[ACTION OF L-CARNITINE, CORVITIN AND THEIR COMBINATION ON FUNCTIONAL STATE OF LIVER IN EXPERIMENTAL MODEL OF REYE SYNDROME IN RATS].

Administration of Aacetylsalicylic acid in children with viral infections (influence B, chickenpox) can be related with development of Reye syndrome - severe encephalopathy and liver insufficiency with mortality in 50% of cases. During Reye syndrome most important is deficiency of carnitine and hepatocyte damage. Decreased amount of carnitine impairs the energy function of mitochondria and gluconeogenesis as well as production of urea. As a result develops toxic encephalopathy and liver insufficiency. The goal of the research was assessment of efficacy of L-Carnitine, Corvitin and their combination on functional state of liver in experimental model of Reye Syndrome in rats. The study was performed on mature white male Wistar rates with body mass 150-180g. 50 rats were randomly divided into 5 groups (10 rats in each group). The model of Reye syndrome was induced in accordance with A.Vengersky's method. Intraperitoneal administration of 4-pentenoic acid was performed once daily during seven days, the used dosage was 20mg/kg. The treatment of toxic hepatitis was carried with intraperitoneal administration of L-Carnitine 300mg/kg, Corvitine 100mg/kg and concurrent administration of these drugs. Monotherapy with Corvitin and L-Carnitin successfully improved liver function and equally decreased indicators of hepatocyte's cytolyses and increased levels of glucose and urea. The markers of cholestasis was slightly more improved during use of L-Carnitine. Simultaneous use of both drugs was effective in rats with Reye syndrome, indicators of liver damage normalized and herewith, no mortality outcome was observed. The most pronounced hepatoprotective effect of concurrent administration of L-Carnitine and Corvitin may be due to synergic action of these drugs and such regime can be recommended for correction of liver function during Reye syndrome.

Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.

The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Reye syndrome and liver transplantation.

Reye syndrome is a rare, but severe and often fatal disease. The etiology of the classical Reye syndrome is unknown, but it is typically preceded by a viral infection with a free interval of three to five days. The main physiopathological hypothesis is a mitochondrial metabolism insult causing acute liver failure and encephalopathy. Survivors present serious neurological sequelae. The treatment of Reye syndrome is usually medical with intensive care management. Herein, we present the clinical case of a six-month-old baby diagnosed with Reye syndrome with a fulminant hepatitis, who was successfully liver transplanted with an auxiliary partial orthotopic liver transplantation.

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.

The blind men 'see' the elephant-the many faces of fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual's immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis 'NAFLD' can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.

Ca2+ responses to interleukin 1 and tumor necrosis factor in cultured human skin fibroblasts. Possible implications for Reye syndrome.

Elevated concentrations of cytokines were found in the plasma of patients acutely ill with Reye syndrome (RS) but not in control subjects or recovered RS patients. To determine whether this disorder involves a genetically determined abnormal response to cytokines, the effects of tumor necrosis factor (TNF) and IL-1 on intracellular free Ca2+ were compared in cultured skin fibroblasts from control subjects and patients with RS. IL-1 and TNF caused rapid, transient, and concentration-dependent increases in cytosolic free Ca2+. The peak cytosolic free Ca2+ was greater and occurred at higher concentrations of IL-1 and TNF in patient cells than in cells from age-matched controls. In control cells, the Ca2+ transient diminished sharply with increasing amounts of IL-1 or TNF above the maximum stimulatory concentration. In contrast, in patient fibroblast this bell-shaped curve of concentration dependency was much less apparent. Bradykinin-stimulated Ca2+ transients were similar in the two groups and did not exhibit the bell-shaped concentration dependency. Thus, plasma cytokine levels are elevated in RS patients and the Ca2+ response to cytokines is increased in cells derived from these patients. We propose that the increased response reflects a genetic defect in cytokine receptor-modulated signal transduction.

EEG correlations with biochemical abnormalities in Reye syndrome.

A patient with Reye syndrome was studied throughout the course of the illness with continuous EEG monitoring, and these patterns were correlated with serial determinations of serum ammonia and short-chain fatty acid concentrations. There was high correlation between degree of EEG abnormality, clinical symptoms, and elevations of the short-chain fatty acids, while serum ammonia concentrations correlated poorly with the EEG and with the clinical state.

Hepatic and encephalopathic components of Reye's syndrome: factor analysis of admission data from 209 patients.

Factor analysis of admission data from 209 Reye's syndrome patients yielded three factors. Factor 1 was associated with encephalopathy, blood ammonia, creatinine kinase (CK), uric acid and, to a lesser extent, bilirubin. This factor was linked to the encephalopathy and hypermetabolic changes in muscle, possibly prostaglandin-mediated proteolysis. Factor 2 was associated with serum alanine aminotransferase (AlaAT) and aspartate aminotransferase (AspAT), and was identified as a hepatic lesion component. These factors correspond to two etiologic components of Reye's syndrome. Salicylate was only weakly associated with neuropathic and hypercatabolic indicators and not at all associated with the hepatic damage indicators.

Reye syndrome: serum-induced alterations in brain mitochondrial function are blocked by fatty-acid-free albumin.

Oxygen utilization and pH changes were monitored simultaneously in mitochondria isolated from rat brain. Addition of serum from four patients with Reye syndrome stimulated the resting respiratory rate, decreased respiratory control, stimulated ATPase activity, and decreased the rate of phosphorylation as measured by changes in pH. Serum from normal individuals did not have these effects. Convalescent serum from the three surviving patients showed a return of values toward normal. These changes were most marked with serum from the more deeply comatose patients. Contrary to a previous study of rat liver mitochondria, the changes were blocked by preincubation of the patients' sera with fatty-acid-free albumin. The serum factor responsible for the impairment in mitochondrial function may be a short- or medium-chain fatty acid.

Studies on the pathophysiology of encephalopathy in Reye's syndrome; Hyperammonemia in Reye's syndrome.

The initial acid-base status of eight survivors of Reye's syndrome was characterized by acute respiratory alkalosis (Pco2=32 mm Hg; Hco3-=22.0 mEq/liter) while that of eight children who died was associated with metabolic acidosis as well (HCO3-=10.0 mEg/liter). Arterial-internal jugular venous ammonia concentration differences on day 1 (299 mg/100 ml) and day 2 (90 mg/100 ml) reflected cerebral uptake of ammonia while those on days 3 and 4 (-43 and -55 mg/100 ml) demonstrated cerebral release. Arterial blood hyperammonemia can be detoxified safely in the brain as long as the levels do not exceed approximately 300mug/100 ml. Beyond that level lactic acidosis is observed, particularly in cerebral venous drainage. Arterial blood hyperammonemia was also related to the extent of alveolar hyperventilation. These findings are very similar to those seen in experimental hyperammonemia and support the concept that neurotoxicity in children with Reye's syndrome is at least partly due to impaired oxidative metabolism secondary to hyperammonemia.

Intracranial pressure: monitoring and normalization therapy in children.

The clinical course of 42 children with intracranial pressure monitoring was reviewed. Intracranial hypertension was documented in a variety of diagnostic categories. Therapy was titrated to maintain a baseline intracranial pressure of less than 15 torr (mm Hg), and to decrease the frequency of spontaneous and reactive pressure waves. Ventricular drainage, controlled hyperventilation, intravenous glycerol osmotherapy, therapeutic hypothermia, and barbiturate loading were employed as needed to achieve those goals. Survival was significantly related to average and peak intracranial pressure levels and to the degree of serum hyperosmolality that developed during therapy.

Prolonged continuous monitoring of intracranial pressure in severe Reye's syndrome.

Evidence from both clinical and pathological investigations suggests that increased intracranial pressure (ICP) is a significant factor in the mortality of patients with Reye's syndrome. This, coupled with a critical review of our previous 22 patients, which failed to document the efficacy of exchange transfusion, led us to include continous ventricular pressure monitoring in the supportive care of children with Reye's syndrome. To date, three children, ages 3 to 5 years, have been managed with continuous ICP monitoring. All had stage IV coma by both clinical and electroencephalographic criteria. Peak blood ammonia concentrations were 1,036, 316, and 56micronug/100 ml; all had elevations of serum glutamic oxaloacetic transaminase level, prothrombin time, and creatine phosphokinase level as well. Rapid, unprediatble increases in ICP occurred for many days in all children. Therapeutic measures most successful in controlling ICP were the intravenous administration of mannitol and hyperventilation. Elevations in ICP occurred despite serum osmolality as high as 418 mOsm and following oral administration of glycerol. Rapid increases in ICP also resulted from routine manipulation of the patients (e.g., postural drainage). Exchange transfusion, used in two of the three patients, increased ICP in one child and had no effect in the other. All three children have achieved complete recovery and are doing well 6 months after their illness. Our experience with these children suggests that vigorous supportive therapy, including careful monitoring of ICP, should be used as a basis of comparison when evaluating claims of specific treatment in Reye's syndrome.

Reye's syndrome: salicylates and mitochondrial functions.

The effects of aspirin (acetylsalicylate, ASA) and related compounds in the presence of Ca2+ on the oxidative metabolism of isolated rat liver mitochondria were studied. Intact mitochondrial preparations preincubated with ASA + Ca2+ exhibited a transient stimulation of the state 4 respiratory rate with NAD+-linked substrates, followed by an inhibition which could not be released by the addition of ADP or uncoupler. Maximum respiratory rates were achieved by subsequent addition of NAD+ or succinate. The Ca2+-transport inhibitors ruthenium red and ethylene glycol-bis-(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA) prevented these effects. Five brands of commercial aspirin were tested and were as effective as purified ASA. Tylenol (acetaminophen) could reproduce these effects only at much higher (greater than or equal to 10-fold) concentrations. Other salicyl derivatives showed results qualitatively similar to ASA, with potencies in the order: acid much much greater than ASA much greater than alcohol greater than or equal to catechol greater than amide, salicylate being approximately 10-fold more potent than ASA. The magnitude of the effect seen depended on the Ca2+ (endogenous + exogenous) and salicylate concentrations/mg mitochondrial protein, and on the length of the preincubation. Added inorganic phosphate was also required. That salicylate + Ca2+ induces an increase in the permeability of the mitochondrial inner membrane was demonstrated by the observation that 90% of the intramitochondrial NAD(P)+ was released into the surrounding medium upon preincubation of intact mitochondria with these agents. Salicylate + Ca2+ had virtually no effect on respiration with succinate (+ rotenone) as substrate at salicylate concentrations which markedly affected NAD+-linked substrate oxidation. The presence of rotenone in the preincubation mixture prevented the damaging effects of salicylate + Ca2+ on the mitochondrial membrane, suggesting that the redox state of intramitochondrial pyridine nucleotides can modulate these effects. The results reported here are similar to those reported previously by our laboratory for the effects of Reye's plasma and allantoin + Ca2+, and indicate that, like these agents, salicylate and salicyl compounds can potentiate the Ca2+-induced damage to the mitochondrial inner membrane and may be another factor responsible for Reye's syndrome.

In vivo proton magnetic resonance spectroscopy in a case of Reye's syndrome.

A case of a 14-year-old boy with Reye's syndrome (RS) and complete neurologic recovery is presented. 1H magnetic resonance spectroscopy was performed on days 1 (admission to ICU), 8 and 62: During the acute phase of RS substantial cerebral metabolic imbalances were observed and their normalization monitored. The spectra from day 1 featured extremely high glutamine content (approximately 18 mmol/kg excess) and low concentrations of choline compounds pounds (approximately 1 mmol/kg deficit). Also some excess lactate was present. The subsequent spectra demonstrated the return to an almost normal brain metabolite profile.

Hepatic metabolic alterations in rats treated with low-dose endotoxin and aspirin: an animal model of Reye's syndrome.

The administration of a sublethal dose of endotoxin (LPS) followed one hour later by a low dose of aspirin (LPS + ASA) to fasted rats leads to biochemical perturbations similar to Reye's syndrome. In this study hepatic energy metabolism was assessed in freeze-clamped liver samples (12 hours posttreatment) obtained from (250 to 300 g Sprague-Dawley) rats. The administration of aspirin alone to fasted rats did not significantly alter the hepatic levels of adenine nucleotides, total ketones, or acyl-CoA thioesters as compared to controls. In contrast, in both LPS and LPS + ASA samples, there were declines in ATP/ADP ratio (P less than .005), total ketones (P less than .001) and acetyl CoA (P less than .005) compared to their respective controls. A striking alteration in acyl-CoA thioesters was observed in LPS + ASA-treated animals. Unlike control, aspirin, or LPS-treated animals, LPS + ASA-treated animals accumulated relatively large amounts of unusual CoA esters, including propionyl-CoA, (iso)butyryl-CoA, beta-methylcrotonyl-CoA, and isovaleryl-CoA, metabolites of the branch chain amino acid and odd-chain fatty acid oxidation pathways. The acyl-CoA profile is similar to that obtained in patients with Reye's syndrome. Like human patients with Reye's syndrome, these rats showed hyperammonemia, compromised fatty acid oxidation, and accumulation of branched chain amino acid oxidation metabolites. Accumulation of these intermediates with LPS + ASA is a possible mechanism for the potentiation of Reye's syndrome by aspirin. These findings provide biochemical evidence that sublethal doses of LPS + ASA administered to fasted rats produces an animal model of Reye's syndrome.

The influenza B virus mouse model of Reye's syndrome: clinical, virologic and morphologic studies of the encephalopathy.

The influenza B virus mouse model of Reye's syndrome was studied to learn more about the encephalopathy in Reye's syndrome. One to 3 days after intravenous influenza B/Lee virus, Balb/c mice became lethargic, seized and lapsed into a fatal coma. Wide-spread cerebral edema without inflammation developed 1-3 days after virus inoculation. Swollen astrocytic foot processes containing increased glial fibrillary acidic protein were located around capillaries. Viral particles were not seen by electron microscopy and complete viral replication did not occur. Immunohistochemical studies demonstrated influenza B viral antigen within many endothelial cells but not within other brain cells. Qualitative (Evans blue dye) and quantitative (percent brain water and technetium -99 pertechnetate) studies of the blood-brain barrier demonstrated abnormalities. This model reproduced many clinical, virologic and pathologic features of the Reye's syndrome encephalopathy. In addition, a non-permissive viral infection of brain endothelial cells occurred which may be important in the pathogenesis of the mouse encephalopathy and may participate in the encephalopathy of Reye's syndrome.

Evaluation of level of consciousness by the Glasgow coma scale in children with Reye's syndrome.

The Glasgow Coma Scale, which was designed to evaluate level of consciousness after head trauma, has been compared to the Lovejoy scale in 21 patients with Reye's syndrome. Like other investigators, we have noted a poorer prognosis in those patients with higher peak NH3 levels and rapid progression of disease. However, we have also noted that the Glasgow coma scale provides a better, earlier indicator of progressive central nervous system disease than the Lovejoy scale and, therefore, helps physicians caring for such patients to institute intracranial pressure (ICP) monitoring and vigorous measures for the control of elevated ICP earlier than they might otherwise.

Inaccurate pressure readings for subarachnoid bolts.

The subarachnoid bolt has been used extensively to monitor intracranial pressure in a variety of conditions. We have had two patients who had subarachnoid bolts in place that were thought to be functional in whom evidence of increased pressure was present. In one case, the patient had Reye's syndrome with seizure activity, decerebrate posturing, fixed and dilated pupils, and cardiac arrest. Although autopsy revealed evidence of cerebellar and uncal herniation, verifying the presence of pressure cones, the subarachnoid bolt pressure was never elevated and had a good wave form. In the other case, the patient developed an epidural hematoma postoperatively while a subarachnoid bolt was in place. The subarachnoid bolt was measuring pressures of less than 15 mm Hg with a good wave form despite clinical and, subsequently, computed tomographic evidence of an evolving mass. The use of a pressure monitor such as the subarachnoid bolt should not replace frequent clinical assessment of the patient.

Evoked somatosensory potentials to common peroneal nerve stimulation in man.

This study was undertaken to identify the normal somatosensory evoked potential pattern from stimulation of the common peroneal nerve in order to provide basic data for clinical use in diagnosis and management of patients with spinal cord lesions. Thirty-four adult volunteers, free of neurological disease, and 12 patients were tested. The recording technique is described and is similar to that reported by Perot. The primary evoked response (P1) was easily visualized in 88% of the recordings from normal subjects. The peak latency of the primary response was 38.9 msec, and the deflection was positive. A vertex potential (P4) was a relatively consistent peak that appeared at approximately 240 msec in 78% of the subjects. Additional components of the waveform are also described and are compared to previous studies. Clinically, the presence of primary response seems to correlate with a favorable neurological outcome, and recovery of the primary response may precede major clinical improvement. The literature is reviewed and results compared to the current study.