Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

The impact of social and physical distancing measures on COVID-19 activity in England: findings from a multi-tiered surveillance system

BACKGROUND: A multi-tiered surveillance system based on influenza surveillance was adopted in the United Kingdom in the early stages of the coronavirus disease (COVID-19) epidemic to monitor different stages of the disease. Mandatory social and physical distancing measures (SPDM) were introduced on 23 March 2020 to attempt to limit transmission. AIM: To describe the impact of SPDM on COVID-19 activity as detected through the different surveillance systems. METHODS: Data from national population surveys, web-based indicators, syndromic surveillance, sentinel swabbing, respiratory outbreaks, secondary care admissions and mortality indicators from the start of the epidemic to week 18 2020 were used to identify the timing of peaks in surveillance indicators relative to the introduction of SPDM. This timing was compared with median time from symptom onset to different stages of illness and levels of care or interactions with healthcare services. RESULTS: The impact of SPDM was detected within 1 week through population surveys, web search indicators and sentinel swabbing reported by onset date. There were detectable impacts on syndromic surveillance indicators for difficulty breathing, influenza-like illness and COVID-19 coding at 2, 7 and 12 days respectively, hospitalisations and critical care admissions (both 12 days), laboratory positivity (14 days), deaths (17 days) and nursing home outbreaks (4 weeks). CONCLUSION: The impact of SPDM on COVID-19 activity was detectable within 1 week through community surveillance indicators, highlighting their importance in early detection of changes in activity. Community swabbing surveillance may be increasingly important as a specific indicator, should circulation of seasonal respiratory viruses increase

Oral health status of 12-year-old school children in Khartoum state, the Sudan; a school-based survey

<p>Abstract</p> <p>Background</p> <p>Few studies have investigated the prevalence of dental caries among school children in the past decades in Sudan rendering it difficult to understand the status and pattern of oral health.</p> <p>Methods</p> <p>A school-based survey was conducted using stratified random cluster sampling in Khartoum state, Sudan. Data was collected through interviews and clinical examination by a single examiner. DMFT was measured according to WHO criteria. Gingival index (GI) of Loe & Silness and Plaque index (PI) of Silness & Loe were used.</p> <p>Results</p> <p>The mean DMFT for 12-year-olds was found to be 0.42 with a significant caries index (SiC) of 1.4. Private school attendees had significantly higher DMFT (0.57) when compared to public school attendees (0.4). The untreated caries prevalence was 30.5%. In multivariate analysis caries experience (DMFT > 0) was found to be significantly and directly associated with socioeconomic status. The mean GI for the six index teeth was found to be 1.05 (CI 1.03 – 1.07) and the mean PI was 1.30 (CI 1.22 – 1.38).</p> <p>Conclusion</p> <p>The prevalence of caries was found to be low. The school children with the higher socioeconomic status formed the high risk group.</p

A novel application of motion analysis for detecting stress responses in embryos at different stages of development.

Motion analysis is one of the tools available to biologists to extract biologically relevant information from image datasets and has been applied to a diverse range of organisms. The application of motion analysis during early development presents a challenge, as embryos often exhibit complex, subtle and diverse movement patterns. A method of motion analysis able to holistically quantify complex embryonic movements could be a powerful tool for fields such as toxicology and developmental biology to investigate whole organism stress responses. Here we assessed whether motion analysis could be used to distinguish the effects of stressors on three early developmental stages of each of three species: (i) the zebrafish Danio rerio (stages 19 h, 21.5 h and 33 h exposed to 1.5% ethanol and a salinity of 5); (ii) the African clawed toad Xenopus laevis (stages 24, 32 and 34 exposed to a salinity of 20); and iii) the pond snail Radix balthica (stages E3, E4, E6, E9 and E11 exposed to salinities of 5, 10 and 15). Image sequences were analysed using Sparse Optic Flow and the resultant frame-to-frame motion parameters were analysed using Discrete Fourier Transform to quantify the distribution of energy at different frequencies. This spectral frequency dataset was then used to construct a Bray-Curtis similarity matrix and differences in movement patterns between embryos in this matrix were tested for using ANOSIM

Modelling Cell Polarization Driven by Synthetic Spatially Graded Rac Activation

The small GTPase Rac is known to be an important regulator of cell polarization, cytoskeletal reorganization, and motility of mammalian cells. In recent microfluidic experiments, HeLa cells endowed with appropriate constructs were subjected to gradients of the small molecule rapamycin leading to synthetic membrane recruitment of a Rac activator and direct graded activation of membrane-associated Rac. Rac activation could thus be triggered independent of upstream signaling mechanisms otherwise responsible for transducing activating gradient signals. The response of the cells to such stimulation depended on exceeding a threshold of activated Rac. Here we develop a minimal reaction-diffusion model for the GTPase network alone and for GTPase-phosphoinositide crosstalk that is consistent with experimental observations for the polarization of the cells. The modeling suggests that mutual inhibition is a more likely mode of cell polarization than positive feedback of Rac onto its own activation. We use a new analytical tool, Local Perturbation Analysis, to approximate the partial differential equations by ordinary differential equations for local and global variables. This method helps to analyze the parameter space and behaviour of the proposed models. The models and experiments suggest that (1) spatially uniform stimulation serves to sensitize a cell to applied gradients. (2) Feedback between phosphoinositides and Rho GTPases sensitizes a cell. (3) Cell lengthening/flattening accompanying polarization can increase the sensitivity of a cell and stabilize an otherwise unstable polarization

Circadian Integration of Glutamatergic Signals by Little SAAS in Novel Suprachiasmatic Circuits

Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood.Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS.Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock

The insecure airway: a comparison of knots and commercial devices for securing endotracheal tubes

BACKGROUND: Endotracheal Tubes (ETTs) are commonly secured using adhesive tape, cloth tape, or commercial devices. The objectives of the study were (1) To compare degrees of movement of ETTs secured with 6 different commercial devices and (2) To compare movement of ETTs secured with cloth tape tied with 3 different knots (hitches). METHODS: A 17 cm diameter PVC tube with 14 mm "mouth" hole in the side served as a mannequin. ETTs were subjected to repeated jerks, using a cable and pulley system. Measurements: (1) Total movement of ETTs relative to "mouth" (measure used for devices) (2) Slippage of ETT through securing knot (measure used for knots). RESULTS: Among commercial devices, the Dale(® )showed less movement than other devices, although some differences between devices did not reach significance. Among knots, Magnus and Clove Hitches produced less slippage than the Cow Hitch, but these differences did not reach statistical significance. CONCLUSION: Among devices tested, the Dale(® )was most secure. Within the scope offered by the small sample sizes, there were no statistically significant differences between the knots in this study

cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents

The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions

Effects of food on physical and sleep complaints in children with ADHD: a randomised controlled pilot study

Attention deficit/hyperactivity disorder (ADHD), a common behavioural disorder in children, may be associated with comorbid physical and sleep complaints. Dietary intervention studies have shown convincing evidence of efficacy in reducing ADHD symptoms in children. In this pilot study, we investigated the effects of an elimination diet on physical and sleep complaints in children with ADHD. A group of 27 children (3.8–8.5 years old), who all met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD, were assigned randomly to either a diet group (15/27) or a control group (12/27). The diet group followed a 5-week elimination diet; the control group adhered to their normal diet. Parents of both groups had to keep an extended diary and had to monitor the behaviour and the physical and sleep complaints of their child conscientiously. The primary endpoint was the clinical response, i.e. a decrease of physical and sleep complaints, at the end of the trial, based on parent ratings on a Physical Complaints Questionnaire. The number of physical and sleep complaints was significantly decreased in the diet group compared to the control group (p < 0.001), with a reduction in the diet group of 77% (p < 0.001, effect size = 2.0) and in the control group of 17% (p = 0.08, effect size = 0.2). Specific complaints that were significantly reduced were in three domains: headaches or bellyaches, unusual thirst or unusual perspiration, and sleep complaints. The reduction of complaints seemed to occur independently of the behavioural changes (p = 0.1). However, the power of this comparison was low. A positive correlation existed between the reduction of physical and behavioural symptoms (p < 0.01). The reduction did not differ between children with or without an atopic constitution (p = 0.7). An elimination diet may be an effective instrument to reduce physical complaints in children with ADHD, but more research is needed to determine the effects of food on (functional) somatic symptoms in children with and without ADHD. This trial was registered as an International Standard Randomised Controlled Trial, ISRCTN47247160