Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival

Inactivation of the FANC-BRCA pathway via promoter methylation of the FANCF gene renders cells sensitive to DNA crosslinking agents, and has been identified in ovarian cancer cell lines and sporadic primary tumor tissues. We investigated epigenetic alterations in the FANC-BRCA pathway in head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) using methylation-specific PCR. Promoter methylation of FANCF occurred in 15% (13/89) of HNSCCs and 14% (22/158) of NSCLCs. Methylation of BRCA1 occurred only in 6/158 NSCLC, and was limited to adenocarcinomas and large-cell carcinomas of the lung. No methylation of BRCA2 was detected. FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P=0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC. In adenocarcinomas of the lung, FANCF promoter methylation was a significant predictor of poor survival with a hazard ratio of 3.1 (95% CI 1.2-7.9). This study demonstrates that inactivation of the FANC-BRCA pathway is relatively common in solid tumors and may be related to tobacco and alcohol exposure and survival of these patients.     

Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for v-Ha-ras gene (R+) were crossed with transgenic C57BL/6 mice that harbor E6/E7 of HPV16 (E+). Beginning at about 3 months of age, the bitransgenic E(+)R(+)(C57BL/6 x FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E(+)R+ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E(-)R+) and 0, 0 and 0% (E(+)R-), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E(-)R+, E(+)R-). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice.     

The Ontario Cardiac Rehabilitation Pilot Project: Recommendations for health planning and policy

BACKGROUND: Expansion of cardiac rehabilitation (CR) could save both lives and costs by reducing illness and use of health care services. In February 2001, the Ontario Ministry of Health and Long-Term Care (the Ministry) announced a pilot project (the Pilot) to implement and evaluate a comprehensive, multifactoral model of CR service delivery at 17 centres across Ontario. OBJECTIVES: To design, coordinate and evaluate a coordinated model of CR service delivery, and to collect and evaluate an extensive set of clinical and administrative data. METHODS AND RESULTS: The Pilot was a large, province-wide observational investigation of a health service delivery model for CR and secondary prevention care. The present paper is the third in a three-part, policy-related series. In the present paper, the results of the evaluation of the service delivery model and the final health policy recommendations that were made to the Ministry in September 2002 are presented. CONCLUSIONS: Within approximately one year, 4922 patients were enrolled in the Pilot at participating sites throughout Ontario; 88% of sites implemented all elements of the comprehensive services model, either on-site or through internal/external partnerships, and 94% of sites implemented the multidisciplinary Pilot staffing model. Based on this rapid and near-total implementation of the Pilot model, it was concluded that the Pilot model of care was generalizable. Furthermore, regional coordination was achieved through operationalization of the coordinating centres' roles in quality management, regional planning and program development, education and outreach.     

The Ontario Cardiac Rehabilitation Pilot Project

In February 2001, the Ontario Ministry of Health and Long-Term Care announced a $9.6 million, 15-month pilot project (the Pilot) to implement and evaluate a comprehensive, multifactoral model of cardiac rehabilitation (CR) service delivery at 17 sites across Ontario. This is the second paper in a three-part, policy-related series which provides a summary of the Ontario CR Pilot model and the Pilot implementation and evaluation methodology. The aim of the present paper was to outline the goals of the Pilot, the Pilot model of care, the organizational structure that facilitated implementation of the model, and the operational procedures that were put in place to evaluate patient outcomes and the generalizability of a regional model of CR service delivery. The model was based on the findings and recommendations of the Cardiac Care Network of Ontario's 1999 Consensus Panel on Cardiac Rehabilitation and Secondary Prevention, which was described in part one of this series. An upcoming final paper will describe the outcomes of the project and its recommendations for CR health policy decisions in Ontario.     

The psychological health of emergency physicians in Australasia

Objective: To evaluate the psychological health of ACEM Fellows and the important factors that impact on this health. Methods: A cross‐sectional, mail survey utilizing validated psychological instruments. Results: Three hundred and twenty‐three (63.5%) of 510 physicians responded. Most were recently graduated males. Compared to a general population sample, their psychological health was good with greater optimism and mastery (P < 0.001), less anxiety, depression and physical symptoms (P < 0.001), better life satisfaction (P = 0.04) and similar perceived stress (P = 0.20). The mean work stress score (1 = low, 10 = high) was 5.6 ± 2.1 (moderate stress) although 63 (19.5%) had very high scores (8–10). The mean work satisfaction score was 6.3 ± 2.1 (moderate satisfaction) although 43 (13.3%) had very low scores (1–3). Perceptions of control over hours worked and mix of professional activities were positively associated with work and life satisfaction (P < 0.001) and negatively associated with work stress and measures of wellbeing (P < 0.001). Most employed adaptive coping strategies. However, maladaptive strategies (alcohol/drugs, denial, disengagement) were positively associated with anxiety, depression and stress (P < 0.001). Conclusions: Most physicians are psychologically healthy. However, there appears to be a subgroup that is not thriving. Workplace stress should be addressed promptly and greater flexibility provided over hours worked and mix of professional activities.     

Workplace factors leading to planned reduction of clinical work among emergency physicians

Objective: There is anecdotal evidence that ACEM Fellows are reducing or planning to reduce their clinical workload. We investigated the extent of, and reasons for, these reductions. Methods: An anonymous, cross‐sectional postal survey utilizing a study‐specific questionnaire. Results: Three hundred and twenty‐three Fellows (63.5%) responded. Most were recently graduated males. In the last 5 years, the mean number of clinical hours worked per week has reduced significantly (P < 0.001) for both junior (40.6–28.9 h) and senior Fellows (30.4–23.1 h). Further significant (P < 0.001) reductions are planned. The most frequently reported reasons for reducing clinical workload were excessive workload, family life and emotional health effects, shift work and work stress. The most stressful aspects of work reported were access block, dealing with management, insufficient staffing, workload pressures and staff supervision. Clinical work reportedly impacts most upon family life, social life and emotional health. Conclusions: Fellows are significantly reducing their clinical workload largely in response to excessive workload and lack of resources. These findings have important implications for professional longevity and work force planning. Re‐evaluation of workplace practice, especially identified stressors, is indicated.     

Detection of chronic kidney disease with laboratory reporting of estimated glomerular filtration rate and an educational program

BACKGROUND: Serum creatinine concentration is an inadequate screening test for chronic kidney disease, especially in elderly patients. We hypothesized that laboratory reporting of estimated glomerular filtration rate (GFR) accompanied with an educational intervention would improve recognition of chronic kidney disease (CKD). METHODS: We conducted a before-and-after study at an outpatient family medicine practice. Patients 65 years or older for whom a Cockcroft-Gault GFR could be calculated from their medical record were included. The intervention consisted of automatic reporting of estimated GFR by the hospital laboratory along with an educational intervention directed toward the primary care physicians. The primary outcome was the recognition of CKD (defined as a Cockroft-Gault GFR <60 mL/min [<1.0 mL/s]) by the primary care physician. Factors associated with the recognition of CKD were also determined. RESULTS: The study population comprised 324 patients. Prior to the study intervention, 22.4% of patients with CKD were recognized, which increased to 85.1% after the intervention. Before the intervention, recognition was more likely in male subjects (odds ratio, 4.3; 95% confidence interval, 1.9-9.8) and patients with diabetes (odds ratio, 3.4; 95% confidence interval, 1.6-7.6). These associations were no longer statistically significant after the intervention. CONCLUSION: Laboratory reporting of estimated GFR coupled with an educational program markedly improves the recognition of CKD in the primary care setting.     

Onychotillomania: 2 case reports

Onychotillomania is an uncommon condition characterized by self-destruction of the fingernails and/or toenails by compulsive manipulation. We report 2 cases of onychotillomania with differing presentations in a young man and in an older man. Onychotillomania may be a form of obsessive-compulsive disorder (OCD), and we discuss the psychologic factors and current treatments for this condition.     

Neural cell adhesion molecule (NCAM) null mice do not show a deficit in odour discrimination learning

Polysialylated neural cell adhesion molecule (PSA-NCAM) is predominantly expressed during development where it regulates biological functions including axon targeting and neuronal precursor cell migration. Although dramatically down regulated after birth in most regions of the nervous system, PSA-NCAM remains highly expressed into adulthood in areas that have ongoing regeneration and plasticity such as in the olfactory bulb and hippocampus. Consequently, lack of PSA-NCAM in NCAM null mice results in distinct morphological changes to these areas. The functional correlates of these changes are not well defined although there have been reports that learning is impaired in NCAM null mice. In the present study, we assessed the ability of old and young NCAM null mice to learn an odour discrimination task. We tested male and female experimental and control animals of two different ages: 30-60 days and 12-15 months. During 4 days of training, NCAM null and C57BL/6J received trials where one odour (CS+) was paired with sugar while another odour (CS-) was not. In a subsequent preference test, conducted in the absence of sugar, all animals, regardless of strain or age, spent significantly more time digging in the CS+ odour than in the CS- odour. In addition, there was no significant difference in digging behaviour in the CS+ between the NCAM null and the control animals. These data indicate that deletion of the NCAM gene may change the morphology of the olfactory bulb but does not interfere with the ability to learn an odour discrimination task.