Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia.

Friedreich ataxia (FRDA) is due to mutations in the FRDA gene (FRDA). When the gene homologous to FRDA is knocked out in yeast, there is accumulation of iron in mitochondria and reduced respiratory function. So far, there is only indirect evidence to support the hypothesis that FRDA is due to accumulation of mitochondrial iron leading to increased production of free radicals. We show here that mitochondrial iron is significantly higher in fibroblasts from patients with FRDA than in control fibroblasts. This is the first direct evidence that the findings in yeast are reproducible in cells from patients with FRDA.     

Levodopa treatment of presenile dementia

In Parkinson's disease as well as presenile dementia there is a dopamine deficit in the basal ganglia. Extrapyramidal symptoms are common in presenile dementia, and dementia is a common trait in Parkinsonism. It is reasonable to suggest a partial common etiology and pathophysiology, and the logical consequence is an investigation of levodopa substitution in presenile dementia. Unitil now very few reports of such studies have been published. The investigations have been uncontrolled or carried out on small or inhomogeneous materials. This investigation is triple-blind, clinically controlled, and the material is very homogeneous. After 6 months' levodopa treatment no significant effect is shown either on a broad spectrum of psychiatric items or in cognitive functioning. This negative result is discussed. The probability of a specific Parkinson dementia is mentioned and the significance of the modifying effect of an imbalance in other transmitter systems is emphasized.     

Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis

Dysferlin is a muscle protein involved in cell membrane repair and its deficiency is associated with muscular dystrophy. We describe that dysferlin is also expressed in leaky endothelial cells. In the normal central nervous system (CNS), dysferlin is only present in endothelial cells of circumventricular organs. In the inflamed CNS of patients with multiple sclerosis (MS) or in animals with experimental autoimmune encephalomyelitis, dysferlin reactivity is induced in endothelial cells and the expression is associated with vascular leakage of serum proteins. In MS, dysferlin expression in endothelial cells is not restricted to vessels with inflammatory cuffs but is also present in noninflamed vessels. In addition, many blood vessels with perivascular inflammatory infiltrates lack dysferlin expression in inactive lesions or in the normal-appearing white matter. In vitro, dysferlin can be induced in endothelial cells by stimulation with tumor necrosis factor-alpha. Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis.     

Histamine as a neurotransmitter in the stomatogastric nervous system of the spiny lobster

Histamine is a putative neurotransmitter in mammals and molluscs, but its role in the nervous systems of other animals is not known. This study examines the possibility that histamine is a neurotransmitter in an arthropod. Results show that first, 14 neurons in the stomatogastric ganglion of the spiny lobster respond to histamine. The response is inhibitory, is mediated by an increased conductance to chloride, and desensitizes with repeated applications of histamine. These same 14 neurons receive one type of synaptic potential from two extrinsic neurons, the "through-fibers" of the inferior ventricular nerve. This synaptic potential is also inhibitory, is mediated by an increased conductance to chloride, and is blocked when histamine receptors are desensitized. Second, assays of endogenous histamine indicate that histamine is distributed nonuniformly throughout the stomatogastric nervous system and that its distribution correlates with the axonal pathways and terminal arborizations of the inferior ventricular nerve through-fibers. Lastly, histamine is present in relatively high concentrations in the cell bodies of the through-fibers, whereas it is not detectable in other neurons in the stomatogastric system. These results suggest that histamine may be a transmitter in the lobster.     

Status epilepticus in children

Status epilepticus is defined as a continuous seizure lasting for at least 30 minutes or recurrent seizures persisting for over 30 minutes, without recovery of consciousness. The estimated incidence in childhood is approximately 20 per 100,000 children per year. The incidence is higher in those under one year of age, with an incidence of approximately 50 per 100,000 per year. Among 1-4 year olds, approximately 30 per 100,000 per year will have an episode of status and in those aged 5-9 years, the incidence is approximately 10 per 100,000 per year. Those aged 10-15 years have the lowest incidence (approximately 2 per 100,000 per year). The mortality associated with status epilepticus in children is estimated at 2.5-5%, and is primarily related to the underlying cause of the episode of status. Neurological morbidity is seen in less than 15% of affected children. In most cases, the episode of status is either a single isolated event or is the first manifestation of epilepsy. Only 12% of cases occur in children with a prior diagnosis of epilepsy. It is essential to have an organized approach for dealing with status epilepticus. There is little data to support the contention that one protocol is better than another. It is recommended that each center should decide on a protocol that is rational and is standard practice for their patients. Most centers initiate therapy with either buccal or intravenous lorazepam. Alternate initial therapies include diazepam or midazolam. Early treatment is generally recommended although, in humans, there is minimal evidence that the length of seizure directly affects outcome. There is however, abundant evidence in animals, which indicates that longer seizures are harmful and result in poorer outcome. Early intervention does, however, increase the likelihood of attaining seizure control in humans. The optimal management of the child in a prolonged seizure therefore demands an understanding of the potential causes, appropriate investigations, and therapy.     

Effect of thyroid deficiency on postnatal cell formation in the rat brain: a biochemical investigation.

In thyroid deficiency, interference with postnatal cell formation seems to be confined to those regions of the brain where postnatal neurogenesis is significant. In comparison with controls the increase in cell number in the cerebellum is retarded in the second week of life, but a normal number is reached by 35 days. In contrast the DNA content of the olfactory bulbs is apparently irreversibly depressed. Mitotic activity, in terms of incorporation of [2-14C]thymidine into DNA, is mainly affected in the cerebellum: in thyroid deficient rats, it is depressed below control levels at day 12, but it is about 4 times higher than in controls at day 21 when, under normal conditions, cell proliferation has virtually ceased. The time course (15-240 min) of [14C]thymidine metabolism at day 14 shows regional differences in control rats. The rate of conversion of [14C]thymidine to [14C]thymidine nucleotides, and of these in turn to [14C]DNA is slower in the forebrain - where cell proliferation occurs on a smaller scale - than in the cerebellum. Consequently, in the forebrain nearly linear DNA synthesis rate is maintained for a longer time than in the cerebellum (1 h vs. 0.5 h), and since less 14C is conserved in DNA a significant efflux of unconverted [14C]thymidine is evident during the experimental period. The effect of thyroid deficiency on [14C]thymidine metabolism in the brain is only slight, and is due to an abnormally large supply of [14C]thymidine consequent to depressed systemic utilization of this precursor.     

The initiation of voluntary movements by the supplementary motor area

The hypothesis is formulated that in all voluntary movements the initial neuronal event is in the supplementary motor areas (SMA) of both cerebral hemispheres. Experimental support is provided by three lines of evidence. 1. In voluntary movements many neurones of the SMA are activated probably up to 200 ms before the pyramidal tract discharge. 2. Investigations of regional cerebral blood flow by the radioactive Xenon technique reveal that there is neuronal activity in the SMA of both sides during a continual series of voluntary movements, and that this even occurs when the movement is thought of, but not executed. 3. With voluntary movement there is initiation of a slow negative potential (the readiness potential, RP) at up to 0.8 s before the movement. The RP is maximum over the vertex, i.e. above the SMA, and is large there even in bilateral Parkinsonism when it is negligible over the motor cortex. An account is given of the SMA, particularly its connectivities to the basal ganglia and the cerebellum that are active in the preprogramming of a movement. The concept of motor programs is described and related to the action of the SMA. It is proposed that each mental intention acts on the SMA in a specific manner and that the SMA has an 'inventory' and the 'addresses' of stored subroutines of all learnt motor programs. Thus by its neuronal connectivities the SMA is able to bring about the desired movement. There is a discussion of the manner in which the mental act of intention calls forth neural actions in the SMA that eventually lead to the intended movement. Explanation is given on the basis of the dualist-interactionist hypothesis of mind-brain liaison. The challenge is to the physicalists to account for the observed phenomena in voluntary movement.     

Recruitment order of motor units in man: significance of pre-existing state of facilitation

It has been shown in previous investigations that the recruitment order of motor units is different in tonic and in phasic voluntary activity. The significance of the pre-existing state of facilitation in the motoneurone pool for the recruitment of units is studied, using the phasic flexion reflex in the anterior tibial muscle as test reflex. It is shown that the recruitment order of units in a series of reflexes (1) is unstable if the subject does not expect the stimulus; (2) is stable and identical with that in tonic activity if the subject subliminally facilitates the motoneurone pool before the reflex activation; (3) is stable and almost identical with that in tonic activity if the subject expects the stimulus and therefore involuntarily influences the motoneurone pool; (4) is stable and similar to that in phasic voluntary activity if the subject inhibits the motoneurone pool before the activation and the stimulus strength thus consequentially is increased; and (5) is influenced by blockade of the proprioceptive afferent impulses from the muscle. It is concluded that normal man can select in advance the recruitment order of motor units most appropriate for the work intended.     

Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis

Some people who repeatedly use stimulant drugs, such as amphetamine (AMPH), develop an AMPH-induced psychosis that is similar to paranoid schizophrenia. There has been, therefore, considerable interest in characterizing the effects of chronic stimulant drug treatment on brain and behavior in non-human animals, and in developing an animal model of AMPH psychosis. A review of this literature shows that in non-human animals chronic AMPH treatment can produce at least two different syndromes, and both of these have been proposed as animal models of AMPH psychosis. The first syndrome is called 'AMPH neurotoxicity', and is produced by maintaining elevated brain concentrations of AMPH for prolonged periods of time. AMPH neurotoxicity is characterized by what has been termed 'hallucinatory-like' behavior, which occurs in association with brain damage resulting in the depletion of striatal DA and other brain monoamines. The second syndrome is called 'behavioral sensitization', and is produced by the repeated intermittent administration of lower doses of AMPH. Behavioral sensitization is characterized by a progressive and enduring enhancement in many AMPH-induced behaviors, and is not accompanied by brain damage or monoamine depletion. It is argued that the changes in the brain and behavior associated with the phenomenon of behavioral sensitization provide a better 'model' of AMPH psychosis than those associated with AMPH neurotoxicity. Much of the review involves a critical analysis of hypotheses regarding the biological basis of behavioral sensitization. Research on this question has focused on mesotelencephalic DA systems, and suggestions that behavioral sensitization is accompanied by: an increase in postsynaptic DA receptors; an increase in DA synthesis; an increase in DA utilization and/or release; and a decrease in DA autoreceptors, are evaluated. It is concluded that there is not convincing evidence for an increase in postsynaptic DA receptors or in DA synthesis in animals sensitized to AMPH. In contrast, there is strong evidence to support the notion that behavioral sensitization is due to enhanced mesotelencephalic DA release, especially upon re-exposure to the drug. The evidence that this enhancement in DA release is due to autoreceptor subsensitivity was found to be equivocal, and therefore other hypotheses should be entertained. Lastly, evidence is discussed in support of the idea that behavioral sensitization is not unique to the psychopharmacology of stimulant drugs, but may be produced by many environmental stimuli that directly or indirectly activate brain catecholamine systems.(ABSTRACT TRUNCATED AT 400 WORDS)     

The influence of 5-methoxytryptophol,a pineal compound,on comb growth,ovarian weight,follicular growth and egg production of juvenile,maturing and adult white leghorn hens (Gallus domesticus L.)

Summary Administration of 5-methoxytryptophol (5-MTL) in juvenile, maturing and adult white leghorn hens causes age dependent effects. In juvenile birds ovarian growth is stimulated, while in maturing animals this is inhibited. In adult experimental hens ovarian weight is not significantly different from that of the control animals. Follicular weight, however, is not influenced in maturing white leghorn hens, while in adults it is significantly lower than in the control animals. It is suggested that 5-MTL stimulates FSH production in juvenile as well as in maturing and adult hens.     

Conduction in unmyelinated fibres in experimental neuropathy

Conduction velocity of autonomic unmyelinated fibres has been measured in the cervical sympathetic trunk of normal rats, and in rats intoxicated by acrylamide or by isoniazid. The mean maximal conduction velocity in nerves from normal rats is 2·0 m/sec. There is no significant reduction in velocity of the unmyelinated fibres in nerves from intoxicated rats, although histological studies of the sural nerve confirmed severe degeneration of myelinated fibres in the same animals. It is shown that the amplitude of the compound nerve action potential is proportional to the resistance between the recording electrodes. If this is taken into account, there is no reduction in the amplitude of the monophasic action potential of unmyelinated fibres recorded from the cervical sympathetic trunk of intoxicated rats. The amplitude of the A component of the sural nerve compound action potential is markedly reduced in rats intoxicated by acrylamide or by isoniazid, but there is no significant reduction in the amplitude of the C component in the same nerve. It is concluded that in the rat an insignificant number of unmyelinated fibres of autonomic or dorsal root origin are affected in the neuropathy produced by acrylamide or isoniazid. The relevance of these findings to human neuropathies is discussed.     

Persistent discrepancy in international diagnostic practice since 1970

National admission statistics by diagnosis since 1970, were available from seven WHO member countries. All had officially introduced the ICD 8, but only two countries strictly adhered to the ICD categories in practice. The new 3-digit category 298 (Other psychosis) has met with no success, nor did the new subgroups of schizophrenia with a favourable outcome (295.4, 295.5 and 295.7) gain much acceptance. The discrepancy in diagnostic distribution is virtually unchanged from that before 1970 with a persistent wide concept of schizophrenia in U.S.A. and of depressive illness in England. A new feature is the striking increase in non-psychotic admissions at a time when there is a marked decline in the hospital population. This is taken to indicate that the social stigma attached to the term psychosis persists, and is met with evasion. A preference for unspecified terms (fourth digit 9) is evident, as is the use of terms which leave open whether the patient is psychotic or not (311 in ICD 9). Evidently, instruction in the use of the WHO glossary is called for. In the U.S.A. the replacement of the ICD by the local classification DSM-III is likely to accelerate the reluctance to accept international standards. Moreover, the development of local diagnostic systems for research purposes in England and U.S.A. is not without problems, as there is a disturbing lack of consensus in diagnosis between these two national systems. Obviously, we need the ICD with its clear concepts, and above all the ICD is valuable for securing continuity in diagnostic classification.     

抑郁性神经症患者甲状腺功能初步研究

目的 研究抑郁性神经症甲状腺功能水平。方法 对２４例抑郁性神经症患者进行了甲状腺功能测定。结果 抑郁性神经症患者ＦＴ４水平明显高于对照组（Ｐ〈０．０１）。结论 烫崾疽钟粜陨窬⒂胍钟糁⒓鬃聪俟δ芩讲煌徊⑻崾荆疲裕此狡驼撸⒉∮找蛎魅，治疗效果好。     

Oxidative stress in amyotrophic lateral sclerosis

The pathogenesis of amyotrophic lateral sclerosis is poorly understood. In one or two percentage of patients, mutations in the SOD1 gene are known to underly the disease. Even in these cases, the mechanism of cell death remains unclear. Most researchers agree that damage by reactive oxygen species is involved in this process, but whether the latter plays a primary role or is an epiphenomenon is uncertain. As evidence for oxidative stress is not only found in mutant SOD1-related familial amyotrophic lateral sclerosis, but also in sporadic amyotrophic lateral sclerosis, it is tempting to speculate that a similar mechanism is at work in both forms of the disease.     

Diagnostic aspects of anxiety disorders]

A concise review is presented of epidemiological, family- and genetic studies in anxiety disorders. Special emphasis is given to recent developments in the classification of anxiety disorders. The literature in which a more central role of panic attacks is suggested, is critically reviewed. Based upon the studies reviewed it is questionable whether the diagnosis agoraphobia without panic attacks is justified.     

Scoliosis

Scoliosis is a structural lateral curvature of the spine with a rotatory component. Imaging in scoliosis is important. Most cases of scoliosis are idiopathic, and imaging is used routinely in monitoring the changes of the deformity that take place during growth. Imaging is also crucial in determining the underlying etiology in non-idiopathic cases of scoliosis and is used in pre- and postoperative monitoring.     

Studies in man of phenytoin absorption and its implications.

The absorption of phenytoin was studied in man. It is concluded that phenytoin absorbed from the intestine is recirculated via the bile, so that blood levels do not accurately reflect absorption. Phenytoin is loosely bound to serum proteins and is found in red cells in concentrations similar to those in plasma. It is rapidly lost from the blood stream after intravenous administration, which is an important factor to be considered in the treatment of status epilepticus.     

The ictal bradycardia syndrome

The ictal bradycardia syndrome is an uncommon diagnosis in which bradycardia is accompanied by simultaneous epileptic discharges in the EEG. We describe a patient who was referred to the emergency ward because of syncope. Ictal semeiology and EEG-EG findings are discussed and compared with those published in the literature. Therapeutic options are discussed in relation with those published in the literature. The ictal bradycardia syndrome is probably underdiagnosed, while its recognition is of utmost importance because of potential life threatening complications such as asystole. Up to now, its aetiology is poorly understood, its ictal semeiology is often described insufficiently and its therapy is still discussed.     

Phenylethylaminergic modulation of catecholaminergic neurotransmission.

1. PE is present in the brain in tiny quantities; it is heterogeneously distributed and present in synaptosomes. 2. It is synthesised from phenylalanine by L-AADC and oxidatively deaminated by MAO-B. Its turnover is remarkably fast. 3. Its concentration, particularly in the caudate nucleus, is affected by MAO inhibition (increased), lesion of the Substantia nigra (decreased), amine depletion (increased) and antipsychotic drugs (increased). 4. When iontophoresed (or injected) it amplifies the effects of DA and NA (and their agonists) but is without effect on other neurotransmitters. 5. It is suggested that it acts postsynaptically as a neuromodulator of catecholaminergic neurotransmission and that it is involved in the mechanism of action of Deprenyl; it is also suggested that it, or its principal metabolite PAA, may be involved in the aetiology of schizophrenia, depression and aggression as well as perhaps in other neuropsychiatric conditions.     

Hepatolenticular degeneration

Hepatolenticular degeneration (Wilson's disease) is a hereditary disease in which metabolic disorder of copper leads to its accumulation in the liver, brain, cornea and kidneys with consequent pathologic changes in those organs. Hereditary mechanism of the disease is autosomal recessive with prevalence of 30-100 per 1,000,000 inhabitants. Etiology of this disease is not yet explained. There are two hypotheses. The first one is that it is the disorder of ceruloplasmine metabolism caused by insufficient synthesis of normal ceruloplasmine, or synthesis of functionally abnormal ceruloplasmine. The second one is: the block of copper biliar excretion which is the consequence of the liver lysosomes functional defect. Pathogenetic mechanism of disease is firstly long-term accumulation of copper in the liver, and later, when the liver depo is full, its releasing in circulation and accumulation in the brain, cornea, kidneys and bones, which causes adequate pathologic changes. Toxic activity of copper is the consequence of its activity on enzymes, particularly on those with -SH group. There are two basic clinical forms of the disease: liver disease or neurologic disease. Before puberty the liver damage is more frequent, while in adolescents and young adults neurologic form of the disease is usual. The liver disease is nonspecific and characterized by symptoms of cirrhosis and chronic aggressive hepatitis. The only specificity is hemolytic anemia which, in combination with previous symptoms, is important for diagnosis of the disease. Neurologic symptoms are the most frequent consequence of pathologic changes in the basal ganglia. In our patients the most frequent symptoms were tremor (63%); dysarthria, choreoathetosis and rigor (38%); ataxia and mental disorders (31%); dysphagia and dystonia (12%), diplopia, hypersalivation, nystagmus and Babinski's sign (6%). Among pathologic changes in other tissues and organs the most important is the finding of Kayser-Fleischer ring in the cornea as a result of copper accumulation. Its importance for precise diagnosis is great. The diagnosis of the disease is based on anamnesis, clinical examination, specific and nonspecific laboratory tests. The therapy of choice is penicillamine. If we use it early, the result will be good remission in the majority of patients. Late diagnosis or delay in treatment cause death which is the result of bleeding from esophageal varices or basal ganglia disease. Immunologic damages caused by penicillamine demand interruption of therapy and substitution by three-ethyl-tetra-amine (TETA). We also use zinc salts and tetratiomolibdate in therapy of this disease. Pathogenesis, clinical picture and therapy of the disease are based on our own results.