Introduction and Objectives

Benign prostate-specific antigen (BPSA) and [-2]pro-prostate-specific antigen ([-2]proPSA) have been shown to be predictive of prostate cancer and benign prostatic hyperplasia treatment, but little is known about longitudinal changes in these markers and how they relate to outcomes.

Methods

In 1990, a 25% subsample from a cohort of Caucasian men aged 40–79 years randomly selected from Olmsted County, MN residents completed a detailed clinical examination. BPSA and [-2]proPSA were measured from frozen sera. Subjects were evaluated biennially (median follow-up 7 years; range: 0–8.8 years). Mixed-effects regression models were used to estimate longitudinal changes in BPSA and [-2]proPSA levels overall and by outcomes. Spearman correlations were used to compare these changes with baseline levels and annualized changes in urologic measures.

Results

Median (25th, 75th percentiles) annualized percent change for [-2]proPSA and BPSA were 3.7% (2.5%, 5.2%) and 7.3% (6.8%, 7.7%), respectively. Annualized percent change for both markers were correlated with baseline and annualized changes in PSA and prostate volume. Annualized percent change increased with increasing age decade for [-2]proPSA, but not BPSA. The median (25th, 75th percentiles) rate of increase in [-2]proPSA was significantly greater for men who developed enlarged prostates (3.5% (2.6%, 4.4%)) or prostate cancer (8.1% (6.6%, 9.8%)) compared to those who did not develop enlarged prostates (1.9% (0.9%, 3.0%)) or prostate cancer (3.5% (2.3%, 4.8%)).

Conclusions

BPSA and [-2]proPSA levels increase over time. The annualized percent change in [-2]proPSA increases with age and may be a useful predictor of development of prostate cancer.

Purpose

To describe the cross-sectional associations of benign prostate-specific antigen (BPSA) with clinical urologic measures, and to examine the risk of future urologic outcomes in two population-based cohorts of black and white men.

Materials and Methods

Two population-based, cohort studies were established to characterize the natural history and risk factors for progression of prostate disease in white and black male residents of Olmsted County, Minnesota and Genesee County, Michigan, respectively.

Results

The distribution of BPSA levels was similar in blacks (median (25th, 75th percentiles) =32.9 (17.3, 68.0) pg/mL) and whites (median=32.2 (16.6,68.9) pg/mL), p=0.71, but much lower than previous reports. For Olmsted County men in the upper quartile of BPSA, there was a 15-fold increased risk of prostate cancer (CaP; hazard ratio (HR): 14.6 95% confidence interval (CI): 3.1, 68.6) and a 2-fold higher risk of treatment for benign prostatic hyperplasia (BPH; HR: 2.2, 95% CI: 1.2, 4.2) after adjusting for age. After additional adjustment for baseline PSA, the association between BPSA and CaP risk was attenuated, but remained nearly 9-fold higher for men in the upper BPSA quartile (HR: 8.7, 95% CI: 1.8, 42.4). The 2-fold higher risk of treatment for BPH also remained after adjustment for baseline PSA for men in the upper BPSA quartile (HR: 1.9, 95% CI: 0.9, 4.0).

Conclusions

These results suggest that elevated BPSA level may help to identify men at risk of treatment for BPH and identify men with prostate cancer.

Purpose

To provide cross-sectional normative data for [-2]pro-prostate-specific antigen ([-2]proPSA) from the Olmsted County Study of Urinary Symptoms and Health Status among Men (OCS) and the Flint Men’s Health Study (FMHS) and to describe the associations with clinical urologic measures and risk of prostate cancer diagnosis.

Materials and Methods

Measurements of [-2]proPSA were obtained from n=420 white men from Olmsted County, Minnesota and n=328 black men from Genesee County, Michigan. Cross-sectional associations between [-2]proPSA and prostate enlargement / elevated PSA level were assessed. Cox proportional hazard models were used to assess associations between [-2]proPSA and incident diagnosis of prostate cancer.

Results

Baseline [-2]proPSA level was slightly higher among black men (median (25th, 75th percentiles) =6.3 (4.1, 8.9) pg/mL) than among white men (median=5.6 (3.9, 7.7) pg/mL), p=0.01. Baseline [-2]proPSA level was highly predictive of biopsy-confirmed prostate cancer (CaP) in the OCS cohort. Relative to men in the lower quartile of [-2]proPSA, men in the upper quartile had almost an 8-fold increase in the risk of CaP (hazard ratio (HR): 7.8, 95% confidence interval (CI): 2.2, 27.8) after adjustment for age and baseline PSA.

Conclusions

Levels of [-2]proPSA in these cohorts of community-dwelling black and white men are much lower than seen in previous studies. These data suggest that levels of [-2]proPSA may help identify prostate cancer in men with serum PSA levels in an indeterminate range, although the reference ranges for white and black men may differ slightly.

Objectives

To measure prostate volume doubling times (PVDTs) for a large sample of community men followed serially by transrectal ultrasonography (TRUS), and to determine whether specific characteristics are associated with a rapid PVDT.

Subjects and Methods

A subsample of 446 subjects from a larger cohort of American white men aged 40–79 years were evaluated biennially for a median (range) follow-up of 10 (3–14) years. Mixed-effects regression models were used to estimate prostate growth rates and PVDT for subjects with three or more or with five or more serial biennial TRUS PV measurements.

Results

The median (25–75th percentile) PVDT was 32.6 (24.6–44.0) years. The average annual increase in PV was 2.2%. The PVDT distribution was constant in men of all age groups studied (r < 0.001, P = 0.99). The factor most strongly associated with PVDT was baseline transition zone volume (r = −0.55, P < 0.001). Baseline total prostate-specific antigen (PSA) level, free PSA and total PV were also significantly inversely associated with PVDT (r = −0.30, −0.44 and −0.32, respectively, all P < 0.001). Age, baseline anthropomorphic measurements, hormone levels and specific lifestyle characteristics were not significantly correlated with PVDT.

Conclusion

These data indicate that PVDT might be a useful future measure of benign prostatic growth. They provide a basis to forecast PV at 10, 20, or 30 years later, after one baseline TRUS measurement of prostate volume, and can be presented in a simple nomogram.

Objectives

We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, the metabolic syndrome and plasma C-reactive protein (CRP).

Background

Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.

Methods

We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA).

Results

Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjusting for age, gender, traditional risk factors and Framingham Risk Scores (FRS) [tobit regression ratio 2.42 (95% CI 1.48–3.95, p=0.002)] and further adjusting for metabolic syndrome and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.

Conclusion

In SIRCA, while both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.

Condensed Abstract

Adipokines are fat-secreted biomolecules with pleiotropic actions and represent novel markers for cardiovascular risk. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic Caucasians. Leptin was positively (top vs. bottom quartile) associated with higher CAC even after adjustment for age, gender, traditional risk factors, Framingham Risk Score, metabolic syndrome, and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. Adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.

Mutations in genes encoding neuronal voltage-gated sodium channel subunits have been linked to inherited forms of epilepsy. The majority of mutations (>100) associated with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) occur in SCN1A encoding the NaV1.1 neuronal sodium channel α-subunit. Previous studies demonstrated functional heterogeneity among mutant SCN1A channels, revealing a complex relationship between clinical and biophysical phenotypes. To further understand the mechanisms responsible for mutant SCN1A behavior, we performed a comprehensive analysis of the single-channel properties of heterologously expressed recombinant WT-SCN1A channels. Based on these data, we then determined the mechanisms for dysfunction of two GEFS+-associated mutations (R1648H, R1657C) both affecting the S4 segment of domain 4. WT-SCN1A has a slope conductance (17 pS) similar to channels found in native mammalian neurons. The mean open time is ∼0.3 ms in the −30 to −10 mV range. The R1648H mutant, previously shown to display persistent sodium current in whole-cell recordings, exhibited similar slope conductance but had an increased probability of late reopening and a subfraction of channels with prolonged open times. We did not observe bursting behavior and found no evidence for a gating mode shift to explain the increased persistent current caused by R1648H. Cells expressing R1657C exhibited conductance, open probability, mean open time, and latency to first opening similar to WT channels but reduced whole-cell current density, suggesting decreased number of functional channels at the plasma membrane. In summary, our findings define single-channel properties for WT-SCN1A, detail the functional phenotypes for two human epilepsy-associated sodium channel mutants, and clarify the mechanism for increased persistent sodium current induced by the R1648H allele.

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.