A three-state mathematical model of hyperthermic cell death

Thermal treatments for tissue ablation rely upon the heating of cells past a threshold beyond which the cells are considered destroyed, denatured, or killed. In this article, a novel three-state model for cell death is proposed where there exists a vulnerable state positioned between the alive and dead states used in a number of existing cell death models. Proposed rate coefficients include temperature dependence and the model is fitted to experimental data of heated co-cultures of hepatocytes and lung fibroblasts with very small RMS error. The experimental data utilized include further reductions in cell viabilities over 24 and 48 h post-heating and these data are used to extend the three-state model to account for slow cell death. For the two cell lines employed in the experimental data, the three parameters for fast cell death appear to be linearly increasing with % content of lung fibroblast, while the sparse nature of the data did not indicate any co-culture make-up dependence for the parameters for slow cell death. A critical post-heating cell viability threshold is proposed beyond which cells progress to death; and these results are of practical importance with potential for more accurate prediction of cell death.     

Differential effects of methylphenidate and atomoxetine on attentional processes in children with ADHD: An event-related potential study using the Attention Network Test

Methylphenidate (MPH) and atomoxetine (ATX) are effective medications in the treatment of attention deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate differential effects of MPH and ATX on attentional functions at the performance and the neuronal level in children with ADHD. Using the Attention Network Test (ANT), differential effects of both medications on the noradrenergic alerting network and the dopaminergic executive attention network were considered. Nineteen children with ADHD performed the ANT three times while event-related potentials (ERPs) were recorded. The baseline testing was conducted without medication. In two medication blocks of 8 weeks each, medication was individually titrated for each child (cross-over design, balanced order). At the end of the medication blocks the testing was repeated. While both medications comparably reduced ADHD symptomatology, MPH had some advantages over ATX with regard to performance measures on the ANT and the underlying neuronal mechanisms. Compared with ATX, MPH led to a larger reduction in reaction time variability, which was accompanied by an MPH-related increase in the contingent negative variation (CNV) compared to the baseline testing. Contrary to our expectations, specific alerting network effects were not observed with ATX. Due to the chosen study design, it remains unresolved to what extent e.g. shortened reaction times and smaller conflict scores that were observed with both medications reflect practice or medication effects. The differential pattern of MPH vs. ATX effects on attentional functions in children with ADHD may be explained by the dopaminergic effects of MPH within the cortico-striato-thalamo-cortical circuit.     

White matter pathology in ALS and lower motor neuron ALS variants: a diffusion tensor imaging study using tract-based spatial statistics

The aim of this work was to investigate white-matter microstructural changes within and outside the corticospinal tract in classical amyotrophic lateral sclerosis (ALS) and in lower motor neuron (LMN) ALS variants by means of diffusion tensor imaging (DTI). We investigated 22 ALS patients and 21 age-matched controls utilizing a whole-brain approach with a 1.5-T scanner for DTI. The patient group was comprised of 15 classical ALS- and seven LMN ALS-variant patients (progressive muscular atrophy, flail arm and flail leg syndrome). Disease severity was measured by the revised version of the functional rating scale. White matter fractional anisotropy (FA) was assessed using tract-based spatial statistics (TBSS) and a region of interest (ROI) approach. We found significant FA reductions in motor and extra-motor cerebral fiber tracts in classical ALS and in the LMN ALS-variant patients compared to controls. The voxel-based TBSS results were confirmed by the ROI findings. The white matter damage correlated with the disease severity in the patient group and was found in a similar distribution, but to a lesser extent, among the LMN ALS-variant subgroup. ALS and LMN ALS variants are multisystem degenerations. DTI shows the potential to determine an earlier diagnosis, particularly in LMN ALS variants. The statistically identical findings of white matter lesions in classical ALS and LMN variants as ascertained by DTI further underline that these variants should be regarded as part of the ALS spectrum.     

A food-based formulation provides lycopene with the same bioavailability to humans as that from tomato paste

Lycopene from fresh and unprocessed tomatoes is poorly absorbed by humans. Absorption of lycopene is higher from processed foods such as tomato paste and tomato juice heated in oil. The aim of the present study was to develop a food-grade lycopene formulation that is bioavailable in humans. A formulation of lycopene named "lactolycopene" has been designed in which lycopene is entrapped with whey proteins. Healthy subjects (n = 33; 13 men and 20 women) participated and were allocated randomly to one of the three treatment groups. After a 3-wk deprivation of dietary lycopene, subjects ingested 25 mg lycopene/d for 8 wk from lactolycopene, tomato paste (positive control) or a placebo of whey proteins while consuming their self-selected diets. Plasma lycopene concentrations reached a maximum after 2 wk of supplementation in both lycopene-treated groups and then a plateau was maintained until the end of the treatment. Increases in plasma lycopene at wk 8 were not different between supplemented groups (mean +/- SEM): 0.58 +/- 0.13 micromol/L with lactolycopene and 0.47 plus minus 0.07 micromol/L with tomato paste, although they were different from the control (P < 0.001). Similar time-concentration curves of lycopene incorporation were observed in buccal mucosa cells. Although lycopene was present mainly as all-trans isomers (>90%) in both lycopene supplements, plasma lycopene enrichment consisted of 40% as all-trans and 60% as cis isomers. The precursor of lycopene, phytofluene, was better absorbed than lycopene itself. The lactolycopene formulation and tomato paste exhibited similar lycopene bioavailability in plasma and buccal mucosa cells in humans.     

An approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber

The development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key players in plaque rupture could provide improved triage of patients. However, so far the efficiency of contrast agents targeting human pathologies can only be examined in animal experiments, which do not necessarily reflect human in vivo conditions. We therefore describe application of a contrast agent targeting activated human platelets in an MRI tissue flow chamber, allowing detection and characterization of contrast agent binding. Microparticles of iron oxide (MPIO) were conjugated to an antibody targeting ligand‐induced binding sites (LIBS) on the activated platelet glycoprotein IIb/IIIa‐receptor or to control antibody, resulting in LIBS–MPIO or control–MPIO contrast agent. Human endarterectomy specimens from patients with acute stroke or transient ischemic attack were imaged ex vivo before and after contrast agent perfusion using a 9.4 T MRI system. Specimens were measured under static (n = 18) or flow conditions (n = 18) in a specially designed flow chamber setup, simulating physiological conditions in a stenosed vessel. A significant MPIO‐induced negative contrast was achieved in MRI by LIBS–MPIO in specimens under static and flow conditions (LIBS–MPIO vs control–MPIO: p < 0.01), and the location of LIBS–MPIO binding corresponded well between histology and MRI (p < 0.05). The number of MPIOs per platelet area on endarterectomy specimens in histology was significantly higher with LIBS–MPIO (p < 0.001). Furthermore, the intensity of contrast agent binding and signal change showed the potential to reflect the severity of clinical symptoms. LIBS–MPIO allows the detection of activated platelets on the surface of symptomatic atherosclerotic human plaques using molecular MRI. Furthermore, the MRI tissue flow chamber setup described could help to evaluate binding properties of contrast agents, and might therefore be an interesting tool for contrast agent development from animal experiments towards clinical application. Copyright © 2012 John Wiley & Sons, Ltd.