A multiscale model of the electrohysterogram the BioModUE_PTL project.

The electrohysterogram (EHG) is a promising means of monitoring pregnancy and of detecting a risk of preterm labor. To improve our understanding of the EHG as well as its relationship with the physiologic phenomena involved in uterine contractility, we plan to model these phenomena in terms of generation and propagation of uterine electrical activity. This activity can be realistically modeled by representing the principal ionic dynamics at the cell level, the propagation of electrical activity at the tissue level and then the way it is reflected on the skin surface through the intervening tissue. We present in this paper the different steps leading to the development and validation of a biophysics based multiscale model of the EHG, going from the cell to the electrical signal measured on the abdomen.

Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment.

Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1, encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1. Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.

Bivariate piecewise stationary segmentation; improved pre-treatment for synchronization measures used on non-stationary biological signals.

Analysis of synchronization between biological signals can be helpful in characterization of biological functions. Many commonly used measures of synchronicity assume that the signal is stationary. Biomedical signals are however often strongly non stationary. We propose to use a bivariate piecewise stationary pre-segmentation (bPSP) of the signals of interest, before the computation of synchronization measures on biomedical signals to improve the performance of standard synchronization measures. In prior work we have shown how this can be achieved by using the auto-spectrum of either one of the signals under investigation. In this work we show how major improvements of the performance of synchronization measures can be achieved using the cross-spectrum of the signals to detect stationary changes which occur independently in either signal. We show on synthetic as well as on real biological signals (epileptic EEG and uterine EMG) that the proposed bPSP approach increases the accuracy of the measures by making a good tradeoff between the stationarity assumption and the length of the analyzed segments, when compared to the classical windowing method.

Gastrointestinal Mucormycosis following a Streptococcus pyogenes Toxic Shock Syndrome in a Previously Healthy Patient: A Case Report.

Mucormycosis is an uncommon opportunistic infection and the gastrointestinal form is the rarest. Rhizopus sp. is the most frequent pathogen and infection occurs almost exclusively in immunocompromised patients. We describe the first case of intestinal mucormycosis occurring after a Streptococcus pyogenes toxic shock syndrome in a previously healthy patient caused by Rhizopus microsporus var. azygosporus.

Differential expression of the enzymatic system controlling synthesis, metabolism, and transport of PGF2 alpha in human fetal membranes.

The present study investigated the expression of genes and proteins associated with PGF2alpha biosynthesis, catabolism, and transport in matched amnion and choriodecidua of human term placenta. The concentration of PGF2alpha within fetal membranes depends on the balance between complex enzymatic systems responsible for, respectively, its synthesis-by prostaglandin-endoperoxide synthase 2 (PTGS2) and members of the aldo-keto reductase (AKR) family, AKR1C3 and AKR1B1-and its catabolic inactivation-through hydroxy-prostaglandin-dehydrogenase (HPGD). We observed that AKR1C3 shows equal basal expression (mRNA and protein) in choriodecidua and amnion but that AKR1B1 exhibits preferential expression in the choriodecidua. Expression of HPGD and solute carrier organic anion transporter family member 2A1 (SLCO2A1) was found primarily in the choriodecidua. We also evaluated whether an inflammatory environment induced by the gram-negative bacterial endotoxin lipopolysaccharide (LPS) affects expression of each candidate enzymes. The amnion responded to LPS with a small but significant decrease of AKR1B1 mRNA expression. In contrast, we found a significant increase in PTGS2 and AKR1C3 mRNA expression in choriodecidua after LPS challenge, but such regulation was confirmed only at protein levels for PTGS2 and not for AKR1C3. Our results suggest that the choriodecidua appears to be the main tissue, which expresses maximally all the components (synthesis, degradation, and transport) controlling PGF2alpha levels.

Mathematical modeling of electrical activity of uterine muscle cells.

The uterine electrical activity is an efficient parameter to study the uterine contractility. In order to understand the ionic mechanisms responsible for its generation, we aimed at building a mathematical model of the uterine cell electrical activity based upon the physiological mechanisms. First, based on the voltage clamp experiments found in the literature, we focus on the principal ionic channels and their cognate currents involved in the generation of this electrical activity. Second, we provide the methodology of formulations of uterine ionic currents derived from a wide range of electrophysiological data. The model is validated step by step by comparing simulated voltage-clamp results with the experimental ones. The model reproduces successfully the generation of single spikes or trains of action potentials that fit with the experimental data. It allows analyzing ionic channels implications. Likewise, the calcium-dependent conductance influences significantly the cellular oscillatory behavior.

AIDS patient death caused by novel Cryptococcus neoformans x C. gattii hybrid.

Interspecies hybrids of Cryptococcus neoformans and C. gattii have only recently been reported. We describe a novel C. neoformans x C. gattii hybrid strain (serotype AB) that was previously described as C. gattii and that caused a lethal infection in an AIDS patient from Canada.

Ridge extraction from the time-frequency representation (TFR) of signals based on an image processing approach: application to the analysis of uterine electromyogram AR TFR.

Time-frequency representations (TFRs) of signals are increasingly being used in biomedical research. Analysis of such representations is sometimes difficult, however, and is often reduced to the extraction of ridges, or local energy maxima. In this paper, we describe a new ridge extraction method based on the image processing technique of active contours or snakes. We have tested our method on several synthetic signals and for the analysis of uterine electromyogram or electrohysterogram (EHG) recorded during gestation in monkeys. We have also evaluated a postprocessing algorithm that is especially suited for EHG analysis. Parameters are evaluated on real EHG signals in different gestational periods. The presented method gives good results when applied to synthetic as well as EHG signals. We have been able to obtain smaller ridge extraction errors when compared to two other methods specially developed for EHG. The gradient vector flow (GVF) snake method, or GVF-snake method, appears to be a good ridge extraction tool, which could be used on TFR of mono or multicomponent signals with good results.

Fatal zygomycosis caused by Mucor indicus in a child with an implantable left ventricular assist device.

Mucor indicus is a rare, emerging cause of zygomycosis with 7 cases previously reported since 1975. We report the first case of endovascular M. indicus infection in a pediatric recipient of the Incor (Berlin Heart AG, Germany) implantable left ventricular assist device, and review the literature to describe the broadening clinical spectrum of zygomycosis caused by this emerging fungal pathogen.

Epidemiology and antifungal susceptibility of bloodstream Candida isolates in Quebec: Report on 453 cases between 2003 and 2005.

BACKGROUND: Between May 2003 and April 2005, a population-based surveillance of Candida bloodstream infections was conducted in Quebec. A total of 453 episodes of candidemia (464 yeast isolates) from 54 participating hospitals were studied. RESULTS: The annual incidence rate was three per 100,000 population. Global hospital mortality was 38%. The most common predisposing factors were the presence of an intravascular catheter (80%), use of antibacterial therapy (67%), stay in an intensive care unit (49%), use of parenteral nutrition (32%) and intra-abdominal surgery (31%). Fluconazole alone or in association with other antifungals was used for treatment in over 80% of cases. Candida albicans comprised 62% of isolates, followed by Candida glabrata (17%), Candida parapsilosis (9%), Candida tropicalis (5%), Candida lusitaniae (3%) and Candida krusei (3%). Of the 288 C albicans isolates, seven (2%) were resistant to flucytosine, one to fluconazole and none to itraconazole or voriconazole. Of the 75 non-C albicans species isolates with reduced susceptibility to fluconazole (minimum inhibitory concentration [MIC] 16 mug/mL or greater), none were susceptible to itraconazole (MIC 0.12 mg/L or lower), whereas 71 (95%) were susceptible to voriconazole (MIC 1 mug/mL or lower). However, only five of 12 (42%) fluconazole-resistant isolates were susceptible to voriconazole. Posaconazole, ravuconazole and caspofungin displayed a broad spectrum of activity against these isolates, with MICs of 1 mg/L or lower in 56%, 92% and 100% of isolates, respectively. Overall, a correlation (r(2)>0.87) was observed among increasing fluconazole MICs and the geometric mean MICs of itraconazole, voriconazole, posaconazole and ravuconazole. CONCLUSIONS: These surveillance results when compared with those of the 1993 to 1995 survey confirm little variation in the distribution of species causing invasive Candida infection over a 10-year period in Quebec, as well as the continuous excellent overall in vitro activity of fluconazole.

Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium.

BACKGROUND: Studies on the human myometrium have reported on different microarrays containing different sets of genes or ESTs. However each study profiled only a small number of patients due to various constraints. More profiling information would be an addition to our knowledge base of parturition. METHODS: We compiled from five human studies, transcriptional differences between the non pregnant myometrium (NP), preterm myometrium (PTNIL), term myometrium not in labor (TNIL) and term myometrium in labor (TIL). Software modules developed by the Draghici's group at Wayne State University (Detroit, MI, USA) were used to propose a hierarchical list of several KEGG pathways most likely adjusted to changes observed in microarray experiments. RESULTS: The differential expression of 118 genes could be dispatched in 14 main KEGG pathways that were the most representative of the changes seen in NP and PTNIL, versus TNIL or TIL. Despite the potential of multiple pitfalls inherent to the use of the microarray technology, gene module analysis of the myometrial transcriptome reveals the activation of precise signaling pathways, some of which may have been under evaluated. CONCLUSION: The remodelling and maturation processes that the uterus undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. It is attested by the nature of the main signaling pathways represented, in the comparison of the PTNIL versus TNIL uterus. Comparatively, the onset of labor is a phenomenon which remains less well characterized by these methods of analysis, possibly because it is a phenomenon occurring in too short a window to have been grasped by the studies carried out up to now.

Preterm labour detection by use of a biophysical marker: the uterine electrical activity.

BACKGROUND: The electrical activity of the uterine muscle is representative of uterine contractility. Its characterization may be used to detect a potential risk of preterm delivery in women, even at an early gestational stage. METHODS: We have investigated the effect of the recording electrode position on the spectral content of the signal by using a mathematical model of the women's abdomen. We have then compared the simulated results to actual recordings. On signals with noise reduced with a dedicated algorithm, we have characterized the main frequency components of the signal spectrum in order to compute parameters indicative of different situations: preterm contractions resulting nonetheless in term delivery (i.e. normal contractions) and preterm contractions leading to preterm delivery (i.e. high-risk contractions). A diagnosis system permitted us to discriminate between these different categories of contractions. As the position of the placenta seems to affect the frequency content of electrical activity, we have also investigated in monkeys, with internal electrodes attached on the uterus, the effect of the placenta on the spectral content of the electrical signals. RESULTS: In women, the best electrode position was the median vertical axis of the abdomen. The discrimination between high risk and normal contractions showed that it was possible to detect a risk of preterm labour as early as at the 27th week of pregnancy (Misclassification Rate range: 11-19.5%). Placental influence on electrical signals was evidenced in animal recordings, with higher energy content in high frequency bands, for signals recorded away from the placenta when compared to signals recorded above the placental insertion. However, we noticed, from pregnancy to labour, a similar evolution of the frequency content of the signal towards high frequencies, whatever the relative position of electrodes and placenta. CONCLUSION: On human recordings, this study has proved that it is possible to detect, by non-invasive abdominal recordings, a risk of preterm birth as early as the 27th week of pregnancy. On animal signals, we have evidenced that the placenta exerts a local influence on the characteristics of the electrical activity of the uterus. However, these differences have a small influence on premature delivery risk diagnosis when using proper diagnosis tools.

In vitro and in vivo pharmacological characterization of ethyl-4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl)amino]-phenoxy]propyl) amino]cyclohexyl]benzoate hydrochloride (SAR150640), a new potent and selective human beta3-adrenoceptor agonist for the treatment of preterm labor.

Ethyl-4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl)amino] phenoxy]propyl) amino]cyclohexyl]benzoate hydrochloride (SAR150640) was characterized as a new potent and selective beta(3)-adrenoceptor agonist for the treatment of preterm labor. SAR150640 and its major metabolite, the corresponding acid 4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl) amino] phenoxy]propyl)amino]cyclohexyl]benzoic acid (SSR500400), showed high affinity for beta(3)-adrenoceptors (K(i) = 73 and 358 nM) and greater potency than (-)-isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma cells (SKNMC), which express native beta(3)-adrenoceptors (pEC(50) = 6.5, 6.2, and 5.1, respectively). SAR150640 and SSR500400 also increased cAMP production in membrane preparations from human uterine smooth muscle cells (UtSMC), which also express native beta(3)-adrenoceptors (pEC(50) = 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca(2+) mobilization and extracellular signal-regulated kinase 1/2 phosphorylation. SAR150640 and SSR500400 had no beta(1)- or beta(2)-agonist or antagonist activity in guinea pig atrium and trachea, or in human isolated atrium and bronchus preparations. Both compounds concentration-dependently inhibited spontaneous contractions in human near-term myometrial strips, with greater potency than salbutamol and 4-[3-[(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) (pIC(50) = 6.4, 6.8, 5.9, and 5.8, respectively), but with similar potency to (-)-isoproterenol and atosiban (oxytocin/vasopressin V(1)a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and prostaglandin F(2alpha). In vivo, after intravenous administration, SAR150640 (1 and 6 mg/kg), but not atosiban (6 mg/kg), dose-dependently inhibited myometrial contractions in conscious unrestrained female cynomolgus monkeys, with no significant effects on heart rate or blood pressure. In contrast, salbutamol (50 and 250 microg/kg) had no inhibitory effect on uterine contractions, but it dose-dependently increased heart rate. These findings indicate a potential for the therapeutic use of SAR150640 in mammals during preterm labor.

Oxidative stress-inducible antioxidant adaptive response during prostaglandin F2alpha-induced luteal cell death in vivo.

Oxidative stress-induced antioxidant adaptive response would be particularly important to cells in high reactive oxygen species (ROS) environments. We aimed to determine the dynamic adaptive response of antioxidant enzymatic systems in sheep corpus luteum (CL) during PGF2alpha-induced luteal cell death. Activities of superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GSR), and in situ DNA fragmentation were determined in CL at day 10 of the estrous cycle (0 h) and at 12, 24 or 48 h after PGF2alpha injection. A decrease in plasma progesterone concentration was first observed at 6 h after treatment (P < 0.05). Apoptotic cells were rarely observed in the CL at 0 h (less than 0.7%), and their incidence increased (P < 0.01) by 12 h post-PGF2alpha (11.7%) and remained thereafter elevated through 48 h. Activities of SOD1, SOD2, GPX and GSR were not changed at any time points after PGF2alpha treatment. CAT activity increased at 12 h (P < 0.01) and at 24 h (P < 0.05) after PGF2alpha treatment as compared to that at 0 h. These findings demonstrate that PGF2alpha induce luteal cell death without depressing the activity of antioxidant enzymes. It is suggested that transient increase in CAT activity is an adaptive response of the CL to oxidative stress induced by PGF2alpha.

PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation.

The aim of this study was to explore the anti-inflammatory properties of phosphodiesterase-4 (PDE4) inhibitors in vivo and their potential ability to prevent inflammation-induced preterm delivery. Indeed, intrauterine inflammation is the major etiology of very preterm delivery, the leading cause of neonatal mortality and morbidity. Intrauterine injection of Escherichia coli LPS in 15-day-pregnant mice induced an increase of PDE4 activity and PDE4B expression at the maternofetal interface, a rise of amniotic fluid levels of TNF-alpha, IL-1beta, IL-6, and IL-10 and provoked massive preterm delivery and fetal demise. Selective PDE4 inhibition by rolipram prevented the rise in the proinflammatory cytokines. Following the nuclear translocation of the transcription factor NFkappaB, as a marker of cellular activation after the inflammatory challenge, showed a time-dependent sequential activation of the gestational tissues, from the uterine mesometrial to the fetal compartment, particularly in the glycogen-trophoblastic cells of the placenta. This activation was disrupted by PDE4 inhibition, and inflammation-induced preterm delivery and fetal demise were prevented. PDE4 selective inhibitors may thus represent a novel effective treatment to delay inflammation-induced preterm delivery and to prevent adverse outcomes in infants.

Hospital-acquired phaeohyphomycosis due to Exserohilum rostratum in a child with leukemia.

The present study describes a case of cutaneous phaeohyphomycosis caused by Exserohilum rostratum in a child undergoing treatment for leukemia. The infection was possibly due to contaminated intravenous dressings and was successfully treated with surgical excision combined with liposomal amphotericin B. Consequently, new infection control policies have been implemented at CHU Sainte-Justine (Montreal, Quebec).

Successful treatment of invasive Rhizopus infection in a child with thalassemia.

The accepted standard for treatment of zygomycetes is amphotericin B and surgical debridement, however recent data suggest that combined treatment modalities may be optimal. Newer anti-fungal agents show success in vitro and in animal models. We present the case of a 10-year-old boy with invasive Rhizopus microsporus var. rhizopodoformis who was successfully treated with a combination of modalities.

PDR16-mediated azole resistance in Candida albicans.

Many Candida albicans azole-resistant (AR) clinical isolates overexpress the CDR1 and CDR2 genes encoding homologous multidrug transporters of the ATP-binding cassette family. We show here that these strains also overexpress the PDR16 gene, the orthologue of Saccharomyces cerevisiae PDR16 encoding a phosphatidylinositol transfer protein of the Sec14p family. It has been reported that S. cerevisiae pdr16Delta mutants are hypersusceptible to azoles, suggesting that C. albicans PDR16 may contribute to azole resistance in these isolates. To address this question, we deleted both alleles of PDR16 in an AR clinical strain overexpressing the three genes, using the mycophenolic acid resistance flipper strategy. Our results show that the homozygous pdr16Delta/pdr16Delta mutant is approximately twofold less resistant to azoles than the parental strain whereas reintroducing a copy of PDR16 in the mutant restored azole resistance, demonstrating that this gene contributes to the AR phenotype of the cells. In addition, overexpression of PDR16 in azole-susceptible (AS) C. albicans and S. cerevisiae strains increased azole resistance by about twofold, indicating that an increased dosage of Pdr16p can confer low levels of azole resistance in the absence of additional molecular alterations. Taken together, these results demonstrate that PDR16 plays a role in C. albicans azole resistance.

Gene and protein expression in the myometrium in pregnancy and labor.

Microarray technologies widen our comprehension of the major structural and metabolic transformations which affect the myometrium from the very beginning of pregnancy until parturition. The results are coherent with the mass of information which was accumulated previously, primarily on the basis of studies of selected critical factors. They highlight the activation of precise signaling pathways, some of which may have been previously under evaluated. The remodelling and maturation processes that the myometrium undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. Comparatively, the onset of labor is perhaps the phenomenon which remains the least well described by these methods of analysis. Nevertheless, genomic studies constitute a necessary first step of orientation and help establishing new links between the generic signaling pathways that are activated during the normal or pathological gestation. These studies also represent an indicative step that will have to be paralleled, in the future, with the results of the systematic proteomic analysis of the myometrium.

Changes in activities of superoxide dismutase, nitric oxide synthase, glutathione-dependent enzymes and the incidence of apoptosis in sheep corpus luteum during the estrous cycle.

Anti-oxidative enzymes play a role in protecting cells from oxidative stress-induced cell death. The present study was conducted to evaluate whether the anti-oxidant and pro-oxidant enzymatic capacities of the sheep corpus luteum (CL) are correlated with steroidogenic and structural status of the gland during the estrous cycle. Steroidogenic activity, apoptosis and superoxide dismutase (SOD1 and SOD2), nitric oxide synthase (NOS), glutathione peroxidase (GPX), glutathione reductase (GSR) and glutathione S-transferase (GST) activities were determined in the CL at specific developmental stages of the luteal phase. The intensity of apoptotic DNA fragmentation, characteristic of physiological cell death, was much greater in CL at late luteal phase than at early and mid-luteal phase, concomitantly with the diminution in the plasma progesterone concentrations from mid-to late luteal phase. SOD1 and GPX activities increased from early to mid-luteal phase, and increased further at late luteal phase. SOD2 and GST activities were not different between early and mid-luteal phase, but increased at late luteal phase. GSR activity was not different between any luteal phase examined. NOS activity decreased from early to mid- and late luteal phase. These results show that the activities of SOD1, SOD2, NOS, GPX, GSR and GST in the sheep CL are subject to major changes during the estrous cycle, and that the anti-oxidant and pro-oxidant enzymatic capacities of luteal cells are not correlated with cell steroidogenic status and integrity during the late luteal phase.