Impaired prostate tumorigenesis in Egr1-deficient mice.

The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.

Non-use of cancer information services among people experiencing cancer in Ireland.

PURPOSE: The purpose of this study was to explore the reasons for non-use of a national cancer society's cancer information services among people experiencing cancer. METHOD: This study used a qualitative design. Semi-structured interviews were conducted with a total of 17 participants who had not previously utilised the Cancer Society's information services. Data were analysed using Thematic Analysis. RESULTS: The key themes to emerge from the date were 'living in the here and now' and 'awareness of the Cancer Society'. For most participants, not utilising cancer information services was a means of coping with the initial diagnosis and the impact of treatment. Those who progressed to being ready to seek information identified the multi-disciplinary team as the primary source of trusted information, with particular mention of cancer nurse specialists. For participants with children, their role as a parent was central in how they managed their diagnosis. The majority of participants lacked awareness of the range of services provided by the Cancer Society. CONCLUSIONS: Reasons for non-use of cancer information services were identified as: readiness to seek information and a lack of knowledge of the Cancer Societies' services. Cancer information services need to continue make a concerted effort to enhance visibility and awareness of its services to optimise patient engagement.

Decline in research publications from the United Kingdom in anaesthesia journals from 1997 to 2006.

We undertook this survey to identify the trend in the published output of original research in anaesthesia emanating from the United Kingdom (UK) in a 10-year period from 1997 to 2006, inclusive. We examined seven major anaesthetic journals for each of the 10 years, and four other specialist journals for the years 1997, 2000, 2003 and 2006. We included papers on experimental research, randomised controlled clinical trials, large observational studies and case series, formal equipment and apparatus assessments, but we excluded editorials, comments, reviews including systematic reviews, special articles, small case series and case reports, questionnaire surveys of clinical practice and correspondence. We found a highly significant reduction in published research output from the UK in the period under study (% change per year; -5.7 (95% CI -7.4 to -4.0), a trend which was significantly different (p < 0.001) from the trend of changes in research publications worldwide (-1.0% change per year; 95% CI -1.7 to 0.0). We discuss the implications of these findings for UK anaesthesia research strategy.

Regional variation in prescribing for chronic conditions among an elderly population using a pharmacy claims database.

BACKGROUND: Age, gender and geographical regions are recognised factors in inequalities in prescribing for chronic diseases in the elderly. AIM: To compare the health board regional distribution of chronic disease among the elderly and to examine variation in quality prescribing across age, gender and regions. METHODS: Population based study of prescribing for chronic disease using a national pharmacy claims database. All individuals aged 70 years and over (n = 271,518) were eligible. RESULTS: Over 60% of the elderly in all regions received cardiovascular related medication. The South Eastern, North Western and Western Health Boards had below average prescribing for many chronic conditions. Logistic regression identified age, gender and regional variations in prescribing of preventative therapies for CVD and diabetes. CONCLUSION: There is a high prevalence of prescribing for chronic conditions in the elderly in Ireland, and there is evidence of gender, age and residing health board inequalities in prescribing.

Folate absorption in alcoholic pigs: in vitro hydrolysis and transport at the intestinal brush border membrane.

We used the miniature pig to evaluate the effect of ethanol ingestion on the hydrolysis of pteroylpolyglutamate and on the uptake of pteroylmonoglutamate (PteGlu) by the intestinal brush border membrane, processes that are required for folate absorption. After feeding ethanol or sucrose at 60% of calories for 11 mo, the uptake of PteGlu by jejunal brush-border-membrane vesicles was similar in both groups of animals. Jejunal brush border pteroylpolyglutamate hydrolase was decreased by one-half in the ethanol-fed group. Jejunal brush-border-membrane fluidity, measured by fluorescence polarization, was similar in both groups. Acute exposure of the jejunal vesicles to ethanol increased membrane fluidity and decreased hydrolase activity but had no effect on PteGlu transport. Inhibition of jejunal folate hydrolase by chronic exposure to ethanol may be an early effect in the pathogenesis of folate malabsorption and deficiency in chronic alcoholism.

Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma.

The transcription factor EGR1 is frequently overexpressed in human prostate cancer and regulates the expression of several genes important for tumor progression. In addition, mice lacking the Egr1 gene show a defect in prostate tumorigenesis. NAB2 is a novel corepressor molecule that modulates EGR1 activity and is induced by the same stimuli that induce EGR1. The human NAB2 gene has been localized to 12q13.3-14.1, within a chromosomal region that is thought to harbor a prostate tumor suppressor. We have examined the expression of NAB2 in human prostate carcinoma specimens. We show here that NAB2 protein expression is lost in a majority of primary prostate carcinoma specimens, including many samples that have high EGR1 levels. This loss occurs early in the tumorigenic process and is sustained, as it is seen in precursor prostatic intraepithelial neoplasia lesions as well as in metastases. Furthermore, loss of NAB2 did not correlate with the tumor grade or stage. Our findings suggest that high levels of EGR1 coupled with low levels of NAB2 can result in high, unrestrained EGR1 transcriptional activity in human prostate cancers.

Clinical and pathologic tumor characteristics of prostate cancer as a function of the number of biopsy cores: a retrospective study.

OBJECTIVES: Many men with negative prostate biopsies and persistently elevated serum total prostate-specific antigen (tPSA) values will have cancer detected on a repeated biopsy. An important issue is whether the cancer would have been detected on the initial biopsy had more biopsy samples been obtained. The objective of our study was to retrospectively characterize the clinical and pathologic tumor features associated with men who underwent sextant core biopsies compared with men who needed more than six core biopsies during one or more biopsy sessions to detect prostate cancer. Transrectal ultrasound (TRUS)-estimated prostatic volume was evaluated to determine whether the number of biopsy cores needed for prostate cancer detection was influenced by gland size. METHODS: We retrospectively evaluated the number of biopsy core samples obtained in 185 men (mean age 63+/-6 years) enrolled in our PSA-based screening study for prostate cancer who were found to have prostate cancer and elected radical prostatectomy as treatment. Correlation coefficients were calculated and univariate analyses were performed to evaluate clinical (age, tPSA, TRUS volume, PSA density) and pathologic (Gleason score, pathologic weight, organ confinement, "possibly harmless" cancer) characteristics associated with men who required more biopsy cores to detect the cancer. RESULTS: Of the 185 men, 103 (56%) had 6 or fewer total biopsy cores taken and 82 (44%) had more than 6 cores (44 [24%] of 185 had 7 to 12 cores and 38 [20%] of 185 had 13 or more cores). There was a positive correlation between age, serum tPSA, TRUS-determined prostate volume, and pathologic specimen weight and an increasing number of total cores (all P values < 0.05). The number of biopsy cores was not associated with PSA density, Gleason score, cancer volume, organ confinement, or "possibly harmless" cancers (all P values > 0.05). Men with a TRUS volume 30 cc or less (46%) required a mean of 8 total cores to detect the cancer compared with a mean of 11 cores (P = 0.003) in men with a TRUS volume greater than 30 cc (54%). A greater percentage of men with a TRUS prostate volume greater than 30 cc compared with men whose volume was 30 cc or less would have had their cancer missed with only a six-core biopsy (64% versus 46%, P = 0.01). CONCLUSIONS: Sextant core biopsies may be inadequate to detect prostate cancer in some men. These data support the performance of more than six core biopsies to detect clinical prostate cancer. A prospective trial using TRUS-determined prostate volume to determine the number of cores to take is needed to accurately assess this issue.

Reasons for prolonged hospital stays following heart surgery.

Improvements in cardiac surgery techniques and after care have resulted in a reduction in postoperative stay. Ten years ago the average length of stay following surgery was 13-15 days (Sanchez et al, 1994). Today it is more likely to be 4-7 days (Bemat, 1997). A recent audit provided information on postoperative hospitalization in a cardiac population that was deemed suitable for immediate high dependency care rather than intensive care. The authors carried out retrospective examination of patients' notes in order to detect the possible causes for delayed discharge. The audit was conducted over a 3-month period and information was collected on 210 postoperative cardiac patients. The study population was restricted to all cardiac patients transferred directly to the hospital's 'overnight intensive recovery' unit. These patients are regarded as low- to medium-risk cardiac patients. Thirty seven per cent of the study population experienced a prolonged hospital stay, i.e. greater than 7 days. In the majority of cases the reasons for delayed discharge were non-cardiac in origin. The authors reviewed the literature to identify strategies that may reduce the incidence of preventable complications leading to prolonged hospitalization. They concluded that nurses have a fundamental role to play in reducing the incidence and severity of postoperative complications through patient education, motivation and early identification of potential problems.

A comparison of antibiotic point prevalence survey data from four Irish regional/general hospitals.

INTRODUCTION: Point prevalence surveys (PPS) are increasingly used to examining and compare hospital antibiotic consumption. The aim of this study was to identify the (1) point prevalence of antibiotic use in one regional hospital and (2) compare PPS data from similar regional/general hospitals. METHODS: Data were collected on all inpatients with an active antibiotic prescription and on all prescriptions issued in the emergency department over a 24-h period. Point prevalence data were obtained from three other regional/general hospitals. RESULTS: The frequency of antibiotic use was hospital A = 29%, B = 38%, C = 34% and D = 37%. Overall, the most commonly prescribed antibiotic was co-amoxiclav (30%), followed by macrolides (12%). However, new generation broad-spectrum antibiotics, such as piperacillin/tazobactam or ciprofloxacin, were also commonly used. Prescribing for common conditions such as respiratory infection or cellulites showed diverse antibiotic selection. CONCLUSION: Point prevalence survey data using a standardised methodology could facilitate both local audit and national benchmarking to monitor antibiotic use.

The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers.

Transcriptomic screens in breast cancer cell lines have identified a protein named anterior gradient-2 (AGR2) as a potentially novel oncogene overexpressed in estrogen receptor (ER) positive tumours. As targeting the ER is responsible for major improvements in cure rates and prevention of breast cancers, we have evaluated the pro-oncogenic function of AGR2 in anti-hormone therapeutic responses. We show that AGR2 expression promotes cancer cell survival in clonogenic assays and increases cell proliferation and viability in a range of cancer cell lines. Chromatin immunoprecipitation and reporter assays indicate that AGR2 is transcriptionally activated by estrogen through ERalpha. However, we also found that AGR2 expression is elevated rather than inhibited in response to tamoxifen, thus identifying a novel mechanism to account for an agonistic effect of the drug on a specific pro-oncogenic pathway. Consistent with these data, clinical analysis indicates that AGR2 expression is related to treatment failure in ERalpha-positive breast cancers treated with tamoxifen. In contrast, AGR2 is one of the most highly suppressed genes in cancers of responding patients treated with the anti-hormonal drug letrozole. These data indicate that the AGR2 pathway represents a novel pro-oncogenic pathway for evaluation as anti-cancer drug developments, especially therapies that by-pass the agonist effects of tamoxifen.

The impact of age on 6-month survival in patients with cardiovascular risk factors undergoing elective non-cardiac surgery.

An increasing number of patients aged>or=70 years are presenting for elective non-cardiac surgery. We undertook this study to: (i) compare the nature and distribution of cardiovascular disease (CVD) risk factors in an at risk population of patients aged>or=70 years undergoing elective surgery compared with a younger at risk cohort; and (ii) identify the impact of age and other risk factors on 6-month survival. We conducted a prospective observational study of patients undergoing elective non-cardiac surgery. A total of 1622 patients aged>or=40 years with recognised surgical or patient-specific risk factors for CVD were identified. The patients were divided into two groups; group 1 (aged: 40-69 years) and group 2 (aged>or=70 years). Logistic regression was used to identify the factors associated with 6-month mortality. Odds ratios (OR) and 95% confidence interval (CI) are presented. In hospital, mortality was similar in both groups. However, 6-month mortality in those aged>or=70 years was significantly higher (p=0.001). Cardiovascular symptoms were significantly more common in group 2 (p<0.001) as were cardiovascular-related deaths (p=0.04) at 6 months follow-up. Preoperative cardiovascular preventative therapy was under prescribed in the elderly cohort. Factors independently associated with 6-month mortality were aged>or=70 (OR=3.57, 95% CI: 2.22-5.73), angina (OR=2.0, 95% CI: 1.26-3.20), renal impairment (OR=2.39, 95% CI: 1.17-4.89) also operation type and duration. Despite similar in-hospital mortality, those aged>or=70 years had significantly higher 6-month mortality than the younger surgical cohort. Cardiovascular deaths were significantly higher in patients aged>or=70 years. Effective identification and the management of cardiovascular risk factors may improve 6-month survival.

Retrograde endopyelotomy in association with active distal ureteral dilation: a contraindication for the use of the 7F ureteral "tail" stent.

Since its introduction in 1997, the 7F "Tail" stent has been used after a variety of endourologic procedures. We describe 2 patients who underwent retrograde endopyelotomy with distal ureteral dilation; in both patients, after placement of a 7F "Tail" stent, a clinically significant urinoma developed. We believe that in the setting of extensive distal ureteral manipulation or distal active ureteral dilation to greater than 10F, placement of a "Tail" stent is contraindicated.

Impact of transrectal ultrasound guided prostate biopsy on quality of life: a prospective randomized trial comparing 6 versus 12 cores.

PURPOSE: Recent studies advocating an increase in the number of cores of sextant transrectal ultrasound guided biopsy of the prostate to improve the cancer detection rate often have not addressed the impact on quality of life. We performed a prospective randomized trial comparing 6 to 12 prostate biopsy cores to determine the impact on the cancer detection rate, pain and morbidity, and quality of life. We report the impact on health related and screening specific quality of life in men undergoing 6 versus 12 core transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS: We prospectively randomized 244 men with a mean age plus or minus standard deviation of 65 +/- 8 years, serum total prostate specific antigen between 2.5 and 20.0 ng./ml., and/or digital rectal examination findings suspicious of cancer to undergo 6 or 12 core peripheral zone tissue biopsy. Of the men 71 (29%) were black. All patients completed a self-administered questionnaire before, and 2 questionnaires 2 and 4 weeks after the procedure. Health related quality of life was measured using 2 subscales (emotional well-being and role limitation due to physical health) of the short form 36-Item Health Survey. Screening specific quality of life was addressed by questions on the functional consequences of the procedure (return to daily activity, work-employment and sports-exercise). Health related and screening specific quality of life responses were compared in the groups. RESULTS: After controlling for cancer diagnosis, patient age, race, education, report of pain and baseline emotional well-being there was no significant difference in the mean change in emotional well-being scores at 2 and 4 weeks in the 6 and 12 core groups (p = 0.7 and 0.3, respectively). Similarly after controlling for these factors and baseline role limitation due to physical health there was no significant difference in the mean change in role limitation due to physical health scores at 2 and 4 weeks in the 2 groups (p = 0.3 and 0.5, respectively). There was no difference in the percent of men returning to routine daily activity (p = 0.6), work-employment (p = 0.5) or sports-exercise (p = 0.3) at 0 to 1, 2 to 3 and 4 to 7 days or longer than 1 week after the procedure in the groups. CONCLUSIONS: Doubling the sextant biopsy does not affect the quality of life in regard to emotional well-being, role limitation due to physical health, or return to routine daily activity, work-employment or sports-exercise.

Pathophysiology of varicoceles in male infertility.

Varicoceles are found in 19 to 41% of infertile men, and is one treatable form of male infertility. The mechanism by which varicoceles cause the variable effect on male infertility and spermatogenesis is still unknown. Experimental animal models play a useful (but limited) role due to the sudden and variable iatrogenic nature of the varicoceles and the duration of the studies. Much of the human data are derived by the characterization of associated differences in measurable parameters between men with and without varicoceles. The role of hyperthermia, testicular blood flow and venous pressure changes, reflux of renal/adrenal products, hormonal dysfunction, autoimmunity, defects in acrosome reaction, and oxidative stress, in the pathophysiology of varicocele will be discussed.

Pain and morbidity of transrectal ultrasound guided prostate biopsy: a prospective randomized trial of 6 versus 12 cores.

PURPOSE: An increasing number of studies suggest that 6-sector transrectal ultrasound guided biopsy of the prostate provides insufficient material to detect all clinically important prostate cancers and more cores may improve detection rates. We performed a prospective, randomized study to determine the effect of increasing the number of cores from 6 to 12 on pain and other morbidity associated with the biopsy procedure. MATERIALS AND METHODS: A total of 160 men (44 black, 28%) with a mean age plus or minus standard deviation of 65+/-8 years who had serum prostate specific antigen between 2.5 and 20.0 ng./ml. and/or digital rectal examination findings suspicious for cancer were prospectively randomized to undergo 6 or 12-core biopsy. Patients completed a self-administered questionnaire addressing pain and other morbidity before, and immediately and 2 and 4 weeks after biopsy. RESULTS: There was no difference between groups in mean pain scale with time for abdominal and rectal pain. For probe insertion, needle insertion and overall pain there was a significant increase in pain recalled at 2 which persisted at 4 weeks compared to immediately after biopsy. However, there was no difference for these 3 post-biopsy pain measures between the 6 and 12-core groups. In the 12-core group there was a statistically significant increase in hematochezia and hematospermia (24% versus 10%, p = 0.04 and 89% versus 71%, p = 0.01, respectively) but no significant difference between groups reporting morbidity as a moderate or major problem. There was no significant change in International Prostate Symptom Score, fever or hospitalization in the 12-core group. CONCLUSIONS: The 12-core prostate biopsy procedure is generally well tolerated and can be safely performed with no significant difference in pain or morbidity compared to the 6-core procedure.

A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection.

PURPOSE: Several studies suggest that sextant transrectal ultrasound guided biopsy of the prostate provides insufficient material to detect all clinically important prostate cancer, and obtaining more biopsy cores may improve the cancer detection rate. We performed a prospective randomized trial comparing 6 to 12 prostate biopsy cores to determine the impact on the cancer detection rate. MATERIALS AND METHODS: We prospectively randomized 244 men, including 71 (29%) black men, with a mean age plus or minus standard deviation of 65 +/- 8 years to undergo biopsy with 6 or 12 peripheral zone tissue cores. In our study subjects serum total prostate specific antigen (PSA) was between 2.5 and 20 ng./ml., and/or digital rectal examination was suspicious for cancer. All men completed a self-administered pre-biopsy and 2 post-biopsy questionnaires at 2 and 4 weeks. Cancer detection rates were compared in the groups and correlated with race, biopsy history, digital rectal examination findings, total PSA, transrectal ultrasound volume and PSA density, as determined by the formula, total PSA/transrectal ultrasound volume. RESULTS: The cancer detection rate in the 6 and 12 core groups was almost identical (26% and 27%, p = 0.9). There was no significant difference in cancer detection in the 2 trial arms with respect to subject race, biopsy history, digital rectal examination findings, total PSA, transrectal ultrasound volume or PSA density. However, our study did not have the statistical power to rule out small differences. CONCLUSIONS: The overall cancer detection rate is not materially increased by 12 core, peripheral zone biopsy in men in whom prostate cancer was mainly detected by screening.

Laparoscopic cyst marsupialization in patients with autosomal dominant polycystic kidney disease.

PURPOSE: Autosomal dominant polycystic kidney disease is characterized by progressively enlarging renal cysts associated with hypertension, renal failure, pain, hematuria and infection. We explored the role of laparoscopic cyst marsupialization for managing cyst related problems. MATERIALS AND METHODS: In 4 male and 11 female adults with autosomal dominant polycystic kidney disease who had preserved renal function laparoscopic cyst marsupialization was done for pain unilaterally and bilaterally in 9 and 6, respectively. An average of 204 cysts per kidney (range 11 to 635) were decorticated or drained. RESULTS: Average operative time was 5.5 hours. Patients were discharged from the hospital after an average of 3.2 days. At a mean followup of 2.2 years (range 0.5 to 5) pain was decreased an average of 62% (range 30% to 90%) in 11 cases (73%). One patient had no improvement and 1 had subsequent worsening of pain postoperatively. Two patients with initial improvement had pain recurrence 4 and 36 months postoperatively, respectively. Hypertension resolved in 1 patient (7%), improved in 20% and did not change in 40%. In 33% of the cases hypertension worsened, requiring additional antihypertensive medication. Renal function remained stable in 13 patients (87%), improved in 1 (6.5%) and worsened in 1 (6.5%). Overall patients who underwent a bilateral procedure had better long-term pain relief and more improvement in hypertension. CONCLUSIONS: Laparoscopic cyst marsupialization may effectively decrease cyst associated pain. In some cases hypertension may be improved. Renal function remained stable in all except 1 patient. At a mean followup of 2.2 years the benefits of aggressive laparoscopic cyst decortication appear to be relatively long lasting when bilateral decortication is indicated. The benefits of unilateral cyst decortication are less predictable and of shorter duration.

Comparison of clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery.

BACKGROUND AND OBJECTIVE: We set out to compare the efficacy of clevidipine and sodium nitroprusside infusions in the control of blood pressure and the haemodynamic changes they produce in hypertensive patients after operation for elective coronary bypass grafting. METHODS: Thirty patients were randomly allocated to receive either clevidipine or sodium nitroprusside after their mean arterial pressure (MAP) had reached > 90 mmHg for at least 10 min in the postoperative period. The MAP was continuously measured and related to time. Thus, the efficacy of the drugs in controlling arterial pressure could be inversely related to the total area under the MAP-time curve outside a target MAP range of 70-80 mmHg normalized per hour (AUC(MAP) mmHg min h(-1)). Haemodynamic variables and the number of dose-rate adjustments required to maintain MAP were also studied. RESULTS: There was no statistically significant difference in the efficacy (AUC(MAP) mmHg min h(-1)) of clevidipine (106 +/- 25 mmHg min h(-1)) compared with sodium nitroprusside (101 +/- 28 mmHg min h(-1)). Nor was any significant difference found in the total number of dose adjustments required to control MAP within the target range. The heart rate in patients receiving clevidipine increased less than in those given sodium nitroprusside. Stroke volume, central venous pressure and pulmonary artery pressure were significantly reduced upon administration of sodium nitroprusside but not of clevidipine. CONCLUSIONS: There was no significant difference between clevidipine and sodium nitroprusside in their efficacy in controlling MAP. The haemodynamic changes, including tachycardia, were less pronounced with clevidipine than with sodium nitroprusside.

Factors determining the duration of tracheal intubation in cardiac surgery: a single-centre sequential patient audit.

BACKGROUND AND OBJECTIVE: The study was designed to identify those factors associated with early tracheal extubation following cardiac surgery. Previous studies have tended to concentrate on surgery for coronary artery bypass or on other selected cohorts. METHODS: Sequential cohort analysis of 296 unselected adult cardiac surgery patients was performed over 3 months. RESULTS: In total, 39% of all patients were extubated within 6 h, 89% within 24 h and 95% within 48 h. Delayed extubation (>6 h after surgery) appeared unrelated to age, gender, body mass index, a previous pattern of angina or myocardial infarction, diabetes, preoperative atrial fibrillation, and preoperative cardiovascular assessment, as well as other factors. Delayed tracheal extubation was associated with poor left ventricular, renal and pulmonary function, a high Euroscore, as well as the type, duration and urgency of surgery. Early extubation (<6 h) was not associated with a reduced length of stay in either the intensive care unit or in hospital compared with patients who were extubated between 6 and 24 h. In these groups, it is presumed that organizational and not clinical factors appear to be responsible for a delay in discharge from intensive care. Patients who were extubated after 24 h had a longer duration of hospital stay and a greater incidence of postoperative complications. Postoperative complications were not adversely affected by early tracheal extubation. CONCLUSIONS: In an unselected sequential cohort, both patient- and surgery-specific factors may be influential in determining the duration of postoperative ventilation of the lungs following cardiac surgery. In view of the changing nature of the surgical population, regular re-evaluation is useful in reassessing performance.