The renal origin of sodium valproate-induced hyperammonemia in fasting humans.

Acute administration of 1,500 mg of sodium valproate or chronic administration of 30 mg/kg/24 hours induced a more than twofold increase of renal ammoniagenesis in fasting subjects. Hyperammonemia was moderate, as normal hepatic ammonia detoxification persisted. Renal uptake of glutamine increased simultaneously.

Increase of valproate-induced hyperammonemia in normal subjects by carbohydrate intake.

Sodium valproate-induced hyperammonemia in normal subjects is increased by the intake of carbohydrates--rapidly or slowly absorbed sugars, given by mouth or IV injection. The hyperammonemia is maximal about 3 hours after carbohydrate administration. This relation between carbohydrate and ammonia metabolism has not been described previously.

Regulation of uveal sympathetic neurotransmission by peroxides.

PURPOSE: To investigate the effect of naturally occurring and synthetic peroxides on norepinephrine release from isolated iris-ciliary bodies of several mammalian species. METHODS: Hemiirides (bovine) and iris-ciliary bodies (human, rabbit, and rat) were incubated in Krebs solution containing [3H]-norepinephrine ([3H]NE) for 60 minutes. After incubation, tissues were set up for studies of [3H]NE release using the superfusion method. Release of [3H]NE was elicited through electrical field stimulation. RESULTS: In bovine irides, hydrogen peroxide (H2O2), cumene hydroperoxide (cuOOH), and tert-butyl hydroperoxide (buOOH) caused a concentration-dependent potentiation of field-stimulated [3H]NE release with the following rank order of potency: cuOOH > H2O2 > buOOH. Furthermore, the free radical scavenger, melatonin (2 mM), prevented the enhancement of evoked [3H]NE overflow elicited by H2O2 and cuOOH. At equimolar concentrations, H2O2 (1 mM) increased stimulated [3H]NE release from rabbit, human (mean age, 29.7; range, 15 to 48 years), and Fischer 344 rat (4 months old) iris-ciliary bodies by 98%, 50%, and 40%, respectively. However, H2O2 (1 mM) caused a 9% increase in evoked [3H]NE release in tissue from aged Fischer 344 rats (30 months old) and a 5% decrease in neurotransmitter release in tissue from old human donors (mean age, 72.3 years; range, 69 to 74 years). CONCLUSIONS: Peroxides such as H2O2 can potentiate sympathetic neurotransmission in the anterior uvea of several mammalian species. In bovine irides, H2O2-induced enhancement of neurotransmitter release can be mimicked by synthetic peroxides and may involve the generation of reactive oxygen species.

Effects of 2,4-dinitrophenol on renal ammoniagenesis in the rat.

Injection of anesthetized rats with the uncoupling agent, 2,4-dinitrophenol (2,4-DNP) 10 or 20 mg/kg induced a systemic hyperammonemia unaccompanied by blood acid-base status changes and related to an increased release of ammonium from the kidney into the renal vein. Ammonium excretion into the urine did not increase. The renal uptake of circulating glutamine rose. The antiepileptic drug sodium valproate (VPA), a short-chain, branched fatty acid, had the same effects on rat and man. These findings suggest that VPA stimulates renal ammoniagenesis by the same mechanisms as 2,4-DNP.

Sodium valproate-induced hyperammonemia in the rat: role of the kidney.

The intravenous injection of sodium valproate (VPA) 200 mg/kg provoked in fasting rats a 100% increase in the arterial NH+4 concentration by the 10th min. The increase persisted at this level for at least 100 min. Simultaneous measurements of NH+4 and glutamine concentrations in the carotid artery, renal vein and suprahepatic vein showed that there were increases in the release of NH+4 and the uptake of glutamine by the kidney while the [NH+4] of suprahepatic venous blood remained stable. In binephrectomized rats injected with VPA, NH+4 levels did not change. These results suggest that the VPA-induced arterial hyperammonemia depended on the accelerated catabolism or possibly the reduced synthesis of glutamine by the kidneys. The liver of fasting rats does not seem to play a preponderant role in the VPA-induced hyperammonemia.

Decrease of valproate-induced hyperammonemia in normal subjects by lipid ingestion.

Sodium valproate (VPA), a branched short-chain fatty acid, always causes a hyperammonemia of renal origin in fasting man. The intake of medium-length, straight-chain fatty acids abolishes the VPA-induced hyperammonemia, and VPA free fraction increases concomitantly. Accordingly, fatty acids could be useful in preventing and treating hyperammonemia-accompanied stuporous states which are complications of VPA medication.

Neurotransmitter modifications in human cerebrospinal fluid and serum during hepatic encephalopathy.

The concentrations of catecholamines, serotonin, histamine and GABA as well as some of their precursors and metabolites were measured in the CSF and the serum of human patients at different grades of hepatic encephalopathy. In all grades the CSF concentrations of the neurotransmitters were much increased over control levels, while the amount of metabolites varied with the grade of coma. The data suggest modifications of the cerebral turnover of dopamine, norepinephrine and serotonin. The "false transmitters" also occurred in high concentration in all grades of hepatic coma and could play a role in the alterations of synaptic transmission. The present results suggest that the biochemical changes between grade 2 and grade 4 hepatic coma could be due to an inhibition of dopamine beta-hydroxylase. Moreover, the levels of neurotransmitter precursors, tyrosine and 5-hydroxytryptophan, showed enhancement in grades 2 and 3 followed by an important reduction in grade 4. Finally, it seems that the biogenic amines measured in the CSF are of central origin and that their quantification in human lumbar fluid gives new information on the central mechanisms involved in hepatic encephalopathy.

[Sodium valproate: a hyperammonemic drug. Study in the epileptic and healthy volunteer]. / Le valproate de sodium: une drogue hyperammonemiante. Etude chez l'épileptique et chez le volontaire sain.

Sodium valproate (VPA) consistently induces an arterial hyperammonemia in epileptics tolerant of this drug and in normal subjects. The hyperammonemia appears with the first oral or intravenous dose of the drug, 15-25 mg/kg, and is established within minutes following drug absorption. In 20 epileptics treated with VPA alone for 4 days, the mean arterial ammonemia measured 2-3 h after breakfast and the day's first VPA dose was 72 +/- 9 mumols/l in non-alcoholics, and 77 +/- 7 mumols/l in alcoholics. Hyperammonemia persisted during chronic treatment; in 10 epileptics who had had received only VPA for over a month, the mean hyperammonemia was 87 +/- 6 mumols/l (normal value means +/- 2 SD = 28 +/- 12 mumols/l). The ammonemia varied in the course of the day; sharp peaks 7 or more times the base value were observed. These variations, differing among subjects, depended on the VPA plasma concentration, and above all on the meal composition and the relative timing of the meal and the drug administration. No secondary effects were seen; in particular, hepatic and pancreatic tests were normal. The hyperammonemia would seem to be due to physiopathological mechanisms other than those giving rise to the hepatic complications occasionally observed with VPA. The permanence and the extent of the hyperammonemia raise questions as to its origin, its relation to the stuporous states induced by VPA, and its eventual repercussions on the functioning of neurons.

The effect of glucose oral administration on hyperammonemia in cirrhotics.

In order to investigate the controverted effect of glucose on hyperammonemia the diet of eight advanced cirrhotics was supplemented hourly, between 9 a.m. and 5 p.m., with 20 g of glucose orally. Plasma insulin and arterial and median cubital venous ammonia levels were measured hourly and the results were compared to those of a control test performed in the same patients without glucose supplementation. In the control test the lunch (protein meal) induced an identical rise in arterial and venous ammonia levels (+40 +/- 3 and +36 +/- 5 microgram/100 ml, respectively). With glucose supplementation plasma insulin rose significantly and the arterial ammonia increase produced by lunch (+42 +/- 3 microgram/100 ml) did not differ from that observed in the control test; but the rise in venous ammonemia was lower (+12 +/- 4 microgram/100 ml; p less than 0.01) with a significant increase in arterio-venous ammonia difference. These results suggest that oral glucose administration increases the peripheral muscular ammonia uptake through a mechanism which remains to be elucidated but which is inefficient for arterial hyperammonemia.

Cephalic phase insulin secretion in relation to food presentation in normal and overweight subjects.

The existence of a preabsorptive insulin reflex is well known in animals but remains controversial in humans. Glycemia and insulin variations following olfactive and visual presentation of a standard meal were studied in 25 subjects, 10 of them (5 men and 5 women) of normal weight and 15 overweight (7 men and 8 women), after a 15 hour fast. Blood samples were collected continuously, every minute for 16 minutes after the meal was presented. The presentation produced an early blood insulin increment, variable in magnitude and time course and occurring between the 3rd and 9th minute, in both normal and overweight subjects. Glycemia variations were not significant. Our study demonstrated a positive correlation between the reflex insulin release, body weight and a conscious effort to maintain current body weight. However, the differences between overweight and normal subjects remained small. The physiological and psychological determinants of the cephalic phase of insulin secretion are discussed.

Variations in blood ammonia and glutamine levels after hepatectomy and/or abdominal evisceration in the rat.

In order to specify the role of peripheral muscular tissue in ammonia metabolism, we studied, in rats, the variations of ammonia and glutamine levels in arterial and femoral venous blood after hepatectomy and abdominal evisceration with nephrectomy. In non-fasting rats this operation was immediately followed by an important hyperammonemia which was due to ammonia muscular release; glutamine blood levels increased only slightly without any modification in their arterio-femoral venous differences. The hyperammonemia induced by hepatectomy-evisceration was greatly reduced in animals which had been fasting for 48 hours but was not modified by a 72hrs preoperative sucrose feeding. These nutritional conditions did not change the blood glutamine variations which were first related to the abdominal evisceration. Indeed, in abdominal eviscerated rats without hepatectomy there was an important hyperglutaminemia with only a slight increase in blood ammonia. These results indicate that in rat 1) the liver plays an important part in skeletal muscle ammonia metabolism, 2) this metabolism is related to food ingestion, 3) the gastrointestinal tissue intervenes in glutamine metabolism.

[Renal origin of hyperammonemia induced by an high-protein diet in normal rats or those with portal stricture]. / Origine rénale de l'hyperammoniémie provoquée par un régime hyperprotidique chez le rat normal ou porteur d'une stricture portale.

Hyperammonemia is observed in high protein diet fed cirrhotic and is thought to be related to an increased intestinal ammoniagenesis. We studied this problem in control rats and rats with a portal stricture and portal systemic shunts given a high protein or a standard diet. In those animals the systemic, portal and renal venous ammonemia and glutaminemia were measured. In rats with portal stricture on a high protein diet, the increase in systemic ammonemia did not significantly differ from that found in animals on a standard diet. In contrast, the control group exhibited a higher level (P less than 0.001) of systemic ammonemia after a high protein (102 +/- 7 SEM mumol/l) than after standard diet (36 +/- 1). This hyperammonemia appeared to be of renal origin since there was a significantly higher ammonia difference between renal venous and arterial blood with the high protein than with standard feeding, both in rats with a portal stricture (+ 229 +/- 32 vs. + 24 +/- 8 mumol/l; P less than 0.001). and in control rats (+ 196 +/- 23 vs. + 2 +/- 11; P less than 0.001). This increased renal ammonia release into the circulation induced by the high protein diet was associated with a high renal uptake of circulating glutamine. Moreover, a decreased ammonia passage from the digestive tract into the portal vein and disappearance of intestinal uptake of circulating glutamine was also observed with the high protein feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

[Adult Still's disease: an unrecognized cause of acute febrile hepatic cytolysis. Study of twelve patients]. / Maladie de Still de l'adulte: une cause méconnue de cytolyse hépatique aiguë fébrile.

OBJECTIVE: Certain liver test abnormalities have been described in adult Still's disease. The objective of the present study was to analyze their type and frequency. PATIENTS: In a 10 year retrospective study, patients were included if they fulfilled Kahn's and/or Yamaguchi's diagnostic criteria (median follow-up: 6.5 years). RESULTS: Twelve patients were selected. The median age was 25 years old and the sex ratio H/F was 2.7. Fever was present in 100% of patients and hepatomegaly in 41%. Liver test abnormalities were identified in 92% of patients: moderate cytolysis (level of transaminases between 2 and 5 N) (83%), severe cytolysis (level of transaminases > 5 N) (17%), cholestasis (elevated levels of GGT and/or alkaline phosphatase) (75%), and an increase in the LDH level (41%). All these liver abnormalities resolved spontaneously or during treatment (83%), within a median of 18 days. CONCLUSION: Our study confirms the high frequency of liver test abnormalities (> 2/3 of the patients) in adult Still's disease. These abnormalities are generally moderate and asymptomatic (3/4 of the cases), but severe cytolysis may exist. This emphasizes the need to consider a diagnosis of adult Still's disease in the presence of fever and elevated transaminase activity.

[Renal glutamine metabolism in man during treatment with sodium valproate]. / Métabolisme rénal de la glutamine chez l'homme au cours des traitements par le valproate de sodium.

The administration of 1500 mg sodium valproate to 20 patients provoked in the kidney an increased glutamine uptake correlated with an increased ammonia release, as shown by the changes of the renal arterial-venous concentration differences of glutamine and ammonia. VPA's action on the renal cell may perhaps constitute a valid model for elucidating the effects of this drug on neurons.

[Role of hyperammonemia in stuporous states induced by sodium valproate]. / Rôle de l'hyperammoniémie dans les états stuporeux induits par le valproate de sodium.

Stuporous states induced by sodium valproate (VPA) are accompanied by an isolated marked hyperammonemia. In reality, hyperammonemia occurs after administration of VPA even in the absence of neurological complications. The hyperammonemia is of purely renal origin and results from modifications in glutamine metabolism, this compound being the main precursor of amino acid neurotransmitters. Combined administration of VPA and phenobarbitone increases the level of hyperammonemia due to lack of detoxification by the liver of the excess of ammonia produced by the kidneys. The anatomical site of origin of the ammoniogenesis, and its intensity, were studied in two patients with a history of stuporous states during combined VPA-phenobarbitone treatment. A single injection of VPA at a later date when they were being treated by combined phenobarbitone-carbamazepine therapy, induced disturbances in ammonia metabolism which did not differ qualitatively from those observed when intolerance to VPA is lacking. It is therefore not possible to rely on simple biological tests to detect patients at risk. Correlation is also lacking between the degree of hyperammonemia and disorders of vigilance. Ammonia does not therefore appear to be the only factor responsible for neurological complications and the role of other factors must be investigated. These include: disturbances of metabolism of inhibitory and excitatory aminoacid neurotransmitters, the condition of the cerebral parenchyma, and the excitatory effect of sodium valproate which could act to varying degrees in synergy with the hyperammonemia to provoke a stuporous state.

[Effects of blood transfusion on the serum assays of iron, the total binding capacity of transferrin, vitamin B12 and folates]. / Effets de la transfusion sanguine sur les dosages sériques du fer, de la capacité totale de fixation de la transferrine, de la ferritine, de la vitamine B12 et des folates.

To evaluate the influence of blood transfusion on the serum levels of different nutrients, the levels of total iron binding capacity, ferritin, cobalamin and folate were determined before and 24 hours after 2 or 3 packed red cell transfusions, by forty patients with anemia of various causes. No significant change was found in these levels before and after blood transfusion, except for iron and folate.

[Acute myelitis in the post-eruptive phase of measles]. / Myélite aiguë à la phase postéruptive d'une rougeole.

An acute isolated myelitis occurring at the post-eruptive phase of measles is reported. This unusual complication of measles has a favourable outcome in the most of cases. An immunological mechanism, identical to this responsible of perivenous encephalitis seems to be involved.

[Sternal site of sarcoidosis]. / Localisation sternale d'une sarcoïdose.

Sarcoidosis is seldom revealed by bone lesions since these are almost exclusively seen in the chronic forms of an already diagnosed disease. We report a case of sarcoidosis where sternal lesions were the first to appear. The diagnosis was suggested by radiological findings and confirmed by the presence of other manifestations of sarcoidosis, notably lymph node involvement. Pain and functional impairment were such that we had recourse to corticosteroid therapy.

[POEMS syndrome: role and value of interleukin-6]. / Syndrome POEMS: rôles et intérêts de l'interleukine 6.

POEMS syndrome is a systemic disorder with peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. The association of POEMS syndrome with lympho-proliferative disorder is very commun. The pathogenesis remains poorly understood but implication of cytokines (interleukins 1 and 6) is suspected. We report a case of a classic POEMS syndrome (with polyneuropathy, hepatomegaly, diabetes melitus, hyperpigmentation, monoclonal IgG lambda, anasarca and solitary plasmocytoma), associated with high serum levels of interleukin 6.

[Cerebral amyloid angiopathy apropos of a case. Review of the literature]. / Angiopathie amyloïde cérébrale: à propos d'un cas. Revue de la littérature.

The authors present the case of an 83 year-old man with cerebral amyloid angiopathy who had three successive lobar intracerebral hematomas within 4 weeks. There were neither a predisposing familial factor nor cardiovascular risk factors nor any other cause favouring cerebral bleeding. The autopsy revealed amyloid deposits in small cortical and meningeal arteries. No other lesions of the Alzheimer's disease was found.