SOFA is superior to MOD score for the determination of non-neurologic organ dysfunction in patients with severe traumatic brain injury: a cohort study

INTRODUCTION: The objective of the present study was to compare the discriminative ability of the Sequential Organ Failure Assessment (SOFA) and Multiple Organ Dysfunction (MOD) scoring systems with respect to hospital mortality and unfavorable neurologic outcome in patients with severe traumatic brain injury admitted to the intensive care unit. METHOD: We performed a prospective cohort study at Foothills Medical Centre, the sole adult tertiary care trauma center servicing southern Alberta (population about 1.3 million). All patients aged 16 years or older with severe traumatic brain injury and intensive care unit length of stay greater than 48 hours between 1 May 2000 and 31 April 2003 were included. Non-neurologic organ dysfunction was measured using the SOFA and MODS scoring systems. Determination of organ dysfunction for each non-neurologic organ system was compared between the two systems by calculating the proportion of patients with SOFA and MOD component score defined organ failure. Consistent with previous literature, organ system failure was defined as a component score of three or greater. RESULTS: The odds of death and unfavorable neurologic outcome in patients with SOFA defined cardiovascular failure were 14.7 times (95% confidence interval [CI] 5.9–36.3) and 7.6 times (95% CI 3.5–16.3) that of those without cardiovascular failure, respectively. The development of SOFA-defined cardiovascular failure was a reasonable discriminator of hospital mortality and unfavorable neurologic outcome (area under the receiver operating characteristic [ROC] curve 0.75 and 0.73, respectively). The odds of death and unfavorable neurologic outcome in patients with MOD-defined cardiovascular failure were 2.6 times (95% CI 1.24–5.26) and 4.1 times (95% CI 1.3–12.4) that of those without cardiovascular failure, respectively. The development of MOD-defined cardiovascular failure was a poor discriminator of hospital mortality and unfavorable neurologic outcome (area under the ROC curve 0.57 and 0.59, respectively). Neither SOFA-defined nor MOD-defined respiratory failure was significantly associated with hospital mortality. CONCLUSION: In patients with brain injury, the SOFA scoring system has superior discriminative ability and stronger association with outcome compared with the MOD scoring system with respect to hospital mortality and unfavorable neurologic outcome

Matched case-control studies: a review of reported statistical methodology

Background: Case-control studies are a common and efficient means of studying rare diseases or illnesses with long latency periods. Matching of cases and controls is frequently employed to control the effects of known potential confounding variables. The analysis of matched data requires specific statistical methods. Methods: The objective of this study was to determine the proportion of published, peer-reviewed matched case-control studies that used statistical methods appropriate for matched data. Using a comprehensive set of search criteria we identified 37 matched case-control studies for detailed analysis. Results: Among these 37 articles, only 16 studies were analyzed with proper statistical techniques (43%). Studies that were properly analyzed were more likely to have included case patients with cancer and cardiovascular disease compared to those that did not use proper statistics (10/16 or 63%, versus 5/21 or 24%, P = 0.02). They were also more likely to have matched multiple controls for each case (14/16 or 88%, versus 13/21 or 62%, P = 0.08). In addition, studies with properly analyzed data were more likely to have been published in a journal with an impact factor listed in the top 100 according to the Journal Citation Reports index (12/16 or 69%, versus 1/21 or 5%, P Conclusion: The findings of this study raise concern that the majority of matched case-control studies report results that are derived from improper statistical analyses. This may lead to errors in estimating the relationship between a disease and exposure, as well as the incorrect adaptation of emerging medical literature.</p

Prolonged refractory status epilepticus following acute traumatic brain injury: a case report of excellent neurological recovery

INTRODUCTION: Refractory status epilepticus (RSE) secondary to traumatic brain injury (TBI) may be under-recognized and is associated with significant morbidity and mortality. METHODS: This case report describes a 20 year old previously healthy woman who suffered a severe TBI as a result of a motor vehicle collision and subsequently developed RSE. Pharmacological coma, physiological support and continuous electroencephalography (cEEG) were undertaken. RESULTS: Following 25 days of pharmacological coma, electrographic and clinical seizures subsided and the patient has made an excellent cognitive recovery. CONCLUSION: With early identification, aggressive physiological support, appropriate monitoring, including cEEG, and an adequate length of treatment, young trauma patients with no previous seizure history and limited structural damage to the brain can have excellent neurological recovery from prolonged RSE

The Myxoma Poxvirus Protein, M11L, Prevents Apoptosis by Direct Interaction with the Mitochondrial Permeability Transition Pore

M11L, an antiapoptotic protein essential for the virulence of the myxoma poxvirus, is targeted to mitochondria and prevents the loss of mitochondrial membrane potential that accompanies cell death. In this study we show, using a cross-linking approach, that M11L physically associates with the mitochondrial peripheral benzodiazepine receptor (PBR) component of the permeability transition (PT) pore. Close association of M11L and the PBR is also indicated by fluorescence resonance energy transfer (FRET) analysis. Stable expression of M11L prevents the release of mitochondrial cytochrome c induced by staurosporine or protoporphyrin IX (PPIX), a ligand of the PBR. Transiently expressed M11L also prevents mitochondrial membrane potential loss induced by PPIX, or induced by staurosporine in combination with PK11195, another ligand of the PBR. Myxoma virus infection and the associated expression of early proteins, including M11L, protects cells from staurosporine- and Fas-mediated mitochondrial membrane potential loss and this effect is augmented by the presence of PBR. We conclude that M11L regulates the mitochondrial permeability transition pore complex, most likely by direct modulation of the PBR

Molecular Composition of Staufen2-Containing Ribonucleoproteins in Embryonic Rat Brain

Messenger ribonucleoprotein particles (mRNPs) are used to transport mRNAs along neuronal dendrites to their site of translation. Numerous mRNA-binding and regulatory proteins within mRNPs finely regulate the fate of bound-mRNAs. Their specific combination defines different types of mRNPs that in turn are related to specific synaptic functions. One of these mRNA-binding proteins, Staufen2 (Stau2), was shown to transport dendritic mRNAs along microtubules. Its knockdown expression in neurons was shown to change spine morphology and synaptic functions. To further understand the molecular mechanisms by which Stau2 modulates synaptic function in neurons, it is important to identify and characterize protein co-factors that regulate the fate of Stau2-containing mRNPs. To this end, a proteomic approach was used to identify co-immunoprecipitated proteins in Staufen2-containing mRNPs isolated from embryonic rat brains. The proteomic approach identified mRNA-binding proteins (PABPC1, hnRNP H1, YB1 and hsc70), proteins of the cytoskeleton (α- and β-tubulin) and RUFY3 a poorly characterized protein. While PABPC1 and YB1 associate with Stau2-containing mRNPs through RNAs, hsc70 is directly bound to Stau2 and this interaction is regulated by ATP. PABPC1 and YB1 proteins formed puncta in dendrites of embryonic rat hippocampal neurons. However, they poorly co-localized with Stau2 in the large dendritic complexes suggesting that they are rather components of Stau2-containing mRNA particles. All together, these results represent a further step in the characterization of Stau2-containing mRNPs in neurons and provide new tools to study and understand how Stau2-containing mRNPs are transported, translationally silenced during transport and/or locally expressed according to cell needs

Rôles de la région COOH-terminale des isoenzymes de la fructose-1, 6-bisphosphate aldolase dans le mécanisme et la spécificité enzymatique

La fructose-1,6-bisphosphate aldolase est une enzyme glycolytique abondante qui catalyse de façon réversible le clivage du fructose-1,6-bisphosphate en glycéraldéhyde-3- phosphate et dihydroxyacétone phosphate. Chez les mammifères, trois formes d'isoenzyme (A, B ou C) existent et exhibent des différences considérables au niveau de la catalyse et de la spécificité envers leurs substrats. En utilisant le modelage moléculaire ("computer modelling") avec les coordonées cristallographiques de l’aldolase de muscle de lapin de concert avec l'alignement des séquences d'acides aminés des diverses aldolases, le domaine COOH-terminal a été identifié comme étant la région qui pouvait être responsable des variations enzymologiques observées. Afin de tester cette hypothèse, un système d'expression du cDNA de 1'aldolase de maïs dans E.coli a été développé et l'enzyme recombinante fut caractérisée. L'aldolase de maïs recombinante purifiée a une masse moléculaire, un assemblage tétramérique de ses sous-unités et un mécanisme de réaction correspondant à ceux attendus pour les aldolases de classe I. La mutagénèse dirigée a ensuite été utilisée pour étudier le rôle fonctionnel du domaine COOH-terminal. Dans un premier temps, une seule mutation a été produite à chacun des neuf derniers acides aminés. Les mutations apportées à la région COOH-terminale ont influencé très significativement les profils d'activité catalytique de l'aldolase de maïs originale. Les effets des mutations sur les vitesses de clivage du Fru-1,6-P2 et du Fru-l-P, la vitesse de condensation des trioses phosphates et la vitesse d'oxydation de 1'intermédiaire carbanion-ènamine ont été caractérisés. Cette caractérisation cinétique nous a permis de démontrer que les mutations ponctuelles affectent de façon prédominante l'échange du proton au complexe enzyme-dihydroxyacétonephosphate à 1'étape de l'intermédiaire carbanion-ènamine et que cette dernière étape représente probablement l'étape limitante dans le mécanisme catalytique de l'aldolase de maïs recombinante. Les cDNAs des aldolases de maïs et de foie humain ont ensuite été utilisés afin de produire plusieurs (huit) aldolases chimériques (aldolases comportant des domaines COOH-terminaux provenant d'autres aldolases). Les résultats obtenus avec les aldolases chimériques combinés avec ceux des mutants ponctuels ont permis de montrer que le domaine COOH-terminal agit comme puissant modulateur de l'activité enzymatique (augmentation par un facteur 3.3 ou diminution par un facteur 10) et que cette modulation est accomplie via l'altération de processus cinétiques ou par la modification de la stabilité d'un ou plusieurs complexe(s) central(aux). Nos résultats ont aussi permis de montrer l'importance des acides aminés non-homologues adjacents à la tyrosine terminale lors de la catalyse. Le fait qu'un nombre restreint de substitutions d'acides aminés dans la région COOH-terminale permette une modulation significative du profil cinétique des isoenzymes parentales suggère que la séquence de la région COOH-terminale pourrait avoir été une cible privilégiée ("hot spot") utilisée afin de générer une diversité de propriétés cinétiques

Roles de la région COOH-terminale des isoenzymes de la fructose-1, 6-bisphosphate aldolase dans le mécanisme et la spécificité enzymatique

La fructose-1,6-bisphosphate aldolase est une enzyme glycolytique abondante qui catalyse de façon réversible le clivage du fructose-1,6-bisphosphate en glycéraldéhyde-3- phosphate et dihydroxyacétone phosphate. Chez les mammifères, trois formes d'isoenzyme (A, B ou C) existent et exhibent des différences considérables au niveau de la catalyse et de la spécificité envers leurs substrats. En utilisant le modelage moléculaire ("computer modelling") avec les coordonées cristallographiques de l’aldolase de muscle de lapin de concert avec l'alignement des séquences d'acides aminés des diverses aldolases, le domaine COOH-terminal a été identifié comme étant la région qui pouvait être responsable des variations enzymologiques observées. Afin de tester cette hypothèse, un système d'expression du cDNA de 1'aldolase de maïs dans E.coli a été développé et l'enzyme recombinante fut caractérisée. L'aldolase de maïs recombinante purifiée a une masse moléculaire, un assemblage tétramérique de ses sous-unités et un mécanisme de réaction correspondant à ceux attendus pour les aldolases de classe I. La mutagénèse dirigée a ensuite été utilisée pour étudier le rôle fonctionnel du domaine COOH-terminal. Dans un premier temps, une seule mutation a été produite à chacun des neuf derniers acides aminés. Les mutations apportées à la région COOH-terminale ont influencé très significativement les profils d'activité catalytique de l'aldolase de maïs originale. Les effets des mutations sur les vitesses de clivage du Fru-1,6-P2 et du Fru-l-P, la vitesse de condensation des trioses phosphates et la vitesse d'oxydation de 1'intermédiaire carbanion-ènamine ont été caractérisés. Cette caractérisation cinétique nous a permis de démontrer que les mutations ponctuelles affectent de façon prédominante l'échange du proton au complexe enzyme-dihydroxyacétonephosphate à 1'étape de l'intermédiaire carbanion-ènamine et que cette dernière étape représente probablement l'étape limitante dans le mécanisme catalytique de l'aldolase de maïs recombinante. Les cDNAs des aldolases de maïs et de foie humain ont ensuite été utilisés afin de produire plusieurs (huit) aldolases chimériques (aldolases comportant des domaines COOH-terminaux provenant d'autres aldolases). Les résultats obtenus avec les aldolases chimériques combinés avec ceux des mutants ponctuels ont permis de montrer que le domaine COOH-terminal agit comme puissant modulateur de l'activité enzymatique (augmentation par un facteur 3.3 ou diminution par un facteur 10) et que cette modulation est accomplie via l'altération de processus cinétiques ou par la modification de la stabilité d'un ou plusieurs complexe(s) central(aux). Nos résultats ont aussi permis de montrer l'importance des acides aminés non-homologues adjacents à la tyrosine terminale lors de la catalyse. Le fait qu'un nombre restreint de substitutions d'acides aminés dans la région COOH-terminale permette une modulation significative du profil cinétique des isoenzymes parentales suggère que la séquence de la région COOH-terminale pourrait avoir été une cible privilégiée ("hot spot") utilisée afin de générer une diversité de propriétés cinétiques

A cost-utility analysis of decompressive hemicraniectomy in patients with malignant middle cerebral artery (mca) infarction

Bibliography: p. 84-92Decompressive hemicraniectomy improves survival in patients with large hemispheric strokes and cerebral edema, but a significant proportion of these survivors have moderate to severe disability. Given that decompressive hemicraniectomy is a very resource intensive therapy, whether it offers good value for money is an important question that has not been addressed previously. Our objective was to determine the costs and benefits of decompressive hemicraniectomy in adults with hemispheric strokes associated with cerebral edema and compare these with medical therapy as an alternative treatment strategy. Cost-utility and cost-effectiveness analyses were performed. The performance of decompressive hemicraniectomy in patients with malignant MCA infarction was associated a gain of 2.77 quality adjusted life years (QAL Ys) compared to 0.84 QAL Ys for standard care. The expected cost of a surgical strategy was CAN$225 931 compared to CAN$ 101 826 for standard care. The incremental cost per QAL Y gained (ICER) of treating patients with decompressive hemicraniectomy was CAN$64 220. When the measure of effectiveness was life years gained, the incremental cost per life year gained was CAN$ 32,180. ii Sensitivity and scenario suggest a likely ICER range of 50,000 to 100,000 dollars per QAL Y gained in appropriately selected patients. Sensitivity analyses suggest that delayed surgery (beyond 48 hours) and surgery performed in older patients could be associated with a much higher ICER. We feel that decompressive hemicraniectomy should be offered to patients with large strokes complicated by cerebral edema as it is a potentially life-saving procedure in a young patient population and it has a similar ICER when compared to therapies that are already funded within the Canadian health care system. Our study results suggest that directing this surgery towards younger patients who can be operated in within 48 hours might optimize use of resources. However, it is associated with an incremental cost and decision makers will need to weight its costs and benefits with other therapies being considered for funding. ii