ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE IN HUMAN PROSTATE CANCER

PURPOSE: To investigate the level of expression, activation state, and functional significance of extracellular signal regulated kinase (ERK) in prostate cancer. MATERIALS AND METHODS: Human prostate tissue samples (n = 22) were obtained from patients undergoing radical prostatectomy for localized adenocarcinoma of the prostate (n = 16, age range 44 to 72 years) or normal prostate specimens (n = 6, age ranges 19 to 47 years) obtained from rapid autopsy. Immunoblots, in vitro kinase assays, and immunohistochemistry were used to determine the expression and activation state of ERK in human prostate cancer. RESULTS: Immunoblot and in vitro kinase assays demonstrated a 15-fold increase in ERK activation in prostate cancer specimens compared with normal human prostate tissue; however, ERK expression levels were only 1.3-fold higher in cancer. Immunohistochemical analysis demonstrated similar expression of ERK in cancer and normal tissues; however, phosphorylated ERK demonstrated greater intensity in the cancer specimens. Experiments conducted on a prostate cancer cell line demonstrated that EGF induced activation of ERK and cellular proliferation was partially inhibited by PD98059, a chemical inhibitor of the immediate upstream signaling component responsible of activation of ERK. CONCLUSIONS: Collectively, these data demonstrate a dramatic increase in ERK activation in prostate cancer compared with normal prostate tissue and suggest that inhibitors designed to target this signal transduction cascade might have therapeutic benefit in the treatment of prostate cancer.     

Knowledge of residual curarization: an Italian survey

Background: The use of neuromuscular blocking agents (NMBAs) is widespread in anesthetic practice; little is known about the current use of these drugs in Italy. This survey was conducted to obtain information about the most commonly used clinical tests and the train‐of‐four (TOF) ratios that are considered as being reliable for assessing recovery from neuromuscular blockade at the end of anesthesia and the estimated occurrence rates of post‐operative paralysis in Italian hospitals. Methods: The questionnaire was given to Italian anesthesiologists attending the 62nd National Congress of the Italian Society of Anesthesia, Analgesia and Intensive Therapy. Collected data were stratified by age and the total number of surgical procedures performed in the hospitals concerned. Results: Seven hundred and fifty‐four correctly compiled questionnaires were collected (response rate 88.7%). Seventy three percent of the respondents only used clinical tests for monitoring the level of neuromuscular blockade. The main clinical tests cited for the evaluation of residual paralysis were keeping the head lifted up for 5 s, protruding the tongue and opening the eyes. TOF was used by 35% of the respondents on a routine basis. Only 24% of the interviewed anesthesiologists reported that before extubation, a TOF ratio of at least 0.9 should be reached. Conclusions: Most Italian anesthetists assess the recovery from neuromuscular blockade only by clinical signs. There is poor awareness about the inability of such techniques to indicate even a significant amount of residual neuromuscular block. A more extensive use of quantitative instrumental monitoring is required for the more rational use of NMBAs.     

Endocrine, seminal and peripheral effects of depot medroxyprogesterone acetate and testosterone enanthate in men

Depot medroxyprogesterone acetate (D-MPA, 250 mg) and testosterone enanthate (TE, 200 mg) were administered twice with a 4-week interval to nine healthy men, and the levels in blood of steroids, gonadotrophins, lipoproteins, sex hormone binding globulin (SHBG) and prostaglandins (PGs) were measured, as well as steroid levels in semen and the sperm count and motility. The hormones analysed were: MPA, testosterone, androstenedione (A), dihydrotestosterone (DHT), oestradiol (E2), cortisol (C), luteinizing hormone (LH), follicle stimulating hormone (FSH) and the sulphoconjugated forms (-S) of testosterone, DHT, pregnenolone (5-P) and dehydroepiandrosterone (DHEA). Peak values of MPA (10.2 +/- 4.6 nmol/l) and testosterone (28.0 +/- 10.0) were found in the first blood samples 2 days after each injection. Thereafter the levels of MPA decreased gradually and reached the limit of detection 18-20 weeks after the second injection. Blood levels of testosterone fell sharply from the peak values and were grossly subnormal 2 weeks after each injection; levels did not return to pretreatment values during 24 weeks of follow-up. The pattern of change of DHT, A, E2 and sulphonated androgens was similar to that of testosterone. These data suggest that D-MPA and TE are absorbed at similar rates, and that the TE is metabolized rapidly. The subsequent reduction in the levels of A, testosterone-S and DHT-S was less marked and reached pretreatment values earlier than did the testosterone levels. No obvious changes were found in the levels of C, 5-P-S and DHEA-S or in the seminal plasma levels of the various steroids studied. The blood levels of LH and FSH fell precipitously 2 days after the first injection, then started to increase 4 weeks after the second injection to reach pretreatment values 12 weeks later. Of the lipoproteins studied only the levels of HDL-cholesterol and SHBG were found suppressed after treatment. Severe oligozoospermia and the complete absence of progressively motile sperm, in at least one semen sample, was observed in all subjects at 3-7 and at 5-16 weeks, respectively, after the last injection, suggesting that the men were infertile for at least 1 month after treatment. A spurious increase in the PG content of semen was also observed. In spite of the low blood testosterone levels, no subject reported changes in sexual behaviour or other signs of anabolic imbalance during or after the study. However, the increase in levels of E2 in some individuals should be kept in mind as a possible cause of side-effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hypercortisolism after opioid discontinuation in rapid detoxification of heroin addicts

Long-term opioid consumption can induce hypoadrenalism through impairment of the hypothalamic-pituitary-adrenal axis. Results of the present study showed that, in heroin addicts, saliva cortisol concentrations varied according to the amount of recently consumed heroin and the time elapsed since the last self-administration. Hypercortisolism was observed either after abrupt withdrawal of heroin or the last dose of methadone. Post-detoxification hypercortisolism was still present on day 16 after the last opioid consumption, whereas it was not observed in abstinent addicts for a mean period of 4 months. During detoxification treatment, mean AUC_8–24 cortisol in saliva of clonidine or guanfacine-treated patients was significantly higher than that in methadone- treated patients. It may be hypothesized that elevated cortisol levels may account for untoward effects of adrenergic agonist therapy which, in turn, may represent an added risk factor for relapse during detoxification. Further studies are necessary to correlate the severity of withdrawal symptoms to cortisol levels in opioid addicts detoxified with α₂-adrenergic agonist substitution.