Mitochondria, Cybrids, Aging, and Alzheimer's Disease.

Mitochondrial and bioenergetic function change with advancing age and may drive aging phenotypes. Mitochondrial and bioenergetic changes are also documented in various age-related neurodegenerative diseases, including Alzheimer's disease (AD). In some instances AD mitochondrial and bioenergetic changes are reminiscent of those observed with advancing age but are greater in magnitude. Mitochondrial and bioenergetic dysfunction could, therefore, link neurodegeneration to brain aging. Interestingly, mitochondrial defects in AD patients are not brain-limited, and mitochondrial function can be linked to classic AD histologic changes including amyloid precursor protein processing to beta amyloid. Also, transferring mitochondria from AD subjects to cell lines depleted of endogenous mitochondrial DNA (mtDNA) creates cytoplasmic hybrid (cybrid) cell lines that recapitulate specific biochemical, molecular, and histologic AD features. Such findings have led to the formulation of a "mitochondrial cascade hypothesis" that places mitochondrial dysfunction at the apex of the AD pathology pyramid. Data pertinent to this premise are reviewed.

Differential inspiratory timing is genetically linked to mouse chromosome 3.

Genetic control of differential inspiratory timing (TI) at baseline has been previously demonstrated among inbred mouse strains. The inheritance pattern for TI between C3H/HeJ (C3; 188 +/- 3 ms) and C57BL/6J (B6; 111 +/- 2 ms) progenitors was consistent with a two-gene model. By using the strain distribution pattern for recombinant inbred strains derived from C3 and B6 progenitors, 100% concordance was established between TI phenotypes and DNA markers on mouse chromosome 3. This genotype-phenotype hypothesis was tested by typing 52 B6C3F2 (F2) progeny by using simple sequence repeat DNA markers (n = 21) polymorphic between C3 and B6 strains on mouse chromosome 3. Linkage analysis compared marker genotypes to baseline ventilatory phenotypes by computing log-likelihood values. A putative quantitative trait locus located in proximity to D3Mit119 was significantly associated with baseline TI phenotypes. At the peak (log-likelihood = 3.3), the putative quantitative trait locus determined 25% of the phenotypic variance in TI among F2 progeny. In conclusion, this genetic model of ventilatory characteristics demonstrated an important linkage between differential baseline TI and a candidate genomic region on mouse chromosome 3.

Changes in blood pressure, serum potassium and electrolytes with a combination of triamterene and a low dose of chlorthalidone.

A controlled study was carried out in patients with mild to moderate hypertension to compare the efficacy and tolerability of chlorthalidone alone and chlorthalidone combined with the potassium-sparing diuretic triamterene. After a 4-week period on placebo, 129 patients were allocated at random to receive 1 tablet daily of either 25 mg chlorthalidone (67 patients) or 25 mg chlorthalidone plus 50 mg triamterene (62 patients) for 10 weeks. Ninety-one patients (48 who had received chlorthalidone alone and 43 the combination) entered the third part of the study. During this 6-week period there was a partial crossover, approximately half continuing with their existing medication and the other half with the alternative treatment. All patients were then treated for a final 2 weeks with placebo. The placebo periods were single-blind, the active treatment periods were double-blind. Patients were seen at regular intervals throughout the trial. At each visit, measurements were taken of blood pressure and pulse rate and routine haematological and biochemical tests made. The results showed that both treatments produced similar, clinically significant reductions in blood pressure within the first 4 weeks of active medication and by the end of the 10-week period 51% of those on chlorthalidone alone and 57% on the combination showed a decrease of at least 10 mmHg or to less than 90 mmHg in standing diastolic pressure. Serum potassium decreased with both therapies but was less with the combination than with chlorthalidone alone, and the incidence of a serum potassium less than 3.5 mmol/l was significantly less with the combination. After crossover, blood pressure control was maintained but serum potassium decreased in patients changed from the combination to chlorthalidone alone and increased in those changed from chlorthalidone alone to the combination. Few adverse effects were reported and were generally mild and similar in frequency with the two therapies.