Current concepts in the pharmacotherapy of benign prostatic hyperplasia

Benign prostatic hyperplasia is a major men's health issue, with approximately 80% of all men developing this condition within their lifetime. A variety of oral treatments is available, including alpha-adrenoceptor antagonists (alpha-blockers), 5alpha reductase inhibitors, aromatase inhibitors and phytotherapy. A large number of alpha-blockers can be administered, but no single agent has demonstrated a clear superiority over the other drugs. 5alpha Reductase inhibitors have demonstrated similar efficacy in larger volume prostates but most evidence suggests that there is no benefit in combining them with alpha-blockers. The use of phytotherapy is not entirely novel but requires further long-term evaluation before it can be endorsed for clinical use in benign prostatic hyperplasia.     

Genetic determination of biological age in the Mennonites of the Midwestern United States

Numerous studies have shown that longevity is moderately heritable in human populations. Longevity, however, contains limited information on functional status, since individuals may exhibit differential survival patterns. In this study, we employed a stepwise multiple regression approach to estimate biological aging in a Mennonite population, using chronological age as a dependent variable and various predictors of chronological age including subphenotypes related to diabetes, coronary heart disease, hypertension, renal function, and markers of functional ability. The residual (the difference between chronological and predicted ages) is considered a marker of biological age. In fact, two different data sets were used to obtain residuals due to the availability of data. In each analysis, chronological age was regressed on predictor variables in a stepwise manner, retaining the variables significant at the 5% level. The first analysis (N=729) included 6 significant predictors (R(2)=44.3%): glucose, blood urea nitrogen (BUN), cholesterol, albumin, systolic blood pressure (SBP), and ln potassium, and the second analysis (N=232) included 9 significant predictors (R(2)=71.5%): BUN, albumin, SBP, low-density lipoprotein cholesterol, forced expiratory volume in 1 sec (FEV1), grip strength, trunk flexibility, reaction time, and FEV1xsex. Using a variance components approach, we found that the data set-specific residuals were significantly heritable (h(2)+/-SE): first analysis=0.265+/-0.106, and second analysis=0.469+/-0.180. The residuals from the second data set appear to be more informative for biological aging, perhaps due to the inclusion of functional ability-related phenotypes in addition to the blood chemistry variables. In summary, we have shown that markers of biological aging in Mennonites are under substantial additive genetic influences.     

The BK channel beta1 subunit gene is associated with human baroreflex and blood pressure regulation

BACKGROUND : The baroreflex, which is important for the minute-to-minute regulation of blood pressure and heart rate, is influenced by genetic variance. Ion channels are important to baroreflex afferent and efferent function. Mice missing the beta1 subunit of the Ca2+-sensitive potassium channel (BK) are hypertensive and have a reset baroreflex. We tested the hypothesis that variants in the gene (KCNMB1) coding for the BK beta1 subunit are associated with baroreflex function. METHODS : We studied six single-nucleotide polymorphisms (SNPs) in KCNMB1. RESULTS : Four SNPs in intron 3, exon 4a, exon 4b and exon 4c gave significant results. For instance, exon 4b SNP AA individuals had higher heart rate variability, compared to CA, or CC persons, in particular in the high-frequency range. The low-frequency range showed no association. Consistent with the heart rate variability data, homozygous AA persons had greater baroreflex slopes than CA or CC persons, also in the high-frequency range. These associations could not be shown in the low-frequency range for heart rate variability and baroreflex slopes. CONCLUSIONS : These data support the notion that variants in channel genes may be responsible for the great range in heart rate variability and baroreflex function observed in humans. Such variation may also play a role in the development of hypertension.     

A gene expression analysis in rat kidney following high and low salt intake

BACKGROUND : The effects of salt intake on renal regulation have been investigated for decades. To find new pathways and to demonstrate the utility of oligonucleotide expression arrays, we studied whole kidneys. METHODS : Eight Sprague-Dawley rats were divided into two groups. One group received a 6% salt (by weight) diet, while the other group received a 0.3%, otherwise identical, salt diet for 7 days. The rats were sacrificed after 7 days and the left kidney was subjected to RNA extraction. Oligonucleotide expression arrays (Affymetrix) were used to determine downregulation and upregulation, comparing high with low salt intake. Four rats from each group were studied separately. RESULTS : The experiments were reproducible. Thirty genes were downregulated with the high-salt diet, while 35 genes were upregulated. The renin gene, beta-2 glycoprotein-1, retinol binding protein, annexin VI, and the PTP2C protein tyrosine phosphatase were among the downregulated genes. The angiotensin II receptor type 1B receptor, HMG-CoA reductase, B7 antigen, and the rat calcium channel beta subunit III were among the upregulated genes. Differentially regulated were the p55 subunit (upregulated) and the p50 subunit (downregulated) of the phosphatidyl inositol 3-kinase enzyme complex. We verified our results by selecting a high-salt downregulated gene (renin) and an upregulated gene (B7 antigen) and subjecting these genes to real-time polymerase chain reaction. The results were consistent. CONCLUSION : Oligonucleotide expression arrays can detect novel genes encoding for proteins not generally associated with responses to varied salt intake. Experiments of this nature have substantial limitations and require detailed verification. However, overall, the utility is promising.