High prevalence of vertebral fractures in women with breast cancer starting aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe bone status in a large cohort of postmenopausal women with nonmetastatic breast cancer, at the initiation of aromatase inhibitor therapy. PATIENTS AND METHODS: A prospective, transversal and clinical study was conducted. Each woman had an extensive medical history, a biological evaluation, a bone mineral density (BMD) measurement and spinal X-rays. RESULTS: Four hundred and ninety-seven women aged 63.8 ± 9.6 years were included in this study. Eighty-five percent of these women had a 25-OH vitamin D concentration <75 nmol/l. One hundred and fifty-six women (31.4%) had a T-score < -2 at one of the three site measurements. Ninety-five women (19.1%) had a history of nonvertebral fracture with a total of 120 fractures. Spine X-rays evaluation revealed that 20% of the women had at least one vertebral fracture. The presence of vertebral fracture was associated with nonvertebral fracture history [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.4] and with spine BMD (OR 1.4, 95% CI 1.1-1.7). The prevalence of vertebral fracture reached 62.9% in women with age above 70 years and femoral T-score < -2.5. CONCLUSION: Before starting aromatase inhibitor therapy for breast cancer, a large proportion of women had a vitamin D insufficiency and vertebral fractures.

Sympathetic B antagonist prevents bone mineral density decrease induced by labyrinthectomy.

We previously showed that bilateral vestibular lesion in rats induces a bone loss in weight bearing bones. To determine whether this effect is mediated by the sympathetic nervous system (SNS), bone mineral density (BMD) was measured in 4 groups of 10 female Wistar rats: bilateral labyrinthectomy (Bilab), Bilab with propranolol treatment, sham operated with or withoutpropranolol. In untreated rats, 30 days after lesion Bilab animals showed a reduced BMD in distal femoral metaphysis comparatively to intact rats (p < 0.001). In treated rats, there was no difference in BMD 30 days after lesion. This protective effect of propranolol against bone loss suggests that the vestibular system influence on bone remodeling is mediated by SNS. If this hypothesis is correct, this could have important consequences in devising countermeasures to spaceflight induced bone loss.

Osteopetrosis-like phenotype in latent TGF-beta binding protein 3 deficient mice.

LTBPs are extracellular matrix proteins resembling fibrillins. LTBP-1, 3, and 4 covalently bind latent TGF-beta and modulate tissue levels of this potent cytokine through regulation of its secretion, localization, and/or activation. To address LTBP function in vivo, we generated Ltbp-3 null mice. Ltbp-3-/- animals developed craniofacial abnormalities due to early ossification of the skull base synchondroses and displayed reduced body size. In addition, histological examination of Ltbp-3-/- skeletons revealed an increase in bone mass. The osteoblast numbers and mineral apposition rates were decreased in Ltbp-3-/- mice, whereas the osteoclast numbers were similar in null and wild type mice. Histological examination revealed persistence of cartilage remnants in Ltbp-3-/- trabecular bone. Taken together, these results indicate that the Ltbp-3-/- high bone mass phenotype was due to a defect in bone resorption. We hypothesize that lack of Ltbp-3 results in decreased levels of TGF-beta in bone and cartilage, which leads to compromised osteoclast function and decreased bone turnover.

Identification of genes whose expression patterns differ in benign lymphoid tissue and follicular, mantle cell, and small lymphocytic lymphoma.

Improved methods for diagnosing small B-cell lymphomas (SBCLs) and predicting patient response to therapy are likely to result from the ongoing discovery of molecular markers that better define these malignancies. In this report, we identify 120 genes whose expression patterns differed between reactive lymph node tissue and three types of SBCL: follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. Whereas previously published studies have generally analyzed the gene expression profiles of one type of SBCL, work presented in this paper was intended to identify genes that are differentially expressed between three SBCL subtypes. This analysis was performed using mRNA pooled from multiple specimens representing each tissue type. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to validate the differential expression of 23 of these genes. Among the 23 validated genes were cyclin D1 (CCND1) and B-cell CLL/lymphoma 2, which have well-known roles in lymphoma pathogenesis. The remaining 21 genes have no currently established role in lymphoma development. Using qRT-PCR, the expression of CCND1 and seven additional genes was further studied in a panel of individual specimens. Genes identified in this study are of biological interest and represent candidate diagnostic markers.

Oxalic acid production and aluminum tolerance in Pseudomonas fluorescens.

13C NMR studies on intact cells from Al-stressed Pseudomonas fluorescens incubated with citric acid or Al-citrate yielded peaks at 158 and 166 ppm that were attributable to free and complexed oxalic acid, respectively. The presence of oxalic acid was further confirmed with the aid of oxalate oxidase. These peaks were not discernable in experiments performed with cells taken from control cultures. Enzymatic analyses of cell fractions showed the highest production of oxalic acid in the inner membrane fraction of Al-stressed cells incubated with glyoxylate. There was an eight-fold increase in the synthesis of oxalic acid in the inner membrane fraction from the Al-stressed cells compared to the control cells. Although oxalic acid production was observed when citrate, Al-citrate and isocitrate were utilized as substrates, the inner membrane fraction did not mediate the formation of oxalic acid from glycine/pyruvate, glycolic acid, oxaloacetate or ascorbate. These data suggest that the increased oxalic acid production in response to Al stress is effected via the oxidation of glyoxylate.

Behavioral responses of C57BL/6, FVB/N, and 129/SvEMS mouse strains to traumatic brain injury: implications for gene targeting approaches to neurotrauma.

Recent studies have suggested that mouse models of traumatic brain injury may be useful for evaluating the role of single gene products in brain trauma. In the present study, we report that three background strains (C57BL/6, FVB/N, and 129/SvEMS), commonly used in genetically altered mice, exhibit significantly different behavioral responses when subjected to sham surgery (n = 9 per group) or moderate controlled cortical impact (CCI) injury (n = 12 per group). Injured animals from all three strains showed delayed recovery of pedal withdrawal and righting reflexes compared to sham-operated controls. Significant deficits in both a forepaw contraflexion and rotarod task were evident for up to 7 days after injury, with no significant difference among strains. Sham-operated C57BL/6 mice performed significantly better than FVB/N and 129/SvEMS sham controls in a beam walking task up to 4 weeks after surgery. However, CCI-injured FVB/N mice outperformed injured animals from both other strains in this same task. Significant impairment of place learning in the Morris water maze and Barnes circular maze was observed at 7-10 days and 21-24 days after injury, respectively, in C57BL/6 mice when compared with sham controls. Sham-operated FVB/N and 129/SvEMS mice were unable to learn either task, and performance did not differ significantly from respective CCI injured animals. Our results suggest that background strain should be carefully considered with experiments involving genetically altered mice, especially when planning behavioral outcome measures after CNS injury.

[AA amyloidosis complicating sarcoidosis]. / Amylose AA compliquant une sarcoïdose.

INTRODUCTION: Amyloidosis combined with sarcoidosis has been very rarely described. EXEGESIS: We report the case of a 72-year-old man presenting with sarcoidosis and amyloidosis AA. The association of peripheral and retroperitoneal adenopathies accompanied by loss of weight and histopathological results conducted to the diagnosis of sarcoidosis, excluding other causes. Corticosteroid therapy led to a decrease in clinical manifestations and after 2 years, clinical signs of amyloidosis have not progressed. CONCLUSION: According to results previously described in the literature and the description of the present case, we conclude that sarcoidosis can be complicated by amyloidosis AA, the presence of which may justify corticosteroid therapy.

Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse.

A mouse model of traumatic brain injury was developed using a device that produces controlled cortical impact (CCI), permitting independent manipulation of tissue deformation and impact velocity. The left parietotemporal cortex was subjected to CCI [1 mm tissue deformation and 4.5 m/s tip velocity (mild), or 6.0 m/s (moderate)] or sham surgery. Injured animals showed delayed recovery of pedal withdrawal and righting reflexes compared to sham-operated controls. Significant severity-related deficits in forepaw contraflexion and performance on a rotarod device were evident for up to 7 days. Using a beam walking task to measure fine motor coordination, pronounced deficits were apparent for at least 2 and 4 weeks following mild and moderate CCI, respectively. Cognitive function was evaluated using the water maze. Impairment of place learning, related to injury severity, was observed in mice trained 7-10 days following CCI. Similarly, working memory deficits were evident in a variation of this task when examined 21-23 days postinjury. Mild CCI caused necrosis of subcortical white matter with minimal damage to somatosensory cortex. Moderate CCI produced extensive cortical and subcortical white matter damage. Triple fluorescence labeling with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), antineuronal nuclear protein (NeuN), and Hoechst 33258 of parallel sections showed frequent apoptotic neurons. These findings demonstrate sustained and reproducible deficits in sensory/motor function and spatial learning in the CCI-injured mouse correlating with injury severity. Mechanisms of neuronal cell death after trauma as well as strategies for evaluating novel pharmacological treatment strategies may be identified using this model.

Mammary epithelial cells support and transfer productive human T-cell lymphotropic virus infections.

OBJECTIVES: To investigate whether luminal and basal human mammary epithelial cells (HMEC) are susceptible to productive infection by human T-cell lymphotropic virus types I and II (HTLV-I and HTLV-II) and whether HTLV infection of breast epithelial cells could contribute to the seeding of milk with HTLV infectivity and support virus transmission from mother to nursing infant. STUDY DESIGN/METHODS: Primary cultures of basal epithelial cells were infected by coculture with mitomycin-C-treated HTLV-producer T-cell lines and HTLV-infected milk epithelial cells, and the transfer of infection was monitored by polymerase chain reaction (PCR) amplification and immunocytochemical staining. RESULTS: Basal mammary epithelial cells were found to be susceptible to HTLV infection and capable of transferring HTLV infection to normal peripheral blood lymphocytes (PBL). CONCLUSIONS: A reservoir for HTLV infectivity could exist in mammary epithelial cells and contribute to the introduction of HTLV infectivity into milk by infecting lymphocytes that traverse the epithelium and by the release of infected epithelial cells, infectious cell fragments, and free virions directly into the milk.

Effect of traumatic brain injury on mouse spatial and nonspatial learning in the Barnes circular maze.

Controlled cortical impact (CCI) is a relatively new model of traumatic brain injury in the mouse, which, in combination with behavioral and histological methods, has potential for elucidating underlying mechanisms of neurodegeneration using genetically altered animals. Previously, we have demonstrated impaired spatial learning in a water maze task following CCI injury at a moderate level. There are many difficulties associated with this task, however, such as stress, physical demand, and the multiple trials over days required for satisfactory training. As a potential alternative to the water maze, we adapted the Barnes circular maze to our mouse model and assessed spatial/nonspatial learning following injury. Mice were trained to locate a dark tunnel, hidden beneath one of 40 holes positioned around the perimeter of a large, flat, plastic disk, brightly illuminated by four overhead halogen lamps. Sham-operated animals rapidly acquired this task, exhibiting reduced latency to find the tunnel and a more efficient search strategy as compared with injured mice. This difference was not due to visuomotor deficits, as all mice performed equally well in a cued version of the same task. These results demonstrate spatial learning impairment following CCI injury in a task that offers an efficient alternative to the water maze.

Effects of dimethylformamide on in vivo fatigue and metabolism in rat skeletal muscle measured by 31P-NMR.

Dimethylformamide (DMF) is widely used as an industrial solvent in spite of well-established hepatotoxicity and adverse effects on in vitro muscle contractility. The doses used in the studies describing these effects were higher than the doses required to solubilize drugs to be injected at very low levels and the potential effects of DMF at very low levels has not yet been explored. The goal of this work was to study the effects of an acute, low dose of DMF (3 mu/100 g body weight, administered i.p.) on mechanical parameters and energy metabolism of contracting rat skeletal muscle. Metabolic changes were followed by 31P nuclear magnetic resonance spectroscopy. Tension was significantly lower during the fatigue test in DMF-treated rats than in controls. Phosphomonoesters and inorganic phosphorus level were lower, and intracellular pH was higher in DMF-treated rats than in controls, showing that energy metabolism was activated to a lesser degree, in relation with the lower mechanical performance, after DMF. Skeletal muscle is a target organ for dimethylformamide which has a major effect on muscle contractility by decreasing the tension developed. The effects of DMF suggest that it is unsuitable for use as a drug vehicle for in vivo injections, even at a very low nonhepatotoxic doses.

Glucose transporter localization in brain using light and electron immunocytochemistry.

A polyclonal antibody to a synthetic 13 amino acidpeptide found at the carboxyl-terminal end of the glucose transporter protein was raised in rabbit and used in light and electron immunocytochemical studies of human and canine brain. This antibody identified a broad band of polypeptide of average Mr 55,000 on immunoblots (immunogold-silver stains) of electrophoresed membrane proteins from human red blood cells. A similar polypeptide band (Mr 45,000-60,000) was identified on immunoblots of microvessel membrane proteins isolated from canine cerebrum, suggesting that this antibody is a useful tool for studying the distribution and abundance of the glucose transporter protein in mammalian nervous tissue. Peroxidase antiperoxidase stains of cerebrum using this antibody demonstrated that transporters are abundant in the intima pia, in the endothelium of blood vessels in the subarachnoid space, and in the endothelium of arterioles, venules, and capillaries of gray and white matter. In cerebellum, reaction product was localized in the vessels of the subarachnoid space and in microvessels of the molecular layer, the granular layer, and the white matter. However, transporters were not found in the intima pia of cerebellum. In medulla oblongata, transporters were found in the intima pia, the endothelium of some subarachnoid vessels, and the microvessels of gray and white matter. In pituitary, microvessels in adenohypophysis contained no reaction product, but the antigen was detected in some microvessels in neurohypophysis. Electron microscopy of cerebral cortex using a protein A-gold technique demonstrated that glucose transporters are equally abundant on the luminal and abluminal membranes of microvessel endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)