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.

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.

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.

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.

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.

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.

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.

Genital Tract Pathology in Female Pet Guinea Pigs (Cavia porcellus): a Retrospective Study of 655 Post-mortem and 64 Biopsy Cases.

Disorders of the female genital tract are among the most common disorders in pet guinea pigs (Cavia porcellus); however, knowledge of many aspects of these disorders is sparse, especially regarding their incidence and age distribution. Ovarian cysts, as the most common genital tract disorder in guinea pigs, have been investigated in detail; however, information on the nature of these cysts is inconsistent. The present study reviewed genital tract disorders occurring within 655 full post-mortem examinations of intact female pet guinea pigs and 64 female genital tract biopsies examined over a 22.5 year period. Age distribution was determined from 550 post-mortem examinations of animals of known age. Genital tract disorders were found in 295 post-mortem examinations (45.0%) in animals with a median age of 52 months. Additionally, disorders were found in all genital tract biopsy samples from guinea pigs with a median age of 48 months. The incidence of genital tract diseases increased from 1.5% in guinea pigs ≤6 months of age to up to 77.8% in animals >6 years of age. Ovarian cysts were the most common genital tract disorder, found in 245 of the 655 post-mortem cases (37.4%) and 38 of 43 ovarian biopsy samples (88.4%). The incidence of ovarian cysts increased with advancing age, reaching 75.6% in animals >6 years. In 119 cases, histopathology and immunohistochemistry confirmed cystic rete ovarii as the only cyst type. A Fallopian tube adenoma was found in a single case, so disorders of the Fallopian tube should be considered rare. Uterine disorders were diagnosed in 17.4% of the post-mortem examinations and 98.1% of uterine biopsy samples. Uterine neoplasia, hyperplasia and inflammation were common, but occurred at different ages. The incidence of uterine neoplasia and hyperplasia was higher in older animals (>15% in guinea pigs >6 years), while the incidence of uterine inflammation was the highest (17.9%) in animals aged 7-12 months. An association between ovarian cysts and uterine neoplasia or hyperplasia was not evident. Vaginal disorders were rare and included leiomyoma, polyps and vaginitis.

Genital Tract Pathology in Female Pet Rabbits (Oryctolagus cuniculus): a Retrospective Study of 854 Necropsy Examinations and 152 Biopsy Samples.

Genital tract disorders, especially uterine disorders, are the most common conditions of the female pet rabbit (Oryctolagus cuniculus); however, there have been few large studies of diseases of the female genital tract of this species. The present study examined diseases of the ovaries, Fallopian tubes, uterus and vagina, retrospectively over a period of 22 years, and included 854 full post-mortem examinations of female pet rabbits and 152 female genital tract biopsy samples. The age distribution of uterine neoplasia, endometrial hyperplasia and uterine inflammation was determined in the post-mortem cases. Uterine disorders were a common finding, occurring in 26.8% of all full necropsy examinations and in almost all genital tract biopsy samples. Uterine tumours (n = 205) were the most common uterine pathology, with adenocarcinoma being the most frequent tumour type. Metastasis was found in 46.2% of rabbits with uterine adenocarcinomas diagnosed at post-mortem examination, with metastatic spread to the lung occurring in 79.1% of these animals. The second most common uterine pathology was endometrial hyperplasia, which was glandular-cystic in most cases. The incidence of uterine tumours and endometrial hyperplasia increased with age, while endometrial hyperplasia was found more commonly in slightly younger animals. In contrast, uterine inflammation, the third most common finding, was found predominately in young to middle-aged rabbits. Ovarian disorders were found rarely at post-mortem examinations (3.3% of all animals), but comprised 16.9% of biopsy samples. Of these, ovarian cysts, especially follicular cysts, and secondary tumours were found most frequently. Disorders of the Fallopian tube and the vagina were found in <1% of cases and should be considered rare.

Contraction of collecting lymphatics: organization of pressure-dependent rate for multiple lymphangions.

The paper describes the extension of a previously developed model of pressure-dependent contraction rate to the case of multiple lymphangions. Mechanical factors are key modulators of active lymphatic pumping. As part of the evolution of our lumped-parameter model to match experimental findings, we have designed an algorithm whereby the time until the next contraction depends on lymphangion transmural pressure in the contraction just completed. The functional dependence of frequency on pressure is quantitatively matched to isobaric contraction experiments on isolated lymphatic segments. When each of several lymphangions is given this ability, a scheme for their coordination must be instituted to match the observed synchronization. Accordingly, and in line with an experiment on an isolated lymphatic vessel segment in which we measured contraction sequence and conduction delay, we took the fundamental principle to be that local timing can be overridden by signals to initiate contraction that start in adjacent lymphangions, conducted with a short delay. The scheme leads to retrograde conduction when the lymphangion chain is pumping against an adverse pressure difference, but antegrade conduction when contractions occur with no or a favourable pressure difference. Abolition of these conducted signals leads to chaotic variation of cycle-mean flow-rate from the chain, diastolic duration in each lymphangion, and inter-lymphangion delays. Chaotic rhythm is also seen under other circumstances. Because the model responds to increasing adverse pressure difference by increasing the repetition rate of contractions, it maintains time-average output flow-rate better than one with fixed repetition rate.