Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey

Between 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1887 of the urine specimens. In 1971 we reported that subnormal amounts of urinary A and E were associated with a significantly increased risk of breast cancer. The cohort has been followed regularly during the 37 years since inception of the study and, by May 1998, 248 women had been diagnosed with breast cancer. Urinary androgen metabolites had been measured in 116 of these cases. Analysis of these data confirmed that women diagnosed in the first decade of the study were more likely to have low levels of urinary androgen metabolites. In the following decades, however, those who developed breast cancer were more likely to have manifested an increased A and E excretion. The reversal in the relationship between androgen metabolite excretion and risk suggests that age, or probably more importantly, menopausal status at diagnosis is an important modifying factor. Dichotomizing at age 50 it was found that in the younger age group (predominantly premenopausal) the rate ratios in the lowest tertile of A or E excretion were two- to threefold greater than for those in the highest tertile (χ21= 3.57;P = 0.06: χ21= 4.70;P = 0.03 for A and E respectively). In contrast, in the older age group comprising predominantly post-menopausal women, the rate ratios associated with the lowest tertile of A or E were half that of those in the highest tertile (χ21= 4.10;P = 0.04; χ21= 8.72;P = 0.003 for A and E respectively). This suggests that there may be different endocrine promotional factors for pre-and post-menopausal breast cancer. Hormonal risk factors may vary during the lifetime of an individual woman and this may have profound consequences for prevention strategies. © 2000 Cancer Research Campaig

Eerste Harthulp: wat gebeurt er met patiënten die niet meteen worden opgenomen?

The clinical course of the first six weeks after discharge after consultation was studied in 527 patient contacts in 460 patients who were evaluated for acute cardiac symptoms in a six-month period at the acute cardiac care facility 'Eerste Harthulp' in the Academic Medical Centre. Analysis revealed that the initial diagnosis of acute ischaemia (261 cases) was correct in 118 (45%) and the initial diagnosis of arrhythmia (114 cases) in 92 (81%). In 220 patients there was no cardiac history; in those instances the initial diagnosis of acute ischaemia was confirmed in only 40% but the initial diagnosis of arrhythmia in 78%. Three patients died within six weeks after evaluation and 28 patients were admitted within that period. Patients without cardiac history and without a clear cardiac diagnosis consulted their general practitioner moderately frequently in the first six weeks and used specialist care only rarel

Regulation of CXCR4 conformation by the small GTPase Rac1: Implications for HIV infection

The chemokine receptor CXCR4 is a critical regulator of cell migration and serves as a coreceptor for HIV-1. The chemokine stromal cell derived factor-1, also known as CXCL12, binds to CXCR4 and exerts its biologic functions partly through the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). We show in different cell types, including CD34 + hematopoietic stem and progenitor cells, that inhibition of Rac1 causes a reversible conformational change in CXCR4, but not in the related receptors CXCR7 or CCR5. Biochemical experiments showed that Rac1 associates with CXCR4. The conformational change of CXCR4 on Rac1 inhibition blocked receptor internalization and impaired CXCL12-induced G αi protein activation. Importantly, we found that the conformation adopted by CXCR4 after Rac1 inhibition prevents HIV-1 infection of both the U87-CD4-CXCR4 cell line and of primary peripheral blood mononuclear cells. In conclusion, our data show that Rac1 activity is required to maintain CXCR4 in the responsive conformation that allows receptor signaling and facilitates HIV-1 infection; this implies that Rac1 positively regulates CXCR4 function and identifies the Rac1-CXCR4 axis as a new target for preventing HIV-1 infection