Expression of osteonectin mRNA in human breast tumours is inversely correlated with oestrogen receptor content

Osteonectin is a secreted glycoprotein which is detected in a number of normal and neoplastic human tissues in vivo. It is an extracellular matrix (ECM)-associated protein which is postulated to regulate cell migration, adhesion, proliferation and matrix mineralisation and previous reports suggest that it may be modulated by steroid hormones in target tissues. The aim of this study was to measure osteonectin mRNA and protein expression in breast tumour biopsies and compare these with oestrogen (ER) and progesterone receptor (PR) levels in the same tumours. An inverse correlation was seen between osteonectin mRNA expression and ER level. Samples with low ER protein expression had a mean osteonectin mRNA level which was almost 4-fold greater than the mean level of expression observed in tumours containing high concentrations of ER protein. This inverse correlation was statistically significant. Despite the strong inverse relationship between osteonectin mRNA levels and tumour ER content, no correlation was seen when osteonectin protein concentration was measured in tumour cytosols on immunoblots and compared to ER and PR levels in the same tumours. However, since it is a secreted protein, osteonectin protein expression may not reflect cellular osteonectin levels in breast tumours. In summary, these data suggest that ER-mediated suppression of osteonectin gene expression may contribute to the less aggressive characteristics associated with receptor-positive tumours and that loss of ER expression may lead to over-expression of osteonectin and contribute to a poorer differentiated, more invasive phenotype.     

The hindfoot alignment view

A modification of Cobey's method for radiographically imaging the coronal plane alignment of the hindfoot is described. Using this view, we estimated the moment arm between the weightbearing axis of the leg and the contact point of the heel. Normative data on 57 asymptomatic adult subjects are presented. The weightbearing line of the tibia falls within 8 mm of the lowest calcaneal point in 80% of subjects and within 15 mm of the lowest calcaneal point in 95% of subjects. The technique for measuring coronal plane hindfoot alignment is reliable, with an interobserver correlation coefficient of 0.97. This radiographic technique should help in the evaluation of complex hindfoot malalignments.     

DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens

Positive results in the in vitro assay for chromosome aberrations sometimes occur with test chemicals that apparently do not react with DNA, being negative in tests for mutation in bacteria, for DNA strand breaks, and for covalent binding to DNA. These chromosome aberrations typically occur over a narrow concentration range at toxic doses, and with mitotic inhibition. Indirect mechanisms, including oxidative damage, cytotoxicity and inhibition of DNA synthesis induced by chemical exposure, may be involved. Understanding when such mechanisms are operating is important in evaluating potential mutagenic hazards, since the effects may occur only above a certain threshold dose. Here, we used two-parameter flow cytometry to assess DNA synthesis inhibition (uptake of bromodeoxyuridine [BrdUrd]) associated with the induction of aberrations in CHO cells by DNA-reactive and non-reactive chemicals, and to follow cell cycle progression. Aphidicolin (APC), a DNA polymerase inhibitor, induces aberrations without reacting with DNA; 50 microM APC suppressed BrdUrd uptake during a 3-h treatment to <10% of control levels. Several new drug candidates induced aberrations concomitant with marked reductions in cell counts at 20 h (to 50-60% of controls) and suppression of BrdUrd uptake (<15% of control). Several non-mutagenic chemicals and a metabolic poison, which induce DNA double strand breaks and chromosome aberrations at toxic dose levels, also suppressed DNA synthesis. In contrast, the alkylating agents 4-nitroquinoline-1-oxide, mitomycin C, methylnitrosourea, ethylnitrosourea, methylmethane sulfonate and ethylmethane sulfonate, and a topoisomerase II inhibitor, etoposide, produced many aberrations at concentrations that were less toxic (cell counts >/=73% of controls) and gave little inhibition of DNA synthesis during treatment (BrdUrd uptake >/=85% of controls), although cell cycle delay was seen following the 3-h treatment. Thus, inhibition of DNA synthesis at the time of treatment is supporting evidence for an indirect mechanism of aberrations, when there is no direct DNA reactivity.     

Managed care and unintended pregnancy

This article assesses the adequacy of coverage of contraceptive services and supplies for US women in the various types of managed care plans, with special attention to Medicaid. Between 1993 and 1995, the percent of insured private-sector employees enrolled in managed care plans rose from 51% to 73%. By 1996, the health care of 40% of low-income Medicaid recipients was also under managed care administration. Although 84% of managed care plans cover oral contraceptives--a rate substantially higher than that for traditional indemnity plans, several logistic factors impede access to this and other reproductive health benefits. The requirement of preauthorization may delay access to care when timely presentation is essential to the prevention of unwanted pregnancy. Some plans restrict members to one visit per year with an obstetrician-gynecologist. Coordination of an enrollee's total health care through the primary care physician can raise confidentiality problems for those who seek sensitive reproductive health services. There are fewer restrictions on the access of Medicaid recipients to family planning providers and services, but treatment of sexually transmitted diseases may not be part of the reproductive health package. The explosion of managed care onto the US health care market has led to public sector regulation legislation--a process that is proceeding in a piecemeal rather than comprehensive way. Because of the importance of reproductive health care to the lives of women, communities, and the broader society, more systematic action on this front is essential.     

Bridging town and gown: building research partnerships between community-based professional providers and academia

Interleukin 1 (IL-1) is postulated to function in maintaining homeostasis, however, over-action of this cytokine may lead to disruption of homeostasis due to it's wide spectrum of activities. To understand the endogenous regulation of this cytokine, we examined the existence of IL-1 receptor antagonist (IL-1Ra) in tissues from healthy rabbits. IL-1Ra was constitutively produced in all tissues examined (lung, liver, spleen, thymus, caecum, skin, kidney, heart, and brain), as estimated by ELISA. Immunoprecipitation, RT-PCR and immunohistochemical studies indicated that all tissues produced secreted form of IL-1Ra (sIL-1Ra), whereas thymus, caecum, skin and kidney produced both sIL-1Ra and intracellular of IL-1Ra. All tissue IL-1Ra purified using anti-IL-1Ra IgG affinity chromatography had inhibitory activity on the IL-1-induced thymocyte proliferative response, and the activity was totally abolished by anti-IL-1Ra mAb. No IL-1 activity was detected in any tissues except skin and heart, however, after preincubation of the samples with anti-IL-1Ra, the activity was first visible in the tissues. Under these conditions, IL-1 activity in skin and heart was enhanced to 170% and 280%, respectively. Taken together, we conclude that tissue IL-1Ra is involved in health maintenance by masking co-existing IL-1 activity present in tissues.     

Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group

BACKGROUND: This report presents the results of a survival update based on the combined data from two studies that compared the efficacy and tolerability of anastrozole (1 or 10 mg once daily), a selective, nonsteroidal aromatase inhibitor administered orally, and megestrol acetate (40 mg 4 times daily) in the treatment of postmenopausal women with advanced breast carcinoma whose disease had progressed after treatment with tamoxifen. METHODS: Two randomized, parallel-group, multicenter trials were conducted, involving a total of 764 patients. The two trials were identical in design; both were double blind for anastrozole and open label for megestrol acetate. Overview analyses were conducted with the intent of strengthening the interpretation of results from each trial. The median follow-up duration for this survival update was 31 months. RESULTS: At the clinical dose of 1 mg daily, anastrozole demonstrated a statistically significant survival advantage over megestrol acetate, with a hazard ratio of 0.78 (P < 0.025)(0.60 < 97.5% confidence interval [CI] <1.0). The 1 mg anastrozole group also had a longer median time to death (26.7 months) compared with 22.5 months for the megestrol acetate group. The 10 mg anastrozole group also had a survival benefit over the megestrol acetate group, with a hazard ratio of 0.83 (P=0.09, not significant)(0.64 < 97.5% CI < 1.1). Higher 2-year survival rates were observed for both anastrozole treatment groups than for the megestrol acetate group (56.1%, 54.6%, and 46.3% for the groups given 1 mg anastrozole, 10 mg anastrozole, and megestrol acetate, respectively). CONCLUSIONS: This combined analysis of two trials of postmenopausal patients with advanced breast carcinoma has clearly demonstrated that, after disease progression with tamoxifen, treatment with anastrozole 1 mg once daily results in a statistically and clinically significant advantage over a standard treatment, megestrol acetate. This important benefit, in addition to the good tolerability profile of anastrozole, supports the use of this drug as a valuable new treatment option for this patient population.     

Differences in fine control of forces generated by the tongue, lips and fingers in humans

This study compared the fine control of forces generated by the tongue, lips and fingers in middle-aged adults. The aims were to determine whether (1) the articulatory organs (tongue, lips) and fingers differed in the manner of motor control, (2) force control of the various articulatory organs was similar, and (3) control of forces generated by males was different from that of forces generated by females. The relation among several variables of the ramp-and-hold force contraction and target force level was quantified for the articulatory organs and the fingers in 14 normal individuals (7 males and 7 females). Using visual feedback, participants produced ramp-and-hold compression forces as rapidly and accurately as possible to targets ranging from 0.25 to 2 N. The results showed differences in the profiles of forces generated by the articulatory organs and fingers. In particular, the forefingers were characterized by a greater accuracy of force control and precision of movement, a greater stability of the hold phase, but by slower velocities than the articulatory organs. Motor control of the lower lip differed from that of the upper lip and tongue. Mostly, the lower lip was characterized by a greater precision of contraction, faster development of the force, and greater stability of the hold phase than the upper lip and tongue. Gender was a distinguishing factor in the force task; males were able to produce forces with higher velocities and greater precision than females.