Molecular biology in prostate cancer

Summary Genes involved in cancer generation are usually tumor suppressors and oncogenes. Progressive genetic alterations in these genes are involved in the mechanisms of tumorigenesis. In prostate cancer, additionally several chromosomal loci that should harbor mutated genes have been proposed. Some genes have been found altered in prostate cancer, such as PTEN, TP53, AR, RNASEL (HPC1), ELAC2 (HPC2), CDKN2A and MSR1 and those can be natural targets for new strategies of treatment. Besides, gene therapy has been suggested to be suitable for prostate cancer treatment. This approach includesex vivo corrective therapy, suicide, and antisense therapy.     

Distribution and function of cholinergic receptors in the sheep detrusor muscle

The distribution of cholinergic nerve fibres, as well as the characterization of the muscarinic receptors responsible for the contraction, were determined in the detrusor smooth muscle of the sheep. The results obtained demonstrated a rich presence of acetylcholinesterase (AChE)-positive fibres distributed throughout the bladder body forming dense neuromuscular, subepithelial and perivascular plexuses. Furthermore, intramural ganglia containing AChE-positive cell bodies were identified. However, acetylcholine and carbachol induced a dose-dependent contraction of detrusor smooth muscle. The effect observed with carbachol was competitively antagonized by atropine (pA2: 8.94), pirenzepine (pA2: 7.38), AF-DX 116 (pA2: 7.35), 4-DAMP (pA2: 9.26) and hexahydroxiladifenidol (HHSiD) (pA2: 8.49). The pA2 value for pirenzepine is intermediate between M1- and M2-receptors which suggests that this antagonist does not act on M1- or M2-receptors, but that it does on M3-receptors. The pA2 value for AF-DX 116 is consistent with the presence of M2-receptors in this tissue. Moreover, the pA2 values obtained for both 4-DAMP and HHSiD are in agreement with the presence of M3-receptors, due to the lack of effect of pirenzepine on M1-muscarinic receptors. These results indicate the existence of a rich parasympathetic innervation in the sheep detrusor muscle and suggest that its contraction could be mediated by the stimulation of muscarinic receptors belonging to both M3- and M2-subtypes.     

Skeletal muscle characteristics of sprint cyclists and nonathletes

Muscle fiber distribution and muscle enzyme activity (m. vastus lat.) were investigated in 10 elite sprint cyclists and 12 nonathletes. The ratio of fast to slow muscle fibers was 2:3 in cyclists and 3:2 in nonathletes. The mean diameter of each muscle fiber type was significantly higher in the athletes. The mean enzyme activity values in mu kat X g-1 w.w. for cyclists and nonathletes, respectively, were as follows: triosephosphate dehydrogenase (TPDH), 6.2 and 3.78; lactate dehydrogenase (LDH), 4.4 and 4.59; citrate synthase (CS), 0.154 and 0.13; hydroxyacyl-CoA dehydrogenase (HAD), 0.041 and 0.07. The mean difference between groups in TPDH and in (TPDH + LDH)/(CS + HAD) ratio were statistically significant. Maximum voluntary isometric strength (knee extension) was about 17% greater in cyclists than the mean value for Czechoslovakian men of the same age. A strong positive correlation (r = 0.72) between the percent of fast glycolytic fibers (type II B) and isometric strength was observed in the cyclists. Furthermore, mean weight-compensated maximal oxygen consumption (VO2 max, ml X kg-1 X min-1) for all subjects (n = 22) was significantly related to percent of slow oxidative fibers (type I) (r = 0.75) and to the mean diameter of type II B (r = 0.58), fast oxidative-glycolytic fibers (type II A) (r = 0.68) and type I fibers (r = 0.59).     

Application of the Population Health Approach to Drinking Water System Surveillance

A drinking water supply is a complicated system in its construction,operation,maintenance and need for public health surveillance.     

Strategies for Reducing Risks in Smoking: Opportunity or Threat?

The smoking control policies recommended by the World Health Organisation have achieved a slight decrease in smoking prevalence in developed countries, although associated mortality is still very high. The use of tobacco products other than cigarettes and even medicinal nicotine (known as nicotine replacement therapy [NRT]) has been proposed as a risk reduction strategy. Among the tobacco products with less individual risk than cigarettes would be any type of tobacco without smoke (smokeless) with a low content in nitrosamines and modified cigarettes; both forms included under the PREP (Potentially Reduced Exposure Products) concept. The idea would be to promote these products among patients who cannot quit smoking or wish to reduce their risk without giving up nicotine intake. The possible effects of risk reduction strategies, including PREP, on the decreased prevalence and morbidity and mortality are reviewed, and the possible implications that this measure could have in Spain are analysed. Tobacco control measures in Spain have only been made recently and are still insufficient. Therefore, the current priority in Spain is to develop control policies that have proven to be more than effective. The marketing and advertising of new tobacco products, even with reduced potential risk, seems more a serious threat than an opportunity for developing smoking control policies.     

Enhanced dispersion of atrial refractoriness as an electrophysiological substrate for vulnerability to atrial fibrillation in patients with paroxysmal atrial fibrillation.

Atrial electrical remodeling plays a part in recurrence of atrial fibrillation (AF). It has been related to an increase in heterogeneity of atrial refractoriness that facilitates the occurrence of multiple reentry wavelets and vulnerability to AF. AIM: To examine the relationship between dispersion of atrial refractoriness (Disp_A) and vulnerability to AF induction (A_Vuln) in patients with clinical paroxysmal AF (PAF). METHODS: Thirty-six patients (22 male; age 55+/-13 years) with > or =1 year of history of PAF (no underlying structural heart disease--n=20, systemic hypertension--n=14, mitral valve prolapse--n=1, surgically corrected pulmonary stenosis--n=1), underwent electrophysiological study (EPS) while off medication. The atrial effective refractory period (AERP) was assessed at five different sites--high (HRA) and low (LRA) lateral right atrium, high interatrial septum (IAS), proximal (pCS) and distal (dCS) coronary sinus--during a cycle length of 600 ms. AERP was taken as the longest S1-S2 interval that failed to initiate a propagation response. Disp_A was calculated as the difference between the longest and shortest AERP. A_Vuln was defined as the ability to induce AF with 1-2 extrastimuli or with incremental atrial pacing (600-300 ms) from the HRA or dCS. The EPS included analysis of focal electrical activity based on the presence of supraventricular ectopic beats (spontaneous or with provocative maneuvers). The patients were divided into group A--AF inducible (n=25) and group B--AF not inducible (n=11). Disp_A was analyzed to determine any association with A_Vuln. Disp_A and A_Vuln were also examined in those patients with documented repetitive focal activity. Logistic regression was used to determine any association of the following variables with A_Vuln: age, systemic hypertension, left ventricular hypertrophy, left atrial size, left ventricular function, duration of PAF, documented atrial flutter/tachycardia and Disp_A. RESULTS: There were no significant differences between the groups with regard to clinical characteristics and echocardiographic data. AF was inducible in 71% of the patients and noninducible in 29%. Group A had greater Disp_A compared to group B (105+/-78 ms vs. 49+/-20 ms; p=0.01). Disp_A was >40 ms in 50% of the patients without A_Vuln and in 91% of those with A_Vuln (p=0.05). Focal activity was demonstrated in 14 cases (39%), 57% of them with A_Vuln. Disp_A was 56+/-23 ms in this group and 92+/-78 ms in the others (p=0.07). Using logistic regression, the only predictor of A_Vuln was Disp_A (p=0.05). CONCLUSION: In patients with paroxysmal AF, Disp_A is a major determinant of A_Vuln. Nevertheless, the degree of nonuniformity of AERP appears to be less important as an electrophysiological substrate for AF due to focal activation.     

Impact of a specialized outpatient heart failure follow-up program on hospitalization frequency and functional status of patients with advanced heart failure.

BACKGROUND: High rates of morbidity and mortality are observed in patients with advanced heart failure (AHF). AHF is now considered the most costly syndrome in cardiology owing to the substantial economic burden associated with hospitalizations for acute decompensation. A management program that involves specialized follow-up by a multidisciplinary team has been suggested as a desirable strategy for improving outcomes for these patients. ObjectivE: To evaluate the impact of a specialized outpatient heart failure (HF) follow-up program for patients with AHF on frequency and duration of hospitalization for HF and functional status. METHODS: We retrospectively studied 167 consecutive patients with AHF who were referred to the outpatient HF follow-up program in our institution between January and November 2002, of whom 147 followed for > or =30 days were included in the analysis. In addition to demographic and baseline clinical characteristics, HF medication and NYHA functional class, the number and duration of hospitalizations for HF during the previous 12 months were recorded and compared at the time of referral and after a follow-up period of 6.5+/-3 months. RESULTS: Of the 147 patients analyzed (aged 60.8+/-13 years; 79% male; left ventricular ejection fraction 27+/-11%), 67% were in NYHA functional class III, 20% in class II and 13% in class IV at the time of referral. There was a significant improvement in functional class during the mean follow-up period: 55% of the patients were in class III, 37% in class II, 5% in class I and 3% in class IV (p<0.0001). The proportion of patients on beta-blockers or spironolactone increased from 33% and 51% at the time of referral to 69% and 71% respectively after referral (p<0.0001). In the 12 months before referral, 39% of the patients had been hospitalized for acute decompensation of HF (87 hospitalizations - mean 7.2/month) versus 13% of the patients during the mean follow-up period (25 hospitalizations - 3.8/month, p<0.0001). No significant differences were found in the proportion of patients on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, digoxin or diuretics, or in the mean duration of hospitalization before and after referral. ConclusioN: The specialized follow-up of patients with AHF by a team with expertise in HF resulted in significant therapeutic optimization. Increased use of beta-blockers and spironolactone was associated with significant improvement in functional capacity and significant reduction in hospitalizations.     

Capillary blood flow as an index of the therapeutic effect of folinic acid in ischemia-reperfusion syndrome]

OBJECTIVE: An intestinal reperfusion study with two aims: a) to assess the usefulness of intestinal capillary blood flow measurement by laser-Doppler for intestinal reperfusion studies; and b) to compare the effects of racemic and levo forms of folinic acid in treating the syndrome. EXPERIMENTAL DESIGN: A murine model of intestinal ischemia by completely clamping the superior mesenteric artery for 90 minutes. A comparison was made of three treatment groups: saline, folinic acid, and levo-folinic acid. The following factors were analyzed: changes in biochemical parameters (levels of creatine kinase, lactic dehydrogenase, and alkaline phosphatase at 60 minutes, and at two and seven days after restoring blood flow), capillary flow in the jejunum and ileum by laser-Doppler (during ischemia and after the first hour of reperfusion), intestinal mucosa injury, and survival curve. RESULTS: Laser-Doppler provided reliable data on how the different treatments affected capillary flow during intestinal reperfusion. Levo-folinic acid improved capillary flow in the ileum after 25 minutes of reperfusion, and also reduced mucosal injury in the same stretch of intestine by the seventh day post-reperfusion (p<0.05). On the other hand, it produced an initial increase in serum enzymes during reperfusion, and did not modify survival. CONCLUSIONS: The changes observed in intestinal capillary blood flow measurement by laser-Doppler have similarities with the effects of drugs on pathological mucosal changes. We could not prove that the levo form of folinic acid has a stronger protective effect versus racemic folinic acid in intestinal ischemia-reperfusion syndrome.