Chronic murine myocarditis due to Trypanosoma cruzi: an ultrastructural study and immunochemical characterization of cardiac interstitial matrix

In an attempt to define the mouse-model for chronic Chagas' disease, a serological, histopathological and ultrastructural study as well as immunotyping of myocardium collagenic matrix were performed on Swiss mice, chronically infected with Trypanosoma cruzi strains: 21 SF and mambaí (Type II); PMN and Bolivia (Type III), spontaneously surviving after 154 to 468 days of infection. Haemagglutination and indirect immunofluorescence tests showed high titres of specific antibodies. The ultrastructural study disclosed the cellular constitution of the inflammatory infiltrate showing the predominance of monocytes, macrophages with intense phagocytic activity, fibroblasts, myofibroblasts and abundant collagen matrix suggesting the association of the inflammatory process with fibrogenesis in chronic chagasic cardiomyopathy. Artertolar and blood capillary alterations together with dissociation of cardiac cells from the capillary wall by edema and inflammation were related to ultrastructural lesions of myocardial cells. Rupture of parasitized cardiac myocells contribute to intensify the inflammatory process in focal areas. Collagen immunotyping showed the predominance of Types III and IV collagen. Collagen degradation and phagocytosis were present suggesting a reversibility of the fibrous process. The mouse model seems to be valuable in the study of the pathogenetic mechanisms in Chagas cardiomyopathy, providing that T. cruzi strains of low virulence and high pathogenecity are used.

Maladies infectieuses [Infectious diseases]

In 2008, several publications have highlighted the role of climate change and globalization on the epidemiology of infectious diseases. Studies have shown the extension towards Europe of diseases such as Crimea-Congo fever (Kosovo, Turkey and Bulgaria), leismaniosis (Cyprus) and chikungunya virus infection (Italy). The article also contains comments on Plasmodium knowlesi, a newly identified cause of severe malaria in humans, as well as an update on human transmission of the H5NI avian influenza virus. It also mentions new data on Bell's palsy as well as two vaccines (varicella-zoster and pneumococcus), and provides a list of recent guidelines for the treatment of common infectious diseases.

Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1.

The voltage-gated cardiac potassium channel hERG1 (human ether-à-gogo-related gene 1) plays a key role in the repolarization phase of the cardiac action potential (AP). Mutations in its gene, KCNH2, can lead to defects in the biosynthesis and maturation of the channel, resulting in congenital long QT syndrome (LQTS). To identify the molecular mechanisms regulating the density of hERG1 channels at the plasma membrane, we investigated channel ubiquitylation by ubiquitin ligase Nedd4-2, a post-translational regulatory mechanism previously linked to other ion channels. We found that whole-cell hERG1 currents recorded in HEK293 cells were decreased upon neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2) co-expression. The amount of hERG1 channels in total HEK293 lysates and at the cell surface, as assessed by Western blot and biotinylation assays, respectively, were concomitantly decreased. Nedd4-2 and hERG1 interact via a PY motif located in the C-terminus of hERG1. Finally, we determined that Nedd4-2 mediates ubiquitylation of hERG1 and that deletion of this motif affects Nedd4-2-dependent regulation. These results suggest that ubiquitylation of the hERG1 protein by Nedd4-2, and its subsequent down-regulation, could represent an important mechanism for modulation of the duration of the human cardiac action potential.

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2.

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.

Death caused by cardioinhibitory reflex cardiac arrest--a systematic review of cases.

Forensic pathologists often refer to the cardioinhibitory reflex cardiac arrest (CiRCA) following short neck trauma as a mechanism of death. We sought via a systematic review of the literature to identify circumstances under which carotid bifurcation stimulation could lead to death. Two independent reviewers selected case studies or reports from Medline, ISI Web of Knowledge, and Embase. Circumstances and contributory factors were extracted for each case. From the available data, authors independently assessed whether CiRCA was highly probable (no alternative explanation possible), probable (alternative explanation possible), or unlikely (alternative explanation highly probable). A narrative approach was used to define circumstances in which CiRCA remained possible. From the 48 published cases evoking CiRCA as a possible cause of death between 1881 and 2009, 28 were most likely to result of other mechanism of death (i.e., cerebral hypoxia due to carotid compression, mechanical asphyxia, myocardial infarction). CiRCA remained possible for 20 cases (including five based on anecdotal evidence only) with only one case with no alternative explanation other than CiRCA. Our findings support the presumption that reflex cardiac arrhythmia due to carotid bifurcation stimulation cannot provoke death alone. Actual state of knowledge suggests CiRCA might be contributory to death in the presence of drug abuse and/or cardiac pathology, often associated with physical and/or mental excitation.

Men and women differ in their cardiovascular responses to affective pictures

Empirical evidence supports the hypothesis that emotional states might contribute to cardiovascular disease and health through multiple pathways. To the extent that the acute cardiovascular response to emotional events plays a role in cardiovascular health and disease, an essential step in order to understand this possible link is to define the hemodynamic response to affective challenges. This was the aim of the present study. We assessed blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output, and total peripheral resistance (TPR) in response to 13 picture series in 18 men and 19 women (mean age 26) in order to investigate their hemodynamic responses associated with activation of the appetitive and defensive motivational systems underlying emotional experience. The hemodynamic parameters were recorded by finger-cuff photoplethysmography with Finometer™ (FMS Finapres Medical Systems, Amsterdam) and electrocardiography with the Lifeshirt system (VivoMetrics Inc., Ventura, California). Participants rated self-perceived pleasantness and arousal for each series. In men, BP and SV, but not TPR, increased with increasing self-rated arousal both for appetitive and defensive activation, whereas in women these relationships were almost absent, especially, for defensive activation. HR decelerated more in response to negative than positive and neutral pictures, and more so in men than women. These findings indicate striking sex differences. In particular, it is suggested that the sympathetic inotropic effect to the heart increases with increasing self-rated arousal strongly in men but only weakly in women. Regardless of sex differences, the modulation of the cardiovascular response to affective pictures along the dimensions of pleasantness and arousal is primarily myocardial, and the pattern of cardiovascular response is consistent with a configuration of cardiac sympathetic-parasympathetic coactivation. One possible implication of the observed sex differences concerns the link between affective states and cardiovascular health and disease. Men have a higher incidence of cardiovascular diseases than premenopausal women, and exaggerated sympathetic reactivity to emotional events is a potential pathophysiological mechanism. These findings extend current knowledge showing that under several acute behavioral challenges men demonstrate stronger cardiovascular reactivity than women.

Microbiota abnormalities in inflammatory airway diseases - Potential for therapy.

Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of 'health-promoting' bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

Establishing an association between a peri-operative perfusion score system (PerfSCORE) and post-operative patient morbidity/mortality during CPB cardiac surgery.

BACKGROUND: To date, there is no quality assurance program that correlates patient outcome to perfusion service provided during cardiopulmonary bypass (CPB). A score was devised, incorporating objective parameters that would reflect the likelihood to influence patient outcome. The purpose was to create a new method for evaluating the quality of care the perfusionist provides during CPB procedures and to deduce whether it predicts patient morbidity and mortality. METHODS: We analysed 295 consecutive elective patients. We chose 10 parameters: fluid balance, blood transfused, Hct, ACT, PaO2, PaCO2, pH, BE, potassium and CPB time. Distribution analysis was performed using the Shapiro-Wilcoxon test. This made up the PerfSCORE and we tried to find a correlation to mortality rate, patient stay in the ICU and length of mechanical ventilation. Univariate analysis (UA) using linear regression was established for each parameter. Statistical significance was established when p < 0.05. Multivariate analysis (MA) was performed with the same parameters. RESULTS: The mean age was 63.8 +/- 12.6 years with 70% males. There were 180 CABG, 88 valves, and 27 combined CABG/valve procedures. The PerfSCORE of 6.6 +/- 2.4 (0-20), mortality of 2.7% (8/295), CPB time 100 +/- 41 min (19-313), ICU stay 52 +/- 62 hrs (7-564) and mechanical ventilation of 10.5 +/- 14.8 hrs (0-564) was calculated. CPB time, fluid balance, PaO2, PerfSCORE and blood transfused were significantly correlated to mortality (UA, p < 0.05). Also, CPB time, blood transfused and PaO2 were parameters predicting mortality (MA, p < 0.01). Only pH was significantly correlated for predicting ICU stay (UA). Ultrafiltration (UF) and CPB time were significantly correlated (UA, p < 0.01) while UF (p < 0.05) was the only parameter predicting mechanical ventilation duration (MA). CONCLUSIONS: CPB time, blood transfused and PaO2 are independent risk factors of mortality. Fluid balance, blood transfusion, PaO2, PerfSCORE and CPB time are independent parameters for predicting morbidity. PerfSCORE is a quality of perfusion measure that objectively quantifies perfusion performance.

Impact of duration of chest tube drainage on pain after cardiac surgery.

OBJECTIVE: This study was designed to analyze the duration of chest tube drainage on pain intensity and distribution after cardiac surgery. METHODS: Two groups of 80 cardiac surgery adult patients, operated on in two different hospitals, by the same group of cardiac surgeons, and with similar postoperative strategies, were compared. However, in one hospital (long drainage group), a conservative policy was adopted with the removal the chest tubes by postoperative day (POD) 2 or 3, while in the second hospital (short drainage group), all the drains were usually removed on POD 1. RESULTS: There was a trend toward less pain in the short drainage group, with a statistically significant difference on POD 2 (P=0.047). There were less patients without pain on POD 3 in the long drainage group (P=0. 01). The areas corresponding to the tract of the pleural tube, namely the epigastric area, the left basis of the thorax, and the left shoulder were more often involved in the long drainage group. There were three pneumonias in each group and no patient required repeated drainage. CONCLUSIONS: A policy of early chest drain ablation limits pain sensation and simplifies nursing care, without increasing the need for repeated pleural puncture. Therefore, a policy of short drainage after cardiac surgery should be recommended.

The effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan on perioperative brain injury in children undergoing cardiac surgery with cardiopulmonary bypass: results of a pilot study.

Experimental evidence indicates a role of the N-methyl-D-aspartate receptor in the pathogenesis of brain injury occurring during cardiac surgery with cardiopulmonary bypass (CPB). Dextromethorphan is a noncompetitive antagonist of this receptor with a favorable safety profile. Thirteen children age 3-36 months undergoing cardiac surgery with expected CPB of 60 minutes or more were randomly assigned to treatment with dextromethorphan (36-38 mg/kg/day) or placebo administered by naso-gastric tube. Dextromethorphan was absorbed well and reached putative therapeutic levels in blood and cerebrospinal fluid. Adverse effects were not observed. Mild hemiparesis developed after operation in one child of each group, and severe encephalopathy in one of the placebo group. Sharp waves were recorded in postoperative continuous electroencephalography in all placebo (n = 7) but only in 2/6 dextromethorphan treated children (p = 0.02). Pre- and postoperative cranial magnetic resonance imaging (MRI) revealed less pronounced ventricular enlargement in the dextromethorphan group (not significant). An increase of periventricular white matter lesions was visible in two placebo-treated children only. No elevations of cerebrospinal fluid enzymes were observed in either group. Although children with dextromethorphan showed less abnormalities in electroencephalography and MRI, dissimilarities of the treatment groups by chance diminished conclusions to possible protective effects of dextromethorphan at this time.

Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models.

BACKGROUND: Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans. RESULTS: We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans. CONCLUSIONS: We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury.