Case report: Complete and durable response to larotrectinib (TRK inhibitor) in an infant diagnosed with angiosarcoma harbouring a KHDRBS1-NTRK3 fusion gene.

Significant improvements in the survival rates of paediatric cancer have been achieved over the past decade owing to recent advances in therapeutic and diagnostic strategies. However, disease progression and relapse remain a major challenge for the clinical management of paediatric angiosarcoma. Comprehensive genomic profiling of these rare tumours using high-throughput sequencing technologies may improve patient stratification and identify actionable biomarkers for therapeutic intervention. Here, we describe the clinical, histopathological, immunohistochemical and molecular profile of a novel and precision medicine-informed case where a KHDRBS1-NTRK3 fusion determined by next-generation sequencing-based comprehensive genomic profiling led to complete and sustained remission (clinical and radiological response) in an otherwise incurable disease. Our patient represents the first paediatric angiosarcoma harbouring a targetable NTRK3 fusion in the literature and demonstrates the first example of targeting this alteration in angiosarcoma using larotrectinib, an NTRK inhibitor. Clinical and radiological remission was achieved in under two months of therapy, and the patient is currently in complete remission, 4 month after stopping larotrectinib therapy, which was given over 17 months with only mild side effects reported. Therefore, this remarkable case exemplifies the true essence of precision-based care by incorporating conventional pathology with the why, when, and how to test for rare oncogenic drivers and agnostic biomarkers in paediatric angiosarcoma.

Impact of a Targeted Project for Shortening of Imaging Diagnostic Waiting Time in Patients with Suspected Oncological Diseases in Hungary.

Background and Objectives: Medical imaging is a key element in the clinical workup of patients with suspected oncological disease. In Hungary, due to the high number of patients, waiting lists for Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) were created some years ago. The Municipality of Budapest and Semmelweis University signed a cooperation agreement with an extra budget in 2020 (HBP: Healthy Budapest Program) to reduce the waiting lists for these patients. The aim of our study was to analyze the impact of the first experiences with the HBP. Material and Methods: The study database included all the CT/MRI examinations conducted at Semmelweis University with a referral diagnosis of suspected oncological disease within the first 13 months of the HBP (6804 cases). In our retrospective, two-armed, comparative clinical study, different components of the waiting times in the oncology diagnostics pathway were analyzed. Using propensity score matching, we compared the data of the HBP-funded patients (n = 450) to those of the patients with regular care provided by the National Health Insurance Fund (NHIF) (n = 450). Results: In the HBP-funded vs. the NHIF-funded patients, the time interval from the first suspicion of oncological disease to the request for imaging examinations was on average 15.2 days shorter (16.1 vs. 31.3 days), and the mean waiting time for the CT/MRI examination was reduced by 13.0 days (4.2 vs. 17.2 days, respectively). In addition, the imaging medical records were prepared on average 1.7 days faster for the HBP-funded patients than for the NHIF-funded patients (3.4 vs. 5.1 days, respectively). No further shortening of the different time intervals during the subsequent oncology diagnostic pathway (histological investigation and multidisciplinary team decision) or in the starting of specific oncological therapy (surgery, irradiation, and chemotherapy) was observed in the HBP-funded vs. the NHIF-funded patients. We identified a moderately strong negative correlation (r = -0.5736, p = 0.0350) between the CT/MR scans requested and the active COVID-19 case rates during the pandemic waves. Conclusion: The waiting lists for diagnostic CT/MR imaging can be effectively shortened with a targeted project, but a more comprehensive intervention is needed to shorten the time from the radiological diagnosis, through the decisions of the oncoteam, to the start of the oncological treatment.

MRI Characteristics of Pediatric Renal Tumors: A SIOP-RTSG Radiology Panel Delphi Study.

BACKGROUND: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics. PURPOSE: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors. STUDY TYPE: Consensus process using a Delphi method. POPULATION: Not applicable. FIELD STRENGTH/SEQUENCE: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T. ASSESSMENT: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions. STATISTICAL TESTS: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale. RESULTS: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors. DATA CONCLUSION: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3.

IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia.

The hormone hepcidin plays a central role in controlling iron homeostasis. Iron-mediated hepcidin synthesis is triggered via the BMP/SMAD pathway. At inflammation, mainly IL-6 pro-inflammatory cytokine mediates the regulation of hepcidin via the JAK/STAT signalling pathway. Microglial cells of the central nervous system are able to recognize a broad spectrum of pathogens via toll-like receptors and initiate inflammatory response. Although the regulation of hepcidin synthesis is well described in many tissues, little is known about the inflammation mediated hepcidin regulation in microglia. In this study, we investigated the pathways, which are involved in HAMP regulation in BV2 microglia due to inflammatory mediators and the possible relationships between the iron regulatory pathways. Our results showed that IL-6 produced by resting BV2 cells was crucial in maintaining the basal HAMP expression and hepcidin secretion. It was revealed that IL-6 neutralization decreased both STAT3 and SMAD1/5/9 phosphorylation suggesting that IL-6 proinflammatory cytokine is necessary to maintain SMAD1/5/9 activation. We revealed that IL-6 influences BMP6 and TMPRSS6 protein levels, moreover it modified TfR2 expression, as well. In this study, we revealed that BV2 microglia increased their hepcidin secretion upon IL-6 neutralization although the major regulatory pathways were inhibited. Based on our results it seems that both at inflammation and at normal condition the absence of IL-6 triggered HAMP transcription and hepcidin secretion via the NFκB pathway and possibly by the autocrine effect of TNFα cytokine on BV2 microglia.

Fractalkine Induces Hepcidin Expression of BV-2 Microglia and Causes Iron Accumulation in SH-SY5Y Cells.

Fractalkine (CX3CL1) is a potent inflammatory mediator of the central nervous system, which is expressed by neurons and regulates microglial functions by binding to fractalkine receptor (CX3CR1). It has been demonstrated that neuroinflammation plays an important role in iron accumulation of the brain leading to neuronal cell death. The major regulator of iron homeostasis is the peptide hormone hepcidin. Hepcidin expression is triggered by inflammatory conditions, which may contribute to the neuronal iron accumulation. In the present study, we established a bilaminar co-culture system of differentiated SH-SY5Y cells and BV-2 microglia as a neuronal model to examine the effect of soluble fractalkine on iron homeostasis of microglia and SH-SY5Y cells. We determined the hepcidin expression of fractalkine-treated microglia which showed significant elevation. We examined the relation between increased hepcidin secretion, the known hepcidin regulators and the signalling pathways controlled by fractalkine receptor. Our data revealed that TMPRSS6 and alpha 1-antitrypsin levels decreased due to fractalkine treatment, as well as the activity of NFκB pathway and the tyrosine phosphorylation of STAT5 factor. Moreover, fractalkine-induced hepcidin production of microglia initiated ferroportin internalisation of SH-SY5Y cells, which contributed to iron accumulation of neurons. Our results demonstrate that soluble form of fractalkine regulates hepcidin expression of BV-2 cells through fractalkine-mediated CX3CR1 internalisation. Moreover, fractalkine indirectly contributes to the iron accumulation of SH-SY5Y cells by activating ferroportin internalisation and by triggering the expressions of divalent metal transporter-1, ferritin heavy chain and mitochondrial ferritin.

Relationship of Iron Metabolism and Short-Term Cuprizone Treatment of C57BL/6 Mice.

One of the models to investigate the distinct mechanisms contributing to neurodegeneration in multiple sclerosis is based on cuprizone (CZ) intoxication. CZ is toxic to mature oligodendrocytes and produces demyelination within the central nervous system but does not cause direct neuronal damage. The CZ model is suitable for better understanding the molecular mechanism of de- and remyelination processes of oligodendrocytes. CZ is a copper chelating agent and it also affects the iron metabolism in brain and liver tissues. To determine the early effect of CZ treatment on iron homeostasis regulation, cytosolic and mitochondrial iron storage, as well as some lipid metabolism genes, we investigated the expression of respective iron homeostasis and lipid metabolism genes of the corpus callosum (CC) and the liver after short-term CZ administration. In the present study C57BL/6 male mice aged four weeks were fed with standard rodent food premixed with 0.2 w/w% CZ for two or eight days. The major findings of our experiments are that short-term CZ treatment causes significant changes in iron metabolism regulation as well as in the expression of myelin and lipid synthesis-related genes, even before apparent demyelination occurs. Both in the CC and the liver the iron uptake, utilization and storage are modified, though not always the same way or to the same extent in the two organs. Understanding the role of iron in short-term and long-term CZ intoxication could provide a partial explanation of the discrepant signs of acute and chronic MS. These could contribute to understanding the development of multiple sclerosis and might provide a possible drug target.

The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors.

Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.

Effect of Inflammatory Mediators Lipopolysaccharide and Lipoteichoic Acid on Iron Metabolism of Differentiated SH-SY5Y Cells Alters in the Presence of BV-2 Microglia.

Lipopolysaccharide (LPS) and lipoteichoic acid (LTA), the Gram-negative and the Gram-positive bacterial cell wall components are important mediators of neuroinflammation in sepsis. LPS and LTA are potent activators of microglial cells which induce the production of various pro-inflammatory cytokines. It has been demonstrated that disturbance of iron homeostasis of the brain is one of the underlying causes of neuronal cell death but the mechanisms contributing to this process are still questionable. In the present study, we established monocultures of differentiated SH-SY5Y cells and co-cultures of differentiated SH-SY5Y cells and BV-2 microglia as neuronal model systems to selectively examine the effect of inflammatory mediators LPS and LTA on iron homeostasis of SH-SY5Y cells both in mono- and co-cultures. We monitored the IL-6 and TNFα secretions of the treated cells and determined the mRNA and protein levels of iron importers (transferrin receptor-1 and divalent metal transporter-1), and iron storing genes (ferritin heavy chain and mitochondrial ferritin). Moreover, we examined the relation between hepcidin secretion and intracellular iron content. Our data revealed that LPS and LTA triggered distinct responses in SH-SY5Y cells by differently changing the expressions of iron uptake, as well as cytosolic and mitochondrial iron storage proteins. Moreover, they increased the total iron contents of the cells but at different rates. The presence of BV-2 microglial cells influenced the reactions of SH-SY5Y cells on both LPS and LTA treatments: iron uptake and iron storage, as well as the neuronal cytokine production have been modulated. Our results demonstrate that BV-2 cells alter the iron metabolism of SH-SY5Y cells, they contribute to the iron accumulation of SH-SY5Y cells by manipulating the effects of LTA and LPS proving that microglia are important regulators of neuronal iron metabolism at neuroinflammation.

The C19S Substitution Enhances the Stability of Hepcidin While Conserving Its Biological Activity.

Hepcidin, the key hormone of iron homeostasis is responsible for lowering the serum iron level through its interaction with iron exporter ferroportin. Thus, hepcidin agonists provide a promising opportunity in the treatment of iron disorders caused by lacking or decreased hepcidin expression. We investigated the importance of each of the eight highly conserved cysteines for the biological activity of hepcidin. Eight cysteine mutants were created with site directed mutagenesis. The binding ability of these hepcidin mutants to the hepcidin receptor ferroportin was determined using bacterial two-hybrid system and WRL68 human hepatic cells. The biological activity of hepcidin mutants was determined by western blot analysis of ferroportin internalization and ferroportin ubiquitination. To investigate the effect of mutant hepcidins on the iron metabolism of the WRL68 cells, total intracellular iron content was measured with a colorimetric assay. The stability of M6 hepcidin mutant was determined using ELISA technique. Our data revealed that serine substitution of the sixth cysteine (M6) yielded a biologically active but significantly more stable peptide than the original hormone. This result may provide a promising hepcidin agonist worth testing in animal models.

Effective BRAF inhibitor vemurafenib therapy in a 2-year-old patient with sequentially diagnosed Langerhans cell histiocytosis and Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib.

Primary alveolar rhabdomyosarcoma of the bone: two cases and review of the literature.

BACKGROUND: Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin and comprises the largest category of soft-tissue sarcomas both in children and adolescents. From a pediatric oncology point of view, RMS has traditionally been classified into alveolar (ARMS) and embryonal (ERMS) subtypes. The anatomical localization of the tumor may vary, but commonly involve the head/neck regions, male and female urogenital tract or the trunk and extremities. CASE PRESENTATION: Here, we report two challenging cases involving 17- and 9-years-olds males where diffuse and multiplex bone lesions suggested either a hematological disease or a primary bone tumor (mesenchymal chondrosarcoma). Biopsies, proved a massive infiltration of the bone marrow cavity with rhabdomyosarcoma. In both cases, the ARMS subtype was confirmed using FOXO1 break-apart probes (FISH). Radiological examination could not identify primary soft tissue component in any localization at the time of diagnosis in either cases. CONCLUSIONS: Primary alveolar rhabdomyosarcoma of the bone as a subtype of ARMS, seems to be a distinct clinico-pathological entity with challenging diagnostic difficulties and different, yet better, biological behavior in comparison to soft tissue ARMS. However, it is difficult to be characterized or predict its prognosis and long-term survival as only sporadic cases (four) were reported so far.

User Interaction in Semi-Automatic Segmentation of Organs at Risk: a Case Study in Radiotherapy.

Accurate segmentation of organs at risk is an important step in radiotherapy planning. Manual segmentation being a tedious procedure and prone to inter- and intra-observer variability, there is a growing interest in automated segmentation methods. However, automatic methods frequently fail to provide satisfactory result, and post-processing corrections are often needed. Semi-automatic segmentation methods are designed to overcome these problems by combining physicians' expertise and computers' potential. This study evaluates two semi-automatic segmentation methods with different types of user interactions, named the "strokes" and the "contour", to provide insights into the role and impact of human-computer interaction. Two physicians participated in the experiment. In total, 42 case studies were carried out on five different types of organs at risk. For each case study, both the human-computer interaction process and quality of the segmentation results were measured subjectively and objectively. Furthermore, different measures of the process and the results were correlated. A total of 36 quantifiable and ten non-quantifiable correlations were identified for each type of interaction. Among those pairs of measures, 20 of the contour method and 22 of the strokes method were strongly or moderately correlated, either directly or inversely. Based on those correlated measures, it is concluded that: (1) in the design of semi-automatic segmentation methods, user interactions need to be less cognitively challenging; (2) based on the observed workflows and preferences of physicians, there is a need for flexibility in the interface design; (3) the correlated measures provide insights that can be used in improving user interaction design.

[Diagnosis and treatment of childhood soft tissue sarcomas]. / Gyermekkori lágyrészsarcomák diagnosztikája és kezelése.

Malignant tumors of mesenchymal origin are called sarcomas. Mesenchymal cells normally mature into skeletal muscle, smooth muscle, fat, fibrous tissue, bone and cartilage. Rhabdomyosarcoma (RMS) arises from immature mesenchymal cells that are committed to skeletal muscle lineage. However, it can also arise in tissues in which striated muscle is normally not found (such as the urinary tract). Undifferentiated sarcomas cannot be ascribed to any specific lineage. Treatment results improved significantly in the last decade by combined treatment (chemotherapy, surgery, irradiation, in some cases targeted therapy). Good treatment results can be achieved in pediatric oncology centers by early diagnosis and adequate treatment according to international treatment protocols.

An archived serum sample as a clue for identifying the primary source of a nosocomial hepatitis C virus outbreak in a haemodialysis unit.

Due to an unexpected technical error, patients at a dialysis unit who were seronegative for hepatitis C virus (HCV) were temporarily transferred to another dialysis unit next to a ward reserved for HCV-seropositive patients. In the following 7 months, 17 patients were diagnosed as anti-HCV positive. The aim of the study was to reveal the cause of this nosocomial infection. Anti-HCV-positive sera were further tested by molecular methods. Data collection and on-site epidemiologic inspections were carried out. The source of the nosocomial infection proved to be a seropositive patient treated at the unit, who died before the outbreak was recognized. The exact date of the infection was determined.

[Management of Fabry disease]. / Fabry-betegség - terápiás útmutató

Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive and the first symptoms usually present in childhood. Consequences of the disease are disability and premature death. The disease in females could be as severe as in males although women may be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline has been summarized by a Hungarian multi-disciplinary working group consisting of physicians who are involved in diagnosis and care of Fabry patients. Previous clinical studies, published articles, and recently established international treatment guidelines were reviewed by the group.

Isolation and analysis of bioactive constituents of sour cherry (Prunus cerasus) seed kernel: an emerging functional food.

A plant-based diet reduces the risk for the development of several chronic diseases, such as ischemic heart disease or cancer due to natural compounds found in plants. Numerous cereals, berries, fruits, and vegetables, including sour cherry (Prunus cerasus), which is a favored fruit worldwide, contain biological active components. The antioxidant components of the sour cherry seed kernel have not been investigated until now. The aim of our study was to isolate and analyze the bioactive constituents of sour cherry seed kernel. We separated the oil fraction of the kernel; then the remaining solid fraction was dried, and the oil-free kernel extract was further analyzed. Our results show that sour cherry seed kernel oil contains vegetable oils including unsaturated fatty acids, oleic acids, alpha-tocopherol, tocotrienols, and tocopherol-like components. The components of the solid fraction include various bioactive structures such as polyphenols, flavonoids, vegetable acids, and pro- and anthocyanidins, which could have useful therapeutic effects in the prevention of various vascular diseases.

[Fabry disease--diagnostic guideline]. / Fabry-betegség. Diagnosztikai útmutató.

Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive, first symptoms usually present in childhood. Consequencies of the diseases are disability and premature death. The disease in females could be as severe as in males although women may also be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline was established by a Hungarian multi-disciplinary working group, consisting of physicians who are involved in health care of Fabry patients. Previous clinical studies, published materials, and recently established international treatment guidelines were reviewed by the group.

The electrophysiological "delayed effect" of focal interictal epileptiform discharges. A low resolution electromagnetic tomography (LORETA) study.

UNLABELLED: Collating the findings regarding the role of focal interictal epileptiform discharges (IEDs) on CNS functions raises the possibility that IEDs might have negative impact that outlasts the duration of the spike-and-wave complexes. The aim of this study was the electrophysiological demonstration of the "delayed effect" of the IEDs. 19-channel, linked-ears referenced, digital waking EEG records of 11 children (aged 6-14 years, eight with idiopathic, three with cryptogenic focal epilepsy, showing a single spike focus) were retrospectively selected from our database. A minimum of 20 (preferably, 30), 2-s epochs containing a single focal spike-and-wave complex were selected (Spike epochs). Thereafter, Postspike-1 (Ps1), Postspike-2 (Ps2) and Postspike-3 (Ps3) epochs were selected, representing the first and second seconds (Ps1), the third and fourth seconds (Ps2) and the fifth and sixth seconds (Ps3) after the Spike epoch, respectively. Interspike epochs (Is) were selected at a distance at least 10s after the Spike epoch. Individual analysis: the frequency of interest (FOI=the individual frequency of the wave component of the IEDs), and the region of interest (ROI=the site of the IEDs) were identified by reading the raw EEG waveform and the instant power spectrum. Very narrow band LORETA (low resolution electromagnetic tomography) analysis at the FOI and ROI was carried out. Age-adjusted, Z-transformed LORETA "activity" (=current source density, amperes/meters squared) was compared in the Spike, Ps1, Ps2, Ps3 and Is epochs. FINDINGS: the greatest (uppermost pathological) Z-scores and the greatest spatial extension of the LORETA-abnormality were always found in the Spike epochs, followed by the gradual decrease of activity in terms of severity and spatial extension in the Ps1, Ps2, Ps3 epochs. The lowest (baseline) level and extension of the abnormality was found in the Is epochs. Group analysis: average values of activity across the patients were computed for the temporal decrease of the abnormality. FINDINGS: a clear tendency for the decrease of abnormality was demonstrated. CONCLUSION: the "delayed effect" of the IEDs was demonstrated electrophysiologically and quantified. The method may be utilized in the individual assessment of the effect of IEDs on cortical activity, the degree and temporo-spatial extension of the abnormality.

Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin.

The resveratrol-induced cardiac protection was studied in Zucker obese rats. Rats were divided into five groups: group 1, lean control; group 2, obese control (OC); group 3, obese rats treated orally with 5 mg kg(-1) day(-1) of resveratrol (OR) for 2 wk; group 4, obese rats received 10% glucose solution ad libitum for 3 wk (OG); and group 5, obese rats received 10% glucose for 3 wk and resveratrol (OGR) during the 2nd and 3rd wk. Body weight, serum glucose, and insulin were measured, and then hearts were isolated and subjected to 30 min of ischemia followed by 120 min of reperfusion. Heart rate, coronary flow, aortic flow, developed pressure, the incidence of reperfusion-induced ventricular fibrillation, and infarct size were measured. Resveratrol reduced body weight and serum glucose in the OR compared with the OC values (414 +/- 10 g and 7.08 +/- 0.41 mmol/l, respectively, to 378 +/- 12 g and 6.11 +/- 0.44 mmol/l), but insulin levels were unchanged. The same results were obtained for the OG vs. OGR group. Resveratrol improved postischemic cardiac function in the presence or absence of glucose intake compared with the resveratrol-free group. The incidence of ventricular fibrillation and infarct size was reduced by 83 and 20% in the OR group, and 67 and 16% in the OGR group, compared with the OC and OG groups, respectively. Resveratrol increased GLUT-4 expression and reduced endothelin expression and cardiac apoptosis in ischemic-reperfused hearts in the presence or absence of glucose intake. Thus the protective effect of resveratrol could be related to its direct effects on the heart.