Prostate cancer incidence in men with prostate-specific antigen below 3 ng/mL: The Finnish Randomized Study of Screening for Prostate Cancer

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.     

Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats

1. Age-associated deterioration of arterial function may result from long-lasting oxidative stress. Since coenzyme Q (Q₁₀) has been suggested to protect the vascular endothelium from free radical-induced damage, we investigated the effects of long-term dietary Q₁₀ supplementation on arterial function in senescent Wistar rats.
2. At 16 months of age, 18 rats were divided into two groups. The control group was kept on a standard diet while the other group was supplemented with Q₁₀ (10 mg kg⁻¹ day⁻¹). In addition, nine rats (age 2 months) also ingesting a standard diet were used as the young control group. After 8 study weeks the responses of the mesenteric arterial rings in vitro were examined.
3. Endothelium-independent arterial relaxations to isoprenaline and nitroprusside (SNP) were attenuated in aged rats. Increased dietary Q₁₀ clearly enhanced the relaxation to isoprenaline, but did not affect the response to SNP. In addition, vasodilation of noradrenaline-precontracted rings to acetylcholine (ACh), which was also impaired in aged vessels, was improved after Q₁₀ supplementation. Cyclooxygenase inhibition with diclofenac enhanced the relaxation to ACh only in young rats, while it abolished the difference between the old controls and Q₁₀ supplemented rats, suggesting that the improved endothelium-dependent vasodilation observed in Q₁₀ supplemented rats was largely mediated by prostacyclin (PGI₂).
4. In conclusion, long-term Q₁₀ supplementation improved endothelium-dependent vasodilation and enhanced β-adrenoceptor-mediated arterial relaxation in senescent Wistar rats. The mechanisms underlying the improvement of endothelial function may have included augmented endothelial production of PGI₂, increased sensitivity of smooth muscle to PGI₂, or both.

     

Variability gene effects of DNA polymorphisms at the apo B, apo AI/C III and apo E loci on serum lipids: the Cardiovascular Risk in Young Finns Study

We studied the influence of selected genetic markers on the intra-individual long-term variability in serum lipid levels. The study cohort consisted of a sub-sample from a large follow-up study of atherosclerosis precursors in children and young adults. A total of 320 subjects had determinations of apo B XbaI RFLP genotypes, 305 subjects had apo AI/CIII SstI RFLP genotype determinations and 1581 subjects had their apo E phenotypes determined. Complete data on serum lipids were available at 3-year intervals over a 6-year follow-up period. The subjects were healthy and aged 3–18 years at baseline. Intra-individual variability was assessed with a nested analysis of variance procedure. Each of the genetic markers studied here significantly affected intra-individual variability of serum lipid levels. No clear sex influence was observed, although the differences in variability tended to be more significant in males. Apo B XbaI genotypes significantly influenced intra-individual variability of total and LDL-cholesterol levels in both sexes. A marked effect of the XbaI geno-type was also found on triglyceride variability. In males the standardized intra-individual triglyceride variances were 0.71 and 0.34 in genotypes X1X1 and X2X2, respectively (p < 0.001), with a clear gene dosage effect. The apo AI/CIII genotype had an influence only on the variability of total cholesterol and LDL-cholesterol levels and only in males. The apo E phenotypes were associated with intra-individual variability in total and LDL-cholesterol levels but again, only in males. The lowest variability was observed in the phenotype E4/3 where high mean values were also observed. We also examined the effect of combined genetic markers. Up to 7 times greater variability was found in the combination E3/2 + S1S1 compared to combination E4/3 + S1S2 (p < 0.001). In addition, mean levels of, e.g., LDL-cholesterol were 70% greater in the combination of E4/3 +S1S2 compared to E3/2 + S1S1. This implies that subjects with both these genetic markers have high LDL-cholesterol values that also tend to remain constantly elevated. In conclusion, it is evident that many of the presently known DNA polymorphisms of the coronary heart disease candidate gene loci also influence intraindividual variability of serum lipid or lipoprotein levels. These findings can be used to further refine our ability to predict the risk of a cardiovascular event.     

Ezrin expression in stromal cells of capillary hemangioblastoma. An immunohistochemical survey of brain tumors.

Ezrin is a cytoskeleton-associated protein that appears to link actin filaments to the plasma membrane. Immunocytochemical studies suggest that ezrin is expressed in epithelial cells but not in mesenchymal cells. In addition, ezrin is expressed by certain epithelial tumors, such as renal cell adenocarcinomas. Ezrin serves as a tyrosine kinase substrate, and is phosphorylated in epidermal growth factor-stimulated cells. Ezrin may thus mediate regulatory signals in different cell functions. We studied the distribution of ezrin in 104 cases of primary tumors of the central nervous system (CNS) by immunocytochemistry. Special interest was focused on capillary hemangioblastoma, owing to its resemblance to renal cell adenocarcinoma, and on malignant gliomas, owing to their frequent epidermal growth factor receptor amplification. The stromal cells of hemangioblastomas were found to be strongly positive for ezrin. No expression was detected in gliomas and, except for hemangioblastomas, ezrin expression was restricted to those few CNS tumors that show epithelial differentiation, ie, choroid plexus papillomas, craniopharyngiomas, ependymomas, and cysts. The diffuse cytoplasmic expression of ezrin in the stromal cells of capillary hemangioblastoma may indicate that stromal cells overexpress ezrin or express ezrin with deficient binding properties.     

Event-Related Brain Potentials in Selective Listening to Frequent and Rare Stimuli

Our previous event-related brain potential (ERP) results suggest that during selective listening, relevant stimuli are selected for further processing by comparing each stimulus to an “attentional trace,” a neuronal representation of the physical features of the relevant stimuli that distinguish them from the irrelevant stimuli. This comparison process is reflected by the early component of the processing negativity (PN), which is largest and longest to the relevant stimuli (perfectly matching with the trace). In the present study, the subjects selectively listened to designated tone stimuli which randomly appeared among irrelevant tones of a different pitch. The probability of relevant stimuli in a block was varied. The processing negativity elicited by relevant stimuli was smaller the less frequent they were. The results support the attentional-trace theory of selective attention, which proposes that, in addition to active maintenance, the trace also depends on the rate of sensory reinforcement provided by the relevant stimuli.