Taming the Biological Activity of Pd(II) and Pt(II) Complexes with Triazolato "Protective" Groups: 1H, 77Se Nuclear Magnetic Resonance and X-ray Crystallographic Model Studies with Selenocysteine to Elucidate Differential Thioredoxin Reductase Inhibition.

The biological activity of Pd(II) and Pt(II) complexes toward three different cancer cell lines as well as inhibition of selenoenzyme thioredoxin reductase (TrxR) was modulated in an unexpected way by the introduction of triazolate as a "protective group" to the inner metal coordination sphere using the iClick reaction of [M(N3)(terpy)]PF6 [M = Pd(II) or Pt(II) and terpy = 2,2':6',2″-terpyridine] with an electron-poor alkyne. In a cell proliferation assay using A549, HT-29, and MDA-MB-231 human cancer cell lines, the palladium compound was significantly more potent than the isostructural platinum analogue and exhibited submicromolar activity on the most responsive cell line. This difference was also reflected in the inhibitory efficiency toward TrxR with IC50 values of 0.1 versus 5.4 µM for the Pd(II) and Pt(II) complexes, respectively. UV/Vis kinetic studies revealed that the Pt compound binds to selenocysteine faster than to cysteine [k = (22.9 ± 0.2)·10-3 vs (7.1 ± 0.2)·10-3 s-1]. Selective triazolato ligand exchange of the title compounds with cysteine (Hcys) and selenocysteine (Hsec)─but not histidine (His) and 9-ethylguanine (9EtG)─was confirmed by 1H, 77Se, and 195Pt NMR spectroscopy. Crystal structures of three of the four ligand exchange products were obtained, including [Pt(sec)(terpy)]PF6 as the first metal complex of selenocysteine to be structurally characterized.

Electrospray Mass Spectrometry to Study Combinatorial iClick Reactions and Multiplexed Kinetics of [Ru(N3)(N∧N)(terpy)]PF6 with Alkynes of Different Steric and Electronic Demand.

In a combinatorial approach, a family of ruthenium(II) azido complexes [Ru(N3)(N∧N)(terpy)]PF6 with terpy = 2,2':6',2″-terpyridine and N∧N as a bidentate chelator derived from 2,2'-biypridine and its 4,4'-disubstituted derivatives, 2,2'-bipyrimidine, and 1,10-phenanthroline were reacted with different internal and terminal alkynes to give access to a total of 7 × 7 = 49 triazolato complexes in a room-temperature catalyst-free iClick reaction. The reactants were mixed in a repurposed high-performance liquid chromatography (HPLC) autosampler, and the reaction progress was monitored by direct injection into an electrospray mass spectrometer. The ratio of the peak intensities of [Ru(N3)(N∧N)(terpy)]+ and [Ru(triazolato)(N∧N)(terpy)]+ was converted to a colored heat map for facile visual inspection of the conversion ratio. By automated multiple injections of the reaction mixture in fixed time intervals and plotting peak intensities over reaction time, pseudo-first-order rate constants were easily determined. Finally, nonoverlapping isotope patterns of the azido starting materials and triazolato products enabled multiplexed parallel determination of rate constants for four different ruthenium(II) azido complexes from a single sample vial, thereby reducing experiment time by 75%.

Genetic and epigenetic characterization of posterior pituitary tumors.

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.

Ultrafast photochemistry of a molybdenum carbonyl-nitrosyl complex with a triazacyclononane coligand.

Transition metal complexes capable of releasing small molecules such as carbon monoxide and nitric oxide upon photoactivation are versatile tools in various fields of chemistry and biology. In this work, we report on the ultrafast photochemistry of [Mo(CO)2(NO)(iPr3tacn)]PF6 (iPr3tacn = 1,4,7-triisopropyl-1,4,7-triazacyclononane), which was characterized under continuous illumination and with femtosecond UV-pump/UV-probe and UV-pump/MIR-probe spectroscopy, as well as with stationary calculations. The experimental and theoretical results demonstrate that while the photodissociation of one of the two CO ligands upon UV excitation can be inferred both on an ultrafast timescale as well as under exposure times of several minutes, no evidence of NO release is observed under the same conditions. The binding mode of the diatomic ligands is impacted by the electronic excitation, and transient intermediates are observed on a timescale of tens of picoseconds before CO is released from the coordination sphere. Furthermore, based on calculated potential energy scans, we suggest that photolysis of NO could be possible after a subsequent excitation of an electronically excited state with a second laser pulse, or by accessing low-lying excited states that otherwise cannot be directly excited by light.

Manganese complex [Mn(CO)3(tpa-κ3N)]Br increases antibiotic sensitivity in multidrug resistant Streptococcus pneumoniae.

OBJECTIVES: The emergence of multidrug-resistance (MDR) in Streptococcus pneumoniae clones and non-vaccine serotypes necessitate the development of novel treatment strategies. This work aimed to determine the efficacy of the Mn complex [Mn(CO)3(tpa-κ3N)]Br against clinically important MDR strains of S. pneumoniae. METHODS: Twenty MDR clinicalS. pneumoniae strains were included in this study. Minimum inhibitory concentrations (MICs) of [Mn(CO)3(tpa-κ3N)]Br were determined via broth microdilution alone and in combination with other antimicrobial agents using checkerboard assays and/or disc diffusion tests. In vitro efficacy was assessed by time-kill assays while in vivo efficacy was tested using the insect model Galleria mellonella. RESULTS: [Mn(CO)3(tpa-κ3N)]Br showed moderate in vitro efficacy against S. pneumoniae coupled with bactericidal activity. Checkerboard and disc diffusion assays showed synergy between [Mn(CO)3(tpa-κ3N)]Br and tetracycline, and the combination of both agents caused rapid kill-kinetics and reduced the MIC below the susceptibility breakpoint of 1 mg/L even for tetracycline-resistant strains of S. pneumoniae. Similar results were observed for the erythromycin- and the co-trimoxazole-Mn complex combination. In the G. mellonella infection model, mortality and morbidity rates at 96 h were significantly lower in larvae treated with [Mn(CO)3(tpa-κ3N)]Br than phosphate buffered saline, while treatment with the tetracycline-Mn complex combination was superior to monotherapy, resulting in significantly lower mortality and morbidity rates (p < 0.049). CONCLUSIONS: We show that [Mn(CO)3(tpa-κ3N)]Br has in vitro and in vivo antibacterial activity against clinically relevant strains of S. pneumoniae and has the potential to be used in combination with currently available antibiotics to increase their effectiveness against MDR S. pneumoniae.

Biological activity of manganese(i) tricarbonyl complexes on multidrug-resistant Gram-negative bacteria: From functional studies to in vivo activity in Galleria mellonella.

Three new manganese(i) tricarbonyl complexes [Mn(bpqa-κ3N)(CO)3]Br, [Mn(bqpa-κ3N)(CO)3]Br, and [Mn(CO)3(tqa-κ3N)]Br as well as the previously described compound [Mn(CO)3(tpa-κ3N)]Br with bpqa = bis(2-pyridinylmethyl)(2-quinolinylmethyl)amine, bqpa = bis(2-quinolinylmethyl)(2-pyridinylmethyl)amine, tqa = tris(2-quinolinylmethyl)amine, and tpa = tris(2-pyridinylmethyl)amine were examined for their antibacterial activities on 14 different multidrug-resistant clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa, in recognition of the current antimicrobial resistance (AMR) concerns with these pathogens. Minimal inhibitory concentrations (MIC) of the most potent tqa compound were in the mid-micromolar range and generally lower than that of the free ligand. Activity against both bacterial species increased with the number of quinolinylmethyl groups and lipophilicity in the order of tpa < bpqa < bqpa ≈ tqa, consistent with measured increases in release of ATP, a uniquely cytoplasmic biomolecule and induced permeability to exogenous fluorescent intercalating compounds. [Mn(CO)3(tqa-κ3N)]Br was also evaluated in the Galleria mellonella model of infection, and displayed a lack of host toxicity combined with effective bacterial clearance.

A manganese photosensitive tricarbonyl molecule [Mn(CO)3(tpa-κ3N)]Br enhances antibiotic efficacy in a multi-drug-resistant Escherichia coli.

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ3N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ3N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ3N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ3N)]Br.

Antimicrobial Activity of the Manganese Photoactivated Carbon Monoxide-Releasing Molecule [Mn(CO)3(tpa-κ(3)N)](+) Against a Pathogenic Escherichia coli that Causes Urinary Infections.

AIMS: We set out to investigate the antibacterial activity of a new Mn-based photoactivated carbon monoxide-releasing molecule (PhotoCORM, [Mn(CO)3(tpa-κ(3)N)](+)) against an antibiotic-resistant uropathogenic strain (EC958) of Escherichia coli. RESULTS: Activated PhotoCORM inhibits growth and decreases viability of E. coli EC958, but non-illuminated carbon monoxide-releasing molecule (CORM) is without effect. NADH-supported respiration rates are significantly decreased by activated PhotoCORM, mimicking the effect of dissolved CO gas. CO from the PhotoCORM binds to intracellular targets, namely respiratory oxidases in strain EC958 and a bacterial globin heterologously expressed in strain K-12. However, unlike previously characterized CORMs, the PhotoCORM is not significantly accumulated in cells, as deduced from the cellular manganese content. Activated PhotoCORM reacts avidly with hydrogen peroxide producing hydroxyl radicals; the observed peroxide-enhanced toxicity of the PhotoCORM is ameliorated by thiourea. The PhotoCORM also potentiates the effect of the antibiotic, doxycycline. INNOVATION: The present work investigates for the first time the antimicrobial activity of a light-activated PhotoCORM against an antibiotic-resistant pathogen. A comprehensive study of the effects of the PhotoCORM and its derivative molecules upon illumination is performed and mechanisms of toxicity of the activated PhotoCORM are investigated. CONCLUSION: The PhotoCORM allows a site-specific and time-controlled release of CO in bacterial cultures and has the potential to provide much needed information on the generality of CORM activities in biology. Understanding the mechanism(s) of activated PhotoCORM toxicity will be key in exploring the potential of this and similar compounds as antimicrobial agents, perhaps in combinatorial therapies with other agents. Antioxid. Redox Signal. 24, 765-780.

Amino acid bioconjugation via iClick reaction of an oxanorbornadiene-masked alkyne with a Mn(I)(bpy)(CO)3-coordinated azide.

The catalyst-free room temperature iClick reaction of an unsymmetrically 2,3-disubstituted oxanorbornadiene (OND) as a "masked" alkyne equivalent with [Mn(N3)(bpy(CH3,CH3))(CO)3] leads to isolation of a phenylalanine ester bioconjugate, in which the model amino acid is linked to the metal moiety via a N-2-coordinated triazolate formed in a cycloaddition-retro-Diels-Alder (crDA) reaction sequence, in a novel approach to bioorthogonal coupling reactions based on metal-centered reactivity.

Introducing [Mn(CO)3(tpa-κ(3)N)](+) as a novel photoactivatable CO-releasing molecule with well-defined iCORM intermediates - synthesis, spectroscopy, and antibacterial activity.

[Mn(CO)3(tpa-κ(3)N)]Br was prepared as a novel photoactivatable CO-releasing molecule (PhotoCORM) from [MnBr(CO)5] and tris(2-pyridylmethyl)amine (tpa) for the delivery of carbon monoxide to biological systems, with the κ(3)N binding mode of the tetradentate tpa ligand demonstrated by X-ray crystallography. The title compound is a CORM prodrug stable in solution in the dark for up to 16 h. However, photoactivation at 365 nm leads to CO release from the metal coordination sphere and transfer to haem proteins, as demonstrated by the standard myoglobin assay. Different iCORM intermediates could be detected with solution IR spectroscopy and assigned using DFT vibrational calculations. The antibacterial activity of the complex was studied on Escherichia coli. No effects were observed when the cultures were either kept in the dark in the presence of PhotoCORM or illuminated in the absence of metal complex. However, photoactivation of [Mn(CO)3(tpa-κ(3)N)]Br at 365 nm led to the appearance of the spectral signatures of CO-coordinated haems in the terminal oxidases of the bacterial electron transport chain in whole-cell UV/Vis absorption spectra. Significant internalization of the PhotoCORM was demonstrated by ICP-MS measurement of the intracellular manganese concentration. In particular when using medium with succinate as the sole carbon source, a very pronounced and concentration-dependent decrease in the E. coli growth rate could be observed upon illumination in the presence of metal complex, which is attributed to the constrained energy metabolism under these conditions and a strong indicator of terminal oxidase inhibition by carbon monoxide delivered from the PhotoCORM.

New modular manganese(I) tricarbonyl complexes as PhotoCORMs: in vitro detection of photoinduced carbon monoxide release using COP-1 as a fluorogenic switch-on probe.

Five manganese(i) tricarbonyl complexes of the general formulae [Mn(bpea(N=CHC6H4R))(CO)3]PF6 and [Mn(bpea(NHCH2C6H4R))(CO)3]PF6 based on the tridentate bis(pyrazolyl)ethylamine (bpea) ligand, each containing a pendant 4-substituted phenyl group with R = H, I, and C≡C-H, were synthesized and fully characterized, including X-ray structure analysis for three compounds. All complexes are stable in the dark in aqueous buffer for an extended period of time. However, CO-release could be triggered by illumination at 365 nm, establishing these compounds as novel photoactivatable CO-releasing molecules (PhotoCORMs). The influence of the imine vs. amine group in the ligands on the electronic structure and the photophysical behavior was investigated with the aid of DFT and TDDFT calculations. Solution IR studies on selected compounds allowed identification of intermediates resulting from the photoreaction. Finally, light-induced CO release from a model compound was demonstrated both in PBS buffer and in vitro in human umbilical vein endothelial cells (HUVECs) using COP-1 as a fluorescent switch-on probe.

Ultrafast Photochemistry of a Manganese-Tricarbonyl CO-Releasing Molecule (CORM) in Aqueous Solution.

Ultraviolet irradiation of a manganese-tricarbonyl CO-releasing molecule (CORM) in water eventually leads to the liberation of some of the carbon monoxide ligands. By ultraviolet pump/mid-infrared probe femtosecond transient absorption spectroscopy in combination with quantum chemical calculations, we could disclose for the exemplary compound [Mn(CO)3(tpm)](+) (tpm = tris(2-pyrazolyl)methane) that only one of the three carbonyl ligands is photochemically dissociated on an ultrafast time scale and that some molecules may undergo geminate recombination.

Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients.

We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses.

Clinical presentation, immunohistochemistry and electron microscopy indicate neurofibromatosis type 2-associated gliomas to be spinal ependymomas.

Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome. The hallmark of NF2 is bilateral vestibular schwannoma. In addition, glioma is one of the diagnostic criteria of NF2. In this retrospective study the clinical presentation and histopathological features of 12 spinal gliomas from NF2 patients were assessed. Ten tumors were previously diagnosed as ependymomas and two as astrocytomas. However, upon re-evaluation both astrocytomas expressed epithelial membrane antigen in a dot-like fashion and in one case it was possible to perform electron microscopy revealing junctional complexes and cilia typical for ependymoma. The findings suggest that NF2-associated spinal gliomas are ependymomas. Based on the fact that NF2-associated gliomas are almost exclusively spinal and that no NF2 mutations have been found in sporadic cerebral gliomas, we suggest that "glioma" in the current diagnostic criteria for NF2 should be specified as "spinal ependymoma".

Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome.

Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder.

Efficacy and versatility of the 2-micron continuous wave laser in neuroendoscopic procedures.

Laser-assisted techniques offer a huge potential in neurosurgery, but have achieved little acceptance to date. One reason is the concern regarding heat production, uncontrollable and distant penetration, and tissue interaction.We describe our experience with a 2-micron continuous wave laser (RevoLix jr.; LISA Laser Products OHG, Katlenburg-Lindau, Germany) for neuroendoscopic intraventricular procedures.The laser beam is delivered through flexible fibers. In an aqueous medium, the effect is restricted to <2 mm in front of the tip with tissue penetration depth of 500 µm.Forty-four patients (25 adults, 19 children) were operated on using the endoscopic, laser-assisted technique for treatment of obstructive hydrocephalus (n = 39), pure cyst fenestration (n = 4), or pure tumor biopsy (n = 1). All 53 procedures were successfully performed in those 44 operations, with the laser being the main effective instrument used (except for biopsy). Besides one clinically silent small intracisternal hemorrhage and one worsening of a preexisting oculomotor palsy (following fenestration of multiple midbrain cysts), no procedure-related complications occurred.The 2-micron continuous wave laser is a most valuable and useful tool, in our experience with safe applicability for endoscopic intracranial procedures in patients of all ages.

Atypical teratoid/rhabdoid tumors may show morphological and immunohistochemical features seen in choroid plexus tumors.

Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive embryonal tumors having a poor prognosis and are associated with mutations in the tumor suppressor gene hSNF5/SMARCB1/INI1. Differential diagnosis includes choroid plexus carcinoma which has occasionally been attributed as showing an inactivation of INI1/SMARCB1 nuclear staining in immunohistochemistry. However, these findings have been challenged by others. We therefore examined eight AT/RTs from six patients by immunohistochemistry for membranous expression of the inward rectifier potassium channel Kir7.1, which was in the central nervous system so far considered specific for choroid plexus tumors and normal choroid plexus epithelium. Two AT/RT cases exhibited membranous staining of Kir7.1, indicating a plexus epithelial differentiation of these tumors. The implications of these results on tumor diagnosis are discussed.

WT1 expression in normal and neoplastic cranial and peripheral nerves is independent of grade of malignancy.

OBJECTIVE: Wilms' tumor protein (WT1) expression is usually absent in normal glial cells of the CNS but is highly upregulated in brain tumor cells and its expression correlates with tumor grade. However, knowledge on WT1 expression in tumors of the peripheral nerve system (PNS) is limited. As WT1 antibodies not only serve as biomarker for cancerous tissue but also are considered for cancer immunotherapy, knowledge of WT1 expression in tumorous and normal peripheral nerve tissue is important for therapeutical purposes. METHODS: We analyze the immunohistochemical expression of WT1 in 101 samples consisting of 13 normal nerves, 10 neurofibromas, 69 schwannomas and 9 malignant peripheral nerve sheath tumors (MPNST). Tumor samples included 14 specimen from patients with a proven neurocutaneous disorder (neurofibromatosis type 1 and 2) and 3 cases of schwannomatosis. In 50 vestibular schwannomas tumor growth extension was correlated to WT1 expression. RESULTS: WT1 expression is present in Schwann cells of the majority of normal human nerves (11/13). In peripheral nerve sheath tumors, cytoplasmic WT1 protein is expressed in the cytoplasm of the neoplastic cells in all tumors, including MPNST, neurofibromas and schwannomas. The WT1 expression is independent of tumor malignancy or tumor growth extension and is not associated with a neurocutaneous disorder. CONCLUSION: WT1 expression in normal and neoplastic tissue differs in the peripheral and the central nervous system. These findings may point to a different functional role of WT1 in the PNS and the CNS.

Continuous monitoring of cerebrovascular autoregulation after subarachnoid hemorrhage by brain tissue oxygen pressure reactivity and its relation to delayed cerebral infarction.

BACKGROUND AND PURPOSE: Disturbances of cerebrovascular autoregulation are thought to be involved in delayed cerebral ischemia and infarction after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that the continuous monitoring of brain tissue oxygen (PtiO(2)) pressure reactivity enables the detection of impaired autoregulation after SAH and that impaired autoregulation is associated with delayed infarction. METHODS: In 67 patients after severe SAH, continuous monitoring of cerebral perfusion pressure (CPP) and PtiO(2) was performed for an average of 7.4 days. For assessment of autoregulation, the index of PtiO(2) pressure reactivity (ORx) was calculated as a moving correlation coefficient between values of CPP and PtiO(2). Higher ORx values indicate disturbed autoregulation, whereas lower ORx values signify intact autoregulation. RESULTS: Twenty patients developed delayed cerebral infarction, and 47 did not. Mean ORx was significantly higher in the infarction group compared with the noninfarction group (0.43+/-0.09 vs 0.23+/-0.14, respectively; P<0.0001). In a day-by-day analysis, ORx did not differ between groups from days 1 to 4 after SAH but was significantly higher from day 5 onward in the infarction group, indicating a deficit of autoregulatory capacity. In a logistic-regression model, ORx values from days 5 and 6 after SAH carried predictive value for the occurrence of delayed infarction but before this event ultimately occurred (P=0.003). CONCLUSIONS: ORx indicates impaired autoregulation in patients who develop delayed infarction after SAH. Furthermore, this index may distinguish between patients who finally develop delayed infarction and those who do not.