Exercise, illness and drug use: guiding principles for approaching a complex triad

Regular, low to moderate intensity exercise is considered beneficial to the human body, not only having ergogenic advantages, but also being anti-inflammatory, cardio- and neuroprotective.1 On the other hand, although high intensity training (HIT) is able to exaggerate cardiac conditions, e.g., hypertension2 as well as exacerbate inflammatory and oxidative stress responses,1,3 such exercise programs are becoming more popular as they too have shown demonstrable health benefits if performed appropriately. Indeed, various studies have reported on the superior beneficial cardiac and vascular effects of high intensity exercise programs over that of moderate intensity continuous training (MICT),4-7 contributing to the growing popularity of such time-efficient programs. As such, exercise can accurately be described as a double-edged sword ­ able to induce positive, beneficial physiological effects when performed chronically at lower intensities, but generating harmful effects when performed at high intensities without sufficient recovery periods. From a toxicological point of view, exercise mediates hormesis, i.e., the biphasic dose response to an environmental agent characterised by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect.8

The anatomical basis of venographic filling defects of the transverse sinus.

Obstruction of the intracranial dural venous sinuses would result in an increase in intracranial dural venous pressure. This intracranial hypertension is not only the result of poor cerebral venous drainage but also life threatening. The aim of this study was to identify the structures, which may show signs of potential venographic filling defect qualities, including trabeculae/septa (also described as "fibrous bands") and arachnoid granulations, which ultimately can lead to increased intracranial dural sinus venous pressure. A total of 102 cadavers and living patients were used for the study. Fifty-three percent of the subjects presented with structures in their transverse sinuses that could be potential venous filling defects. Thirty percent of the subjects presented with arachnoid granulations in the right transverse sinus, which were found to be significantly dominant (Chi-square; p < 0.05). The study also revealed the presence of 1 to 5 septa in 29.4% of the subjects. The septa were found to be more dominant in the central (30%) and lateral (22%) thirds of the right transverse sinuses, while the central third of the left transverse sinus proved to be the least dominant occurring site (8%). In general, the right transverse sinus is highly more significantly dominant in septal occurrence (Chi-square; p < 0.01) than the left transverse sinus. We conclude from the statistical evidence that the right transverse sinus demonstrates significantly more potential venographic filling defects than the left sinus and submit that this information may assist in management options for patients diagnosed with idiopathic intracranial hypertension as well as direct future research.

Inhibition of human MAO-A and MAO-B by a compound isolated from flue-cured tobacco leaves and its neuroprotective properties in the MPTP mouse model of neurodegeneration.

Prompted by the findings that smokers have lowered brain and blood platelet monoamine oxidase-A and -B activities compared to non-smokers and that smokers have a lowered incidence of Parkinson's disease, we have examined the neuroprotective properties of an MAO inhibitor, 2,3,6-trimethyl-1,4-naphthoquinone (TMN), which is present in the tobacco plant and smoke in the MPTP C57BL/6 mouse model of neurodegeneration. Dopamine (DA) levels in the striata of mice treated with TMN prior to the administration of MPTP were significantly higher than DA levels in the striata of mice receiving MPTP only, thus indicating a degree of neuroprotection in this model of Parkinson's disease. The potential consequences on MAO activity of long term exposure to this compound need to be evaluated. Furthermore, there is evidence for the presence of other inhibitors in the tobacco leaf and smoke, including compounds with irreversible MAO inhibitory properties. Although there is no evidence to link the lowered activities of MAO to the lowered incidence of Parkinson's disease in smokers, the neuroprotective effects of TMN in the MPTP mouse model suggest that such a relationship is worthy of further evaluation.

Rescue of dying neurons by (R)-deprenyl in the MPTP-mouse model of Parkinson's disease does not include restoration of neostriatal dopamine.

Chronic (8- to 10-week) administration of the selective, potent, and irreversible monoamine oxidase B inhibitor (R)-deprenyl has been shown to increase the tyrosine hydroxylase immunoreactivity in the substantia nigra of mice that had been treated three days earlier with a neurotoxic dose of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This reported rescuing of lesioned nigrostriatal cell bodies by (R)-deprenyl prompted us to investigate if this (R)-deprenyl treatment also could restore neostriatal dopamine levels that are depleted by MPTP. The results of these experiments show that long term (8 or 10 weeks) treatment with (R)-deprenyl beginning three days post MPTP administration did not result in restoration of depleted neostriatal dopamine levels in C57BL/6 mice. We conclude that, although (R)-deprenyl may rescue MPTP-injured nigrostriatal neurons, it does not lead to functional recovery of these neurons as measured by the restoration of neostriatal dopamine levels.

The effects of age, sex, and shoulder dominance on range of motion of the shoulder.

To determine the effects of age, sex, and arm dominance on shoulder range of motion, we measured active and passive forward elevation, abduction, internal and external rotation at 90 degrees of abduction, external rotation with the arm adducted, and extension bilaterally in 280 subjects ranging in age from 4 to 70 years. Linear regression analyses were performed for all motions except forward elevation. This motion, which showed a nonlinear pattern of decline with age, was evaluated with 3-way analysis of variance. Shoulder range of motion decreased with age for all measured motions with the exception of internal rotation, which increased with age. Female subjects had a significantly greater range of motion than male subjects for all motions measured. Dominant arms displayed significantly greater external rotation than nondominant, regardless of whether the arm was abducted or adducted at the time of measurement. However, nondominant shoulders demonstrated significantly greater internal rotation and extension than dominant. No significant differences were found between dominant and nondominant sides for forward elevation or abduction.

Neuroprotection in the MPTP Parkinsonian C57BL/6 mouse model by a compound isolated from tobacco.

Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than in nonsmokers. This evidence, together with the lower levels of brain monoamine oxidase (MAO) activity in smokers and the potential neuroprotective properties of MAO inhibitors, prompted studies which led to the isolation and characterization of 2,3,6-trimethyl-1,4-naphthoquinone (TMN), an MAO-A and MAO-B inhibitor which is present in tobacco and tobacco smoke. Results of experiments reported here provide evidence that this compound protects against the MPTP-mediated depletion of neostriatal dopamine levels in the C57BL/6 mouse. These results support the hypothesis that the inhibition of MAO by constituents of tobacco smoke may be related to the decreased incidence of Parkinson's disease in smokers.

Selective inhibition of MAO-B through chronic low-dose (R)-deprenyl treatment in C57BL/6 mice has no effect on basal neostriatal dopamine levels.

C. Thiffault, L. Lamarre-Théroux, R. Quirion, and J. Poirier (1997, Mol. Brain Res. 44: 238-244) recently reported that chronic treatment of young (12 week old) C57BL/6 mice with (R)-deprenyl, a mechanism-based inactivator of monoamine oxidase B (MAO-B), leads to a more than fourfold increase in neostriatal dopamine levels. Such an effect could complicate the interpretation of results obtained from mechanistic studies designed to evaluate the putative neuroprotective effects of (R)-deprenyl in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. In contrast to the results of Thiffault et al., we have found that neostriatal dopamine levels in mature (32 week old) C57BL/6 mice were unaltered by chronic (R)-deprenyl treatment even though brain monoamine oxidase B activity was reduced by more than 80%. Neostriatal dopamine levels also were unaltered in both young and mature mice when the (R)-deprenyl treatment period was doubled compared to that reported by Thiffault et al. Consequently, studies on the putative neuroprotective properties of (R)-deprenyl in MPTP-lesioned mice are unlikely to be complicated by the possibility that inhibition of MAO-B alone will lead to an increase in neostriatal dopamine levels.

Isolation and characterization of a monoamine oxidase inhibitor from tobacco leaves.

Recent positron emission tomography imaging studies have demonstrated a significant decrease in both monoamine oxidase A and B (MAO-A and MAO-B) activities in the brains of smokers. Normal levels of activity are observed in former smokers, suggesting the presence of one or more compounds in tobacco smoke that may inhibit these enzymes. In this paper, we report the results of efforts to identify compounds present in flue-cured tobacco leaves that inhibit MAO. The isolation procedure was guided by estimating the inhibitory properties of tobacco leaf extracts on the liver mitochondrial MAO-B-catalyzed oxidation of 1-methyl-4-(1-methylpyrrol-2-yl)-1,2,3, 6-tetrahydropyridine to the corresponding dihydropyridinium metabolite. Fractionation of extracts from flue-cured tobacco leaves led to the isolation of a competitive inhibitor of human MAO-A (K(i) = 3 microM) and MAO-B (K(i) = 6 microM), the structure of which could be assigned by classical spectroscopic analysis and confirmed by synthesis. This information may help to provide insights into some aspects of the pharmacology and toxicology of tobacco products.

p-Fluorophenylglycine in the urine of baboons treated with HPTP, the tetrahydropyridine analog of haloperidol.

We report the presence of p-fluorophenylglycine (p-FPG) in the urine of six baboons treated with HPTP, the tetrahydropyridine dehydration product of haloperidol (HP). Oxidative N-dealkylation, the major metabolic pathway of HP, gives rise to 3-(4-fluorobenzoyl)propionic acid (p-FBPA). Subsequent beta-oxidation of p-FBPA produces p-fluorophenylacetic acid (p-FPA). The presence of p-FPA argues for the formation also of p-fluorophenylglyoxylic acid (p-FPGA) derived from beta-oxidation of p-FBPA. Plasma aminotransferases should convert p-FPGA to p-FPG. The presence of p-FPG in these animals suggest the presence of phenylglycine aminotransferases in the baboon and possibly also in other primates, including the human. Reports by other authors found that treatment with alpha-phenylglycine (alpha-PG), an "unnatural" amino acid, leads to striatal dopamine (DA) depletion in rabbits--an effect explained on the basis of alpha-PG competing with DA for the neuronal vesicular storage sites. We performed in vitro DA release assays in mouse striatal synaptosomal preparations but found that neither alpha-PG nor p-FPG released any DA. It therefore remains unclear whether p-FPG may be a contributing factor to neurologic side-effects such as tardive dyskinesia (TD) found in patients after long-term HP treatment.

Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins.

The pyridinium metabolites formed in the MAO-B catalyzed oxidation of 1-methyl-4-substituted-1,2,3,6-tetrahydropyridinyl derivatives, such as the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), cause the selective degeneration of nigrostriatal neurons, presumably by inhibition of mitochondrial respiration and depletion of ATP stores. The possibility that other partially oxidized piperidinyl derivatives also may be biotransformed to toxic pyridinium metabolites has led us to examine the metabolic fate of the neuroleptic agent haloperidol (HP) and its tetrahydropyridinyl dehydration product 4-(4-chlorophenyl)-1[4-(4-fluorophenyl)-4-oxobutyl]- 1,2,3,6-tetrahydropyridine (HPTP). In vitro metabolic studies employing tissue preparations isolated from rodents, baboons and humans have documented that cytochrome P4503A enzymes catalyze the biotransformation of both HP and HPTP to yield the corresponding pyridinium metabolite HPP+. An analogous biotransformation profile has been observed with "reduced haloperidol" (RHP), an abundant, circulating metabolite of HP formed by the stereospecific reduction of the benzoyl carbonyl group of HP. In vivo studies also have documented these pathways in humans, baboons and rodents. Although both HPP+ and RHPP+ are found in the urine and plasma of HP treated patients and HP or HPTP treated baboons, attempts to identify an MPTP-type lesion in baboons following long-term treatment with HPTP have failed. On the other hand, evidence for a lesion of the nucleus basalis of Meynert has been obtained. Additionally, the urinary excretion of abnormal organic acids and acylcarnitine conjugates suggests that HP and/or metabolites derived from HP interfere with energy production pathways.

Metabolic defects caused by treatment with the tetrahydropyridine analog of haloperidol (HPTP), in baboons.

Mounting evidence suggests that compromised cellular energy production is a major contributor to idiopathic and drug-induced degenerative processes. Our interest in neurotoxins have prompted us to examine in the baboon the effects of HPTP, the tetrahydropyridine dehydration product of haloperidol, on urinary chemical markers that reflect defects in mitochondrial respiration. Urinary dicarboxylic acid and conjugate profiles, similar to those seen in humans with inborn errors of mitochondrial metabolism and toxin-induced Jamaican vomiting sickness (JVS) were observed in the treated baboons. We interpret these results as evidence that HPTP and/or HPTP metabolites inhibit mitochondrial respiration in the baboon and speculate that analogous effects may occur in haloperidol-treated individuals.

Mortality of an asbestos-exposed birth cohort. A pilot study.

A pilot study on the health effects of environmental exposure to asbestos (in particular the development of mesothelioma) is almost complete. This is a record linkage study, using birth and death records as the primary sources of data. The vital status and, if applicable, the cause of death was examined for each of the 1227 members of the 'pilot' cohort (birth years 1932-1936). Preliminary results are presented. Eighty-seven per cent (399) of the white cohort members have been traced and the vital status of each has been determined. Sixty-six whites have died, 6 from mesothelioma. It is almost impossible to trace the black and coloured cohort members and the main study, covering the years of birth 1917-1936, may have to be restricted to whites.

Occupational health services in Johannesburg and Randburg.

Questionnaires were posted to 760 manufacturing organisations sampled from the 1986 Workmen's Compensation tape in the Johannesburg and Randburg areas. A response rate of 51% was obtained. The results indicate a general deficiency in the quantity of occupational health services offered. For example, only 57 factories (18%) offered a medical service on the premises, while pre-employment examinations were provided by 59. More larger factories than smaller ones provided occupational health services. There were also variations in the occupational health benefits provided, and salaried employees were generally better off than wage earners. For example, 62 factories (25%) did not provide medical schemes for wage earners, while only 5 (2%) did not provide medical schemes for salaried employees. Since the Erasmus Commission's findings were published in 1976, there does not appear to have been a substantial change in the provision of occupational health services in the manufacturing industry. With increasing urbanisation it is important that something be done to improve this situation.