The Lymphatic Vascular System: Does Nonuniform Lymphangion Length Limit Flow-Rate?

A previously developed model of a lymphatic vessel as a chain of lymphangions was investigated to determine whether lymphangions of unequal length reduce pumping relative to a similar chain of equal-length ones. The model incorporates passive elastic and active contractile properties taken from ex vivo measurements, and intravascular lymphatic valves as transvalvular pressure-dependent resistances to flow with hysteresis and transmural pressure-dependent bias to the open state as observed experimentally. Coordination of lymphangion contractions is managed by marrying an autonomous transmural pressure-dependent pacemaker for each lymphangion with bidirectional transmission of activation signals between lymphangions, qualitatively matching empirical observations. With eight lymphangions as used here and many nonlinear constraints, the model is capable of complex outcomes. The expected flow-rate advantage conferred by longer lymphangions everywhere was confirmed. However, the anticipated advantage of uniform lymphangions over those of unequal length, compared in chains of equal overall length, was not found. A wide variety of dynamical outcomes was observed, with the most powerful determinant being the adverse pressure difference, rather than the arrangement of long and short lymphangions. This work suggests that the wide variation in lymphangion length which is commonly observed in collecting lymphatic vessels does not confer disadvantage in pumping lymph.

Competition between Coulomb and van der Waals Interactions in Xe-Cs

Microscopic insight into interactions is a key for understanding the properties of heterogenous interfaces. We analyze local attraction in noncovalently bonded Xe-Cs^{+} aggregates and monolayers on Cu(111) as well as repulsion upon electron transfer. Using two-photon photoemission spectroscopy, scanning tunneling microscopy, and coupled cluster calculations combined with an image-charge model, we explain the intricate impact Xe has on Cs^{+}/Cu(111). We find that attraction between Cs^{+} and Xe counterbalances the screened Coulomb repulsion between Cs^{+} ions on Cu(111). Furthermore, we observe that the Cs 6s electron is repelled from Cu(111) due to xenon's electron density. Together, this yields a dual, i.e., attractive or repulsive, response of Xe depending on the positive or negative charge of the respective counterparticle, which emphasizes the importance of the Coulomb interaction in these systems.

What is in? What is out? Updating the British Society for Cutaneous Allergy facial series.

BACKGROUND: Allergic contact dermatitis (ACD) to cosmetics is widely reported. To ensure we are accurately diagnosing ACD, patch test series should be continually reviewed to identify relevant and emerging allergens and highlight those that are outdated. The current British Society for Cutaneous Allergy (BSCA) facial series recommends 26 allergens and was last modified in 2012. OBJECTIVES: To review and update the BSCA facial series. METHODS: We retrospectively reviewed the results from 12 UK and Ireland patch test centres' facial series from January 2016 to December 2017. We recorded the number of allergens tested in each centre and the detection rate for each allergen. Using a 0·3% positive rate as the inclusion threshold, we established which allergens in the BSCA facial series had positive patch test rates < 0·3% and > 0·3%. Allergens not in the BSCA facial series that had a positive patch test rate > 0·3% were identified. RESULTS: Overall, 4224 patients were patch tested to the facial series. The number of allergens included in individual centres' facial series ranged from 24 to 66, with a total of 103 allergens tested across all centres. Twelve of the 26 allergens in the BSCA facial series had a positive patch test rate < 0·3% and 14 had a rate > 0·3%. Twenty-five allergens not recommended in the BSCA facial series had a positive patch test rate > 0·3%. CONCLUSIONS: This audit has highlighted the significant variation in practice that exists among patch test centres, despite a recommended facial series. The BSCA facial series has been updated and now contains 24 allergens. Fifteen allergens remain, 11 allergens have been dropped and nine new allergens have been added.

Inhibition of Contraction Strength and Frequency by Wall Shear Stress in a Single-Lymphangion Model.

The phasic contractions of collecting lymphatic vessels are reduced in strength and occur at diminished frequency when a favorable pressure difference and the resulting antegrade flow create large fluid shear stresses at the luminal surface. This paper describes a minimal phenomenological model of this mechanism that is applied to a previously validated numerical model of a phasically contracting lymphangion. The parameters of the inhibition model are quantitatively matched to observations in isolated segments of rat lymphatic vessel, first for mesenteric lymphatics then for thoracic duct, and outcomes from the numerical model are then qualitatively compared with recent observations in isolated segments of rat thoracic duct.

A Poroelastic Fluid/Structure-Interaction Model of Cerebrospinal Fluid Dynamics in the Cord With Syringomyelia and Adjacent Subarachnoid-Space Stenosis.

An existing axisymmetric fluid/structure-interaction (FSI) model of the spinal cord, pia mater, subarachnoid space, and dura mater in the presence of syringomyelia and subarachnoid-space stenosis was modified to include porous solids. This allowed investigation of a hypothesis for syrinx fluid ingress from cerebrospinal fluid (CSF). Gross model deformation was unchanged by the addition of porosity, but pressure oscillated more in the syrinx and the subarachnoid space below the stenosis. The poroelastic model still exhibited elevated mean pressure in the subarachnoid space below the stenosis and in the syrinx. With realistic cord permeability, there was slight oscillatory shunt flow bypassing the stenosis via the porous tissue over the syrinx. Weak steady streaming flow occurred in a circuit involving craniocaudal flow through the stenosis and back via the syrinx. Mean syrinx volume was scarcely altered when the adjacent stenosis bisected the syrinx, but increased slightly when the syrinx was predominantly located caudal to the stenosis. The fluid content of the tissues over the syrinx oscillated, absorbing most of the radial flow seeping from the subarachnoid space so that it did not reach the syrinx. To a lesser extent, this cyclic swelling in a boundary layer of cord tissue just below the pia occurred all along the cord, representing a mechanism for exchange of interstitial fluid (ISF) and cerebrospinal fluid which could explain recent tracer findings without invoking perivascular conduits. The model demonstrates that syrinx volume increase is possible when there is subarachnoid-space stenosis and the cord and pia are permeable.

Cortical regulation of dopaminergic neurons: role of the midbrain superior colliculus.

Dopaminergic (DA) neurons respond to stimuli in a wide range of modalities, although the origin of the afferent sensory signals has only recently begun to emerge. In the case of vision, an important source of short-latency sensory information seems to be the midbrain superior colliculus (SC). However, longer-latency responses have been identified that are less compatible with the primitive perceptual capacities of the colliculus. Rather, they seem more in keeping with the processing capabilities of the cortex. Given that there are robust projections from the cortex to the SC, we examined whether cortical information could reach DA neurons via a relay in the colliculus. The somatosensory barrel cortex was stimulated electrically in the anesthetized rat with either single pulses or pulse trains. Although single pulses produced small phasic activations in the colliculus, they did not elicit responses in the majority of DA neurons. However, after disinhibitory intracollicular injections of the GABAA antagonist bicuculline, collicular responses were substantially enhanced and previously unresponsive DA neurons now exhibited phasic excitations or inhibitions. Pulse trains applied to the cortex led to phasic changes (excitations to inhibitions) in the activity of DA neurons at baseline. These were blocked or attenuated by intracollicular administration of the GABAA agonist muscimol. Taken together, the results indicate that the cortex can communicate with DA neurons via a relay in the SC. As a consequence, DA neuronal activity reflecting the unexpected occurrence of salient events and that signaling more complex stimulus properties may have a common origin.

Modelling the coupling of the M-clock and C-clock in lymphatic muscle cells.

Chronic dysfunction of the lymphatic vascular system results in fluid accumulation between cells: lymphoedema. The condition is commonly acquired secondary to diseases such as cancer or the associated therapies. The primary driving force for fluid return through the lymphatic vasculature is provided by contractions of the muscularized lymphatic collecting vessels, driven by electrochemical oscillations. However, there is an incomplete understanding of the molecular and bioelectric mechanisms involved in lymphatic muscle cell excitation, hampering the development and use of pharmacological therapies. Modelling in silico has contributed greatly to understanding the contributions of specific ion channels to the cardiac action potential, but modelling of these processes in lymphatic muscle remains limited. Here, we propose a model of oscillations in the membrane voltage (M-clock) and intracellular calcium concentrations (C-clock) of lymphatic muscle cells. We modify a model by Imtiaz and colleagues to enable the M-clock to drive the C-clock oscillations. This approach differs from typical models of calcium oscillators in lymphatic and related cell types, but is required to fit recent experimental data. We include an additional voltage dependence in the gating variable control for the L-type calcium channel, enabling the M-clock to oscillate independently of the C-clock. We use phase-plane analysis to show that these M-clock oscillations are qualitatively similar to those of a generalised FitzHugh-Nagumo model. We also provide phase plane analysis to understand the interaction of the M-clock and C-clock oscillations. The model and methods have the potential to help determine mechanisms and find targets for pharmacological treatment of lymphoedema.

Simulation of a chain of collapsible contracting lymphangions with progressive valve closure.

The aim of this investigation was to achieve the first step toward a comprehensive model of the lymphatic system. A numerical model has been constructed of a lymphatic vessel, consisting of a short series chain of contractile segments (lymphangions) and of intersegmental valves. The changing diameter of a segment governs the difference between the flows through inlet and outlet valves and is itself governed by a balance between transmural pressure and passive and active wall properties. The compliance of segments is maximal at intermediate diameters and decreases when the segments are subject to greatly positive or negative transmural pressure. Fluid flow is the result of time-varying active contraction causing diameter to reduce and is limited by segmental viscous and valvular resistance. The valves effect a smooth transition from low forward-flow resistance to high backflow resistance. Contraction occurs sequentially in successive lymphangions in the forward-flow direction. The behavior of chains of one to five lymphangions was investigated by means of pump function curves, with variation of valve opening parameters, maximum contractility, lymphangion size gradation, number of lymphangions, and phase delay between adjacent lymphangion contractions. The model was reasonably robust numerically, with mean flow-rate generally reducing as adverse pressure was increased. Sequential contraction was found to be much more efficient than synchronized contraction. At the highest adverse pressures, pumping failed by one of two mechanisms, depending on parameter settings: either mean leakback flow exceeded forward pumping or contraction failed to open the lymphangion outlet valve. Maximum pressure and maximum flow-rate were both sensitive to the contractile state; maximum pressure was also determined by the number of lymphangions in series. Maximum flow-rate was highly sensitive to the transmural pressure experienced by the most upstream lymphangions, suggesting that many feeding lymphatics would be needed to supply one downstream lymphangion chain pumping at optimal transmural pressure.

Death in four RHDV2-vaccinated pet rabbits due to rabbit haemorrhagic disease virus 2 (RHDV2).

OBJECTIVES: To create awareness of single RHDV2 infections and cases of death despite immunisation with RHDV2-specific vaccine. MATERIALS AND METHODS: Retrospective case series of four companion rabbits. Patient signalment, vaccination history, pathology and molecular examinations were obtained from the medical records. RESULTS: The animals died peracutely or with nonspecific symptoms like apathy and inappetence. Pathological examination indicated and molecular biological findings confirmed RHDV2 infection in four animals. Several partner animals died at the same time under the same circumstances. CLINICAL SIGNIFICANCE: This is the first report of fatalities in RHDV2-vaccinated companion rabbits due to rabbit haemorrhagic disease virus 2 infection with documented case and vaccination history. Veterinarians should be aware of possible single fatal RHDV2 infections despite vaccination, should initiate the clarification of suspected cases and inform vaccine manufacturers and competent authorities.

Evaluation by fluid/structure-interaction spinal-cord simulation of the effects of subarachnoid-space stenosis on an adjacent syrinx.

A finite-element numerical model was constructed of the spinal cord, pia mater, filum terminale, cerebrospinal fluid in the spinal subarachnoid space (SSS), and dura mater. The cord was hollowed out by a thoracic syrinx of length 140 mm, and the SSS included a stenosis of length 30 mm opposite this syrinx. The stenosis severity was varied from 0% to 90% by area. Pressure pulse excitation was applied to the model either at the cranial end of the SSS, simulating the effect of cranial arterial pulsation, or externally to the abdominal dura mater, simulating the effect of cough. A very short pulse was used to examine wave propagation; a pulse emulating cardiac systole was used to examine the effects of fluid displacement. Additionally, repetitive sinusoidal excitation was applied cranially. Bulk fluid flow past the stenosis gave rise to prominent longitudinal pressure dissociation ("suck") in the SSS adjacent to the syrinx. However, this did not proportionally increase the longitudinal motion of fluid in the syrinx. The inertia of the fluid in the SSS, together with the compliance of this space, gave a resonance capable of being excited constructively or destructively by cardiac or coughing impulses. The main effect of mild stenosis was to lower the frequency of this resonance; severe stenosis damped out to-and-fro motions after the end of the applied excitation. Syrinx fluid motion indicated the fluid momentum and thus the pressure developed when the fluid was stopped by the end of the syrinx; however, the tearing stress in the local cord material depended also on the instantaneous local SSS pressure and was therefore not well predicted by syrinx fluid motion. Stenosis was also shown to give rise to a one-way valve effect causing raised SSS pressure caudally and slight average cord displacement cranially. The investigation showed that previous qualitative predictions of the effects of suck neglected factors that reduced the extent of the resulting syrinx fluid motion and of the cord tearing stress, which ultimately determines whether the syrinx lengthens.

Case report: Fresh-stored osteochondral allograft for treatment of osteochondritis dissecans the femoral head.

Osteochondral defects of the femoral head are exceedingly rare, with limited treatment options. Restoration procedures for similar defects involving the knee and ankle have been well described. In this report, we present a young patient who had a symptomatic osteochondral defect of the femoral head develop secondary to trauma and underwent subsequent treatment using a fresh-stored osteochondral allograft via a trochanteric osteotomy. At the 1-year followup, the patient was symptom free with near-complete incorporation of the graft radiographically. Our observations in this case suggest osteoarticular implantation may be an appropriate alternative to consider when treating osteochondral defects of the femoral head.

Modelling secondary lymphatic valves with a flexible vessel wall: how geometry and material properties combine to provide function.

A three-dimensional finite-element fluid/structure interaction model of an intravascular lymphatic valve was constructed, and its properties were investigated under both favourable and adverse pressure differences, simulating valve opening and valve closure, respectively. The shear modulus of the neo-Hookean material of both vascular wall and valve leaflet was varied, as was the degree of valve opening at rest. Also investigated was how the valve characteristics were affected by prior application of pressure inflating the whole valve. The characteristics were parameterised by the volume flow rate through the valve, the hydraulic resistance to flow, and the maximum sinus radius and inter-leaflet-tip gap on the plane of symmetry bisecting the leaflet, all as functions of the applied pressure difference. Maximum sinus radius on the leaflet-bisection plane increased with increasing pressure applied to either end of the valve segment, but also reflected the non-circular deformation of the sinus cross section caused by the leaflet, such that it passed through a minimum at small favourable pressure differences. When the wall was stiff, the inter-leaflet gap increased sigmoidally during valve opening; when it was as flexible as the leaflet, the gap increased more linearly. Less pressure difference was required both to open and to close the valve when either the wall or the leaflet material was more flexible. The degree of bias of the valve characteristics to the open position increased with the inter-leaflet gap in the resting position and with valve inflation pressure. The characteristics of the simulated valve were compared with those specified in an existing lumped-parameter model of one or more collecting lymphangions and used to estimate a revised value for the constant in that model which controls the rate of valve opening/closure with variation in applied pressure difference. The effects of the revised value on the lymph pumping efficacy predicted by the lumped-parameter model were evaluated.

Correction to: A computational model of a network of initial lymphatics and pre-collectors with permeable interstitium.

In the published paper, we argued that, although there appear to be no data available on the subject, it is inherently unlikely that lymph having traversed a network of initial lymphatics and pre-collectors then encounters an abrupt transition to vessels with all of the typical properties of collecting lymphatics.

A computational model of a network of initial lymphatics and pre-collectors with permeable interstitium.

Initial lymphatic vessels are made up of overlapped endothelial cells that act as unidirectional valves enabling one-way drainage of tissue fluid into the lumen of the initial lymphatics when there is a favourable pressure gradient. Initial lymphatics subsequently drain this fluid into the collecting lymphatics. This paper describes a computational model for a network of passive rat mesenteric lymphatic vessels with sparse secondary valves. The network was simulated with the secondary valves both operational and non-operational. The effects on the cycle-mean outflow-rate from the network of both inflammation and the resistance of the surrounding interstitium were considered. The cycle-mean outflow-rate is sensitive to vessel stiffness. If the influence of primary-valve resistance is reduced relative to that of interstitial resistance and intravascular resistance, there is no absolute advantage of extrinsic pumping, since maximum outflow-rate occurs when vessels are rigid. However, there is relative advantage, in that the outflow-rate at intermediate stiffness is higher with the secondary valves functioning than when they are deactivated. If primary-valve resistance dominates, then extrinsic pumping of non-rigid vessels provides absolute advantage. The nonlinear relation between pressure drop and flow-rate of the endothelial primary valves, combined with downstream compliance and pulsatile external pressure, constitutes a separate mechanism of pumping. By enabling the consideration of interactions between multiple phenomena (primary valves, secondary valves, a real network geometry with multiple branches, deformable vessel walls, interstitial resistance and external pressures), the model offers a perspective for delineating physiological phenomena that have not yet been fully linked to the biomechanics of fluid flow through initial lymphatic networks.

General anesthesia increases temporal precision and decreases power of the brainstem auditory-evoked response-related segments of the electroencephalogram.

BACKGROUND: Brainstem auditory-evoked responses (BAEP) have been reported to be unchanged in the presence of drugs used for induction and maintenance of general anesthesia. The aim of this study was to investigate if the signal segments after the auditory stimulus that are used to average the evoked response change under the influence of general anesthesia. METHODS: BAEPs of 156 patients scheduled for elective surgery under general anesthesia were investigated. Anesthetic regimen was randomized as a combination of one of four hypnotic drugs supplemented by one of four opioids. Signal segments after the auditory stimulus were obtained at six different periods of anesthesia. Power and phase properties of wavelet-filtered single-sweep auditory-evoked activity accounting for the waveform of the averaged BAEP wave V and the stability of amplitude and latency of the averaged BAEP wave V over periods were analyzed. RESULTS: Amplitude and latency of wave V change slightly with no significant difference between the periods. During anesthesia, however, the power of single sweeps is significantly reduced, whereas phase-locking properties of the according signal segments are significantly enhanced. This effect is independent of the anesthetic or opioid used. CONCLUSIONS: General anesthesia affects phase and power of the segments of the electroencephalogram related to BAEP wave V. This study's results support the idea that temporally precise responses from a large number of neurons in the brainstem might play a crucial role in encoding and passing sensory information to higher subcortical and cortical areas of the brain.

Fluid flow in distensible vessels.

1. Flow in single vascular conduits is reviewed, divided into distended and deflated vessels. 2. In distended vessels with pulsatile flow, wave propagation and reflection dominate the spatial and temporal distribution of pressure, determining the shape, size and relative timing of measured pressure waveforms, as well as the instantaneous pressure gradient everywhere. Considerable research has been devoted to accessing the information on pathological vascular malformations contained in reflected waves. Slow waves of contraction of vessel wall muscle, responsible for transport of oesophageal, ureteral and gut contents, have also been modelled. 3. The pressure gradient in a vessel drives the flow. Flow rate can be predicted both analytically and numerically, but analytical theory is limited to idealized geometry. The complex geometry of biological system conduits necessitates computation instead. Initially limited to rigid boundaries, numerical methods now include fluid-structure interaction and can simultaneously model solute transport, thus predicting accurately the environment of the mechanosensors and chemosensors at vessel surfaces. 4. Deflated vessels display all phenomena found in distended vessels, but have additional unique behaviours, especially flow rate limitation and flow-induced oscillation. Flow rate limitation is widespread in the human body and has particular diagnostic importance in respiratory investigation. Because of their liquid lining, the pulmonary airways are also characterized by important two-phase flows, where surface tension phenomena create flows and determine the patency and state of collapse of conduits. 5. Apart from the vital example of phonation, sustained self-excited oscillation is largely avoided in the human body. Where it occurs in snoring, it is implicated in the pathological condition of sleep apnoea.