Mitochondrial calcium and the permeability transition in cell death.

Dysregulation of Ca(2+) has long been implicated to be important in cell injury. A Ca(2+)-linked process important in necrosis and apoptosis (or necrapoptosis) is the mitochondrial permeability transition (MPT). In the MPT, large conductance permeability transition (PT) pores open that make the mitochondrial inner membrane abruptly permeable to solutes up to 1500 Da. The importance of Ca(2+) in MPT induction varies with circumstance. Ca(2+) overload is sufficient to induce the MPT. By contrast after ischemia-reperfusion to cardiac myocytes, Ca(2+) overload is the consequence of bioenergetic failure after the MPT rather than its cause. In other models, such as cytotoxicity from Reye-related agents and storage-reperfusion injury to liver grafts, Ca(2+) appears to be permissive to MPT onset. Lastly in oxidative stress, increased mitochondrial Ca(2+) and ROS generation act synergistically to produce the MPT and cell death. Thus, the exact role of Ca(2+) for inducing the MPT and cell death depends on the particular biologic setting.

Management of acute mitochondriopathy and encephalopathy syndrome in pediatric intensive care unite: a new clinical entity.

Acute mitochondriopathy and encephalopathy syndrome (AMES) is described differently by different authors in the literature. As a new clinical entity, we aimed to present the clinical signs and symptoms, diagnosis and treatment algorithm of our patients with AMES. 56 patients aged between 2 months and 18 years who were followed up in pediatric intensive care units of Konya Training and Research Hospital and Selcuk University Medical Faculty Hospital, between January 2010 and June 2017 were included. Patients' data were obtained retrospectively from the intensive care unit patient files. 34 (60.7%) of the patients were male and 22 (39.3%) were female. The median age of our patients was 10.0 months. At the time of admission, 42 (75%) of the patients had fever, 35 (62.5%) vomiting, 27 (48.2%) abnormal behaviour and agitation and 28 (50%) convulsion. The etiological classification of patients with AMES was divided into four groups as infection, metabolic disorder, toxic, and hypoxic-ischemic. 39 (69.6%) patients were found to have infection, 10 (17.9%) patients hypoxia, 7 (12.5%) patients metabolic disorders. AMES occurs rarely, but should be kept in mind in the differential diagnosis of patients with any encephalopathy of unknown origin especially in those with a history of ingestion of drugs, previous viral infection and vomiting. Early recognition and treatment is imperative to reduce morbidity and mortality in children with AMES.

[A case of Reye's-like syndrome due to suspected Bordetella pertussis infection in an adult].

We report a rare case of Reye's-like syndrome associated with suspected pertussis infection. A 26-year-old woman admitted comatose and found in laboratory studies to have acute liver dysfunction, severe hypoglycemia and prolonged prothrombin time, was diagnosed with clinical Reye's-like syndrome due to aspirin use. Her child was probably infected with pertussis, which she contracted and which, in turn, triggered Reye's-like syndrome.

Unusual clinical manifestations of dengue disease - Real or imagined?

The disease caused by each of the four serotypes of dengue virus (DENV) have plagued humans since last century. Symptoms of dengue virus (DENV) infection range from asymptomatic to dengue fever (DF) to severe dengue disease (SDD). One third of the world's population lives in regions with active urban DENV transmission, and thousands of serologically naïve travelers visit these areas annually, making a significant portion of the human population at risk of being infected. Even though lifelong immunity to the homotypic serotype is achieved after a primary DENV infection. Heterotypic DENV infections may be exacerbated by a pre-existing immune memory to the primary infection and can result in an increased probability of severe disease. Not only, age, comorbidities and presence of antibodies transferred passively from dengue-immune mother to infants are considered risk factors to dengue severe forms. Plasma leakage and multiple organ impairment are well documented in the literature, affecting liver, lung, brain, muscle, and kidney. However, unusual manifestation, severe or not, have been reported and may require medical attention. This review will summarize and discuss the increasing reports of unusual manifestations in the clinical course of dengue infection.

Reye syndrome and reye-like syndrome.

Reye syndrome is an acute metabolic encephalopathy, largely affecting children and adolescents. In Reye-like syndrome, because of inborn errors of metabolism, hypoglycemia, hypoketonemia, elevated ammonia, and organic aciduria are often evident. It is well-known that fatty-acid oxidation defects can present as Reye-like syndrome. The most commonly diagnosed metabolic disorder in association with Reye syndrome has been medium-chain acyl coenzyme A dehydrogenase deficiency. The present consensus seems to be that Reye syndrome is very rare, and that any child suspected of manifesting this disorder should undergo investigations for inborn errors of metabolism. We recently treated a child with "Reye-like illness" who possibly manifested a long-chain acyl dehydrogenase deficiency, and who had also ingested aspirin. We discuss the possible pathogenesis of the disorder in this child. The end results of mitochondrial dysfunction in Reye syndrome and Reye-like illness may be similar.

Reye's and Reye's-like syndromes.

The review reports various questions about Reye's syndrome and Reye's-like syndromes. Although there is a significant decrease in the classic Reye's syndrome cases, because of the reduced employment of salicylates in children (salicylate seems to be the most important inducing factor of the syndrome in paediatric subjects affected by viral infection), the problem is still of interest considering the presence of different Reye's-like forms. All these pathological situations are associated with various aetiologic or predisposing causes that are examined in the text. Particular attention is placed on metabolic disorders, especially of fatty acid metabolism, and also of one amino acid. In fact, a latent form can also be the basis of possible biochemical disturbances induced by various exogenous factors such as viral infections, particularly of the respiratory tract (more rarely of bacterial aetiology), or produced by microbial toxins, or by chemical substances, including some therapeutic drugs. A full discussion of biochemical mechanisms of salicylate-induced Reye's syndrome is reported. Finally a possible diagnostic differentiation from classic Reye's syndrome and Reye's-like syndromes plus therapeutic prospects are briefly examined.

Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome.

This study examines the relationship between impaired fatty acid oxidation and the pathogenesis of Reye syndrome. We present a hypothesis proposing that many clinical signs of this childhood disease are caused by accumulation of unusual acyl CoA esters, precursors to deacylated metabolites found in the patients' blood and urine. A new method was developed to measure acyl CoA compounds in small human liver biopsy samples, offering several advantages over previous techniques. A major finding was an accumulation in Reye syndrome patients of short- and medium-chain acyl CoA intermediates of fatty acid and branched-chain amino acid oxidation. These metabolites included octanoyl, isovaleryl, butyryl, isobutyryl, propionyl, and methylmalonyl CoA esters. The findings were explained in a model of hepatic fatty acid oxidation involving three interrelated pathways: mitochondrial beta-oxidation, peroxisomal beta-oxidation, and omega-oxidation in the endoplasmic reticulum. The results suggest that pathogenesis in Reye syndrome stems from generalized mitochondrial damage resulting in accumulation of acyl CoA esters. High levels of these compounds lead to inhibition of mitochondrial pathways for ureogenesis, gluconeogenesis, and fatty acid oxidation. The inhibited pathways, in turn, could cause the hyperammonemia, hypoglycemia, and hypoketonemia observed in patients. The model also explains underlying biochemical differences between patients with Reye syndrome and medium-chain acyl CoA dehydrogenase deficiency, another disorder of fatty acid metabolism. Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients.

Aspirin and Reye syndrome: a review of the evidence.

Reye syndrome is an extremely rare but severe and often fatal disease. Death occurs in about 30-40% of cases from brainstem dysfunction. The disease typically is preceded by a viral infection with an intermediate disease-free interval of 3-5 days. The biochemical explanation for Reye-like symptoms is a generalized disturbance in mitochondrial metabolism, eventually resulting in metabolic failure in the liver and other tissues. The etiology of 'classical' Reye syndrome is unknown. Hypothetically, the syndrome may result from an unusual response to the preceding viral infection, which is determined by host genetic factors but can be modified by a variety of exogenous agents. Thus, several infections and diseases might present clinically with Reye-like symptoms. Exogenous agents involve a number of toxins, drugs (including aspirin [acetylsalicylic acid]), and other chemicals. The 'rise and fall' in the incidence of Reye syndrome is still poorly understood and unexplained. With a few exceptions, there were probably no new Reye-like diseases reported during the last 10 years that could not be explained by an inherited disorder of metabolism or a misdiagnosis. This may reflect scientific progress in the better understanding of cellular and molecular dysfunctions as disease-determining factors. Alternatively, the immune response to and the virulence of a virus might have changed by alteration of its genetic code. The suggestion of a defined cause-effect relationship between aspirin intake and Reye syndrome in children is not supported by sufficient facts. Clearly, no drug treatment is without side effects. Thus, a balanced view of whether treatment with a certain drug is justified in terms of the benefit/risk ratio is always necessary. Aspirin is no exception.

Reye's syndrome: the case for a causal link with aspirin.

Reye's syndrome is a serious, acute encephalopathy that has been linked with aspirin (acetylsalicylic acid) use in children and teenagers <18 years of age. Although others may disagree, it is my belief that any objective analysis of published material in the last 20 years must conclude that there is a close link between the devastating encephalopathy Reye's syndrome and ingestion of aspirin during the febrile prodrome. The drug appears to act as a co-factor in susceptible individuals. Although some of the epidemiological data indicate an association between the two, the burden of evidence suggests actual causality and is both consistent and specific as well as strong and time related. Some of the evidence points to illness severity being dose related although it seems that in the presence of a viral infection, no dose of aspirin can be considered safe. No published work, using methodology that can be critically evaluated, has shown evidence to contradict these conclusions and they have been widely accepted. Since government health warnings were appended to aspirin-containing formulations, the decline in case numbers on both sides of the Atlantic has been nothing short of remarkable. Recent in vitro findings have pinpointed the site of action of the drug on the long chain hydroxyacyl-CoA dehydrogenase enzyme (a component of the mitochondrial trifunctional enzyme) and, even at therapeutic concentrations, oxidation is impaired in cultured fibroblasts from patients who have recovered from the disorder. This is quite unlike that seen in cells from normal controls. Even when major influenza outbreaks occur in the future, Reye's syndrome is preventable provided government health warnings are heeded and the cogent evidence set forth here is acted upon by the parents of feverish children and self-medicating teenagers.

Inborn Errors of Metabolism That Cause Sudden Infant Death: A Systematic Review with Implications for Population Neonatal Screening Programmes.

BACKGROUND: Many inborn errors of metabolism (IEMs) may present as sudden infant death (SID). Nowadays, increasing numbers of patients with IEMs are identified pre-symptomatically by population neonatal bloodspot screening (NBS) programmes. However, some patients escape early detection because their symptoms and signs start before NBS test results become available, they even die even before the sample for NBS has been drawn or because there are IEMs which are not included in the NBS programmes. OBJECTIVES AND METHODS: This was a comprehensive systematic literature review to identify all IEMs associated with SID, including their treatability and detectability by NBS technologies. Reye syndrome (RS) was included in the search strategy because this condition can be considered a possible pre-stage of SID in a continuum of aggravating symptoms. RESULTS: 43 IEMs were identified that were associated with SID and/or RS. Of these, (1) 26 can already present during the neonatal period, (2) treatment is available for at least 32, and (3) 26 can currently be identified by the analysis of acylcarnitines and amino acids in dried bloodspots (DBS). CONCLUSION: We advocate an extensive analysis of amino acids and acylcarnitines in blood/plasma/DBS and urine for all children who died suddenly and/or unexpectedly, including neonates in whom blood had not yet been drawn for the routine NBS test. The application of combined metabolite screening and DNA-sequencing techniques would facilitate fast identification and maximal diagnostic yield. This is important information for clinicians who need to maintain clinical awareness and decision-makers to improve population NBS programmes.

Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity.

Severe and prolonged impairment of mitochondrial beta-oxidation leads to microvesicular steatosis, and, in severe forms, to liver failure, coma and death. Impairment of mitochondrial beta-oxidation may be either genetic or acquired, and different causes may add their effects to inhibit beta-oxidation severely and trigger the syndrome. Drugs and some endogenous compounds can sequester coenzyme A and/or inhibit mitochondrial beta-oxidation enzymes (aspirin, valproic acid, tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine); they may inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhexestrol), or they may impair mitochondrial DNA transcription (interferon-alpha), or decrease mitochondrial DNA replication (dideoxynucleoside analogues), while other compounds (ethanol, female sex hormones) act through a combination of different mechanisms. Any investigational molecule should be screened for such effects.

Reye's syndrome in adults. A case report and review of the literature.

Adult Reye's syndrome (ARS) is an infrequently diagnosed condition that typically affects patients younger than age 35 years. We describe a 61-year-old man with ARS occurring after influenza B-USSR infection and aspirin use. The diagnosis of ARS was confirmed by oil-red-O stain of liver biopsy tissue and subsequent electron microscopy. We review the literature on ARS and compare the clinical features and management of ARS with pediatric Rye's syndrome. This case is of interest to practitioners treating adult patients because it demonstrates that the patient population at risk for Reye's syndrome is broader than generally believed.

Case-control research. Temporal precedence and other problems of the exposure-disease relationship.

We assessed the principle of temporal precedence in recent case-control studies demonstrating the alleged associations between tampon use and toxic shock syndrome and between aspirin use and Reye's syndrome. For both relationships, we considered four components of the exposure-disease association, including: (1) establishing that the agent preceded the disease, (2) selecting an index time, (3) defining criteria for classifying a patient as "exposed," and (4) avoiding the bias that occurs when use of the etiologic agent was influenced by an early manifestation of the disease. The problems can be minimized by interviewing patients early during the course of their illness and by improving strategies for data analysis.

The sequence of changes in liver and brain in the influenza B virus mouse model of Reye's syndrome.

The time course of morphologic changes in the influenza B mouse model of Reye's syndrome is described and compared to the clinical, virologic, and biochemical changes. Following an intravenous inoculation of a lethal dose of an egg adapted strain of influenza B/Lee/40 virus, mice first showed clinical signs of lethargy and ruffled fur at 12 hours (h) post inoculation (pi). The earliest morphologic changes in the liver occurred at 12 h pi, and consisted of a slight increase in fat and loss of glycogen in hepatocytes. Over the next 36 h, the accumulation of microvesicular fat increased, and mitochondrial abnormalities such as pleomorphism and loss of dense bodies developed. There was no increase in peroxisomes. In the brain, focal cerebral edema was detected as early at 6-12 h pi. The edema, manifested as swelling of astrocytic foot processes, increased in severity with time. Endothelial cells were not abnormal. Myelin sheath splitting rarely was observed. Since changes occurred simultaneously in the liver and in the brain, we suggest that influenza B virus caused a simultaneous primary insult to both organs.

Electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) deficiency in an adult.

A 19-year-old woman with mild myopathic symptoms from age 6 and fasting intolerance presented with a Reye-like syndrome and a myopathy. Investigations disclosed a lipid storage myopathy, type II glutaric acidemia, and carnitine deficiency in skeletal muscle. Riboflavin and carnitine treatment corrected the metabolic abnormalities and she improved clinically. She later died from pulmonary complications secondary to aspiration. Subsequent studies established electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) deficiency (fibroblast ETF:QO activity was 2.9 mU/mg, normal range is 14.1 +/- 3.8 mU/mg) as the cause of her illness. This is the first documented case of ETF:QO diagnosed in an adult.

Carnitine deficiency, organic acidemias, and Reye's syndrome.

Relative carnitine deficiency is important in the pathophysiology of several disorders, including Reye's syndrome and organic acidemias. In acute clinical crises, carnitine serves as a "buffer," trapping toxic acyl compounds. Mitochondrial failure develops in carnitine deficiency when there is insufficient tissue carnitine available to buffer toxic acyl-CoA metabolites. Toxic levels of acyl-CoA impair the citrate cycle, gluconeogenesis, the urea cycle, and fatty-acid oxidation. Carnitine replacement therapy is safe and induces excretion of toxic acyl groups in the urine.

A nationwide outbreak of Reye's Syndrome. Its epidemiologic relationship of influenza B.

Between December 15 and June 30, 1974, 379 cases of confirmed Reye's syndrome were reported to the Center for Disease Control. Of these, 316 occurred during February and March 1974. A simultaneous surveillance system for influenza B indicated that this clustering of cases of Reye's syndrome correlated both temporally and geographically with influenza B outbreaks. The incidence of Reye's syndrome was higher in rural than in urban centers. Epidemiologically, two groups of cases of Reye's syndrome emerge: those which occur in older children (median age 11 years), cluster in time and geographic region, and are associated with antecedent influenza B infection; and those which occur sporadically thoughout the year, are isolated in occurrence, occur in younger children (median age 6 years), and are associated with a wide variety of antecedent viral illnesses.

Severe illness with influenza B.

Fifteen patients with recent influenza B infection were admitted to three Dallas hospitals in the first 11 weeks of 1977. The patients' ages ranged from five to 73 years, with a median of 18 years. Most had no significant underlying disease. The spectrum of clinical illness included postinfluenzal bacterial pneumonia (three cases), other severe chest disease (two cases), hyperpyrexia and possible rhabdomyolysis in the elderly (two cases), onset of toxemia of pregnancy, thyroid dysfunction, Stevens-Johnson syndrome, neurologic disorders (two cases), and Reye's syndrome (three cases). Two patients died. Two elderly men with high fever and weakness entered the hospital within three days of illness and two of three patients with Reye's syndrome were admitted four days after the onset of influenza, but the 11 other patients gave a history of seven to 31 days of symptoms before being hospitalized. Morbidity and mortality with influenza B are neither trivial nor restricted to debilitated hosts.

National Reye syndrome surveillance, 1982.

Despite the fact that influenza B was the primary influenza virus strain during the winter of 1981-1982, only 213 cases of Reye syndrome were reported to the Centers for Disease Control (CDC) between Dec 1, 1981 and Nov 30, 1982. This national reported incidence of 0.33 cases per 100,000 children less than 18 years of age is the lowest reported incidence since the Centers for Disease Control began surveillance in 1973. This relatively low incidence probably reflected, at least in part, the fact the influenza B activity was spotty and the illness relatively mild the winter of 1981-1982. The 213 cases were reported from 43 states; and in 56% of the patients, Reye syndrome occurred following a respiratory illness. The mean age of the children was 7.0 years; there were equal numbers of girls and boys; and 93% were white. Of the ten black patients, 80% were less than 1 year of age compared with 9% of the white patients. Of the 208 patients with reported admission stage, 45% were admitted in stage I or 0, a slightly lower proportion than that observed in the previous 2 years. Salicylate levels were obtained in 55% of the patients and were reported as "detectable" in 81% compared with 96% in 1981 (P = .003, chi 2). Of the 200 patients with known outcome, 70 patients died (a case fatality ratio of 35%).