Dynamics of the seizure states caused by the action of ligands of the inhibitory transmitter system, as a consequence of evolution of stochastic neuronal populations

A probabilistic model describing functioning of the elements of a neuronal population is suggested. The model includes subsystems: synaptically interconnected inhibitory and excitatory neurons. The probability of the occurrence of the intercellular signal at varying levels of the endogenous transmitter and the effects of exogenous ligands (agonists, antagonists, etc.) of the inhibitory (GABA_A) transmitter system is considered. Comparison of the computer simulation with the experimental data showed that their paroxysmal EEG activity recorded after applications of strychnine, corazol, bicuculline, or picrotoxin to the neocortical surface, as well as during seizures following intravenous administrations of these drugs, is characterized by a consequent mild and rigid loss of stability, followed by a decrease in the share of active neurons in the population. The reason for these phenomena is a periodical asynchronous decrease in the efficiency of excitatory and inhibitory intercellular signals in the neuronal population.     

Nitric Oxide Down-Regulates Topoisomerase I and Induces Camptothecin Resistance in Human Breast MCF-7 Tumor Cells

Camptothecin (CPT), a topoisomerase I poison, is an important drug for the treatment of solid tumors in the clinic. Nitric oxide (^·NO), a physiological signaling molecule, is involved in many cellular functions, including cell proliferation, survival and death. We have previously shown that ^·NO plays a significant role in the detoxification of etoposide (VP-16), a topoisomerase II poison in vitro and in human melanoma cells. ^·NO/^·NO-derived species are reported to modulate activity of several important cellular proteins. As topoisomerases contain a number of free sulfhydryl groups which may be targets of ^·NO/^·NO-derived species, we have investigated the roles of ^·NO/^·NO-derived species in the stability and activity of topo I. Here we show that ^·NO/^·NO-derived species induces a significant down-regulation of topoisomerase I protein via the ubiquitin/26S proteasome pathway in human colon (HT-29) and breast (MCF-7) cancer cell lines. Importantly, ^·NO treatment induced a significant resistance to CPT only in MCF-7 cells. This resistance to CPT did not result from loss of topoisomerase I activity as there were no differences in topoisomerase I-induced DNA cleavage in vitro or in tumor cells, but resulted from the stabilization/induction of bcl2 protein. This up-regulation of bcl2 protein in MCF-7 cells was wtp53 dependent as pifithrine-α, a small molecule inhibitor of wtp53 function, completely reversed CPT resistance, suggesting that wtp53 and bcl2 proteins played important roles in CPT resistance. Because tumors in vivo are heterogeneous and contaminated by infiltrating macrophages, ^·NO-induced down-regulation of topoisomerase I protein combined with bcl2 protein stabilization could render certain tumors highly resistant to CPT and drugs derived from it in the clinic.     

The canine isolate Lactobacillus acidophilus LAB20 adheres to intestinal epithelium and attenuates LPS-induced IL-8 secretion of enterocytes in vitro

Background

For a good probiotic candidate, the abilities to adhere to intestinal epithelium and to fortify barrier function are considered to be crucial for colonization and functionality of the strain. The strain Lactobacillus acidophilus LAB20 was isolated from the jejunum of a healthy dog, where it was found to be the most pre-dominant lactobacilli. In this study, the adhesion ability of LAB20 to intestinal epithelial cell (IECs) lines, IECs isolated from canine intestinal biopsies, and to canine, porcine and human intestinal mucus was investigated. Further, we studied the ability of LAB20 to fortify the epithelial cell monolayer and to reduce LPS-induced interleukin (IL-8) release from enterocytes.

Results

We found that LAB20 presented higher adhesion to canine colonic mucus as compared to mucus isolated from porcine colon. LAB20 showed adhesion to HT-29 and Caco-2 cell lines, and importantly also to canine IECs isolated from canine intestinal biopsies. In addition, LAB20 increased the transepithelial electrical resistance (TER) of enterocyte monolayers and thus strengthened the intestinal barrier function. The strain showed also anti-inflammatory capacity in being able to attenuate the LPS-induced IL-8 production of HT-29 cells.

Conclusion

In conclusion, canine indigenous strain LAB20 is a potential probiotic candidate for dogs adhering to the host epithelium and showing intestinal barrier fortifying and anti-inflammatory effects.

Electronic supplementary material

The online version of this article (doi:10.1186/s12866-014-0337-9) contains supplementary material, which is available to authorized users.     

Potential for epidemic take-off from the primary outbreak farm via livestock movements

Background

We consider the potential for infection to spread in a farm population from the primary outbreak farm via livestock movements prior to disease detection. We analyse how this depends on the time of the year infection occurs, the species transmitting, the length of infectious period on the primary outbreak farm, location of the primary outbreak, and whether a livestock market becomes involved. We consider short infectious periods of 1 week, 2 weeks and 4 weeks, characteristic of acute contagious livestock diseases. The analysis is based on farms in Scotland from 1 January 2003 to 31 July 2007.

Results

The proportion of primary outbreaks from which an acute contagious disease would spread via movement of livestock is generally low, but exhibits distinct annual cyclicity with peaks in May and August. The distance that livestock are moved varies similarly: at the time of the year when the potential for spread via movements is highest, the geographical spread via movements is largest. The seasonal patterns for cattle differ from those for sheep whilst there is no obvious seasonality for pigs. When spread via movements does occur, there is a high risk of infection reaching a livestock market; infection of markets can amplify disease spread. The proportion of primary outbreaks that would spread infection via livestock movements varies significantly between geographical regions.

Conclusions

In this paper we introduce a set-up for analysis of movement data that allows for a generalized assessment of the risk associated with infection spreading from a primary outbreak farm via livestock movements, applying this to Scotland, we assess how this risk depends upon the time of the year, species transmitting, location of the farm and other factors.     

Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13

A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.