Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer

Serum prostatic specific antigen and prostatic acid phosphatase levels were measured retrospectively and evaluated in 357 men with benign prostatic hypertrophy and in 209 men with various stages of prostatic carcinoma. Although prostatic specific antigen values were elevated in 21 per cent of the patients with benign prostatic hypertrophy, the elevations usually were low and did not interfere with clinical interpretation. Prostatic specific antigen was elevated in 98 per cent of 86 men with active stage D2 disease; in 22 per cent of the men prostatic specific antigen was the only elevated marker. In contrast, prostatic acid phosphatase was the only elevated marker in 1 per cent of the patients with stage D2 disease and neither marker was elevated in 2 per cent. Among 74 patients in whom prostatic specific antigen and prostatic acid phosphatase determinations were made before radical prostatectomy, prostatic specific antigen was elevated substantially (greater than 10 ng. per ml.) in 59 per cent (26 of 44) with extracapsular disease and in only 7 per cent (2 of 30) without extracapsular disease. More importantly, of those 28 patients with substantially elevated prostatic specific antigen levels 26 (93 per cent) had extracapsular disease. Serial serum measurements showed that prostatic specific antigen either reflected or predicted clinical status in more than 97 per cent of the patients. We conclude that prostatic specific antigen is an excellent serum tumor marker for monitoring patients with prostatic carcinoma and that it surpasses prostatic acid phosphatase in this regard. Prostatic specific antigen also may be useful in staging prostatic carcinoma and it may change our attitudes significantly about the therapeutic responses to this cancer.     

Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice

In eukaryotic cells, the inactivation of the cyclic nucleotide signal depends on a complex array of cyclic nucleotide phosphodiesterases (PDEs). Although it has been established that multiple PDE isoenzymes with distinct catalytic properties and regulations coexist in the same cell, the physiological significance of this remarkable complexity is poorly understood. To examine the role of a PDE in cAMP signaling in vivo, we have inactivated the type 4 cAMP-specific PDE (PDE4D) gene, a mammalian homologue of the Drosophila dunce. This isoenzyme is involved in feedback regulation of cAMP levels. Mice deficient in PDE4D exhibit delayed growth as well as reduced viability and female fertility. The decrease in fertility of the null female is caused by impaired ovulation and diminished sensitivity of the granulosa cells to gonadotropins. These pleiotropic phenotypes demonstrate that PDE4D plays a critical role in cAMP signaling and that the activity of this isoenzyme is required for the regulation of growth and fertility.     

Mimotopes of the hepatitis C virus hypervariable region 1, but not the natural sequences, induce cross-reactive antibody response by genetic immunization

The hypervariable region 1 (HVR1) of the putative envelope protein E2 of hepatitis C virus (HCV) contains a principal neutralization epitope, and anti-HVR1 antibodies have been shown to possess protective activity in ex vivo neutralization experiments. However, the high rate of variability of this antigenic fragment may play a major role in the mechanism of escape from host immune response and might represent a major obstacle to developing an HCV vaccine. Thus, even if direct experimental evidence of the neutralizing potential of anti-HVR1 antibodies by active immunization is still missing, the generation of a vaccine candidate with a cross-reactive potential would be highly desirable. To overcome the problem of HVR1 variability, we have engineered cross-reactive HVR1 peptide mimics (mimotopes) at the N terminus of the E2 ectodomain in plasmid vectors suitable for genetic immunization. High levels of secreted and biologically active mimotope/E2 chimeras were obtained by transient transfection of these plasmids in cultured cells. All plasmids elicited anti-HVR1 antibodies in mice and rabbits with some of them leading to a cross-reacting response against many HVR1 variants from natural isolates. Epitope mapping revealed a pattern of reactivity similar to that induced by HCV infection. In contrast, plasmids encoding naturally occurring HVR1 sequences displayed either on full-length E2 in the context of the whole HCV structural region, or on a soluble, secreted E2 ectodomain, did not induce a cross-reacting anti-HVR1 response.     

Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant

OBJECTIVE: The role of the renin-angiotensin-aldosterone system (RAAS) genes on predisposition to develop stroke, a multifactorial and polygenic cardiovascular trait, is still under investigation. In the present study we characterized the contributory role of RAAS genes in the susceptibility to develop ischemic stroke in humans. METHODS: Allele and genotype frequencies of RAAS genes were characterized in a population of 215 cases (including only atherothrombotic and lacunar forms) and 236 controls selected in Sardinia, a large Mediterranean island with a well-known segregated population. Statistical analysis was performed in the whole population and, based on a significant interaction between angiotensin II receptor (AT1) genotype and hypertension, was also repeated in the hypertensive subgroup. RESULTS: A significant association of the C1166/AT1 gene allelic variant with stroke was found when assuming a dominant model of transmission [unadjusted odds ratio (OR)=1.5, 95% confidence interval (CI) 1.1-2.2, P=0.024]. The strength of the association became more evident in the subgroup of hypertensive individuals (135 cases and 110 controls). In fact, in this cohort the independent OR for the AT1 gene was 2.1, 95% CI 1.2-3.7, P=0.006 in the dominant model and 2.0, 95% CI 1.3-3.2, P=0.002 in the additive model. No other RAAS gene was identified as a contributor to stroke. CONCLUSIONS: Our findings support a predisposing role of an AT1 gene variant in the development of ischemic stroke. In particular, the AT1 gene variant exerted a major impact on ischemic stroke occurrence in the presence of hypertension.     

Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients

Vascular disease accounts for the majority of the clinical complications in diabetes mellitus. As an exaggerated oxidative stress degree has been postulated as the link between diabetes mellitus and endothelial function, a possible positive effect of plasma vitamin E (Vit.E) administration on brachial reactivity could be postulated. Our study aims at investigating the possible effect of chronic Vit.E administration on brachial reactivity, oxidative stress indexes, and intracellular magnesium and calcium content in type II diabetic patients free of diabetic complications. Forty adult, type II diabetic patients were enrolled in the study, which was deigned as a double blind, randomized vs. placebo trial. At baseline all patients underwent the following tests: 1) anthropometric and metabolic examinations, 2) evaluation of oxidative stress indexes, 3) intracellular magnesium and calcium measurements, and 4) determination of arterial compliance and distensibility. Then, all patients were randomly assigned to Vit.E treatment at a dose of 600 mg/day (Evion Forte; n = 20) or placebo (n = 20) over 8 weeks. At the end of this treatment period, a complete reevaluation of the patients was made. Vit.E treatment was associated with a significant improvement in the percent change in brachial artery diameter (P<0.03) and oxidative stress indexes (P< 0.005). In the Vit.E group, the percent change in brachial artery diameter correlated positively with the percent change in oxidative stress indexes (oxidized/reduced glutathione, Trolox-equivalent antioxidant capacity, thiobarbituric acid reaction products, lipid peroxides) and intracellular cation content (magnesium and calcium). After adjustment for age, sex, body mass index, and wait/hip ratio, all of these correlations remained significant (P<0.03 for all). Furthermore, adjusting for glycosylated hemoglobin, plasma total cholesterol, and homeostatic model index, brachial artery diameter was still correlated with the percent change in oxidative stress indexes (P<0.04 for all). Nevertheless, the relationship between the percent change in brachial artery diameter and oxidative stress indexes was no longer significant after adjustment for intracellular Mg and Ca2+. In conclusion, our study demonstrates that chronic administration of Vit.E improves brachial artery reactivity in patients with type II diabetes mellitus. Such an effect seems mediated by a reduction in oxidative stress and a regulation of intracellular calcium and magnesium contents.     

Mean arterial blood pressure and serum levels of the molar ratio of insulin-like growth factor-1 to its binding protein-3 in healthy centenarians

OBJECTIVE: Healthy centenarians have a greater molar ratio of plasma insulin-like growth factor-1 to insulin-like growth factor binding protein-3 than that of aged subjects. We investigated the question of whether differences in mean arterial pressure and in this plasma ratio were related in healthy centenarians. SUBJECTS AND METHODS: We studied 52 subjects in total, 30 aged subjects (70-99 years) and 22 healthy centenarians (> 100 years) to determine differences in mean arterial pressure, endothelial function and intracellular cation levels. RESULTS: In the healthy centenarians, the molar ratio of fasting plasma insulin-like growth factor-1 to its binding protein-3 was significantly correlated with mean arterial pressure (r = -0.66, P < 0.001). Baseline (19.3 +/- 1.5 versus 27.6 +/- 2.2 mumol/l, P < 0.05) and L-arginine-stimulated percentage increases in the plasma total nitrate: nitrite ratio (67 +/- 3.4 versus 48 +/- 4.5%, P < 0.03) were greater in the healthy centenarians than in the aged subjects. An L-arginine bolus elicited an increase in forearm blood flow which was correlated with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.79, P < 0.001) and with the fasting erythrocyte magnesium concentration (r = 0.80, P < 0.001) in healthy centenarians. Both correlations remained significant (P < 0.01) after adjustment for sex, body mass index and the waist: hip ratio. Moreover, the fasting plasma molar ratio of insulin-like growth factor-1 to its binding protein-3 was correlated with the percentage increase in forearm blood flow (r = 0.59, P < 0.005) and with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.54, P < 0.009) in healthy centenarians. The centenarians had higher baseline total erythrocyte magnesium and lower calcium concentrations than the aged subjects. The addition of insulin growth factor-1 to the incubation medium increased the total intracellular erythrocyte magnesium content and decreased the calcium content in both groups of subjects. Nevertheless, the percentage increase in total erythrocyte magnesium (33 +/- 3.8 versus 12 +/- 3.4%, P < 0.03) and decline in intracellular calcium (17 +/- 2.8 versus 8 +/- 3.1%, P < 0.02) concentrations were greater in the healthy centenarians than the aged subjects. CONCLUSION: In healthy centenarians, insulin-like growth factor-1 may preserve endothelial function and modulate the intracellular cation content, thus contributing to a lower mean arterial pressure than that in aged subjects.