Confounders for prognostic accuracy of neuron-specific enolase after cardiac arrest: A retrospective cohort study.

AIM: To evaluate neuron-specific enolase (NSE) thresholds for prediction of neurological outcome after cardiac arrest and to analyze the influence of hemolysis and confounders. METHODS: Retrospective analysis from a cardiac arrest registry. Determination of NSE serum concentration and hemolysis-index (h-index) 48-96 hours after cardiac arrest. Evaluation of neurological outcome using the Cerebral Performance Category score (CPC) at hospital discharge. Separate analyses considering CPC 1-3 and CPC 1-2 as good neurological outcome. Analysis of specificity and sensitivity for poor and good neurological outcome prediction with and without exclusion of hemolytic samples (h-index larger than 50). RESULTS: Among 356 survivors three days after cardiac arrest, hemolysis was detected in 28 samples (7.9%). At a threshold of 60 µg/L, NSE predicted poor neurological outcome (CPC 4-5) in all samples with a specificity of 92% (86-95%) and sensitivity of 73% (66-79%). In non-hemolytic samples, specificity was 94% (89-97%) and sensitivity 70% (62-76%). At a threshold of 100 µg/L, specificity was 98% (95-100%, all samples) and 99% (95-100%, non-hemolytic samples), and sensitivity 58% (51-65%) and 55% (47-63%), respectively. Possible confounders for elevated NSE in patients with good neurological outcome were ECMO, malignancies, blood transfusions and acute brain diseases. Nine patients with NSE below 17 µg/L had CPC 5, all had plausible death causes other than hypoxic-ischemic encephalopathy. CONCLUSIONS: NSE concentrations higher than 100 µg/L predicted poor neurological outcome with high specificity. An NSE less than 17 µg/L indicated absence of severe hypoxic-ischemic encephalopathy. Hemolysis and other confounders need to be considered. INSTITUTIONAL PROTOCOL NUMBER: The local ethics committee (board name: Ethikkommission der Charité) approved this study by the number: EA2/066/23, approval date: 28th June 2023, study title "'ROSC' - Resuscitation Outcome Study."

Electrolyte profiles with induced hypothermia: A sub study of a clinical trial evaluating the duration of hypothermia after cardiac arrest.

BACKGROUND: Electrolyte disturbances can result from targeted temperature treatment (TTM) in out-of-hospital cardiac arrest (OHCA) patients. This study explores electrolyte changes in blood and urine in OHCA patients treated with TTM. METHODS: This is a sub-study of the TTH48 trial, with the inclusion of 310 unconscious OHCA patients treated with TTM at 33°C for 24 or 48 h. Over a three-day period, serum concentrations were obtained on sodium potassium, chloride, ionized calcium, magnesium and phosphate, as were results from a 24-h diuresis and urine electrolyte concentration and excretion. Changes over time were analysed with a mixed-model multivariate analysis of variance with repeated measurements. RESULTS: On admission, mean ± SD sodium concentration was 138 ± 3.5 mmol/l, which increased slightly but significantly (p < .05) during the first 24 h. Magnesium concentration stayed within the reference interval. Median ionized calcium concentration increased from 1.11 (IQR 1.1-1.2) mmol/l during the first 24 h (p < .05), whereas median phosphate concentration dropped to 1.02 (IQR 0.8-1.2) mmol/l (p < .05) and stayed low. During rewarming, potassium concentrations increased, and magnesium and ionizes calcium concentration decreased (p < .05). Median 24-h diuresis results on days one and two were 2198 and 2048 ml respectively, and the electrolyte excretion mostly stayed low in the reference interval. CONCLUSIONS: Electrolytes mostly remained within the reference interval. A temporal change occurred in potassium, magnesium and calcium concentrations with TTM's different phases. No hypothermia effect on diuresis was detected, and urine excretion of electrolytes mostly stayed low.

Hypoxic-Ischemic Encephalopathy Evaluated by Brain Autopsy and Neuroprognostication After Cardiac Arrest.

Importance: Neuroprognostication studies are potentially susceptible to a self-fulfilling prophecy as investigated prognostic parameters may affect withdrawal of life-sustaining therapy. Objective: To compare the results of prognostic parameters after cardiac arrest (CA) with the histopathologically determined severity of hypoxic-ischemic encephalopathy (HIE) obtained from autopsy results. Design, Setting, and Participants: In a retrospective, 3-center cohort study of all patients who died following cardiac arrest during their intensive care unit stay and underwent autopsy between 2003 and 2015, postmortem brain histopathologic findings were compared with post-CA brain computed tomographic imaging, electroencephalographic (EEG) findings, somatosensory-evoked potentials, and serum neuron-specific enolase levels obtained during the intensive care unit stay. Data analysis was conducted from 2015 to 2020. Main Outcomes and Measures: The severity of HIE was evaluated according to the selective eosinophilic neuronal death (SEND) classification and patients were dichotomized into categories of histopathologically severe and no/mild HIE. Results: Of 187 included patients, 117 were men (63%) and median age was 65 (interquartile range, 58-74) years. Severe HIE was found in 114 patients (61%) and no/mild HIE was identified in 73 patients (39%). Severe HIE was found in all 21 patients with bilaterally absent somatosensory-evoked potentials, all 15 patients with gray-white matter ratio less than 1.10 on brain computed tomographic imaging, all 9 patients with suppressed EEG, 15 of 16 patients with burst-suppression EEG, and all 29 patients with neuron-specific enolase levels greater than 67 µg/L more than 48 hours after CA without confounders. Three of 7 patients with generalized periodic discharges on suppressed background and 1 patient with burst-suppression EEG had a SEND 1 score (<30% dead neurons) in the cerebral cortex, but higher SEND scores (>30% dead neurons) in other oxygen-sensitive brain regions. Conclusions and Relevance: In this study, histopathologic findings suggested severe HIE after cardiac arrest in patients with bilaterally absent cortical somatosensory-evoked potentials, gray-white matter ratio less than 1.10, highly malignant EEG, and serum neuron-specific enolase concentration greater than 67 µg/L.

RBM3 and CIRP expressions in targeted temperature management treated cardiac arrest patients-A prospective single center study.

BACKGROUND: Management of cardiac arrest patients includes active body temperature control and strict prevention of fever to avoid further neurological damage. Cold-shock proteins RNA-binding motif 3 (RBM3) and cold inducible RNA-binding protein (CIRP) expressions are induced in vitro in response to hypothermia and play a key role in hypothermia-induced neuroprotection. OBJECTIVE: To measure gene expressions of RBM3, CIRP, and inflammatory biomarkers in whole blood samples from targeted temperature management (TTM)-treated post-cardiac arrest patients for the potential application as clinical biomarkers for the efficacy of TTM treatment. METHODS: A prospective single center trial with the inclusion of 22 cardiac arrest patients who were treated with TTM (33°C for 24 hours) after ROSC was performed. RBM3, CIRP, interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and inducible nitric oxide synthase (iNOS) mRNA expressions were quantified by RT-qPCR. Serum RBM3 protein concentration was quantified using an enzyme-linked immunosorbent assay (ELISA). RESULTS: RBM3 mRNA expression was significantly induced in post-cardiac arrest patients in response to TTM. RBM3 mRNA was increased 2.2-fold compared to before TTM. A similar expression kinetic of 1.4-fold increase was observed for CIRP mRNA, but did not reached significancy. Serum RBM3 protein was not increased in response to TTM. IL-6 and MCP-1 expression peaked after ROSC and then significantly decreased. iNOS expression was significantly increased 24h after return of spontaneous circulation (ROSC) and TTM. CONCLUSIONS: RBM3 is temperature regulated in patients treated with TTM after CA and ROSC. RBM3 is a possible biomarker candidate to ensure the efficacy of TTM treatment in post-cardiac arrest patients and its pharmacological induction could be a potential future intervention strategy that warrants further research.

Unresponsive wakefulness or coma after cardiac arrest-A long-term follow-up study.

OBJECTIVE: To investigate the clinical course and early prognostic markers in cardiac arrest (CA) patients discharged from the intensive care unit (ICU) in an unresponsive wakefulness syndrome (UWS) or coma. METHODS: 89 patients were identified from a prospective CA database. Follow-up was conducted by telephone interviews with legal guardians, evaluation of re-admission and rehabilitation reports assessing core elements of the coma recovery scale-revised (CRS-R). Somatosensory evoked potential (SSEP) and electroencephalography (EEG) original recordings were re-analyzed, the gray-white-matter ratio (GWR) was determined from brain computed tomography (CT) and neuron-specific enolase (NSE) serum concentrations were retrieved. RESULTS: Follow-up was successful for 32/50 (64%) patients admitted between 2001-2009 and 31/39 (79%) between 2009-2015. Median ICU stay was 27 days (IQR 20-36). Neurological improvement beyond UWS was found in 2 of 63 patients. Among 61 patients with successful follow-up and no improvement, NSE serum concentrations within the reference range, SSEP amplitudes above 2.5 µV or continuous reactive EEG were found in 5%, 3% and 2% of those tested. NSE > 90 µg/L, SSEP ≤ 0.3 µV, highly malignant EEG or GWR < 1.10 were found in 44%, 49%, 35% and 22% of those tested. CONCLUSIONS: Neurological recovery was rare in CA patients discharged in UWS after prolonged ICU treatment. Status epilepticus requiring prolonged deep sedation is one potential reason for delayed awakening. Sensitivity for established poor outcome parameters to predict persistent UWS early after CA was moderate. SSEP, EEG and NSE may indicate absence of severe HIE early after CA.

Neuron-Specific Enolase Predicts Poor Outcome After Cardiac Arrest and Targeted Temperature Management: A Multicenter Study on 1,053 Patients.

OBJECTIVE: Outcome prediction after cardiac arrest is important to decide on continuation or withdrawal of intensive care. Neuron-specific enolase is an easily available, observer-independent prognostic biomarker. Recent studies have yielded conflicting results on its prognostic value after targeted temperature management. DESIGN, SETTING, AND PATIENTS: We analyzed neuron-specific enolase serum concentrations 3 days after nontraumatic in-hospital cardiac arrest and out-of-hospital cardiac arrest and outcome of patients from five hospitals in Germany, Austria, and Italy. Patients were treated at 33°C for 24 hours. Cerebral Performance Category was evaluated upon ICU discharge. We performed case reviews of good outcome patients with neuron-specific enolase greater than 90 µg/L and poor outcome patients with neuron-specific enolase less than or equal to 17 µg/L (upper limit of normal). MEASUREMENTS AND MAIN RESULTS: A neuron-specific enolase serum concentration greater than 90 µg/L predicted Cerebral Performance Category 4-5 with a positive predictive value of 99%, false positive rate of 0.5%, and a sensitivity of 48%. All three patients with neuron-specific enolase greater than 90 µg/L and Cerebral Performance Category 1-2 had confounders for neuron-specific enolase elevation. An neuron-specific enolase serum concentration less than or equal to 17 µg/L excluded Cerebral Performance Category 4-5 with a negative predictive value of 92%. The majority of 14 patients with neuron-specific enolase less than or equal to 17 µg/L who died had a cause of death other than hypoxic-ischemic encephalopathy. Specificity and sensitivity for prediction of poor outcome were independent of age, sex, and initial rhythm but higher for out-of-hospital cardiac arrest than for in-hospital cardiac arrest patients. CONCLUSION: High neuron-specific enolase serum concentrations reliably predicted poor outcome at ICU discharge. Prediction accuracy differed and was better for out-of-hospital cardiac arrest than for in-hospital cardiac arrest patients. Our "in-the-field" data indicate 90 µg/L as a threshold associated with almost no false positives at acceptable sensitivity. Confounders of neuron-specific enolase elevation should be actively considered: neuron-specific enolase-producing tumors, acute brain diseases, and hemolysis. We strongly recommend routine hemolysis quantification. Neuron-specific enolase serum concentrations less than or equal to 17 µg/L argue against hypoxic-ischemic encephalopathy incompatible with reawakening.

Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.

Aberrant DNA methylation is a hallmark of various human disorders, indicating that the spatial and temporal regulation of methylation readers and modifiers is imperative for development and differentiation. In particular, the cross-regulation between 5-methylcytosine binders (MBD) and modifiers (Tet) has not been investigated. Here, we show that binding of Mecp2 and Mbd2 to DNA protects 5-methylcytosine from Tet1-mediated oxidation. The mechanism is not based on competition for 5-methylcytosine binding but on Mecp2 and Mbd2 directly restricting Tet1 access to DNA. We demonstrate that the efficiency of this process depends on the number of bound MBDs per DNA molecule. Accordingly, we find 5-hydroxymethylcytosine enriched at heterochromatin of Mecp2-deficient neurons of a mouse model for Rett syndrome and Tet1-induced reexpression of silenced major satellite repeats. These data unveil fundamental regulatory mechanisms of Tet enzymes and their potential pathophysiological role in Rett syndrome. Importantly, it suggests that Mecp2 and Mbd2 have an essential physiological role as guardians of the epigenome.

Visuo-spatial memory deficits following medial temporal lobe damage: A comparison of three patient groups.

The contributions of the hippocampal formation and adjacent regions of the medial temporal lobe (MTL) to memory are still a matter of debate. It is currently unclear, to what extent discrepancies between previous human lesion studies may have been caused by the choice of distinct patient models of MTL dysfunction, as disorders affecting this region differ in selectivity, laterality and mechanisms of post-lesional compensation. Here, we investigated the performance of three distinct patient groups with lesions to the MTL with a battery of visuo-spatial short-term memory tasks. Thirty-one subjects with either unilateral damage to the MTL (postsurgical lesions following resection of a benign brain tumor, 6 right-sided lesions, 5 left) or bilateral damage (10 post-encephalitic lesions, 10 post-anoxic lesions) performed a series of tasks requiring short-term memory of colors, locations or color-location associations. We have shown previously that performance in the association task critically depends on hippocampal integrity. Patients with postsurgical damage of the MTL showed deficient performance in the association task, but performed normally in color and location tasks. Patients with left-sided lesions were almost as impaired as patients with right-sided lesions. Patients with bilateral post-encephalitic lesions showed comparable damage to MTL sub-regions and performed similarly to patients with postsurgical lesions in the association task. However, post-encephalitic patients showed additional impairments in the non-associative color and location tasks. A strikingly similar pattern of deficits was observed in post-anoxic patients. These results suggest a distinct cerebral organization of associative and non-associative short-term memory that was differentially affected in the three patient groups. Thus, while all patient groups may provide appropriate models of medial temporal lobe dysfunction in associative visuo-spatial short-term memory, additional deficits in non-associative memory tasks likely reflect damage of regions outside the MTL. Importantly, the choice of a patient model in human lesion studies of the MTL significantly influences overall performance patterns in visuo-spatial memory tasks.

A rare case of neuroleptic malignant syndrome presenting with serious hyperthermia treated with a non-invasive cooling device: a case report.

INTRODUCTION: A rare side effect of antipsychotic medication is neuroleptic malignant syndrome, mainly characterized by hyperthermia, altered mental state, haemodynamic dysregulation, elevated serum creatine kinase and rigor. There may be multi-organ dysfunction including renal and hepatic failure as well as serious rhabdomyolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The prevalence of neuroleptic malignant syndrome is between 0.02% and 2.44% for patients taking neuroleptics and it is not necessary to fulfil all cardinal features characterizing the syndrome to be diagnosed with neuroleptic malignant syndrome. Because of other different life-threatening diseases matching the various clinical findings, the correct diagnosis can sometimes be hard to make. A special problem of intensive care treatment is the management of severe hyperthermia. Lowering of body temperature, however, may be a major clinical problem because hyperthermia in neuroleptic malignant syndrome is typically unresponsive to antipyretic agents while manual cooling proves difficult due to peripheral vasoconstriction. CASE PRESENTATION: A 22-year-old Caucasian man was admitted unconscious with a body temperature of 42 degrees C, elevated serum creatine phosphokinase, tachycardia and hypotonic blood pressure. In addition to intensive care standard therapy for coma and shock, a non-invasive cooling device (Arctic Sun 2000((R)), Medivance Inc., USA), originally designed to induce mild therapeutic hypothermia in patients after cardiopulmonary resuscitation, was used to lower body temperature. After successful treatment it became possible to obtain information from the patient about his recent ambulant treatment with Olanzapin (Zyprexa(R)) for schizophrenia. CONCLUSION: Numerous case reports have been published about patients who developed neuroleptic malignant syndrome due to Olanzapin (Zyprexa(R)) medication. Frequently hyperthermia has been observed in these cases with varying outcomes. In our case the only residual impairment for the patient is dysarthria with corresponding symmetric cerebellar pyramidal cell destruction demonstrated by increased signal intensity in T2-weighted magnetic resonance imaging, most likely caused by the excessive hyperthermia.

Therapy-refractory Panton Valentine Leukocidin-positive community-acquired methicillin-sensitive Staphylococcus aureus sepsis with progressive metastatic soft tissue infection: a case report.

We report a case of fulminant multiple organ failure including the Acute Respiratory Distress Syndrome (ARDS), haemodynamic, and renal failure due to community-acquired methicillin-sensitive Panton Valentine Leukocidin (PVL) positive spa-type 284 (ST121) Staphylococcus aureus septic shock. The patient's first clinical symptom was necrotizing pneumonia. Despite organism-sensitive triple antibiotic therapy with linezolid, imipenem and clindamycin from the first day of treatment, progressive abscess formation in multiple skeletal muscles was observed. As a result, repeated surgical interventions became necessary. Due to progressive soft tissue infection, the anti-microbial therapy was changed to a combination of clindamycin and daptomycin. Continued surgical and antimicrobial therapy finally led to a stabilisation of the patients' condition. The clinical course of our patient underlines the existence of a "PVL-syndrome" which is independent of in vitro Staphylococcus aureus susceptibility. The PVL-syndrome should not only be considered in patients with soft tissue or bone infection, but also in patients with pneumonia. Such a condition, which may easily be mistaken for uncomplicated pneumonia, should be treated early, aggressively and over a long period of time in order to avoid relapsing infection.

OrthoGUI: graphical presentation of Orthostrapper results.

SUMMARY: Orthostrapper is a program that calculates orthology support values for pairs of sequences in a multiple alignment (Storm and Sonnhammer, Bioinformatics, 18, 92-99, 2002). Here we present OrthoGUI, a web interface and display tool for Orthostrapper analysis. OrthoGUI visualizes the Orthostrapper output in both tabular and tree representations, and can also apply a clustering algorithm to identify groups of multiple orthologs, which are indicated by colour coding. AVAILABILITY: http://www.cgb.ki.se/OrthoGUI CONTACT: erik.sonnhammer@cgb.ki.se