Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.

The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression

Early-Life Exposures and Early-Onset Uterine Leiomyomata in Black Women in the Sister Study

Background: Uterine leiomyomata (fibroids) are hormonally responsive tumors, but little is known about risk factors. Early-life exposures may influence uterine development and subsequent response to hormones in adulthood. An earlier analysis of non-Hispanic white women who participated in the Sister Study found associations between several early-life factors and early-onset fibroids

Determinants of response to a parent questionnaire about development and behaviour in 3 year olds: European multicentre study of congenital toxoplasmosis.

Background: We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres. Methods: Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks. Results: The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres. Conclusion: Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies

Supervision and feedback for junior medical staff in Australian emergency departments: findings from the emergency medicine capacity assessment study

<p>Abstract</p> <p>Background</p> <p>Clinical supervision and feedback are important for the development of competency in junior doctors. This study aimed to determine the adequacy of supervision of junior medical staff in Australian emergency departments (EDs) and perceived feedback provided.</p> <p>Methods</p> <p>Semi-structured telephone surveys sought quantitative and qualitative data from ED Directors, Directors of Emergency Medicine Training, registrars and interns in 37 representative Australian hospitals; quantitative data were analysed with SPSS 15.0 and qualitative data subjected to content analysis identifying themes.</p> <p>Results</p> <p>Thirty six of 37 hospitals took part. Of 233 potential interviewees, 95 (40.1%) granted interviews including 100% (36/36) of ED Directors, and 96.2% (25/26) of eligible DEMTs, 24% (19/81) of advanced trainee/registrars, and 17% (15/90) of interns. Most participants (61%) felt the ED was adequately supervised in general and (64.2%) that medical staff were adequately supervised. Consultants and registrars were felt to provide most intern supervision, but this varied depending on shift times, with registrars more likely to provide supervision on night shift and at weekends. Senior ED medical staff (64%) and junior staff (79%) agreed that interns received adequate clinical supervision. Qualitative analysis revealed that good processes were in place to ensure adequate supervision, but that service demands, particularly related to access block and overcrowding, had detrimental effects on both supervision and feedback.</p> <p>Conclusions</p> <p>Consultants appear to provide the majority of supervision of junior medical staff in Australian EDs. Supervision and feedback are generally felt to be adequate, but are threatened by service demands, particularly related to access block and ED overcrowding.</p

Genes harbouring susceptibility SNPs are differentially expressed in the breast cancer subtypes

Recently, genome-wide association studies of breast cancer revealed single nucleotide polymorphisms (SNPs) in five genes with novel association to susceptibility. While there is little doubt that the novel susceptibility markers produced from such highly powered studies are true, the mechanisms by which they cause the susceptibility remain undetermined. We have looked at the expression levels of the identified genes in tumours and found that they are highly significantly differentially expressed between the five established breast cancer subtypes. Also, a significant association between SNPs in these genes and their expression in tumours was seen as well as a significantly different frequency of the SNPs between the subtypes. This suggests that the observed genes are associated with different breast cancer subtypes, and may exert their effect through their expression in the tumours. Thus, future studies stratifying patients by their molecular subtypes may give much more power to classic case control studies, and genes of no or borderline significance may appear to be high-penetrant for certain subtypes and, therefore, be identifiable

Towards integration of general practitioner posts and accident and emergency departments: a case study of two integrated emergency posts in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Accident and emergency (A&E) departments and general practitioner (GP) posts are often used inappropriately, leading to overcrowding. In the Netherlands, increasingly more integrated emergency posts (IEPs) are being created, integrating the care provided by GP posts and A&E departments, in order to improve the provision of the emergency care.</p> <p>Methods</p> <p>This explorative study compares the efficiency and patient and employee satisfaction in IEPs with those in two GP posts and two A&E departments. To this end, information was retrieved from hospital and GP patient records for the first quarter of the year before and of the year after the creation of IEPs. Patients and employees were sent a questionnaire to measure their satisfaction. Lastly, groups of hospital doctors, GPs, GP assistants, and nurses were interviewed.</p> <p>Results</p> <p>After the creation of IEPs, there was a shift of more than fifteen percent from secondary care to primary care for emergency consultations and waiting/consultation times were shortened by more than ten percent. Compared with the control settings, patients were more satisfied about telephone contact with an IEP, but professionals working at the IEP were less satisfied with several aspects of their work.</p> <p>Conclusion</p> <p>IEPs could be a promising innovation to organize emergency care more efficiently; however, it might take time to convince professionals of the possible advantages. Studies involving more IEPs and longer follow-up times are needed to determine whether such integration should be stimulated.</p