Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier–Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system’s components taken in isolation

A systematic review of the effects of prolonged cow-calf contact on behavior, welfare, and productivity

Separation of calves from cows within hours or days of birth is common on dairy farms. Stakeholders have conflicting perspectives on whether this is harmful or beneficial for the animals’ welfare and production. Our objective was to critically evaluate the scientific evidence for both acute and long-term effects of early separation versus an extended period of cow-calf contact. The outcomes investigated were the behavior, welfare (excluding physical health) and performance (milk yield and growth, respectively) of dairy cows and calves. Primary research papers were found through targeted Web of Science searches, the reference lists of recent reviews for each topic, and the reference lists of papers identified from these sources. Studies were included if they were published in English, the full text was accessible, and they compared treatments with and without contact between dairy cows and calves for a specified period. Early separation (within 24 h post-partum) was found to reduce acute distress responses of cows and calves. However, longer cow-calf contact typically had positive longer-term effects on calves, promoting more normal social behavior, reducing abnormal behavior and sometimes reducing responses to stressors. In terms of productivity, allowing cows to nurse calves generally decreased the volume of milk available for sale during the nursing period, but there was no consistent evidence of reduced milk production over a longer period. Allowing a prolonged period of nursing increased calf weight gains during the milk-feeding period. In summary, extended cow-calf contact aggravates the acute distress responses and reduces the amount of saleable milk while the calves are suckling, but can have positive effects on behaviors relevant to welfare in the longer term and benefit calf growth. The strength of these conclusions is limited, however, given that relatively few studies address most of these effects and that experimental design including timing of contact and observations are often inconsistent across studies. Few studies presented indicators of long-term welfare effects other than abnormal and social behavior of the calves

Identification of Conserved and HLA Promiscuous DENV3 T-Cell Epitopes

Anti-dengue T-cell responses have been implicated in both protection and immunopathology. However, most of the T-cell studies for dengue include few epitopes, with limited knowledge of their inter-serotype variation and the breadth of their human leukocyte antigen (HLA) affinity. In order to expand our knowledge of HLA-restricted dengue epitopes, we screened T-cell responses against 477 overlapping peptides derived from structural and non-structural proteins of the dengue virus serotype 3 (DENV3) by use of HLA class I and II transgenic mice (TgM): A2, A24, B7, DR2, DR3 and DR4. TgM were inoculated with peptides pools and the T-cell immunogenic peptides were identified by ELISPOT. Nine HLA class I and 97 HLA class II novel DENV3 epitopes were identified based on immunogenicity in TgM and their HLA affinity was further confirmed by binding assays analysis. A subset of these epitopes activated memory T-cells from DENV3 immune volunteers and was also capable of priming naïve T-cells, ex vivo, from dengue IgG negative individuals. Analysis of inter- and intra-serotype variation of such an epitope (A02-restricted) allowed us to identify altered peptide ligands not only in DENV3 but also in other DENV serotypes. These studies also characterized the HLA promiscuity of 23 HLA class II epitopes bearing highly conserved sequences, six of which could bind to more than 10 different HLA molecules representing a large percentage of the global population. These epitope data are invaluable to investigate the role of T-cells in dengue immunity/pathogenesis and vaccine design. © 2013 Nascimento et al

Modeling Brain Resonance Phenomena Using a Neural Mass Model

Stimulation with rhythmic light flicker (photic driving) plays an important role in the diagnosis of schizophrenia, mood disorder, migraine, and epilepsy. In particular, the adjustment of spontaneous brain rhythms to the stimulus frequency (entrainment) is used to assess the functional flexibility of the brain. We aim to gain deeper understanding of the mechanisms underlying this technique and to predict the effects of stimulus frequency and intensity. For this purpose, a modified Jansen and Rit neural mass model (NMM) of a cortical circuit is used. This mean field model has been designed to strike a balance between mathematical simplicity and biological plausibility. We reproduced the entrainment phenomenon observed in EEG during a photic driving experiment. More generally, we demonstrate that such a single area model can already yield very complex dynamics, including chaos, for biologically plausible parameter ranges. We chart the entire parameter space by means of characteristic Lyapunov spectra and Kaplan-Yorke dimension as well as time series and power spectra. Rhythmic and chaotic brain states were found virtually next to each other, such that small parameter changes can give rise to switching from one to another. Strikingly, this characteristic pattern of unpredictability generated by the model was matched to the experimental data with reasonable accuracy. These findings confirm that the NMM is a useful model of brain dynamics during photic driving. In this context, it can be used to study the mechanisms of, for example, perception and epileptic seizure generation. In particular, it enabled us to make predictions regarding the stimulus amplitude in further experiments for improving the entrainment effect

Amendments to Interpretations of SAAF Inclinometer Data from the Furggwanghorn Rock Glacier, Turtmann Valley, Switzerland: Results from 2010 to 2012

Raw data processing from a ShapeAccelArray field (SAAF) inclinometer were made using proprietary software from Measurand, the manufacturer of the SAAF inclinometer. When the inclinometer data obtained from the same borehole were reprocessed with an updated software version, the results were found to differ significantly from the values derived using the previous version of software. Neither the absolute displacements, nor the curve representing displacements with depth, agreed with the previous values, despite best attempts to compare data with alternative sparse field measurements of surface displacements. There was a change in inclination of the segments above the shear zone, and the strain rates in the shear zone were reduced significantly during the winter months. In contrast, there was no change in the depth of the shear zone. Therefore, the ground model presented in the original study is still considered to be the optimal ground model of the Furggwanghorn rock glacier. Finally, a simple trigonometrical approach was conducted to investigate the validity of both software versions. The simplified recalculations could confirm mostly the results of the updated software version.ISSN:1539-166