FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia.

In an Italian population of 275 unrelated men affected by adult-onset sporadic progressive cerebellar ataxia, the authors found six patients carrying an FMR1 gene premutation. Age at onset (range, 53 to 69 years) and clinical-neuropathologic findings were consistent with the fragile-X tremor ataxia syndrome (FXTAS), although tremor was not as common as previously described. FXTAS accounted for 4.2% of the cases diagnosed at >50 years, suggesting that it is a frequent genetic cause of late-onset sporadic ataxia.

Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes.

There is evidence of oxidative injury in postmortem brain, spinal cord, and CSF of patients with sporadic amyotrophic lateral sclerosis (SALS patients). We investigated the oxidative metabolism and calcium homeostasis in peripheral blood lymphocytes from such patients and did not find statistical differences in the basal oxygen consumption rate (QO2), cytochrome c oxidase activity, catalase activity, and lactate production. However the increase in QO2, induced by an uncoupler of oxidative phosphorylation, was depressed and the basal (resting) level of free cytosolic calcium ([Ca2+]in) was higher in lymphocytes from SALS patients (p < 0.01). Further increase in free [Ca2+]in challenged by a K+ channel blocker or by an uncoupler of oxidative phosphorylation was similar in SALS and control lymphocytes. The results show that systemic changes consistent with the presence of mitochondrial and of calcium metabolism dysfunction are present in SALS.

Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat.

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg) using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5) than when administered only once, suggesting that rat cardiotoxicity is related Cmax rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with i.v. F-ddA administration when the F-ddA plasma concentration approaches 300 microM, 30-50 times the anticipated therapeutic level in humans.

Effects of pyridostigmine, corticotropin-releasing hormone and growth hormone-releasing hormone on the pituitary-adrenal axis and on growth hormone secretion in dementia.

Alterations of neuroendocrinological indices determined by the impaired regulating effects of cholinergic neurotransmission have been described in primary dementia. In this study we have evaluated the effects of acetylcholinesterase inhibition by pyridostigmine on growth hormone (GH), adrenocorticotropic hormone (ACTH) and cortisol secretion and on their responses to GH-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) in 7 patients with primary degenerative dementia and in 8 sex- and age-matched controls. Demented subjects showed higher cortisol basal levels and lower ACTH levels than controls. Pyridostigmine increased the GH response to GHRH in both groups, the effect being significantly enhanced in patients. An increase of ACTH and cortisol levels was found in both groups after pyridostigmine and CRH administration. Pyridostigmine pretreatment significantly increased the ACTH response to CRH in controls but not in patients. The obtained data may indicate that a muscarinic receptor upregulation and an impairment of somatostatinergic function are operative in the regulation of GH secretion in dementia. An underlying hyperactivity of the hypothalamic-pituitary-adrenal axis impairs the responses of ACTH and cortisol to CRH in this disorder.

Glutamate and GABA levels in CSF from patients affected by dementia and olivo-ponto-cerebellar atrophy.

The modifications in the CSF content of glutamate and GABA in patients afflicted with primary degenerative dementia (PDD) and olivo-ponto-cerebellar atrophy (OPCA) have been evaluated. Control subjects (with disk herniation) were also included in the study. The amino-acids assays were carried out utilizing enzymatic-bioluminescence technique. GABA levels in controls were 803 +/- 98 (n = 7) and in demented patients 702 +/- 98 (n = 7) pmol/ml. Glutamate levels were 2067 +/- 244 (n = 10) in controls, 1190 +/- 81 (n = 16) pmol/ml (vs controls p less than 0.01) in demented patients, and 1116 +/- 146 (vs controls p less than 0.01) in OPCA patients. These results suggest that CSF glutamate levels in severely demented patients might be a result of generalized neuronal loss in the brain with a reactive gliosis.

Effects of calcium antagonists on glycolysis of rat brain synaptosomes.

The effects of calcium antagonists nimodipine, nicardipine and flunarizine on lactate production and specific activities of some enzymes regulating glycolytic flux have been evaluated in synaptosomes isolated from rat whole brain and submitted to in vitro chemical hypoxia induced by rotenone, an inhibitor of mitochondrial respiration. The following enzymes have been tested; hexokinase (ATP: D-hexose-6-phosphotransferase, EC2.7.1.1), phosphofructokinase (ATP: D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) and pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40). The results show that rotenone increases by about eight times the production of lactate; nicardipine and nimodipine, starting from a concentration of 10(-4) M, were able to counteract the rotenone-induced stimulation of glycolysis, but flunarizine was without effect. The dihydropyridines but not flunarizine decreased the maximum activity of phosphofructokinase. This effect was already detectable at a concentration of 10(-5) M. Neither hexokinase nor pyruvate kinase were affected by any of the drugs studied.

[Cardiac involvement in juvenile rheumatoid arthritis]. / L'interessamento cardiaco in corso di artrite reumatoide infantile.

Four cases with cardiac involvement in patients suffering from systemic outset of juvenile rheumatoid arthritis are reported. The cases were chosen out of 83 juvenile rheumatoid arthritis patients studied from 1975 to 1988. They developed respectively myopericarditis (case 1), myocarditis (case 2), endopericarditis (case 3), myopericarditis (case 4). The drug employed in the acute disease phase was exclusively prednisone; in all subjects the acute inflammatory stage resolved.

Cholinergic modulation of growth hormone-releasing hormone effects on growth hormone secretion in dementia.

An impairment of cholinergic and somatostatinergic neurotransmission have been reported in dementia. Both acetylcholine and somatostatin are involved in the regulation of growth hormone (GH) secretion. The effects of GH-releasing hormone (GHRH) 1-44 on GH release have been studied before and after the pretreatment with pyridostigmine or pirenzepine in subjects with senile dementia of the Alzheimer type, multi-infarct dementia and mixed dementia. The data have been compared with those obtained in an age-matched healthy control group. The GH response to GHRH is similar in the patients and in the controls, though the peak occurrence is significantly delayed in dementia. The cholinesterase inhibitor pyridostigmine enhances significantly the GH response to GHRH in both groups. The responses obtained in demented subjects are significantly larger than those found in the controls. Pirenzepine, a muscarinic receptor blocker, inhibits the GHRH effect on GH secretion in both groups. The findings may be interpreted in terms of an underlying impairment of the hypothalamic cholinergic neurotransmission, with an acetylcholine receptor supersensitivity that becomes apparent when the cholinergic tonus is enhanced by the inhibition of cholinesterase by pyridostigmine. No significant differences, due to the type of dementia, have been observed.

[Depression and home environment]. / Depressione e ambiente domestico.

The Authors consider the higher frequency of depressive disorders in women and examine the correlations between psychopathological expressions of depression and women's social and cultural roles. The condition of life at home, that is peculiar to housewife, sometimes can be a psychopathological risk factor or psychosocial stressor, as well as other work conditions (whether the woman is employed or not), that have to be examined in relation to each person, according to the individual's biological, psychosocial and cultural features.

Thyrotropin and prolactin responses to different doses of thyrotropin-releasing hormone in depression.

The effects of low doses of thyrotropin-releasing hormone (TRH, 50 and 200 micrograms) on thyrotropin (TSH) and prolactin levels have been studied in depressed women and compared with the depressive condition and with the results of the dexamethasone suppression test (DST). TRH administration elicited blunted hormonal responses that were not correlated either with the age of the patients or with DST results. Different effects were observed in subgroups of depressive patients classified according to DSM III and ICD. No correlation was found between hormone responses and the scores of Hamilton Rating Scale and Montgomery Depression Scale. The effects of 50 micrograms on TSH were significant and inversely correlated with Anxiety Rating Scale scores. No dose-response effect was apparent of prolactin and TSH in depressed patients, suggesting an impaired function of pituitary TRH receptors.

Chemiluminescent determination of choline in cerebrospinal fluid and red blood cells.

The concentration of choline in the cerebrospinal fluid (CSF) of patients affected by primary dementia and in red blood cells (RBC) of depressed patients before and after treatment with lithium salts was determined using a chemiluminescent assay. The mean CSF concentration of choline was found to be 60 pmoles/ml (SD = 20 pmoles/ml) and this was lower than values obtained previously by spectrophotometric-colorimetric methods. Mean RBC choline concentrations before and after therapy with lithium salts were 20 nmoles/ml (SD = 16 nmoles/ml and 328 nmoles/ml (SD = 206 nmoles/l) respectively and these are similar to those reported previously (obtained by chemiluminescent and non-chemiluminescent methods).

Amitriptyline action on sympathetic neuronal function in depressed women.

1. Noradrenaline plasma levels and cardiovascular function modifications with orthostatic challenge during therapy were studied in 59 female depressed inpatients treated with 100 mg amitriptyline daily by intramuscular route for 4 weeks. 2. Therapy induced an increase in pulse rate in supine and upright positions, a decrease of noradrenaline levels and modified standing systolic and (partially) diastolic blood pressure, particularly in elderly subjects. 3. No correlation between neurotransmitter or functional changes and drug plasma levels was noted. 4. The supposed lower noradrenergic output together with blood pressure drop in both positions suggests a reduced sympathetic tone.

Viloxazine in depressed women: clinical response and cardiovascular effects.

The antidepressant effect of viloxazine (300 and 500 mg/day) was investigated for 4 weeks in 26 depressed women. The decrease in the Hamilton Depression Rating Scale score indicated a prompt overall clinical improvement, the depressed mood and suicide items showing the highest percent diminution. The highest plasma level of viloxazine was reached at day 7 and decreased during treatment only with the 500 mg dosage. Blood pressure and pulse rate responses to orthostatic stress were slightly affected and showed few untoward cardiovascular reactions to drug treatment. The decrease of noradrenaline plasma levels in both postural positions might indicate a lower sympathetic nervous system tone.

[Female alcoholism and household conditions]. / Alcolismo femminile e condizione casalinga.

Alcoholism in women, above all in housekeepers, tends to destroy both families and society. This kind of alcoholism is frequently based on neurosis and depression. Alcoholism in women is supposed to be caused by: genetic factors, psychological factors and social factors. Therefore these components are linked both to neuroendocrinology of female and the way of life of housekeepers.

Dissociation between CSF and plasma B-endorphin in major depressive disorders: evidence for a different regulation.

Plasma and cerebrospinal fluid (CSF) levels of ACTH, B-lipotropin (B-LPH) and B-endorphin (B-EP) were simultaneously measured in 10 patients with major depression (35-57 yr) with a disease history of 10-34 yr, 7 of them with recurrent episodes, and in 13 age-matched healthy controls. In patients, lumbar puncture was performed after a 10 days drug-free period. Plasma B-EP and B-LPH levels were measured by RIA after silicic acid plasma extraction and Sephadex G-75 column chromatography. Plasma ACTH concentrations were measured by IRMA. For CSF assays the extraction step was avoided. In depressed patients, plasma ACTH (16.2 +/- 6.9 fmol/ml, mean +/- SD), B-LPH (19.8 +/- 8.5) and B-EP (17.8 +/- 7.0) levels were significantly higher (p less than 0.01) than in controls. On the contrary, CSF levels of the three peptides were similar in the two groups. No correlations were found between plasma or CSF concentrations and duration of the disease or severity of the actual episode. These data add further evidence to the independent regulation between central and peripheral POMC-related peptides. They also reduce the possibility that peptides of pituitary origin, directly from the gland or through the peripheral circulation, could penetrate the CSF.

Motor and psychomotor functions in amyotrophic lateral sclerosis evaluated by tests of motor ability.

18 patients with typical sporadic Amyotrophic Lateral Sclerosis (ALS) were investigated by the Motor Accuracy and Speed Test (MAST) and 18 healthy age- and-sex-matched volunteers, acted as controls. All performed each of the five tests 10 times with both the right and the left hands and repeated the experiment after one week by the same procedure. Motor performances were better in the controls than in the ALS patients only in the first three tasks. At retest, one week later, the controls generally improved while ALS patients did not. The mean percentages of changes showed a statistically significant difference in the fifth task. Analysis of the results suggests the possibility that, among the other mechanisms, a disturbance of motor learning ability could be operating in ALS patients.