Quantum Chemical Modeling of the Effects of Hydrated Lime (Calcium Hydroxide) as a Filler in Bituminous Materials.

Hydrated lime is widely used as a mineral filler to improve several properties of bituminous materials such as reducing the susceptibility of the composite to moisture-induced damage. Although experimental evidence supports the efficacy of using hydrated lime as a mineral filler, the molecular scale mechanism of reactivity of hydrated lime within the bitumen to reduce moisture damage is not understood. This is important when considering the durability of structural applications of bituminous materials such as asphalt concrete pavements subjected to both environmental and loading extremes. In this study, the interaction between hydrated lime and the key molecular building blocks of bitumen is modeled using density functional theory and compared against analogues of other common fillers such as calcite and quartz. Free energies of dissociation (ΔG dissoc) are calculated, and the nature of the bonds is characterized with contour maps of the Laplacian of the electron density. Hydrated lime is capable of reacting with specific functional groups in bitumen moieties and developing strong, water-resistant complexes. Among the functional groups investigated, carboxylic acids are the preferential reaction sites between hydrated lime and the bitumen moieties. Values as high as ΔG dissoc = +49.42 kcal/mol are reported for hydrated lime with water as the surrounding solvent. In contrast, analogues of calcite (ΔG dissoc = +15.84 kcal/mol) and quartz (ΔG dissoc = +4.76 kcal/mol) are unable to chemically react as strongly as hydrated lime in the presence of water. Contour maps of the Laplacian of the electron density indicate that the bonds between hydrated lime and model asphalt moieties are of an ionic nature. The atomistic modeling results correlate with thermodynamic calculations derived from experimental constants and are consistent with infrared spectrometric data.

Tissue mimetic hyaluronan bioink containing collagen fibers with controlled orientation modulating cell migration and alignment.

Biofabrication is providing scientists and clinicians the ability to produce engineered tissues with desired shapes and gradients of composition and biological cues. Typical resolutions achieved with extrusion-based bioprinting are at the macroscopic level. However, for capturing the fibrillar nature of the extracellular matrix (ECM), it is necessary to arrange ECM components at smaller scales, down to the micron and the molecular level. Herein, we introduce a bioink containing the tyramine derivative of hyaluronan (HA; henceforth known as THA) and collagen (Col) type 1. In this bioink, similar to connective tissues, Col is present in the fibrillar form, and HA functions as a viscoelastic space filler. THA was enzymatically cross-linked under mild conditions allowing simultaneous Col fibrillogenesis, thus achieving a homogeneous distribution of Col fibrils within the viscoelastic HA-based matrix. The THA-Col composite displayed synergistic properties in terms of storage modulus and shear thinning, translating into good printability. Shear-induced alignment of the Col fibrils along the printing direction was achieved and quantified via immunofluorescence and second-harmonic generation. Cell-free and cell-laden constructs were printed and characterized, analyzing the influence of the controlled microscopic anisotropy on human bone marrow-derived mesenchymal stromal cell (hMSC) migration. Anisotropic HA-Col showed cell-instructive properties modulating hMSC adhesion, morphology, and migration from micropellets stimulated by the presence and the orientation of Col fibers. Actin filament staining showed that hMSCs embedded in aligned constructs displayed increased cytoskeleton alignment along the fibril direction. Based on gene expression of cartilage/bone markers and ECM production, hMSCs embedded in the isotropic bioink displayed chondrogenic differentiation comparable with standard pellet culture by means of proteoglycan production (safranin O staining and proteoglycan quantification). The possibility of printing matrix components with control over microscopic alignment brings biofabrication one step closer to capturing the complexity of native tissues.

Cutaneous pH landscape as a facilitator of melanoma initiation and progression.

Melanoma incidence is on the rise and currently causes the majority of skin cancer-related deaths. Yet, therapies for metastatic melanoma are still insufficient so that new concepts are essential. Malignant transformation of melanocytes and melanoma progression are intimately linked to the cutaneous pH landscape and its dysregulation in tumour lesions. The pH landscape of normal skin is characterized by a large pH gradient of up to 3 pH units between surface and dermis. The Na+ /H+ exchanger NHE1 is one of the major contributors of acidity in superficial skin layers. It is also activated by the most frequent mutation in melanoma, BRAFV600E , thereby causing pH dysregulation during melanoma initiation. Melanoma progression is supported by an extracellular acidification and/or NHE1 activity which promote the escape of single melanoma cells from the primary tumour, migration and metastatic spreading. We propose that viewing melanoma against the background of the acid-base physiology of the skin provides a better understanding of the pathophysiology of this disease and allows the development of novel therapeutic concepts.

Power in sports: A literature review on the application, assumptions, and terminology of mechanical power in sport research.

The quantification of mechanical power can provide valuable insight into athlete performance because it is the mechanical principle of the rate at which the athlete does work or transfers energy to complete a movement task. Estimates of power are usually limited by the capabilities of measurement systems, resulting in the use of simplified power models. This review provides a systematic overview of the studies on mechanical power in sports, discussing the application and estimation of mechanical power, the consequences of simplifications, and the terminology. The mechanical power balance consists of five parts, where joint power is equal to the sum of kinetic power, gravitational power, environmental power, and frictional power. Structuring literature based on these power components shows that simplifications in models are done on four levels, single vs multibody models, instantaneous power (IN) versus change in energy (EN), the dimensions of a model (1D, 2D, 3D), and neglecting parts of the mechanical power balance. Quantifying the consequences of simplification of power models has only been done for running, and shows differences ranging from 10% up to 250% compared to joint power models. Furthermore, inconsistency and imprecision were found in the determination of joint power, resulting from inverse dynamics methods, incorporation of translational joint powers, partitioning in negative and positive work, and power flow between segments. Most inconsistency in terminology was found in the definition and application of 'external' and 'internal' work and power. Sport research would benefit from structuring the research on mechanical power in sports and quantifying the result of simplifications in mechanical power estimations.

Experimental estimation of energy absorption during heel strike in human barefoot walking.

Metabolic energy expenditure during human gait is poorly understood. Mechanical energy loss during heel strike contributes to this energy expenditure. Previous work has estimated the energy absorption during heel strike as 0.8 J using an effective foot mass model. The aim of our study is to investigate the possibility of determining the energy absorption by more directly estimating the work done by the ground reaction force, the force-integral method. Concurrently another aim is to compare this method of direct determination of work to the method of an effective foot mass model. Participants of our experimental study were asked to walk barefoot at preferred speed. Ground reaction force and lower leg kinematics were collected at high sampling frequency (3000 Hz; 1295 Hz), with tight synchronization. The work done by the ground reaction force is 3.8 J, estimated by integrating this force over the foot-ankle deformation. The effective mass model is improved by dropping the assumption that foot-ankle deformation is maximal at the instant of the impact force peak. On theoretical grounds it is clear that in the presence of substantial damping that peak force and peak deformation do not occur simultaneously. The energy absorption results, due the vertical force only, corresponding to the force-integral method is similar to the results of the improved application of the effective mass model (2.7 J; 2.5 J). However the total work done by the ground reaction force calculated by the force-integral method is significantly higher than that of the vertical component alone. We conclude that direct estimation of the work done by the ground reaction force is possible and preferable over the use of the effective foot mass model. Assuming that energy absorbed is lost, the mechanical energy loss of heel strike is around 3.8 J for preferred walking speeds (≈ 1.3 m/s), which contributes to about 15-20% of the overall metabolic cost of transport.

Investigation into the visual perceptive ability of anaesthetists during ultrasound-guided interscalene and femoral blocks conducted on soft embalmed cadavers: a randomised single-blind study.

BACKGROUND: Errors may occur during regional anaesthesia whilst searching for nerves, needle tips, and test doses. Poor visual search impacts on decision making, clinical intervention, and patient safety. METHODS: We conducted a randomised single-blind study in a single university hospital. Twenty trainees and two consultants examined the paired B-mode and fused B-mode and elastography video recordings of 24 interscalene and 24 femoral blocks conducted on two soft embalmed cadavers. Perineural injection was randomised equally to 0.25, 0.5, and 1.0 ml volumes. Tissue displacement perceived on both imaging modalities was defined as 'target' or 'distractor'. Our primary objective was to test the anaesthetists' perception of the number and proportion of targets and distractors on B-mode and fused elastography videos collected during femoral and sciatic nerve block on soft embalmed cadavers. Our secondary objectives were to determine the differences between novices and experts, and between test-dose volumes, and to measure the area and brightness of spread and strain patterns. RESULTS: All anaesthetists recognised perineural spread using 0.25 ml volumes. Distractor patterns were recognised in 133 (12%) of B-mode and in 403 (38%) of fused B-mode and elastography patterns; P<0.001. With elastography, novice recognition improved from 12 to 37% (P<0.001), and consultant recognition increased from 24 to 53%; P<0.001. Distractor recognition improved from 8 to 31% using 0.25 ml volumes (P<0.001), and from 15 to 45% using 1 ml volumes (P<0.001). CONCLUSIONS: Visual search improved with fusion elastography, increased volume, and consultants. A need exists to investigate image search strategies.

Getting in shape: Reconstructing three-dimensional long-track speed skating kinematics by comparing several body pose reconstruction techniques.

In gait studies body pose reconstruction (BPR) techniques have been widely explored, but no previous protocols have been developed for speed skating, while the peculiarities of the skating posture and technique do not automatically allow for the transfer of the results of those explorations to kinematic skating data. The aim of this paper is to determine the best procedure for body pose reconstruction and inverse dynamics of speed skating, and to what extend this choice influences the estimation of joint power. The results show that an eight body segment model together with a global optimization method with revolute joint in the knee and in the lumbosacral joint, while keeping the other joints spherical, would be the most realistic model to use for the inverse kinematics in speed skating. To determine joint power, this method should be combined with a least-square error method for the inverse dynamics. Reporting on the BPR technique and the inverse dynamic method is crucial to enable comparison between studies. Our data showed an underestimation of up to 74% in mean joint power when no optimization procedure was applied for BPR and an underestimation of up to 31% in mean joint power when a bottom-up inverse dynamics method was chosen instead of a least square error approach. Although these results are aimed at speed skating, reporting on the BPR procedure and the inverse dynamics method, together with setting a golden standard should be common practice in all human movement research to allow comparison between studies.

An evaluation of soil chemistry in human cadaver decomposition islands: Potential for estimating postmortem interval (PMI).

Soil samples from the Forensic Anthropology Research Facility (FARF) at Texas State University, San Marcos, TX, were analyzed for multiple soil characteristics from cadaver decomposition islands to a depth of 5centimeters (cm) from 63 human decomposition sites, as well as depths up to 15cm in a subset of 11 of the cadaver decomposition islands plus control soils. Postmortem interval (PMI) of the cadaver decomposition islands ranged from 6 to 1752 days. Some soil chemistry, including nitrate-N (NO3-N), ammonium-N (NH4-N), and dissolved inorganic carbon (DIC), peaked at early PMI values and their concentrations at 0-5cm returned to near control values over time likely due to translocation down the soil profile. Other soil chemistry, including dissolved organic carbon (DOC), dissolved organic nitrogen (DON), orthophosphate-P (PO4-P), sodium (Na+), and potassium (K+), remained higher than the control soil up to a PMI of 1752days postmortem. The body mass index (BMI) of the cadaver appeared to have some effect on the cadaver decomposition island chemistry. To estimate PMI using soil chemistry, backward, stepwise multiple regression analysis was used with PMI as the dependent variable and soil chemistry, body mass index (BMI) and physical soil characteristics such as saturated hydraulic conductivity as independent variables. Measures of soil parameters derived from predator and microbial mediated decomposition of human remains shows promise in estimating PMI to within 365days for a period up to nearly five years. This persistent change in soil chemistry extends the ability to estimate PMI beyond the traditionally utilized methods of entomology and taphonomy in support of medical-legal investigations, humanitarian recovery efforts, and criminal and civil cases.

Design and verification of a simple 3D dynamic model of speed skating which mimics observed forces and motions.

Advice about the optimal coordination pattern for an individual speed skater, could be addressed by simulation and optimization of a biomechanical speed skating model. But before getting to this optimization approach one needs a model that can reasonably match observed behaviour. Therefore, the objective of this study is to present a verified three dimensional inverse skater model with minimal complexity, which models the speed skating motion on the straights. The model simulates the upper body transverse translation of the skater together with the forces exerted by the skates on the ice. The input of the model is the changing distance between the upper body and the skate, referred to as the leg extension (Euclidean distance in 3D space). Verification shows that the model mimics the observed forces and motions well. The model is most accurate for the position and velocity estimation (respectively 1.2% and 2.9% maximum residuals) and least accurate for the force estimations (underestimation of 4.5-10%). The model can be used to further investigate variables in the skating motion. For this, the input of the model, the leg extension, can be optimized to obtain a maximal forward velocity of the upper body.

A mathematical model for cell infiltration and proliferation in a chondral defect.

We develop a mathematical model to describe the regeneration of a hydrogel inserted into an ex vivo osteochondral explant. Specifically we use partial differential equations to describe the evolution of two populations of cells that migrate from the tissue surrounding the defect, proliferate, and compete for space and resources within the hydrogel. The two cell populations are chondrocytes and cells that infiltrate from the subchondral bone. Model simulations are used to investigate how different seeding strategies and growth factor placement within the hydrogel affect the spatial distribution of both cell types. Since chondrocyte migration is extremely slow, we conclude that the hydrogel should be seeded with chondrocytes prior to culture in order to obtain zonal chondrocyte distributions typical of those associated with healthy cartilage.

The individual time trial as an optimal control problem.

In a cycling time trial, the rider needs to distribute his power output optimally to minimize the time between start and finish. Mathematically, this is an optimal control problem. Even for a straight and flat course, its solution is non-trivial and involves a singular control, which corresponds to a power that is slightly above the aerobic level. The rider must start at full anaerobic power to reach an optimal speed and maintain that speed for the rest of the course. If the course is flat but not straight, then the speed at which the rider can round the bends becomes crucial.

Trainee anaesthetist diagnosis of intraneural injection-a study comparing B-mode ultrasound with the fusion of B-mode and elastography in the soft embalmed Thiel cadaver model.

BACKGROUND: The incidence of intraneural injection during trainee anaesthetist ultrasound guided nerve block varies between 16% in experts and up to 35% in trainees. We hypothesized that elastography, an ultrasound-based technology that presents colour images of tissue strain, had the potential to improve trainee diagnosis of intraneural injection during UGRA, when integrated with B-Mode ultrasound onto a single image. METHODS: We recorded 40 median nerve blocks randomly allocated to 0.25 ml, 0.5 ml, 1 ml volumes to five sites, on both arms of two soft embalmed cadavers, using a dedicated B-Mode ultrasound and elastography transducer. We wrote software to fuse elastogram and B-Mode videos, then asked 20 trainee anaesthetists whether injection was intraneural or extraneural when seeing B-Mode videos, adjacent B-Mode and elastogram videos, fusion elastography videos or repeated B-Mode ultrasound videos. RESULTS: Fusion elastography improved the diagnosis of intraneural injection compared with B-Mode ultrasound, Diagnostic Odds Ratio (DOR) (95%CI) 21.7 (14.5 - 33.3) vs DOR 7.4 (5.2 - 10.6), P < 0.001. Compared with extraneural injection, intraneural injection was identified on fusion elastography as a distinct, brighter translucent image, geometric ratio 0.33 (95%CI: 0.16 - 0.49) P < 0.001. Fusion elastography was associated with greater trainee diagnostic confidence, OR (95%CI) 1.89 (1.69 - 2.11), P < 0.001, and an improvement in reliability, Kappa 0.60 (0.55 - 0.66). CONCLUSIONS: Fusion elastography improved the accuracy, reliability and confidence of trainee anaesthetist diagnosis of intraneural injection.

KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34.

In the recent decades, ion channels became the focus of cancer biologists, as many channels are overexpressed in tumour tissue and functionally they are linked to abnormal cell behaviour with processes including apoptosis, chemo- and radioresistance, proliferation and migration. KCa3.1 is a Ca2+-activated K+ channel that plays a central role in tumour progression in many cancer types. Therefore, the aim of the present study was to investigate KCa3.1 expression in pancreatic cancer cells and assess possible implications to disease progression. Using qPCR technique, we found abundant expression of KCa3.1 in pancreatic cancer cell lines. Patch clamp measurements on MiaPaCa-2 cells revealed a Ca2+-activated K+ current that matched biophysical characteristics as described for KCa3.1. Moreover, the current was sensitive to the commonly used channel modulators TRAM-34, clotrimazole and DC-EBIO, and it was abolished following transient gene knockdown of KCa3.1. We utilized both pharmacology and RNAi to assess a possible role of the channel in tumour cell behaviour. We found that the channel supported MiaPaCa-2 cell proliferation. Using RNAi protocols, we also identified KCa3.1 as important entity in cell invasion. However, TRAM-34 had unexpected stimulatory effects on cell migration and invasion estimated in various assays. Moreover, TRAM-34 increased intracellular Ca2+. In conclusion, we found prominent functional expression of KCa3.1 in pancreatic cancer cells. We provide evidence that the channel has a key role in cell proliferation and for the first time identify KCa3.1 as important entity in PDAC cell migration. We further reveal anomalous effects of TRAM-34.

In silico analysis of the transportome in human pancreatic ductal adenocarcinoma.

The altered expression and/or activity of ion channels and transporters (transportome) have been associated with malignant behavior of cancer cells and were proposed to be a hallmark of cancer. However, the impact of altered transportome in epithelial cancers, such as pancreatic ductal adenocarcinoma (PDAC), as well as its pathophysiological consequences, still remains unclear. Here, we report the in silico analysis of 840 transportome genes in PDAC patients' tissues. Our study was focused on the transportome changes and their correlation with functional and behavioral responses in PDAC tumor and stromal compartments. The dysregulated gene expression datasets were filtered using a cut-off of fold-change values ≤-2 or ≥2 (adjusted p value ≤0.05). The dysregulated transportome genes were clearly associated with impaired physiological secretory mechanisms and/or pH regulation, control of cell volume, and cell polarity. Additionally, some down-regulated transportome genes were found to be closely linked to epithelial cell differentiation. Furthermore, the observed decrease in genes coding for calcium and chloride transport might be a mechanism for evasion of apoptosis. In conclusion, the current work provides a comprehensive overview of the altered transportome expression and its association with predicted PDAC malignancy with special focus on the epithelial compartment.

Mtss1 is a critical epigenetically regulated tumor suppressor in CML.

Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI-resistant CML stem cells in patients.

[Ultrasonographic measurement of the optical nerve sheath for the diagnosis of intracranial hypertension in the emergency room : a case report]. / Le cas clinique du mois. Mesure échographique du diamètre de la gaine des nerfs optiques et diagnostic de l'hypertension intracrânienne au Service des Urgences.

Early diagnosis and treatment of intracranial hypertension (ICHT) are major components of the management of neurological emergencies. The optic nerve sheath diameter is closely dependent on intracranial pressure and can be measured by bedside ultrasound (US). We report the story of a 70-year-old COPD patient initially admitted to the emergency room for a sepsis of pulmonary origin. An unusual confusion prompted us to perform an US of the optic nerve sheath. This exam clearly suggested the presence of an ICHT. Hence, the diagnostic approach was proceeded and a herpetic encephalitis was demonstrated and successfully treated. In this clinical report, the optic nerve sheath US guided the diagnostic approach and, eventually, therapeutic decision. Several papers have shown the close relationship between increased optic nerve sheath diameter and intracranial hypertension, but we still need further studies to validate a threshold value of this diameter. The clinical relevance of the US optic nerve diameter measure appears interesting. However, further studies on larger samples of patients are needed to confirm this and to establish a validated threshold value.

La précocité du diagnostic et du traitement de l'hypertension intracrânienne (HTIC) est un élément majeur de la prise en charge des pathologies neurologiques aux urgences. Le diamètre de la gaine des nerfs optiques est le reflet direct de la pression intracrânienne et peut être mesuré à l'aide de l'échographie au lit du patient. Nous relatons le cas d'un patient de 70 ans, initialement pris en charge pour un sepsis d'origine pulmonaire dans un contexte de BPCO, et chez qui une confusion inhabituelle a mené à la réalisation d'une échographie de la gaine des nerfs optiques. Celle-ci ayant mis en évidence une HTIC, la démarche diagnostique a été poussée plus en avant et une encéphalite zostérienne a été mise en évidence et traitée précocement avec efficacité. Dans ce cas clinique, l'échographie des nerfs optiques occupe une place prépondérante dans la démarche diagnostique et thérapeutique. L'efficacité de la mesure de la gaine des nerfs optiques pour diagnostiquer une HTIC est démontrée; cependant, il n'existe pas, à l'heure actuelle, de consensus sur une valeur «seuil¼ de diamètre de la gaine. De nouvelles études sont nécessaires pour préciser ce paramètre.

hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.

BACKGROUND: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. METHODS: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-Kras(G12D/+),LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. RESULTS: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. CONCLUSIONS: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo.