Long-term adjuvant tamoxifen in early breast cancer: effect on bone mineral density in postmenopausal women

The decrease in sex steroid hormone levels after the onset of menopause is associated with bone loss and subsequent osteoporosis. Tamoxifen has antiestrogenic properties and may thus theoretically decrease bone mineral density, particularly after long-term treatment. Bone mineral density (BMD) was assessed in 75 recurrence-free postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen (40 mg daily) for 2 or 5 years versus no adjuvant endocrine therapy. The measurements were done about 7 years after the initial randomization. BMD was measured with single-photon absorptiometry (SPA) at two levels of the distal forearm representing cortical and trabecular bone. The BMD was found to be similar among tamoxifen patients compared with the controls. For cortical bone, the BMD was 1.03 g/cm2 (95% confidence interval [Cl], 0.97 to 1.09) among tamoxifen patients and 1.03 g/cm2 (95% Cl, 0.96 to 1.11) in controls. For trabecular bone, the values were 0.74 g/cm2 (95% Cl, 0.70 to 0.79) and 0.73 g/cm2 (95% Cl, 0.68 to 0.79), respectively. The results thus did not indicate an accelerated postmenopausal bone loss with long-term adjuvant tamoxifen.     

Spinal cord-projecting vasopressinergic neurons in the rat paraventricular hypothalamus.

The paraventricular hypothalamic nucleus (PVH) is a key structure for the maintenance of homeostasis. Homeostatic regulation includes modulation of signaling in the spinal cord. This may be exerted by neurons in the PVH with spinal projections. However, the PVH is not a homogeneous structure, but consists of anatomically and functionally distinct subdivisions. In this study, we have analyzed the distribution of spinal cord-projecting PVH neurons that express vasopressin, an important neuropeptide in autonomic regulation. Vasopressinergic neurons were identified with a radiolabeled riboprobe complementary to vasopressin mRNA combined with immunohistochemical labeling of retrogradely transported cholera toxin subunit b in spinally projecting neurons. More than 40% of the spinally projecting neurons in the PVH of naive Sprague-Dawley rats were found to express vasopressin mRNA. The lateral parvocellular subdivision and the ventral part of the medial parvocellular subdivision contained the densest distribution of spinal cord-projecting vasopressin mRNA-expressing neurons. The magnocellular subdivisions displayed large numbers of vasopressin mRNA-expressing neurons, but very few of those projected to the spinal cord. The dorsal parvocellular subdivision contained a large number of spinally projecting neurons, but very few of those expressed vasopressin mRNA. These findings show that the PVH gives rise to a major vasopressinergic projection to the spinal cord and that the spinal cord-projecting vasopressinergic neurons are parceled into anatomically distinct cell groups. This provides an anatomical basis for a selective activation of functionally different groups in the PVH as part of a behaviorally adaptive response, including modulation of autonomic activity and pain processing at the spinal level.     

On the bias caused by regression toward the mean in studying the relation between change and initial value

In studies of treatment effects in clinical trials and longitudinal followup investigations, it is not unusual to inquire as to whether a relationship exists between the change of a variable and its initial value, for example pocket depth Such studies must be carried out with great care, since the results are biassed by the regression towards the mean (RTM) effect. Examples are presented, the magnitude of the RTM effect is estimated and means of dealing with the RTM problem are discussed. RTM also appears as a selection phenomenon, emphasizing the need to include control groups in order to make possible adjustments for the bias caused by RTM.     

Maps of receptor binding parameters in the human brain--a kinetic analysis of PET measurements

A kinetic method is described for the estimation of neuroreceptor density as well as the rate constants for association and dissociation of rapidly equilibrating radioligands. The method is exemplified by positron emission tomographic measurements of the human brain using 11C-raclopride, a D 2 dopamine receptor antagonist, and 11C-Ro 15-1788, a benzodiazepine receptor antagonist. Using a linear non iterative algorithm, regional binding characteristics were calculated and displayed pixel by pixel in brain maps. Data from repeated experiments on the same subject with different amounts of the unlabeled ligand were utilized. The binding characteristics were determined according to a two step procedure in which the time course of the free radioligand concentration was estimated from a reference region considered to be free of specific receptor binding sites. Alternative methods to determine the concentration of free radioligand are discussed.     

Application of a kinetic model on the methionine accumulation in intracranial tumours studied with positron emission tomography

Eleven patients were studied with positron emission tomography (PET) using 11C-methionine. They all had low-grade astrocytomas (Kernohan grade II). The PET studies were analyzed with a metabolic model to obtain values for the influx, the accumulation rate and the partition coefficient of methionine in normal and tumourous tissue. Seven of the tumours showed an increased accumulation of methionine as compared with normal tissue on the static PET scans and also had higher values as to the kinetic parameters. Four tumours had a methionine accumulation equal to or lower than that of normal tissue and the kinetic parameters were also lower. Application of the kinetic model did not aid significantly in the delineation of the tumours. There was a correlation between the three parameters indicating an adaptation of the transport of methionine to the regional metabolic demand. The accumulation rate for normal cortical tissue was 0.49 nmol/g/min, the influx 0.97 nmol/ml and the partition coefficient 0.45 ml/g. These values are considerably higher than those previously reported. The differences might be attributed to differences in the corrections introduced for i.a. the occurrence of labelled metabolites in serum. With the use of a kinetic model, more information about the tracer is utilized and gained compared with the previously used graphic approach.     

Deep venous contribution to hydrostatic blood volume change in the human leg

The causes of orthostatic intolerance following prolonged bed rest, head-down tilt or exposure to zero gravity are not completely understood. One possible contributing mechanism is increased venous compliance and peripheral venous pooling. The present study attempted to determine what proportion of the increased calf volume during progressive venous occlusion is due to deep venous filling. Deep veins in the leg have little sympathetic innervation and scant vascular smooth muscle, so their compliance may be determined primarily by the surrounding skeletal muscle. If deep veins make a large contribution to total leg venous compliance, then disuse-related changes in skeletal muscle mass and tone could increase leg compliance and lead to decreased orthostatic tolerance. The increase in deep venous volume during progressive venous occlusion at the knee was measured in 6 normal subjects using calf cross-sectional images obtained with magnetic resonance imaging. Conventional plethysmography was used simultaneously to give an independent second measurement of leg volume and monitor the time course of the volume changes. Most of the volume change at all occlusion levels (20, 40, 60, 80 and 100 mm Hg) could be attributed to deep venous filling (90.2% at 40 mm Hg and 50.6% at 100 mm Hg). It is concluded that a large fraction of the calf volume change during venous occlusion is attributable to filling of the deep venous spaces. This finding supports theories postulating an important role for physiological mechanisms controlling skeletal muscle tone during orthostatic stress.     

Peripheral Lipopolysaccharide Administration Induces Cytokine mRNA Expression in the Viscera and Brain of Fever-Refractory Mice Lacking Microsomal Prostaglandin E Synthase-1

We examined the expression of interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF) α in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1), which neither produce prostaglandin E₂, nor mount a febrile response upon immune challenge. Intraperitoneal lipopolysaccharide (LPS) injection resulted in a strongly induced expression of all three cytokines in the brain and viscera, similar to wild-type animals. Several brain regions additionally showed modest induction of receptors for these cytokines in both genotypes. Telemetric recordings of body temperature showed that the mPGES-1 deficient mice remained afebrile upon LPS challenge, in contrast to the prominent fever displayed by the wild-type mice. These data demonstrate that LPS-induced cytokine expression occurs independently of prostaglandin E₂, and imply that endogenously expressed IL-1β, IL-6, and TNFα are not pyrogenic per se , supporting the role of prostaglandin E₂ as the final and obligatory mediator of LPS-induced fever.     

Breast tumors from <Emphasis Type="Italic">CHEK2 1100delC-</Emphasis> mutation carriers: genomic landscape and clinical implications

Introduction  

Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers.