Measurements of cortical cellular pH by intracranial tonometer in severe head injury

Yamamoto, Yasuhiro; Naoe, Yasutaka; Fuse, Akira; Sato, Hidetaka; Unemoto, Kyoko; Kurokawa, Akira

doi:10.1097/00003246-200009000-00025

Cited by 19 publications

(13 citation statements)

References 17 publications

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“…15,20 It has also been previously demonstrated that following human TBI, acidosis is associated with deranged lactate metabolism and increased mortality. 18,21,22 However, the relationship between hypoxia and acidosis and their impact on energy metabolism, including other biochemical markers, in our view warrants further exploration. The aim of the present study was, therefore, to test the hypothesis that the presence of cerebral acidosis with or without hypoxia indicates a more profound metabolic derangement, compared with the periods of hypoxia without acidosis or when normal oxygenation and pH are present.…”

Section: Introductionmentioning

confidence: 80%

Extracellular Brain Ph with or without Hypoxia is a Marker of Profound Metabolic Derangement and Increased Mortality after Traumatic Brain Injury

Timofeev

Nortje

Al-Rawi

et al. 2012

J Cereb Blood Flow Metab

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Cerebral hypoxia and acidosis can follow traumatic brain injury (TBI) and are associated with increased mortality. This study aimed to evaluate a relationship between reduced pH bt and disturbances of cerebral metabolism. Prospective data from 56 patients with TBI, receiving microdialysis and Neurotrend monitoring, were analyzed. Four tissue states were defined based on pH bt and P bt O 2 : 1-low P bt O 2 /pH bt , 2-low pH bt /normal P bt O 2 , 3-normal pH bt /low P bt O 2 , and 4-normal pH bt /P bt O 2 ). Microdialysis values were compared between the groups. The relationship between P bt O 2 and lactate/pyruvate (LP) ratio was evaluated at different pH bt levels. Proportional contribution of each state was evaluated against mortality. As compared with the state 4, the state 3 was not different, the state 2 exhibited higher levels of lactate, LP, and glucose and the state 1-higher LP and reduced glucose (Po0.001). A significant negative correlation between LP and P bt O 2 (rho ¼ À 0.159, Po0.001) was stronger at low pH bt (rho ¼ À 0.201, Po0.001) and nonsignificant at normal pH bt (P ¼ 0.993). The state 2 was a significant discriminator of mortality categories (P ¼ 0.031). Decreased pH bt is associated with impaired metabolism. Measuring pH bt with P bt O 2 is a more robust way of detecting metabolic derangements.

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Section: Introductionmentioning

confidence: 80%

Extracellular Brain Ph with or without Hypoxia is a Marker of Profound Metabolic Derangement and Increased Mortality after Traumatic Brain Injury

Timofeev

Nortje

Al-Rawi

et al. 2012

J Cereb Blood Flow Metab

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“…Ischemia produces decreases in pHi in brain 9 and heart 8 and decreases cell-cell coupling. 6,7 Whereas rapid uncoupling in response to low pHi apparently involves conformational changes in the connexin molecule itself, 12 prolonged intracellular acidification induces relocalization of Cx43 protein from the plasma membrane to the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…9 Cardiac ischemia leads to electrical uncoupling 10 as well as to dephosphorylation and internalization of Cx43. 11 Changes in the composition of gap junction complexes attributable to sustained intracellular acidification may therefore be fundamental in determining the extent of ischemic damage and, in the case of heart, development of life-threatening ventricular arrhythmias.…”

mentioning

confidence: 99%

Regulation of Connexin43 Protein Complexes by Intracellular Acidification

Duffy

Ashton

O’Donnell

et al. 2004

Circulation Research

121

108

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Abstract-Ischemia-induced acidification of astrocytes or cardiac myocytes reduces intercellular communication by closing gap junction channels and subsequently internalizing gap junction proteins. To determine whether such coupling changes might be attributable to altered interactions between connexin43 (Cx43) and other proteins, we applied the nigericin/high K ϩ method to vary intracellular pH (pHi) in cultured cortical astrocytes. Intracellular acidification was accompanied by internalization of Cx43 with retention of Cx43 scaffolding protein Zonula Occludens-1 (ZO-1) at cell surfaces, suggesting that ZO-1 and Cx43 dissociate at low pHi. Coimmunoprecipitation studies revealed decreased binding of ZO-1 and increased binding of c-Src to Cx43 at low pHi. Resonant mirror spectroscopy was used to quantify binding of the SH3 domain of c-Src and the PDZ domains of ZO-1 to the carboxyl terminal domain of Cx43 (Cx43CT). Data indicate that the c-Src/Cx43CT interaction is highly pH dependent whereas the ZO-1/Cx43CT interaction is not. Moreover, binding of c-Src to Cx43CT prevented and reversed ZO-1/Cx43CT binding. We hypothesize that increased affinity of c-Src for Cx43 at low pHi aids in separation of Cx43 from ZO-1 and that this may facilitate internalization of Cx43. These data suggest that protracted acidification may remodel protein-protein interactions involving Cx43 and thus provide an important protective mechanism to limit lesion spread after ischemic injury. Key Words: gap junctions Ⅲ ischemia Ⅲ protein-protein interactions Ⅲ resonant mirror spectroscopy Ⅲ central nervous system C onnexins are membrane proteins that oligomerize to form gap junction channels, through which ions and small molecules diffuse between cells. The present view is that these channels are not passive pores insulated from the rest of the molecular environment but rather are dynamic protein complexes that can both filter and amplify passage of information between cells. Among proteins known to associate with Connexin43 (Cx43) (the most abundant gap junction in heart and in astrocytes 1 ) are the scaffolding protein Zonula Occludens-1 (ZO-1) and the tyrosine kinase c-Src. [2][3][4][5] Recent studies show that this association is potentially interlinked, because binding of Cx43 to constitutively active c-Src is correlated with a decrease in the Cx43/ZO-1 interaction. 4,5 Still unclear are whether there is a direct interdependence to these interactions and whether these associations are modified by factors that close gap junctions. The present study centers on the pH dependence of interactions of Cx43 with ZO-1 and c-Src.Intracellular acidification leads to closure of gap junction channels, 6,7 which is relevant in the context of ischemia, where a drop in intracellular pH (pHi) has been demonstrated both in heart 8 and in brain. 9 Cardiac ischemia leads to electrical uncoupling 10 as well as to dephosphorylation and internalization of Cx43. 11 Changes in the composition of gap junction complexes attributable to sustained intracellular acidifi...

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“…Specific agonal conditions, including coma, hypoxia, pyrexia, seizures, dehydration, hypoglycemia, multiple organ failure, head injury, and ingestion of neurotoxic substances at time of death have been evaluated with regard to influences on brain acidosis and RNA integrity in postmortem brain tissues (Barton et al 1993;Harrison et al 1991aHarrison et al , 1991b Harrison et al , 1994bHarrison et al , 1995Hynd et al 2003; Johnston et al 1997;Miller et al 1990;Morrison-Bogorad et al 1995;Roberge and Krenzelok 2001;Yokota et al 2000). The combination of these specific agonal conditions and the duration of the agonal phase, which might adversely affect RNA integrity in postmortem brain tissue (Barton et al 1993;Hardy et al 1985;Harrison et al 1991a; Johnston et al 1997;Wester et al 1985), are referred to as agonal factors.…”

Section: Evaluation Of Agonal and Postmortem Factorsmentioning

confidence: 99%

Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain

Tomita

Vawter

Walsh

et al. 2004

Biological Psychiatry

303

260

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There are major concerns that specific agonal conditions, including coma and hypoxia, might affect ribonucleic acid (RNA) integrity in postmortem brain studies. We report that agonal factors significantly affect RNA integrity and have a major impact on gene expression profiles in microarrays. In contrast to agonal factors, gender, age, and postmortem factors have less effect on gene expression profiles. The Average Correlation Index is proposed as a method for evaluating RNA integrity on the basis of similarity of microarray profiles. Reducing the variance due to agonal factors is critical in investigating small but validated gene expression differences in messenger RNA levels between psychiatric patients and control subjects. KeywordsAdenine; Uracil-rich elements; bipolar disorder; freezer interval; iron-responsive element; major depressive disorder; postmortem interval Microarray studies using postmortem brains have become particularly valuable in profiling gene expression patterns related to psychiatric disorders of unknown etiology (Bahn et al 2001;Bunney et al 2003;Hakak et al 2001;Mirnics et al 2001;Van Deerlin et al 2002). In studies using postmortem brain tissue, the variability of ribonucleic acid (RNA) integrity has been a major concern. There have been two major factors that affect RNA integrity in gene expression studies using postmortem brain: 1) agonal factors, defined as specific agonal conditions at the time of death and agonal duration; and 2) postmortem factors, defined as the condition of the postmortem brain tissue after death, including the delay between death and the time the tissue is frozen (postmortem interval [PMI]) and the duration the brain tissue is stored in a freezer (freezer interval [FI]). Prior studies have indicated that agonal factors markedly affect the integrity of RNA, whereas postmortem factors have relatively small effects on RNA integrity (Bahn et al 2001;Barton et al 1993;Gilmore et al 1993;Harrison et al 1995;Johnson et al 1986;Kingsbury et al 1995;Leonard et al 1993;Perrett et al 1988;Ravid et al 1992;Van Deerlin et al 2002). However, because messenger (m)RNAs have been shown to vary in their vulnerability to agonal factors (Barton et al 1993;Burke et al 1991;Harrison et al 1994Harrison et al , 1995, attention should be drawn to the limitation of previous postmortem studies in this area, in which investigators have only analyzed restricted numbers of transcripts. Expression data for thousands of genes obtained by microarray technology facilitate a comprehensive evaluation of the integrity of RNA samples.In this article, we discuss issues concerning evaluation of agonal and postmortem factors and RNA integrity in microarray study of postmortem brains. The hypothesis raised in the present study was that agonal factors adversely affect integrity of mRNAs and influence microarray expression profiles more than the postmortem factor or other biological factors, such as gender, age, or diagnosis of psychiatric disorder. The hypothesis was tested with 40 well-characte...

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Measurements of cortical cellular pH by intracranial tonometer in severe head injury

Abstract: Our study suggests the usefulness of measurement of cortical cellular pH by intracranial tonometer for evaluating the severity of focal anaerobic cerebral metabolism and predicting patient prognosis.

Cited by 19 publications

References 17 publications

Extracellular Brain Ph with or without Hypoxia is a Marker of Profound Metabolic Derangement and Increased Mortality after Traumatic Brain Injury

Extracellular Brain Ph with or without Hypoxia is a Marker of Profound Metabolic Derangement and Increased Mortality after Traumatic Brain Injury

Regulation of Connexin43 Protein Complexes by Intracellular Acidification

Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain

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