Pramipexole Extended Release: A Novel Treatment Option in Parkinson's Disease

Pramipexole, the most commonly prescribed dopamine agonist worldwide, meanwhile serves as a reference substance for evaluation of new drugs. Based on numerous clinical data and vast experiences, efficacy and safety profiles of this non-ergoline dopamine agonist are well characterized. Since October 2009, an extended-release formulation of pramipexole has been available for symptomatic treatment of Parkinson's disease. Pramipexole administration can be cut down from three times to once a day due to the newly developed extended-release formulation. This is considerable progress in regard to minimizing pill burden and enhancing compliance. Moreover, the 24 h continuous drug release of the once-daily extended-release formulation results in fewer fluctuations in plasma concentrations over time compared to immediate-release pramipexole, given three times daily. The present study summarizes pharmacokinetics and all essential pharmacological and clinical characteristics of the extended-release formulation. In addition, it provides all study data, available so far, with regard to transition and de-novo administration of extended-release formulation for patients with Parkinson's disease. It further compares efficacy and safety data of immediate-release pramipexole with the extended-release formulation of pramipexole

Effects of Incorporation of Sainfoin (\u3ci\u3eOnobrychis viciafolia\u3c/i\u3e Scop.) with Cool Season Grasses on \u3ci\u3ein vitro\u3c/i\u3e Digestibility and CH4 Emission

Sainfoin (Onobrychis viciafolia Scop.) is an important non-bloating perennial leguminous forage. The tannins in sainfoin alter protein metabolism in the rumen and have been implicated in altering both nitrous oxide and methane emissions. However, the effect of sainfoin when mixed with cool-season forages is unknown. Therefore, in this study, we evaluated the in-vitro fermentation of sainfoin hay mixed with two other perennial cool-season forages, meadow bromegrass and orchardgrass at five ratios (0:100, 25:75, 50:50, 75:50, and 100:0). Data on dry matter disappearance (DMD), neutral detergent fiber disappearance (NDFD), gas production (GP) methane (CH4) emissions, and ammonia production were collected 48 h post incubation. Ruminal fluid was sourced from three heifers fed with forage hay. Incubations were conducted with and without PEG (polyethylene glycol) as PEG negates the biological activity of tannins. Sainfoin had a higher nutritive value than the other two grass species as evidenced by the higher proportion of total nitrogen and lower proportion of ADF and NDF. The change in DMD, ammonia-N, NDFD, GP, and CH4 emissions between sainfoin and grass only hay were 3.1, 9.2, -36.8, -1.76, and -1.2% respectively with the intermediate results for the mixture. The inclusion of sainfoin with cool-season grasses has positive effects on ruminal fermentation and lowered in vitro methane emissions as compared to grass alon

University of Minnesota aquifer thermal energy storage (ATES) project report on the third long-term cycle

The University of Minnesota aquifer thermal energy storage (ATES) system has been operated as a field test facility (FTF) since 1982. The objectives were to design, construct, and operate the facility to study the feasibility of high-temperature ATES in a confined aquifer. Four short-term and two long-term cycles were previously conducted, which provided a greatly increased understanding of the efficiency and geochemical effects of high-temperature aquifer thermal energy storage. The third long-term cycle (LT3) was conducted to operate the ATES system in conjunction with a real heating load and to further study the geochemical impact that heated water storage had on the aquifer. For LT3, the source and storage wells were modified so that only the most permeable portion, the Ironton-Galesville part, of the Franconia-Ironton-Galesville aquifer was used for storage. This was expected to improve storage efficiency by reducing the surface area of the heated volume and simplify analysis of water chemistry results by reducing the number of aquifer-related variables which need to be considered. During LT3, a total volume of 63.2 {times} 10{sup 3} m {sup 3} of water was injected at a rate of 54.95 m{sup 3}/hr into the storage well at a mean temperature of 104.7{degrees}C. Tie-in to the reheat system of the nearby Animal Sciences Veterinary Medicine (ASVM) building was completed after injection was completed. Approximately 66 percent (4.13 GWh) of the energy added to the aquifer was recovered. Approximately 15 percent (0.64 GWh) of the usable (10 building. Operations during heat recovery with the ASVM building`s reheat system were trouble-free. Integration into more of the ASVM (or other) building`s mechanical systems would have resulted in significantly increasing the proportion of energy used during heat recovery

Alternatively spliced tissue factor and full-length tissue factor protect cardiomyocytes against TNF-α-induced apoptosis

Tissue Factor (TF) is expressed in various cell types of the heart, such as cardiomyocytes. In addition to its role in the initiation of blood coagulation, the TF:FVIIa complex protects cells from apoptosis. There are two isoforms of Tissue Factor (TF): “full length” (fl)TF – an integral membrane protein; and alternatively spliced (as)TF – a protein that lacks a transmembrane domain and can thus be secreted in a soluble form. Whether asTF or flTF affect apoptosis of cardiomyocytes is unknown

Evaluation of the effect of ultrasonic degassing on components produced by low pressure die casting

Ultrasonic processing is known to be an efficient means of aluminium melt degassing with additional benefits of being economical and environment friendly. This paper describes the performance of ultrasonic degassing in preparing melt for low pressure die casting (LPDC). Efficiency of ultrasonic degassing is compared with conventional Ar rotary degassing by direct measurements of hydrogen concentration in the melt with a Foseco Alspek-H probe and by reduced pressure test in different stages of the casting process. Significant reduction in dross formation along with similar efficiency of hydrogen degassing was shown for ultrasonic degassing as compared with conventional Ar rotary degassing. Mechanical properties, microstructure and porosity level of the components produced by LPDC after both degassing techniques are determined. Results show that the components produced after ultrasonic degassing treatment have similar hardness, tensile properties, porosity level and microstructure as the components degassed with conventional Ar rotary degassing.The European Union’s Seventh Framework Program managed by the Research Executive Agency (REA;FP7/2007–2013) under grant agreement number 286344 (www.ultragassing.eu)

Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis

Non-small cell lung cancer (NSCLC) comprises of 75% of all lung cancers. Human full length tissue factor (flHTF), the physiological initiator of blood coagulation, is aberrantly expressed in certain solid tumors. FlHTF and its soluble isoform, alternatively spliced human tissue factor (asHTF), have been shown to contribute to thrombogenicity of the blood of healthy individuals. The aim of this study was to quantify flHTF and asHTF on mRNA and protein levels (using immunohistochemistry, immunoblotting, and ELISA) on a panel of human NSCLC tissue and plasma specimens. The tissue factor (TF) expression of 21 pulmonary adenomatous (AC) and 12 normal healthy tissues was assessed by real-time qRT-PCR. The TF protein concentration was quantified by ELISA in a subset of 11 AC and 9 normal tissue specimens as well as in the plasma of 13 lung cancer patients and 15 healthy controls. We found a significant increase in the ratio of flHTF/HGAPDH mRNA in AC (0.24±0.06 vs. 0.07±0.01; p=0.02 vs. controls) and in asHTF/HGAPDH mRNA (0.027±0.01 vs. 0.004±0.001; p=0.03 AC vs. controls). AsHTF mRNA expression was significantly lower in patients with stage IA disease compared to patients with higher grade stages, pointing to TF as being a marker of malignancy and metastases. TF protein of lung tumors was significantly increased in AC (p=0.004 vs. controls). TF in plasma was up-regulated in lung cancer patients (334.9±95.4 vs. 124.1±14.8 pg/ml; p=0.02 vs. controls). Immunohistochemical and immunoblotting data are in line with the increased TF expression, showing elevated blood thrombogenicity of NSCLC patients. The up-regulation of flHTF and, especially, asHTF in AC suggests not only a raised risk of thrombosis, but also of tumor progression, thereby, indicating a poor prognosis in these patients

Metabolic engineering of astaxanthin biosynthesis in maize endosperm and characterization of a prototype high oil hybrid

Maize was genetically engineered for the biosynthesis of the high value carotenoid astaxanthin in the kernel endosperm. Introduction of a β-carotene hydroxylase and a β-carotene ketolase into a white maize genetic background extended the carotenoid pathway to astaxanthin. Simultaneously, phytoene synthase, the controlling enzyme of carotenogenesis, was over-expressed for enhanced carotenoid production and lycopene ε-cyclase was knocked-down to direct more precursors into the β-branch of the extended ketocarotenoid pathway which ends with astaxanthin. This astaxanthin-accumulating transgenic line was crossed into a high oil- maize genotype in order to increase the storage capacity for lipophilic astaxanthin. The high oil astaxanthin hybrid was compared to its astaxanthin producing parent. We report an in depth metabolomic and proteomic analysis which revealed major up- or down- regulation of genes involved in primary metabolism. Specifically, amino acid biosynthesis and the citric acid cycle which compete with the synthesis or utilization of pyruvate and glyceraldehyde 3-phosphate, the precursors for carotenogenesis, were down-regulated. Nevertheless, principal component analysis demonstrated that this compositional change is within the range of the two wild type parents used to generate the high oil producing astaxanthin hybrid

Functional analysis of genes involved in the biosynthesis of isoprene in Bacillus subtilis

In comparison to other bacteria Bacillus subtilis emits the volatile compound isoprene in high concentrations. Isoprene is the smallest representative of the natural product group of terpenoids. A search in the genome of B. subtilis resulted in a set of genes with yet unknown function, but putatively involved in the methylerythritol phosphate (MEP) pathway to isoprene. Further identification of these genes would give the possibility to engineer B. subtilis as a host cell for the production of terpenoids like the valuable plant-produced drugs artemisinin and paclitaxel. Conditional knock-out strains of putative genes were analyzed for the amount of isoprene emitted. Differences in isoprene emission were used to identify the function of the enzymes and of the corresponding selected genes in the MEP pathway. We give proof on a biochemical level that several of these selected genes from this species are involved in isoprene biosynthesis. This opens the possibilities to investigate the physiological function of isoprene emission and to increase the endogenous flux to the terpenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate, for the heterologous production of more complex terpenoids in B. subtilis

Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis

Metabolic networks in biological systems are interconnected, such that malfunctioning parts can be corrected by other parts within the network, a process termed adaptive metabolism. Unlike Bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis (Mtb) better manages its intracellular lifestyle by executing adaptive metabolism. Here, we used metabolomics and identified glutamate synthase (GltB/D) that converts glutamine to glutamate (Q → E) as a metabolic effort used to neutralize cytoplasmic pH that is acidified while consuming host propionate carbon through the methylcitrate cycle (MCC). Methylisocitrate lyase, the last step of the MCC, is intrinsically downregulated in BCG, leading to obstruction of carbon flux toward central carbon metabolism, accumulation of MCC intermediates, and interference with GltB/D mediated neutralizing activity against propionate toxicity. Indeed, vitamin B12 mediated bypass MCC and additional supplement of glutamate led to selectively correct the phenotypic attenuation in BCG and restore the adaptive capacity of BCG to the similar level of Mtb phenotype. Collectively, a defective crosstalk between MCC and Q → E contributes to attenuation of intracellular BCG. Furthermore, GltB/D inhibition enhances the level of propionate toxicity in Mtb. Thus, these findings revealed a new adaptive metabolism and propose GltB/D as a synergistic target to improve the antimicrobial outcomes of MCC inhibition in Mtb