Biomedical subjects
Publications and source records attributed to G K Shaw.
When managing alcohol withdrawal the aim is to prevent the development of serious complications, such as fitting and delirium tremens. In alcoholics who are heavily chemically dependent, the rational use of sedative-type drugs is generally necessary. Chlormethiazole is effective in preventing the development of serious complications. It is a safe drug and has the additional advantage of a short half-life.
Human red blood cell transketolase has been resolved into two components by gel filtration. One component has its thiamine diphosphate coenzyme firmly bound whilst the other variant of the enzyme is a smaller molecule which is inactive without added thiamine diphosphate, for which it has a reduced affinity. It is concluded that the failure to detect an increase in activation in the commonly used clinical test of red cell transketolase activation by raising the thiamine diphosphate concentration above about 0.3 mmol/l is likely to be due to masking of the effect of activation of the low affinity variant in haemolysates from normal red blood cells by the inhibitory effect of excess thiamine diphosphate upon the activity of the high affinity form of the enzyme with which it is mixed. Increased activation by higher thiamine diphosphate concentrations is sometimes seen in haemolysates from the blood of chronic alcoholics, as well as in the low molecular weight fraction separated from normal haemolysates. It is considered likely that there are at least two variants of the enzyme and that the low molecular weight variant represents a damaged form of the enzyme normally present in small amounts but formed in larger proportions in vivo in abnormal conditions like chronic alcoholism and thiamine deficiency as well as by enzyme breakdown in vitro. In the light of these conclusions some recently proposed hypotheses regarding the role of transketolase in the genesis of brain damage in thiamine deficiency are reconsidered and a modified mechanism is proposed consistent with these and other recent findings.
A minority of alcoholics will show obvious evidence of dementia but the majority will appear clinically intact. Despite the fact that almost 50% of those 'intact' alcoholics will be found to have structural brain damage, on routine tests of intelligence they will fall in the normal range. More detailed psychometric testing will however reveal deficits in non-verbal abstracting ability, tactile performance and psychomotor speed with a perceptual component. Neither consumption variables nor the extent of structural brain damage are closely related to the degree of impairment. Age and premorbid intelligence are however so related. Much of the impairment is recoverable with time but visuo-spatial abilities and abstract problem solving may remain impaired for a year or two and some aspects of long-term memorising may be permanently impaired. In general, older alcoholics show less capacity for recovery. The possibility that brain damage and cognitive impairment may antedate the alcoholism is considered as is the possibility that alcohol may be particularly damaging to the ageing brain. The relevance of pathophysiological disturbances and nutritional deficiency is also considered. Evidence is now accumulating that cognitive defect is an important predictor of outcome following treatment. In the management of states of impairment attention should be paid to remedying nutritional deficiencies and the general principles of rehabilitation should be borne in mind.
Plasma cortisol levels were estimated by the competitive protein binding (CPB) method with radioactive selenium-75 in 32 male chronic alcoholics with depression. The degree of depression was rated by the Hamilton Depression Rating Scale (HDRS). Duration of drinking ranged from 5-25 years with an average daily amount of ethanol intake of 100-150 g (equivalent to half a bottle of spirits). Plasma cortisol levels were often raised in drinking chronic alcoholics and there was a strongly positive and statistically highly significant correlation between them and depression ratings (r = +0.56; P = 0.001). It is possible that the diurnal rhythm of cortisol secretion is disturbed or adreno-cortical activity is stimulated in these patients due to chronic ethanol ingestion. It is further suggested that brain serotonin deficiency known to occur in chronic alcoholics might lead to raised plasma cortisol levels in ethanol-induced depression.
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A prospective randomized double-blind trial of (+)-cyanidanol-3 at a dose of 2 g daily (500 mg qds) for six months versus placebo has failed to demonstrate statistically significant clinical, biochemical or histological benefit in patients with biopsy-proven alcoholic liver disease although certain trends were identified. The group receiving the active drug tended to drink more both before and during the trial and had mean serum aspartate aminotransferase (AsT) and gamma-glutamyltranspeptidase (gamma-GT) levels which were higher on admission to the trial. After the fourth week of treatment, the mean serum levels of these enzymes remained consistently lower in the group receiving the active drug. In order to reproduce the beneficial effects of the drug observed in the rat, it is suggested that further trials be conducted with the dosage so far used in man (ca. 20-40 mg/kg daily) increased toward that successfully employed in animal experiments (200 mg/kg daily).
A modified procedure for the preparation of transketolase from erythrocytes by dialysis and column ion-exchange resin chromatography is described. Changes have been made in the resin used, the column dimensions and the elution procedure so as to separate the enzyme with improved resolution, prepare the apoenzyme free of thiamine pyrophosphate and study the kinetics of its activation or reactivation by the coenzyme. On the basis of the elution profile of the enzyme activity from the chromatographic column, two different samples of the transketolase have been isolated, which differ not only in their isoelectric properties, but also in the proportion of the transketolase present in the apoenzyme form. Not only do the apoenzymes isolated from each of the two fractions differ in the way in which they recombine with thiamine pyrophosphate but kinetic analysis of the results shows that each fraction contains at least two variants of transketolase differing in their affinity for thiamine pyrophosphate. Three, probably four, separate variants have been identified which differ in their affinities for thiamine pyrophosphate over a range greater than 10(4). It is concluded that these two fractions of the enzyme must contain different subsets of the eight isoenzymes of transketolase of differing isoelectric points and that some of these isoenzymes must differ also in their affinity for the coenzyme. The implications of these findings for the Blass and Gibson hypothesis about the pathogenesis of the Wernicke-Korsakoff syndrome are considered.
Results are presented of the performance by 103 alcoholics and 90 controls on six computer-administered tests of cognitive function. The main analysis compared performance of the two groups when pre-existing differences in intellectual capacity, as estimated by NART, were accounted for statistically. The performance of the alcoholics was worse, at a statistically significant level, on 18 of 23 measures. Procedurally, the tests were found to offer practical advantages over conventional procedures.
A six-months out-patient study of chronic alcoholics with undecompensated liver disease has shown a statistically significant inverse correlation between the change in mean corpuscular volume and the change in body weight (r = -0.4, P less than 0.01). A fall in body weight over this period was the best clinical indicator of apparently continuing alcohol abuse. Previous anthropometric studies have indicated that reduced adipose tissue is one cause of lower body weights in such patients. To determine whether this is due to the effects of alcohol or of poor nutrition, the epididymal fat pad weights of rats following 28 days administration of alcohol (36% of total calories) as part of a nutritionally adequate liquid diet were compared with those of pair-fed controls initially matched for body weight. At the end of the experiment, body weight gain was the same in both groups but the mean weight of the fat pads of alcohol-fed animals (371.7 mg +/- 60.0 mg SD) all of which developed hepatic steatosis was 29% greater than that of pair-fed controls (288.7 mg +/- 42.4 mg). This difference was statistically significant (P less than 0.025). This study shows that alcohol intake per se does not prevent an increase in body weight or fat even if hepatic steatosis is induced and that loss of adipose tissue in chronic alcoholics who continue to drink is probably due to simultaneous inadequate nutritional intake.
Changes or imbalances in plasma amino acid patterns during withdrawal from ethanol were recorded in six randomly selected male chronic alcoholic patients (age range 23-47 years). Duration of drinking ranged from 4-15 years and their average daily amount of ethanol intake was more than 100G. Plasma amino acids (taurine, threonine, serine, glutamate, glutamine, proline, glycine, alanine, cysteine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, histidine, tryptophan, ornithine, lysine and arginine) were estimated by autoanalyzer in all patients on admission before starting conventional detoxification therapy for ethanol withdrawal syndrome, and during therapy on day 3 and day 6. On admission, there was a statistically significant rise in the plasma levels of almost all aminoacids, particularly glutamate, glutamine, phenylalanine, proline, glycine, methionine, cysteine, lysine, tyrosine, valine, isoleucine, leucine, serine, threonine, alanine and arginine (in comparison to those of normal controls) in five out of six patients. During the following six days of treatment and total abstinence, the pattern of plasma aminoacid levels did not change significantly despite considerable clinical improvement. Plasma tryptophan levels were undetectable in all patients on admission, day 3 and also on day 6 except in one patient with lesser amount and shorter duration of drinking, the levels just returned to within normal range only on day 6. Plasma levels of histidine and taurine were found to be slightly lower than normal.
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Plasma vitamin E (alpha-tocopherol) concentrations were estimated by high performance liquid chromatography (HPLC) in 50 consecutively admitted chronic alcoholics (M = 44;F = 6;mean age +/- S.D. = 42.94 +/- 10.97;age range = 28-70 years) on admission and in 25 of them it was repeated during abstinence (6th day) while undergoing conventional detoxification therapy with polyvitamins (except vitamin E) and hypno-sedative drugs. Thirty percent of the patients were found to be deficient on admission and while on routine hospital diet during therapy, 20% of the patients were still deficient. It is, therefore, suggested that chronic alcoholics should be treated routinely with vitamin E along with other polyvitamins during detoxification in alcoholic units.
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The utilization status of vitamin A (retinol) (treated with oral retinol - 2500 I.U. daily (=250 micrograms) x 5 days - "OROVITE -7", Bencard, England) in 25 patients (M = 23, F = 2; mean age +/- S.D. = 43.88 +/- 12.67; range = 28-70 years), 3 out of 25 patients (12%) were found to be deficient in the vitamin and during treatment further improvement of the blood levels of the vitamin was observed in all except one elderly male patient (age 61 years) and the mean levels on admission (661.04 micrograms/l) was also slightly improved after treatment (662.84 micrograms/l). Night blindness, alcoholic liver disease and hypogonadism are commonly seen in chronic alcoholic patients. Falling plasma levels of the vitamin indicate exhaustion of its hepatic storage. It is therefore suggested that chronic alcoholics should be given vitamin A supplementation along with other polyvitamins during conventional detoxification therapy for ethanol withdrawal syndrome in order to prevent dangerous manifestations of hypovitaminosis A, such as night blindness, cancer, hypogonadism and alcoholic liver disease.
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Plasma urea and creatinine concentrations were estimated by Auto-Analyzer in 128 chronic alcoholics (103 males, 25 females; mean age +/- SD = 42.73 +/- 6.53; age range 20-60 years). Plasma levels of both urea (mean +/- SD = 3.46 +/- 1.31; normal range 2.0-6.5 mmol/l) and creatinine (mean +/- SD = 87.86 +/- 15.45; normal range 60-120 mumol/l) were found to be within normal limits. It is concluded from our observations that chronic ethanol ingestion per se is not nephrotoxic. The kidney seems to be the only vital organ generally spared in chronic alcoholics without advanced alcoholic liver disease or hepato-renal syndrome.