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Objective: Reye's syndrome (RS) appeared suddenly in the 1950s and disappeared almost as quickly in the late 1980s. A number of metabolic disorders were discovered in the 1980s that could completely mimic RS. This study was undertaken to reassess the original diagnosis of RS in light of newly described metabolic disorders., Intervention: The medical records of 26 patients who had survived RS and were originally studied in Australia in the 1980s were reexamined 10 yrs later, and families were interviewed to ascertain if the diagnosis had changed. The 49 original patients with RS from Australia were also reanalyzed using more precise diagnostic criteria for RS to ascertain how many of the patients would continue to fit the more precise diagnosis of RS., Measurements and Main Results: Of 26 original patients with RS who had survived, 18 (69%) were subsequently diagnosed as having other diseases, most commonly inborn errors of metabolism. The most commonly diagnosed metabolic disorder was medium-chain acyl-coenzyme-A dehydrogenase deficiency. Of the 18 patients rediagnosed with diseases other than RS, 15 (83%) are now known to have metabolic disorders. By using more precise diagnostic criteria for RS, none of the original 49 patients with RS could be diagnosed as having certain RS. Only six patients had probable RS, two patients had possible RS, 23 patients had unlikely RS, and 18 patients were excluded as RS cases., Conclusion: With better diagnostic techniques and criteria, most patients originally diagnosed with RS are now known to have metabolic disorders. The disappearance of RS was probably related to the discovery and ability to diagnose inborn errors of metabolism that mimicked RS clinically, biochemically, and pathologically.

Introduction: Reye's syndrome is a metabolic encephalopathy of infancy which is often fatal. Epidemiological studies have shown associated factors including having taken Aspirin for viral illness. Some patients with this disorder may have preexisting organic acidemia such as dicarboxylic aciduria., Objective: To study the behavior of Reye's syndrome in a group of patients during the years 1990-1996 in a provincial paediatric hospital and review variables such as age, sex, race, prodromal illness, previous consumption of Aspirin, hospital stay, mortality, diagnosis of dicarboxylic aciduria, etc., Patients and Methods: We selected patients with Reye's syndrome seen during the period mentioned and considered the above variables., Results: All 10 patients seen with Reye's syndrome were boys. Their ages were between 3 months and 2 years. Most (nine) of the patients were Caucasian. All patients had influenza as the prodromal illness, and all took Aspirin as an antipyretic. There was considerable variation in the length of their stay in the hospital. In our series there was a high mortality and only two patients survived. One boy had dicarboxylic aciduria., Conclusions: The fatal character of Reye's syndrome has been shown, as has its relation to the use Aspirin. In our environment there seems to be a tendency for Caucasian boys to be affected.

Background: Reye's syndrome is characterized by encephalopathy and fatty degeneration of the liver, usually after influenza or varicella. Beginning in 1980, warnings were issued about the use of salicylates in children with those viral infections because of the risk of Reye's syndrome., Methods: To describe the pattern of Reye's syndrome in the United States, characteristics of the patients, and risk factors for poor outcomes, we analyzed national surveillance data collected from December 1980 through November 1997. The surveillance system is based on voluntary reporting with the use of a standard case-report form., Results: From December 1980 through November 1997 (surveillance years 1981 through 1997), 1207 cases of Reye's syndrome were reported in patients less than 18 years of age. Among those for whom data on race and sex were available, 93 percent were white and 52 percent were girls. The number of reported cases of Reye's syndrome declined sharply after the association of Reye's syndrome with aspirin was reported. After a peak of 555 cases in children reported in 1980, there have been no more than 36 cases per year since 1987. Antecedent illnesses were reported in 93 percent of the children, and detectable blood salicylate levels in 82 percent. The overall case fatality rate was 31 percent. The case fatality rate was highest in children under five years of age (relative risk, 1.8; 95 percent confidence interval, 1.5 to 2.1) and in those with a serum ammonia level above 45 microg per deciliter (26 micromol per liter) (relative risk, 3.4; 95 percent confidence interval, 1.9 to 6.2)., Conclusions: Since 1980, when the association between Reye's syndrome and the use of aspirin during varicella or influenza-like illness was first reported, there has been a sharp decline in the number of infants and children reported to have Reye's syndrome. Because Reye's syndrome is now very rare, any infant or child suspected of having this disorder should undergo extensive investigation to rule out the treatable inborn metabolic disorders that can mimic Reye's syndrome.

Onset of the cyclosporin-A-sensitive mitochondrial permeability transition (MPT) in individual mitochondria within living cells can be visualized by laser scanning confocal microscopy. The MPT is a causative event in many types of necrotic and apoptotic cell death, including oxidative stress, ischemia/reperfusion injury, Ca2+ ionophore toxicity and tumor necrosis factor alpha (TNF alpha) induced apoptosis, and may contribute to Reye's-related drug toxicity. Pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and increased mitochondrial Ca2+ and pH can each promote onset of the MPT in situ. The MPT can also be directly visualized during TNF alpha-induced apoptosis to hepatocytes. Mitochondria spontaneously depolarize in situ after nutrient deprivation before entering an acidic lysosomal compartment, suggesting that the MPT precedes the normal process of mitochondrial autophagy. We propose a model in which onset of the MPT to increasing numbers of mitochondria leads progressively to autophagy, apoptosis and necrotic cell death.

Aspirin is strongly implicated in the pathogenesis of Reye's syndrome, a childhood disorder characterized by hyperammonemia, microvesicular steatosis, and encephalopathy. Previously, we showed that salicylate, the active metabolite of aspirin, induces the mitochondrial permeability transition (MPT) in isolated mitochondria, as do several other chemicals implicated in Reye's-related disorders. Opening of a high conductance, cyclosporin A-sensitive pore in the mitochondrial inner membrane causes the MPT, leading to swelling, depolarization, and uncoupling of oxidative phosphorylation. The goal of this study was to characterize the role of the MPT in salicylate toxicity to cultured rat hepatocytes. Salicylate (0.3-5 mM) caused concentration-dependent cell killing. In Krebs-Ringer buffer, half-maximal cell killing occurred 150 min after 3 mM salicylate. Increasing Ca2+ enhanced salicylate lethality. Salicylate-dependent cell killing was blocked by 0.5-5 microM cyclosporin A and its nonimmunosuppresive analog, 4-methylvaline cyclosporin, implicating the MPT in the pathogenesis of cell killing. The contribution of the MPT to lethal cell injury was confirmed by laser scanning confocal microscopy, which demonstrated the redistribution of the fluorophore calcein from the cytosol into mitochondria prior to cell killing, an event blocked by cyclosporin A. Salicylate toxicity was enhanced at high extracellular Ca2+. In the range of 10-100 microM, several chemically diverse calcium antagonists blocked or reduced salicylate toxicity including verapamil, diltiazem, chlorpromazine, nifedipine, and nisoldipine. Calcium antagonists also blocked the increase of mitochondrial free Ca2+ in high Ca2+ buffer, as determined by confocal imaging of the fluorophore Rhod-2. These data with salicylate suggest that onset of the MPT may be the common pathophysiologic mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities. Further, elevated intramitochondrial Ca2+ may be a predisposing condition promoting onset of the MPT by Reye's-related chemicals.

Reye's syndrome (RS) is a biphasic illness that occurs predominately in children and adolescents. A prodromal viral illness (frequently influenza A or B or chicken pox) is followed by protracted vomiting and neurologic changes that start 3 to 5 days later, just when the child seems to be recovering. Aspirin has been identified as one factor contributing to the metabolic disorder that occurs. Since 1986 the FDA has required labels on all aspirin products warning about the association of aspirin use and RS. Media messages heightened public awareness regarding the alternatives to aspirin for analgesia and antipyretic use. Since 1988, the incidence of RS has decreased dramatically. RS is now more prevalent in older adolescents who may self-medicate. Because early recognition of the disease is associated with decreased morbidity and mortality, it is important for health care providers to recognize the symptoms of RS. Unexpected vomiting and disturbed brain functioning following a viral illness are symptoms of RS in children and adolescents. In infants, the symptoms of RS may be more subtle, including diarrhea, respiratory disturbances, and seizures.

Reye's syndrome is a rare disorder appearing almost always in childhood. It is characterized by acute encephalopathy and fatty degeneration of the viscera. The mortality is high and many survivors have neurologic sequelae. A viral illness, particularly varicella or influenza B, usually precedes the syndrome. It has been associated with the use of aspirin during such infections. The number of cases has declined in countries where there has been a public education campaign and aspirin products have been withdrawn from sale. It is suggested that the same campaign is initiated in Denmark.

Reye's syndrome is most frequently seen in children but has also been described in adults. This syndrome is usually associated with ingestion of 5-aminosalicylates (ASA) or infection with influenza A, influenza B, or varicella virus. A case of Reye's syndrome in a 47 year old, previously healthy woman precipitated by ingestion of ASA and acute hepatitis A virus infection is described. Reye's syndrome was diagnosed on the basis of her clinical course, and the presence of hepatic microvesicular steatosis and characteristic electron microscopic changes in the hepatocyte mitochondria. The diagnosis of hepatitis A was based on higher amino-transferase values than would be expected in Reye's syndrome alone, viral serology including the presence of hepatitis A IgM and the demonstration of hepatitis A virus RNA on liver biopsy by in situ hybridisation. Mitochondrial injury has been demonstrated in acute hepatitis A which, in addition to ASA, may have precipitated Reye's syndrome in this patient. The association between hepatitis A and Reye's syndrome has not been reported before. As hepatitis A virus infection is not sought routinely in patients with Reye's syndrome, the frequency of this association is unknown.

Several neurological complications associated with Influenza virus infection are known as a febrile convulsion, polyneuritis, meningitis, encephalomyelitis and encephalopathy. Influenza encephalopathy is the most severe complication associated with Influenza. It may be classified into several subtypes according to the clinical symptoms and laboratory data. In this review, Reye's syndrome, acute necrotizing encephalopathy and hemorrhagic shock and encephalopathy syndrome (HSE) are described in detail. The 1995 influenza pandemia in Nagasaki prefecture was markedly neurovirulent and lethal. Twelve cases developed influenza encephalopathy, and the mortality rate between them was 50%. Almost all of them had never be inoculated of influenza vaccine before.

An adult male presented at 28 years of age with muscle weakness and liver dysfunction. His brother had died suddenly 2 years earlier after presenting with Reye's syndrome. Urine organic acid analysis and muscle and cultured fibroblast fatty acid oxidation studies confirmed a diagnosis of ethylmalonic/adipic aciduria-an inherited defect of fatty acid oxidation. The patient responded favourably to treatment with a low fat/high carbohydrate diet supplemented with riboflavin. This case highlights the importance of considering inborn errors of metabolism, in particular fatty acid oxidation defects, in adults with liver disease, muscle disease or Reye's syndrome.

Forty children with Reye syndrome (RS) or Reye-like illnesses were investigated to elucidate the underlying aetiologies. Extensive biochemical studies including patterns of organic acids and amino acids, liver histopathology, and, if available, a DNA approach were performed. In addition to classical RS (n = 10), the causes of Reye-like conditions included hereditary organic acidaemias (n = 13), urea cycle defects (n = 4), mitochondrial disorders (n = 3), fulminant hepatitis (n = 2), tyrosinaemia (n = 1), valproate-associated hepatotoxicity (n = 1), and other non-specific generalized organic acid disorders (n = 6). It is important to collect specimens when encephalopathy with liver dysfunction of unknown causes is noted. When the underlying inherited metabolic disorders are confirmed, the prevention of the recurrence by adequate diet control and medications, and genetic counselling become possible.

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.

In the literature the separation between RS and RLS is confusing and makes it difficult to plan an appropriate preventive action or to develop new therapeutic approaches. We suggest that the generalized damage and encephalopathy seen in both RS and RLS may be due to a wide variety of causative agents that contribute to a common derangement, principally involving mitochondrial oxidative pathway. Fasting status and infections increase the catabolism and the subsequent flux of metabolites from peripheral tissues to the liver (FA and amino acids); cytokines (TNF, IL-1, and IL-6), in particular, mediate this effect during infection and experimental endotoxemia. Some drugs and other toxic compounds induce functional and morphological liver mitochondrial derangement. Oxidative metabolism is impaired, with subsequent stimulation of alternative pathways of oxidation, following production of unusual toxic acyl CoAs and dicarboxylic acids. Toxic compounds accumulate in the liver, deranging its functions and causing energy depletion, and are also released in the circulation from which they reach other tissues, including the brain. Neurons and astrocytes in the brain may be affected differently: Neurons suffer from the lack of energy and the effect of toxic compounds arriving from the bloodstream, and astrocytes may be directly affected by the beta-oxidation derangement. Very important may be genetic predisposition, which, by making the patient more sensitive to a particular causative agent, may facilitate the onset of RS and RLS. The therapeutic approach is, presently, mainly symptomatic, directed as it is to counteracting each alteration shown, depending by the clinical gravity. Other pharmacological approaches are only studied experimentally, like carnitine supplementation and PGE2 administration, or theoretically envisaged, like monoclonal antibody therapy directed at LPS or at pro-inflammatory cytokines or treatment with interferon-alpha.

Reye's syndrome is considered a disease of the pediatric age. It is characterized by a prodrome of viral illness followed by vomiting and encephalopathy with associated hepatic dysfunction. This syndrome is potentially life-threatening with high morbidity and mortality rates. There are 27 other cases of adult onset Reye's syndrome reported in the literature. We describe a 18-year-old woman who developed varicella and four days later started with vomiting, delirium and in the following day she became comatose. Laboratory tests of liver function and pathology of a liver biopsy proved the diagnosis. The patient survived. A review of the proposed pathogenic mechanisms are presented. Our patient represents case the number 28 in world literature and the first in the mexican literature.

The Authors report a case of Reye's syndrome associated with an hemophagocytic histiocytosis in a 16-month-old baby. The vaccination against measles, mumps and rubella administrated 15 days before the onset of symptoms is suggested as the etiologic factor of both diseases. The Authors believe that the vaccine, composed of alive viruses was responsible of immunodepression and, as a common viral infection, of Reye's syndrome and hemophagocytic histiocytosis in the child constitutionally predisposed.

For several years it has been recommended that aspirin should be avoided in children under the age of 12 years because of the risk of Reye's Syndrome. In this study we investigated the reported use of analgesics among children who attended the Children's Department of the Dental Hospital in Newcastle upon Tyne. In addition the study also investigated the complaints that led to use of analgesics, the dose and frequency of administration of the analgesic, and past and current contact with medical services. Of 179 children investigated, 129 were under 12 years-old; of these 129 children under 12 years-of-age, 72 (56%) had taken an analgesic within the previous six months, 12 (17%) of whom took aspirin. Three of these children who had taken aspirin were reported to have had a serious illness in their lives, and would therefore have had significant contact with medical services. One-quarter of all children who had taken an analgesic did so for toothache. Inappropriate use of aspirin in children under 12 years-of-age indicates that health education about the possible risks of Reye's Syndrome needs to be improved.

Reye's syndrome is an acute metabolic encephalopathy largely affecting children and adolescents. Its aetiopathogenesis, although controversial, is at least partially understood. Its study has helped to create a greater awareness of inherited disorders of intermediary metabolism. Although these are individually rare, when combined they constitute a significant cause of morbidity and mortality.

The case of a previously healthy child who developed progressive systemic varicella with purpura is reported. The clinical course of this patient is outlined, and the range of potential complications of chickenpox in children is reviewed. Familiarity with the usual uncomplicated natural history of primary varicella infection should alert the clinician to signs and symptoms that signal significant systemic involvement.

The authors report on one case of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMG-Co A lyase) deficiency in a 3 year-old girl, presenting as Reye's syndrome. Urinary organic profile suggested this inherited metabolic disease; decreased activity of HMG-Co A lyase was demonstrated in cultured fibroblasts. The metabolic etiologies of Reye's syndrome are summarized; clinical, biological, and therapeutic assessment of HMG Co A lyase deficiency are developed. The pattern of organic aciduria must be studied in all patients presenting with Reye's syndrome.

The Reye's syndrome (RS) surveillance scheme for the British Isles, jointly organised by the British Paediatric Association and the PHLS Communicable Disease Surveillance Centre, was established in 1981. In the ten years that have followed, there has been a gradual decline in the number, and the age, of cases reported. However, the proportion of cases whose diagnosis was subsequently revised to that of an inherited metabolic disorder, has increased. These trends have been influenced by the change from 'passive' to 'active' case ascertainment in 1986; the aspirin warning issued by the Committee on Safety of Medicines in June 1986; the 1989 influenza epidemic; and the increasing awareness of conditions that mimic RS, particularly inherited metabolic disorders involving defects of fatty acid oxidation. The cases reported in 1990/91 showed the lowest annual incidence recorded so far and a median age of less than ten months (compared with 15 months in the first six years of surveillance). There was a reduction in the case fatality rate in 1990/91 (although still high at 38%) but it is of concern that two children had had pre-admission exposure to aspirin. Parents should be kept aware of the dangers of giving aspirin preparations to children with feverish illnesses.

Reye's syndrome (RS), originally known by the more descriptive name "encephalopathy with fatty degeneration of the viscera," was first described in children and is still seen mostly in them. However, there have been a few case reports of adult Reye's Syndrome (ARS) since the mid-1970s. The following report is a case of ARS in a previously healthy 26-year-old woman. Although the clinical description and the pathophysiology are well known in RS, the etiology and the pathogenesis are still far from clear. From available evidence a multifactorial cause seems likely, encompassing genetic susceptibility, environmental factors, and the convincing role of aspirin. Moreover, as there is increasing awareness of metabolic mimics, questions arise about the validity of some of the diagnoses of RS, even in Reye's original cases.

A role for lipopolysaccharides (endotoxins, LPS) in 7 the pathogenesis of Reye's syndrome (RS) has previously been suggested. Impairment of hepatic LPS clearance can lead to systemic endotoxemia as previous studies by this and other laboratories have suggested for several hepatic disorders including RS. Systemic LPS may mediate many of the clinical findings associated with RS by eliciting monokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interleukin-8. Monoclonal antibody therapy directed at LPS, and monokines may represent a novel approach to the treatment of RS.

Between January 1, 1981, and December 31, 1990, 83 previously well children and 20 with stable underlying conditions were hospitalized because of complications of varicella. The mean hospital stay was 4.5 days and one child with pneumonia died. Skin or soft tissue infections and pneumonia were the most common complications. Central nervous system complications (15), dehydration (8) and Reye's syndrome (6) accounted for 75% of the nonsuppurative complications. Cellulitis (7), pneumonia (3) and encephalitis (3) were the most common diagnoses among the 20 children hospitalized greater than or equal to 7 days. No cases of Reye's syndrome were diagnosed after 1984. An increase in the number of soft tissue infections caused by Group A beta-hemolytic streptococci and involving an extremity was noted during the last 5 years. Chickenpox continues to cause significant morbidity in the pediatric population.

Authors discuss the possible etiopathogenesis of Reye syndrome (RS) on the base of eight own cases presented in this paper and others previously described. The febrile infection was observed on the beginning of the disease in all actually analysed cases and was followed by symptoms of acute damage of liver and brain. The central nervous system lesions present the changes increasing with time from brain oedema to the necrosis of nerve tissue. The oedematous changes could be recognized as a principal cause of unconsciousness and even of coma in RS. When the etiology of RS remain unknown the clinico-pathological observations of such cases incline to formulate three questions: Is an genetically conditioned background necessary which facilitate toxic or infectious factors to induce the RS? Is the etiology of RS only genetically conditioned? Is an specific viral infection the cause of RS?

We have previously reported that a single meal of an arginine-free diet rapidly induces hyperammonemia in young ferrets and that aspirin administration in conjunction with influenza B infection and arginine-free diet results in clinical and biochemical alterations consistent with Reye's syndrome. The objective of the present study was to test whether ibuprofen administration, either alone or in combination with influenza infection and arginine-free diet, produces a similar effect. Two-mo-old ferrets were inoculated intranasally with influenza B virus, treated with therapeutic doses of ibuprofen, and fed a single meal of an arginine-free diet. Arginine-free diet caused a significant increase in plasma ammonia and a small increase in plasma aspartate aminotransferase activity. All ferrets fed an arginine-free diet recovered within 6 to 7 h after ingesting the diet. Ibuprofen treatment, either solely or in combination with influenza infection, did not produce significant change in the plasma levels of aspartate or ornithine aminotransferase activities. A combination of ibuprofen treatment, influenza infection, and arginine-free diet caused a significant increase in the mortality and plasma ammonia levels. Plasma aspartate aminotransferase and ornithine carbamyl transferase activities were elevated, and liver ornithine carbamyl transferase activity was decreased. However, other mitochondrial enzymes such as ornithine aminotransferase were not altered, whereas the activity of cytoplasmic enzymes such as arginase were decreased. These results suggest that ibuprofen administration resulted in generalized hepatopathy rather than specific mitochondrial injury and Reye's syndrome-like changes associated with aspirin in our previous model.

From 65 reported cases of medium chain acyl-CoA dehydrogenase deficiency, we found an average presenting age of 13.5 months and a mean age at death of 18.5 months. One quarter of patients died of a Reye-like syndrome and/or sudden infant death. In half the cases there had been at least one sibling death. Asymptomatic cases were not uncommon (12% of cases). The crises were generally induced by a prolonged fast and after a viral prodromal phase in three quarters of cases. The crises consisted of somnolence progressing to lethargy which could lead to coma. Vomiting was frequent (60% of cases). Seizures, which were found in 29% of cases, represented a bad prognosis. The physical examinations revealed frequently a variable and regressive anicteric hepatomegaly. Blood and urine analysis revealed in most instances hypoglycaemia (96% of cases) with hypoketonuria and sometimes metabolic acidosis. Hepatic and muscular cytolytic enzymes were frequently raised, as were plasma ammonia, urea, and uric acid. Plasma total or free carnitine concentrations, especially non-fasting, were diminished in most cases. Plasma saturated medium chain fatty acids and particularly unsaturated cis-4-decenoate were on the other hand raised during the crises or during fasting. Urinary organic acid analysis revealed a characteristic profile of medium chain aciduria: C6-C10 dicarboxylic acids, hydroxy acids, glycine conjugates, and carnitine conjugates. Oral loading tests with carnitine or phenylpropionate allow a precise diagnosis. The diagnosis is confirmed by specific assays in various tissues. Avoidance of prolonged fasting seems to be the mainstay of treatment.

A seven-month-old girl was admitted to the Pediatrics Department of Mackay Memorial Hospital with the following symptoms and signs: (1) high fever for more than five days; (2) injection of bilateral conjunctiva; (3) bright red lips with strawberry tongue; (4) edematous change of palms and soles, followed by digit desquamation; (5) an ill-defined, erythematous plaque on the scar of the BCG. Kawasaki disease was diagnosed, and high dose aspirin (100 mg/kg/day) and intravenous gamma-globulin (IVIG) (400 mg/kg/day) were given for four days. The patient was afebrile on the second day after IVIG infusion, and was discharged six days after admission. A small single daily dose of aspirin (10 mg/kg/day) was given after the afebrile days. Unfortunately, vomiting and consciousness disturbance were noted one day after discharge. Laboratory data showed elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ammonia. Hypoglycemia and prolonged PT and PTT were also noted. Reye syndrome was suspected, and the patient was admitted to the intensive care unit for further management. A liver biopsy gave findings consistent with Reye syndrome. In spite of intensive treatment, the infant expired on the second day after admission. In a review of the literature, no correlation between these two syndromes was found. This rare case is presented to warn that Reye syndrome may follow Kawasaki disease when aspirin has been prescribed at a high dose.

Administration of either aspirin or salicylic acid (3 mmol.kg-1 b.wt. i.p.) decreased by 50 and 65%, respectively, the in vivo oxidation of [U-14C]palmitic acid to [14C]CO2 in mice; after salicylic acid administration, exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 87, 33 and 38%, respectively. Inhibition lasted 9 hr. It was associated with markedly decreased blood glucose concentrations and increased plasma ketone bodies. Repeated administration of salicylic acid (2 mmol.kg-1 i.p. every 8 hr) tripled hepatic triglycerides and produced mild microvesicular steatosis of the liver at 22 hr in fasted mice. In vitro, salicylic acid (1.5 mM) had no or little effect on the formation of beta-oxidation products from [1-14C]octanoic or [1-14C]palmitoyl-L-carnitine, in the presence of ATP, carnitine (40 microM) and coenzyme A (40 microM), but decreased by 51% that from [1-14C]palmitic acid. In the latter system, increasing the concentrations of coenzyme A and carnitine to 200 microM suppressed the inhibitory effect of salicylic acid. Salicylic acid (1.5 mM) decreased by 80% the in vitro mitochondrial formation of palmitoyl-coenzyme A from [1-14C]palmitic acid and 10 microM coenzyme A; again, increasing the concentration of coenzyme A prevented inhibition. We conclude that salicylic acid decreases the mitochondrial activation and thus beta-oxidation of long chain fatty acids, presumably by sequestering extramitochondrial coenzyme A and possibly carnitine.

To develop an animal model of Reye's syndrome using a virus associated with the human disease, mice were intravenously inoculated with influenza A/PR8 virus (LD50 4000 haemagglutinin units). One to 3 days later the mice developed lethargy, seizures, coma and death. The cerebrospinal fluid cell count was normal. Serum aspartate aminotransferase levels increased 24-fold. Diffuse microvesicular fatty metamorphosis along with multiple small foci of necrosis developed in the liver. Influenza virus-like particles were seen by electron microscopy in the liver, primarily in areas of liver necrosis, but were not seen in the brain. Cerebral oedema without inflammation developed in the brain. Limited viral replication occurred within the liver. Influenza viral antigens were seen in 5-20% of hepatocytes from both necrotic and non-necrotic areas as well as in brain endothelial cells. Many of the clinical, biochemical and pathologic features of the mouse illness resemble those seen in Reye's syndrome. However, this model differs from the human disease in that focal areas of liver necrosis occurred along with limited complete viral replication in liver.

We describe an eight-month-old infant who had an unusually fulminant and fatal course of Reye's syndrome. The patient died 36 hours after admission because of irreversible circulatory failure not associated with clinical symptoms of increased intracranial pressure or cerebral herniation. Autopsy revealed the pathognomonic fatty degeneration of the liver and heart of Reye's syndrome, but the brain was normal. In addition, a marked inflammatory infiltration of the myocardium was also observed, which indicated that acute myocarditis had been the preceding underlying disease. This case report emphasizes the fact that the viral prodrome preceding Reye's syndrome may not be as benign as often observed with influenza and varicella. Acute myocarditis and Reye's syndrome are also a combination which may result in fatal cardiovascular collapse.

A survey about the Reye-syndrome including diagnosis, symptoms, therapy, and differential diagnosis is actually presented. The related problems of its pathogenesis, etiology and epidemiology are discussed. It is recommended to diagnosis this disease for registrating its frequency and distribution on the area of Germany.

Aflatoxins have been incriminated, mainly on circumstantial evidence, in hepatocellular carcinoma, acute hepatic failure and Reye's syndrome, but other possible effects of continuous or intermittent dietary exposure to aflatoxins, which occurs widely in the tropics, have received little study. Over the past 10 years evidence has steadily accumulated that incriminates aflatoxins in the aetiology of kwashiorkor, a widespread and serious disorder of children in the tropics, previously believed to be caused by protein deficiency. Investigation of human breast milk, undertaken initially to elucidate the pathogenesis of kwashiorkor in breastfed infants, has revealed widespread and serious exposure to aflatoxins from this source. Extension of these studies to pregnant women, in turn, revealed widespread and serious prenatal aflatoxin exposure. In laboratory and farm animals, such exposure has serious implications for immune and hepatic functions, and is detrimental to growth and development. Recent analysis of heroin samples show that heroin addicts may also be exposed to these toxins. These findings show that human exposure to aflatoxins may begin prenatally, persist during breastfeeding, and continue into adult life. It is postulated that aflatoxins (i) play a role in the aetiology of kwashiorkor, (ii) increase neonatal susceptibility to infection and jaundice, (iii) increase childhood susceptibility to infections and malignant disease, (iv) compromise immune responses to prophylactic immunisations and (v) may play a role in the pathogenesis of diseases in heroin addicts. There are indications also that acute, fatal aflatoxin poisoning which masquerades as 'hepatitis' may occur more frequently than is currently appreciated.

The hepatic steatosis observed in the influenza B virus mouse model of Reye syndrome has been attributed to infectious virus or, alternately, to decreased food intake in the virus-treated mice or impurities in the virus preparation. To resolve this issue, 4- to 6-wk-old male Balb C mice were given, by intravenous injection, 12,800 hemagglutination units of influenza B Lee/40 virus in phosphate buffered saline/1% bovine serum albumin using virus prepared by ultra-centrifugation from infected allantoic fluid, by sucrose density-gradient purification of virus prepared by ultracentrifugation from infected allantoic fluid or by irradiation of virus prepared by ultracentrifugation from infected allantoic fluid to inactivate virus. The infectivity titer of virus prepared by ultracentrifugation from infected allantoic fluid was much higher than that of sucrose density-gradient purified virus prepared from infected allantoic fluid: 50% egg infectious dose for virus prepared by ultracentrifugation from infected allantoic fluid was 3.9 x 10(4)/hemagglutination unit vs. 8.7 50% egg infectious dose/hemagglutination unit for sucrose density-gradient purified virus prepared from infected allantoic fluid. Control mice received phosphate-buffered saline/1% bovine serum albumin or uninfected allantoic fluid diluted in phosphate-buffered saline/1% bovine serum albumin. Mice were fasted to eliminate dietary variation, and livers were obtained 36 hr after virus administration. Of the above treatments, only virus prepared by ultracentrifugation from infected allantoic fluid caused clinical illness and increased hepatic triglycerides (p less than 0.02) compared with controls. Hepatic triglycerides in virus prepared by ultracentrifugation from infected allantoic fluid correlated with histopathological vacuolization scores (r = 0.5773; p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

We have examined the effects of salicylate on fluxes of lactate metabolism in rat hepatocytes using a steady state model. Salicylate produces an uncoupling effect, an inhibition of gluconeogenesis, a marked activation of pyruvate dehydrogenase flux, and an inhibition of endogenous fatty acid oxidation. Agents with known functions such as dinitrophenol and dichloroacetate were also compared in this system. The in vitro inhibition of gluconeogenesis caused by salicylate is not primarily related to the uncoupling effect. The fact that octanoate, but not palmitate, overcomes the salicylate inhibition of gluconeogenesis suggests that salicylyl CoA is involved in the inhibition. To relate in vitro studies to Reye's syndrome in vivo, in which medium chain dicarboxylic acids accumulate, we have also examined the effects of monomethyl suberate on liver lactate metabolism. This half ester is taken up by the hepatocytes, and causes inhibition of lactate gluconeogenesis, and uncoupling. Both salicylate and monomethyl suberate inhibit the oxidation of 0.2 mM octanoate by hepatocytes.

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.

FABPs in the various tissues play an important role in the intracellular fatty acid transport and metabolism. Reye's syndrome (RS) and multisystemic lipid storage (MLS) are human disorders characterized by a disturbance of lipid metabolism of unknown etiology. We investigated for the first time L-FABP in these two conditions. Affinity purified antibodies against chicken L-FABP were raised in rabbits, and found to cross-react specifically with partially purified human L-FABP. L-FABP content in liver samples of two patients with RS and MLS was investigated by immuno-histochemistry, SDS-PAGE and ELISA. L-FABP immuno-histochemistry showed increased reactivity in the liver of RS patient and normal reactivity in MLS liver. L-FABP increase in RS liver was confirmed by densitometry of SDS-PAGE and ELISA method. By these two methods the increase amounted to 180% and 199% (p less than 0.02), respectively, as compared to controls. A possible role of L-FABP in the pathogenesis of RS is discussed.