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Biomedical subjects

J F Giguère

Publications and source records attributed to J F Giguère.

At least 19 recordsLinked to original sources
PubMed2001

When the auditory cortex turns visual.

We studied visually guided behavior and the visual response properties of single auditory cortex (A1) neurons in neonatally operated hamsters with surgically induced, permanent, ectopic retinal projections to auditory thalamic nuclei and to visual thalamic nuclei which normally receive little direct retinal input. The surgically induced retino-thalamo-cortical pathways can mediate visual guided behaviors whose normal substrate, the pathway from the retina to the primary visual cortex via the primary thalamic visual nucleus, is missing. The visually evoked response properties of A1 neurons resemble in many respects those of neurons in V1 of normal hamsters: many A1 neurons have well-defined visual receptive fields and preferences for orientation or direction of movement. In addition, some visually responsive cells in A1 are bimodal--they also respond to auditory stimuli. The visually responsive neurons in A1 probably account for the capacity of the auditory cortex to mediate visual behavior in 'rewired hamsters'.

Animals↗
PubMed1998

Airbags and children: a spectrum of C-spine injuries.

Over 30 children who were improperly restrained or in rear facing safety seats have been reported killed in motor vehicle accidents (MVA) involving airbags. The authors report one minor and two major injuries in properly restrained children in the front passenger seat. In case 1, A 10-year-old seat-belted boy was involved in an MVA (40 km/h) with deployment of both airbags. Physical examination findings showed right hyphema with corneal abrasion, right cheek abrasion and minimal cervical tenderness. C-spine x-ray was normal. He was treated for whiplash and facial burns resulting from contact with hot gas released by the airbags and discharged. In case 2, a 4-year-old boy wearing a lapbelt was in a MVA (20 km/h) with airbag deployment. On arrival, his Glasgow coma score was 3 and he was hemodynamically unstable. Secondary survey after stabilization showed left neck abrasions and ecchymoses, quadraplegia, priapism, and absent rectal tone. C-spine x-ray showed atlanto-occipital dislocation with possible complete spinal cord transection at C1. Aggressive maneuvers were withheld, and the patient was pronounced dead. Autopsy findings confirmed the clinical diagnosis. In case 3, a 3-year-old boy in a forward-facing safety seat was in a MVA (60 km/h) with air bag deployment. The patient was fully awake. C-spine x-rays were normal. Because of fluctuating level of consciousness, he underwent head computed tomography (CT) scan, which demonstrated a posterior fossa subarachnoid hemorrhage and a hematoma posterior to the odontoid, suggesting a ligamentous tear. He remained asymptomatic and was discharged on day 6. A head CT scan at 1 month showed a periosteal reaction in the area of the alar ligament suggestive of partial ligamentous avulsion; this injury was the forerunner of atlanto-occipital dislocation. Airbags deploy by releasing a hot effluent at 300 km/h. Mechanisms of injury include direct contact of hot gas with facial skin and energy transmitted directly from the airbag system to the child's head and neck. These cases illustrate a spectrum of C-spine injuries caused by airbag deployment and support the recommendation that children under 12 years of age travelling in a car equipped with dual airbags be seated in the back.

Accidents, Traffic↗
PubMed1994

Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial.

Previous reports have suggested that "endogenous" benzodiazepines could contribute to neural inhibition in hepatic encephalopathy. RO 15-1788 (flumazenil), a specific antagonist of brain benzodiazepine receptors, could thus reverse the neurological symptoms of hepatic encephalopathy. To test this possibility, we conducted a double-blind, placebo-controlled crossover trial of the efficacy of flumazenil in cirrhotic patients in hepatic coma. Seventy-seven cirrhotic patients in hepatic coma were evaluated. Fifty-six were excluded from the trial because of multiorgan failure or because coma was precipitated by prior use of benzodiazepines, and 21 patients were randomly assigned to the flumazenil group (11 patients) or the placebo group (10 patients). Treatment was administered intravenously as a 20-ml solution (placebo or 2 mg flumazenil); seven patients were crossed over. Clinical status was assessed blindly by two observers, using a modified Glasgow scale, every 15 min for 6 hr. Electroencephalogram tracings obtained before and after drug administration were evaluated blindly by two independent observers. Serum concentrations of benzodiazepines before treatment were measured by means of a fluorescence polarization immunoassay. Improvement in neurological symptoms was observed in six patients treated with flumazenil, whereas none in the placebo group showed improvement (p < 0.05; Fisher's exact test). Improvements in electroencephalogram tracings were demonstrated in four patients treated with flumazenil, compared with two patients in the placebo group (p = NS). Benzodiazepines were found in the serum of four patients treated with flumazenil (two responders and two nonresponders); all of these patients had received pharmaceutical benzodiazepines 4 to 6 days before the trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.

Using radioenzymatic assays, activities of MAOA and MAOB were measured in autopsied brain tissue from cirrhotic patients who died in hepatic coma and in material from an equal number of age-matched subjects who were free from hepatic, neurological or psychiatric disorders. Activities of both MAOA and MAOB were significantly increased in frontal cortex and caudate nucleus, two brain regions shown previously to be the site of functional and morphological alterations of astrocytes and increased concentrations of the acid metabolites of dopamine and serotonin. These findings suggest that increased monoamine metabolism and subsequent modifications of monoaminergic synaptic function could contribute to the pathogenesis of hepatic encephalopathy.

Aged↗
PubMed1993

Region-selective reductions in activities of glutamine synthetase in rat brain following portacaval anastomosis.

Portacaval anastomosis in the rat results in liver atrophy, sustained hyperammonemia and mild encephalopathy. Previous studies have demonstrated region-selective alterations of glutamine and other ammonia-related amino acids in brain following portacaval anastomosis. Ammonia removal by brain relies on glutamine synthesis and the enzyme responsible, glutamine synthetase, has an almost exclusively astrocytic localization. Glutamine synthetase activities were measured using a radioenzymatic assay in homogenates of seven brain regions of rats four weeks after end-to-side portacaval anastomosis. Enzyme activities were significantly reduced in hippocampus (by 25%, p < 0.01), in cerebellum (by 29%, p < 0.01) and in cerebral cortex (by 14%, p < 0.05). Enzyme activities in other brain regions were within normal limits. Region-selective reductions of glutamine synthetase following portacaval anastomosis could result in disruption of neuron-glial metabolic interactions and in a deficit of glutamatergic synaptic regulation. Similar mechanisms could be implicated in the pathogenesis of hepatic encephalopathy accompanying chronic liver disease in humans.

Ammonia↗
PubMed1992

Increased densities of binding sites for the 'peripheral-type' benzodiazepine receptor ligand [3H]PK 11195 in rat brain following portacaval anastomosis.

Using quantitative receptor radioautography, binding sites for the 'peripheral-type' benzodiazepine receptor ligand [3H]PK 11195 were studied in rats 4 week after end-to-side portacaval anastomosis and in sham-operated controls. Portacaval anastomosis resulted in region-selective increases in density of [3H]PK 11195 binding sites in cerebellum, pons greater than thalamus, cerebral cortex greater than hippocampus greater than striatum. Possible mechanisms implicated in these changes include (i) the action of endogenous ligands for the mitochondrial benzodiazepine receptor such as octadecaneuropeptide and (ii) neurotoxic actions of ammonia. In view of the proposed role of these receptors as modulators of intermediary metabolism and neurosteroid biosynthesis, such changes could contribute to the neurochemical mechanisms responsible for portal-systemic encephalopathy.

Animals↗
PubMed1991

Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy.

Increased brain and CSF lactate have been described in human and experimental portal-systemic encephalopathy (PSE). Using a recently described cisterna magna catheter technique, CSF lactate was measured in relation to deterioration of neurological status in portacaval shunted rats administered ammonium acetate to precipitate severe PSE. Loss of righting reflex (precoma stage of PSE) was accompanied by 2-3 fold increased CSF lactate and onset of coma by 4-fold increases of lactate (p less than 0.001 compared to either sodium acetate treated portacaval shunted rats or sham-operated controls administered ammonium acetate). The most likely explanation for increased CSF lactate is ammonia-induced inhibition of malate-aspartate shuttle and/or inhibition of tricarboxylic acid cycle flux in brain. Similar mechanisms could be involved in the pathogenesis of PSE in patients with chronic liver disease.

Animals↗
PubMed1989

Pharmacokinetics of benzodiazepine antagonist Ro 15-1788 in cirrhotic patients with moderate or severe liver dysfunction.

Ro 15-1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15-1788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score less than 10, Group II) and eight patients with severe liver dysfunction (Pugh score greater than 10, Group III). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15-1788 over 5 min, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15-1788 had a high plasma clearance [16.3 +/- 2.6 ml per min per kg (mean +/- S.D.)], a short half-life (45.7 +/- 8.5 min), a large volume of distribution (0.62 +/- 0.09 liter per kg) and a low plasma protein binding (45 +/- 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (-57 and -74%, respectively); the volume of distribution was unchanged in Group II and moderately increased in Group III (+37%). The elimination half-life was markedly prolonged in Groups II and III (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p less than 0.001). The plasma protein binding of Ro 15-1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group II; +44% in Group III).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Regional differences in the capacity for ammonia removal by brain following portocaval anastomosis.

Portocaval anastomosis (PCA) in the rat leads, within 4 weeks, to severe liver atrophy, sustained hyperammonemia, and increased brain ammonia. Because brain is not equipped with an effective urea cycle, removal of ammonia involves glutamine synthesis and PCA results in significantly increased brain glutamine. Glutamine synthetase activities, however, are decreased by 15% in cerebral cortex and are unchanged in brainstem of shunted rats. Administration of ammonium acetate to rats following PCA results in severe encephalopathy (loss of righting reflex and, ultimately, coma). Glutamine concentrations in brainstem of comatose rats are increased a further two-fold, whereas those of cerebral cortex are unchanged. Consequently, ammonia levels in cerebral cortex reach disproportionately high levels (of the order of 5 mM). These findings suggest a limitation in the capacity of cerebral cortex to remove additional blood-borne ammonia by glutamine formation following PCA. Such mechanisms may explain the hypersensitivity of rats with PCA and of patients with portal-systemic shunting to small increases of blood ammonia. Disproportionately high levels of brain ammonia in certain regions, such as cerebral cortex, may then result in alterations of inhibitory neurotransmission and, ultimately, loss of cellular (astrocytic) integrity.

Ammonia↗
PubMed1987

Activities of thiamine-dependent enzymes in two experimental models of thiamine deficiency encephalopathy: 3. Transketolase.

Chronic thiamine deprivation in the rat leads to ataxia, loss of righting reflex and neuropathological damage to lateral vestibular nucleus. Before onset of neurological symptoms, transketolase (TK) activities were found to be selectively reduced by 25% in lateral vestibular nucleus and surrounding pons. Further progression of thiamine deprivation resulted in a generalized reduction in TK activity. Measurement of enzyme activity in the presence of added TPP cofactor in vitro did not lead to normalisation of enzyme activities suggesting loss of apoenzyme. Administration of thiamine to symptomatic thiamine-deprived rats resulted in reversal of neurological symptoms and to normalisation of defective TK activities in less vulnerable structures such as cerebral cortex, striatum and hippocampus; reduction of TK activity, however, persisted in brainstem and cerebellar regions. Pyrithiamine treatment results, within 3 weeks, in loss of righting reflex, convulsions and more widespread neuropathological damage compared to that observed following thiamine deprivation. TK activity was found to be significantly decreased before the onset of neurological symptoms in all brain regions and appearance of symptoms was accompanied by more severe reductions of TK. In contrast to chronic thiamine deprivation, TK activities following pyrithiamine treatment were: equally reduced in magnitude in vulnerable and non-vulnerable brain structures, unchanged following reversal of neurological abnormalities by thiamine administration.

Animals↗
PubMed1987

Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy.

Activities of the gamma-aminobutyric acid (GABA) and cholinergic nerve-terminal marker enzymes glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) as well as the astrocytic enzyme glutamine synthetase (GS) were measured in homogenates of dissected brain tissue obtained at autopsy from nine cirrhotic patients dying in hepatic encephalopathy and an equal number of control subjects matched for age, agonal status, and time interval from death to freezing of autopsied material. GAD activities varied as a function of agonal status in control samples, confirming a previous report, but were unchanged in brain tissue from cirrhotic patients, suggesting no loss of integrity of presynaptic GABA nerve terminals in this disease. On the other hand, GS activities were selectively decreased by 25% (P less than 0.01) in caudate nuclei of cirrhotic patients, reflecting, no doubt, the severe astrocytosis consistently observed in this brain structure. CAT activities, expressed per milligram of protein, were found to be increased by 30% (P less than 0.01) in the prefrontal cortex of cirrhotic patients. Whether such changes result from a relative increase in CAT as a consequence of losses of astrocytic protein or reflect altered cholinergic function in hepatic encephalopathy associated with chronic liver disease awaits further study.

Aged↗
PubMed1987

Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.

Brain tissue was obtained at autopsy from nine cirrhotic patients dying in hepatic coma and from an equal number of controls, free from neurological, psychiatric, or hepatic diseases, matched for age and time interval from death to freezing of dissected brain samples. Glutamine, glutamate, aspartate, and gamma-aminobutyric acid (GABA) levels were measured in homogenates of cerebral cortex (prefrontal and frontal), caudate nuclei, hypothalamus, cerebellum (cortex and vermis), and medulla oblongata as their o-phthalaldehyde derivatives by HPLC using fluorescence detection. Glutamine concentrations were found to be elevated two- to fourfold in all brain structures, the largest increases being observed in prefrontal cortex and medulla oblongata. Glutamate levels were selectively decreased in prefrontal cortex (by 20%), caudate nuclei (by 27%), and cerebellar vermis (by 17%) from cirrhotic patients. On the other hand, GABA content of autopsied brain tissue from these patients was found to be within normal limits in all brain structures. It is suggested that such region-selective reductions of glutamate may reflect loss of the amino acid from the releasable (neurotransmitter) pool. These findings may be of significance in the pathogenesis of hepatic encephalopathy resulting from chronic liver disease.

Aged↗
PubMed1986

Activities of thiamine-dependent enzymes in two experimental models of thiamine-deficiency encephalopathy. 2. alpha-Ketoglutarate dehydrogenase.

Chronic thiamine deprivation in the rat leads to selective neuropathological damage to pontine structures. Onset of neurological symptoms of thiamine deprivation (ataxia, loss of righting reflex) was accompanied by selective decreases (of the order of 30%) in the activity of alpha-ketoglutarate dehydrogenase (alpha KGDH) in lateral vestibular nucleus and hypothalamus. Enzyme activities were decreased to a lesser extent in medulla oblongata, striatum and hippocampus and were unchanged in other brain structures. No changes in alpha KGDH occurred prior to the onset of neurological signs of thiamine deprivation. Administration of the central thiamine antagonist, pyrithiamine, results within 3 weeks in loss of righting reflex and convulsions and in more widespread neuropathological changes than those observed following thiamine deprivation. alpha KGDH activities were found to be substantially diminished in all brain regions studied following pyrithiamine treatment with most severe changes occurring in brain regions found to be vulnerable to pyrithiamine (lateral vestibular nucleus, hypothalamus, midbrain, medulla-pons). In some cases, alpha KGDH changes preceded the appearance of neurological symptoms of pyrithiamine treatment. Such decreases in alpha KGDH may explain previous findings of region-selective changes in energy metabolism and of decreased synthesis of glucose-derived neurotransmitters (acetylcholine, GABA, glutamate) in pyrithiamine-treated rat brain. Thiamine administration to symptomatic pyrithiamine treated rats resulted in reversal of neurological signs of encephalopathy and in normalisation of defective alpha KGDH activity in all brain regions. These findings suggest that the reversible neurological symptoms associated with Wernicke's Encephalopathy in man likely result from region-selective impairment of alpha KGDH.

Animals↗
PubMed1986

Cerebral aminoacids in portal-systemic encephalopathy: lack of evidence for altered gamma-aminobutyric acid (GABA) function.

Construction of an end-to-side portocaval anastomosis in the rat resulted, 4 weeks later, in sustained hyperammonemia and two- to threefold increases in brain ammonia. Measurement of cerebral amino acids using a sensitive double-isotope dansyl microtechnique revealed substantial increases in the glutamine content of cerebral cortex and brain stem. Glutamate levels were found to be concomitantly reduced in both brain regions compared to those of sham-operated controls. The gamma-aminobutyric acid (GABA) content of cerebral cortex and brain stem was unaffected by portocaval shunting, as were activities of the GABA nerve-terminal marker enzyme glutamic acid decarboxylase (GAD). These findings suggest that impaired GABA function may not play a major role in the pathogenesis of hepatic encephalopathy associated with portocaval shunts. Preliminary evidence suggests that decreased cerebral glutamate may reflect its loss from the releasable (neurotransmitter) pool.

Amino Acids↗
PubMed1984

Amino acid changes in regions of the CNS in relation to function in experimental portal-systemic encephalopathy.

Sustained hyperammonemia resulting from portocaval anastomosis (PCA) in the rat, is accompanied by neurological symptoms and reversible morphological changes in brain, the nature and distribution of which suggest selective vulnerability of certain brain structures. The present study was initiated to investigate the effects of increasing CNS ammonia on the distribution of amino acids in regions of the rat brain in relation to the degree of neurological impairment in PCA rats. Four weeks following PCA, rats were administered ammonium acetate (5.2 mmol/kg, i.p.) to precipitate neurological symptoms of encephalopathy which included diminished locomotor activity, loss of hindlimb extension and righting reflexes and ultimately coma. At various stages during the development of encephalopathy, rats were sacrificed and the amino acids glutamine, glutamate and aspartate measured simultaneously, using a sensitive double-isotope dansyl microassay. Homogenates of the following regions of the CNS were assayed: cerebral cortex, hippocampus, striatum, midbrain, hypothalamus, cerebellum, medulla-pons, spinal cord (gray matter) and spinal cord (white matter). Sustained hyperammonemia associated with PCA alone resulted in a non-uniform 2-4 fold increase of glutamine in all regions of the CNS. Glutamate, on the other hand, was selectively increased in striatum and cerebellum, two regions of brain shown to exhibit early morphologically-characterised astrocytic abnormalities in rats with PCA. Onset of severe neurological dysfunction was accompanied by significantly decreased glutamine and glutamate in striatum and cerebellum. Thus, sustained hyperammonemia in association with portocaval shunting results in region-selective effects with respect to glutamine-glutamate metabolism in the CNS.

Acetates↗
PubMed1984

Amino acids in autopsied human spinal cord. Selective changes in Friedreich's ataxia.

The distribution of glycine, glutamate, aspartate, glutamine, and taurine was measured at autopsy in 10 normal human spinal cords, and in 4 spinal cords from Friedreich's Ataxia patients, using a sensitive double-isotope microassay of their dansyl derivatives. Transverse sections of spinal cord from cervical, thoracic, and lumbar levels were dissected to afford samples of gray matter, posterior columns, dorsal white matter, and ventral white matter. Levels of glycine, glutamate, and glutamine were found to be elevated in lumbar gray matter, being 2-3 times higher than those found in white matter structures. Aspartate and taurine, on the other hand, were found to be distributed more evenly in autopsied human spinal cord. Selective abnormalities of amino acid distribution in Friedreich's Ataxia included decreased glutamate and glutamine in lumbar gray matter and posterior columns and increased taurine content of lumbar spinal cord. These changes may be of pathophysiological significance in this hereditary neurodegenerative disease.

Adolescent↗
PubMed1984

Pyruvate dehydrogenase activity in regions of the rat brain during postnatal development.

Activity of the pyruvate dehydrogenase complex (PDHC) was measured in seven brain regions of the male rat at various times during the postnatal period using an arylamine acetyltransferase coupled assay. Three days after birth, PDHC activity was found to be less than 15% of adult values in all brain regions with the exception of hypothalamus and medulla-pons (30% of adult values in each case). Activity of the enzyme complex in these latter regions attained adult levels by 21 days postnatally, some 5-15 days ahead of that found in cerebral cortex, striatum, hippocampus, and cerebellum. Such differences in PDHC maturation reflect the greater degree of early maturity of the phylogenetically older brain structures. Cerebellar PDHC developed more slowly than in other brain regions to attain only 40% of adult levels by the time of weaning. The pattern of maturation of cerebellar PDHC is paralleled by increased incorporation of glucose into cerebral amino acids and by the pattern of development of parallel fiber synaptogenesis. These findings suggest that PDHC may play a key role in the regional development of metabolic compartmentation and the associated maturation of cerebral function in the rat.

Animals↗