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Contrary to the belief that basal-like breast cancers develop from mammary stem cells in BRCA1 mutation carriers, an aberrant luminal progenitor population might be the target for transformation in basal tumors in these individuals ( pages 842–844 ). Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro . Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell–enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT ) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1 -associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1 -associated basal tumors .

The transcription factor Gata-3 is a defining marker of the 'luminal' subtypes of breast cancer 1 , 2 , 3 , 4 . To gain insight into the role of Gata-3 in breast epithelial development and oncogenesis, we have explored its normal function within the mammary gland by conditionally deleting Gata-3 at different stages of development. We report that Gata-3 has essential roles in the morphogenesis of the mammary gland in both the embryo and adult. Through the discovery of a novel marker (β 3 -integrin) of luminal progenitor cells and their purification, we demonstrate that Gata-3 deficiency leads to an expansion of luminal progenitors and a concomitant block in differentiation. Remarkably, introduction of Gata-3 into a stem cell-enriched population induced maturation along the alveolar luminal lineage. These studies provide evidence for the existence of an epithelial hierarchy within the mammary gland and establish Gata-3 as a critical regulator of luminal differentiation.

Suppressor of cytokine signalling (SOCS) proteins are critical attenuators of cytokine‐mediated signalling in diverse tissues. To determine the importance of Socs3 in mammary development, we generated mice in which Socs3 was deleted in mammary epithelial cells. No overt phenotype was evident during pregnancy and lactation, indicating that Socs3 is not a key physiological regulator of prolactin signalling. However, Socs3 ‐deficient mammary glands exhibited a profound increase in epithelial apoptosis and tissue remodelling, resulting in precocious involution. This phenotype was accompanied by augmented Stat3 activation and a marked increase in the level of c‐myc. Moreover, induction of c‐myc before weaning using an inducible transgenic model recapitulated the Socs3 phenotype, and elevated expression of likely c‐myc target genes, E2F‐1, Bax and p53, was observed. Our data establish Socs3 as a critical attenuator of pro‐apoptotic pathways that act in the developing mammary gland and provide evidence that c‐myc regulates apoptosis during involution.

Patients with cleft lip and/or palate can undergo numerous procedures to improve appearance, speech, dentition and hearing. We developed a cleft-specific patient-reported outcome instrument to facilitate rigorous international measurement and benchmarking. Data were collected from patients aged 8–29 years with cleft lip and/or palate at 30 hospitals in 12 countries between October 2014 and November 2016. Rasch measurement theory analysis was used to refine the scales and to examine reliability and validity. Normative CLEFT-Q values were computed for age, sex and cleft type. Analysis led to the refinement of an eating and drinking checklist and 12 scales measuring appearance (of the face, nose, nostrils, teeth, lips, jaws and cleft lip scar), health-related quality of life (psychological, social, school, speech distress) and speech function. All scales met the requirements of the Rasch model. Analysis to explore differential item functioning by age, sex and country provided evidence to support the use of a common scoring algorithm for each scale for international use. Lower (worse) scores on CLEFT-Q scales were associated with having a speech problem, being unhappy with facial appearance, and needing future cleft-related treatments, providing evidence of construct validity. Normative values for age, sex and cleft type showed poorer outcomes associated with older age, female sex and having a visible cleft. The CLEFT-Q represents a rigorously developed instrument that can be used internationally to collect and compare evidence-based outcomes data from patients aged 8–29 years of age with cleft lip and/or palate.

Normative CLEFT-Q values were computed for age, sex and cleft type. INTERPRETATION: The CLEFT-Q represents a rigorously developed instrument that can be used internationally to collect and compare evidence-based outcomes data from patients aged 8-29 years of age with cleft lip and/or palate.

The social change model of leadership (SCM) is a widely used leadership model in higher education. StrengthsQuest is conceptually similar to the individual values of the SCM in its aim to identify and grow individual talents. This model is based on the idea that individuals perform at higher levels when they build upon their identified talents (Clifton & Harter, 2003). Prior studies have not examined the relationship of hope or one’s belief in their identified StrengthsQuest talents to the individual values of the SCM. This study examines that relationship using the adult-trait hope and strengths self-efficacy scales. The relationship between these constructs along and other predictors of social change capacity were explored using canonical correlation analysis. Strengths self-efficacy, hope, and student engagement were statistically significant (73% of the variability among the individual values of the SCM). Gender, race, and community service were not statistically significant in this study.

Escherichia coli O157 infections cause an estimated 60 deaths and 73000 illnesses annually in the United States. A marked summer peak in incidence is largely unexplained. We investigated an outbreak of E. coli O157 infections at an agricultural fair in Ohio and implicated consumption of beverages made with fairground water and sold by a geographically localized group of vendors who were all on the same branch of the fairground water distribution system. To examine county fair attendance as a risk factor for infection, we conducted two further epidemiological studies. In the first, we enhanced surveillance for E. coli O157 infections in 15 Northeast Ohio counties during the 2000 agricultural fair season and showed increased risk of E. coli O157 infection among fair attendees. In the second study, we examined Ohio Public Health Laboratory Information Service (PHLIS) data for 1999 using a time-varying covariate proportional hazards model and demonstrated an association between agricultural fairs and E. coli O157 infections, by county. Agricultural fair attendance is a risk factor for E. coli O157 infection in the United States and may contribute to the summer peak in incidence. Measures are needed to reduce transmission of enteric pathogens at agricultural fairs.

Chronic Conditions series. Recommendations in the NICE guideline 'Early Identification and Management of Chronic Kidney Disease' (2008) relevant to health professionals in primary care. Screening, measurement of renal function and the early identification and management of chronic kidney disease, highlighting patients most at risk of cardiovascular disease and progression, are discussed. [(BNI unique abstract)] 42 references