The influence of vascular anatomy on carotid artery stenting: A parametric study for damage assessment

Carotid artery stenting is emerging as an alternative technique to surgery for the treatment of symptomatic severe carotid stenosis. Clinical and experimental evidence demonstrates that both plaque morphology and biomechanical changes due to the device implantation can be possible causes of an unsuccessful treatment. In order to gain further insights of the endovascular intervention, a virtual environment based on structural finite element simulations was built to emulate the stenting procedure on generalized atherosclerotic carotid geometries which included a damage model to quantify the injury of the vessel. Five possible lesion scenarios were simulated by changing both material properties and vascular geometrical features to cover both presumed vulnerable and stable plaques. The results were analyzed with respect to lumen gain and wall stresses which are potentially related to the failure of the procedure according to previous studies. Our findings show that an elliptic lumen shape and a thinner fibrous cap with an underlying lipid pool result in higher stenosis reduction, while large calcifications and fibrotic tissue are more prone to recoil. The shielding effect of a thicker fibrous cap helps to reduce local compressive stresses in the soft plaque. The presence of a soft plaque reduces the damage in the healthy vascular structures. Contrarily, the presence of hard plaque promotes less damage volume in the fibrous cap and reduces stress peaks in this region, but they seem to increase stresses in the media-intima layer. Finally the reliability of the achieved results was put into clinical perspective.     

Does human genome editing reinforce or violate human dignity?

Germline genome editing is often disapproved of at the international policy level because of its possible threats to human dignity. However, from a critical perspective the relationship between this emerging technology and human dignity is relatively understudied. We explore the main principles that are referred to when ‘human dignity' is invoked in this context; namely, the link with eugenics, the idea of a common genetic heritage, the principle of equal birth and broader equality and justice concerns. Yet the concept is also used in favour of germline genome editing as it might improve the overall well-being of future generations. We conclude that dignity concerns do not justify a complete ban on safe heritable genome editing but should inform the implementation of side constraints to ensure that the value judgements about human traits that are inherent in this practice do not result in a diminished basic respect for those people affected by them.     

Limitations of Doppler echocardiography for the post-operative evaluation of aortic coarctation.

Doppler blood flow measurements and derived pressure differences, through the Bernoulli equation, are used in the diagnosis of aortic coarctation, a congenital stenosis distal to the left subclavian artery. Doppler velocities remain elevated at the coarctation site after successful repair of coarctation, leading to high Doppler derived pressure differences without significant arm-leg pressure differences. We studied this apparent contradiction of two diagnostic methods, in vivo using patient and control data, and in vitro using a hydraulic model. Clinical and echocardiographic data from 31 patients, aged 13.0 +/- 4.0, 10.5 +/- 4.7 yr after coarctectomy by end-to-end anastomosis, and 18 age-matched healthy subjects were reviewed. Doppler peak velocities at the aortic isthmus were elevated in patients (2.2 +/- 0.4 vs. 1.2 +/- 0.2m/s, P < 0.001), corresponding to significant Doppler differences (20 +/- 7 mmHg), however, without significant arm-leg pressure differences. In all patients, a mild anatomic stenosis could still be observed. Local stiffness was increased. The hypothesis that the less distensible surgical scar in post-coarctectomy patients leads to a significant dynamic obstruction in systole was validated in a latex model of the aorta. Rigid rings (0.5-1.5 cm), matching the unloaded aortic diameter, were mounted around the aorta. Under loading conditions, Doppler peak velocities increased by 40 +/-7%, yielding Doppler differences of 21 +/- 3 mmHg, without a significant pressure drop. An alternative expression to calculate pressure differences, using both velocity and geometric information, was validated in the model. In conclusion, post-operatively, Doppler velocities remain elevated due to a mild anatomical and significant dynamic narrowing, but the specific geometry, resembling a tubular hypoplasia rather than an abrupt stenosis, permits an almost complete pressure recovery explaining the occurrence of Doppler differences in disagreement with the negligible arm-leg pressure difference.     

Modelling the left ventricle using rapid prototyping techniques

Biomechanical research of left ventricular function involves the assessment and understanding of both ventricular wall mechanics and deformation and intraventricular flow patterns, as well as how they interact. Experimental research using hydraulic bench models should therefore aim for an as realistic as possible simulation of both. In previous experimental investigations, wall deformation was studied by means of thin-walled passive experimental models, consisting of a silicone membrane in a closed box, which is squeezed passively by an externally connected piston pump. Although the pump function of these models has already been well established, the membrane deformation remains unpredictable and the effect of muscle contraction – and hence natural wall deformation – cannot be simulated. In this study, we propose a new design of an experimental hydraulic left ventricular model in which left ventricular wall deformation can be controlled. We built this model by a combination of rapid prototyping techniques and tested it to demonstrate its wall deformation and pump function. Our experiments show that circumferential and longitudinal contraction can be attained and that this model can generate fairly normal values of pressure and flow.     

The ‘rotiferologist’ effect and other global correlates of species richness in monogonont rotifers

Global biodiversity patterns are often driven by different environmental variables at different scales. However, it is still controversial whether there are general trends, whether similar processes are responsible for similar patterns, and/or whether confounding effects such as sampling bias can produce misleading results. Our aim is twofold: 1) assessing the global correlates of diversity in a group of microscopic animals little analysed so far, and 2) inferring the influence of sampling intensity on biodiversity analyses. As a case study, we choose rotifers, because of their high potential for dispersal across the globe. We assembled and analysed a new worldwide dataset of records of monogonont rotifers, a group of microscopic aquatic animals, from 1960 to 1992. Using spatially explicit models, we assessed whether the diversity patterns conformed to those commonly obtained for larger organisms, and whether they still held true after controlling for sampling intensity, variations in area, and spatial structure in the data. Our results are in part analogous to those commonly obtained for macroorganisms (habitat heterogeneity and precipitation emerge as the main global correlates), but show some divergence (potential absence of a latitudinal gradient and of a large‐scale correlation with human population). Moreover, the effect of sampling effort is remarkable, accounting for >50% of the variability; this strong effect may mask other patterns such as latitudinal gradients. Our study points out that sampling bias should be carefully considered when drawing conclusions from large‐scale analyses, and calls for further faunistic work on microorganisms in all regions of the world to better understand the generality of the processes driving global patterns in biodiversity.     

Predicting systolic and diastolic aortic blood pressure and stroke volume in the intact sheep.

We developed a mathematical model describing the interaction between the heart and the arterial system. The model was constructed and tested on basis of invasive hemodynamic data in six sheep. Data from a first group of three animals (49 cardiac cycles) were used to assess a template time-varying elastance curve for the left ventricle, while the baseline steady-state data of a second group of three animals were used to assess reference cardiac and arterial parameters in sheep. The model is fully characterized by nine parameters, which were converted into 6 dimensionless numbers using the Buckingham pi theorem. The model was then used to generate LV pressure and volume and aortic pressure and flow for 86 conditions obtained by varying parameters 50 to 200% of their reference value. Systolic (SBP) and diastolic (DBP) blood pressure and stroke volume (SV) were determined from these model-generated curves and multiple linear regression analysis yielded the following expressions: SBP = Pisovolumic [0.638 - 0.0773 Emax C + 0.0507 RC/T] (r2 = 0.89); DBP = Pisovolumic [0.438-0.0712 Emax C + 0.0655RC/T] (r2 = 0.88) and SV = LVEDV [1.265-1.040 LVEDV/(LVEDV - Vd) + 0.125 Emax C-0.0777RC/T] (r2 = 0.93) with Pisovolumic = Emax (LVEDV - Vd), Emax and Vd being the slope and intercept of the end-systolic pressure-volume relation, R and C the total peripheral resistance and compliance, LVEDV the left ventricular end-diastolic volume, and T the cardiac cycle length. These expressions were validated using data from the second group of three animals obtained during vena cava occlusion at baseline and during administration of dobutamine (61 cycles). The correlation between measured and predicted values was 0.98, 0.97 and 0.92 for SBP, DBP and SV, respectively. Compared to the measured values, SBP and DBP were, on average, underestimated by 5 and 6mmHg, respectively, and SV overestimated by 1.4 ml. We conclude that the derived expressions for blood pressure and stroke volume remain valid in the intact sheep for various hemodynamic conditions, and, taking into account their dimensionless form, may hold in other species and in humans.     

Light microscopical detection of leukocyte cell surface antigens with a one-nanometer gold probe.

The potential of ultrasmall gold particles for the light microscopical detection of leukocyte cell surface differentiation antigens was investigated. Suspensions and cytocentrifuge preparations of peripheral blood leukocytes were first incubated with monoclonal antibodies and then with goat antimouse antibodies coupled to colloidal gold particles of 1-nanometer diameter. Cytocentrifuge preparations were made from the cell suspensions. Silver enhancement was performed on all preparations. Then they were counterstained with May-Grünwald Giemsa and examined in light microscopy. The immunostaining appeared as fine dark granules on the surface membrane of the cells. Labeling conditions were determined which gave a dense specific immunostaining and a low background. High dilutions of the ultrasmall gold probe could be used to detect all antigen expressing cells in the samples. The labeling efficiency of the IGSS method with the 1 nanometer probe was comparable to that described earlier for 5 nanometer gold particles. Lymphocyte subsets enumerated with this method in normal peripheral blood were similar to those found with immunofluorescence microscopy. We concluded that one nanometer probes do not offer a major advantage in comparison with 5 nanometer probes for the study of cell surface antigens.     

Do maternal food deprivation and offspring predator cues interactively affect maternal effort in fish?

The state of the environment parents are exposed to during reproduction can either facilitate or impair their ability to take care of their young. Thus, the environmental conditions experienced by parents can have a transgenerational impact on offspring phenotype and survival. Parental energetic needs and the variance in offspring predation risk have both been recognized as important factors influencing the quality and amount of parental care, but surprisingly, they are rarely manipulated simultaneously to investigate how parents adjust care to these potentially conflicting demands. In the maternally mouthbrooding cichlid Simochromis pleurospilus, we manipulated female body condition before spawning and exposure to offspring predator cues during brood care in a two‐by‐two factorial experiment. Subsequently, we measured the duration of brood care and the number and size of the released young. Furthermore, we stimulated females to take up their young by staged predator attacks and recorded the time before the young were released again. We found that food‐deprived females produced smaller young and engaged less in brood care behaviour than well‐nourished females. Final brood size and, related to this, female protective behaviour were interactively determined by nutritional state and predator exposure: well‐nourished females without a predator encounter had smaller broods than all other females and at the same time were least likely to take up their young after a simulated predator attack. We discuss several mechanisms by which predator exposure and maternal nutrition might have influenced brood and offspring size. Our results highlight the importance to investigate the selective forces on parents and offspring in combination, if we aim to understand reproductive strategies.     

The impact of simplified boundary conditions and aortic arch inclusion on CFD simulations in the mouse aorta: a comparison with mouse-specific reference data

Computational fluid dynamics (CFD) simulations allow for calculation of a detailed flow field in the mouse aorta and can thus be used to investigate a potential link between local hemodynamics and disease development. To perform these simulations in a murine setting, one often needs to make assumptions (e.g. when mouse-specific boundary conditions are not available), but many of these assumptions have not been validated due to a lack of reference data. In this study, we present such a reference data set by combining high-frequency ultrasound and contrast-enhanced micro-CT to measure (in vivo) the time-dependent volumetric flow waveforms in the complete aorta (including seven major side branches) of 10 male ApoE -/- deficient mice on a C57Bl/6 background. In order to assess the influence of some assumptions that are commonly applied in literature, four different CFD simulations were set up for each animal: (i) imposing the measured volumetric flow waveforms, (ii) imposing the average flow fractions over all 10 animals, presented as a reference data set, (iii) imposing flow fractions calculated by Murray's law, and (iv) restricting the geometrical model to the abdominal aorta (imposing measured flows). We found that - even if there is sometimes significant variation in the flow fractions going to a particular branch - the influence of using average flow fractions on the CFD simulations is limited and often restricted to the side branches. On the other hand, Murray's law underestimates the fraction going to the brachiocephalic trunk and strongly overestimates the fraction going to the distal aorta, influencing the outcome of the CFD results significantly. Changing the exponential factor in Murray's law equation from 3 to 2 (as suggested by several authors in literature) yields results that correspond much better to those obtained imposing the average flow fractions. Restricting the geometrical model to the abdominal aorta did not influence the outcome of the CFD simulations. In conclusion, the presented reference dataset can be used to impose boundary conditions in the mouse aorta in future studies, keeping in mind that they represent a subsample of the total population, i.e., relatively old, non-diseased, male C57Bl/6 ApoE -/- mice.     

Synthesis and antibacterial evaluation of a novel series of 2-(1,2-dihydro-3-oxo-3H-pyrazol-2-yl)benzothiazoles

The 2‐(1,2‐dihydro‐3‐oxo‐3H‐pyrazol‐2‐yl)benzothiazole scaffold was selected as a central core structure for the discovery of novel antibacterial compounds. A systematic variation of the substituents on the oxo‐pyrazole moiety, as well as on the benzo moiety, led to the creation of a small and focused library of benzothiazoles that was subjected to antibacterial screening. In a first round of screening, activity of the compounds against six representative microorganisms was established. For the most potent congeners, MIC values against S. aureus and P. aeruginosa were determined. The structure activity relationship study clearly revealed that subtle structural variations influence the antibacterial activity to a large extent. The most potent congeners displayed MIC values of 3.30 μM .