animal models being demanded for translational research. Ovine stroke models may represent a promising approach but are currently limited by insufficient knowledge regarding the venous system of the cerebral angioarchitecture. The present study was intended to provide a comprehensive anatomical analysis of the intracranial venous system in sheep as a reliable basis for the interpretation of experimental results in such ovine models. We used corrosion casts as well as contrast-enhanced magnetic resonance venography to scrutinize blood drainage from the brain. This combined approach yielded detailed and, to some extent, novel findings. In particular, we provide evidence for chordae Willisii and lateral venous lacunae, and report on connections between the dorsal and ventral sinuses in this species. For the first time, we also describe venous confluences in the deep cerebral venous system and an 'anterior condylar confluent' as seen in humans. This report provides a detailed reference for the interpretation of venous diagnostic imaging findings in sheep, including an assessment of structure detectability by in vivo (imaging) versus ex vivo (corrosion cast) visualization methods. Moreover, it features a comprehensive interspecies-comparison of the venous cerebral angioarchitecture in man, rodents, canines and sheep as a relevant large animal model species, and describes possible implications for translational cerebrovascular research.

Capability of a space-based space surveillance system to detect and track objects in GEO, MEO and LEO orbits

In this paper we present the results from the coverage and the orbit determination accuracy simulations performed within the recently completed ESA study “Assessment Study for Space Based Space Surveillance (SBSS) Demonstration System” (Airbus Defence and Space consortium). This study consisted in investigating the capability of a space based optical sensor (SBSS) orbiting in low Earth orbit (LEO) to detect and track objects in GEO (geosynchronous orbit), MEO (medium Earth orbit) and LEO and to determinate and improve initial orbits from such observations. Space based systems may achieve better observation conditions than ground based sensors in terms of astrometric accuracy, detection coverage, and timeliness. The primary observation mode of the proposed SBSS demonstrator is GEO surveillance, i.e. the systematic search and detection of unknown and known objects. GEO orbits are specific and unique orbits from dynamical point of view. A space-based sensor may scan the whole GEO ring within one sidereal day if the orbit and pointing directions are chosen properly. For an efficient survey, our goal was to develop a leak-proof GEO fence strategy. Collaterally, we show that also MEO, LEO and other (GTO,Molniya, etc.) objects would be possible to observe by the system and for a considerable number of LEO objects to down to size of 1 cm we can obtain meaningful statistical data for improvement and validation of space debris environment models

Periacetabular osteotomy through the pararectus approach: technical feasibility and control of fragment mobility by a validated surgical navigation system in a cadaver experiment

PURPOSE The pararectus approach has been validated for managing acetabular fractures. We hypothesised it might be an alternative approach for performing periacetabular osteotomy (PAO). METHODS Using four cadaver specimens, we randomly performed PAO through either the pararectus or a modified Smith-Petersen (SP) approach. We assessed technical feasibility and safety. Furthermore, we controlled fragment mobility using a surgical navigation system and compared mobility between approaches. The navigation system's accuracy was tested by cross-examination with validated preoperative planning software. RESULTS The pararectus approach is technically feasible, allowing for adequate exposure, safe osteotomies and excellent control of structures at risk. Fragment mobility is equal to that achieved through the SP approach. Validation of these measurements yielded a mean difference of less <1 mm without statistical significance. CONCLUSION Experimental data suggests the pararectus approach might be an alternative approach for performing PAO. Clinical validation is necessary to confirm these promising preliminary results.