Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

Stories of despair: a Kierkegaardian read of suffering and selfhood in survivorship

Medicine, Health Care and Philosophy - A life-threatening illness such as cancer can bring about much existential suffering and a disconnect to self in spite of surviving cancer. In my recent...     

Effects of heterozygosity for the E180 splice mutation causing growth hormone receptor deficiency in Ecuador on IGF-I, IGFBP-3, and stature.

CONTEXT & OBJECTIVE: The Ecuadorian GH receptor deficiency (GHRD)/Laron syndrome population is the only large cohort with a single GHR mutation (E180 splice), permitting identification of numerous carrier and noncarrier first-degree relatives, to ascertain effects of heterozygosity on GH-dependent IGF-I and IGFBP-3 concentrations and on growth. DESIGN: First-degree relatives (n=212) of GHRD patients had specimens taken for IGF-I, IGFBP-3, and GHR genotyping. Normal statured (n=40) and short statured (n=40) unrelated controls had measurement of IGF-I, IGFBP-3, and stature. RESULTS: There were no significant differences between heterozygous and homozygous normal relatives in IGF-I or IGFBP-3 standard deviation scores (SDS). Heterozygous relatives had lower mean height SDS than did homozygous normals, but with extensive overlap between genotype groups in both child and adult relatives. Height SDS in general did not relate to IGF-I or IGFBP-3 concentrations. CONCLUSIONS: GH-dependent IGF-I and IGFBP-3 secretion is not affected by heterozygosity for the E180 splice mutation that causes GHRD/Laron syndrome in the Ecuadorian population. Heterozygosity is associated with reduction in mean statural SDS, but this is not sufficient to be clinically important and not mediated through measurable differences in circulating IGF-I or IGFBP-3 related to genotype.     

Case Study of Institution-Building by Nurse Bertha Wright and Colleagues

Purpose: To illuminate the history of nurses' participation in institution-building in the early 1900s, using the Baby Hospital in Oakland, California (now called Children's Hospital Oakland) as a case.
Design: Historical research using a framework of women's history theory focused on the women who founded Oakland's Baby Hospital, 1910–1930.
Method: Data collection included studying original sources, archival material, and interviews. Data evaluation included external criticism for authenticity and genuineness, and internal criticism for accuracy and bias.
Findings: In 1912, nurse Bertha Wright and social worker Mabel Weed, with a circle of community women, including Jessica Peixotto and Jean Howard McDuffie, established the Baby Hospital. Their activism included home visits, education, research, publications, political lobbying, and state policy and program development. At the center of this activity, was the lifelong commitment of Wright and Weed, who created new definitions of family. With social changes in the late 1920s, the male Board of Directors seized control of the hospital, and relegated women to auxiliary roles.
Conclusions: Health and social issues of the United States at the turn of the century are still problematic as a new century approaches and pertain to maternal-child health, foster care, and immigration. Feminists, including nurses, have played a central role in creating solutions. Knowledge of some of their incredible effort has been lost, particularly nursing's history in the western United States.     

Accuracy of women's recall of opportunistic recruitment for cervical cancer screening in general practice

Abstract: Evaluation of strategies to improve opportunistic recruitment via general practice of women overdue for a cervical smear requires an accurate behavioural measure. As part of an experimental trial to evaluate the effect of a postgraduate workshop on preventive care, we conducted this methodological study to determine the accuracy of women's recall of an opportunistic discussion about cervical screening, by comparing it against audiotapes ( n = 524). Taking the taped evidence of the trainee's verbal behaviour as the gold standard, sensitivity was 85 per cent (95 per cent confidence interval (CI) 73.1 to 92.0 per cent) and specificity was 78 per cent (CI 73.9 to 81.6 per cent). Given the low rate of opportunistic recruitment by trainees in the main study, only one–third of positive recollections by women of an opportunistic discussion about cervical screening were correct. Until other measures have been validated, women's recall may continue to be used to measure general practitioners' behaviour, but an appreciation of likely bias is recommended.     

Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatric Oncology Group pilot study

Summary We enrolled children with acute lymphoblastic leukemia (ALL) in a Pediatric Oncology Group (POG) pilot study to monitor erythrocyte (RBC) methotrexate (MTX) and folate (F) levels before and during treatment. The mean value for RBCF at diagnosis was 0.86±0.46 nmol/ml RBC in the 214 patients who achieved remission and 1.21±0.74 nmol/ml RBC in the 10 patients who did not (P=0.020). Folate levels tended to increase during remission induction, but they dropped following an intensive consolidation with methotrexate to levels that were sustained throughout chemotherapy treatment. Methotrexate levels reached mean values of approximately 0.15 nmol/ml RBC at the end of an intensive methotrexate consolidation, then fell to levels that were sustained throughout maintenance therapy. There was a weak correlation between improved event-free survival and higher RBCMTX levels after consolidation, but no correlation was found between improved survival and the level of RBCMTX or RBCF during maintenance therapy. A larger study with more complete data is needed to determine whether RBCMTX or RBCF might be useful in predicting event-free survival in patients with ALL.This work was supported in part by grants from the National Cancer Institute and the National Institute of Health (CA-30969, CA-28476, CA29139, CA-159-89, and CA-33587)     

Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus.

Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens.     

Children with deficits in attention,motor control and perception (DAMP) almost grown up: The contribution of various background factors to outcome at age 16 years

Fifty-six children with and forty-five children without deficits in attention, motor control and perception (DAMP) had been recruited from the general population at age 7 years. They were followed up neuropsychiatrically at age 16 years after intermediate term follow up at age 10 and 13 years. Cases were subdivided into those with good and not good outcome on the basis of absence or presence of psychiatric and personality disorders, multiple traumatic accidents and speech and language problems at age 16 years. The presence of DAMP in itself was the strongest predictor of poor outcome. High scores for minor neurological dysfunction, low performance IQ, autistic features at age 7 years and poor reading skills at age 10 and/or 13 years were important background factors in cases with poor outcome. In the small subgroup with poor outcome among those without DAMP at age 7 years, major life events was the most important background factor.

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Zusammenfassung 56 Kinder mit und 45 Kinder ohne Störungen der Aufmerksamkeit, der motorischen Kontrolle und der Wahrnehmung (DAMP) waren aus einer Gesamtpopulation 7jÄhriger rekrutiert worden. Sie wurden neuropsychiatrisch im Alter von 16 jahren nachuntersucht, nachdem zwischenzeitliche Untersuchungen im Alter von 10 und 13 Jahren erfolgt waren. Die Probanden wurden in solche mit gutem und nicht gutem Ausgang unterteilt, in AbhÄngigkeit vom Vorliegen psychiatrischer AuffÄlligkeiten, Persönlichkeitsstörungen, multiplen Traumata und Sprech- und Sprachproblemen im Alter von 16 Jahren. Das Vorhandensein von DAMP war der stÄrkste PrÄdiktor für einen schlechten Ausgang. Hohe Werte für leichte neurologische AuffÄlligkeiten, ein niedriger Handlungs-IQ, autistische Züge im Alter von 7 Jahren und schlechte LesefÄhigkeiten im Alter von 10 und/oder 13 Jahren waren wichtige Hintergrundfaktoren bei den Probanden mit einem schlechten Ausgang. In der kleinen Untergruppe mit einem schlechten Ausgang bei den Kindern, die im Alter von 7 Jahren kein DAMP ausgewiesen hatten, bildeten schwerwiegende Lebensereignisse den wichtigsten Hintergrundfaktor.

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Résumé Cinquante-six enfants atteints et quarante-cinq enfants non atteints de déficits de l'attention, du contrÔle moteur et de la perception (DAMP), ont été recrutés en population générale à l'âge de 7 ans. Ils ont été évalués sur la plan neuropsychiatrique à l'âge de 16 ans, après des évaluations intermédiaires à l'âge de 10 et 13 ans. Les cas ont été subdivisés entre bons et mauvais devenir sur la base de la présence ou de l'absence de troubles de la personnalité, l'importance du nombre d'accidents traumatiques, les difficultés d'élocution et de langage à 16 ans. La présence de DAMP était en soi, le facteur prédictif le plus important de mauvais devenir. Des scores élevés à des dysfonctionnements neurologiques mineurs, un QI bas, des traits autistiques à l'âge de 7 ans, et de mauvaises capacités en lecture à l'âge de 10 ou 13 ans ont été des facteurs importants dans les cas de mauvais devenir. Dans le petit sous-groupe à mauvais devenir caractérisé par une absence de DAMP à l'âge de 7 ans, des événements de vie marquants ont semblé Être des antécédents importants.