Variations in Prkdc and susceptibility to benzene-induced toxicity in mice.

Benzene, a carcinogen that induces chromosomal breaks, is strongly associated with leukemias in humans. Possible genetic determinants of benzene susceptibility include proteins involved in repair of benzene-induced DNA damage. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), encoded by Prkdc, is one such protein. DNA-PKcs is involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here we compared the toxic effects of benzene on mice (C57BL/6 and 129/Sv) homozygous for the wild-type Prkdc allele and mice (129/SvJ) homozygous for a Prkdc functional polymorphism that leads to diminished DNA-PK activity and enhanced apoptosis in response to radiation-induced damage. Male and female mice were exposed to 0, 10, 50, or 100 ppm benzene for 6 h/d, 5 d/week for 2 weeks. Male mice were more susceptible to benzene toxicity compared with females. Hematotoxicity was evident in all male mice but was not seen in female mice. We observed similar, large increases in both micronucleated erythrocyte populations in all male mice. Female mice had smaller but significant increases in micronucleated cells. The p53-dependent response was induced in all strains and genders of mice following benzene exposure, as indicated by an increase in p21 mRNA levels in bone marrow that frequently corresponded with cell cycle arrest in G2/M. Prkdc does not appear to be a significant genetic susceptibility factor for acute benzene toxicity. Moreover, the role of NHEJ, mediated by DNA-PK, in restoring genomic integrity following benzene-induced DSB remains equivocal.     

Factors associated with breast cancer clinical trials participation and enrollment at a large academic medical center.

PURPOSE: The practice patterns of medical oncologists at a large National Cancer Institute Comprehensive Cancer Center in Detroit, MI were evaluated to better understand factors associated with accrual to breast cancer clinical trials. PATIENTS AND METHODS: From 1996 to 1997, physicians completed surveys on 319 of 344 newly evaluated female breast cancer patients. The 19-item survey included clinical data, whether patients were offered clinical trial (CT) participation and enrollment, and when applicable, reasons why they were not. Multivariate analyses using logistic regression were performed to evaluate predictors of an offer and enrollment. RESULTS: The patients were 57% white, 32% black, and 11% other/unknown race. One hundred six (33%) were offered participation and 36 (34%) were enrolled. In multivariate analysis, CTs were less likely offered to older women (mean age, 52 years for those offered v 57 years for those not offered; P =.0005) and black women (21% of blacks offered v 42% of whites; P =.0009). Women with stage 1 disease, poor performance status, and those who were previously diagnosed were also less likely to be offered trials. None of these factors were significant predictors of enrollment. Women were not offered trials because of ineligibility (57%), lack of available trials (41%), and noncompliance (2%). Reasons for failed enrollment included patient refusal (88%) and failed eligibility (12%). CONCLUSION: It is important for cooperative groups to design studies that will accommodate a broader spectrum of patients. Further work is needed to assess ways to improve communication about breast cancer CT participation to all eligible women.     

Development of a Pacifier for Low-Birth-Weight Infants' Nonnutritive Sucking

Nonnutritive sucking can provide low-birth-weight infants with an opportunity to organize their behavior, an important component of developmental care. A pacifier specifically designed for low-birth-weight infants facilitates their nonnutritive sucking to more fully meet their needs. The research and development of a pacifier for low-birth-weight infants incorporated a naturalistic approach and used the best model, the infant thumb, in the design. Clinical trials with infants randomized to control and experimental groups were conducted to compare the prototype pacifier to a commercially available pacifier. Observations using the Anderson Behavioral State Scale demonstrated that infants using the prototype pacifier more often were found to be in an alert state. This pacifier may contribute to infants' state organization for optimum feeding and could be a component in developmental care planning.     

Emotion/cognition-coupling in word recognition memory of depressive patients: an event-related potential study

Depressive patients show deficits in memory functions. However, the underlying mechanisms remain unclear. Experiments with a special emphasis on the link between emotion and cognition appear challenging. The aim of this study is to investigate the influence of the emotional content of words on memory in non-medicated depressive patients (n=11) compared with a control group (n=11) utilizing event-related brain potentials (ERPs). In a continuous word recognition paradigm brain responses to repeated items are characterized by more positive waveforms of ERPs. This recognition effect ('old/new effect') has been shown to be sensitive to parameters relevant for memory processing. For the purpose of this ERP experiment visually presented words were classified into three different categories of emotional content. The ERPs for the correctly detected 'old' (repeated) words showed an increased positivity beginning approximately 250 ms post-stimulus, concurring with a good recognition performance. In addition, old/new effect and behavioral data were sensitive to words' different emotional connotations in the control group. In contrast, the depressive patients performed worse and showed no significant old/new effect. Nevertheless, their recognition performance was also enhanced by the emotional content. Furthermore, a differential effect of the emotional content on frontal ERPs was found between groups. In contrast to the control group, a reduced old/new effect indicates a reduced working memory capacity in the moderately depressed patients. This is suggested to be partially due to changes of the emotion/cognition coupling related to ruminations with preferably negative emotional connotation. However, the emotional content also affects recognition performance in the depressive patients.     

The developmental paediatrician and neonatal follow-up

Recent advances in modern perinatal and neonatal intensive care have led to an increase in the survival of premature infants. This increased survival, unfortunately, has not been accompanied by an improvement in neurodevelopmental outcomes. Premature infants, especially those with an extremely low birth weight (less than 1000 g) or those born at less than 28 weeks’ gestation, are at increased risk of major disabilities and complex, ‘low severity’ dysfunctions that have significant, lasting effects on their school function, academic performance and behaviour, as well as on family function. Neonatal follow-up programs provide a number of functions to centres providing neonatal intensive care, including quality assurance and audits, research and follow-up clinical care to neonatal intensive care unit survivors and their families. The challenge for neonatal follow-up programs is to meet the often competing objectives of providing clinical services to children and their families while providing quality assurance and audits, and high-quality long-term outcome research components, given the available resources. There is also a need for ongoing research to develop and evaluate effective postdischarge intervention programs to improve the long-term outcome of prematurity and other neonatal complications. Developmental paediatricians – with their background and training in the provision of specialized health care to children and their care-givers with respect to developmental and psychosocial well-being, and in conducting developmental and behavioural disabilities research – play a valuable role in the follow-up assessment and care of neonatal intensive care unit graduates, and strengthen the multidisciplinary research groups necessary to assess long-term outcomes and the effects of perinatal and postdischarge interventions.     

Testing and implementing signal impact analysis in a regulatory setting: results of a pilot study.

BACKGROUND AND AIM: Statistical signal detection methods such as proportional reporting ratios (PRRs) detect many drug safety signals when applied to databases of spontaneous suspected adverse drug reactions (ADRs). Impact analysis is a tool that was developed as an aid to prioritisation of such signals. This paper describes a pilot project whereby impact analysis was simultaneously introduced into practice in a regulatory setting and tested in comparison with the existing approach. METHODS: Impact analysis was run on signals detected during a 26-week period from the UK Adverse Drug Reactions On-line Information Tracking (ADROIT) database of spontaneous ADRs that met minimum criteria (PRR>or=3.0, chi2>or=4.0 and >or=3 reported cases) and related to established drugs (i.e. those that have been available for at least 2 years and no longer carry the 'black triangle' symbol). The current method of signal prioritisation (i.e. the collective judgement at a weekly meeting) was initially performed without knowledge of the findings of impact analysis. Subsequently, the meeting was presented with the findings and, where appropriate, given the opportunity to reconsider the judgement made. The categories arising from the two methods were compared and the ultimate action recorded. Inter-observer variation between scientists performing impact analysis was also assessed. RESULTS: Eighty-six separate signals were analysed by impact analysis, of which 5% were categorised as high priority (A), 14% as requiring further information (B), 31% as low priority (C) and 50% as no action required (D). In general, the new method tended to give a higher level of priority to signals than the existing approach. Overall, there was 59% agreement between the impact analysis and the collective judgement at the meetings (kappa statistic=0.30). There was slightly greater agreement between impact analysis and the final action taken (kappa statistic=0.39), indicating that the findings of an impact analysis had an influence on the outcome. Assessment of inter-observer variation demonstrated that the method is repeatable (kappa statistic for overall category=0.77). Almost 70% of those who participated in the pilot study believed that impact analysis represented an improvement in how signals were prioritised. CONCLUSIONS: Impact analysis is a repeatable method of signal prioritisation that tended to give a higher level of priority to signals than the standard approach and which had an influence on the ultimate outcome.     

Cyclin d1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma.

BACKGROUND: The current tumor-node-metastasis system is inadequate to accurately classify patients in terms of prognosis. Thus, with the availability of recently developed molecular tools, considerable interest lies in discovering prognostic markers in order to guide treatment decisions. In this study, we sought to determine the prognostic significance of the cell cycle regulator cyclin D1 in oropharyngeal squamous cell carcinoma (OSCC). EXPERIMENTAL DESIGN: We studied the protein expression levels of cyclin D1 on a tissue microarray composed of 63 OSCCs with long-term follow-up data available. Protein expression was analyzed with an automated in situ quantitative (AQUA) method which allows preservation of tissue morphology while quantifying protein expression in paraffin-embedded tissue. RESULTS: The mean follow-up time was 35 months. High cyclin D1 nuclear expression was associated with increased 5-year local recurrence rate (48% versus 15%), inferior 5-year disease-free survival (16% versus 58%), and inferior 5-year overall survival (17% versus 53%). In multivariate Cox regression, high nuclear cyclin D1 expression was an independent predictor for local recurrence, disease-free survival, and overall survival at 5 years. CONCLUSIONS: Our results indicate that quantitative assessment of nuclear cyclin D1 expression level by automated in situ quantitative analysis is a strong predictor for outcome in OSCC. Thus, cyclin D1 may be a potential target for molecular intervention in patients with oropharyngeal squamous cell cancer.