De novo expansion of intermediate alleles in spinocerebellar ataxia 7

Spinocerebellar ataxia 7 (SCA7) is the eighth neurodegenerative disorder caused by a translated CAG repeat expansion. Normal SCA7 alleles carry from four to 35 CAG repeats, whereas pathological alleles carry from 37 to approximately 200. Intermediate alleles (IAs), with 28-35 repeats in the SCA7 gene are exceedingly rare in the general population and are not associated with the SCA7 phenotype, although they have been found among relatives of four SCA7 families. In two of these families, IAs bearing 35 and 28 CAG repeats gave rise, during paternal transmission, to SCA7 expansions of 57 and 47 repeats, respectively, that were confirmed by haplotype reconstructions in one case and by inference in the other. Furthermore, the four haplotypes segregating with IAs were identical to the expanded alleles in each kindred, but differed among the families, indicating multiple origins of the SCA7 mutation in these families with different geographical origins. Our results provide the first evidence of de novo SCA7 expansions from IAs that are not associated with the phenotype but can expand to the pathological range during some paternal transmissions. IAs that segregate in unaffected branches of the pedigrees might, therefore, constitute a reservoir for future de novo mutations that occur in a recurrent but random manner. This would explain the persistence of the disease in spite of the great anticipation (approximately 20 years/generation) characteristic of SCA7. So far, de novo expansions among the disorders caused by polyglutamine repeats have only been demonstrated in Huntington's disease.     

Chromatic models. Interactions between DNA and polypeptides containing L-lysine L-valine: circular dichroism and thermal denaturation studies

The interaction of calf thymus DNA with statistical copolymers of L-lysine and L-valine [poly(L-Lys100f-Lvalf)] and block copolymers [poly(L-Lys)100f-poly(L-Val)f] were investigated as a function of ionic strength using circular dichroism (CD) spectroscopy. It was found that valine suppresses the ability of the copolymer-DNA complexes to yield a psi-type CD spectra as found for poly(L-Lys)-DNA [Jordan, C.F., Lerman, L.S., and Venable, J.N. (1972), Nature (london), New Biol. 236, 67] and lowers the ionic strength at which CD distortion occurs. Thermal denaturation, simultaneously monitoring 280-nm ellipticity, [theta]280, and hyperchromicity, h280, was carried out on annealed complexes of poly(L-Lys)-DNA, poly(L-Lys84.5-L-Val15.5)-DNA, poly(L-Lys)87.2-poly(L-Val)12.8-DNA, and directly mixed complexes of poly(L-Lys)-DNA, IN 2.5 X 10(-4) MEDTA, pH 7.0 solution. The CD denaturation of uncomplexed DNA at several ionic strengths was also determined to examine pre-melting. Despite the inability of both statistical and block copolymers of L-Lys and L-Val to form psi-type complexes with DNA, they bind as well to DNA as does poly(L-Lys) and give rise to a thermal denaturation pattern showing bound peaks between 90 and 100 degrees C, seen clearly with CD denaturation. The thermal denaturation of mixed and annealed complexes of poly(L-Lys)-DNA shows similar patterns in hyperchromicity changes as a function of temperature but very different CD melts. From the CD melt of annealed poly(L-Lys)-DNA, it appears that aggregation and long-range order of the complex are significant in low salt (2.5 X 10(-4) MEDTA) as well as in 1.0 M NaCl. These studies further illustrate the importance of the nature of nonionic interactions (hydrophobic) between polypeptides and DNA in determining the behavior of their complexes, such as causing condensation into higher order asymmetric structures. In light of these observations, the possible significance to the CD melting of chromatin and the validity of identification of C-form DNA by CD spectroscopy are discussed.     

Failure of LH and/or prolactin to prevent PGF 2alpha-induced luteolysis of ovine corpora lutea

Infusions of phosphate buffered saline, LH (4 microgram/min or 14 microgram/min), prolactin (42 microgram/min) or LH (4 microgram/min) plus prolactin (42 microgram/min) for 12 hr did not prevent luteolysis following intramuscular injections of prostaglandin F2alpha-tham salt two and six hr after beginning the infusion. Likewise, these treatments did not delay luteolysis since a similar rate of decline in peripheral plasma progesterone occurred in all groups. It was concluded that elevation of serum concentrations of LH and prolactin to high levels had no effect on PGF2alpha-induced luteolysis on day 8 following induced ovulation.     

Gastrointestinal disorders: the role of diet in cause and management

Diet has a definite role in certain gastrointestinal disorders, and dietary manipulation often is beneficial. In other cases, such as peptic ulcer, traditional dietary therapy cannot be justified by available evidence.     

Studies of regional coronary flow using radioactive microspheres

Radioactive microspheres accurately measure total coronary blood flow (+/- 10%) if the heart contains at least 400 spheres. Precision of the microsphere method depends upon the number of spheres in the region of interest and the reference sample, not on the radioactivity. Reliable flow can be calculated from reference samples collected from any vessel (carotid or femoral artery or aorta) in the beating, working heart and during cardiopulmonary bypass if the sample contains a minimum of 400 spheres. Spheres of 9 mu are distributed in the heart like diffusible indicators, while spheres greater than 9 mu preferentially stream to the endocardium, causing subendocardial flow to be overestimated. This overestimate is lessened with 15 mu spheres and can be readily taken into account. The microsphere method provides information about flow (ml/100 gm tissue/min) and allows comparisons with other regions (endocardial/epicardial flow ratios) but does not provide information about the adequacy of regional flow or its distribution; this must be assessed by biochemical, histochemical, and functional analysis.     

Evaluation of workers exposed to elemental mercury using quantitative tests of tremor and neuromuscular functions

Workers exposed to metallic mercury vapor were subjects for tremor, EMG, and psychomotor tests. Regression analysis revealed statistically significant trends in these test results related to workers' urine mercury histories. Effects were subclinical, functionally insignificant and most associated with those workers whose urine mercury had exceeded 0.5 mg/L in the previous year. In agreement with previous reports, effects were reversible upon reduction of mercury exposure.