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[Mitochondrial encephalomyopathies and West's syndrome: a frequently underdiagnosed association].

INTRODUCTION: West's syndrome is known to have symptomatic, cryptogenetic and idiopathic forms. Greater knowledge of the different pathologies and the development of new diagnostic techniques have allowed the list of symptomatic forms to be extended and congenital disorders of the metabolism account for a significant percentage as an aetiopathogenic factor. Yet, although it is known that mitochondrial cytopathies can trigger the development of West's syndrome, few reports exist concerning their association. AIMS: Our aim in this paper is to report on four cases of West's syndrome in which a mitochondrial cytopathy was shown to be an aetiopathogenic factor. CASE REPORTS: Two females and two males aged between 2 and 10 months, who were suffering from West's syndrome. Biochemical and neuroimaging findings suggested a possible mitochondrial cytopathy, which was later confirmed in the four cases on observing a partial deficiency of some of the complexes of the mitochondrial respiratory chain in muscles; this was found to be simple in the first three (complexes III, I and IV, respectively) and combined in the fourth (complexes I and IV). CONCLUSIONS: Infantile spasms should be considered as one of the ways mitochondrial encephalomyopathies manifest themselves. As part of the process of diagnosing West's syndrome, we recommend tests be carried out to determine the levels of lactic and pyruvic acid, carnitine and amino acids in plasma, and possibly in the cerebrospinal fluid, as well as those of amino acids and organic acids in urine. A muscular biopsy must also be carried out in patients who are strongly suspected of having a mitochondrial cytopathy, as well as the corresponding molecular genetic study.

Comorbidity↗

[Age-specific changes of carbohydrate metabolism in rat liver in immobilization stress].

We have studied peculiarities of the main pathways of glucose utilization in the liver of adult and old rats under immobilization stress. Our data indicate that in both adult and old rats stress is accompanied by an increase in glycolysis intensity in the liver. In stressed adult rats stimulation of glycolysis is associated with metabolism changes characteristic of decreased oxidative decarboxylation of pyruvate in the liver. In immobilized old rats glycolysis stimulation took place in maintanence of effective oxidation of pyruvic acid and enhancement of glucose catabolism in pentose phosphate pathway.

Aging↗

Ethanol-induced dysfunction of hepatocytes and leukocytes in patients without liver failure.

The repeated intake of a great amount of ethanol is followed by functional and organic changes in the body. The intestinal absorption of alcohol is accompanied by an increased absorption of Gram negative bacteria endotoxins in the portal blood. In the liver, endotoxins stimulate CD14 receptors on the membrane of Kupffer cells, with a secondary inflammatory liver response, consisting in the secretion of proinflammatory cytokines and acute phase proteins. Simultaneously, alcohol metabolism in the hepatocytes by alcohol dehydrogenase, microsomal enzymes and catalase pathways determines a large production of ROS (reactive oxygen species), with secondary oxidative aggression on all liver cells: hepatocytes, Kupffer cells, endothelial sinusoidal cells, hepatic stellate cells and liver s lymphocytes. The oxidative aggression, as well as the intermediary products of the alcohol metabolism, cause a structural change of the antigenic structures of the liver and of the released proteins, that induces an immune response on the both pathways (humoral and cellular). The pathophysiological mechanisms and the paraclinical characteristics of the ethanol-induced liver failure are well known, so we were interested to study the patients with chronic alcoholism, but no clinical or paraclinical sign of liver failure, in order to describe the liver's protective mechanisms. For this reason, 153 patients with chronic alcoholism were divided into four test lots, in order to determine: the activity and the serum level of ceruloplasmin, plasma level of MDA (malondialdehyde), lactic and pyruvic acids, serum level of transferrin, alpha1-antitrypsin, CRP (C reactive protein), C3 fraction of the complement, IgA, IgG, IgM, IL-1beta, IL-6 and IL-8, cytosolic level of the cytochrome c in the circulating leukocytes. An immunophenotype study (as normal markers) on the peripheral blood lymphocytes was performed, too. The results demonstrate an important oxidative aggression induced by three sources: the alcohol metabolism in the hepatocytes, activated Kupffer cells and activated neutrophils that have infiltrated the liver, due to the chemoattractant effect of IL-8. This aggression induces apoptosis and necrosis of the liver cells. The major liver protective factor is, in our opinion, IL-6, due to its important antioxidant, antiapoptotic and proregenerative demonstrated actions. This protective effect of IL-6 is accompanied by antioxidant and antiprotease actions of ceruloplasmin, alpha1-antitrypsin and transferrin. We consider that an increased serum level of IL-6 accompanied by a decreased level of IL-1beta signify that antiapoptotic, antioxidant and proregenerative liver mechanisms prevail against proapoptotic and necrotic mechanisms. On the other hand, the ethanol-induced apoptosis of leukocytes (especially of the B cells) is very important, probably due to the absence of IL-6 protective action on these cells. The apoptosis of the circulating leukocytes is proved by their significant increase of the cytochrome c cytosolic level. The ethanol-induced liver immune response is predominantly cellular, as proved by the decreased ratio T helper (CD4+)/T cytotoxic (CD8+) in the peripheral blood. It is very important to observe that these significant immunologic changes appear before clinical or paraclinical signs of hepatic failure start. All these parameters were investigated in three groups of patients: chronic alcoholics, chronic alcoholics in the first 24 hours of the withdrawal and chronic alcoholics with acute alcohol intoxication, so the aggression types and the protective mechanisms were measured and differentiated in each "ethanolic status".

Adult↗

Study of carbohydrate metabolism in selected tissues of freshwater mussel, Lamellidens marginalis under copper sulphate toxicity.

Sublethal toxicity of copper sulphate on carbohydrate metabolism was studied in selected tissues of freshwater mussel, Lamellidens marginalis. Levels of glycogen and pyruvic acid decreased while lactic acid showed an increase. Activities of LDH, SDH and MDH decreased while G-6-PDH activity increased. There appears to be a shift in the carbohydrate metabolism from aerobic to anaerobic type due to toxicity of copper.

Animals↗

[Study of leukocytic enzymes in patients with diffuse peritonitis].

Under observation were 25 patients with grave diffuse peritonitis. Histochemically, the activity of oxidation-reduction enzymes in leukocytes of peripheral blood was determined. It was found that the control of enzymic activity at the cellular level and determination of the concentration of lactic and pyruvic acids permitted the detection of hypoxic alterations in peritonitis, provided an opportunity to judge the dynamics of the pathological process.

Acid Phosphatase↗

[Effect of diabetes and thyroid hypofunction on carbohydrate and lipid metabolism in heart and liver].

The purpose of this research was to analyse the change in relationships between the basic carbohydrate and lipid metabolisms parameters in the cardiac muscle and liver in the animals with diabetes, in which the thyroidal hypofunction was evoked additionally. The tests were performed on 43 white rats of the Wistar breed that were subdivided into four groups. The first group were reference animals. The second group were the animals with the evoked thyroidal hypofunction with metizol. The group three rats were injected a single dose of alloxan each in order to evoke diabetes. In group four, diabetes and the thyroidal hypofunction were evoked. The levels of glycogen, lactic and pyruvic acids, cholesterol, free fatty acids, triglycerides and phospholipids were determined in the cardiac muscles and livers of all the animals. It was found that the occurrence of both hormonal disorders, i.e. diabetes and the thyroidal hypofunction, in short time leads to harmful changes in the lipid metabolism of the cardiac muscle and liver and noticeably reduces the glycogen reserve in the liver.

Alloxan↗

[Effects of ginseng polysaccharides on reducing blood glucose and liver glycogen].

Ginseng polysaccharides (GH1) 50-200 mg/kg ip or sc reduced blood glucose and liver glycogen of mice. Adrenalectomy did not affect this action. GH1 increased the content of pyruvic acid, but decreased the content of lactic acid by weakening the activity of lactate dehydrogenase. GH1 accelerated oxidative-phosphorylation of carbohydrate since the activities of succinate dehydrogenase (SDH) and cytochrome oxidase (CCO) were obviously stimulated. Besides the promotion of the activity of SDH in human embryonic lung fibroblasts (HELF), GH1 decreased the content of polysaccharides in HELF of the 24th age generation, but increased that of the 40th age generation. On the other hand, GH1 stimulated the release of insulin. It is suggested that the reduction of blood glucose and liver glycogen induced by GH1 be primarily due to the increase of carbohydrate utilization and the decrease of glycogenesis.

Animals↗

Effects of various known and potential cyanide antagonists and a glutathione depletor on acute toxicity of cyanide in mice.

To compare the protective potencies of a large number of known and potential cyanide antagonists in one stock of mice, groups (N = 10) of male CF-1 Swiss-Webster mice were given a single maximal or near-maximal intraperitoneal injection of each substance. Ethyl maleate, a glutathione (GSH) depletor and potential enhancer of cyanide toxicity, was given to other groups. Thirty min later, the mice were given subcutaneous injections of graded doses of KCN. In untreated control mice, the 24-hr median lethal dose (LD50) of KCN was 11 mg/kg of body weight (potency ratio, PR = 1.0). In comparison, protective effects of traditional antagonists thiosulfate and nitrite produced PR values of 1.48 and 2.95, respectively. Tetrathionate, sulfate, dithionite, methionine, hydroxocobalamin, ascorbate, pyridoxal phosphate, alpha-ketoglutarate, alpha-ketobutyrate, GSH, GSH disulfide (GSSG) and selenite were similar in efficacy to thiosulfate (P less than 0.05; PR values 1.35-1.59). Cysteine, diethyldithiocarbamate (DEDC), and cobaltous chloride were more effective than thiosulfate (PR values 1.68, 1.69, and 1.85, respectively). Phentolamine and dicobalt EDTA were ineffective, whereas papaverine enhanced toxicity (PR 0.72). Agents with significant PR values (greater than or equal to 1.14) but which were less effective than thiosulfate included sulfite, dimercaptosuccinic acid, pyruvate, citrate, alpha-ketovalerate, naloxone, and corn oil. Ethyl maleate in corn oil markedly enhanced KCN lethality (PR 0.57 compared to corn oil alone), and caused prolonged illness in several mice. Vitamin E in corn oil had no effect. Dual mixtures of thiosulfate with other selected substances were also tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

[Salsolinol, an endogenous molecule. Possible implications in alcoholism, Parkinson's disease and pain].

Salsolinol can be formed either by condensation of dopamine with acetaldehyde, or by condensation of dopamine with pyruvic acid followed by decarboxylation. Salsolinol has a complex pharmacologic profile. Its opium-like activity may be related to alcohol dependency and to the effectiveness of naloxone during acute alcohol intoxication. Because they had noticed that alcoholism and Parkinson's disease rarely coexist, the authors undertook a study to confirm this fact and attempt to explain it by implicating salsolinol. Urinary excretion of salsolinol was found to increase following ingestion of alcohol, as well as in Parkinson patients under L-dopa treatment. The authors also found that urinary salsolinol was very low in untreated patients with Parkinson's disease. Salsolinol was detected in a number of foods and beverages. Separate assays of enantiomeres showed that the S enantiomere predominates in some foods whereas the R enantiomere is more abundant in humans. Lastly, the antinociceptive effects of salsolinol and its enantiomeres were studied in mice and antidepressant effects were evidenced using predictive tests.

Aged↗

Alpha hydroxy acids: procedures for use in clinical practice.

Alpha hydroxy acids and alpha keto acids applied topically in lower concentrations reduce the thickness of hyperkeratotic stratum corneum by reducing corneocyte cohesion at lower levels of the stratum corneum. This property permits efficient clinical control of dry skin, ichthyosis, follicular hyperkeratosis, and other conditions characterized by retention of stratum corneum. Applied topically in higher concentrations, these acids cause epidermolysis. This property provides a new alternative for treating seborrheic keratoses, keratoses commonly known as "age spots," actinic keratoses, and verrucae vulgares; all of which lesions involve distinct epidermal hyperplasia as well as retention of stratum corneum. Facial wrinkles can be modified with topical alpha hydroxy acids, applied in higher concentrations as office procedures, and concomitant daily home application of lower concentrations.

Acne Vulgaris↗

[Adaptation of myocardial function to conditions of myocardial insufficiency in patients with marked coronary arteriosclerosis].

Relationships between myocardial blood flow, myocardial contractility, anaerobic metabolic products, and myocardial oxygen requirement and uptake were investigated in 52 coronary atherosclerotic patients. Myocardial functioning under the conditions of inadequate myocardial perfusion, where blood supply requirement, determined by myocardial activity, exceeds actual magnitude of coronary blood flow, is shown to be basically possible in patients with marked atherosclerosis of coronary arteries. Specific features of myocardial performance under the circumstances are its partially reduced effectiveness and activated anaerobic carbohydrate oxidation pathway, as evidenced by a negative arteriovenous difference between lactic and pyruvic acid levels in blood from the aorta and the coronary sinus.

Adaptation, Physiological↗

[Intensity of gluconeogenesis in the rat liver in the recovery period after long-term hypokinesis].

Gluconeogenesis was studied in liver tissue of 60 rats within the period of readaptation after 60 days of hypokinesia. Biosynthesis of glucose from alanine, aspartic-, glutamic-, alpha-ketoglutaric and pyruvic acids as well as from glycerol was distinctly inhibited as a result of long-term hypokinesia. Stimulation of gluconeogenesis was noted during the beginning of the readaptation period within 1-7 days, which caused the "superrestoration" of glycogen content in liver tissue. The rate of glucose synthesis was decreased within the later period (15 days) of readaptation. The specific properties of the restoration period should be considered in working out of the rehabilitation courses.

Animals↗

Pharmacology of selective thrombin inhibitors.

Thrombin plays a key role in thrombosis and haemostasis, and is selectively inhibited by hirudin and synthetic inhibitors. Hirudin, a polypeptide (molecular weight 7,000 daltons) extracted from medicinal leeches, can now be produced by gene technology. Hirudin binds selectively to thrombin with high affinity and inhibits its enzymatic properties. Besides heparin, hirudin is not inhibited by platelet factor 4; it prolongs in vitro and ex vivo routine blood coagulation assays and prevents thrombosis in a number of animal models without increasing haemorrhagic risk. In humans, hirudin disappears from the blood with a half-life of 1 h, is devoid of undesirable side effects and has been shown to be efficient in the treatment of chronic disseminated intravascular coagulation (DIC). A number of synthetic direct thrombin inhibitors have been described, including benzamidine derivatives which share identical pharmacological properties with hirudin; however their biological half-life after i.v. injection is shorter. Other derivatives (amidino-phenyl-pyruvic acid) have longer half-lives and have been used to treat chronic DIC in man.

Animals↗

Factors affecting the metabolism of [14C]acetylhydrazine in rats.

Some factors affecting the metabolism of the potent hepatotoxin, acetylhydrazine, were studied in rats. After ip administration of [14C]acetylhydrazine, 36% and 38% of the dose was recovered in the urine and as 14CO2, respectively. The major urinary metabolites were diacetylhydrazine and the pyruvic acid and alpha-oxoglutaric acid acetylhydrazones. The acetylation of acetylhydrazine to diacetylhydrazine was found to be dose-dependent and to be inhibited by coadministered isoniazid and p-aminosalicylic acid. Coadministered acetylisoniazid had no effect on acetylation. The proportion of acetylhydrazine recovered as 14CO2 presumably reflects the amount metabolized by the microsomal oxidation pathway, thought to be responsible for the toxicity, and also possibly by hydrolysis to acetate and hydrazine. This latter pathway could not be confirmed, as only a small proportion of hydrazine administered to rats was recovered. The inhibition of acetylation by p-aminosalicyclic acid, but not isoniazid, significantly increased the excretion of 14CO2, suggesting that isoniazid may also inhibit a pathway resulting in the production of 14CO2. These results indicate that the metabolism and hepatotoxicity of acetylhydrazine may be different when it is produced as a metabolite of isoniazid than when it is given alone.

Acetylation↗

[Methylglyoxal: metabolism and biological activity].

The enzymic formation of methylglyoxal from dihydroxyacetone phosphate and aminoacetone (metabolites of carbohydrates and proteins) is considered. Methylglyoxal transformation into lactic and pyruvic acids is related to energy metabolism, catabolism and anabolism dissociation processes in carbohydrates and proteins, and, probably, to maintenance of asymmetrical entropy in vivo on the constant level. Attention is paid to the methylglyoxal inhibition of enzymes, its interaction with glutathione and polyamines affecting the mechanisms regulating protein synthesis and cellular division. The methods for obtaining and quantitative determination of methylglyoxal are described.

Aldehydes↗

[Effect of komplamin and nikoshpan on brain circulation and metabolism in the postischemic period].

Intravenous administration of komplamin to anesthetized cats before the brain ischemia or in the early period following ischemia prevents the development of the postischemic phenomenon of the cerebral blood flow nonrecovery and beneficially influences the cerebral metabolism: restores oxygen and glucose consumption by the brain, decreases pyruvic acid level in the arterial and venous blood, attenuates the phenomenon of acidosis. Nikoshpan improves the blood supply to the brain, restores oxygen and glucose consumption by the brain in the postischemic period only if administered before the brain ischemia.

Animals↗

[The clinical effect of fosfomycin on cystitis].

Fosfomycin (FOM) is an antibiotic which inhibits phospho(enol)pyruvic acid transferase. Fifty-five patients with cystitis were treated with the drug for 7 days, at oral doses of 1 g for 3 times a day. Adult females under 70 years of age, visiting the clinic within 2 weeks after the onset, were classified as cases with typical simple cystitis with confirming the bladder irritability, pyuria and bacteriuria. The treatment was effective for 95.0% of these cases. Two cases with atypical cystitis caused by Klebsiella pneumoniae poorly responded to the drug.

Administration, Oral↗