Aberrant promoter methylation of multiple genes in malignant ovarian tumors and in ovarian tumors with low malignant potential

BACKGROUND: Methylation-mediated suppression of detoxification, DNA repair, and tumor suppressor genes has been implicated in cancer development and progression. Studies also have indicated that concordant methylation of multiple genes (methylator phenotypes), rather than a single gene, may predict cancer prognosis. The current study was designed to determine whether a methylator phenotype exists in ovarian cancer, whether methylation frequencies differ between malignant ovarian tumors and ovarian tumors with low malignant potential (LMP or borderline), and whether methylation of multiple genes affects patient survival. METHODS: The current study included 234 consecutively diagnosed patients with either LMP (n = 19 patients) or malignant (n = 215 patients) ovarian tumors. DNA samples were extracted from fresh frozen tissues and were analyzed for methylation in the promoter region of 6 genes (p16, breast cancer 1 [BRCA1], insulin-like growth factor-binding protein 3 [IGFBP-3], glutathione S-transferase pi 1 [GSTP1], estrogen receptor-alpha [ER-alpha], and human MutL homologue 1 [hMLH1]) by using methylation-specific polymerase chain reaction analysis. RESULTS: The frequencies of methylation in malignant tumors and LMP tumors were 0% and 0% for GSTP1, respectively; 9% and 0% for hMLH1, respectively; 21% and 5% for BRCA1, respectively; 42% and 21% for p16, respectively; 44% and 26% for IGFBP-3, respectively; and 57% and 42% for ER-alpha, respectively. A methylator phenotype was not detected, but a calculated methylation index (MI) that was based on the total number of genes methylated in each tumor was associated with ovarian cancer risk and progression. A higher MI was associated with malignant tumors (odds ratio, 10.11; 95% confidence interval [95% CI], 1.19-85.75) and disease progression (hazards ratio, 6.53; 95% CI, 1.39-30.65). CONCLUSIONS: Although a methylator phenotype was not identified, the current results suggested that methylation of multiple genes may play an important role in ovarian cancer development and progression and may have clinical implications in prognosis.     

Remifentanil vs fentanyl with a target controlled propofol infusion in patients undergoing craniotomy for supratentorial lesions

AIM: Remifentanil hydrochloride is an ultra-short acting m-opioid receptor agonist. This study compared the use of remifentanil with that of fentanyl during elective supratentorial craniotomy in a target controlled infusion (TCI)-propofol anesthesia regimen and evaluated the quality of recovery from anesthesia. METHODS: After written informed consent for this prospective study, 40 adult patients were randomly divided into 2 groups: in group F analgesia was provided with fentanyl 2-3 mg kg(-1) h(-1) and in group R with remifentanil 0.25 mg kg(-1) h(-1). Anesthesia was induced with thiopental and pancuronium bromide, and maintained with propofol-TCI, pancuronium, air and oxygen and fentanyl (group F) or remifentanil (group R), respectively. After tracheal intubation, infusion rate of remifentanil was reduced and then adjusted to maintain stable hemodynamics. Hemodynamics and recovery time were monitored for 60 min after surgery. Analgesic requirements, propofol intraoperative consumption, nausea and vomiting in postoperative period were monitored. Recovery was evaluated according to a modified Aldrete score. RESULTS: Baseline hemodynamics were similar in both groups. Mean arterial pressure differed between the 2 groups (P<0.05) with the greatest decrease in group R during dura opening (P<0.001). Postoperative mean arterial pressure was higher in group R. Patients in group R exhibited a faster recovery. The incidence of nausea and vomiting was similar in the 2 groups. Noteworthy, there was a reduction in the amount of propofol used in group R. CONCLUSIONS: Remifentanil appears to be a reasonable alternative to fentanyl during elective surgery of supratentorial lesions.     

Neurobehavioral effects of prenatal exposure to AZT: a preliminary investigation with the D1 receptor agonist SKF 38393 in mice

Zidovudine (AZT) is the main therapeutic agent against HIV vertical transmission and is routinely administered to seropositive pregnant women and their newborns. Toxicity after chronic administration as well as citogenetic effects following developmental AZT exposure has been reported. Furthermore, recent animal data indicate alterations of several behavioral endpoints during the entire lifespan of mice and rats after developmental AZT exposure. In this study, we investigated specific central nervous system (CNS) effects of AZT administration during pregnancy on the offspring. CD-1 mouse females were administered twice daily from day 10 of pregnancy until delivery with either AZT (160 mg/kg) or saline (0.9% NaCl). On PND, 60 male offsprings received an intraperitoneal injection of the D1 receptor agonist 2,3,4,5-tetra-hydro-7,8-diol-1-phenyl-(1H)-3-benzazepine (SKF 38393) (0, 3, and 10 mg/kg), and spontaneous behavior was assessed in an automated activity chamber for 40 min. At variance from what observed in control mice that displayed excessive grooming when administered the higher dose of the D1 agonist, SKF 38393 failed to increase duration of grooming in AZT-treated mice. These data suggest that the D1 receptorial dopaminergic subsystem might be hyporesponsive in mice prenatally exposed to AZT.     

Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer's disease

BACKGROUND: Although epidemiological, clinical, and experimental evidence indicates that the inducible isoform of cyclo-oxygenase (COX-2) may be involved in the pathogenesis of several neurodegenerative disorders, the mechanisms whereby COX-2 contributes to Alzheimer's disease are largely unknown. OBJECTIVE: To undertake a longitudinal study of CSF levels of a major product of COX activity, prostaglandin E2 (PGE2), in relation to cognitive decline and survival in patients with Alzheimer's disease. METHODS: CSF PGE2 was measured on at least three annual visits in 35 controls and 33 Alzheimer patients (26 necropsy confirmed) who completed the Cambridge cognitive assessment (CAMCOG). RESULTS: Compared with controls, CSF PGE2 was higher in patients with mild memory impairment, but lower in those with more advanced Alzheimer's disease. The median survival time of patients with higher initial PGE2 levels was five years longer than those with lower levels. CONCLUSIONS: COX activity in Alzheimer's disease varies with stage of the disease. PGE2 levels correlate positively with patient survival. These findings suggest that inhibition of COX activity does not represent a major target for the pharmacological treatment of Alzheimer's disease.     

Obstacles to collaborative quality improvement: the case of ambulatory general medical care.

OBJECTIVE: To assess the effectiveness of inter-site collaboration and report-card style feedback of quality measures on quality improvement in the outpatient setting and to identify major barriers to improvement. DESIGN: A collaborative quality improvement effort consisting of a large cross-sectional data collection effort (chart reviews and patient surveys), feedback of comparative quality of care data to improvement teams, and collaboration between sites. SETTING: Eleven primary care sites in the Boston area. STUDY PARTICIPANTS: Quality improvement teams at each site with physician leaders. INTERVENTION: Education about techniques of rapid-cycle quality improvement, coaching of on-site teams, and report-card style feedback of comparative site-specific quality of care data. RESULTS: Multiple quality improvement projects were undertaken through this collaboration. However, though we were careful to educate teams on methods of continuous quality improvement and to name specific clinical leaders, the degree of collaboration and quality improvement fell short of expectations. Major impediments to improvement included lack of team members' time and resources, lack of incentives, and unempowered team leadership. The primary obstacle to collaboration was the diversity of sites and inability of teams to create interventions that were relevant to other sites. CONCLUSION: Despite ample quality of care data, quality improvement education, and a structured collaborative process, achieving quality improvement in the ambulatory setting is still a difficult challenge. Organizations need to find ways of overcoming the obstacles faced by improvement teams in order to maximize quality improvement.     

Oral contraceptives highlight the genotype-specific association between serum phospholipids and activated factor VII.

The present analysis was undertaken to study the effect of oral contraceptive (OC) use on activated factor VII (FVIIa) in subjects characterized by FVII genotypes, with the further aim of evaluating the role of lipids in this pharmacological interaction. In OC users (n=42) and nonusers (n=130) of comparable age, we examined the FVII phenotypic variables (FVII coagulant activity [FVIIc], FVII antigen, and FVIIa), FVII genotypes (the 353R/Q and 5'F7 polymorphisms analyzed in combination; alleles M1/M2 and A1/A2, respectively), and a number of lipid and lipoprotein parameters: serum concentrations of total cholesterol (chol), low density lipoprotein and high density lipoprotein-chol, triglycerides, phospholipids (PhLs), apolipoprotein A1, and lipoprotein(a). PhLs, triglycerides, apolipoprotein A1, chol, FVII antigen, FVIIc, and high density lipoprotein-chol levels were shown to be statistically higher in users than nonusers. FVII levels, particularly those of FVIIa and FVIIc, were much higher in homozygotes for the A1 and M1 alleles (A11 M11), especially in OC users. A strong association was found between PhL and FVIIa: in the multiple regression analysis, women taking OCs who had elevated PhL concentrations also had very high levels of FVIIa, but only if their genotype was A11 M11. These results indicate that the increased FVII levels in OC users depend on the FVII genotype and that high PhL concentrations predict very high levels of FVIIa and FVIIc.     

Working together to build a respectful workplace: transforming OR culture

Respect is important in the creation of a positive perioperative work environment and effective OR teams. Low scores for respect in the OR on an employee opinion survey and responses on a more customized survey that examined issues associated with respect prompted leaders at the University Health Network to undertake a multiyear organizational strategy to address respect and quality of worklife initiatives. An interprofessional quality of worklife task force convened to create an action plan to address the outcomes of the surveys. The work of the task force included developing and implementing a code of conduct team charter for the OR, empowering leaders to better manage conflict through education and coaching, creating a collaborative, consistent approach to conflict resolution, and designing an education strategy for staff members to enhance communication and conflict resolution. Results of recent employee opinion surveys have reflected positive outcomes. Efforts to sustain the effects of the project include quarterly recognition awards and ongoing education focused on wellness and communication skills.     

Klotho expression in epithelial ovarian cancer and its association with insulin-like growth factors and disease progression

Klotho is an anti-aging hormone and is able to suppress the action of IGFs. High IGF activities are associated with cancer risk and tumor progression. Klotho's role in cancer is unknown. To evaluate Klotho expression in ovarian cancer and its association with IGFs and ovarian cancer progression, a clinical follow-up study of 189 ovarian cancer patients was conducted. Patients were recruited from a teaching hospital at University of Turin in Italy. All patients were diagnosed with epithelial ovarian cancer and underwent surgery for the disease. Fresh tumor tissue was collected from each patient during surgery. Patient clinical and pathological information was collected, including patient age at surgery, disease stage, tumor grade, tumor histology, residual tumor size, debulking result, post-operative chemotherapeutic agent, treatment response, follow-up time and survival outcome. Expressions of total and secreted Klotho as well as IGFs in tumor tissue were analyzed using quantitative real-time PCR. Survival analysis was performed to evaluate the association of Klotho expression with the risk of disease progression and death using Cox proportional hazards regression model. High expression of secreted Klotho was associated with increased risk of disease progression and death. These associations were independent of patient clinical and pathological characteristics. Expression of secreted Klotho was positively correlated with the expression of IGF-I and IGFBP-3 but not with IGF-II. In conclusion, Klotho expression is associated with epithelial ovarian cancer progression, and the protein may serve as an independent marker for ovarian cancer prognosis. Klotho's role in cancer warrants further elucidation.