A systematic evaluation of the influence of macrophage phenotype descriptions on inflammatory dynamics.

Macrophages play a wide range of roles in resolving the inflammatory damage that underlies many medical conditions, and have the ability to adopt different phenotypes in response to different environmental stimuli. Categorising macrophage phenotypes exactly is a difficult task, and there is disparity in the literature around the optimal nomenclature to describe these phenotypes; however, what is clear is that macrophages can exhibit both pro- and anti-inflammatory behaviours dependent upon their phenotype, rendering mathematical models of the inflammatory response potentially sensitive to their description of the macrophage populations that they incorporate. Many previous models of inflammation include a single macrophage population with both pro- and anti-inflammatory functions. Here, we build upon these existing models to include explicit descriptions of distinct macrophage phenotypes and examine the extent to which this influences the inflammatory dynamics that the models emit. We analyse our models via numerical simulation in Matlab and dynamical systems analysis in XPPAUT, and show that models that account for distinct macrophage phenotypes separately can offer more realistic steady state solutions than precursor models do (better capturing the anti-inflammatory activity of tissue resident macrophages), as well as oscillatory dynamics not previously observed. Finally, we reflect on the conclusions of our analysis in the context of the ongoing hunt for potential new therapies for inflammatory conditions, highlighting manipulation of macrophage polarisation states as a potential therapeutic target.

Exploring the constituent mechanisms of hepatitis: a dynamical systems approach.

Hepatitis is the term used to describe inflammation in the liver. It is associated with a high rate of mortality, but the underlying disease mechanisms are not completely understood and treatment options are limited. We present a mathematical model of hepatitis that captures the complex interactions between hepatocytes (liver cells), hepatic stellate cells (cells in the liver that produce hepatitis-associated fibrosis) and the immune components that mediate inflammation. The model is in the form of a system of ordinary differential equations. We use numerical techniques and bifurcation analysis to characterize and elucidate the physiological mechanisms that dominate liver injury and its outcome to a healthy or unhealthy, chronic state. This study reveals the complex interactions between the multiple cell types and mediators involved in this complex disease and highlights potential problems in targeting inflammation in the liver therapeutically.

Prospective multiparametric CMR characterization and MicroRNA profiling of anthracycline cardiotoxicity: A pilot translational study.

Background: Anthracycline cardiotoxicity is a significant clinical challenge. Biomarkers to improve risk stratification and identify early cardiac injury are required. Objectives: The purpose of this pilot study was to prospectively characterize anthracycline cardiotoxicity using cardiovascular magnetic resonance (CMR), echocardiography and MicroRNAs (MiRNAs), and identify baseline predictors of LVEF recovery. Methods: Twenty-four patients (age 56 range 18-75 years; 42 % female) with haematological malignancy scheduled to receive anthracycline chemotherapy (median dose 272 mg/m2 doxorubicin equivalent) were recruited and evaluated at three timepoints (baseline, completion of chemotherapy, and 6 months after completion of chemotherapy) with multiparametric 1.5 T CMR, echocardiography and circulating miRNAs sequencing. Results: Seventeen complete datasets were obtained. CMR left ventricular ejection fraction (LVEF) fell significantly between baseline and completion of chemotherapy (61 ± 3 vs 53 ± 3 %, p < 0.001), before recovering significantly at 6-month follow-up (55 ± 3 %, p = 0.018). Similar results were observed for 3D echocardiography-derived LVEF and CMR-derived longitudinal, circumferential and radial feature-tracking strain. Patients were divided into tertiles according to LVEF recovery (poor recovery, partial recovery, good recovery). CMR-derived mitral annular plane systolic excursion (MAPSE) was significantly different at baseline in patients exhibiting poor LVEF recovery (11.7 ± 1.5 mm) in comparison to partial recovery (13.7 ± 2.7 mm), and good recovery (15.7 ± 3.1 mm; p = 0.028). Furthermore, baseline miRNA-181-5p and miRNA-221-3p expression were significantly higher in this group. T2 mapping increased significantly on completion of chemotherapy compared to baseline (54.0 ± 4.6 to 57.8 ± 4.9 ms, p = 0.001), but was not predictive of LVEF recovery. No changes to LV mass, extracellular volume fraction, T1 mapping or late gadolinium enhancement were observed. Conclusions: Baseline CMR-derived MAPSE, circulating miRNA-181-5p, and miRNA-221-3p were associated with poor recovery of LVEF 6 months after completion of anthracycline chemotherapy, suggesting their potential predictive role in this context. T2 mapping increased significantly on completion of chemotherapy but was not predictive of LVEF recovery.

Primate diversity in the early Miocene Pinturas Formation, southern Patagonia, Argentina.

We report ten new dental specimens of primates from the early Miocene Pinturas Formation, Patagonia, Argentina. The new material includes: a left lower canine and a left upper canine whose affinities remain to be determined; a mandibular fragment preserving part of the symphysis; and right p3-4, practically indistinguishable from Soriacebus adrianae; and a lower molar, probably m2, attributable to S. ameghinorum. A lower molar, probably m3, a P4, and an upper molar resemble Carlocebus carmenensis. Three additional specimens, too damaged for an accurate taxonomic assignment, are tentatively assigned to S. ameghinorum. The specimens here described can be assigned to taxa already known from the Pinturas Formation (S. ameghinorum, S. adrianae, and C. carmenensis) and provide new morphological information.

The Gerbode defect: a case series.

BACKGROUND: The Gerbode defect is a rare abnormal communication between the left ventricle (LV) and right atrium (RA). The lesion is either congenital or acquired. Acquired defects are largely iatrogenic or infective in origin. We present two cases of acquired Gerbode defects with similar clinical presentations but very different outcomes. CASE SUMMARIES: Patient 1 A 64-year-old male presented with features of decompensated cardiac failure and a low-grade temperature. Dehiscence of a recently implanted bioprosthetic aortic valve and high-velocity LV to RA jet (Gerbode defect) was found on echocardiography. Blood cultures grew Staphylococcus warneri and the diagnosis of infective endocarditis was established. The patient was treated with intravenous antibiotics and the aortic valve and Gerbode defect were successfully surgically repaired.Patient 2 An 81-year-old male presented after being found on the floor at home. On admission, he was clinically septic with evidence of decompensated heart failure. No clear infective focus was initially found. Transthoracic echocardiography revealed severe left ventricular impairment, with a normal bioprosthetic aortic valve. He was treated with intravenous antibiotics, but later deteriorated with evidence of embolic phenomena. Repeat echocardiography revealed a complex infective aortic root lesion with bioprosthetic valve dehiscence and flow demonstrated from the LV to RA. Unfortunately, the patient succumbed to the infection and cardiac complications. DISCUSSION: The Gerbode defect is a rare but important complication of infective endocarditis and valve surgery. Care needs to be taken to assess for Gerbode defect shunts on echocardiogram, especially in the context of previous cardiac surgery.

Spatial considerations in the resolution of inflammation: Elucidating leukocyte interactions via an experimentally-calibrated agent-based model.

Many common medical conditions (such as cancer, arthritis, chronic obstructive pulmonary disease (COPD), and others) are associated with inflammation, and even more so when combined with the effects of ageing and multimorbidity. While the inflammatory response varies in different tissue types, under disease and in response to therapeutic interventions, it has common interactions that occur between immune cells and inflammatory mediators. Understanding these underlying inflammatory mechanisms is key in progressing treatments and therapies for numerous inflammatory conditions. It is now considered that constituent mechanisms of the inflammatory response can be actively manipulated in order to drive resolution of inflammatory damage; particularly, those mechanisms related to the pro-inflammatory role of neutrophils and the anti-inflammatory role of macrophages. In this article, we describe the assembly of a hybrid mathematical model in which the spatial spread of inflammatory mediators is described through partial differential equations, and immune cells (neutrophils and macrophages) are described individually via an agent-based modelling approach. We pay close attention to how immune cells chemotax toward pro-inflammatory mediators, presenting a model for cell chemotaxis that is calibrated against experimentally observed cell trajectories in healthy and COPD-affected scenarios. We illustrate how variations in key model parameters can drive the switch from resolution of inflammation to chronic outcomes, and show that aberrant neutrophil chemotaxis can move an otherwise healthy outcome to one of chronicity. Finally, we reflect on our results in the context of the on-going hunt for new therapeutic interventions.

Acceptance Testing of Thermoluminescent Dosimeter Holders.

The U.S. Navy uses the Harshaw 8840/8841 dosimetric (DT-702/PD) system, which employs LiF:Mg,Cu,P thermoluminescent dosimeters (TLDs), developed and produced by Thermo Fisher Scientific (TFS). The dosimeter consists of four LiF:Mg,Cu,P elements, mounted in Teflon® on an aluminum card and placed in a plastic holder. The holder contains a unique filter for each chip made of copper, acrylonitrile butadiene styrene (ABS), Mylar®, and tin. For accredited dosimetry labs, the ISO/IEC 17025:2005(E) requires an acceptance procedure for all new equipment. The Naval Dosimetry Center (NDC) has developed and tested a new non-destructive procedure, which enables the verification and the evaluation of embedded filters in the holders. Testing is based on attenuation measurements of low-energy radiation transmitted through each filter in a representative sample group of holders to verify that the correct filter type and thickness are present. The measured response ratios are then compared with the expected response ratios. In addition, each element's measured response is compared to the mean response of the group. The test was designed and tested to identify significant nonconformities, such as missing copper or tin filters, double copper or double tin filters, or other nonconformities that may impact TLD response ratios. During the implementation of the developed procedure, testing revealed a holder with a double copper filter. To complete the evaluation, the impact of the nonconformities on proficiency testing was examined. The evaluation revealed failures in proficiency testing categories III and IV when these dosimeters were irradiated to high-energy betas.

Demographic and Clinical Characteristics to Predict Paroxysmal Atrial Fibrillation: Insights from an Implantable Loop Recorder Population.

BACKGROUND: There is growing interest in detecting paroxysmal atrial fibrillation (PAF) to identify patients at high risk of thromboembolic stroke. The implantable loop recorder (ILR) is emerging as a powerful new tool in the diagnosis of PAF. Widespread implantation has significant cost implications and their use must be targeted at those patients at most risk. METHODS: We retrospectively studied a population of 200 adult patients who underwent ILR implantation for the investigation of syncope or palpitations. Clinical data, baseline electrocardiogram (ECG) characteristics, and echocardiographic data were collected. All ECGs and electrograms (EGMs) were scrutinized by two blinded investigators. PAF incidence was defined as episodes lasting >30 seconds on EGMs recorded in ILR memory. RESULTS: Our ILR population consists of 200 patients, 111 (56%) male, with a mean age of 61.4 years (range 19-95). PAF was detected in 42 patients. The following factors were significant predictors of PAF by multivariate logistic regression analysis: cigarette smoking (odds ratio [OR] = 3.73, 95% confidence interval [CI] = 1.40-10.24, P = 0.009) and incomplete right bundle branch block (IRBBB; OR = 9.04, 95% CI = 2.51-34.64, P = 0.00088). Significant differences included incidence of IRBBB (P = 0.012), cigarette smoking (P = 0.026), hypercholesterolemia (P = 0.015), age (P = 0.002), estimated glomerular filtration rate (P = 0.031), left atrial volume (P = 0.019), and PR interval (P = 0.031). The PAF group had significantly higher CHA2 DS2 -VASc scores (P = 0.01). CONCLUSIONS: Our study reports predictive factors for PAF in an ILR population. We suggest that cigarette smoking and IRBBB are independently associated with paroxysmal AF in patients presenting with palpitations or syncope.

An audit of persistent foramen ovale closure in 105 divers.

INTRODUCTION: Right-to-left shunt across a persistent foramen ovale (PFO) has been associated with cutaneous, neurological and vestibular decompression illness (DCI). Percutaneous closure of a PFO has been used to reduce the risk of DCI. There are no randomised controlled trial data to support PFO closure for the prevention of decompression illness (DCI), so the need for audit data on the safety and efficacy of this technique has been recognised by the National Institute of Health and Clinical Excellence in the UK. METHOD: Retrospective audit of all transcatheter PFO closures to reduce the risk of DCI performed by a single cardiologist with an interest in diving medicine. RESULTS: A total of 105 eligible divers undergoing 107 procedures was identified. There was a low rate of procedural complications; a rate lower than a recent randomised trial of PFO closure for stroke. Atrial fibrillation required treatment in two patients. One patient with a previously repaired mitral valve had a stroke that was thought to be unrelated to the PFO closure. Sixteen divers had minor post-procedure symptoms not requiring any treatment. Two divers required a second procedure because of residual shunt; both subsequently returned to unrestricted diving. Eighty-one of 95 divers in whom follow-up bubble contrast echocardiography was available returned to unrestricted diving. CONCLUSIONS: The PFO closure procedure appeared to be safe and was associated with the majority of divers being able to successfully return to unrestricted diving.

The high dose response and functional capability of the DT-702/Pd lithium fluoride thermoluminescent dosimeter.

The United States Navy monitors the dose its radiation workers receive using the DT-702/PD thermoluminescent dosimeter, which consists of the Harshaw 8840 holder and the four-element Harshaw 8841 card. There were two main objectives of this research. In the first objective, the dosimeters were exposed to 100 Gy using electron and x-ray beams and found to respond approximately 30-40% lower than the delivered dose. No significant effect on the under-response was found when dose rate, radiation type, dosimeter position on the phantom, and dosimeter material were varied or when the card was irradiated while enclosed in its holder. Since the current naval policy is to remove from occupational use any thermoluminescent dosimeter with an accumulated deep dose equivalent of 0.05 Sv or greater, the functionality of the dosimeter was also investigated at deep dose equivalents of 0.05, 0.15, and 0.25 Sv using 60Co and 137Cs sources as the second main objective. All dosimeters were annealed following exposure and then exposed to 5.0 mSv from a 90Sr source. In all cases, the dosimeters responded within 3% of the delivered dose, indicating that the dosimeters remained functional as defined by naval dosimetry requirements. However, the anneal time required to clear the thermoluminescent dosimeter's reading was found to increase approximately as the cube root with the delivered dose.

STI-GMaS: an open-source environment for simulation of sexually-transmitted infections.

BACKGROUND: Sexually-transmitted pathogens often have severe reproductive health implications if treatment is delayed or absent, especially in females. The complex processes of disease progression, namely replication and ascension of the infection through the genital tract, span both extracellular and intracellular physiological scales, and in females can vary over the distinct phases of the menstrual cycle. The complexity of these processes, coupled with the common impossibility of obtaining comprehensive and sequential clinical data from individual human patients, makes mathematical and computational modelling valuable tools in developing our understanding of the infection, with a view to identifying new interventions. While many within-host models of sexually-transmitted infections (STIs) are available in existing literature, these models are difficult to deploy in clinical/experimental settings since simulations often require complex computational approaches. RESULTS: We present STI-GMaS (Sexually-Transmitted Infections - Graphical Modelling and Simulation), an environment for simulation of STI models, with a view to stimulating the uptake of these models within the laboratory or clinic. The software currently focuses upon the representative case-study of Chlamydia trachomatis, the most common sexually-transmitted bacterial pathogen of humans. Here, we demonstrate the use of a hybrid PDE-cellular automata model for simulation of a hypothetical Chlamydia vaccination, demonstrating the effect of a vaccine-induced antibody in preventing the infection from ascending to above the cervix. This example illustrates the ease with which existing models can be adapted to describe new studies, and its careful parameterisation within STI-GMaS facilitates future tuning to experimental data as they arise. CONCLUSIONS: STI-GMaS represents the first software designed explicitly for in-silico simulation of STI models by non-theoreticians, thus presenting a novel route to bridging the gap between computational and clinical/experimental disciplines. With the propensity for model reuse and extension, there is much scope within STI-GMaS to allow clinical and experimental studies to inform model inputs and drive future model development. Many of the modelling paradigms and software design principles deployed to date transfer readily to other STIs, both bacterial and viral; forthcoming releases of STI-GMaS will extend the software to incorporate a more diverse range of infections.

Congenitally corrected transposition and degenerative severe aortic stenosis.

Congenitally corrected transposition is a rare cardiac anomaly characterized by the combination of discordant atrioventricular and ventriculoarterial connections. Young patients with this lesion can present with congestive cardiac failure, usually secondary to a large ventricular septal defect or pulmonary stenosis. We report here our experience with a lady aged 79, admitted to our unit because of deterioration of her congestive cardiac failure as a consequence of uncorrected congenitally corrected transposition associated with degenerative severe aortic stenosis.

Uptake rates of thorium progeny in a semiarid environment.

The release rates and transformation processes that influence the mobility, biological uptake, and transfer of radionuclides are essential to the assessment of the health effects in the food chain and ecosystem. This study examined concentrations of 222Th in both soil and vegetation at a closed military training site, Kirtland Air Force Base (KAFB), New Mexico. Brazilian sludge was intentionally introduced into the topsoil in the early 1960s to simulate nuclear weapon accidents. Soil (60) and vegetation (120) samples were collected from 1996 to 2000 and analyzed for radionuclides and progeny. High-resolution gamma-ray spectroscopy was used to determine radionuclide activities. The results indicate that the thorium progeny were the predominant contaminant in soil and vegetation. Concentration ratios (CRs) were calculated based on actinium levels.