Friction on incommensurate substrates: Role of anharmonicity and defects.

We present molecular dynamics simulations of one- and two-dimensional bead-spring models sliding on incommensurate substrates after an initial kick, in the case where the coupling to the underlying substrate is weak, i.e., energy can dissipate only into the internal degrees of freedom of the sliding object, but not into the substrate below. We investigate how sliding friction is affected by structural defects and interaction anharmonicity. In their absence, we confirm earlier findings, namely, that at special resonance sliding velocities, friction is maximal. When sliding off-resonance, partially thermalized states are possible, whereby only a small number of vibrational modes becomes excited, but whose kinetic energies are already Maxwell-Boltzmann distributed. Anharmonicity and defects typically destroy partial thermalization and instead lead to full thermalization, implying much higher friction. For sliders with periodic boundaries, thermalization begins with vibrational modes whose spatial modulation is compatible with the incommensurate lattice. For a disk-shaped slider, modes corresponding to modulations compatible with the slider radius are initially the most dominant. By tuning the mechanical properties of the slider's edge, this effect can be controlled, resulting in significant changes in the sliding distance covered.

Incidence, clinical features, and outcomes of special types in breast cancer in a single institution population.

The low incidence of special types of breast cancer hinders adequate clinical research efforts. As such, collecting sufficient data to develop well-established therapy strategies are difficult. The aim of our study was to obtain more data on these special types in order to better understand the different characteristics and optimize therapy strategies. A single-institution retrospective cohort study from January 2007 until September 2015. One hundred and five patients remained after excluding the patients with invasive ductal and lobular carcinoma. The percentage of these so called special types in this population was 4%. Tubular carcinoma, cribriform carcinoma, carcinoma with medullary features, carcinoma with apocrine differentiation, secretory carcinoma, mucinous carcinoma, and invasive papillary carcinoma had a good or excellent prognosis, while invasive micropapillary carcinoma, adenoid cystic carcinoma, metaplastic carcinoma, and carcinoma with neuroendocrine features had a worse prognosis. Special types of breast cancer form a heterogeneous group. Submitting them all to the same treatment modality may lead to both over- and under-treatment. We need to combine our data to optimize treatment strategies for the different special types.

Attitudes of Dutch intensive care unit clinicians towards oxygen therapy.

BACKGROUND: Over the last decade, there has been an increasing awareness for the potential harm of the administration of too much oxygen. We aimed to describe self-reported attitudes towards oxygen therapy by clinicians from a large representative sample of intensive care units (ICUs) in the Netherlands. METHODS: In April 2019, 36 ICUs in the Netherlands were approached and asked to send out a questionnaire (59 questions) to their nursing and medical staff (ICU clinicians) eliciting self-reported behaviour and attitudes towards oxygen therapy in general and in specific ICU case scenarios. RESULTS: In total, 1361 ICU clinicians (71% nurses, 24% physicians) from 28 ICUs returned the questionnaire. Of responding ICU clinicians, 64% considered oxygen-induced lung injury to be a major concern. The majority of respondents considered a partial pressure of oxygen (PaO2) of 6-10 kPa (45-75 mmHg) and an arterial saturation (SaO2) of 85-90% as acceptable for 15 minutes, and a PaO2 7-10 kPa (53-75 mmHg) and SaO2 90-95% as acceptable for 24-48 hours in an acute respiratory distress syndrome (ARDS) patient. In most case scenarios, respondents reported not to change the fraction of inspired oxygen (FiO2) if SaO2 was 90-95% or PaO2 was 12 kPa (90 mmHg). CONCLUSION: A representative sample of ICU clinicians from the Netherlands were concerned about oxygen-induced lung injury, and reported that they preferred PaO2 and SaO2 targets in the lower physiological range and would adjust ventilation settings accordingly.

International round-robin experiment for angle-resolved light scattering measurement.

An international round-robin experiment has been conducted to test procedures and methods for the measurement of angle-resolved light scattering. ASTM E2387-05 has been used as the main guide, while the experience gained should also contribute to the new ISO standard of angle-resolved scattering currently under development (ISO/WD 19986:2016). Seven laboratories from Europe and the United States measured the angle-resolved scattering from Al/SiO2-coated substrates, transparent substrates, volume diffusors, quasi-volume diffusors, white calibration standards, and grating samples at laser wavelengths in the UV, VIS, and NIR spectra. Results were sent to Fraunhofer IOF, which coordinated the experiments and analyzed the data, while ESA-ESTEC, as the project donor, defined conditions and parameters. Depending mainly on the sample type, overall good to reasonable agreements were observed, with largest deviations at scattering angles very close to the specular beam. Volume diffusor characterization unexpectedly turned out to be challenging. Not all participants provided measurement uncertainty ranges according to the Guide to the Expression of Uncertainty in Measurement; often, a single general scatterometer-related measurement uncertainty value was stated. Although relative instrument measurement uncertainties close to 1% are sometimes claimed, the comparison results did not support these claims for specular scattering samples as mirrors, substrates, or gratings.

Guidelines' risk assessment recommendations for venous thromboembolism prophylaxis: A comparison and implementability appraisal.

INTRODUCTION: Venous thromboembolism (VTE) prophylaxis guidelines for non-surgical patients recommend VTE- and bleeding risk assessment to guide prophylactic strategies. These recommendations differ between guidelines and implementation is suboptimal. Assessing a guideline's implementability characteristics helps predicting the ease of implementation and reveals barriers. OBJECTIVES: We aimed to compare guidelines' risk assessment recommendations and critically appraise the implementability characteristics. MATERIAL AND METHODS: Two guidelines, one from the American College of Chest Physicians and one from the National Institute for Health and Care Excellence were selected for comparison. Risk assessment methods and subsequent prophylactic recommendations were compared. Eight experts then appraised the guideline recommendations on intrinsic implementability characteristics using the GuideLine Implementability Appraisal (GLIA) instrument. GLIA identifies barriers and facilitators for guideline implementation in nine dimensions. RESULTS: Eleven out of 20 individual VTE-risk factors and 2 out of 19 individual bleeding-risk factors used, were present in both guidelines. Additionally, a high VTE- or bleeding risk was defined differently between the two guidelines. The GLIA appraisal identified implementation barriers within all recommendations analyzed. On content level, barriers were identified in recommendations addressing bleeding risk assessment, mechanical prophylaxis and critical care patients. On implementability level, barriers were identified in decidability, flexibility, effect on process of care and computability dimensions. CONCLUSION: Depending on the guideline used, VTE-prophylaxis will most likely be provided to different non-surgical patient populations, primarily due to discordance in bleeding risk assessment. Revising the recommendations, taking into account the most apparent implementation barriers, should be considered. However, insufficient evidence to support the recommendations currently complicates this.

Diet-induced weight loss decreases adipose tissue oxygen tension with parallel changes in adipose tissue phenotype and insulin sensitivity in overweight humans.

BACKGROUND/OBJECTIVES: Although adipose tissue (AT) hypoxia is present in rodent models of obesity, evidence for this in humans is limited. Here, we investigated the effects of diet-induced weight loss (WL) on abdominal subcutaneous AT oxygen tension (pO2), AT blood flow (ATBF), AT capillary density, AT morphology and transcriptome, systemic inflammatory markers and insulin sensitivity in humans. SUBJECTS/METHODS: Fifteen overweight and obese individuals underwent a dietary intervention (DI), consisting of a 5-week very-low-calorie diet (VLCD, 500 kcal day-1; WL), and a subsequent 4-week weight stable diet (WS). Body composition, AT pO2 (optochemical monitoring), ATBF (133Xe washout), and whole-body insulin sensitivity were determined, and AT biopsies were collected at baseline, end of WL (week 5) and end of WS (week 9). RESULTS: Body weight, body fat percentage and adipocyte size decreased significantly during the DI period. The DI markedly decreased AT pO2 and improved insulin sensitivity, but did not alter ATBF. Finally, the DI increased AT gene expression of pathways related to mitochondrial biogenesis and non-mitochondrial oxygen consumption. CONCLUSIONS: VLCD-induced WL markedly decreases abdominal subcutaneous AT pO2, which is paralleled by a reduction in adipocyte size, increased AT gene expression of mitochondrial biogenesis markers and non-mitochondrial oxygen consumption pathways, and improved whole-body insulin sensitivity in humans.

Weight loss-induced cellular stress in subcutaneous adipose tissue and the risk for weight regain in overweight and obese adults.

BACKGROUND/OBJECTIVE: Weight loss is often followed by weight regain after the dietary intervention (DI). Cellular stress is increased in adipose tissue of obese individuals. However, the relation between cellular stress and weight regain is unclear. Previously, we observed increased adipose tissue cellular stress of participants regaining weight compared with participants maintaining weight loss. In the current study, we further investigated the relation between weight regain and changes in the expression of stress-related genes and stress protein levels to determine possible predictors of weight regain. PARTICIPANTS/METHODS: In this randomized controlled trial, sixty-one healthy overweight/obese participants followed a DI of either a 5-week very-low-calorie diet (500 kcal per day) or a 12-week low-calorie diet (1250 kcal per day; WL period) with a subsequent 4-week weight stable diet (WS period), and a 9-month follow-up. The WL and WS period taken together was named the DI. Abdominal subcutaneous adipose tissue biopsies were collected in 53 participants for microarray and liquid chromatography-mass spectrometry analysis. RNA and protein levels for a broad set of stress-related genes were correlated to the weight regain percentage. RESULTS: Different gene sets correlated to weight regain percentage during WS and DI. Bioinformatics clustering suggests that during the WS phase-defined genes for actin filament dynamics, glucose handling and nutrient sensing are related to weight regain. HIF-1 (hypoxia-inducible factor-1) is indicated as an important regulator. With regard to DI, clustering of correlated genes indicate that LGALS1, ENO1 and ATF2 are important nodes for conferring risk for weight regain. CONCLUSIONS: Our present findings indicate that the risk for weight regain is related to expression changes of distinct sets of stress-related genes during the first 4 weeks after returning to energy balance, and during the DI. Further research is required to investigate the mechanistic significance of these findings and find targets for preventing weight regain.

Adipose tissue gene expression is differentially regulated with different rates of weight loss in overweight and obese humans.

BACKGROUND/OBJECTIVES: Moderate weight loss (WL) can ameliorate adverse health effects associated with obesity, reflected by an improved adipose tissue (AT) gene expression profile. However, the effect of rate of WL on the AT transcriptome is unknown. We investigated the global AT gene expression profile before and after two different rates of WL that resulted in similar total WL, and after a subsequent weight stabilization period. SUBJECTS/METHODS: In this randomized controlled trial, 25 male and 28 female individuals (body mass index (BMI): 28-35 kg m-2) followed either a low-calorie diet (LCD; 1250 kcal day-1) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal day-1) for 5 weeks (WL period) and a subsequent weight stable (WS) period of 4 weeks. The WL period and WS period together is termed dietary intervention (DI) period. Abdominal subcutaneous AT biopsies were collected for microarray analysis and gene expression changes were calculated for all three periods in the LCD group, VLCD group and between diets (ΔVLCD-ΔLCD). RESULTS: WL was similar between groups during the WL period (LCD: -8.1±0.5 kg, VLCD: -8.9±0.4 kg, difference P=0.25). Overall, more genes were significantly regulated and changes in gene expression appeared more pronounced in the VLCD group compared with the LCD group. Gene sets related to mitochondrial function, adipogenesis and immunity/inflammation were more strongly upregulated on a VLCD compared with a LCD during the DI period (positive ΔVLCD-ΔLCD). Neuronal and olfactory-related gene sets were decreased during the WL period and DI period in the VLCD group. CONCLUSIONS: The rate of WL (LCD vs VLCD), with similar total WL, strongly regulates AT gene expression. Increased mitochondrial function, angiogenesis and adipogenesis on a VLCD compared with a LCD reflect potential beneficial diet-induced changes in AT, whereas differential neuronal and olfactory regulation suggest functions of these genes beyond the current paradigm.

Inflammation in acute CNS injury: a focus on the role of substance P.

Recently, a number of reports have shown that neurogenic inflammation may play a role in the secondary injury response following acute injury to the CNS, including traumatic brain injury (TBI) and stroke. In particular substance P (SP) release appears to be critically involved. Specifically, the expression of the neuropeptide SP is increased in acute CNS injury, with the magnitude of SP release being related to both the frequency and magnitude of the insult. SP release is associated with an increase in blood-brain barrier permeability and the development of vasogenic oedema as well as neuronal injury and worse functional outcome. Moreover, inhibiting the actions of SP through use of a NK1 receptor antagonist is highly beneficial in both focal and diffuse models of TBI, as well as in ischaemic stroke, with a therapeutic window of up to 12 h. We propose that NK1 receptor antagonists represent a novel therapeutic option for treatment of neurogenic inflammation following acute CNS injury.

Biomechanical studies in an ovine model of non-accidental head injury.

This paper presents the head kinematics of a novel ovine model of non-accidental head injury (NAHI) that consists only of a naturalistic oscillating insult. Nine, 7-to-10-day-old anesthetized and ventilated lambs were subjected to manual shaking. Two six-axis motion sensors tracked the position of the head and torso, and a triaxial accelerometer measured head acceleration. Animals experienced 10 episodes of shaking over 30 min, and then remained under anesthesia for 6h until killed by perfusion fixation of the brain. Each shaking episode lasted for 20s resulting in about 40 cycles per episode. Each cycle typically consisted of three impulsive events that corresponded to specific phases of the head's motion; the most substantial of these were interactions typically with the lamb's own torso, and these generated accelerations of 30-70 g. Impulsive loading was not considered severe. Other kinematic parameters recorded included estimates of head power transfer, head-torso flexion, and rate of flexion. Several styles of shaking were also identified across episodes and subjects. Axonal injury, neuronal reaction and albumin extravasation were widely distributed in the hemispheric white matter, brainstem and at the craniocervical junction and to a much greater magnitude in lower body weight lambs that died. This is the first biomechanical description of a large animal model of NAHI in which repetitive naturalistic insults were applied, and that reproduced a spectrum of injury associated with NAHI.

Changes in substance P and NK1 receptor immunohistochemistry following human spinal cord injury.

STUDY DESIGN: An immunohistological assessment of substance P (SP), its NK1 receptor and claudin-5 in human spinal cord injury (SCI) tissue. OBJECTIVE: To determine whether SP and NK1 receptor immunoreactivity are altered following human traumatic SCI. SETTING: Australia. SUMMARY OF BACKGROUND DATA: SP has been implicated in the development of neurogenic inflammation and subsequent edema development following both traumatic brain injury and ischemic stroke. In these conditions, inhibition of its NK1 receptor has been shown to be neuroprotective as reflected in a reduction of edema and improved functional outcome. However, the role of SP following human SCI has not yet been assessed. METHODS: Archived human SCI tissue was grouped according to survival times: control (no injury; n=5); immediate (death within an hour of the incident; n=6); 2-5 h (n=3); 3 days (n=5); 1 week (n=3); and 3-4 weeks (n=6). Sections were assessed for SP, its NK1 receptor and claudin-5 using immunohistochemical techniques. RESULTS: Following SCI, dorsal horn SP immunoreactivity demonstrated a profound decrease compared with control tissue, indicating the loss of SP with SCI. A marked increase in perivascular NK1 staining was demonstrated after SCI compared with control levels. No obvious change in claudin-5 immunoreactivity was present immediately following injury, however, by 1 week post-SCI, decreased levels were noted. CONCLUSION: This study demonstrates that severe acute traumatic human SCI results in decreased SP and an immediate increase in NK1 receptor immunoreactivity, suggesting that there is a neurogenic inflammatory component following human SCI.

Evaluating the role of substance P in the growth of brain tumors.

Recent research has investigated the expression and secretion of neuropeptides by tumors, and the potential of these peptides to facilitate tumor growth and spread. In particular, substance P (SP) and its receptor NK1 have been implicated in tumor cell growth and evasion of apoptosis, although few studies have examined this relationship in vivo. The present study used both in vitro and in vivo models to characterize the role of SP in tumor pathogenesis. Immunohistochemical assessment of human primary and secondary brain tumor tissue demonstrated a marked increase in SP and its NK1 receptor in all tumor types investigated. Of the metastatic tumors, melanoma demonstrated particularly elevated SP and NK1 receptor staining. Subsequently, A-375 human melanoma cell line was examined in vitro and found to express both SP and the NK1 receptor. Treatment with the NK1 receptor antagonist Emend IV resulted in decreased cell viability and an increase in cell death in this cell line in vitro. An animal model of brain tumors using the same cell line was employed to assess the effect of Emend IV on tumor growth in vivo. Administration of Emend IV was found to decrease tumor volume and decrease cellular proliferation indicating that SP may play a role in tumor pathogenesis within the brain. We conclude that SP may provide a novel therapeutic target in the treatment of certain types of brain tumors, with further research required to determine whether the role of SP in cancer is tumor-type dependent.

Pattern of cerebrospinal immediate early gene c-fos expression in an ovine model of non-accidental head injury.

Expression of the immediate early gene, c-fos, was examined in a large animal model of non-accidental head injury ("shaken baby syndrome"). Lambs were used because they have a relatively large gyrencephalic brain and weak neck muscles resembling a human infant. Neonatal lambs were manually shaken in a manner similar to that believed to occur with most abused human infants, but there was no head impact. The most striking c-fos expression was in meningothelial cells of the cranial cervical spinal cord and, to a lesser degree, in hemispheric, cerebellar, and brainstem meninges. Vascular endothelial cells also frequently showed c-fos immunopositivity in the meninges and hemispheric white matter. It was hypothesised that this c-fos immunoreactivity was due to mechanical stress induced by shaking, with differential movement of different craniospinal components.

Main transition in the Pink membrane model: finite-size scaling and the influence of surface roughness.

We consider the main transition in single-component membranes using computer simulations of the Pink model [D. A. Pink et al., Biochemistry 19, 349 (1980)]. We first show that the accepted parameters of the Pink model yield a main transition temperature that is systematically below experimental values. This resolves an issue that was first pointed out by Corvera and co-workers [Phys. Rev. E 47, 696 (1993)]. In order to yield the correct transition temperature, the strength of the van der Waals coupling in the Pink model must be increased; by using finite-size scaling, a set of optimal values is proposed. We also provide finite-size scaling evidence that the Pink model belongs to the universality class of the two-dimensional Ising model. This finding holds irrespective of the number of conformational states. Finally, we address the main transition in the presence of quenched disorder, which may arise in situations where the membrane is deposited on a rough support. In this case, we observe a stable multidomain structure of gel and fluid domains, and the absence of a sharp transition in the thermodynamic limit.

Combined tissue plasminogen activator and an NK1 tachykinin receptor antagonist: an effective treatment for reperfusion injury following acute ischemic stroke in rats.

We have recently reported on the efficacy of an NK1 tachykinin receptor antagonist in improving outcome following stroke, including reduced blood-brain barrier (BBB) disruption, reduced cerebral edema and improved functional outcome. The clinically approved stroke treatment, tissue plasminogen activator (tPA), has been associated with an increased risk of hemorrhage and death, if given at later time points. Accordingly, adjunctive therapies have been investigated to reduce the adverse effects of tPA and improve outcome. The aim of the present study was to characterize the effects of a combination of an NK1 tachykinin receptor antagonist with tPA, on BBB permeability and functional outcome following transient ischemic stroke in rats. Stroke was induced in male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2h, followed by reperfusion. Animals received either 25mg/kg of N-acetyl-l-tryptophan or 1mg/kg of tPA, either alone or in combination, or equal volume saline vehicle, intravenously at the time of reperfusion. Functional outcome was assessed by the rotarod, bilateral asymmetry test, modified neuroscore and open field tests. BBB permeability was assessed by Evans Blue extravasation. Combination therapy of an NK1 tachykinin receptor antagonist with tPA significantly reduced BBB permeability, functional deficits and the incidence of intracerebral hemorrhage and death. As such, combined tPA-NK1 tachykinin receptor antagonist treatment may represent a novel therapeutic intervention for the treatment of reperfusion injury in acute ischemic stroke.

Neuropathological changes in a lamb model of non-accidental head injury (the shaken baby syndrome).

Non-accidental head injury (NAHI), also termed the "shaken baby syndrome", is a major cause of death and severe neurological dysfunction in children under three years of age, but it is debated whether shaking alone is sufficient to produce brain injury and mortality or whether an additional head impact is required. In an attempt to resolve this question, we used a lamb model of NAHI since these animals have a relatively large gyrencephalic brain and weak neck muscles resembling those of a human infant. Three anaesthetised lambs of lower body weight than others in the experimental group died unexpectedly after being shaken, proving that shaking alone can be lethal. In these lambs, axonal injury, neuronal reaction and albumin extravasation were widely distributed in the hemispheric white matter, brainstem and at the craniocervical junction, and of much greater magnitude than in higher body weight lambs which did not die. Moreover, in the eyes of these shaken lambs, there was damage to retinal inner nuclear layer neurons, mild, patchy ganglion cell axonal injury, widespread Muller glial reaction, and uveal albumin extravasation. This study proved that shaking of a subset of lambs can result in death, without an additional head impact being required.

Phase separation in fluids exposed to spatially periodic external fields.

When a fluid is confined within a spatially periodic external field, the liquid-vapor transition is replaced by a different transition called laser-induced condensation (LIC) [Götze et al., Mol. Phys. 101, 1651 (2003)]. In d=3 dimensions, the periodic field induces an additional phase, characterized by large density modulations along the field direction. At the triple point, all three phases (modulated, vapor, and liquid) coexist. At temperatures slightly above the triple point and for low (high) values of the chemical potential, two-phase coexistence between the modulated phase and the vapor (liquid) is observed; by increasing the temperature further, both coexistence regions terminate in critical points. In this paper, we reconsider LIC using the Ising model to resolve a number of open issues. To be specific, we (1) determine the universality class of the LIC critical points and elucidate the nature of the correlations along the field direction, (2) present a mean-field analysis to show how the LIC phase diagram changes as a function of the field wavelength and amplitude, (3) develop a simulation method by which the extremely low tension of the interface between modulated and vapor or liquid phase can be measured, (4) present a finite-size scaling analysis to accurately extract the LIC triple point from finite-size simulation data, and (5) consider the fate of LIC in d=2 dimensions.

Substance P-induced changes in cell genesis following diffuse traumatic brain injury.

Inhibition of substance P (SP) activity through the use of NK1 receptor antagonists has been shown to be a promising neuroprotective therapy following traumatic brain injury (TBI). Conversely, recent research has implicated SP in the stimulation of neurogenesis, suggesting that the neuropeptide has the potential to promote recovery following TBI. This study characterised the effects of SP and the NK1 antagonist, n-acetyl tryptophan (NAT), on cell proliferation following diffuse TBI. Adult male Sprague-Dawley rats were injured using the impact acceleration model of TBI and randomly assigned to one of five treatment groups: sham, vehicle control, NAT alone, SP alone or SP with NAT. Cellular proliferation was assessed with immunostaining for bromodeoxyuridine (BrdU) and cell-specific markers. Infusion of SP (±NAT) promoted cellular proliferation in the subventricular zone and dentate gyrus following TBI. This increase was largely associated with microglial proliferation and did not correspond with functional improvements. These results suggest that NAT treatment results in neuroprotection following TBI, mediated in part via inhibition of microglia.