The neural basis of hostility-related dimensions in schizophrenia.

Hostility and related dimensions like anger, urgency, impulsivity and aggressiveness have been described in non-clinical populations and various serious mental illnesses including schizophrenia. Although representing a mental healthcare challenge, the investigation of such constructs is often limited by the presence of complex and multi-factorial causes and lack of agreement in their conceptualisation and measurement. In this review, we aim to clarify the anatomical basis of hostility-related dimensions in schizophrenia. Imaging studies suggest malfunctioning of a neural circuitry including amygdala, striatum, prefrontal cortex, anterior cingulate cortex, insula and hippocampus to modulate hostile thoughts and behaviours, at least in the subgroup of patients with schizophrenia who exhibit high levels of urgency, impulsivity and aggressiveness.

ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects.

BACKGROUND: Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. METHOD: We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. RESULTS: We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. CONCLUSIONS: Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.

Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort.

In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.

Cortical thickness correlates of psychotic experiences: examining the effect of season of birth using a genetically informative design.

Season of birth has been shown to influence risk for several neuropsychiatric diseases. Furthermore, it has been suggested that season of birth modifies a number of brain morphological traits. Since cortical thickness alterations have been reported across some levels of the psychosis-spectrum, this study was aimed at i) assessing the scarcely explored relationship between cortical thickness and severity of subclinical psychotic experiences (PEs) in healthy subjects, and ii) evaluating the potential impact of season of birth in the preceding thickness-PEs relationship. As both PEs and brain cortical features are heritable, the current work used monozygotic twins to separately evaluate familial and unique environmental factors. High-resolution structural MRI scans of 48 twins (24 monozygotic pairs) were analyzed to estimate cortical thickness using FreeSurfer. They were then examined in relation to PEs, accounting for the effects of birth season; putative differential relationships between PEs and cortical thickness depending on season of birth were also tested. Current results support previous findings indicative of cortical thickening in healthy individuals with high psychometrically assessed psychosis scores, probably in line with theories of compensatory aspects of brain features in non-clinical populations. Additionally, they suggest distinct patterns of cortical thickness-PEs relationships depending on birth seasonality. Familial factors underlying the presence of PEs may drive these effects.

The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

PURPOSE: To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. METHOD: Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. RESULTS: In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. CONCLUSIONS: Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding.

Omega-3 fatty acid supplementation changes intracellular phospholipase A2 activity and membrane fatty acid profiles in individuals at ultra-high risk for psychosis.

The identification of an ultra-high risk (UHR) profile for psychosis and a greater understanding of its prodrome have led to increasing interest in early intervention to delay or prevent the onset of psychotic illness. In a randomized placebo-controlled trial, we have identified long-chain ω-3 (ω-3) polyunsaturated fatty acid (PUFA) supplementation as potentially useful, as it reduced the rate of transition to psychosis by 22.6% 1 year after baseline in a cohort of 81 young people at UHR of transition to psychosis. However, the mechanisms whereby the ω-3 PUFAs might be neuroprotective are incompletely understood. Here, we report on the effects of ω-3 PUFA supplementation on intracellular phospholipase A2 (inPLA(2)) activity, the main enzymes regulating phospholipid metabolism, as well as on peripheral membrane lipid profiles in the individuals who participated in this randomized placebo-controlled trial. Patients were studied cross-sectionally (n=80) and longitudinally (n=65) before and after a 12-week intervention with 1.2 g per day ω-3 PUFAs or placebo, followed by a 40-week observation period to establish the rates of transition to psychosis. We investigated inPLA(2) and erythrocyte membrane FAs in the treatment groups (ω-3 PUFAs vs placebo) and the outcome groups (psychotic vs non-psychotic). The levels of membrane ω-3 and ω-6 PUFAs and inPLA(2) were significantly related. Some of the significant associations (that is, long-chain ω-6 PUFAs, arachidonic acid) with inPLA(2) activity were in opposite directions in individuals who did (a positive correlation) and who did not (a negative correlation) transition to psychosis. Supplementation with ω-3 PUFA resulted in a significant decrease in inPLA(2) activity. We conclude that ω-3 PUFA supplementation may act by normalizing inPLA(2) activity and δ-6-desaturase-mediated metabolism of ω-3 and ω-6 PUFAs, suggesting their role in neuroprogression of psychosis.

Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia.

BACKGROUND: Recent studies have provided strong evidence that variation in the gene neurocan (NCAN, rs1064395) is a common risk factor for bipolar disorder (BD) and schizophrenia. However, the possible relevance of NCAN variation to disease mechanisms in the human brain has not yet been explored. Thus, to identify a putative pathomechanism, we tested whether the risk allele has an influence on cortical thickness and folding in a well-characterized sample of patients with schizophrenia and healthy controls. METHOD: Sixty-three patients and 65 controls underwent T1-weighted magnetic resonance imaging (MRI) and were genotyped for the single nucleotide polymorphism (SNP) rs1064395. Folding and thickness were analysed on a node-by-node basis using a surface-based approach (FreeSurfer). RESULTS: In patients, NCAN risk status (defined by AA and AG carriers) was found to be associated with higher folding in the right lateral occipital region and at a trend level for the left dorsolateral prefrontal cortex. Controls did not show any association (p > 0.05). For cortical thickness, there was no significant effect in either patients or controls. CONCLUSIONS: This study is the first to describe an effect of the NCAN risk variant on brain structure. Our data show that the NCAN risk allele influences cortical folding in the occipital and prefrontal cortex, which may establish disease susceptibility during neurodevelopment. The findings suggest that NCAN is involved in visual processing and top-down cognitive functioning. Both major cognitive processes are known to be disturbed in schizophrenia. Moreover, our study reveals new evidence for a specific genetic influence on local cortical folding in schizophrenia.

Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets.

Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples.

Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 x 10(-4) for SREBF1 (rs11868035, odd ration (OR)=1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 x 10(-5) for SREBF2 (rs1057217, OR=1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.

Dopaminergic modulation of brain systems subserving decision making under uncertainty: a study with fMRI and methylphenidate challenge.

There is evidence that the dopaminergic system is involved in probabilistic reinforcement learning and reward-related decision-making. However, little is known about the effects of external dopaminergic challenges on processing of uncertainty in decision-making tasks. Therefore, the present study examined changes in fMRI activation patterns in a natural sampling paradigm. Decision making under uncertainty was examined before and after administration of a single dose of 40 mg methylphenidate as an acute dopaminergic pharmacological challenge. We found that the level of uncertainty was positively correlated with activations in the prefrontal cortex. Conversely, negative correlations with uncertainty were found in the left hippocampus, right amygdale, and right middle temporal gyrus. The drug intervention with methylphenidate revealed a differential picture. Uncertain information processing was associated with higher activation in the parietal association cortex and posterior cingulate cortex after placebo relative to methylphenidate. The methylphenidate challenge relative to placebo was associated with higher left and right parahippocampal as well as cerebellar activation under uncertainty. Apparently, the pro-dopaminergic pharmacological influence induces a relative shift towards recruitment of hippocampal areas under uncertainty, whereas under placebo conditions, higher levels of parietal cortex activations are involved in the task. The findings suggest a role of dopamine in uncertainty processing and shed light on the pharmacological mechanisms of methylphenidate.

[Severe course of a rare non-tuberculous Mycobacteriosis (M. haemophilum) of the hand - case report and strategic comments]. / Schwerer Verlauf einer seltenen atypischen Mykobakteriose (M. haemophilum) an der Hand - Fallbericht und strategische Anmerkungen.

INTRODUCTION: Mycobacterium haemophilum belongs to the group of atypical mycobacteria and is rarely reported as a cause of upper extremity and hand infections. It is of low virulence. The bacterium seems to be ubiquitous. Sources and mechanism of infection are poorly defined. CASE REPORT: A 48-year-old female patient was admitted with chronic flexor tendon synovitis of the left palm and distal forearm site. Three debridements were carried out and wound swabs were taken. No proof of bacterial colonisation was found. Histologically a granulomatous infection with Langerhans cells was revealed. Effectively calculated monotherapy with ciprofloxacin was begun. Six weeks postoperatively Mycobacterium haemophilum was cultivated in a colaboration with the National Reference Centre for Mycobacteria in Borstel. Medication was changed to triple therapy with clarithromycin, ethambutol and rifabutin. The patient could carry out her daytime job three months postoperatively. One year after first admission functional impairment needed to be treated by scar excision and radical flexor tendon tendolysis. The palmar defect was resurfaced by using a transmetacarpal DMCA 2 flap at the same time. An almost full range of motion was achieved with intensive hand and physiotherapy after a total treatment period of 15 months. DISCUSSION: Patients with upper extremity infections caused by atypical Mycobacteria need qualified hand-surgical care. The decision about need and kind of medicamentous treatment is based on germ differentiation and should be made in cooperation with the National Reference Centre for Mycobacteria in Borstel. To shorten the diagnostic gap between first admission and detection of Mycobacteria in hand infections with a non-typical course of disease we suggest a standardised approach.

Fronto-striatal hypoactivation during correct information retrieval in patients with schizophrenia: an fMRI study.

Working memory (WM) deficits are core symptoms of schizophrenia. Differing behavioral performance is known to represent a potent moderating variable when investigating the neural correlates of working memory in patients with schizophrenia compared with healthy controls. The present functional magnetic resonance imaging study examined performance-matched cerebral activity during correct WM retrieval by balancing the mean number of correct responses as well as the mean response times between patients and controls and analyzing remaining correct trials. Forty-one schizophrenia patients and 41 healthy controls performed an event-related Sternberg task allowing for analysis of correctly remembered trials. Correct retrieval was associated with activation in a bilateral fronto-parieto-occipital network comprising mainly the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex and superior parietal cortex in controls and, to a weaker degree, in patients. Direct group comparison revealed significantly decreased activations in patients in the posterior (Brodmann area (BA) 31) and anterior (BA 32) cingulate cortex (ACC) and the medial caudate bilaterally when matching for performance. When matching for performance and response speed there was additional hypoactivation in the insula. Mean response times were negatively correlated with cingulate and caudate activation only in controls. Present findings suggest that during efficient WM retrieval processing patients exhibit only slightly impaired activation in a task-specific network containing mainly prefrontal and superior parietal areas. However, hypoactivation of areas predominantly responsible for cognitive control and response execution seems to remain even under performance-matched conditions. Given the relevant role of the caudate and the ACC in dopaminergically mediated executive processing, the results bear crucial implications for the psychopathology of schizophrenia.

Temporal modeling demonstrates preserved overlearning processes in schizophrenia: an fMRI study.

Working memory (WM) deficits are a core feature of schizophrenia. However, it has not been examined whether these deficits are related to altered temporal dynamics of information acquisition and changes in executive cognitive control. Therefore, the present study intended to quantify and model the dynamic process of information acquisition during continuous overlearning of WM information. It also aimed at investigating the relation between overlearning-associated change in behavioral performance and brain activity. Thirteen schizophrenic patients and 13 healthy volunteers were studied with functional magnetic resonance imaging (fMRI) while performing a recently developed overlearning paradigm [Koch K, Wagner G, von Consbruch K, Nenadic I, Schultz C, Ehle C, Reichenbach J, Sauer H, Schlösser R (2006) Temporal changes in neural activation during practice of information retrieval from short-term memory: An fMRI study. Brain Res 1107:140-150]. Consistent with the earlier study, short-term learning of stimulus material was associated with significant performance improvements and exponential signal decreases in a fronto-parieto-cerebellar network both in schizophrenic patients and in healthy volunteers. Against expectation patients exhibited stronger signal decreases relative to controls in anterior cingulate (Brodmann area (BA) 32), middle and superior temporal (BA 37, BA 22), superior frontal (BA 8/9, BA 6) and posterior parietal regions (BA 40). Furthermore, the individually modeled exponential decay rate of the blood oxygenation level-dependent signal in the right dorsolateral prefrontal cortex was significantly correlated with exponential decrease in mean behavioral response times in healthy controls while a statistical trend emerged in patients. A relative hyperactivation in the patient group was observable only at the start of the learning process and diminished with continued overlearning. This effect might indicate a gradual reduction of recruited neuronal resources and a practice-associated activation normalization in patients with schizophrenia. Our data suggest that in subacute patients learning and associated decreases in cerebral activation brought about by short-term practice are left unimpaired.

Deformation-based morphometry and its relation to conventional volumetry of brain lateral ventricles in MRI.

Deformation-based morphometry (DBM) is a useful technique to detect morphological differences over the entire brain since it analyses positional differences between every voxel and a standard brain. In this report we compare DBM to semimanual tracing of brain ventricles in a population of 39 patients with schizophrenia. High-resolution T(1)-weighted magnetic resonance images were obtained and processed with DBM and interactive tracing software. We evaluate the validity of the DBM in two different approaches. First, we divide subjects into two groups based on the mean ventricular/brain ratios and compute statistical maps of displacement vectors and their spatial derivatives. This analysis demonstrates a striking consistency of the DBM and visual tracing results. We show that restricting the information about the deformation fields by computing the local Jacobian determinant (as a measure of volume change) provides evidence of the shape of ventricular deformation which is unavailable from ventricular volume measures alone. Second, we compute a mean measure of the Jacobian values over the entire ventricles and observe a correlation of r = 0.962 with visual tracing based ventricular/brain ratios. The results support the usefulness and validity of DBM for the local and global examination of brain morphology.

Time estimation in schizophrenia: an fMRI study at adjusted levels of difficulty.

fMRI was performed in nine male schizophrenia patients and 15 healthy male controls during an auditory time estimation (timing), a frequency (i.e. pitch) discrimination task, and rest. An adaptive psychophysical approach, the weighted up-down method, was used to adjust individual performance to a level of 75% probability for correct answers. Although performing on the same level of individual difficulty, schizophrenia patients revealed less activations in prefrontal cortex and caudate nucleus, comparing time vs rest. Timing specific differences (i.e. timing vs pitch) between patients and controls were found in the posterior putamen, anterior thalamus, and right medial prefrontal cortex, with patients showing relative hypoactivity. Impairment in time estimation in schizophrenia might be mediated by specific fronto-thalamo-striatal dysfunction.

Hypofrontality in unmedicated schizophrenia patients studied with PET during performance of a serial verbal learning task.

Previous research indicates that verbal learning and memory deficits are among the most severe cognitive deficits observed in schizophrenia. However, the concomitant patterns of regional brain function associated with these deficits in schizophrenia are not well understood. The present study examined verbal-memory performance and simultaneous relative glucose metabolic rates (rGMR) with FDG PET in 20 unmedicated schizophrenia patients who met stringent memory-performance criteria and 32 age- and sex-matched normal volunteers. On a modified version of the California Verbal Learning Test, patients recalled fewer correct words using a semantic-clustering strategy and exhibited more intrusions compared with normal subjects. However, patients had higher serial-ordering strategy scores, indicating their use of a less efficient organizational strategy. Among patients, greater use of the serial-ordering strategy was associated with decreased rGMR in frontal cortex and increased rGMR in temporal cortex. Patients had lower rGMR primarily in frontal and temporal cortex, but not parietal and occipital lobe regions. Patients also exhibited hypofrontality (lower ratio of frontal to occipital rGMR) compared with normal subjects. Among the patients, more severe hypofrontality was associated with increased perseveration errors.

Preservation of intraalveolar surfactant in a rat lung ischaemia/reperfusion injury model.

Ischaemia/reperfusion (I/R) injury, a major problem in clinical lung transplantation, is associated with surfactant dysfunction. The present study aimed to test the hypothesis that preservation related improvements in post-ischaemic lung function are associated with improved ultrastructural preservation of pulmonary surfactant. Rat lungs were flush perfused with modified Euro-Collins solutions (ECS), stored for 2 h at 4 degrees C, and reperfused for 40 min. Lungs were preserved with conventional (ECS 115: 115 mmol x L(-1) K+), medium-K+ (ECS 40: 40 mmol x L(-1) K+), or low-K+ (ECS 10: 10 mmol x L(-1) K+) ECS. Functional parameters were monitored during reperfusion (n=10 per group). After reperfusion, left lungs were prepared for electron microscopical and stereological analysis of surfactant (n=5 per group). In all three experimental groups notable I/R injury developed which was lowest in ECS 40 as indicated by significantly less intraalveolar oedema, higher perfusate oxygenation, and lower peak inspiratory pressure. This was associated with a significantly superior preservation of the ultrastructure of the surface active surfactant subtype tubular myelin in ECS 40 compared with ECS 115 and ECS 10. Stereological analysis revealed that the relative amount of tubular myelin was highest in ECS 40 (mean+/-SEM; 6.2+/-0.8%) compared with ECS 115 (3.0+/-1.0%) and ECS 10 (2.7+/-1.6%). Analysis of surfactant in its natural location within the organ showed that the severity of ischaemia/reperfusion injury correlates with differences in intraalveolar surfactant composition. Improved post-ischaemic respiratory function achieved by medium-K+ Euro-Collins solution is associated with superior ultrastructural preservation of tubular myelin. It is concluded that the integrity of surface active tubular myelin represents an important criterion for the assessment of lung preservation quality.

Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion.

Ischemia and reperfusion (I/R) result in surfactant dysfunction. Whether the impairment of surfactant is a consequence or a cause of intraalveolar edema formation is still unknown. The cumulative effects of lung perfusion, ischemic storage, and subsequent reperfusion on surfactant ultrastructure and pulmonary function were studied in a rat isolated perfused lung model. The left lungs were fixed for electron microscopy by vascular perfusion either immediately after excision (control; n = 5) or after perfusion with modified Euro-Collins solution (EC), storage for 2 h at 4 degrees C in EC, and reperfusion for 40 min (n = 5). A stereological approach was chosen to discriminate between intraalveolar surfactant subtypes of edematous regions and regions free of edema. Intraalveolar edema seen after I/R in the EC group occupied 36 +/- 6% (mean +/- SEM) of the gas exchange region as compared with control lungs (1 +/- 1%; p = 0.008). Relative intraalveolar surfactant composition showed a decrease in surface active tubular myelin (3 +/- 1 versus 12 +/- 0%; p = 0.008) and an increase in inactive unilamellar forms (83 +/- 2 versus 64 +/- 5%; p = 0.008) in the EC group. These changes occurred both in edematous (tubular myelin, 3 +/- 1%; unilamellar forms, 88 +/- 6%) and in nonedematous regions (tubular myelin, 4 +/- 3%; unilamellar forms, 77 +/- 5%). The ultrastructural changes in surfactant were associated with an increase in peak inspiratory pressure during reperfusion. In conclusion, surfactant alterations seen after I/R are not directly related to the presence of edema fluid in the alveoli. Disturbances in intraalveolar surfactant after I/R are not merely the result of inactivation due to plasma protein leakage but may instead be responsible for an increased permeability of the blood-air barrier, resulting in a vicious cycle of intraalveolar edema formation and progressing surfactant impairment.