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.     

Use of different combination diphtheria-tetanus-acellular pertussis vaccines does not increase risk of 30-day infant mortality. A population-based linkage cohort study using administrative data from the Australian Childhood Immunisation Register and the National Death Index.

Objective

To determine whether differences in combination DTaP vaccine types at 2, 4 and 6?months of age were associated with mortality (all-cause or non-specific), within 30?days of vaccination.

Distribution of alpha 2-adrenergic receptor mRNAs in the rat CNS.

alpha 2-Adrenergic receptors (ARs) are involved in central nervous system (CNS) control of blood pressure. It is now known that there are three human genes that encode subtypes of alpha 2-ARs, but little is known regarding the distribution of these subtypes throughout the CNS. The availability of receptor clones allows the mapping of mRNAs encoding the individual alpha 2-AR subtypes in the CNS. In this communication, we report that there are three, closely related rat alpha 2-AR genes. We have developed subtype-specific hybridization probes from each of these genes and have used these reagents to measure alpha 2-AR subtype mRNA accumulation in extracts of discrete regions of the rat CNS. We found that mRNAs encoding the alpha 2A-AR and alpha 2C-AR subtypes are distributed widely, but unevenly, throughout the rat CNS. The A subtype is prominent in the midbrain, brainstem, spinal cord, pituitary and diencephalon while the C subtype predominates in basal ganglia and cerebellum. The cortex, olfactory bulb and hippocampus contain roughly equal amounts of the alpha 2A- and alpha 2C-AR mRNAs. A third subtype's (alpha 2B-AR) mRNA is far less abundant in brain tissues, and is only found in the diencephalon.     

Extensor mechanism complications following total knee arthroplasty

Extensor mechanism complications following 281 knee arthroplasties that included patellar resurfacing, performed by two surgeons in one hospital over a 6-year period, were reviewed. The mean follow-up period was 42 months. There were 28 (10%) extensor mechanism complications: 3 quadriceps tendon ruptures, 5 patellar fractures, 4 patellar tendon ruptures, 11 recurring patellar subluxations, 4 cases of patellar pain, and 1 malrotated patella. Nine (3%) required further surgery. Surgical technique may have contributed to the tendon ruptures; patellar fractures occurred mainly in patients who had rheumatoid arthritis. Patients with patellar subluxation had abnormal preoperative valgus deformities of their knees and presented with this subluxation problem an average of 4 months after surgery, but it appeared to cause them less discomfort with time. Patellar resurfacing as part of a knee arthroplasty procedure is recommended but should be performed with care to the integrity and vasculature of the extensor mechanism.     

A role for decorin in cutaneous wound healing and angiogenesis

Decorin is known to influence tissue tensile strength and cellular phenotype. Therefore, decorin is likely to have an impact on tissue repair, including cutaneous wound healing. In this study, cutaneous healing of both excisional and incisional full‐thickness dermal wounds was studied in decorin‐deficient (Dcn^?/?) animals. A statistically significant delay in excisional wound healing in the Dcn^?/? mice occurred at 4 and 10 days postwounding and, in incisional wounds at 4, 10, and 18 days when compared with wild‐type (Dcn^?/?) controls. Fibrovascular invasion into polyvinylalcohol sponges was significantly increased by day 18 in Dcn^?/? mice relative to Dcn^+/+ mice. The 18‐day sponge implants in the Dcn^?/? mice showed a marked accumulation of biglycan when compared with the corresponding implants in Dcn^+/+ mice. Thus, regulated production of decorin may serve as an excellent therapeutic approach for modifying impaired wound healing and harmful foreign body reactions.     

Myocardial Depressant Effects of Desflurane: Mechanical and Electrophysiologic Actions In Vitro

Background: The authors determined whether desflurane altered myocardial excitation-contraction coupling and electrophysiologic behavior in the same manner as isoflurane and sevoflurane.

Methods: The effects of desflurane on isometric force in guinea pig ventricular papillary muscles were studied in modified standard and in 26 mm K+ Tyrode solution with 0.1 [mu]m isoproterenol. Desflurane effects on sarcoplasmic reticulum Ca2+ release were also determined by examining its actions on rat papillary muscles, guinea pig papillary muscles in low-Na+ Tyrode solution, and rapid cooling contractures. Normal and slow action potentials were recorded using a conventional microelectrode technique. Ca2+ and K+ currents of guinea pig ventricular myocytes were examined.

Results: Desflurane (5.3% and 11.6%) decreased peak force to approximately 70% and 40% of the baseline, respectively, similar to the effects of equianesthetic isoflurane concentrations. With isoproterenol in 26 mm K+ Tyrode solution, desflurane markedly depressed late peaking force and modestly depressed early peak force. The rested state contractions of rat myocardium or guinea pig myocardium in low-Na+ Tyrode solution were modestly depressed, whereas rapid cooling contractures were virtually abolished after desflurane administration. Desflurane significantly prolonged the action potential duration. Desflurane reduced L-type Ca2+ current and the delayed outward K+ current but did not alter the inward rectifier K+ current.