Which compartments of the optic nerve and its sheath are associated with intracranial pressure? An exploratory study.

BACKGROUND AND PURPOSE: The optic nerve sheath diameter (ONSD) is a commonly used estimate of intracranial pressure (ICP). The rationale behind this is that pressure changes in the cerebrospinal fluid affect the optic nerve subarachnoid space (ONSAS) thickness. Still, possible effects on other compartments of the optic nerve sheath (ONS) have not been studied. This is the first study ever to analyze all measurable compartments of the ONS for associations with elevated ICP. METHODS: We measured changes in ICP and changes in ONS compartments in 75 patients treated with invasive ICP monitoring at the Karolinska University Hospital. Associations between changes in ICP and changes in ONS compartments were estimated with generalized estimating equations. The potential to identify elevated ICP was assessed with the area under the receiver operating characteristic curve (AUROC) for ONS compartments associated with ICP changes. RESULTS: Both ONSAS and perioptic dura mater thickness were significantly associated with changes in ICP in multivariable modeling. ONSAS was the only compartment that independently predicted changes in ICP, with an AUROC of 0.69 for predicting ICP increase. Still, both the perioptic dura mater thickness and the optic nerve diameter added value in predicting ICP changes in multivariable modeling. CONCLUSIONS: The results from this study challenge the current understanding of the mechanism behind the association between ICP and ONSD. Contrary to the common opinion that ONSAS is the only affected compartment, this study shows a more complex picture. It suggests that all ONS compartments may add value in predicting changes in ICP.

Sex differences in the diagnostic value of optic nerve sheath diameter for assessing intracranial pressure.

The optic nerve sheath diameter (ONSD) can predict elevated intracranial pressure (ICP) but it is not known whether diagnostic characteristics differ between men and women. This observational study was performed at the Karolinska University Hospital in Sweden to assess sex differences in diagnostic accuracy for ONSD. We included 139 patients (65 women), unconscious and/or sedated, with invasive ICP monitoring. Commonly used ONSD derived measurements and associated ICP measurements were collected. Linear regression analyses were performed with ICP as dependent variable and ONSD as independent variable. Area under the receiver operator characteristics curve (AUROC) analyses were performed with a threshold for elevated ICP ≥ 20 mmHg. Analyses were stratified by sex. Optimal cut-offs and diagnostic characteristics were estimated. The ONSD was associated with ICP in women. The AUROCs in women ranged from 0.70 to 0.83. In men, the ONSD was not associated with ICP and none of the AUROCs were significantly larger than 0.5. This study suggests that ONSD is a useful predictor of ICP in women but may not be so in men. If this finding is verified in further studies, this would call for a re-evaluation of the usage and interpretation of ONSD to estimate ICP.

Optic nerve sheath diameter is associated with outcome in severe Covid-19.

Neurological symptoms are common in Covid-19 and cerebral edema has been shown post-mortem. The mechanism behind this is unclear. Elevated intracranial pressure (ICP) has not been extensively studied in Covid-19. ICP can be estimated noninvasively with measurements of the optic nerve sheath diameter (ONSD). We performed a cohort study with ONSD ultrasound measurements in severe cases of Covid-19 at an intensive care unit (ICU). We measured ONSD with ultrasound in adults with severe Covid-19 in the ICU at Karolinska University Hospital in Sweden. Patients were classified as either having normal or elevated ONSD. We compared ICU length of stay (ICU-LOS) and 90 day mortality between the groups. 54 patients were included. 11 of these (20.4%) had elevated ONSD. Patients with elevated ONSD had 12 days longer ICU-LOS (95% CI 2 to 23 p = 0.03) and a risk ratio of 2.3 for ICU-LOS ≥ 30 days. There were no significant differences in baseline data or 90 day mortality between the groups. Elevated ONSD is common in severe Covid-19 and is associated with adverse outcome. This may be caused by elevated ICP. This is a clinically important finding that needs to be considered when deciding upon various treatment strategies.

Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates.

Leukotriene (LT) A(4) hydrolase is a bifunctional zinc metalloenzyme, which converts LTA(4) into the neutrophil chemoattractant LTB(4) and also exhibits an anion-dependent aminopeptidase activity. In the x-ray crystal structure of LTA(4) hydrolase, Arg(563) and Lys(565) are found at the entrance of the active center. Here we report that replacement of Arg(563), but not Lys(565), leads to complete abrogation of the epoxide hydrolase activity. However, mutations of Arg(563) do not seem to affect substrate binding strength, because values of K(i) for LTA(4) are almost identical for wild type and (R563K)LTA(4) hydrolase. These results are supported by the 2.3-A crystal structure of (R563A)LTA(4) hydrolase, which does not reveal structural changes that can explain the complete loss of enzyme function. For the aminopeptidase reaction, mutations of Arg(563) reduce the catalytic activity (V(max) = 0.3-20%), whereas mutations of Lys(565) have limited effect on catalysis (V(max) = 58-108%). However, in (K565A)- and (K565M)LTA(4) hydrolase, i.e. mutants lacking a positive charge, values of the Michaelis constant for alanine-p-nitroanilide increase significantly (K(m) = 480-640%). Together, our data indicate that Arg(563) plays an unexpected, critical role in the epoxide hydrolase reaction, presumably in the positioning of the carboxylate tail to ensure perfect substrate alignment along the catalytic elements of the active site. In the aminopeptidase reaction, Arg(563) and Lys(565) seem to cooperate to provide sufficient binding strength and productive alignment of the substrate. In conclusion, Arg(563) and Lys(565) possess distinct roles as carboxylate recognition sites for two chemically different substrates, each of which is turned over in separate enzymatic reactions catalyzed by LTA(4) hydrolase.

Leukotriene A4 hydrolase.

The leukotrienes (LTs) are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4 is a classical chemoattractant, which triggers adherence and aggregation of leukocytes to the endothelium at only nanomolar concentrations. In addition, leukotriene B4 modulates immune responses, participates in the host-defense against infections, and is a key mediator of PAF-induced lethal shock. Because of these powerful biological effects, leukotriene B4 is implicated in a variety of acute and chronic inflammatory diseases, e.g. nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease. The final step in the biosynthesis of leukotriene B4 is catalyzed by leukotriene A4 hydrolase, a unique bi-functional zinc metalloenzyme with an anion-dependent aminopeptidase activity. Here we describe the most recent developments regarding our understanding of the structure, function, and catalytic mechanisms of leukotriene A4 hydrolase.

Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375.

Leukotriene A4 (LTA4, 5S-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) hydrolase (LTA4H)/aminopeptidase is a bifunctional zinc metalloenzyme that catalyzes the final and rate-limiting step in the biosynthesis of leukotriene B4 (LTB4, 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid), a classical chemoattractant and immune modulating lipid mediator. Two chemical features are key to the bioactivity of LTB4, namely, the chirality of the 12R-hydroxyl group and the cis-trans-trans geometry of the conjugated triene structure. From the crystal structure of LTA4H, a hydrophilic patch composed of Gln-134, Tyr-267, and Asp-375 was identified in a narrow and otherwise hydrophobic pocket, believed to bind LTA4. In addition, Asp-375 belongs to peptide K21, a previously characterized 21-residue active site-peptide to which LTA4 binds during suicide inactivation. In the present report we used site-directed mutagenesis and x-ray crystallography to show that Asp-375, but none of the other candidate residues, is specifically required for the epoxide hydrolase activity of LTA4H. Thus, mutation of Asp-375 leads to a selective loss of the enzyme's ability to generate LTB4 whereas the aminopeptidase activity is preserved. We propose that Asp-375, possibly assisted by Gln-134, acts as a critical determinant for the stereoselective introduction of the 12R-hydroxyl group and thus the biological activity of LTB4.

Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms.

Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into leukotriene B(4), a potent chemoattractant and immune-modulating lipid mediator. Recently, the structure of leukotriene A(4) hydrolase revealed that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of zinc peptidases, and Gln-136 are located at the active site. Here we report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed minimal conformational changes that could not explain the loss of enzyme function. We propose that the carboxylate of Glu-271 participates in an acid-induced opening of the epoxide moiety of leukotriene A(4) and formation of a carbocation intermediate. Moreover, Glu-271 appears to act as an N-terminal recognition site and may potentially stabilize the transition-state during turnover of peptides, a property that most likely pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate functions in two different catalytic reactions, involving lipid and peptide substrates, respectively.