GENETIC POLYMORPHISM OF LIVER ALCOHOL DEHYDROGENASE IN SPANTSH SUBJECTS: SIGNIFICANCE OF ALCOHOL CONSUMPTION AND LIVER DISEASE

Class I alcohol dehydrogenase (ADH) phenotypes have been studiedby starch gel electrophoresis and activity analysis in livertissue obtained at necropsy from 61 non-alcoholic subjects withnormal liver (controls), and in biopsies from 60 chronic alcoholicswith liver disease and from 24 subjects with non-alcoholic liverdisease. Twenty-three per cent of controls exhibited the ADH₂^2–1phenotype, which represents the highest frequency for atypicalADH found in a Caucasian population. Both alcoholic and non-alcoholicpatients with liver disease showed a lower frequency of theatypical phenotype (6.6% and 8.8%, respectively). No differencesin the ADH₂ locus were detected among groups of patients withdifferent severity of alcoholic and non-alcoholic liver disease.Theallele frequencies of the ADH₃ locus for the controls (ADH₃¹= 0.63, ADH₃² = 0.37) are common to those of other Caucasianpopulations. Similar ADH₃ allele frequencies were observed inpatients with alcoholic and non-alcoholic liver disease. Discrepanciesbetween the various phenotyping and genotyping studies now knownfor several populations suggest that local differences may existin the distribution of the ADH polymorphism in even geographicallyclose regions, and that the effect of ADH polymorphism on vulnerabilitytowards alcohol may not be identical in different populations.     

Community initiatives against AIDS in Barcelona

This paper examines community organizations involved in thefight against AIDS and against unjustified fear of AIDS in theCity of Barcelona, Spain. The political and social context forcommunity organizations is reviewed, and the different registeredorganizations that have been involved in community initiativesagainst AIDS are presented, together with their actual role.Public support for community organizations related to AIDS andtheir relationship with the public administrations are studied.Current trends and future prospects are analyzed.     

CYCLIN D1 AND RETINOBLASTOMA GENE EXPRESSION IN HUMAN BREAST CARCINOMA: CORRELATION WITH TUMOUR PROLIFERATION AND OESTROGEN RECEPTOR STATUS

Cyclin D1 (CCND1) and retinoblastoma (Rb) genes are cell cycle regulators which are altered in some breast carcinomas. However, the possible cooperation between CCND1 and Rb, as well as the influence and coincidence of their abnormalities in the proliferative capacity of mammary carcinoma cells in vivo, is still unknown. In order to assess both the significance of the CCND1 gene and Rb alterations in breast carcinomas and their relationship with the proliferative capacity of the tumours and other clinico-pathological factors, CCND1 mRNA expression was studied in 46 cases of primary breast carcinomas and matched normal tissue, 45 of which were also studied immunohistochemically. Rb expression was analysed in the same cases by immunohistochemistry, whereas the proliferative activity of the carcinomas was evaluated by flow cytometry. CCND1 mRNA was overexpressed in 19 tumours (41 per cent). Sixteen cases showed diffuse immunohistochemical expression, ten carcinomas had few positive cells, and 19 were absolutely negative. CCND1 mRNA and protein overexpression was associated with oestrogen receptor (ER) expression by the tumour. Interestingly, lack of ER expression was associated with a decreased CCND1 mRNA signal in non-overexpressed tumours. No association was observed between CCND1 mRNA or protein overexpression and tumour proliferation or other clinico-pathological parameters. Loss of Rb expression was observed in 26 per cent of the tumours. This abnormality was significantly associated with increased mean S-phase (P=0·017) and decreased CCND1 mRNA expression in non-overexpressed tumours, supporting in vivo the postulated regulatory loop between Rb and CCND1 in vitro. We conclude that CCND1 up-regulation is not associated with increased proliferative activity in breast carcinomas, whereas its expression might be regulated in vivo by hormones and Rb. Loss of Rb expression is significantly associated with an increased proliferation of tumour cells, suggesting an important role in the progression of a subset of breast carcinomas, regardless of CCND1 abnormalities. © 1997 John Wiley & Sons, Ltd.     

Renin, aldosterone and renal haemodynamics in cirrhosis with ascites

The interrelationships between the renin-angiotensin-aldosterone system, renal haemodynamics and urinary sodium excretion were investigated in fifty-six non-azotaemic cirrhotics with ascites. In twelve additional patients the renal renin secretion rate was also studied. Plasma renin activity and concentration and plasma aldosterone ranged from normal to very high values. There was a significant inverse relationship between plasma aldosterone and the urinary sodium excretion. Plasma aldosterone showed a highly significant direct correlation with plasma renin activity, and plasma renin concentration was closely and directly related to the estimated renin secretion rate. Neither plasma renin activity, plasma renin concnetration nor the estimated renin secretion rate correlated with the renal plasma flow or the glomerular filtration rate. These results suggest that in non-azotaemic cirrhosis with ascites the renin-angiotensin-aldosterone system is an important factor influencing sodium excretion, increased plasma renin and aldosterone concentrations are mainly due to an increased secretion rate, and total renal perfusion is not a major factor influencing renin secretion.     

VAGAL NEUROPATHY IN CHRONIC ALCOHOLICS: RELATION TO ETHANOL CONSUMPTION

Vagal neuropathy in chronic alcoholics seems more common thansupposed and its reversibility and relationship with alcoholintake and nutritional status remain obscure. We embarked upona study of a series of 70 chronic alcoholics in whom reliablealcoholism history, nutritional status evaluation and cardiovascularreflex tests were performed at the beginning of abstinence.Moreover, an electrophysiological study of peripheral nerveswas carried Out. Five out of 70 patients had symptoms relatedto autonomic neuropathy. Fourteen alcoholics presented abnormalindices in the deep breathing test (DBT) performed, includingthe five patients with clinical manifestations. A strong correlationbetween DBT indices and total lifetime ethanol intake and motorconduction velocity of lower limbs (MCV) was observed. No grossevidence of malnutrition was detected in the alcoholics andthe transketolase erythrocyte activity was normal in all butone. Since the MCV also correlated with total lifetime ethanolintake, it appears that ethanol may exercise a dose-relatedtoxic effect on both the autonomic and peripheral nervous systems. Finally, 12 of 14 patients with abnormal DBT index were re-evaluatedone year later. Eleven who reported complete ethanol abstinencepresented an improvement of this index and nine of them reachedthe normal range. Three of four patients with clinical manifestationsreported an improvement of the symptoms. Thus, vagal neuropathymay reverse in most of the patients who manage to maintain ethanolabstinence.     

Association-dissociation of histone oligomers

The spin label method has been used to obtain information about conformational changes of histone oligomers taking advantage of the fact that at a low ionic strength and in the presence of other histones about 45% of cysteine residues of histone H3 react with the 3-maleimido-2,2,5,5-tetramethyl-l-pyrrolidinyloxyl spin label. For the labeled complexes H3-H4 and Hn? the degree of immobilization of the spin label is a function of the ionic strength. This variation is identical for both complexes within a long range of ionic strengths, including the interval of 0.8-2 M NaCI, under which conditions interactions are known to exist between the tetramer (H3)₂ (H4)₂ and the dimer (H2A) (H2B). This finding suggests a negligible influence of the dimer for modifying the cysteine residue environment of histone H3 on octamer formation. GuHCI treatment at high ionic strength of the labeled complexes gives rise to a non-lineal increase in the degree of mobility of the spin label. This increase, at low GuHCI concentration (0-0.5 M GuHCI), is interpreted as showing a lowering in rigidity for the Cys residue environment, without affecting the general stability of the tetramer (H3)₂ (H4)₂. At higher GuHCI concentration (2–3 M GuHCI) the increase in the spin label mobility is related to a dissociation of the complexes in single histones. Our results are consistent with the view that the overall structure of the tetramer, as well as its conformational changes during complex structuration or denaturation, are not strongly affected by the presence of the dimer (H2A) (H2B).     

Protein secondary structure

A secondary structure prediction technique is proposed which includes nucleation site determination through multiplication of conformational preference parameters as well as weighting factors to represent structurally stabilizing short range interactions. The prediction accuracy of the method is calculated using data bases categorized according to the four protein structural classes and with differing assignments of secondary structural regions. The results indicate that nearest neighbor prediction techniques (a) are insensitive to various assignment criteria for the secondary structural spans, (b) have nearly achieved their upper limit of prediction accuracy, and (c) can be somewhat improved through the use of stereochemical weighting factors and conformational parameters derived from the four structural groups.     

Thyroid peroxidase autoantibody epitopic ‘fingerprints’ in juvenile Hashimoto's thyroiditis: evidence for conservation over time and in families

In Hashimoto's thyroiditis, the humoral component is manifest by autoantibodies to thyroid peroxidase (TPO). Epitopic ‘fingerprinting’ of polyclonal serum TPO autoantibodies has been facilitated by the molecular cloning and expression as Fab of a repertoire of human TPO autoantibody genes. To investigate whether TPO autoantibody fingerprints are (i) stable over long periods of time (~15 years), and (ii) inherited, we studied a cohort of nine patients with juvenile Hashimoto’s thyroiditis and 21 first degree relatives of four of these patients. Fingerprints were determined by competition between four selected Fab and serum autoantibodies for binding to ¹²⁵I-TPO. Regardless of titre, the TPO epitopic profile was stable in 10/12 individuals whose TPO autoantibody levels were sufficient for analysis on two or three occasions over 12–15 years. Although the TPO epitopic fingerprint profiles in two families raised the possibility of inheritance, overall the data from all four families did not reveal an obvious pattern of genetic control. In no family was the TPO epitopic fingerprint associated with HLA A, B or DR. In conclusion, TPO autoantibody epitopic fingerprints are frequently conserved over many years. Studies on additional families are necessary to establish whether or not the epitopic profiles of TPO autoantibodies are inherited.