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The effect of upright posture as a physiological stimulus of the adrenergic nervous system was studied in 56 subjects with benign essential hypertension. The subjects received a controlled-sodium diet. Blood pressure, heart rate, catecholamines, plasma renin activity, and urinary creatinine, sodium, and potassium excretion were measured in the recumbent and upright positions. We found an alteration in the blood pressure response in subjects with benign essential hypertension; the postural increase in the mean blood pressure in normotensive subjects (3.18 ± 1.35 mm Hg) progressively disappeared and was replaced by a postural decrease in subjects with more severe stable hypertension (-6.71 ± 2.42 mm Hg). The hypertensive subjects also lacked the usual increase in urinary excretion of norepinephrine. A significant increase in plasma renin activity associated with a significant decrease in plasma norepinephrine occurred in subjects with labile hypertension with postural tachycardia. Finally, we found a highly significant correlation between the excretion of sodium and potassium in the recumbent position and the retention of both ions in the upright position.

SUMMARY:All clinical laboratory tests carried out in 4 groups of patients with the diagnosis of typical or atypical Friedreich's ataxia have been found to be within the normal range. In this prospective study of 50 patients, a number of findings previously reported to be abnormal in the literature, have not been confirmed.

We have measured in leukocytes the following lysosomal enzymes in II Friedreich disease cases, 11 “atypical” recessive ataxias, 13 neurological controls and 16 normal controls: hexosaminidase A and B; (3-galactosidase and neuraminidase (labile and cold stable, or A and B). The lysosomal enzyme deficiencies known to produce certain forms of spinocerebellar degeneration were not present in Friedreich's disease or the Charievoix-Saguenay syndrome. The very small scale survey of “atypical” recessive ataxias revealed 3 cases of severe deficiencies in hexosaminidase activity. Two adult brothers presenting with the clinical phenotype of Kugelberg-Welander disease (one also with ataxia), were shown to have a severe deficiency of both HEX A and HEX B activity (Sandhoff biochemical pattern). This is the first such report. A further adult female patient, unrelated to the others, had a severe isolated deficiency of HEX B and presented with a very slowly progressive and mild ataxia with severe internal strabismus. These patients and their families are being studied clinically and biochemically in greater detail and will be reported elsewhere. However these preliminary findings justify screening for such lysosomal defects in all cases of “atypical” recessive ataxia.

We analysed the clinical features of 82 patients with dominantly inherited ataxia in a cohort survey. All patients fulfilled the diagnostic criteria for Machado-Joseph disease. The mean age of onset of symptoms was 39.8 (± 12.5) years and the duration of the disease was 9.2 (± 6.7) years. Ataxia, peripheral neuropathy, and fasciculation scores correlated with age of onset and duration of disease. Upper motor neuron scores failed to correlate with age of onset. In a follow-up study we analysed the clinical data of 46 patients two years after the first examination. A paired ttest was used to compare differences between observations. The results are in agreement with those of the cross-section in time, suggesting a deterioration of the symptoms with the evolution of the disease. We conclude that dynamic definition of the disease according to age of onset and duration of symptoms is preferable to subdivision into classical types.

We have evaluated the cardiovascular effects of intracerebroventricular (i.c.v.) injections of neurotensin (NT) in pentobarbital-anesthetized rats. In most animals, the i.c.v. injection of NT (5.4, 10.8 and 16.2 nmol/rat) induced a dose-dependent fall of the arterial blood pressure. This effect was usually rapid in onset (30-60 sec) and of short duration (approximately 1-4 min). It was not preceded nor accompanied by any significant alteration of the heart rate. In about 25% of the animals, the vasodepressor effect of i.c.v. injections of NT was long lasting (30-45 min). Conscious rats were much less sensitive than anesthetized animals. The hypotensive effects of intravenously (i.v.) administered NT was fully maintained in animals made tolerant to the hypotensive effect of centrally administered NT. Similarly, the animals made unresponsive to i.v. injections of NT either by repeated i.v. injections of NT (e.g. tachyphylaxis) or by a chronic treatment with compound 48/80, still responded normally to centrally administered NT. The results suggest the existence of at least two anatomically distinct sites of action through which NT can induce hypotension in rats. One appears to be located in the periphery and the other, in the central nervous system.

SUMMARY:The suppressive effect of various amino acids against ouabaininduced seizures was investigated in young female rats. The amino acids were injected into the left lateral ventricle 10 minutes prior to the intraventricular administration of 5 μg. of ouabain. Animals receiving 1.9 x 10-1M solutions of hypotaurine and of β- alanine were almost completely protected from the ouabain seizures. Administration of L-alanine and of glycine was also effective, although running and leaping seizures still occurred to some extent. Betaine reduced only clonic-tonic and whole body flexion and extension seizures. In contrast, L-proline exclusively suppressed clonic-tonic and focal clonic seizures. Rats injected with isethionic acid showed increases in incidence of running and leaping seizures while L-arginine in high concentrations caused aggravation in clonic-tonic seizures. L-cysteine, even in low concentrations, also brought about an increase in the occurrence and incidence of clonic-tonic seizures. The ED50of hypotaurine was 10.11 x 10-2M for running seizures and 4.63 x 10-2, M for clonictonic seizures; that of β -alanine was 14.01 x 10-2M for running seizures and 5.50 x 10-2M for clonic-tonic seizures. However, hypotaurine and β -alanine, the most effective compounds tested in the present studies, provided less protection than taurine previously examined by us under similar conditions (Izumi et al., 1973).

Resting levels of plasma norepinephrine, epinephrine and dopamine were determined in 9 patients diagnosed as having Friedreich’s Ataxia using a relatively new assay method, HPLC with electrochemical detection. Levels of norepinephrine and dopamine were found to be significantly elevated in patients as compared to controls while epinephrine, though increased, was not significantly higher. These results confirm in most parts previous findings of Pasternak et al. of increased plasma catecholamines and demonstrate the sensitivity and utility of the present method for the routine assay of plasma catecholamines.

The clinical entity of benign essential hypertension is often subdivided into labile essential hypertension and stable essential hypertension. To establish less arbitrary limits between normotension and labile and stable benign essential hypertension, 70 subjects (56 with benign essential hypertension) were classified according to (a) the usual blood pressure index for each subject and (b) the upper limit of variation of the usual blood pressure indexes of a normotensive population. Catecholamines, plasma renin activity, and urinary creatinine, sodium, and potassium were measured in recumbent subjects who had received a controlled-sodium diet. Our findings suggest that (1) benign essential hypertension represents a heterogeneous entity and a continuous spectrum of clinical and biochemical changes when it is related to the level of blood pressure, (2) adrenergic involvement is more evident in labile hypertension, (3) regardless of the urinary excretion of catecholamines in subjects with benign essential hypertension the urinary ratio of dopamine to norepinephrine always remains lower, and (4) a negative correlation exists between urinary sodium excretion and usual blood pressure indexes.

— The overall steady state kinetic mechanism of pyruvate dehydrogenase multienzyme complex purified from rat brain has been investigated. Initial rate patterns were a series of parallel lines regardless of which substrate was varied at several fixed concentrations of other substrates. Product inhibition patterns showed that acetyl CoA is competitive vs CoA, that NADH is competitive vs NAD, and that both acetyl CoA and NADH are uncompetitive vs pyruvate. Both acetyl CoA and NADH are noncompetitive vs NAD and CoASH, respectively. These results are inconsistent with classical ‘hexa uni’ ping-pong mechanisms, but are consistent with a non-classical 3-site ping-pong mechanism.

We have measured the activity of malic enzyme NADP+ dependent in the nuclear, mitochondrial, lysosomal and cytosolic fractions of cultured skin fibroblasts from twelve patients with Friedreich's ataxia and nine control subjects. Hexosaminidase, cytochrome-C-oxidase, lactate dehydrogenase and malic enzyme NAD+ dependent were used as marker enzymes. The activity of malic enzyme NADP+ dependent was not significantly reduced in the mitochondrial fraction of patients with Friedreich's ataxia as compared with controls. When corrected for possible contamination between mitochondrial and cytosolic fractions, malic enzyme NADP+ dependent activity was still not significantly reduced in patients with Friedreich's ataxia. Unless critical methodological differences were overlooked in this or previously published studies, we conclude that mitochondrial malic enzyme deficiency is not the primary genetic defect underlying Friedreich's ataxia.

Neurobehavioral effects of neurotensin and structural analogues in which tyrosine in position 11 was replaced by either its d-isomer [D-Tyr11]-NT, phenylalanine [Phe11]-NT or D-phenylalanine [D-Phe11]-NT were studied. Results demonstrate that whereas neurotensin and [Phe11]-NT significantly decreased motor activity in rats, [D-Tyr11]-NT and [D-Phe11]-NT produced a marked and significant increase in activity. Such dichotomous action between analogues was not found for the hypothermic and muscular relaxation effects of neurotensin.

SUMMARY:The general outline of the complete prospective study of 50 cases of spino-cerebellar degeneration is given. The general protocol followed, the criteria for inclusion and the mode of analysis are described. The aim of this study was to establish a base of clinical, physiological and biochemical facts upon which a logical and systematic approach to pathogenesis and treatment of Friedreich's ataxia could be attempted.

SUMMARY:The present paper analyses the new data accumulated since 1972 concerning the etiology and pathogenesis of Huntington’s chorea. Particular attention is paid to the respective roles of the dopaminergic and GABA-ergic systems.

The diagnosis of Parkinson's disease is not as easy as previously claimed, and presents a number of pitfalls. We present three rules, or aphorisms, to help the general practitioner in overcoming these diagnostic difficulties: 1. 1. Know well the basic disease and its symptoms. 2. 2. Use tricks to elicit apparently absent ‘primary’ symptoms. 3. 3. Beware of unusual symptoms or case histories. Examples of difficulties encountered at each level are given. Such analysis should permit the physician to classify his extrapyramidal patient within one of the many types of ‘parkinsonism’ as shown in Table 1.

We demonstrate that injections of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), 1-methyl-4-phenyl-pyridinium ion (MPP+) and Paraquat (PQ+) produce in Rana Pipiens different behavioral, biochemical and skin pigmentation changes. MPTP causes in frogs the main symptoms of Parkinsonism (rigidity, akinesia and tremor) and it darkens the skin of animals. It also decreases brain and, less so, adrenal medulla dopamine. These effects are blocked by Pargyline. MPP+ causes the same symptoms but more rapidly. In contrast, skin pigmentation is clearly lightened. Brain and particularly adrenal dopamine reserves are nearly abolished. Pargyline increases these effects. Paraquat, in a cumulative fashion, eventually causes the same behavioral changes and a slight increase in pigmentation. It initially produces an increase in brain and adrenal dopamine concentrations, but later a significant dopamine concentration decrease. Pargyline potentiates these long term effects, blocks the dopamine increase, but reverses the PQ+ effect upon melanin, producing the same depigmentation as MPP+ alone.

This paper reviews recent evidence that a number of small peptides found in the brain are active in the central nervous system and behaviorally. Attention is focused on MSH/ACTH 4-10, alpha- and beta-MSH, and the prohormone beta-LPH, as they produce a syndrome of yawning and stretching. Studies with substance P and mainly with MIF-I are also reviewed. It is shown that substance P is an excitatory transmitter or modulator in the dorsal spinal cord with that MIF-I has antiparkinson properties. It is concluded that many polypeptides have direct actions on the central nervous system independent of their neuroendocrine properties.

Recent reports of the in vivo action of L-dihydroxyphenylalanine (L-DOPA) on glutamic acid decarboxylase (GAD) activity are contradictory. This investigation was undertaken to clarify the situation. Both acute (100 mg/kg and 1 g/kg) and chronic (1 g/kg) administration of L-DOPA to rats failed to produce any alteration in the activity of striatal or retinal GAD activity. These results are discussed in the light of a report relating L-DOPA therapy to modification of GAD activity in Parkinson's disease.

Urinary excretion of dopamine, norepinephrine and epinephrine was measured in a group of adult men and women of comparable age during recumbency and then during stimulation by upright posture. Urinary norepinephrine was found to be significantly higher in women (30.3 +/- 4.4 ng/min/m2 B.S.) than in men (18.3 +/- 2.7 ng/min/m2 B.S.) during recumbency; there was no significant sex difference in dopamine and epinephrine excretion. There was no apparent trend indicating a difference in urinary catecholamine excretion during the follicular or luteal phase of the menstrual cycle. In response to upright posture, there was a significant decrease in the urinary dopamine-norepinephrine ratio in both sexes; the magnitude of the decrease was, however, significantly higher in men (-9.9 +/- 3.0) than in women (-2.05 +/- 0.72). The mechanisms of the sex differences in urinary catecholamine excretion are unknown. Clinical studies involving catecholamines have to take these sex differences into account.

SUMMARY:We report a clinical and biochemical survey of 23 patients with Friedreich's ataxia from southern Italy. They were studied clinically and by means of a clinical rating scale devised by us (Inherited Ataxias Clinical Rating Scale). Laboratory tests, based on the Quebec Cooperative Study, were also performed on our patients. No major clinical or biochemical differences were found between Italian and Canadian patients. Investigation of CSF monoamine metabolites showed that HVA decreased after probenecid and metoclopramide loading

• The clinical course and the side effects of high-level levodopa therapy over a six-year period were studied in 80 severely akinetic parkinsonian patients treated for the first time before June 1968. Levodopa improved the quality of life in greater than 53% of patients, but failed to modify the progression of the disease or change the prognosis. Seventeen "idiopathic Parkinson" patients died after a duration of illness of 9.5 years. Despite the drawbacks, levodopa is still the best available treatment for akinetic parkinsonism.

SUMMARY:A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreich's ataxia and control subjects has revealed a number of mathematically significant variations from normal. Of practical physiological importance are the following: a high urinary excretion of alanine with slightly elevated plasma levels; a low plasma and CSF concentration of aspartic acid in the resence of normal urinary values and finally a low CSF concentration of taurine accompanied by normal plasma levels, but elevated urinary output and renal clearance rates. We postulate that the modifications in alanine and aspartic acid are less specific and probably secondary, but there could be a genetic defect in the membrane transport of taurine and the other β-amino acids in Friedreich's ataxia.

Hypokinesia produced by stereotaxic microinjection of solutions of 6-hydroxydopamine into the anterolateral hypothalamus of male rats is accompanied by a generalized reduction in brain noradrenaline levels and a reduction of dopamine in the striatum and cerebral cortex. The hypokinesia is reversed by the putative dopamine-receptor agonists apomorphine, ET-495 and CB-154 as well as by the amino acids L-Dopa and m-tyrosine when administered in combination with the peripheral decarboxylase inhibitor Ro 4–4602. The relative importance of noradrenergic and dopaminergic systems in the mediation of the action of anti-akinesia drugs is discussed.

SummaryThiamine-deficient encephalopathy in the rat is characterized by ataxie gait, loss of righting reflex and curvature of the spine. N euro chemie ai changes include a diminished activity of cerebral pyruvate decarboxylase leading to abnormal pyruvate oxidation. The present study shows that this defective pyruvate oxidation produces a significant depletion of three important amino acid neurotransmitters, namely gamma aminobuiyrie acid (GABA), glutamic acid, andaspartic acid. Such changes could lead to severe neuronal dysfunction and the observed neurological symptoms of thiamine deficiency. Some implications for the pathogenesis of Friedreich's ataxia are discussed.

We report the development of two animal models in amphibians (frogs and salamanders) in whom 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) produces the behavioral (neurological) and biochemical equivalents of the human disease and, in addition, a mesurable modification in at least one form of pigment-bearing cell from the neural crest, the skin melanocyte. We propose that this new approach can become an inexpensive, easily quantifiable model for the study of the effect of MPTP on the central and peripheral nervous systems. We also demonstrate that the toxic effect of MPTP can be completely abolished in vivo by treatment with a monoamine oxidase inhibitor and potentiated by an inhibitor of catechol-0-methyltransferase. MPTP is catabolised by oxidation into toxic metabolites, but 1-methyl-4-phenylpyridinium ion (MPP+), the proposed end-metabolite, is even more toxic than MPTP in this model, possibly through a different mechanism.

Threonine supplementation (500 mg/day) was given to 6 patients with genetic spasticity syndromes for a period of 12 months, followed by a 4-month observation period without medication. All 6 patients showed partial improvement of spasticity, intensity of knee jerks and muscle spasms without changes in true pyramidal tract signs. The improvement in motor performance, objectively measured, averaged 29% (19% in upper limbs and 42% in lower limbs). The range of overall improvement was 19–35% (7–30% for upper limbs; 25–67% for lower limbs). No toxic clinical or biochemical side effects were encountered. Thus threonine, a precursor of glycine, produced the same effect on spasticity than that previously observed with glycine. It is concluded that threonine supplementation is feasible and safe and that it deserves a controlled trial in well defined (preferably genetic) cases of spasticity.

SUMMARY:Pyruvate dehydrogenase (PDH), α -keto gluturate dehydrogenase (α -KGDH) and lipoamide dehydrogenase (LAD) were measured in platelets of II patients with typical Friedreich's ataxia and 10 normal control subjects. Serum LAD was also evaluated in the same patients. No statistically significant changes were found in platelets for the group as a whole, although some patients had low values (more than one standard deviation below control mean). Serum LAD was significantly reduced in the patients with Friedreich's ataxia. This was not due to associated diabetes.

SUMMARY:This paper reviews some recent developments concerning the “non-essential” amino acid Taurine. It is shown that taurine is important in metabolic regulations within the heart, muscle and brain. Particular attention is paid to the neuropharmacology of taurine, such as its possible role in epilepsy.

SUMMARY:We investigated the clinical and metabolic characteristics of Parkinsonian patients whose illness started before the age of 40. A pilot study of 32 of our own such cases revealed the existence of 3 subgroups: 1. Post-Encephalitic, 2. Onset and course with predominant tremor, 3. Onset and course with akinesia and rigidity. In this early onset group of patients, there was a 46% incidence of familial cases (as opposed to 10-15% in the general Parkinson population). The cases with tremor onset had a high prevalence of essential tremor in their families, while those with an akinetorigid onset had a high familial incidence of other cases of Parkinson’s Disease. Familial grey hair, hypertension, diabetes and thyroidopathies appeared to be in higher than expected frequency.These trends were confirmed in a larger series of 135 cases of early onset Parkinson obtained through a mail survey. When the same clinical material was analysed for the familial cases only, two new genetic subgroups emerged: 1) a familial metabolic akineto-rigid syndrome (with hypertension, familial diabetes, hypothyroidism and a more severe course) and, 2) a familial essential tremor-related Parkinsonian syndrome (with familial grey hair trait and hyperthyroidism). These new genetic syndromes along with the recently described “Familial juvenile Parkinsonism” require many further prospectives metabolic and clinical investigations for full characterization, but confirm our hypothesis that “idiopathic” Parkinson’s disease is not a single homogeneous entity.

SUMMARYIn this essay I present a new “global approach hypothesis” to explain the pathophysiology of Parkinson’s disease: “Susceptibility to Parkinsonism is genetically determined and is reflected in all cells. I propose that idiopathic Parkinson’s disease is the combined result of a generalized cell aging process accelerated, in susceptible individuals, by a variety of often repetitive trigger factors. These factors have in common the fact that they cause a transient increase in turnover within catecholamine producing neurons, centrally as well as peripherally. This results in accumulation within these neurons of free radicals. When the level of the toxic substances, in quantity or in time of exposure, exceeds the scavenging capacity of the cell, damage to organelles and to membranes results, leading to the formation of Lewy bodies through an autoimmune reaction to damaged filaments and to cell death, particularly in the pigmented neurons of the brainstem. The progressive cell depletion leads to a compensatory increase in catecholamine turnover in the remaining pigmented cells, and an ever-accelerating degenerative process. The resulting neurotransmitter imbalance in the basal ganglia explains the symptoms of Parkinson’s disease”. In the light of this hypothesis, our research objectives should be (1) to delineate the limits of true Parkinson’s disease from all phenocopies; (2) to identify individuals susceptible to parkinsonism and the most common trigger factors; (3) to reduce the metabolic effects of unavoidable trigger factors and (4) to protect susceptible individuals by increasing the functional availability of free radical trapping agents.

SUMMARY:The 50 patients in this survey were classified by a panel of neurologists into 4 clinical sub-groups: Group la (“typical” Friedreich's ataxia, complete picture), Group lb (“typical” Friedreich's ataxia, incomplete picture), Group Ila (“atypical” Friedreich's ataxia, possible recessive Roussy-Levy syndrome), Group lib (heterogeneous ataxias). The clinical symptoms and signs were analyzed for each of these groups. A constellation of signs constantly present in Friedreich's ataxia and obligatory for diagnosis was described. Other important symptoms, such as the Babinski sign, kyphoscoliosis and pes cavus were found to be progressive, but not essential for the diagnosis at any given time. Finally, a host of other symptoms can only be called accessory. The progression of scoliosis was found to be an important tool in the differential diagnosis of ataxias. Our study also indicates, in contrast to the opinion of some authors, that absent deep tendon reflexes in the lower limbs and early dysarthria are essential in “typical” Friedreich's ataxia.

We demonstrate that 1-methyl-4-phenyl-1,2-dihydropyridine (MPDP) can be generated, in an alternate pathway, from the catalyst action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) upon the iron redox equilibrium reaction. Superoxide and ferric iron are instantaneously produced after addition of MPTP to a solution of ferrous iron. This reaction is oxygen and pH dependent. Superoxide, through a iron dependent Haber-Weiss reaction with peroxide, can generate the cytotoxic hydroxyl radical. A small portion of the superoxide reacts with MPTP to produce the reactive species X. which, in the presence of Fe+3 can also generate MPDP.

β-Endorphin (amino acid sequence 61–91 of β-lipotropin) administered intraventricularly at a dose of 13 n moles in rat induced akinesia and loss of corneal reflex. Apomorphine (20 mg/kg) which had been injected subcutaneously 20 minutes after the administration of β-endorphin fully reversed akinesia and elicited characteristic stereotyped behavior. During complete disappearance of akinesia, the corneal reflex was found to be still absent. Apomorphine (5 mg/kg) only partially reversed akinesia. Pretreatment with α-methyl-p-tyrosine (α-MT, 250 mg/kg) potentiated the effect of β-endorphin upon muscle rigidity. In a biochemical study, rats received β-endorphin (15 n moles) 60 minutes before sacrifice. Concentrations of dopamine (DA) and norepinephrine (NE) were not altered in any brain regions. A significant increase in concentrations of 5-hydroxytryptamine was obtained in the midbrain. In a DA and NE turnover study, rats received α-MT (250 mg/kg) 4 hours prior to β-endorphin and were sacrificed 60 minutes later. β-Endorphin partially corrected the decreased concentrations of DA induced by α-MT in the midbrain. A similar tendency toward correction of the decreased DA concentrations was observed in the striatum. The concentrations of NE decreased by α-MT in the midbrain, striatum and hypothalamus were not modified by β-endorphin

Three groups have reported defective antioxidant mechanisms in substantia nigra of patients with Parkinson's disease, namely a decreased catalase and peroxidase activity, a reduction of glutathione and, more recently, a diminished nigral glutathione peroxidase activity. We decided to investigate these mechanisms in erythrocytes to determine whether these brain defects represent generalized or genetic aberrations, in which case they should also be present in blood cells. The glutathione cycle has been investigated (reduced and oxidized glutathione, glutathione reductase and peroxidase) plus the activities of catalase and superoxide dismutase. The basal malonaldehyde content of erythrocytes was used as an index of endogenous lipid peroxidation. None of the above-mentioned parameters were found altered in erythrocytes of parkinsonians, suggesting that no genetic or generalized biochemical abnormalities underly the deficiencies detected in substancia nigra.

Labile hypertension in patients under 50 years of age (the non-atherosclerotic form) was found to be characterized by higher urinary excretion of catecholamines and particularly of homovanillic acid; when further analyzed it was shown to be a heterogeneous entity with two types of patients clinically and biochemically distinguishable from each other, from control subjects and from patients with stable hypertension. Reactivity to assuming an upright posture distinguishes one type of labile hypertension having a normal postural pulse rate response from another having an excessive postural increase in pulse rate. The first group also showed normal responses of plasma norepinephrine concentration and of urinary cyclic AMP to posture. The group with excessive pulse rate response, in contrast, showed a decrease in plasma norepinephrine and an excessive increase of urinary cyclic AMP excretion in response to upright posture. The results suggest that not only circulating catecholamines but also the reactivity of their target tissues (as probably reflected by cyclic AMP measurements) are important in bringing about signs of adrenergic excess. The hypothesis that cyclic AMP changes reflect beta-adrenergic receptor reactivity is strongly favoured by data indicating qualitative differences in cyclic AMP responses to beta-adrenergic stimulation or inhibition between control subjects and those labile hypertensive patients with clinical signs of excessive sympathetic reactivity. The study stresses the need for more precise definition of labile hypertension, for dynamic clinical and biochemical correlative studies, and for consideration not only of the circulating hormones but also of the "second messengers" (such as cyclic AMP and cyclic GMP) which reflect the cellular action of hormones. Blood pressure is a very labile parameter in health and disease. In one sense, therefore, hypertension can be considered "labile" in every hypertensive patient. Usually, however, labile (or borderline) hypertension is regarded as characterized by a blood pressure over 140/90 mmHg, falling below these values with physical and emotional rest. This clinical entity, which affects some 20% (variously estimated between 16 and 30%) of the adult population, gives rise to uncertainties in both definition and prognosis. In some patients labile hypertension represents the precursor of a fixed hypertensive state, whereas in many others it remains labile throughout life, never progressing to the stable phase nor becoming associated with hypertensive cardiovascular disease.(ABSTRACT TRUNCATED AT 400 WORDS)

The purpose of the present study was to examine the ability of nicotinamide to prevent the appearance of neurobehavioral symptoms induced by 3-acetyl pyridine (3-AP) in rats. Nicotinamide in doses of 5,50 and 500 mg/kg was injected immediately after administration of 65 mg/kg 3-AP, and neurobehavioral measurements were made at 6, 12, 24, 48 and 72 hours after injections. The effects of 500 mg/kg nicotinamide injected at 3 and 6 hours after 3-AP treatment were also investigated. The results indicate that, starting at 50 mg/kg, nicotinamide can protect animals against most of the neurobehavioral effects of 3-AP. However, the muscular rigidity induced by 3-AP can only be reversed by 500 mg/kg nicotinamide, and the depressing influence of 3-AP on locomotor activity is not blocked by any of the doses of nicotinamide tested. In terms of time course, the protective action of 500 mg/kg is seen when injected 3, but not 6 hours after 3-AP.

Oculopharyngeal muscular dystrophy is an autosomal dominant transmitted condition seen mainly in French Canada. The largest number of publications on these patients concerns a Quebec family whose descendants have spread throughout the United States. Families of different ethnic origins have also been reported from around the world, although there is no evidence that the neuromuscular disease reported is the same, despite the similarity of the syndrome. When severe oropharyngeal dysphagia results, these patients can significantly benefit from a cricopharyngeal myotomy.

SUMMARY:The combined metabolic stresses of fasting and the intravenous injection of 50 mg nicotinic acid in Friedreich's ataxia resulted in the delineation of two sub-groups of responses. High bilirubin ataxics maintained abnormally elevated levels of bilirubin, while normal bilirubin ataxics behaved like the normal control group. It is postulated that this finding infers the possible linkage of the gene for Friedreich's ataxia and that for Gilbert's disease.

We have evaluated and compared the hypotensive effects of intravenously (iv) and intracerebroventricularly (icv) injected NT, NT fragments and analogues in pentobarbital-anesthetized rats. The removal of the sequence pGlu1-Leu2-Tyr3-Glu4-Asn5-Lys6-Pro7 reduced only slightly the hypotensive activity of NT injected iv and icv while the deletion of Leu13 or of Tyr11-Ile12-Leu13-OH brought about a large decrease of potency (NT (1–12)) or a complete loss of hypotensive activity (NT (1–10)). The replacement of Tyr11 with Trp produced a minor increase (∼8%) or decrease (15%) of the potency of NT when injected iv and icv respectively. NT analogues in which Tyr11 was replaced with Phe, D-Phe or D-Tyr exhibited large decreases of potency when injected iv but only small reductions of potency when injected icv. [D-Trp11]-NT and [Tyr(Me)11]-NT were relatively weak agonists using both routes of injection. Our results indicate that the chemical groups responsible for the hypotensive effect of peripherally and centrally injected NT are located in the same sequence (e.g. Arg9-Pro10-Tyr11-Ile12-Leu13-OH). The results also suggest that the amino acid Tyr11 contributes to a large extent to the hypotensive activity of peripherally injected NT. The importance of Tyr11 for the hypotensive activity of centrally administered NT remains difficult to evaluate possibly because the receptors which subserve the hypotensive effect of centrally administered NT and/or the mechanisms responsible for the inactivation of NT in the brain and in the periphery, are different.

We demonstrate that the high concentration of transition metals in the substantia nigra could be a major factor responsible for the specificity of cell damage by the Parkinsonism-causing neurotoxin MPTP. It will be shown that these metals in vitro, and MPTP, each potentiate the autoxidation of dopamine and the production of aminochrome through the generation of superoxide, hydroxyl radicals, hydrogen peroxide and reactive semiquinones. Moreover, the same metals contribute to the oxidation of MPTP itself, further enhancing dopamine autoxidation.

Bilateral 6-hydroxydopamine injections into the anterolateral (AL) or posterolateral (PL) portions of the hypothalamus produced hypokinesia, catalepsy, rigidity and severe weight losses due to aphagia and adipsia. Subcutaneous administration of apomorphine, 1 mg/kg, 48 hr after 6-OHDA injections reversed temporarily the hypokinesia in both AL and PL 6-OHDA groups. However, qualitative and quantitative differences in the behavioral responses to the drug were observed. Motor activity as measured by photocell counts was significantly greater in AL 6-OHDA rats. Apomorphine induced stereotyped behavior in both groups; however, the predominant behavioral responses were oral stereotypies in PL 6-OHDA animals and sniffing in AL 6-OHDA rats.

Effects of taurine on tolerance to [D-Ala2, Met5]enkephalinamide (DAME) were investigated in rats. Tolerance was produced by five intraventricular administrations of DAME (50 microgram) during 3 consecutive days. The magnitude of developed tolerance to DAME was not uniform for each behavioral parameter; tolerance to analgesia effects developed more intensively and rapidly from the repeated injections of the peptide than that to akinesia effects. Pretreatment with taurine (9.5 X 10(-2) M) which was injected in a volume of 10 microliter intraventricularly 10 min prior to every administration of DAME suppressed the development of tolerance to both analgesia and akinesia effects of this peptide, whereas pretreatment with L-leucine at the same concentration did not. Spontaneous locomotor activity was measured for 1 h after the 90-min behavioral observation period was completed. That activity increased with the number of the peptide injections. Taurine pretreatment inhibited the induction of 'hyper'-locomotor activity. These results support the view that taurine may possess an ability to inhibit development of tolerance to morphine-like peptides in rats.

SUMMARY:Ouabain, an inhibitor of Na+-K+-ATP'ase, has been administered intraventricularly to rats to study the effect of impairment of membrane transport mechanisms on the genesis of seizures. Running and leaping seizures occur rapidly after injection oj ouabain in a low volume (10μl) when the maximal uptake of ouabain (39.8%) is in the hippocampus. Generalized clonic-lonic seizures are induced by higher volume injections (50μl) associated with wider distribution of ouabain, including the cerebellum and brainstem.Ouabain was injected into cerebral cortex, caudate nucleus, dorsal hippocampus, fastigeal nucleus, ventrolateral mesencephalic reticular formation and cerebellar cortex. The cerebellar injections produced both running and leaping and generalized clonic-lonic seizures. It is suggested that this results from decreased inhibitory effect of vermal and paravermal Purkinje cells on intra-cerebellar nuclei, which alters cerebellar influence on the reticular formation and the limbic system.Diphenylhydantoin, phenobarbitone, phenacemide, carbamezepine and clonazepam but not ethosuximide are effective against generalized clonic-lonic seizures, suggesting that this is a model for “grand mat” but not “petit mal” seizure mechanisms. It is furthermore suggested that running and leaping are subcortical, probably limbic, seizures that are most relevant as a model for temporal lobe seizures.