Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung

Endometrial apoptosis and neutrophil infiltration during menstruation exhibits spatial and temporal dynamics that are recapitulated in a mouse model.

Abstract Menstruation is characterised by synchronous shedding and restoration of tissue integrity. An in vivo model of menstruation is required to investigate mechanisms responsible for regulation of menstrual physiology and to investigate common pathologies such as heavy menstrual bleeding (HMB). We hypothesised that our mouse model of simulated menstruation would recapitulate the spatial and temporal changes in the inflammatory microenvironment of human menses. Three regulatory events were investigated: cell death (apoptosis), neutrophil influx and cytokine/chemokine expression. Well-characterised endometrial tissues from women were compared with uteri from a mouse model (tissue recovered 0, 4, 8, 24 and 48 h after removal of a progesterone-secreting pellet). Immunohistochemistry for cleaved caspase-3 (CC3) revealed significantly increased staining in human endometrium from late secretory and menstrual phases. In mice, CC3 was significantly increased at 8 and 24 h post-progesterone-withdrawal. Elastase+ human neutrophils were maximal during menstruation; Ly6G+ mouse neutrophils were maximal at 24 h. Human endometrial and mouse uterine cytokine/chemokine mRNA concentrations were significantly increased during menstrual phase and 24 h post-progesterone-withdrawal respectively. Data from dated human samples revealed time-dependent changes in endometrial apoptosis preceding neutrophil influx and cytokine/chemokine induction during active menstruation. These dynamic changes were recapitulated in the mouse model of menstruation, validating its use in menstrual research

The transcriptional response of Caenorhabditis elegans to ivermectin exposure identifies novel genes involved in the response to reduced food intake

We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

The specificity of phage testing for MAP — where might it fit into the diagnostic armoury?

The current individual tools available for the diagnosis of Johne's disease are far from suitable to tackle this endemic disease. Culture, polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) tests, when used together can be useful in managing the disease in the later stages of infection at a herd level. They are, however, ill-suited to detecting the causative agent Mycobacterium avium subsp. paratuberculosis (MAP) at the early stages of infection and at an individual level. Phage technology offers another tool in the attempt to better manage and control this disease. Phage-technology has been demonstrated to rapidly and sensitively detect and specifically identify viable MAP in the milk and blood of cattle. Although in relatively-early stages of development phage technology offers a strong addition to the armoury of tests used to detect MAP in blood and milk, and may go on to be part of ongoing control measures to reduce the burden of disease to farmers and veterinarians

IL-33-dependent Type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo

Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. Objectives: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. Methods: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirusinfected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. Conclusions: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33–responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbation

‘Test n Treat (TnT)’– Rapid testing and same-day, on-site treatment to reduce rates of chlamydia in sexually active further education college students: study protocol for a cluster randomised feasibility trial

Background Sexually active young people attending London further education (FE) colleges have high rates of chlamydia, but screening rates are low. We will conduct a cluster randomised feasibility trial of frequent, rapid, on-site chlamydia testing and same-day treatment (Test and Treat (TnT)) in six FE colleges (with parallel qualitative and economic assessments) to assess the feasibility of conducting a future trial to investigate if TnT reduces chlamydia rates. Methods We will recruit 80 sexually active students aged 16–24 years from public areas at each of six colleges. All participants (total n = 480) will be asked to provide samples (urine for males, self-taken vaginal swabs for females) and complete questionnaires on sexual lifestyle and healthcare use at baseline and after 7 months. Participants will be informed that baseline samples will not be tested for 7 months and be advised to get screened separately. Colleges will be randomly allocated to the intervention (TnT) or the control group (no TnT). One and 4 months after recruitment, participants at each intervention college (n = 3) will be texted and invited for on-site chlamydia tests using the 90-min Cepheid GeneXpert system. Students with positive results will be asked to see a visiting nurse health adviser for same-day treatment and partner notification, (backed by genitourinary medicine follow-up). Participants in control colleges (n = 3) will receive ‘thank you’ texts 1 and 4 months after recruitment. Seven months after recruitment, participants from both groups will be invited to complete questionnaires and provide samples for TnT. All samples will be tested, and same-day treatment offered to students with positive results. Acceptability of TnT will be assessed by qualitative interviews of purposively sampled students (n = 30) and college staff (n = 12). We will collect data on costs of TnT and usual healthcare. Discussion Findings will provide key values to inform feasibility, sample size and timescales of a future definitive trial of TnT in FE colleges, including: Recruitment rates TnT uptake rates Follow-up rates Prevalence of chlamydia in participants at baseline and 7 months Acceptability of TnT to students and college staff Estimate of the cost per person screened/treated in TnT versus usual care Trial registration International Standard Randomised Controlled Trials Registry, ID: ISRCTN58038795, Registered on 31 August 2016

Tikhonov adaptively regularized gamma variate fitting to assess plasma clearance of inert renal markers

The Tk-GV model fits Gamma Variates (GV) to data by Tikhonov regularization (Tk) with shrinkage constant, λ, chosen to minimize the relative error in plasma clearance, CL (ml/min). Using 169Yb-DTPA and 99mTc-DTPA (n = 46, 8–9 samples, 5–240 min) bolus-dilution curves, results were obtained for fit methods: (1) Ordinary Least Squares (OLS) one and two exponential term (E1 and E2), (2) OLS-GV and (3) Tk-GV. Four tests examined the fit results for: (1) physicality of ranges of model parameters, (2) effects on parameter values when different data subsets are fit, (3) characterization of residuals, and (4) extrapolative error and agreement with published correction factors. Test 1 showed physical Tk-GV results, where OLS-GV fits sometimes-produced nonphysical CL. Test 2 showed the Tk-GV model produced good results with 4 or more samples drawn between 10 and 240 min. Test 3 showed that E1 and E2 failed goodness-of-fit testing whereas GV fits for t > 20 min were acceptably good. Test 4 showed CLTk-GV clearance values agreed with published CL corrections with the general result that CLE1 > CLE2 > CLTk-GV and finally that CLTk-GV were considerably more robust, precise and accurate than CLE2, and should replace the use of CLE2 for these renal markers

The reliability of plantar pressure assessment during barefoot level walking in children aged 7-11 years

<p>Abstract</p> <p>Background</p> <p>Plantar pressure assessment can provide information pertaining to the dynamic loading of the foot, as well as information specific to each region in contact with the ground. There have been few studies which have considered the reliability of plantar pressure data and therefore the purpose of this study was to investigate the reliability of assessing plantar pressure variables in a group of typically developing children, during barefoot level walking.</p> <p>Methods</p> <p>Forty-five participants, aged 7 to 11 years, were recruited from local primary and secondary schools in East London. Data from three walking trials were collected at both an initial and re-test session, taken one week apart, to determine both the within- and between-session reliability of selected plantar pressure variables. The variables of peak pressure, peak force, pressure-time and force-time integrals were extracted for analysis in the following seven regions of the foot; lateral heel, medial heel, midfoot, 1st metatarsophalangeal joint, 2nd-5th metatarsophalangeal joint, hallux and the lesser toes. Reliability of the data were explored using Intra Class Correlation Coefficients (ICC 3,1 and 3,2) and variability with Coefficients of Variation (CoV's).</p> <p>Results</p> <p>The measurements demonstrated moderate to good levels of within-session reliability across all segments of the foot (0.69-0.93), except the lesser toes, which demonstrated poor reliability (0.17-0.50). CoV's across the three repeated trials ranged from 10.12-19.84% for each of the measured variables across all regions of the foot, except the lesser toes which demonstrated the greatest variability within trials (27.15-56.08%). The between-session results demonstrated good levels of reliability across all foot segments (0.79-0.99) except the lesser toes; with moderate levels of reliability reported at this region of the foot (0.58-0.68). The CoV's between-sessions demonstrated that the midfoot (16.41-36.23%) and lesser toe region (29.64-56.61) demonstrated the greatest levels of variability across all the measured variables.</p> <p>Conclusions</p> <p>These findings indicate that using the reported protocols, reliable plantar pressure data can be collected in children, aged 7 to 11 years in all regions of the foot except the lesser toes which consistently reported poor-to-moderate levels of reliability and increased variability.</p

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO