Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation.

Lactation insufficiency affects many women worldwide. During lactation, a large portion of mammary gland alveolar cells become polyploid, but how these cells balance the hyperproliferation occurring during normal alveologenesis with terminal differentiation required for lactation is unknown. Here, we show that DNA damage accumulates due to replication stress during pregnancy, activating the DNA damage response. Modulation of DNA damage levels in vivo by intraductal injections of nucleosides or DNA damaging agents reveals that the degree of DNA damage accumulated during pregnancy governs endoreplication and milk production. We identify a mechanism involving early mitotic arrest through CDK1 inactivation, resulting in a heterogeneous alveolar population with regards to ploidy and nuclei number. The inactivation of CDK1 is mediated by the DNA damage response kinase WEE1 with homozygous loss of Wee1 resulting in decreased endoreplication, alveologenesis and milk production. Thus, we propose that the DNA damage response to replication stress couples proliferation and endoreplication during mammary gland alveologenesis. Our study sheds light on mechanisms governing lactogenesis and identifies non-hormonal means for increasing milk production.

Nurse-led implementation of the single assessment process in primary care: a descriptive feasibility study.

OBJECTIVE: to determine the resources required to carry out the single assessment process in primary care. DESIGN: prospective descriptive study. SETTING: one urban primary care practice, Southampton. PARTICIPANTS: nine hundred and forty-four people aged 70+ years, registered with the practice, not living in a residential/nursing home, or terminally ill. INTERVENTION: participants were sent the six-item Sherbrooke questionnaire (case-finding tool). Non-responders were re-mailed after 4 weeks. All those scoring 4, 5 or 6 and a randomly selected half of those scoring 2 or 3 were offered overview assessment and comprehensive assessment as indicated by the Minimum Data Set for Home Care protocol. The nurse assessor identified unmet needs and agreed an action plan with participants. Another researcher conducted semi-structured interviews with a purposive sample of 26 participants to elicit their views of the process. MAIN OUTCOME MEASURES: response rates/scores of Sherbrooke questionnaire; numbers/characteristics of people requiring overview and comprehensive assessments; nature of resulting recommendations/referrals and impact on other agencies; resources required; views of service users. RESULTS: eight hundred and sixty-three (91%) participants replied. Five hundred and seven (54%) scored 2+, triggering an overview assessment, which was offered to 307. One hundred and twenty-four participants (40%) accepted; 64 (52%) had unmet needs (median 8 each, range 2-18), resulting in 34 referrals within the practice including four case conferences, and 21 to community/secondary health services. Few participants with a Sherbrooke score of 2 required comprehensive assessment. Users perceived the process as acceptable and useful, but not always relevant to their current needs. CONCLUSION: targeting those scoring 3+ on the Sherbrooke questionnaire (28% of sample) may improve the identification of patients who would benefit from further assessment. A contact approach rather than a case-finding one may improve the relevance of this process to older people.