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Biomedical subjects

M Mamelak

Publications and source records attributed to M Mamelak.

At least 19 recordsLinked to original sources
PubMed2000

The motor vehicle collision injury syndrome.

OBJECTIVE: The objective of this study was to examine the central nervous system changes that may occur after acceleration/deceleration injuries in motor vehicle accidents. BACKGROUND: Occupants of motor vehicles involved in a collision often develop a disabling syndrome consisting of head, neck, and back pain; impaired short-term memory and concentration; fatigue and a loss of stamina; poor balance; and a change in personality. Injury victims experience a loss of motivation, emotional lability, and a decrease in libido. The major features of this injury syndrome are subjective, and there usually are few objective findings on physical examination. The pathogenesis of this syndrome is poorly understood, but it is hypothesized that the collision impact produces an inertial strain injury to the anterior regions of the brain which depresses the functions of the frontotemporal lobes, at the same time, sensitizing somatosensory neural afferent systems. Damage to the orbital surfaces of the frontotemporal lobes, in particular, impairs the gating mechanisms that normally limit sensory input to the brain and further promotes central sensitization. The psychiatric disorders that emerge in the wake of these injuries are likely grounded in these pathologic events. METHOD: The current literature on the biomechanics of head injury and the associated brain imaging findings in minor head injury are reviewed. A summary of some of the biochemical sequelae of strain injury to the brain is also provided, with an emphasis on the changes in energy metabolism and excitatory amino acid release. CONCLUSIONS: Early intervention to arrest the injury-induced metabolic cascade, and treatment with agents that activate cerebral metabolism may mitigate the symptoms of this injury syndrome.

Accidents, Traffic↗
PubMed1997

Neurodegeneration, sleep, and cerebral energy metabolism: a testable hypothesis.

Varying degrees of metabolic arrest are used by many living species to survive in a harsh environment. For example, in hibernating mammals, neuronal activity and cerebral metabolism are profoundly depressed in most regions of the brain and limited energy resources are deployed to maintain vital cell functions. Gathering evidence suggests that energy resources are also limited in both Alzheimer's and Parkinson's diseases, and that this promotes metabolic stress and the degenerative process. Key steps in this process are energy requiring, and this further compromises cell energy reserves. It may be possible to slow the progress of these diseases by inducing slow-wave sleep (SWS) at night with gammahydroxybutyrate. Patients with these diseases sleep poorly and generate little SWS. SWS and hibernation are thought to be on a continuum of energy conservation. Thus, the induction of SWS may retard the degenerative process by depressing cell metabolism and by directing energy utilization to vital cell functions. In this way, GHB-induced SWS may duplicate the effects of hibernation and extend biologic time.

Alzheimer Disease↗
PubMed1996

Narcolepsy secondary to fourth ventricular subependymoma.

BACKGROUND: Secondary (symptomatic) narcolepsy is rare. We report a subependymoma of the fourth ventricle associated with narcolepsy. The patient was a 50-year old woman with a long history of narcolepsy who died of colonic carcinoma with no cerebral metastasis. She was positive for HLA-DR2. At autopsy there was a tumour dorsal to the fourth ventricle which involved the midbrain tectum and rostral pons. Histologic examination of the tumour confirmed it to be a subependymoma. METHODS: Review of the previous cases of secondary narcolepsy was made with particular reference to the anatomical location of the lesions. RESULTS: Most of the lesions were found around the third ventricle and rostral brainstem. CONCLUSIONS: Knowing the anatomical localization of the pathological changes in secondary narcolepsy could be important in improving our understanding of its pathogenesis.

Cerebral Ventricle Neoplasms↗
PubMed1993

High- and low-affinity states of dopamine D1 receptors in schizophrenia.

Using SKF-38393/[3H]SCH-23390 dopamine D1 receptor agonist/antagonist competition binding technique, we showed that schizophrenics distinguished from the neuro-psychiatric and normal controls by exhibiting a significant increase in the density of the low-affinity state, and a concomitant enhancement in the binding affinity of the high-affinity state of D1 dopamine receptors in caudate nucleus. The results suggest that perturbation in dynamic equilibrium of high- and low-affinity states of D1 receptors underlies the pathogenesis of schizophrenia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Cardioprotective action of sodium gamma-hydroxybutyrate against isoproterenol induced myocardial damage.

In this study, the effects of graded doses of isoproterenol (IP) on the heart were examined in untreated gerbils and in gerbils anaesthetized with gamma-hydroxybutyrate (GHB), an endogenous metabolite with energy sparing properties. We were interested in the cardioprotective potential of GHB. IP was administered intraperitoneally in doses of 0.1, 0.3. 2.5 and 10.0 mg/kg to different groups of gerbils. Half the gerbils in each treatment group received 500 mg/kg of GHB 30 min before IP, and 250 mg/kg at three subsequent 2-hour intervals. The remaining gerbils in each treatment group received saline at these time points. The animals were sacrificed after 8 hours. The accumulation of neutral fat droplets in the sarcoplasm was the most consistent effect of IP. The highest dose also produced some scattered myofibre death. The accumulation of fat in the cells could be estimated semi-quantitatively using a histochemical reaction for succinic dehydrogenase, and the volume of fat could be measured more accurately by electron microscopic morphometry. These measurements showed that IP produced a three to five-fold increase in sarcoplasmic fat volume. GHB either abolished or significantly reduced the accumulation of fat and it also completely prevented the myofibre death caused by the highest doses of IP. This cardioprotective effect of GHB was independent of its hypothermic action. Based on this experience, ultrastructural morphometry of sarcoplasmic fat appears to be a promising method for evaluating cardioprotective measures.

Animals↗
PubMed1992

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.

Adult↗
PubMed1991

A model for narcolepsy.

A model for narcolepsy is developed on the basis of data obtained from brains collected at post mortem from three patients with narcolepsy. The concentration of dopamine, noradrenaline, and serotonin and their metabolites was measured in many brain regions. The number and affinity of the 3-H-spiperone and 3-H-prazocin binding sites was also measured in many of these regions to characterize the D-2 dopamine and alpha-1-noradrenergic receptors, respectively. Evidence for significantly increased serotonin levels and serotonin turnover was found in many brain regions. Noradrenaline turnover was increased in the frontal cortex. DOPAC/DA was significantly reduced in the striatum. The number of D-2 dopamine receptors, however, was markedly increased in this region. The number of alpha-1-noradrenergic receptors was significantly decreased in the frontal cortex and amygdala. Our neurochemical data demonstrating increased NA and 5-HT turnover suggest that locus coeruleus noradrenergic neurones and raphe serotonergic neurones are overactive in narcolepsy. Current evidence posits that increased activity in these neurones depresses the activity of cholinergic pedunculopontine (PP) REM sleep effector neurones. PP neurones project to and stimulate the dopaminergic substantia nigra compacta neurones. Decreased PP activity in narcolepsy, thus, could lead to pontine cholinergic supersensitivity and could also reduce the firing rates of dopaminergic neurones, as the low striatal ratio of DOPAC/DA suggests. An increase in the number of D-2 dopamine receptors in the striatum may result. The reason for the increased activity of the noradrenergic and serotonergic neurones remains to be determined, but immune inactivation of alpha-1-noradrenergic receptors may be the initiating event. Low alpha-1-noradrenergic receptor numbers may account for the chronic drowsiness of narcolepsy. The repeated entry into sleep, and into REM sleep in particular, may represent a homeostatic response to increase these receptor numbers and, thus, to increase alertness. Some therapeutic implications of this model are presented in the discussion.

Brain↗
PubMed1990

The effects of a single night's dosing with triazolam on sleep the following night.

This study was undertaken to determine whether a single night's use of triazolam by normal healthy sleepers leads to withdrawal insomnia on the subsequent night, and whether there is a dose response relationship to this phenomenon. Thirty normal sleepers of both sexes were randomly assigned to three parallel treatment groups. All subjects were studied for five consecutive nights by means of pre- and post-sleep questionnaires and all night polysomnography. Multiple sleep latency tests were conducted on the days following the second, third, and fourth nights in the laboratory. All subjects received placebo capsules on the first, second, fourth, and fifth nights in the laboratory and either placebo, 0.25 mg triazolam or 0.5 mg triazolam according to their assigned group on the third night. Both doses of the drug increased subjective estimates of sleep duration, but no objective increase was found. Neither dose altered daytime measures of sleepiness. No changes were found in any of the sleep parameters on withdrawal of the 0.25 mg dose of triazolam. However, discontinuation of the 0.5 mg dose did lead to significant objective and subjective withdrawal effects. It was concluded that higher doses of triazolam could lead to withdrawal effects in normal sleepers even when this drug was used for only a single night.

Adult↗
PubMed1990

The protective effect of gamma-hydroxybutyrate in regional intestinal ischemia in the hamster.

The purpose of this study was to determine whether gamma-hydroxybutyrate provides protection against intestinal ischemia/reperfusion injury and to compare its effect with that of allopurinol and vitamin E. Thirty minutes of total regional ischemia, followed by 3 hours of reperfusion, produced intestinal damage that was completely prevented by gamma-hydroxybutyrate pretreatment. Naloxone partially blocked this protective effect. Allopurinol provided only partial protection against this injury, whereas vitamin E provided none. Treatment with gamma-hydroxybutyrate after ischemia but before reperfusion also provided significant protection. This study clearly demonstrates that gamma-hydroxybutyrate provides significant protection against intestinal ischemic injury and that it may do so via an opiate receptor-mediated mechanism.

Allopurinol↗
PubMed1990

Clinical recovery and sleep architecture degradation.

We achieved a unique and timely recording of cerebral activity in a 70 year old woman immediately pre- and post-stroke, while studying the effect of acute cerebral infarction on sleep-electroencephalogram (EEG) patterns. Normal patterns, except for increased wakefulness, were recorded during two pre-infarct polysomnograms. Immediately following cerebral infarction increased delta activity was recorded from the infarcted hemisphere only. Initially, REM sleep could not be recorded from either side; however, on the third post infarct day REM sleep returned. Background EEG levels from both hemispheres became progressively slower, flatter and simpler. In addition, sleep spindles and the distinctive saw-tooth wave forms of sleep almost disappeared. At one year post-stroke sleep-EEG rhythm recordings from both hemispheres became more similar except for persisting delta activity from the left hemisphere. Unexpected deterioration of sleep-EEG pattern recordings from the undamaged hemisphere taken during the patient's clinical recovery remains unexplained. Serial sleep recording may facilitate the study of brain recovery, activity and reorganization following stroke.

Aged↗
PubMed1989

Psychological, topographic EEG, and CT scan correlates of frontal lobe function in schizophrenia.

This study examined frontal lobe function in a group of 20 patients with schizophrenia, on and off medication, compared to 20 normals matched for age, sex, handedness, intelligence, and educational level. Schizophrenic patients generally did not perform as well as normals on the Wisconsin Card Sorting Test (WCST). Patients off medication performed less well on this test than those on medication. Those on medication did not perform as well as those off medication on the design and word fluency tests, which suggested that medications may affect various aspects of frontal lobe function differently. During the WCST, normal subjects demonstrated an increase in beta mean frequency of the electroencephalogram in frontal and centrotemporal regions which was not statistically significant in either schizophrenic group. This shift in beta mean frequency was found to correlate positively with performance on the WCST in normals, but not in patients. Patients with more negative symptoms tended to show a smaller increase in beta mean frequency during the WCST. Performance on the WCST was correlated negatively with ventricle-brain ratio in all subjects, suggesting that frontal lobe function might be related to computed tomographic measures in the normal population as well as in schizophrenic patients. There was no correlation with performance on the WCST and length of illness.

Adult↗
PubMed1989

Gammahydroxybutyrate: an endogenous regulator of energy metabolism.

Gammahydroxybutyrate is a naturally occurring metabolite of many mammalian tissues. Although its administration produces a wide range of pharmacological effects, its normal function has never been clearly defined. GHB can induce NREM and REM sleep, anaesthesia, hypothermia, and a trance-like state which has been considered a model for petit mal epilepsy. It markedly increases brain dopamine levels. It has been touted as a central neurotransmitter or neuromodulator, and high affinity brain receptors, as well as central mechanisms for its synthesis, uptake and release have been demonstrated in support of this. But GHB is also found in many peripheral tissues and in some of these in higher concentrations than in the brain. No explanation has been offered for its presence in these tissues. A number of studies indicate that GHB can reduce energy substrate consumption in both brain and peripheral tissues, and that it can protect these tissues from the damaging effects of anoxia or excessive metabolic demand. Indeed there is some evidence to suggest that endogenous GHB levels rise under these circumstances. GHB appears to act through the endogenous opioid system, since in the brain, at least, GHB raises dynorphin levels and its metabolic and pharmacological effects can be blocked by naloxone. These, and other observations detailed in this review, suggest that GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited.

Animals↗
PubMed1989

A comparative study on the effects of brotizolam and flurazepam on sleep and performance in the elderly.

This study was undertaken to compare the effects of 0.25 mg of brotizolam, 15 mg of flurazepam, and placebo on the sleep and performance of elderly subjects with chronic insomnia during a 2-week period of administration. Thirty-six male and female subjects who ranged in age from 60-72 years were divided into three treatment groups. All groups received placebo on the first three study nights, the active drug or placebo on the next 14 nights, and placebo again on the two following withdrawal nights. Sleep was assessed by means of questionnaires, and residual effects during the day were studied by means of the multiple sleep latency test and a variety of memory, performance, and vigilance tests. Sleep improved with all treatments. Rebound insomnia was noted on brotizolam withdrawal; flurazepam withdrawal had a milder impact. At the end of this 19-night study, only the placebo-treated group was sleeping significantly longer than at baseline. Both drug treatments increased daytime sleepiness and impaired performance on the first day after their administration. These effects waned after 2 weeks of treatment with brotizolam, but not flurazepam. The results of this study affirm the increased sensitivity of elderly subjects to benzodiazepine hypnotics and their indication for acute or intermittent insomnia, rather than for the more chronic forms of this disorder.

Aged↗
PubMed1988

Serum and quantitative electroencephalographic pharmacokinetics of loprazolam in the elderly.

This study was undertaken to determine the serum pharmacokinetic parameters of loprazolam, a new benzodiazepine hypnotic, in elderly subjects and to compare these with the kinetics of the drug as determined by quantitative EEG analysis. In addition, a 14-day study was undertaken to determine the steady-state serum levels achieved in this population with repeated drug administration. The study was conducted on 16 male and female subjects between the ages of 62 and 72 years, randomly assigned to two groups treated with 0.5 or 1.0 mg of loprazolam. The serum half-life of loprazolam was found to be 5 hours, and the peak serum concentration was reached after 2 hours. Quantitative EEG changes were observed after 30 minutes suggesting rapid access of the drug into the nervous system. Quantitative EEG changes were evident for 9.5 hours, suggesting the persistent effects of an active metabolite. The 14-day study indicated that loprazolam did not accumulate with continued use.

Aged↗
PubMed1987

Effects of flurazepam and zopiclone on the performance of chronic insomniac patients: a study of ethanol-drug interaction.

Three groups of ten middle-aged insomniac patients were treated with placebo, flurazepam, or zopiclone for 12 consecutive days in a study designed to compare the residual daytime effects of long-acting flurazepam and short-acting zopiclone on a variety of cognitive and motor tasks. These effects were examined independently and in combination with ethanol effects. The effects of the drugs on sleep parameters were also subjectively assessed by means of questionnaires during treatment and withdrawal. The study demonstrated persistent performance effects with flurazepam. Testing at the end of the treatment period showed that movement time was impaired in the flurazepam treated group. Flurazepam also enhanced the increment of movement time produced by ethanol. One subject became severely confused when given ethanol after using flurazepam for 12 days. None of these effects were found with zopiclone. The rapid elimination of zopiclone may account for these findings.

Adult↗
PubMed1986

Spectral EEG correlates of dream recall.

Recent studies have shown that dreaming is not limited to rapid eye movement (REM) sleep, but can be found to varying degrees in any stage of sleep. This study attempted to quantify the EEG correlations of dreaming during Stage 2 sleep. Six normal volunteers were studied for 24 nights in the sleep laboratory. Electroencephalogram (EEG) recording prior to awakening from Stage 2 sleep and from other stages without awakening were subjected to computer spectral analysis. Although awakenings associated with dream recall tended to have lower total power, mean frequency in the beta band proved to be the best correlate of mental activity in Stage 2 sleep. Mean frequency had its highest values in REM sleep and wakefulness and declined in Stage 2 and Stage 4 sleep, in keeping with the decline in mental activity reported from these stages. Implications of these findings are discussed with regard to models of dream recall and clinical states.

Adolescent↗