Predicting neurological outcome after cardiac arrest.

Purpose of reviewTherapeutic hypothermia and aggressive management of postresuscitation disease considerably improved outcome after adult cardiac arrest over the past decade. However, therapeutic hypothermia alters prognostic accuracy. Parameters for outcome prediction, validated by the American Academy of Neurology before the introduction of therapeutic hypothermia, need further update.Recent findingsTherapeutic hypothermia delays the recovery of motor responses and may render clinical evaluation unreliable. Additional modalities are required to predict prognosis after cardiac arrest and therapeutic hypothermia. Electroencephalography (EEG) can be performed during therapeutic hypothermia or shortly thereafter; continuous/reactive EEG background strongly predicts good recovery from cardiac arrest. On the contrary, unreactive/spontaneous burst-suppression EEG pattern, together with absent N20 on somatosensory evoked potentials (SSEP), is almost 100% predictive of irreversible coma. Therapeutic hypothermia alters the predictive value of serum markers of brain injury [neuron-specific enolase (NSE), S-100B]. Good recovery can occur despite NSE levels >33 mu g/l, thus this cut-off value should not be used to guide therapy. Diffusion MRI may help predicting long-term neurological sequelae of hypoxic-ischemic encephalopathy.SummaryAwakening from postanoxic coma is increasingly observed, despite early absence of motor signs and frank elevation of serum markers of brain injury. A new multimodal approach to prognostication is therefore required, which may particularly improve early prediction of favorable clinical evolution after cardiac arrest.

A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .

Two component systems: physiological effect of a third component

Signal transduction systems mediate the response and adaptation of organisms to environmental changes. In prokaryotes, this signal transduction is often done through Two Component Systems (TCS). These TCS are phosphotransfer protein cascades, and in their prototypical form they are composed by a kinase that senses the environmental signals (SK) and by a response regulator (RR) that regulates the cellular response. This basic motif can be modified by the addition of a third protein that interacts either with the SK or the RR in a way that could change the dynamic response of the TCS module. In this work we aim at understanding the effect of such an additional protein (which we call ‘‘third component’’) on the functional properties of a prototypical TCS. To do so we build mathematical models of TCS with alternative designs for their interaction with that third component. These mathematical models are analyzed in order to identify the differences in dynamic behavior inherent to each design, with respect to functionally relevant properties such as sensitivity to changes in either the parameter values or the molecular concentrations, temporal responsiveness, possibility of multiple steady states, or stochastic fluctuations in the system. The differences are then correlated to the physiological requirements that impinge on the functioning of the TCS. This analysis sheds light on both, the dynamic behavior of synthetically designed TCS, and the conditions under which natural selection might favor each of the designs. We find that a third component that modulates SK activity increases the parameter space where a bistable response of the TCS module to signals is possible, if SK is monofunctional, but decreases it when the SK is bifunctional. The presence of a third component that modulates RR activity decreases the parameter space where a bistable response of the TCS module to signals is possible.

Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

AIM: Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis. METHODS AND RESULTS: We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease. CONCLUSION: These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic.

Self-navigated isotropic three-dimensional cardiac T2 mapping.

PURPOSE: To implement and characterize an isotropic three-dimensional cardiac T2 mapping technique. METHODS: A self-navigated three-dimensional radial segmented balanced steady-state free precession pulse sequence with an isotropic 1.7-mm spatial resolution was implemented at 3T with a variable T2 preparation module. Bloch equation and Monte Carlo simulations were performed to determine the influence of the heart rate, B1 inhomogeneity and noise on the T2 fitting accuracy. In a phantom study, the accuracy of the pulse sequence was studied through comparison with a gold-standard spin-echo T2 mapping method. The robustness and homogeneity of the technique were ascertained in a study of 10 healthy adult human volunteers, while first results obtained in patients are reported. RESULTS: The numerical simulations demonstrated that the heart rate and B1 inhomogeneity cause only minor deviations in the T2 fitting, whereas the phantom study showed good agreement of the technique with the gold standard. The volunteer study demonstrated an average myocardial T2 of 40.5 ± 3.3 ms and a <15% T2 gradient in the base-apex and anterior-inferior direction. In three patients, elevated T2 values were measured in regions with expected edema. CONCLUSION: This respiratory self-navigated isotropic three-dimensional technique allows for accurate and robust in vitro and in vivo T2 quantification. Magn Reson Med 73:1549-1554, 2015. © 2014 Wiley Periodicals, Inc.

Impact of extracardiac findings during cardiac MR on patient management and outcome.

BACKGROUND: Cardiac magnetic resonance (CMR) is increasingly used to assess heart diseases. Relevant non-cardiac diseases may also be incidentally found on CMR images. The aim of this study was to determine the prevalence and nature of incidental extra-cardiac findings (IEF) and their clinical impact in non-selected patients referred for CMR. MATERIAL/METHODS: MR images of 762 consecutive patients (515 men, age: 56±18 years) referred for CMR were prospectively interpreted by 2 radiologists blinded for any previous imaging study. IEFs were classified as major when requiring treatment, follow-up, or further investigation. Clinical follow-up was performed by checking hospital information records and by calling referring physicians. The 2 endpoints were: 1) non-cardiac death and new treatment related to major IEFs, and 2) hospitalization related to major IEFs during follow-up. RESULTS: Major IEFs were proven in 129 patients (18.6% of the study population), 14% of those being unknown before CMR. During 15±6 month follow-up, treatment of confirmed major IEFs was initiated in 1.4%, and no non-cardiac deaths occurred. Hospitalization occurred in 8 patients (1.0% of the study population) with confirmed major IEFs and none occurred in the remaining 110 patients with unconfirmed/unexplored major IEFs (p<0.001). CONCLUSIONS: Screening for major IEFs in a population referred for routine CMR changed management in 1.4% of patients. Major IEFs unknown before CMR but without further exploration, however, carried a favorable prognosis over a follow-up period of 15 months.

Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in the mouse.

Myocardial ischaemia-reperfusion (MIR) triggers a sterile inflammatory response important for myocardial healing, but which may also contribute to adverse ventricular remodelling. Such inflammation is initiated by molecular danger signals released by damaged myocardium, which induce innate immune responses by activating toll-like receptors (TLRs). Detrimental roles have been recently reported for TLR2, TLR3 and TLR4. The role of other TLRs is unknown. We therefore evaluated the role of TLR5, expressed at high level in the heart, in the development of myocardial damage and inflammation acutely triggered by MIR. TLR5-/- and wild-type (WT) mice were exposed to MIR (30 min ischaemia, 2 h reperfusion). We measured infarct size, markers of cardiac oxidative stress, myocardial phosphorylation state of mitogen-activated protein (MAP) kinases and AKT, expression levels of chemokines and cytokines in the heart and plasma, as well as cardiac function by echography and conductance volumetry. TLR5-deficient mice had normal cardiac morphology and function under physiological conditions. After MIR, the absence of TLR5 promoted an increase in infarct size and myocardial oxidative stress. Lack of TLR5 fostered p38 phosphorylation, reduced AKT phosphorylation and markedly increased the expression of inflammatory cytokines, whereas it precipitated acute LV (left ventricle) dysfunction. Therefore, contrary to the detrimental roles of TLR2, TLR3 and TLR4 in the infarcted heart, TLR5 is important to limit myocardial damage, inflammation and functional compromise after MIR.

Component Architecture for Context-Aware Applications

Mobiililaitteisiin tehdyt sovellukset ovat nykyään laajassa käytössä. Mobiilisovellukset tarjoavat käyttäjälleen usein tietyn ennalta määritellyn toiminnallisuuden eivätkä ne pysty mukautumaan vaihtelevaan käyttöympäristöönsä. Jos sovellus olisi tietoinen käyttöympäristöstään ja sen muutoksista, se voisi tarjota käyttäjälleen tilanteeseen sopivia ominaisuuksia. Käyttöympäristöstään tietoiset hajautetut sovellukset tarvitsevat kuitenkin huomattavasti perinteisiä sovelluksia monimutkaisemman arkkitehtuurin toimiakseen. Tässä työssä esitellään hajautetuille ja kontekstitietoisille sovelluksille tarkoitettu ohjelmistoarkkitehtuuri. Työ perustuu Oulun yliopiston CAPNET-tutkimusprojektissa kehitettyyn, mobiilisovelluksille tarkoitettuun arkkitehtuuriin. Tämän työn tarkoituksena on tarjota ratkaisuja niihin puutteisiin, jotka tulivat esille CAPNET-arkkitehtuurin kehitys- ja testausvaiheessa. Esimerkiksi arkkitehtuurin komponenttien määrittelyä tulisi tarkentaa ja ne tulisi jakaa horisontaalisiin kerroksiin niiden ominaisuuksien ja alustariippuvuuden mukaisesti. Työssä luodaan katsaus olemassa oleviin teknologioihin jotka tukevat hajautettujen ja kontekstitietoisten järjestelmien kehittämistä. Myös niiden soveltumista CAPNET-arkkitehtuuriin analysoidaan. Työssä esitellään CAPNET-arkkitehtuuri ja ehdotetaan uutta arkkitehtuuria ja komponenttien kerrosjaottelua. Ehdotuksessa arkkitehtuurin komponentit ja järjestelmän rakenne määritellään ja mallinnetaan UML-menetelmällä. Työn tuloksena on arkkitehtuurimäärittely, joka jakaa nykyisen arkkitehtuurin komponentit kerroksiin. Komponenttien rajapinnat on määritelty selkeästi ja tarkasti. Työ tarjoaa myös projektiryhmälle hyvän lähtökohdan uuden arkkitehtuurin suunnittelulle ja toteuttamiselle.

Supplier Evaluation on the Standard Material and Component Markets in the Electronic Manufacturing Equipment Industry

Työn tavoitteena oli arvioida ja selvittää toimittajasuhteeseen vaikuttavia tekijöitä JOT Automation Group Oyj.n ja sen alihankkijoiden välisessä yhteistyössä ja muodostaa yrityksen kilpailukykyä parantava toimittaja-arviointiprosessi. Työssä keskityttiin tarkastelemaan yleisillä materiaali- ja komponenttimarkkinoilla toimivia toimittajia elektroniikkateollisuuden tuotantojärjestelmien valmistuksessa. Ensin tutustuttiin toimittajasuhdetta ja sen arviointia käsitelleeseen kirjallisuuteen. Teorian tueksi tehtiin haastatteluja ja kartoitettiin ensisijaisia tarpeita ja tavoitteita arviointiprosessille. Valmis prosessi testattiin käytännössä kahden eri case-esimerkin avulla. Prosessista muodostui kahteen eri työkaluun jakautunut kokonaisuus, joista auditointi arvioi toimittajan kyvykkyyttä vastatta sille asetettuihin vaatimuksiin. Toimittajan suorituskyvyn mittaaminen puolestaan testaa ja vertaa jatkuvasti toiminnan todellista tasoa auditoinnissa saatuihin tuloksiin. Työ sisältää selvityksen ja ohjeistuksen toimittaja-arviointiprosessin käytöstä. Prosessin käyttö alentaa toimittajaan kohdistuvaa materiaalien saatavuuteen ja hankintaan liittyviä riskejä. Esimerkeistä saadut kokemukset osoittivat, että prosessin avulla päästään pureutumaan tärkeisiin ydinalueisiin ja kehittämään niitä sekä toimittajalle, että ostajayritykselle edullisella tavalla. Toimittaja-arviointiprosessista kehittyy toimintatapa yrityksen ja sen toimittajan välisen suhteen ylläpitämiseksi.

Sudden cardiac death in forensic medicine - Swiss recommendations for a multidisciplinary approach.

Sudden cardiac death (SCD) is by definition unexpected and cardiac in nature. The investigation is almost invariably performed by a forensic pathologist. Under these circumstances the role of the forensic pathologist is twofold: (1.) to determine rapidly and efficiently the cause and manner of death and (2.) to initiate a multidisciplinary process in order to prevent further deaths in existing family members. If the death is determined to be due to "natural" causes the district attorney in charge often refuses further examinations. However, additional examinations, i.e. extensive histopathological investigations and/or molecular genetic analyses, are necessary in many cases to clarify the cause of death. The Swiss Society of Legal Medicine created a multidisciplinary working group together with clinical and molecular geneticists and cardiologists in the hope of harmonising the approach to investigate SCD. The aim of this paper is to close the gap between the Swiss recommendations for routine forensic post-mortem cardiac examination and clinical recommendations for genetic testing of inherited cardiac diseases; this is in order to optimise the diagnostic procedures and preventive measures for living family members. The key points of the recommendations are (1.) the forensic autopsy procedure for all SCD victims under 40 years of age, (2.) the collection and storage of adequate samples for genetic testing, (3.) communication with the families, and (4.) a multidisciplinary approach including cardiogenetic counselling.

Influence of heart motion on cardiac output estimation by means of electrical impedance tomography: a case study.

Electrical impedance tomography (EIT) is a non-invasive imaging technique that can measure cardiac-related intra-thoracic impedance changes. EIT-based cardiac output estimation relies on the assumption that the amplitude of the impedance change in the ventricular region is representative of stroke volume (SV). However, other factors such as heart motion can significantly affect this ventricular impedance change. In the present case study, a magnetic resonance imaging-based dynamic bio-impedance model fitting the morphology of a single male subject was built. Simulations were performed to evaluate the contribution of heart motion and its influence on EIT-based SV estimation. Myocardial deformation was found to be the main contributor to the ventricular impedance change (56%). However, motion-induced impedance changes showed a strong correlation (r = 0.978) with left ventricular volume. We explained this by the quasi-incompressibility of blood and myocardium. As a result, EIT achieved excellent accuracy in estimating a wide range of simulated SV values (error distribution of 0.57 ± 2.19 ml (1.02 ± 2.62%) and correlation of r = 0.996 after a two-point calibration was applied to convert impedance values to millilitres). As the model was based on one single subject, the strong correlation found between motion-induced changes and ventricular volume remains to be verified in larger datasets.

Clinical evolution after a non-reactive hypothermic EEG following cardiac arrest.

BACKGROUND: Lack of electroencephalography (EEG) background reactivity during therapeutic hypothermia (TH) has been associated with poor outcome in post-anoxic comatose patients. However, decision on intensive care withdrawal is based on normothermic (NT) evaluations. This study aims at exploring whether patients showing recovery of EEG reactivity in NT after a non-reactive EEG in TH differ from those remaining non-reactive. METHODS: Patients with non-reactive EEG during TH were identified from our prospective registry of consecutive comatose adults admitted after successful resuscitation from CA between April 2009 and June 2014. Variables including neurological examination, serum neuron-specific enolase (NSE), procalcitonin, and EEG features were compared regarding impact on functional outcome at 3 months. RESULTS: Seventy-two of 197 patients (37 %) had a non-reactive EEG background during TH with thirteen (18 %) evolving towards reactivity in NT. Compared to those remaining non-reactive (n = 59), they showed significantly better recovery of brainstem reflexes (p < 0.001), better motor responses (p < 0.001), transitory consciousness improvement (p = 0.008), and a tendency toward lower NSE (p = 0.067). One patient recovering EEG reactivity survived with good functional outcome at 3 months. CONCLUSIONS: Recovery of EEG reactivity from TH to NT seems to distinguish two patients' subgroups regarding early neurological assessment and transitory consciousness improvement, corroborating the role of EEG in providing information about cerebral functions. Understanding these dynamic changes encourages maintenance of intensive support in selected patients even after a non-reactive EEG background in TH, as a small subgroup may indeed recover with good functional outcome.