Genetic counselling for hypertrophic cardiomyopathy: are we ready for it?

Hypertrophic cardiomyopathy (HCM) is a dominant genetic disorder of the myocardium associated with dysfunctional contractile proteins. The major risk of HCM is sudden cardiac death, which may occur even in asymptomatic carriers. Causes are highly heterogeneous. Over 140 different mutations in nine sarcomeric genes have been described to date. The majority of cases (80% or more) may eventually be traced to one of these genes. Although genetic counselling is suggested even if mutations are not known, molecular diagnosis implies new options such as carrier identification or - theoretically - preclinical risk stratification. A scheme according to which cardiologists and clinical and molecular geneticists could cooperate in counselling patients and managing HCM clinically is proposed.     

Studies on the frequency and associations of equine leucocyte antigens in sarcoid and summer dermatitis

The equine leucocyte antigen (ELA) types and the clinical diagnosis for equine sarcoid and summer dermatitis were evaluated in 2026 horses representing five breeds. Data were analysed in unrelated animals and in family material. In the case of equine sarcoid, a strong association was observed between the ELA class II DW13 antigen and its effect on Swiss (cP < 0·001), French (cP < 0·0001) and Irish (cP < 0·01) Warmblood horses. The class I antigen A3 occurred more frequently in sarcoid-affected French horses (cP < 0·001). These results confirm our earlier findings (Gerber et al. 1988). Among Freiberger horses, which lack the ELA DW13 and A3 specificities, a breed-specific class I antigen, ABe108, displayed an increased frequency (cP < 0·05) in the affected group. Among Arabian horses, a tendency for increased frequency of the A1 antigen was observed in the affected animals, but the number of affected horses is too small for statistical significance. The Mendelian segregation in diseased half-siblings by ELA DW13 heterozygous stallions showed a strong association (P < 0·0001) between the inherited DW13 antigen and susceptibility to the sarcoid effect. In the case of summer dermatitis, previously published data (Marti et al. 1992) have been extended. The ELA types in four multiple-case families, founded by the same stallion, were analysed for an association with the effect of sarcoid. Eight out of nine ELA-typed affected offspring inherited the paternal haplotype A15, DW23 in contrast to nonaffected offspring where three out of 12 displayed these antigens (P < 0·005). Moreover, the ELA haplotypes of 11 out of 12 informative affected half-siblings sired by another stallion inherited the paternal haplotype A3, W12, DW23 (P < 0·05). Our findings demonstrate statistically significant associations between certain ELA antigens and two equine diseases. It is still unknown if the major histocompatibility complex (MHC) molecules themselves or another linked gene(s) play a role in the pathogenesis of these conditions.     

DNA sequence analysis of serologically detected ELA class II haplotypes at the equine DQP locus

The genetic diversity at the ELA DQβ locus was investigated using polymerase chain reaction and DNA sequencing. Based upon serological methods 16 class II homozygous animals were selected and their genomic DNA was used. A DQβ gene from an equine cDNA library was also sequenced. Our methology and the similarity between the genomic and the cDNA sequences suggest that the studied locus is expressed on equine lymphocytes. In the predicted amino acid sequence the most extensive variation is located at residues 56–60. The pattern of these five amino acids is strongly correlated to the serological ELA class II specificities (W13, W22, W23, Be200). The alleles corresponding to the W23 specificity are the most divergent among the equine DQβ alleles and also from other mammalian DQβ sequences.     

Deanol Affects Choline Metabolism in Peripheral Tissues of Mice

Abstract: The enzymatic hydrolysis of UDP-galactose in rat and calf brain was studied. The hydrolysis occurs in two steps: The first is the conversion of UDP-galactose to galactose-1-phosphate catalyzed by nucleotide pyrophosphatase (EC 3.6.1.9), and the second is the conversion of the latter to free galactose by alkaline phosphatase (EC 3.1.3.1). The overall conversion has a pH optimum of 9.0, but there is considerable activity at pH 7.4, which is the optimum for UDP-galactose:ceramide galactosyltransferase in the synthesis of cerebrosides. Preparations from cytosol from calf brain cerebellum or stem that were enriched in UDP-galactose hydrolytic activity inhibit cerebroside synthesis under conditions optimal for the synthesis. Microsome-rich and nuclear debris fractions contain the highest apparent specific activity among the subcellular fractions studied. Hydrolysis of UDP-galactose occurs in all areas of brain, brainstem having the highest activity. The apparent specific activity in jimpy mouse brain homogenate is nearly twice as high as in the control brain homogenate.     

Interactions: Dose effect relationships and isoeffect curves

Summary Interaction from several agents, i.e., a greater or smaller effects than expected from the sum of the individual effects can be of essentially two types: a) The agents could act in paralell on the same target, and a term depending on the doses of the agents involved would have to be added to the individual dose effect relationships (parergic interaction). b) The agents could act at different points in the chain of events leading to the observed effect, and the action of the second agent, the promotor, would be, at least in part, contingent on the action of the first inducer agent so that the dose effect relationships are linked in a multiplicative manner (metergic interaction). The dose effect surfaces for interaction depend on the type of dose effect relationship of the individual agents. Formulas are given for the general cases and are exemplified in graphs. Typical isobolic diagrams are also illustrated. These formulas may be adapted to experimental data by means of non-linear regression or maximum-likelihood analysis.     

The polymerase chain reaction: an improved method for the analysis of nucleic acids

Summary The polymerase chain reaction (PCR) is a method for the selective amplification of DNA or RNA segments of up to 2 kilobasepairs (kb) or more in length. Synthetic oligonucleotides flanking sequences of interest are used in repeated cycles of enzymatic primer extension in opposite and overlapping directions. The essential steps in each cycle are thermal denaturation of double-stranded target molecules, primer annealing to both strands and enzymatic synthesis of DNA. The use of the heat-stable DNA polymerase from the archebacterium Thermus aquaticus (Taq polymerase) makes the reaction amenable to automation. Since both strands of a given DNA segment are used as templates, the number of target sequences increases exponentially. The reaction is simple, fast and extremely sensitive. The DNA or RNA content of a single cell is sufficient to detect a specific sequence. This method greatly facilitates the diagnosis of mutations or sequence polymorhisms of various types in human genetics, and the detection of pathogenic components and conditions in the context of clinical research and diagnostics; it is also useful in simplifying complex analytical or synthetic protocols in basic molecular biology. This article describes the principles of the reaction and discusses the applications in different areas of biomedical research.     

The carbon-13 nuclear magnetic resonance spectra of four eudesmane sesquiterpenols

The ¹³C NMR spectra of geosmin, selina-4(14),7(11)-diene-99-ol and two dihydroeudesmol isomers have been obtained and the individual resonances assigned. Several different empirical correlations developed by others have been combined in simple calculations to predict chemical shift values for sesquiterpenols of the eudesmane group.