Dependence of brain intravoxel incoherent motion perfusion parameters on the cardiac cycle.

Measurement of microvascular perfusion with Intravoxel Incoherent Motion (IVIM) MRI is gaining interest. Yet, the physiological influences on the IVIM perfusion parameters ("pseudo-diffusion" coefficient D*, perfusion fraction f, and flow related parameter fD*) remain insufficiently characterized. In this article, we hypothesize that D* and fD*, which depend on blood speed, should vary during the cardiac cycle. We extended the IVIM model to include time dependence of D* = D*(t), and demonstrate in the healthy human brain that both parameters D* and fD* are significantly larger during systole than diastole, while the diffusion coefficient D and f do not vary significantly. The results non-invasively demonstrate the pulsatility of the brain's microvasculature.

D-JNKi, a peptide inhibitor of c-Jun N-terminal kinase, promotes functional recovery after transient focal cerebral ischemia in rats

The c-Jun-N-terminal kinase (JNK) pathway has been shown to play an important role in excitotoxic neuronal death and several studies have demonstrated a neuroprotective effect of D-JNKi, a peptide inhibitor of JNK, in various models of cerebral ischemia. We have now investigated the effect of D-JNKi in a model of transient focal cerebral ischemia (90 min) induced by middle cerebral artery occlusion (MCAo) in adult male rats. D-JNKi (0.1 mg/kg), significantly decreased the volume of infarct, 3 days after cerebral ischemia. Sensorimotor and cognitive deficits were then evaluated over a period of 6 or 10 days after ischemia and infarct volumes were measured after behavioral testing. In behavioral studies, D-JNKi improved the general state of the animals as demonstrated by the attenuation of body weight loss and improvement in neurological score, as compared with animals receiving the vehicle. Moreover, D-JNKi decreased sensorimotor deficits in the adhesive removal test and improved cognitive function in the object recognition test. In contrast, D-JNKi did not significantly affect the infarct volume at day 6 and at day 10. This study shows that D-JNKi can improve functional recovery after transient focal cerebral ischemia in the rat and therefore supports the use of this molecule as a potential therapy for stroke.

JNK inhibition and inflammation after cerebral ischemia.

The c-Jun-N-terminal kinase signaling pathway (JNK) is highly activated during ischemia and plays an important role in apoptosis and inflammation. We have previously demonstrated that D-JNKI1, a specific JNK inhibitor, is strongly neuroprotective in animal models of stroke. We presently evaluated if D-JNKI1 modulates post-ischemic inflammation such as the activation and accumulation of microglial cells. Outbred CD1 mice were subjected to 45 min middle cerebral artery occlusion (MCAo). D-JNKI1 (0.1 mg/kg) or vehicle (saline) was administered intravenously 3 h after MCAo onset. Lesion size at 48 h was significantly reduced, from 28.2+/-8.5 mm(3) (n=7) to 13.9+/-6.2 mm(3) in the treated group (n=6). Activation of the JNK pathway (phosphorylation of c-Jun) was observed in neurons as well as in Isolectin B4 positive microglia. We quantified activated microglia (CD11b) by measuring the average intensity of CD11b labelling (infra-red emission) within the ischemic tissue. No significant difference was found between groups. Cerebral ischemia was modelled in vitro by subjecting rat organotypic hippocampal slice cultures to oxygen (5%) and glucose deprivation for 30 min. In vitro, D-JNKI1 was found predominantly in NeuN positive neurons of the CA1 region and in few Isolectin B4 positive microglia. Furthermore, 48 h after OGD, microglia were activated whereas resting microglia were found in controls and in D-JNKI1-treated slices. Our study shows that D-JNKI1 reduces the infarct volume 48 h after transient MCAo and does not act on the activation and accumulation of microglia at this time point. In contrast, in vitro data show an indirect effect of D-JNKI1 on the modulation of microglial activation.

Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction.

BACKGROUND: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll-like receptor (TLR) family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro-inflammatory signaling pathways (NF-kappaB and MAP kinases) and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyocytes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1), and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. CONCLUSION/SIGNIFICANCE: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility.

Modulation of the gap junction protein Connexin36 in neurons in a mouse model of transient focalcerebral ischemia

Intercellular communication is achieved at specialized regions of the plasma membrane by¦gap junctions. Gap junctions are transmembrane channels allowing direct contacts between¦the cytoplasms of neighboring cells. Each cell participates with one hemichannel, or¦connexon, made of six protein subunits named connexins. Thanks to these junctions, cells¦potentially share a pool of small molecules and metabolites, such as nucleotides, amino acids¦and second messengers.¦In an ischemic (i.e. non-perfused) territory of the brain, irreversible damage progresses over¦time from the centre of the most severe flow reduction to the periphery with less disturbed¦perfusion. Functionally impaired tissue can survive and recover if sufficient reperfusion is reestablished¦within a limited time period, which depends on various factors and mechanisms¦modulating the signaling pathways leading to cell death.¦Observations were made indicating the presence of electrical coupling between neurons which¦resist better to an ischemic insult. This electrical coupling is likely to be mediated by¦Connexin36 (Cx36), a neuron specific connexin isoform. It was demonstrated in the past that¦global ischemia induces a selective upregulation of Cx36 expression in regions with neurons¦that survive the insult whereas others undergo apoptosis and die. These observations raise the¦possibility that the neuronal gap junction Cx36 might play a role in the destiny of neurons¦after cerebral ischemia.¦The aim of this work was to characterize the regulation of Connexin36 in a mouse model of¦transient focal cerebral ischemia by immunofluorescence and Western blot analysis. Our¦immunofluorescence results suggest a specific increase in Cx36 in the penumbral region of¦the ischemic hemisphere.

Chest pain and ST-segment elevation in a patient with Duchenne muscular dystrophy, what really happened?

Introduction: Myocardial infarction is rare in children, if it occurs, findings are almost similar to adults. In Ouchenne muscular dystrophy (OMO), ST segment displacement associated with typical chest pain can occur. We report the case of a young boy with OMO presenting symptoms suggestive of myocardial ischemia. Case report: 7 year old boy, diagnosed with OMO, eoming to the emergency department with complaints of acute chest pain, dyspnoea and anxiety the night before. Clinical examination was not remarkable, with exception of findings of the OMO. ECG showed important ST-segment elevation in right precordial leads. Major increase in troponin 1 42.33 mcg/(normal, <0.04 mcg/I) was found. Echocardiography revealed slight yskinesia of postero-septal wall without decrease in ventricular function. As acute pain had happened more han 12 hours before referral and as the child was asymptomatic, he received anti-platelets therapy. The serum level of troponin 1 declined and the ECG normalised in a few days. Cardiac catheterization did not show any coronary anomaly or eardiac dysfunction. Cardiac biopsy revealed myocardial cell damaged compatible with OMO cardiomyopathy. Tc99m myocardial single-photon emission computed tomography (SPECT) did not show any radionuclide uptake defect. Conclusions: ln this particular context of children with OMO, the classical signs of myocardial ischemia could be misleading, standard investigation failed to demonstrate the cause of chest pain and inerease of troponin l, there was also no evidence of myocarditis. Role of late enhancement (LE) signal in eontrast-enhanced MRI in the understanding of the occurring process has to be evaluated.

Cardiology and Cardiac Surgery Reviews - Seeking Your Views

This consultation pack has been prepared to provide the public, relevant interest groups and health service staff with information on the outcome of the cardiology and cardiac surgery reviews and to invite comments on the reviews and their recommendation. åÊ

Serum and CSF levels of neuron-specific enolase (NSE) in cardiac surgery with cardiopulmonary bypass: a marker of brain injury?

We investigated whether neuron-specific enolase (NSE) in serum or cerebrospinal fluid (CSF) reflects subtle or manifest brain injury in children undergoing cardiac surgery using cardiopulmonary bypass (CPB). NSE was measured in serum (s-NSE) before, and up to, 102 h after surgery in 27 children undergoing cardiac surgery with CPB. In 11 children, CSF-NSE was also measured 48 or 66 h post-surgery. As erythrocytes contain NSE, hemoglobin concentration in the samples was determined spectrophotometrically at 550 nm (cut-off limit: absorbance 0.4 = 560 mg/l) in 14 children and in a further 13 children by spectroscopic multicomponent analysis (cut-off limit 5 micromol/l = 80 mg/l). One hundred and one of 214 post-operative serum samples (47%) had to be discarded because of hemolysis (18% spectrophotometrically at 550 nm and 88% with spectroscopic multicomponent analysis). On the first and second post-operative day, the median s-NSE values were significantly higher when compared with samples taken after 54 h or longer (P = 0.008 and P = 0.002). All CSF-NSE levels were within the normal range and below the s-NSE measured in the same patient. Although in our study elevated s-NSE seems to indicate brain injury in CPB-surgery, the low concentration of NSE in the post-operative CSF of 11 children puts the neuronal origin of s-NSE in question. NSE from other non-neuronal tissues probably contributes to the elevated s-NSE. Additionally, normal post-operative CSF-NSE values in two children with post-operative neurological sequelae might question the predictive value of CSF-NSE with regard to brain injury.

Fonction surrénalienne après bolus d'étomidate en chirurgie cardiaque: une étude rétrospective [Adrenal function after induction of cardiac surgery patients with etomidate: a retrospective study]

OBJECTIVE: A single bolus dose of etomidate decreases cortisol synthesis by inhibiting the 11-beta hydroxylase, a mitochondrial enzyme in the final step of cortisol synthesis. In our institution, all the patients undergoing cardiac surgery receive etomidate at anesthesia induction. The purpose of this study was to assess the incidence of adrenocortical dysfunction after a single dose of etomidate in selected patients undergoing major cardiac surgery and requiring high-dose norepinephrine postoperatively. STUDY DESIGN: Retrospective descriptive study in the surgical ICU of a university hospital. PATIENTS AND METHODS: Sixty-three patients presented acute circulatory failure requiring norepinephrine (>0,2 microg/kg/min) during the 48 hours following cardiac surgery. Absolute adrenal insufficiency was defined as a basal cortisol below 414 nmo/l (15 microg/dl) and relative adrenal insufficiency as a basal plasma cortisol between 414 nmo/l (15 microg/dl) and 938 nmo/l (34 microg/dl) with an incremental response after 250 microg of synthetic corticotropin (measured at 60 minutes) below 250 nmol/l (9 microg/dl). RESULTS: Fourteen patients (22%) had normal corticotropin test results, 10 (16%) had absolute and 39 (62%) relative adrenal insufficiency. All patients received a low-dose steroid substitution after the corticotropin test. Substituted patients had similar clinical outcomes compared to patients with normal adrenal function. CONCLUSION: A high incidence of relative adrenal failure was observed in selected cardiac surgery patients with acute postoperative circulatory failure.

A noninvasive diagnostic tool to differentiate myocarditis from myocardial infarction: late gadolinium enhanced cardiac magnetic resonance.

Studies in adults have shown that late gadolinium enhanced cardiac magnetic resonance is a safe and noninvasive diagnostic tool which allows one to differentiate myocardial infarction from myocarditis. We believe that it may also be highly useful in the paediatric population for the same purpose.

Incidenceof out-of-hospital adult nontraumatic cardiac arrest presenting as a convulsion

Introduction: The majority of convulsions are due to an epileptic seizure or a convulsive syncope. The incidence of out-of-hospital cardiac arrest (OH-CA) presenting as a convulsion is unknown. Objective: This study aimed to measure the incidence of adult nontraumatic OH-CA presenting as a convulsion, a rate that has not been published so far, to the best of our knowledge. Methods: We prospectively collected all incoming calls with an out-of-hospital nontraumatic seizure as the chief complaint in patients >18 years old during a 24-month period. Among these calls, we collected cases identified as OH-CA by paramedics. Results: During the 24-month period, the emergency medical services (EMS) dispatch center received 561 calls for an out-of-hospital nontraumatic convulsion in an adult. Twelve cases were ultimately classified as CA. In this group, one bystander spontaneously reported that the patient was known for epilepsy. The incidence of OH-CA presenting as convulsions was therefore 2.1% of all calls for convulsion. Over the same period, the EMS dispatch center received 1,035 calls related to an adult nontraumatic OH-CA. Therefore, the rate of OH-CA presenting as a convulsion represented 1.2% of all adult nontraumatic OH-CA. Conclusion:L Only 12 cases out of the 531 calls for nontraumatic adult convulsions were confirmed OHCA (2.1%). Nevertheless, this unusual presentation of OH-CA must be recognized by dispatchers, even when a patient is reported by bystander as a known epileptic. Dispatchers should keep bystanders on the line or call them back before paramedics' arrival, and have them confirm the progressive return of a normal pat- tern of breathing and state of consciousness; if not, they should encourage the bystander to initiate CPR when necessary. An intervention should be implemented to improve the detection by dispatchers of OH-CA presenting as convulsion by the development of a specific interview and directed observation. For dispatchers, a past medical history of epilepsy should not be regarded as sufficient information to rule out OH-CA. It is mandatory that known epileptic patients should be monitored in the same way as nonepileptic patients.

Late outcome of spinal cord stimulation for unreconstructable and limb-threatening lower limb ischemia.

OBJECTIVES: To determine whether the initial benefits of spinal cord stimulation (SCS) treatment for critical limb ischemia (CLI) persist over years. DESIGN: Analysis of data prospectively collected for every CLI patient receiving permanent SCS. Follow-up range 12 to 98 months (mean 46+/-23, median 50 months). POPULATION: 87 patients (28% stage III, 72%stage IV) with unreconstructable CLI due (83%) or not (17%) to atherosclerosis and with an initial sitting/supine transcutaneous pO2 gradient >15 mmHg. METHODS: Assessment of actuarial patient survival (PS), limb salvage (LS) and amputation-free patient survival (AFPS). Analysis of the impact of 15 risk factors on long-term outcomes using the Fischer's exact test for categorical variables and the t test for continuous variables. RESULTS: Follow-up was complete for patient and limb survival. A single non-atherosclerotic patient died during follow-up. Among atherosclerotic patients PS decreased from 88% at 1y, to 76% at 3y, 64% at 5y and 57% at 7y. LS reached 84% at 1y, 78% at 2y, 75% at 3y and remained stable thereafter. Diabetes was found to affect LS (p<0.05) and heart disease to reduce PS (p<0.01). AFPS was reduced in heart patients (p<0.01), diabetics (p<0.05) and in patients with previous stroke (p<0.05). CONCLUSIONS: In CLI patients the beneficial effects of SCS persist far beyond the first year of treatment and major amputation becomes infrequent after the second year.

Reducing the Risk: A Strategic Approach - The Report of the Task Force on Sudden Cardiac Death

The Minister for Health and Children established the Task Force on Sudden Cardiac Death (SCD) in the Autumn of 2004, with the following terms of reference:1) Define SCD and describe its incidence and underlying causes in Ireland.2) Advise on the detection and assessment of those at high risk of SCD and their relatives.3) Advise on the systematic assessment of those engaged in sports and exercise for risk of SCD.4) Advise on maximizing access to basic life support (BLS) and automated external defibrillators (AEDs) and on:- appropriate levels of training in BLS and use of AEDs, and on the maintenance of that training- priority individuals and priority groups for such training- geographic areas and functional locations of greatest need- best practice models of first responder scheme and public access defibrillation, and- integration of such training services.5) Advise on the establishment and maintenance of surveillance systems, including a registry of SCD and information systems to monitor risk assessment, and training and equipment programmes.6) Advise and make recommendations on other priority issues relevant to SCD in Ireland.7) Outline a plan for implementation and advise on monitoring the implementation of recommendations made in the Task Force’s report. In undertaking its work the Task Force was mindful of national health policy, relevant national strategies and of the recently reformed structures for health service delivery in Ireland. Read the Report (PDF, 1.66mb)