Solid phase extraction and LC-MS/MS quantification of ibandronate in human plasma

Purpose: To develop and validate a simple, highly sensitive and accurate method for the quantification of ibandronate (IBN) in human plasma.Methods: Electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS) in positive ion mode was applied to obtain optimum signals. The parent ion was acquired under collisionactivated dissociation conditions, and the abundant fragments used to design multiple reaction monitoring experiments for monitoring two ibandronate transitions (m/z 376 to m/z 114, and m/z 376 to m/z 250). The IBN was isolated from plasma with weak anion exchange solid phase extraction columns with ‘on-cartridge’ derivatization using tri-methylsilyl-diazomethane (TMSDZ) reagent to convert IBN to tetra-methyl derivative.Results: The studied drug was successfully extracted from plasma samples without any interference at a retention time of 3.2 min. The matrix effect averaged 110 %, indicating that endogenous materials had little effect on ionization. The relationship between plasma analyte concentration and IBN signal area was satisfactorily linear, with correlation coefficient (r2) ranging from 0.9817 to 0.9942 in the concentration range of 0.5 – 200 ng/ml. The lower and upper limits of quantification (LLOQ and ULOQ) for IBN were 0.5 and 200 ng/ml, respectively. Relative recovery of IBN from plasma after extraction and derivatization at 3 distinct concentrations was 83.93 to 85.06 %, relative to standard solutions. The ranges of intra- and inter-day accuracies of quantification of quality controls were 89.39 - 106.40 %, and 90.50 - 107.96 %, respectively. Processed plasma IBN extracts were stable in autosampler at 4 0C (91.12 to 103.49%). Long-term stability in plasma after 30 days at -24 0C ranged from 89.52 to 113.18 %.Conclusion: This validated LC-MS/MS method can be successfully applied for determination of IBN in pharmacokinetic studies. It is a sensitive and specific assay for plasma IBN in bioequivalence studies. Keywords: Ibandronate, LC-MS/MS, Validation, Derivatization, Solid-phase extractio

CFD modelling of an animal occupied zone using an anisotropic porous medium model with velocity depended resistance parameters

The airflow in dairy barns is affected by many factors, such as the barn's geometry, weather conditions, configurations of the openings, cows acting as heat sources, flow obstacles, etc. Computational fluids dynamics (CFD) has the advantages of providing detailed airflow information and allowing fully-controlled boundary conditions, and therefore is widely used in livestock building research. However, due to the limited computing power, numerous animals are difficult to be designed in detail. Consequently, there is the need to develop and use smart numerical models in order to reduce the computing power needed while at the same time keeping a comparable level of accuracy. In this work the porous medium modeling is considered to solve this problem using Ansys Fluent. A comparison between an animal occupied zone (AOZ) filled with randomly arranged 22 simplified cows' geometry model (CM) and the porous medium model (PMM) of it, was made. Anisotropic behavior of the PMM was implemented in the porous modeling to account for turbulence influences. The velocity at the inlet of the domain has been varied from 0.1 m s(-1) to 3 in s(-1) and the temperature difference between the animals and the incoming air was set at 20 K. Leading to Richardson numbers Ri corresponding to the three types of heat transfer convection, i.e. natural, mixed and forced convection. It has been found that the difference between two models (the cow geometry model and the PMM) was around 2% for the pressure drop and less than 6% for the convective heat transfer. Further the usefulness of parametrized PMM with a velocity adaptive pressure drop and heat transfer coefficient is shown by velocity field validation of an on-farm measurement

LA PREVENTION PRECOCE DES ENTREPRISES EN SITUATION DE DETRESSE FINANCIERE

Today, businesses face financial difficulties due to economic difficulties, declining performance and mismanagement. In other words, the process of financial distress begins with an incubation period characterized by a combination of poor economic conditions and mismanagement.In most cases, financial distress can push businesses to go bankrupt or reduce their reputation. As a result, early prevention of financial distress is one of the most important decision-making issues facing auditors, consultants and business leaders.Due to the seriousness of the issue for businesses, we will try, in the first part of this article, to highlight the symptoms or warning signals that can help business leaders to predict and prevent financial distress in advance. Then, in the second part, we will deal with the preventive measures to manage  the situation of financial distress

Ammonia emission prediction for dairy cattle housing from reaction kinetic modeling to the barn scale

One way to estimate ammonia emission rates from naturally ventilated housing systems is to scale-up mechanistic modeling results. However, obtaining the relevant data to set initial and boundary conditions adequately is usually very challenging and for a whole barn barely possible. This study has investigated the potential of coupling different mechanistic modeling approaches towards an overarching barn scale ammonia emission model, which might permit ammonia emission projections for naturally ventilated housing systems with minimal measurement efforts. To this end, we combined an ammonia volatilization model for shallow urine or slurry puddles with a dynamic mechanistic model of digestion and excretion of nitrogen, an empirical model to estimate urination volumes, semi-empirical models for pH and temperature dynamics of the puddles and a mechanistic air flow model. The ammonia volatilization model was integrated with a time step of one second over a period of twenty-four hours, while the relevant boundary conditions were updated on an hourly base (determined by the other mentioned submodels). Projections and uncertainties of the approach were investigated for a farm case with about ten months of on-farm measurements in a naturally ventilated dairy cattle building with scraped solid floor in Northern Germany. The results showed that the nested model was in general capable to reproduce the long-term emission trend and variability, while the short-term variability was damped compared with the emission measurements. A sensitivity study indicated that particularly a refinement of the submodules for urine puddle alkalizing, urination volume and urea concentration distributions as well as for local near-surface wind speeds have a great potential to further improve the overall model accuracy. The cleaning efficiency of the scraper has turned out to be a crucial and sensitive parameter in the modeling, which so far has been described insufficiently by measurements or modeling approaches

The impact of component performance on the overall cycle performance of small-scale low temperature organic Rankine cycles

Low temperature organic Rankine cycles offer a promising technology for the generation of power from low temperature heat sources. Small-scale systems (~10kW) are of significant interest, however there is a current lack of commercially viable expanders. For a potential expander to be economically viable for small-scale applications it is reasonable to assume that the same expander must have the ability to be implemented within a number of different ORC applications. It is therefore important to design and optimise the cycle considering the component performance, most notably the expander, both at different thermodynamic conditions, and using alternative organic fluids. This paper demonstrates a novel modelling methodology that combines a previously generated turbine performance map with cycle analysis to establish at what heat source conditions optimal system performance can be achieved using an existing turbine design. The results obtained show that the same turbine can be effectively utilised within a number of different ORC applications by changing the working fluid. By selecting suitable working fluids, this turbine can be used to convert pressurised hot water at temperatures between 360K and 400K, and mass flow rates between 0.45kg/s and 2.7kg/s, into useful power with outputs between 1.5kW and 27kW. This is a significant result since it allows the same turbine to be implemented into a variety of applications, improving the economy of scale. This work has also confirmed the suitability of the candidate turbine for a range of low temperature ORC applications

Digital acrometastase as a primary manifestation of a bronchial adenocarcinoma

Bone metastases of the hands and feet (acrometastases) are rare. Their presentation is variable and is generally confused with certain inflammatory conditions such as rheumatoid arthritis, gout, tenosynovitis, fracture or infection (panartius, osteomyelitis). The etiology of non-digital acrometastases is common to primary tumors with bone metastases (prostate, lung, kidney, breast, thyroid, and digestive tube). However, digital acrometastases are seen almost exclusively during bronchial neoplasia. We describe the case of a 43 year-old man admitted for pain and swelling of the middle finger distal phalanx of the left hand. Etiological assessement was in favor of an unusual secondary localization of bronchial adenocarcinoma. Tumoral causes must always be evoked before any inflammatory digital symptomatology, from where the interest of a good interrogation and a targeted paraclinical assessment.

Compact Labelings For Efficient First-Order Model-Checking

We consider graph properties that can be checked from labels, i.e., bit sequences, of logarithmic length attached to vertices. We prove that there exists such a labeling for checking a first-order formula with free set variables in the graphs of every class that is \emph{nicely locally cwd-decomposable}. This notion generalizes that of a \emph{nicely locally tree-decomposable} class. The graphs of such classes can be covered by graphs of bounded \emph{clique-width} with limited overlaps. We also consider such labelings for \emph{bounded} first-order formulas on graph classes of \emph{bounded expansion}. Some of these results are extended to counting queries

Changing treatment patterns for coronary artery revascularization in Canada: the projected impact of drug eluting stents

BACKGROUND: To evaluate current treatment patterns for coronary artery revascularization in Canada and explore the potential impact of drug eluting stents (DES) on these treatment patterns. METHODS: Eleven cardiologists at multiple Canadian academic centers completed a questionnaire on coronary artery revascularization rates and treatment patterns. RESULTS: Participating physicians indicated slightly higher rates of PTCA, CABG, and stent implantation than reported in CCN publications. Participants estimated that 24% of all patients currently receiving bare metal stents (BMS) would receive DES in the first year following DES approval in Canada, although there was a large range of estimates around this value (5% to 65%). By the fifth year following DES approval, it was estimated that 85% of BMS patients would instead receive DES. Among diabetic patients, estimates ranged from 43% in the first year following approval to 91% in the fifth year. For all patients currently receiving CABG, mean use of DES instead was estimated at 12% in the first year to 42% at five years; rates among diabetic patients currently undergoing CABG were 17% in the first year to 49% in the fifth year. CONCLUSIONS: These results suggest a continued increase in revascularization procedures in Canada. Based on the panel's responses, it is likely that a trend away from CABG towards PTCA will continue in Canada, and will be augmented by the availability of DES as a treatment option. The availability of DES as a treatment option in Canada may change the threshold at which revascularization procedures are considered

Identification of osteolineage cell-derived extracellular vesicle cargo implicated in hematopoietic support

Osteolineage cell-derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non-stimulatory osteolineage EVs by next-generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV-derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood-derived CD34+ HSPCs with stimulatory EVs-altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study giv