Plasma atropine concentrations associated with decreased intestinal motility in horses

IntroductionAtropine is an essential part of the treatment protocol for equine uveitis. Topical atropine administration has been associated with decreased intestinal motility and abdominal pain in horses. Experimental studies have indicated that frequent dosing is associated with a higher risk than dosing every 6 h. Unfortunately, no quantitative pharmacodynamic data for inhibition of the equine gut are published. Materials and methodsEight standardbred horses were assigned to receive either atropine or saline (control) to be infused over 30 min in a two-treatment cross-over design. Atropine concentrations in plasma were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. Intestinal motility was measured using borborygmi frequency and electrointestinography (EIG). Experimental data were analyzed using a non-linear mixed effects model. The model was then used to simulate different dosing regimens. ResultsAtropine significantly decreased borborygmi response and EIG response. Six horses developed clinical signs of abdominal pain. The pharmacokinetic typical values were 0.31, 1.38, 0.69, and 1.95 L/kg center dot h for the volumes of the central, the highly perfused, the scarcely perfused compartments, and the total body clearance, respectively. The pharmacodynamic typical values were 0.31 mu g/L and 0.6 and 207 nV(2)7 cpm for the plasma concentration at 50% of the maximum response and the maximum response and the baseline of cecal EIG response, respectively. Six different dosing regimens of topical atropine sulfate to the eye (0.4 and 1 mg every hour, every 3 h, and every 6 h) were simulated. ConclusionThe IV PK/PD data coupled with simulations predict that administration of 1 mg of topical atropine sulfate administered to the eye every hour or every 3 h will lead to atropine accumulation in plasma and decreased intestinal myoelectric activity. Administration every 6 h predicted a safe dosing regimen in full-sized horses. Clinical studies would be valuable to confirm the conclusions. For smaller equids and horses put at risk for colic due to othercauses, droplet bottles that deliver 40 mu l of 1% atropine sulfate per drop or less may be used to lower the risk further

Fine Mapping of Gene Regions Regulating Neurodegeneration

Loss of nerve cells and axons is a common feature of common complex neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. However, also Multiple Sclerosis (MS), primarily an autoimmune disorder, has a prominent neurodegenerative component. In complex disorders, many components affecting disease development and disease progression in combination make up the overall risk. In general, we divide these factors into inherited genetic factors and environmental factors. In addition, there are sometimes complex gene-environment interactions that make it difficult to identify individual risk components. In this thesis, I have focused on a translational approach to find genetic determinants of nerve cell survival in a simplified experimental model of nerve injury-induced neurodegeneration. The aim has been to find novel genes/pathways whose relevance subsequently can be tested in human disease. Through various genetic mapping approaches I demonstrate a strong inverse correlation between neuronal survival and expression and protein levels of an enzyme involved in detoxification of certain oxidation by-products. This enzyme, Glutathione S-Transferase alpha 4 (Gsta4), is highly efficient in catalysing the reduction of the neurotoxic aldehyde 4- hydroxynonenal (HNE), which is generated during lipid peroxidation and has previously been implicated in the pathogenesis of various neurodegenerative disorders. The relevance of this mechanism was also tested in a model of traumatic brain injury, where Gsta4 levels inversely correlate with degree of neuronal loss as well. In addition, rats with higher Gsta4 levels have a more favourable outcome after injection of HNE directly into the cortex. Taken together, these two studies provide strong support for the notion that the identified pathway is highly important for ability to cope with oxidative stress and in turn of relevance for nerve cell survival in different types of acute injury. Finally, a possible role for Gsta4 is tested in experimental autoimmune encephalomyelitis (EAE), a model of MS. No discernible clinical effect was observed between congenic rats with higher Gsta4 expression and the parental strain. However, lower Gsta4 expression was associated with a stronger autoantibody response. Protein modifications by HNE have in other inflammatory models been documented to induce a stronger antibody response, which is consistent with the obtained results. Intrathecal antibody production is an important diagnostic marker in MS, and hypothetically the HNE pathway can play a role for disease course through both neurotoxicity and amplification of the immune response. This was tested in a large case control cohort of MS, where suggested associations both to clinical and immune phenotypes were found. In summary, the results presented encourage further studies on the Gsta4-HNE pathway both in conditions of acute nerve injury and autoimmune neuroinflammation

The Expression of VEGF-A Is Down Regulated in Peripheral Blood Mononuclear Cells of Patients with Secondary Progressive Multiple Sclerosis

BACKGROUND: Most patients with relapsing-remitting multiple sclerosis (RRMS) eventually enter a secondary progressive (SPMS) phase, characterized by increasing neurological disability. The mechanisms underlying transition to SPMS are unknown and effective treatments and biomarkers are lacking. Vascular endothelial growth factor-A (VEGF-A) is an angiogenic factor with neuroprotective effects that has been associated with neurodegenerative diseases. SPMS has a prominent neurodegenerative facet and we investigated a possible role for VEGF-A during transition from RRMS to SPMS. METHODOLOGY/PRINCIPAL FINDINGS: VEGF-A mRNA expression in peripheral blood mononuclear (PBMC) and cerebrospinal fluid (CSF) cells from RRMS (n = 128), SPMS (n = 55) and controls (n = 116) were analyzed using real time PCR. We demonstrate reduced expression of VEGF-A mRNA in MS CSF cells compared to controls (p<0.001) irrespective of disease course and expression levels are restored by natalizumab treatment(p<0.001). VEGF-A was primarily expressed in monocytes and our CSF findings in part may be explained by effects on relative monocyte proportions. However, VEGF-A mRNA expression was also down regulated in the peripheral compartment of SPMS (p<0.001), despite unchanged monocyte counts, demonstrating a particular phenotype differentiating SPMS from RRMS and controls. A possible association of allelic variability in the VEGF-A gene to risk of MS was also studied by genotyping for six single nucleotide polymorphisms (SNPs) in MS (n = 1114) and controls (n = 1234), which, however, did not demonstrate any significant association between VEGF-A alleles and risk of MS. CONCLUSIONS/SIGNIFICANCE: Expression of VEGF-A in CSF cells is reduced in MS patients compared to controls irrespective of disease course. In addition, SPMS patients display reduced VEGF-A mRNA expression in PBMC, which distinguish them from RRMS and controls. This indicates a possible role for VEGF-A in the mechanisms regulating transition to SPMS. Decreased levels of PBMC VEGF-A mRNA expression should be further evaluated as a biomarker for SPMS

Wind Power and Railway Feeding : Solution with three sided converter

In this thesis it is investigated if it would be technically and economicallypossible to combine wind power and railway feeding. As a case studyBlekinge Kustbana (BKB), a railway section in the south of Sweden ischosen. The thesis includes an extensive power and energy flow analysison the railway section where large-scale wind power production is directlyconnected.When the work of this thesis started it was first of all a three sided convertersolution that should be studied. Where three-sided converter consists of aPWM-converter with the wind power connected to the DC-Iink. But duringthe work it was concluded that this solution is not the best solution for thecase. A better solution is the three-sided transformer, were the wind poweris connected through a third winding to the railway transformer on the 50Hzside.Also different railway feeding systems and their influence on how the windpower can be used are investigated.From the conclusions it can be mentioned that it would be profitable todirectly connect 4.5MW wind power to BKB.NR 20140805</p

Wind Power and Railway Feeding : Solution with three sided converter

In this thesis it is investigated if it would be technically and economicallypossible to combine wind power and railway feeding. As a case studyBlekinge Kustbana (BKB), a railway section in the south of Sweden ischosen. The thesis includes an extensive power and energy flow analysison the railway section where large-scale wind power production is directlyconnected.When the work of this thesis started it was first of all a three sided convertersolution that should be studied. Where three-sided converter consists of aPWM-converter with the wind power connected to the DC-Iink. But duringthe work it was concluded that this solution is not the best solution for thecase. A better solution is the three-sided transformer, were the wind poweris connected through a third winding to the railway transformer on the 50Hzside.Also different railway feeding systems and their influence on how the windpower can be used are investigated.From the conclusions it can be mentioned that it would be profitable todirectly connect 4.5MW wind power to BKB.NR 20140805</p