Genetic interactions in the ß-adrenoceptor/G-protein signal transduction pathway and survival after coronary artery bypass grafting: a pilot study.

BACKGROUND: In heart failure, ß-adrenergic receptor (ßAR) stimulation desensitizes the receptor, uncouples the downstream Gαs protein, and diminishes signal transduction. We tested the hypotheses that haplotype-tagging single-nucleotide polymorphisms (htSNPs) within the Gαs gene (GNAS) (i) are functionally active and alter Gαs expression, (ii) influence survival after coronary artery bypass grafting (CABG), and (iii) interact with ßAR SNPs. METHODS: Amplification of GNAS intron 1 was followed by cloning, reporter assays, electrophoretic mobility shift assays, and western blots. In a pilot study, 185 patients on ßAR blockade undergoing CABG were studied prospectively. The primary endpoint was cardiac-related mortality at 1 yr. RESULTS: Two htSNPs defined three common haplotypes with altered reporter activity, allele-specific transcription factor binding, and Gαs protein expression (highest in *3 carriers followed by *2 and *1 haplotypes, P=0.013). After CABG, mortality was GNAS diplotype-dependent: *3/*3: 0%; *3/*2: 2.4%; *3/*1: 2.9%; *2/*2: 4.5%; *2/*1: 9.1%; and *1/*1: 20.0% (P=0.004). While ß(1)AR SNPs were not associated with mortality, ß(2)AR Arg16 allele carriers were at higher risk than Gly16 allele carriers (P=0.008). Gene-gene interaction using gene-related risk alleles demonstrated the number of risk alleles to be independently associated with death (hazard ratio 2.3; 95% confidence interval: 1.5-3.5; P=0.0003). Carriers of the no-risk allele had higher maximum isoproterenol-stimulated adenylyl cyclase activities than risk allele carriers (P=0.003). CONCLUSIONS: Interactions in the ßAR/Gαs pathway may be associated with altered mortality after CABG. This could reconcile previously inconclusive data regarding the effects of ßAR SNPs on cardiovascular prognosis.

G protein beta 3 gene: structure, promoter, and additional polymorphisms.

Recent studies have shown that a polymorphism (C825T) in the gene encoding the G protein beta 3 subunit (GNB3) is associated with hypertension and obesity. We characterized the entire GNB3 gene, which spans 7.5 kb and is composed of 11 exons and 10 introns. Its promoter lacks a TATA box but harbors GC-rich regions. The functional activity of the GNB3 promoter was verified with reporter gene assays that also demonstrated its inducibility by phorbol esters. A novel polymorphism in the promoter region A(-350)G occurred with frequencies (G allele) of 76%, 97%, and 61% in Africans, Chinese, and Germans, respectively. Reporter gene constructs with either the A or the G allele did not differ with regard to inducement of the reporter protein. A silent nucleotide exchange in the coding region (A657T) occurred with T allele frequencies ranging from 0.5% to 2.4%. Another polymorphism (G814A) results in the replacement of glycine by serine at position 272. In Germans, the A allele occurred at a frequency of 10%. Finally, a C1429T polymorphism in the 3' untranslated region of GNB3 was identified that occurred at T allele frequencies of 38%, 17%, and 30% in Africans, Chinese, and Germans, respectively. Haplotype prediction indicated in Germans an almost complete association of GNB3 825T with 1429T, and vice versa. An analysis of these polymorphic loci in nonhuman primates revealed that the ancestral GNB3 gene harbored the (-350)G, 825C, and 1429C alleles. This is the first complete characterization of the human GNB3 gene and its promoter region, which will enable refined epidemiological and biochemical investigations of GNB3 in hypertension and obesity.

[Clinical experience with a self-assessment scale for detecting organic psychological syndromes in cerebrovascular insufficiency]. / Klinické zkusenosti se skálou sebehodnocení k zachycení organického psychosyndromu u cerebrovaskulární insuficience.

Cerebrovascular insufficiency is of great importance from the aspect of social medicine. Using a range of self-assessment conceived for ambulatory use, the authors tried therefore to detect it in an early stage to make prophylactic provisions possible. The range of self-assessment comprises 25 questions pertaining to specific symptoms. The patient indicates the replies on a five-grade verbal and digital scale. In addition to the evaluation of the content, the total value which can be easily calculated indicates the grade of manifested psychosyndrome as the basis for a reduced performance of the brain. The evaluation takes age-dependence into account. In the submitted paper results of a comparative examination are presented. The authors compared subjects with confirmed organic psychosyndrome (psychometry, PEG, CT etc.) with a control group of subjects without reduced brain performance. Both groups differed significantly at the 1% level of significance. The authors selected as the third group neurotic subjects who reported similar difficulties but their intensity was significantly smaller than in subjects of the examined group. Finally the results of the range of self-assessment were compared with differential therapeutic results (vasodilatating agents, nootropic agents).

[Report of experiences with high dosage Hydiphen infusion treatment of depressive syndromes]. / Erfahrungsbericht über hochdosierte Hydiphen-Infusionsbehandlung bei depressiven Syndromen.

25 patients with therapy-resistant depressive syndromes of various origins were treated by the infusion of high Hydiphen doses, a very effective thymoleptic drug with no dissociation between its drive increasing and spirit raising actions. The results yielded by this treatment varied from good to very good in respect of endogenic depressions, in which the mood was observed to change at doses between 150 and 425 mg/d, depending on the severity of the depression. The results of this treatment were less satisfactory in the case of reactive and bran-organically induced depressions.

[Study approach and initial results of the effect of sleep deprivation on the depressive syndrome]. / Untersuchungsansatz und erste Ergebnisse zur Wirkung des Schlafentzugs beim depressive Syndrom.

After a brief review of previous investigations into the antidepressant effect of sleep withdrawal, attention is drawn to problems arising from simultaneous treatment with antidepressants. A method for recording the effects of sleep withdrawal alone is also described. The results indicate that treatment by partial withdrawal of sleep during the second half of the night, tends to have a positive effect on the symptoms of depression and on the psychophysical status of the patients. The author concludes with an overview of the problems still outstanding.