Inflammation propagation modeled as a reaction-diffusion wave.

Inflammation is a physiological process aimed to protect the organism in various diseases and injuries. This work presents a generic inflammation model based on the reaction-diffusion equations for the concentrations of uninflamed cells, inflamed cells, immune cells and the inflammatory cytokines. The analysis of the model shows the existence of three different regimes of inflammation progression depending on the value of a parameter R called the inflammation number. If R>1, then inflammation propagates in cell culture or tissue as a reaction-diffusion wave due to diffusion of inflammatory cytokines produced by inflamed cells. If 0

Effect of permeability on the initiation of Atherosclerosis modeled as an inflammatory process.

This work presents a mathematical model, based on partial differential equations, that analyzes the inflammatory stage of atherosclerosis. Four leading players are taken into consideration: Low Density Lipoproteins, oxidized Low Density Lipoproteins, immune cells and the inflammatory cytokines. In addition to this, the permeability of the endothelial layer is taken into account in the model. A stability analysis of the fixed points of the kinetic system is presented in details followed by the proof of existence of traveling wave solutions of the system of partial differential equations. The mathematical analysis leads to a biological interpretation. We distinguish three main cases of the disease state that correlate with the permeability of the endothelial layer. In fact, having a low permeability indicates the disease free state since no chronic inflammatory reaction occurs due to the non initiation of the inflammation. With intermediate permeability, a wave propagation corresponding to a chronic inflammatory reaction might occur whether the initial perturbation overcomes a threshold or not. With high permeability, even a small perturbation of the disease free state leads to a chronic inflammatory reaction represented by a wave propagation. We perform numerical simulations of the solutions to illustrate the biological results.

Is there a benefit of antenatal corticosteroid when given < 48 h before delivery?

OBJECTIVE: We assessed the association between a short antenatal corticosteroid administration-to-birth interval and neonatal outcome. STUDY DESIGN: A retrospective study was conducted between 2010 and 2020. Eligible cases were singleton preterm live-born neonates born between 24-0/7 and 33-6/7 weeks of gestation and were initiated an ACS course of betamethasone. We divided the first 48 h following the first ACS administration to four time intervals and compared each time interval to those born more than 48 h following ACS administration. The primary outcome was a composite of adverse neonatal outcome, including neonatal mortality or any major neonatal morbidity. RESULTS: A total of 200 women gave birth less than 48 h from receiving the first betamethasone injection, and 172 women gave birth within 2-7 days (48-168 h) from ACS administration. Composite adverse neonatal outcome was higher for neonates born less than 12 h from initial ACS administration compared to neonates born 2-7 days from the first betamethasone injection (55.45% vs. 29.07%, OR 3.45 95% CI [2.02-5.89], p value < 0.0001). However, there was no difference in composite adverse neonatal outcomes between neonates born 12-48 h following ACS administration and those born after 2-7 days. That was also true after adjusting for confounders. CONCLUSIONS: 12-24 h following ACS administration may be sufficient in reducing the same risk of neonatal morbidities as > 48 h following ACS administration. It may raise the question regarding the utility of the second dose of ACS.

Transient fetal hypertrichosis - Three cases.

We Summarize a three cases of transient fetal hypertrichosis in low risk preganant women. Hypertrichosis has been previously associated with over 140 different syndromes (OMIM); however this finding is rarely described in prenatal ultrasound. In this study we describe the finding of hypertrichosis which resolved later in gestation. CASE N1: A prominent unibrow (synophrys) and elongated eyelashes were noted at 24 weeks of gestation with no other abnormal features. CASE N 2: A prenatal ultrasound scan was performed at 24 weeks and revealed: horseshoe kidney and localized hypertrichosis on the lower back. CASE N 3: Ultrasound exam at 24 weeks of gestation demonstrated localized hypertrichosis on the chin. CONCLUSION: Transient localized hypertrichosis with no other major findings has a favorable prenatal outcome.

Mathematical modeling of atherogenesis: Atheroprotective role of HDL.

Atherosclerosis is a chronic inflammatory cardiovascular disease in which arteries harden through the build-up of plaques. This work is devoted to the mathematical modeling and analysis of the inflammatory process of atherosclerosis. We propose a mathematical model formed by three coupled partial differential equations of reaction-diffusion type. We take into account three key-role players: the inflammatory immune cells, the inflammatory cytokines and the oxidized low density lipoproteins. A stability analysis of the kinetic system is performed. It leads to the presence of three stable fixed points relevant to appropriate biological states of atherogenesis; no inflammation, stabilized inflammation (stable plaque) and advanced inflammation (vulnerable plaque). The cases that may occur are subject to the variation of the parameters values. A detailed discussion showing how the model fits the biological phenomena is then established. We investigate as well the existence of solutions of traveling waves type along with numerical simulations that show the wave propagation in different cases. This shows that the inflammatory process propagates inside the intima as a traveling wave. Then, we consider the effect of high density lipoprotein (HDL) on the atherosclerotic plaque formation. To do that, we elaborate a map that determines the level of risk of plaque formation with respect to the prevalence of HDL in the blood. These results confirm but also generalize previous results published in the literature. They also give a deeper understanding to the propagation of the inflammation inside the artery in terms of the interplay among the different main players in the whole process.

Differential effect of frequency and duration of mechanical loading on fetal chick cartilage and bone development.

Developmental engineering strategies aim to recapitulate aspects of development in vitro as a means of forming functional engineered tissues, including cartilage and bone, for tissue repair and regeneration. Biophysical stimuli arising from fetal movements are critical for guiding skeletogenesis, but there have been few investigations of the biomechanical parameters which optimally promote cartilage and bone development events in in vitro explants. The effect of applied flexion-extension movement frequencies (0.33 and 0.67 Hz) and durations (2 h periods, 1, 2 or 3 × per day) on knee (stifle) joint cartilage shape, chondrogenesis and diaphyseal mineralisation of fetal chick hindlimbs, cultured in a mechanostimulation bioreactor, were assessed both quantitatively and qualitatively. It was hypothesised that increasing frequency and duration of movements would synergistically promote cartilage and bone formation in a dose-dependent manner. Increasing loading duration promoted cartilage growth, shape development and mineralisation of the femoral condyles and tibiotarsus. While increasing frequency had a significant positive effect on mineralisation, hyaline cartilage growth and joint shape were unaffected by frequency change within the ranges assessed, and there were limited statistical interactions between the effects of movement frequency and duration on cartilage or bone formation. Increased glycosaminoglycan deposition and cell proliferation may have contributed to the accelerated cartilage growth and shape change under increasing loading duration. The results demonstrated that frequencies and durations of applied biomechanical stimulation differentially promoted cartilage and bone formation, with implications for developmentally inspired tissue engineering strategies aiming to modulate tissue construct properties.

Testing for latent tuberculosis infection using interferon gamma release assays in commercial sex workers at an outreach clinic in Birmingham.

This report demonstrates that using interferon gamma release assays to screen for latent tuberculosis infection in female commercial sex workers in an outreach sexual health clinic is feasible and acceptable. Routine interferon gamma release assay use successfully identified high numbers of latent tuberculosis infection. Innovative approaches to treatment and follow up were required to improve treatment adherence in this group. Direct observation of therapy within the sexual health clinic was also feasible. Successful follow up was dependent on the support of outreach workers, interpreters and tuberculosis nurses.

Foley balloon catheter to prevent or manage bleeding during treatment for cervical and Cesarean scar pregnancy.

OBJECTIVE: To demonstrate the efficacy of placement and inflation of Foley balloon catheters prophylactically to prevent, or as an adjuvant therapy to control, bleeding in women undergoing treatment for Cesarean scar pregnancy (CSP) or cervical pregnancy (CxP). METHODS: This was a retrospective study of 18 women with either CSP (n = 16) or CxP (n = 2), who underwent Foley balloon catheter placement under continuous transvaginal or transabdominal ultrasound guidance to prevent or manage bleeding following treatment, which in most cases comprised local (intragestational sac) and intramuscular (IM) methotrexate (MTX) injections. In eight cases, the balloon catheter was placed immediately following local and/or IM MTX treatment, either because of bleeding or prophylactically; in eight cases, the catheter was placed as part of a two-step protocol, with patients first treated with local and IM MTX injection, then suction aspiration on Day 4 or 5, followed by planned insertion of a balloon catheter; in one patient the balloon was placed on Day 21 after local and IM MTX treatment, due to sudden bleeding; and in one case of a heterotopic pregnancy, one intrauterine and one cervical, the balloon was placed due to severe bleeding. Human chorionic gonadotropin (hCG) levels were evaluated weekly following MTX injection. RESULTS: Gestational ages at balloon placement ranged between 5 and 12 + 2 weeks. All embryos/fetuses, with the exception of the cervical heterotopic one, had heart activity and catheter placement was well-tolerated by all women. The balloon tamponade effectively reduced or prevented maternal vaginal bleeding in all except one patient; this woman had a heterotopic CxP and required abdominal robotic cerclage to control the bleeding. Catheters were kept in place for a mean of 3.6 (range, 1-6) days. hCG levels returned to low or zero levels within 19-82 days following MTX injection. Fifteen women required antibiotic treatment following the procedure. One woman with CSP developed an arteriovenous malformation requiring uterine artery embolization. CONCLUSION: Ultrasound-guided placement and inflation of Foley balloon catheters was easy to perform and well-tolerated by patients undergoing treatment for CSP or CxP, and successfully prevented or helped in the management of bleeding complications. Based on our experience and previous publications we suggest having the option of balloon catheter insertion available when local treatment of CSP or CxP is undertaken.

Prevalence of Trichomonas vaginalis, Mycoplasma genitalium and Ureaplasma urealyticum in men with urethritis attending an urban sexual health clinic.

We conducted a study to determine the prevalence of Trichomonas vaginalis (TV), Mycoplasma genitalium (MG) and Ureaplasma urealyticum (UU) in men with urethritis, attending an urban sexual health clinic, in order to inform screening and treatment policies. Men attending an urban sexual health clinic between June 2011 and January 2012 were evaluated. Urine samples were collected from men with urethritis and tested for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC) and TV using transcription-mediated amplification and for MG and UU using polymerase chain reaction. Eighty-three samples were analysed. The prevalence of CT was 33.7% (28/83), GC was 16.8% (14/83), TV was 3.6% (3/83), MG was 12.0% (10/83) and UU was 4.8% (4/83). Fifteen men had recurrent urethritis. Of these, three were found to have had TV, five to have had MG and none to have had UU, at initial presentation. Given the prevalence of MG in this study, there is an urgent need for further larger studies looking at optimal treatment regimens and screening strategies in urethritis.

Modeling circadian clock-cell cycle interaction effects on cell population growth rates.

The circadian clock and the cell cycle are two tightly coupled oscillators. Recent analytical studies have shown counter-intuitive effects of circadian gating of the cell cycle on growth rates of proliferating cells which cannot be explained by a molecular model or a population model alone. In this work, we present a combined molecular-population model that studies how coupling the circadian clock to the cell cycle, through the protein WEE1, affects a proliferating cell population. We show that the cell cycle can entrain to the circadian clock with different rational period ratios and characterize multiple domains of entrainment. We show that coupling increases the growth rate for autonomous periods of the cell cycle around 24 h and above 48 h. We study the effect of mutation of circadian genes on the growth rate of cells and show that disruption of the circadian clock can lead to abnormal proliferation. Particularly, we show that Cry 1, Cry 2 mutations decrease the growth rate of cells, Per 2 mutation enhances it and Bmal 1 knockout increases it for autonomous periods of the cell cycle less than 21 h and decreases it elsewhere. Combining a molecular model to a population model offers new insight on the influence of the circadian clock on the growth of a cell population. This can help chronotherapy which takes benefits of physiological rhythms to improve anti-cancer efficacy and tolerance to drugs by administering treatments at a specific time of the day.

Reaction-diffusion model of atherosclerosis development.

Atherosclerosis begins as an inflammation in blood vessel walls (intima). The inflammatory response of the organism leads to the recruitment of monocytes. Trapped in the intima, they differentiate into macrophages and foam cells leading to the production of inflammatory cytokines and further recruitment of white blood cells. This self-accelerating process, strongly influenced by low-density lipoproteins (cholesterol), results in a dramatic increase of the width of blood vessel walls, formation of an atherosclerotic plaque and, possibly, of its rupture. We suggest a 2D mathematical model of the initiation and development of atherosclerosis which takes into account the concentration of blood cells inside the intima and of pro- and anti-inflammatory cytokines. The model represents a reaction-diffusion system in a strip with nonlinear boundary conditions which describe the recruitment of monocytes as a function of the concentration of inflammatory cytokines. We prove the existence of travelling waves described by this system and confirm our previous results which suggest that atherosclerosis develops as a reaction-diffusion wave. The theoretical results are confirmed by the results of numerical simulations.

Maternal lipopolysaccharide alters the newborn oxidative stress and C-reactive protein levels in response to an inflammatory stress.

Maternal infection is associated with oxidative stress (OS) and inflammatory responses. We have previously shown that maternal exposure to lipopolysaccharide (LPS) at E18 alters the subsequent offspring immune response. As immune responses are mediated, in part, by OS, we sought to determine if maternal inflammation during pregnancy programs offspring OS and C-reactive protein (CRP) levels. Pregnant Sprague-Dawley rats received intraperitoneal (i.p.) injections of saline or LPS at 18 days' gestation (n = 4), and pups delivered spontaneously at term. At postnatal day 24, male and female offspring received i.p. injection of LPS. Serum lipid peroxides formation (PD) and CRP levels were determined before and at 4 h following the LPS injection. Pups of LPS-exposed dams had significantly higher basal OS (PD 29.4 ± 5.4 v. 10.1 ± 4.8 nmol/ml) compared with controls. In response to LPS, CRP levels (20.4 ± 2.8 v. 5.7 ± 1.0 ng/ml) were significantly higher among pups of LPS-exposed dams than controls. Prenatal maternal exposure to LPS increases baseline OS levels in neonates and CRP levels in response to LPS. These results suggest that maternal inflammation during the antenatal period may induce long-term sequelae in the offspring that may predispose to adult disease.

Mathematical modelling of atherosclerosis as an inflammatory disease.

Atherosclerosis is an inflammatory disease. The atherosclerosis process starts when low-density lipoproteins (LDLs) enter the intima of the blood vessel, where they are oxidized (ox-LDLs). The anti-inflammatory response triggers the recruitment of monocytes. Once in the intima, the monocytes are transformed into macrophages and foam cells, leading to the production of inflammatory cytokines and further recruitment of monocytes. This auto-amplified process leads to the formation of an atherosclerotic plaque and, possibly, to its rupture. In this paper we develop two mathematical models based on reaction-diffusion equations in order to explain the inflammatory process. The first model is one-dimensional: it does not consider the intima's thickness and shows that low ox-LDL concentrations in the intima do not lead to a chronic inflammatory reaction. Intermediate ox-LDL concentrations correspond to a bistable system, which can lead to a travelling wave that can be initiated by certain conditions, such as infection or injury. High ox-LDL concentrations correspond to a monostable system, and even a small perturbation of the non-inflammatory case leads to travelling-wave propagation, which corresponds to a chronic inflammatory response. The second model we suggest is two-dimensional: it represents a reaction-diffusion system in a strip with nonlinear boundary conditions to describe the recruitment of monocytes as a function of the cytokines' concentration. We prove the existence of travelling waves and confirm our previous results, which show that atherosclerosis develops as a reaction-diffusion wave. The results of the two models are confirmed by numerical simulations. The latter show that the two-dimensional model converges to the one-dimensional one if the thickness of the intima tends to zero.

Mastitis caused by Yersinia pseudotuberculosis in Israeli dairy cattle and public health implications.

Yersinia pseudotuberculosis was isolated from mastitis cases in nine dairy cows in Israel. Six cases occurred on one farm (three instances of two cows, 2 months apart) and three cases on one farm each. Seven cows suffered from clinical and two from subclinical mastitis. All but two of the cows were culled. The literature describing cases of bovine mastitis caused by Y. pseudotuberculosis is reviewed and the human public health implications are discussed.

Peripheral polymorphonuclear leukocyte priming contributes to oxidative stress in early pregnancy.

OBJECTIVE: The cause of elevated blood leukocyte count in pregnancy is unknown. We hypothesized that priming of peripheral polymorphonuclear leukocytes (PMNL) caused this elevation. METHODS: Eleven women in the first trimester of pregnancy were included in this prospective study. Peripheral venous blood was drawn twice from each woman, before and after a medical abortion (pregnant and nonpregnant, respectively). Complete blood cell count, plasma alkaline phosphatase (ALP), and rate of superoxide release from separated phobrol 12-myristate-13-acetate (PMA)-stimulated PMNL were determined. RESULTS: The PMNL count in early pregnancy was significantly higher, with a significant increase in the PMNL rate of superoxide release compared to the nonpregnant state. A linear correlation between the rates of superoxide release and PMNL counts before and during pregnancy was found. ALP levels were significantly elevated in early pregnancy. CONCLUSION: The increased PMNL count is probably a compensatory response to PMNL priming. The increased rate of superoxide release from primed PMNL may contribute to oxidative stress in early pregnancy.

Macrophage recruitment and activation: a model for comparing resistance to Salmonella enteritidis in different broiler breeds.

A model for comparing resistance to Salmonella Enteritidis was evaluated in different broiler breeds. The recruitment and phagocytic activity of peritoneal macrophages were assessed in three different broiler breeds (A, B and C) which are farmed world-wide. Assessment was performed after three days of intraperitoneal (i.p.) administration of 3% Sephadex G-200 (10 ml), initiated at twenty-one days of age, followed by contact with i.p. live S. Enteritidis (10 ml, 1.2 x 10(8) colony forming units/ml) for 45 min. Assessment included determination of the number of i.p. macrophages recruited, the number of i.p. phagocytized S. Enteritidis cells per macrophage, the levels of degranulated i.p. beta-glucuronidase and beta-galactosidase, and the count of surviving S. Enteritidis cells. Confirmation of the significance of the model was obtained by comparing resistance to field infection by S. Enteritidis in the three broiler breeds. The recruitment of i.p. macrophages in response to challenge with Sephadex and S. Enteritidis was significantly higher (P < 0.05) in birds of breed A (mean cumulative i.p. macrophage count, in 10 fields of microscopic slide smear magnified at x1,000, was equal to 81.7), compared to recruitment in birds of breed B (33.3) or breed C (41.2). The mean number of phagocytized S. Enteritidis cells per i.p. macrophage in birds of breed A (2.68) was significantly higher (P < 0.05) than in breed B (0.83) and insignificantly higher (P > 0.05) than in breed C (2.35). In addition, the highest level of recruitment and phagocytic activity of macrophages, in birds of breed A, was associated with a higher significant mean i.p. beta-glucuronidase activity (10,425.5 units/ml) than in breed B (3,438.2 units/ml) or breed C (3,356.94 units/ml) (P < 0.05). Moreover, birds of breed A demonstrated a higher mean i.p. beta-galactosidase activity (2.225 units/ml) than birds of breed B (0.852 units/ml) or breed C (1.852 units/ml) (P > 0.05). The higher level of recruitment and activity of i.p. macrophages and the higher rate of degranulation of i.p. enzymes in breed A were associated with a greater number of surviving i.p. S. Enteritidis cells. In response to outbreaks of S. Enteritidis in the field, the average mortality was significantly higher in flocks of breed A (3.2%) than in flocks of breed B (1.2%) or breed C (0.96%) (P < 0.05). These data provide an indication of the significance of the model in reflecting the differences in resistance of S. Enteritidis of broiler breeds reared in a farm environment.