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Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC)., Methods: Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months., Results: In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported., Conclusions: In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626)., Clinical Trial Registration: NCT03694522., (© 2024. The Author(s).)

Background: Outcomes are poor in patients with HER2-negative, advanced gastric or gastro-oesophageal junction adenocarcinomas. In this study, we investigated efficacy and safety of the first-in-class, afucosylated, humanised IgG1 anti-fibroblast growth factor receptor 2 isoform IIb (FGFR2b) monoclonal antibody bemarituzumab with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma., Methods: In the randomised, double-blind, placebo-controlled phase 2 trial (FIGHT), patients aged 18 years and older with HER2 non-positive, FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 were recruited from 144 clinical sites across 17 countries. Patients with previous treatment with any selective inhibitor of the FGF-FGFR pathway were excluded. Eligible patients were randomly assigned (1:1), using permuted-block randomisation (block size of four) and a central interactive voice-web-based response system, stratified by geographical region, previous treatment with curative intent, and administration of mFOLFOX6 while being screened for FGFR2b status, to either bemarituzumab (15 mg/kg of bodyweight) or matched placebo intravenously every 2 weeks. All patients also received mFOLFOX6 (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , and 5-fluorouracil as a 400 mg/m 2 bolus followed by 2400 mg/m 2 over approximately 46 h) intravenously every 2 weeks. Patients were given treatment until disease progression (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1), unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all patients randomly assigned to treatment). Safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, NCT03694522, and is now complete., Findings: Between Nov 14, 2017, and May 8, 2020, 910 patients were screened and 155 were randomly assigned to the bemarituzumab (n=77) or placebo group (n=78). Median age was 60·0 years (IQR 51·0-67·0), 44 (28%) participants were women, 111 (72%) were men, 89 (57%) were Asian, and 61 (39%) were White. At the time of the primary analysis and at a median follow-up of 10·9 months (IQR 6·3-14·2), median progression-free survival was 9·5 months (95% CI 7·3-12·9) in the bemarituzumab group and 7·4 months (5·8-8·4) in the placebo group (hazard ratio [HR] 0·68 [95% CI 0·44-1·04; p=0·073). Common grade 3 or worse adverse events were decreased neutrophil count (23 [30%] of 76 in the bemarituzumab group vs 27 [35%] of 77 in the placebo group), cornea disorder (18 [24%] vs none), neutropenia (ten [13%] vs seven [9%]), stomatitis (seven [9%] vs one [1%]), and anaemia (six [8%] vs ten [13%]). Serious treatment-emergent adverse events were reported in 24 (32%) patients in the bemarituzumab group and 28 (36%) in the placebo group. Serious mFOLFOX6 treatment-related adverse events occurred in nine (12%) patients in the bemarituzumab group and in 15 (19%) patients in the placebo group. All-grade corneal events (adverse events of special interest) occurred in 51 (67%) patients in the bemarituzumab group and eight (10%) in the placebo group; grade 3 corneal events were reported only in 18 (24%) patients in the bemarituzumab group. Treatment-related deaths occurred in three patients in the bemarituzumab group (two due to sepsis, one due to pneumonia) and none in the placebo group., Interpretation: In this exploratory phase 2 study, despite no statistically significant improvement in progression-free survival, treatment with bemarituzumab showed promising clinical efficacy. Confirmatory phase 3 trials of bemarituzumab plus mFOLFOX6 powered to demonstrate statistical significance are being investigated in patients with previously untreated, FGFR2b-overexpressing, advanced gastric or gastro-oesophageal junction adenocarcinoma., Funding: Five Prime Therapeutics., Competing Interests: Declaration of interests ZAW reports fees for consulting or advisory roles from Array BioPharma, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Five Prime Therapeutics, Ipsen, Lilly, Macrogenics, Merck, Merck KGaA, and Novartis; research funding paid to their institution from Five Prime Therapeutics, Merck, Novartis, Pfizer, and Plexxikon; and travel, accommodations, and expenses from Bayer, Lilly, and Merck. PCE reports fees for consulting or advisory roles from ALX Oncology, Arcus Biosciences, Astellas, AstraZeneca, Blueprint Medicines, Chimeric Therapeutics, Celgene, Coherus, Daiichi Sankyo, Five Prime Therapeutics, Ideava, Istari, Legend, Lilly, Loxo, Merck, Novartis, Ono, Servier, Taiho, Takeda, Turning Point Therapeutics, Xencor, and Zymeworks. Y-KK reports fees for consulting or advisory roles from ALX Oncology, Amgen, Bristol-Myers Squibb, DAEHWA Pharmaceutical, Macrogenics, Novartis, Surface Oncology, and Zymeworks. KY reports fees for consulting or advisory roles from Bristol-Myers Squibb Japan and Daiichi Sankyo; fees for speakers' bureau participation from Bristol-Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Lilly, Merck, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda; and research funding paid to their institution from Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, MSD Oncology, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, and Yakult Honsha. AS reports fees for consulting or advisory roles from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo/UCB Japan, Exelixis, Five Prime Therapeutics, Merck Sharp & Dohme, and Pfizer; and research funding paid to their institution from Actuate Therapeutics, Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Daiichi Sankyo/UCB Japan, Exelixis, Five Prime Therapeutics, KAHR Medical, Merck Sharp & Dohme, and Seattle Genetics. JL reports fees for speakers' bureau participation from AstraZeneca and Lilly. AT reports fees for participation on advisory boards from Roche, Novartis, Pfizer, and Merck Serono. CB reports fees for consulting or advisory roles from Merck Sharp & Dohme, Pierre Fabre, Roche, and SERVIER; research funding from Roche; and travel, accommodation, and expenses from Amgen, Bayer, and Merck Sharp & Dohme. AAU reports travel, accommodation, and expenses from Amgen, Angellini, Janssen, Merck Sharp & Dohme, Pfizer, and Roche. GGC reports travel, accommodation, and expenses from Lilly, Merck Sharp & Dohme, and Roche. HC and YY report employment with Five Prime Therapeutics and stock and other ownership interests in Five Prime Therapeutics. SM reports employment with Five Prime Therapeutics and Gilead Sciences, and stock and other ownership interests in Five Prime Therapeutics and Gilead Sciences. DVTC reports honoraria from Amgen, Archer, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo/UCB Japan, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, Gritstone Bio, Guardant Health, Lilly, Merck, Natera, Pieris Pharmaceuticals, QED Therapeutics, Seattle Genetics, Taiho Pharmaceutical, Tempus, and Zymeworks; fees for consulting or advisory roles from Amgen, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo/UCB Japan, Genentech/Roche, Guardant Health, Lilly, Merck, Seattle Genetics, Taiho Pharmaceutical, and Zymeworks; and fees for speakers' bureau participation from Foundation Medicine, Genentech, Guardant Health, Lilly, Merck, and Tempus. K-WL reports honoraria from Bristol-Myers Squibb, Genexine, and Lilly; fees for consulting or advisory roles from Bayer and ISU Abxis; research funding paid to their institution from ABL Bio, ALX Oncology, Array BioPharma, AstraZeneca/MedImmune, BeiGene, Daiichi Sankyo, Five Prime Therapeutics, Green Cross, LSK BioPharma, MacroGenics, Merck KGaA, Merck Sharp & Dohme, Oncologie, Ono Pharmaceutical, Pfizer, Pharmacyclics, Taiho Pharmaceutical, Y-Biologics, and Zymeworks. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

O - GlcNAcylation of serine/threonine residues on target proteins occurs dynamically in postmitotic neurons of the hippocampus and may serve to control both the stability and activity of target proteins. Remarkably, the addition and removal of the O-GlcNAc posttranslational modifications are catalyzed by a pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). More than thousands of proteins are modified by O-GlcNAcylation including epigenetic modifying enzymes. A critical target of OGT is the polycomb repressive complex 2 (PRC2) containing the histone lysine methyltransferase EZH2 that mediates trimethylation of lysine 27 on histone H3 (H3K27me3). However, whether OGT and PRC2 activity in the hippocampus couple to regulate gene transcription mechanisms during memory consolidation remains unknown. Here, we found increases in OGT expression and global O-GlcNAcylation levels in dorsal area CA1 of the hippocampus during memory consolidation. Additionally, we observed that OGT exerts control over epigenetic regulation via EZH2-H3K27me3 during memory consolidation. Blocking O-GlcNAc signaling via RNAi within dorsal area CA1 led to the global and site-specific loss of activity-dependent epigenetic plasticity at genes regulated by H3K27me3 and impairment of hippocampus-dependent memory. Together, these findings illustrate a unique epigenetic role of OGT via regulation of histone methylation mediated by EZH2 during memory consolidation of fear conditioned memories., (© 2019 Butler et al.; Published by Cold Spring Harbor Laboratory Press.)

Tumorigenic and non-neoplastic tissue injury occurs via the ischemic microenvironment defined by low oxygen, pH, and nutrients due to blood supply malfunction. Ischemic conditions exist within regions of pseudopalisading necrosis, a pathological hallmark of glioblastoma (GBM), the most common primary malignant brain tumor in adults. To recapitulate the physiologic microenvironment found in GBM tumors and tissue injury, we developed an in vitro ischemic model and identified chromodomain helicase DNA-binding protein 7 (CHD7) as a novel ischemia-regulated gene. Point mutations in the CHD7 gene are causal in CHARGE syndrome (a developmental disorder causing coloboma, heart defects, atresia choanae, retardation of growth, and genital and ear anomalies) and interrupt the epigenetic functions of CHD7 in regulating neural stem cell maintenance and development. Using our ischemic system, we observed microenvironment-mediated decreases in CHD7 expression in brain tumor-initiating cells and neural stem cells. Validating our approach, CHD7 was suppressed in the perinecrotic niche of GBM patient and xenograft sections, and an interrogation of patient gene expression datasets determined correlations of low CHD7 with increasing glioma grade and worse patient outcomes. Segregation of GBM by molecular subtype revealed a novel observation that CHD7 expression is elevated in proneural versus mesenchymal GBM. Genetic targeting of CHD7 and subsequent gene ontology analysis of RNA sequencing data indicated angiogenesis as a primary biological function affected by CHD7 expression changes. We validated this finding in tube-formation assays and vessel formation in orthotopic GBM models. Together, our data provide further understanding of molecular responses to ischemia and a novel function of CHD7 in regulating angiogenesis in both neoplastic and non-neoplastic systems. Stem Cells 2019;37:453-462., (© AlphaMed Press 2019.)

Background: Data on the true burden of hyperkalemia (HK) in patients with chronic kidney disease (CKD) in a real-world setting are scarce., Methods: The incidence rate of HK [first blood test with an elevated blood potassium level level >5.0 mmol/L] in primary or hospital care was assessed in a population-based cohort of all newly diagnosed CKD patients [second estimated glomerular filtration rate (eGFR) measurement <60 mL/min/1.73 m2 or hospital diagnosis] in northern Denmark. Risk factors and clinical outcomes were compared for CKD patients with HK and matched CKD patients without HK., Results: Of 157 766 patients with CKD, 28% experienced HK, for an overall HK incidence rate of 70/1000 person-years. Among patients with Stage 3A, 3B, 4 or 5 CKD, 9, 18, 31 and 42%, respectively, experienced HK within the first year. Important HK risk factors included diabetes {prevalence ratio [PR] 1.74 [95% confidence interval (CI) 1.69-1.79]}, heart failure [PR 2.31 (95% CI 2.23-2.40)] and use of angiotensin-converting enzyme inhibitors [PR 1.45 (95% CI 1.42-1.48)], potassium supplements [PR 1.59 (95% CI 1.55-1.62)] or spironolactone [PR 2.53 (95% CI 2.44-2.63)]. In CKD patients who developed HK, 34% had any acute hospitalization 6 months before the HK event, increasing to 57% 6 months after HK [before-after risk ratio 1.72 (95% CI 1.69-1.74)]. The 6-month mortality following HK was 26%, versus 6% in matched non-HK patients. Compared with non-HK patients, 6-month hazard ratios for any acute hospitalization in HK patients were 2.11-fold higher, including hazard ratios of 2.07 for cardiac diagnoses, 2.29 for ventricular arrhythmias, 3.26 for cardiac arrest, 4.77 for intensive care and 4.85 for death., Conclusions: More than one in four CKD patients develops HK. Patients with severe CKD, diabetes, heart failure or use of spironolactone are at high risk. HK is associated with severe clinical outcomes.

Epigenetic mechanisms such as DNA methylation and histone methylation are critical regulators of gene transcription changes during memory consolidation. However, it is unknown how these epigenetic modifications coordinate control of gene expression following reactivation of a previously consolidated memory. Here, we found that retrieval of a recent contextual fear conditioned memory increased global levels of H3 lysine 4-trimethylation (H3K4me3) and DNA 5-hydroxymethylation (5hmC) in area CA1 of the dorsal hippocampus. Further experiments revealed increased levels of H3K4me3 and DNA 5hmC within a CpG-enriched coding region of the Npas4, but not c-fos, gene. Intriguingly, retrieval of a 30-day old memory increased H3K4me3 and DNA 5hmC levels at a CpG-enriched coding region of c-fos, but not Npas4, in the anterior cingulate cortex, suggesting that while these two epigenetic mechanisms co-occur following the retrieval of a recent or remote memory, their gene targets differ depending on the brain region. Additionally, we found that in vivo siRNA-mediated knockdown of the H3K4me3 methyltransferase Mll1 in CA1 abolished retrieval-induced increases in DNA 5hmC levels at the Npas4 gene, suggesting that H3K4me3 couples to DNA 5hmC mechanisms. Consistent with this, loss of Mll1 prevented retrieval-induced increases in Npas4 mRNA levels in CA1 and impaired fear memory. Collectively, these findings suggest an important link between histone methylation and DNA hydroxymethylation mechanisms in the epigenetic control of de novo gene transcription triggered by memory retrieval., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Self-reported outcome measures of athlete health, wellbeing and performance add information to that obtained from clinical measures. However valid, universally accepted outcome measures are required., Objective: To determine which athlete-reported outcome measures of performance have been used to measure the impact of injury and illness on performance in sport and assess evidence to support their validity., Methods: The authors searched Ovid MEDLINE, Ovid EMBASE, CINAHL Plus, SPORTDiscus with Full Text and Cochrane library to January 2016. Predefined inclusion and exclusion criteria were applied and papers included if an outcome measure of performance, assessed in relation to illness, injury or a related intervention, was reported by an elite, adult, able-bodied athlete. A checklist was used to assess eligible outcome measures for aspects of validity. Reporting of this study was guided by PRISMA guidelines for systematic reviews., Results: Twenty athlete-reported outcome measures in 21 papers were identified. Of these 20, only four cited validation. Of these four, three reported evidence to support validity in elite athlete groups as defined by the predetermined checklist. Fifteen patient-reported outcome measures were identified, of which four demonstrated validity in young athletic populations., Conclusions: Most athlete-reported outcome measures of performance have been designed for individual studies with no reported assessment of validity. Despite some limitations, the Oslo Sports Trauma Centre overuse injury questionnaire demonstrates validity and potential utility to investigate the self-reported impact of pre-defined conditions on athletic performance across different sports.

The region of Antioquia in northeastern Colombia has the highest number of reported leptospirosis cases in the country. It also shows high seroprevalence indexes in the general population and socio-environmental conditions favourable for the transmission of the disease between humans and animals. In this study, 25 Leptospira isolates from Colombia's Antioquia department were identified to the species level as L. santarosai (12), L. interrogans (9) and L. meyeri (4) using phylogenetic analysis of the Amidohydrolase gene. Typing at the serovar level was performed using multilocus sequence typing (MLST) and monoclonal antibodies. The serovars Canalzonae, Babudieri, Alice, Beye, and Copenhageni have been identified as causing human or animal infections in Antioquia, Colombia. The four environmental isolates were not identified to the serovar level. L. santarosai serovar Canalzonae and Alice were identified as new etiologic agents of human leptospirosis in Antioquia, Colombia. This paper reports species and serovars that were previously unknown in the region.

Background: Cardiac surgery with cardiopulmonary bypass (CPB) evokes a systemic inflammatory response involving the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1, IL-6, IL-8 and anti-inflammatory cytokines such as IL-10. Like IL-10, opioids downregulate the immune responses in vivo and in vitro, including the activity of the cytokine-producing monocytes and granulocytes. The proinflammatory cytokines are potent inducers of the hepatic acute-phase protein synthesis. The aim of the present study was to investigate if choice of anaesthesia, based on high-dose opioids (fentanyl) versus low-dose opioids influenced the release of IL-6, IL-8, and IL-10. Secondly, it was investigated whether serum amyloid P-component (SAP) is an acute-phase protein in man such as C-reactive protein (CRP), with which it is physically and structurally related., Methods: Sixteen patients submitted to elective coronary artery bypass grafting (CABG) surgery were randomized to either low-dose opioid anaesthesia consisting of thoracic epidural analgesia combined with inhalational anaesthesia (group I) or high-dose fentanyl anaesthesia (group II). From each patient 18 blood samples were taken perioperatively. Cytokine analyses were performed with ELISA, CRP and SAP mere measured with rocket immunoelectrophoresis (RIE)., Results: Surgery and CPB elicited a marked, transient and almost simultaneous proinflammatory and anti-inflammatory cytokine response with no differences between the groups. The cytokine levels returned to preoperative levels 1-3 d after operation. Anaesthesia and surgery did not affect SAP plasma levels while patients showed a major increase in CRP concentrations preceding the cytokine responses., Conclusion: CABG performed during two different anaesthetic techniques, high-dose fentanyl versus low-dose opioid anaesthesia, elicited a well-defined cytokine response with minor variation in the time course of each cytokine. The cytokine production was not modified by type of anaesthesia. Finally, SAP is not an acute-phase protein in men.

Exogenous morphine downregulates the activity of immunocompetent cells such as lymphocytes, granulocytes and macrophages. Furthermore, morphine increases the secretion of CRH, ACTH and glucocorticoids, i.e. substances with inhibitory effects on the immune system. In the present study we tested the hypothesis that endogenous morphine production is increased as part of the antiinflammatory response to cardiac surgery. Sixteen patients submitted to elective coronary artery bypass grafting (CABG) surgery were randomized to either thoracic epidural analgesia combined with general anaesthesia (group I) or high-dose fentanyl anaesthesia (group II). Patients in group I did not receive morphine while patients in group II received systemic morphine for postoperative pain relief. From each patient 18 blood samples were taken perioperatively and tested for morphine. Furthermore, monocyte function with respect to motility and shape was determined by computer-assisted image analysis. A steep increase in plasma morphine concentrations was demonstrated on the first postoperative day in patients in group I (not given morphine). Plasma morphine levels remained significantly elevated during the following five postoperative days. Patients in group II given morphine as pain treatment showed a larger and earlier morphine peak related to the morphine administration. Computer-assisted image analysis of leukocyte behaviour revealed a biphasic increase in cell motility. In conclusion, we demonstrate for the first time that endogenous morphine levels increase after the trauma of surgery. We surmise that morphine is part of the antiinflammatory response to cardiac surgery.