The Alzheimer diseases

Our understanding of the etiologies of the Alzheimer diseases is advancing rapidly, led by the discovery of relevant genetic mutations for autosomal-dominant forms of the disease and widespread confirmation of the role played by apolipoprotein E, the major susceptibility gene for the common form of Alzheimer's disease. New hypotheses are being generated and old hypotheses are being modified to account for the wealth of new information.     

Peroxo-iron and oxenoid-iron species as alternative oxygenating agents in cytochrome P450-catalyzed reactions: switching by threonine-302 to alanine mutagenesis of cytochrome P450 2B4

Among biological catalysts, cytochrome P450 is unmatched in its multiplicity of isoforms, inducers, substrates, and types of chemical reactions catalyzed. In the present study, evidence is given that this versatility extends to the nature of the active oxidant. Although mechanistic evidence from several laboratories points to a hypervalent iron-oxenoid species in P450-catalyzed oxygenation reactions, Akhtar and colleagues [Akhtar, M., Calder, M. R., Corina, D. L. & Wright, J. N. (1982) Biochem. J. 201, 569-580] proposed that in steroid deformylation effected by P450 aromatase an iron-peroxo species is involved. We have shown more recently that purified liver microsomal P450 cytochromes, including phenobarbital-induced P450 2B4, catalyze the analogous deformylation of a series of xenobiotic aldehydes with olefin formation. The investigation presented here on the effect of site-directed mutagenesis of threonine-302 to alanine on the activities of recombinant P450 2B4 with N-terminal amino acids 2-27 deleted [2B4 (delta2-27)] makes use of evidence from other laboratories that the corresponding mutation in bacterial P450s interferes with the activation of dioxygen to the oxenoid species by blocking proton delivery to the active site. The rates of NADPH oxidation, hydrogen peroxide production, and product formation from four substrates, including formaldehyde from benzphetamine N-demethylation, acetophenone from 1-phenylethanol oxidation, cyclohexanol from cyclohexane hydroxylation, and cyclohexene from cyclohexane carboxaldehyde deformylation, were determined with P450s 2B4, 2B4 (delta2-27), and 2B4 (delta2-27) T302A. Replacement of the threonine residue in the truncated cytochrome gave a 1.6- to 2.5-fold increase in peroxide formation in the presence of a substrate, but resulted in decreased product formation from benzphetamine (9-fold), cyclohexane (4-fold), and 1-phenylethanol (2-fold). In sharp contrast, the deformylation of cyclohexane carboxaldehyde by the T302A mutant was increased about 10-fold. On the basis of these findings and our previous evidence that aldehyde deformylation is supported by added H202, but not by artificial oxidants, we conclude that the iron-peroxy species is the direct oxygen donor. It remains to be established which of the many other oxidative reactions involving P450 utilize this species and the extent to which peroxo-iron and oxenoid-iron function as alternative oxygenating agents with the numerous isoforms of this versatile catalyst.     

True synovial metaplasia of breast implant capsules: a light and electron microscopic study

High resolution chromosome analysis, molecular cytogenetics, and study of the association between specific chromosome rearrangements and single gene disorders have provided a chromosomal basis to a number of mendelian diseases. Deletions and duplications of small regions, usually less than 3 Mb in size, result in an alteration of normal gene dosage of a number of unrelated genes physically close to each other and are responsible for contiguous gene syndromes. For example, haploinsufficiency is implicated for del 8q24.1 in Langer-Giedion syndrome, del 17p13.3 in Miller-Dieker syndrome, and del 22q11.2 in DiGeorge and Velo-cardiofacial syndromes. Another chromosomal mechanism causing mendelian phenotypes is translocation, which may eventually interrupt a disease gene. It is assumed that translocation breakpoints are running through a relevant gene, hindering the production of the gene product. An example is breakage 16p13.3 associated with Rubinstein-Taybi syndrome. Females with X/autosome translocations have an almost exclusive inactivation of the normal X. Interruption of a disease gene in the translocated X causes the expression of a mendelian phenotype in the presence of an allelic recessive mutation onto the nonrearranged X. Finally, if a human gene shows exclusive expression from a single parental homologue, ie, it is imprinted, deletion of the chromosomal segment containing the active allele results in structural monosomy and functional nullisomy. This situation is illustrated by Prader-Willi and Angelman syndromes. Over seventy human genes have been precisely assigned to chromosomal regions using a cytogenetic approach. Chromosome techniques combined with molecular methods have proved to have powerful and sensitive diagnostic capabilities.     

Isolation, study of activity, and characteristics of an immunosuppressive liver factor causing apoptosis of EL-4 thymoma cells in vitro

Immunosuppressive factor (ISFnp) which inhibits proliferation and viability of thymoma EL-4 cells was isolated from mouse liver. The testing procedure based on the biotransformation of MTT-tetrazolium by mitochondrial enzymes of viable cells allowed us to purify this factor as individual peak of protein, that allowed to obtain polyclonal rabbit antibodies to this factor. By the methods of double immunodiffusion, gel-filtration and SDS-PAGE with subsequent immunoblotting we shown that this factor specifically localized in liver and consists two subunits of 40 and 42 kDa which form dimers with apparent M(r) about 70-80 kDa. This factor induced olygonucleosomal DNA cleavage in EL-4 cells in vitro similar to dexamethasone-induced DNA-degradation in thymocytes. This cleavage preceded to lysis of EL-4 cells assessed by 51Cr-release, that strongly suggested an involvement of apoptosis in cell death mechanism. ISFnp strongly inhibited blast-transformation and proliferation in MLC-responses to mutant MHC class 2 molecule. This effect was not due to deletion of allo-reactive clones, because removing of this factor from MLC cultures treated with one for 4 days resulted in blast-transformation without any reduction of the number of viable cells as well as their capacity for secondary responses to the same antigen as compared with control cultures.     

Thyroxine and triiodothyronine levels in hyperthyroid patients during treatment with propranolol

In the last few years, there has been an active effort in Italy to involve the population in solving health problems at the community level. This movement had its origin in the industrial setting, where workers succeeded in promoting legislation which gives them control over matters affecting their health. This experience lead to the development of a health education methodology based on the following principles: (a) the assessment of health needs must be based on the subjective experience of the people who have acquired knowledge and interest in health problems; (b) the evaluation of health needs by professionals serves to complement and integrate the assessment of needs as experienced by the community; (c) the self-diagnosis of the community -- in particular of homogenous community groups exposed to similar health risks and experiencing the same needs--and the diagnosis of the professionals must undergo cross-validation and be accepted by both parties; (d) on the basis of this mutual agreement, community health programmes should be planned and carried out jointly by the professionals and the people.     

Verbal and nonverbal abilities in the Williams syndrome phenotype: evidence for diverging developmental trajectories

One commonly cited feature of Williams syndrome is a characteristic dissociation between relatively spared language skills and severely impaired nonverbal abilities. However, the actual evidence for a dissociation between verbal and nonverbal abilities in Williams syndrome is equivocal. In two separate studies we examined these abilities in 16 individuals showing the Williams syndrome phenotype. When considered as a whole, the group did have significantly superior verbal abilities, but this difference was caused by a large discrepancy in abilities in only a small number of individuals. In both studies there was a clear, linear relation between individuals' verbal ability, and the magnitude of their verbal-nonverbal discrepancy. We suggest that these results are best explained in terms of verbal ability developing at a faster rate than nonverbal ability in this disorder. We discuss how this model of differential rates of development has the potential to reconcile the apparently inconsistent findings in this area.