An astrocyte-dependent mechanism for neuronal rhythmogenesis

Communication between neurons rests on their capacity to change their firing pattern to encode different messages. For several vital functions, such as respiration and mastication, neurons need to generate a rhythmic firing pattern. Here we show in the rat trigeminal sensori-motor circuit for mastication that this ability depends on regulation of the extracellular Ca2+ concentration ([Ca2+]e) by astrocytes. In this circuit, astrocytes respond to sensory stimuli that induce neuronal rhythmic activity, and their blockade with a Ca2+ chelator prevents neurons from generating a rhythmic bursting pattern. This ability is restored by adding S100b, an astrocytic Ca2+-binding protein, to the extracellular space, while application of an anti-S100b antibody prevents generation of rhythmic activity. These results indicate that astrocytes regulate a fundamental neuronal property: the capacity to change firing pattern. These findings may have broad implications for many other neural networks whose functions depend on the generation of rhythmic activity

FRAX (R): Prediction of Major Osteoporotic Fractures in Women from the General Population: The OPUS Study

Purposes: The aim of this study was to analyse how well FRAXH predicts the risk of major osteoporotic and vertebral fractures over 6 years in postmenopausal women from general population. Patients and methods: The OPUS study was conducted in European women aged above 55 years, recruited in 5 centers from random population samples and followed over 6 years. The population for this study consisted of 1748 women (mean age 74.2 years) with information on incident fractures. 742 (43.1%) had a prevalent fracture; 769 (44%) and 155 (8.9%) of them received an antiosteoporotic treatment before and during the study respectively. We compared FRAXH performance with and without bone mineral density (BMD) using receiver operator characteristic (ROC) c-statistical analysis with ORs and areas under receiver operating characteristics curves (AUCs) and net reclassification improvement (NRI). Results: 85 (4.9%) patients had incident major fractures over 6 years. FRAXH with and without BMD predicted these fractures with an AUC of 0.66 and 0.62 respectively. The AUC were 0.60, 0.66, 0.69 for history of low trauma fracture alone, age and femoral neck (FN) BMD and combination of the 3 clinical risk factors, respectively. FRAXH with and without BMD predicted incident radiographic vertebral fracture (n = 65) with an AUC of 0.67 and 0.65 respectively. NRI analysis showed a significant improvement in risk assignment when BMD is added to FRAXH. Conclusions: This study shows that FRAXH with BMD and to a lesser extent also without FN BMD predict major osteoporotic and vertebral fractures in the general population

The inhibitory effects of plumbagin on the NF-қB pathway and CCL2 release in racially different triple-negative breast cancer cells.

Breast cancer (BC) is the second leading cause of death among women in the US, and its subtype triple-negative BC (TNBC) is the most aggressive BC with poor prognosis. In the current study, we investigated the anticancer effects of the natural product plumbagin (PL) on racially different TNBC cells. The PL effects were examined in two TNBC cell lines: MDA-MB-231 (MM-231) and MDA-MB-468 (MM-468), representing Caucasian Americans and African Americans, respectively. The results obtained indicate that PL inhibited cell viability and cell proliferation and induced apoptosis in both cell lines. Notably, MM-468 cells were 5-fold more sensitive to PL than MM-231 cells were. Testing PL and Taxol® showed the superiority of PL over Taxol® as an antiproliferative agent in MM-468 cells. PL treatment resulted in an approximately 20-fold increase in caspase-3 activity with 3 μM PL in MM-468 cells compared with an approximately 3-fold activity increase in MM-231 cells with 8 μM PL. Moreover, the results indicate a higher sensitivity to PL in MM-468 cells than in MM-231 cells. The results also show that PL downregulated CCL2 cytokine expression in MM-468 cells by 30% compared to a 90% downregulation in MM-231 cells. The ELISA results confirmed the array data (35% vs. 75% downregulation in MM-468 and MM-231 cells, respectively). Moreover, PL significantly downregulated IL-6 and GM-CSF in the MM-231 cells. Indeed, PL repressed many NF-қB-regulated genes involved in the regulation of apoptosis, proliferation, invasion, and metastasis. The compound significantly downregulated the same genes (BIRC3, CCL2, TLR2, and TNF) in both types of cells. However, PL impacted five more genes in MM-231 cells, including BCL2A1, ICAM1, IKBKE, IL1β, and LTA. In conclusion, the data obtained in this study indicate that the quinone compound PL could be a novel cancer treatment for TNBC in African American women

Ultrasound-based estimates of cortical bone thickness and porosity are associated with non-traumatic fractures in postmenopausal women: A pilot study

International audienceRecent ultrasound axial transmission techniques exploit the multimode waveguide response of long bones to yield estimates of cortical bone structure characteristics. This pilot cross-sectional study aimed to evaluate the performance at the one-third distal radius of a bidirectional axial transmission (BDAT) device to discriminate between fractured and non-fractured postmenopausal women. Cortical thickness (Ct.Th) and porosity (Ct.Po) estimates were obtained for 201 postmenopausal women, among whom 109 were non-fractured (62.6±7.8 years), 92 with one or more non-traumatic fractures (68.8±9.2 years), 17 with hip fractures (66.1±10.3 years), 32 with vertebral fractures (72.4±7.9 years), and 17 with wrist fractures (67.8±9.6 years). The areal bone mineral density (aBMD) was obtained using dual-energy X-ray absorptiometry (DXA) at the femur and spine. Femoral aBMD correlated weakly but significantly with Ct.Th (R=0.23, p < 0.001) and Ct.Po (R=-0.15, p < 0.05). Femoral aBMD and both ultrasound parameters were significantly different between the subgroup of all non-traumatic fractures combined and the control group (p < 0.05). The main findings were (i) that Ct.Po was discriminant for all non-traumatic fractures combined (odds ratio OR=1.39; area under the receiver operating characteristic curve AUC=0.71), for vertebral (OR=1.96; AUC=0.84) and wrist fractures (OR=1.80; AUC=0.71), while Ct.Th was discriminant for hip fractures only (OR=2.01; AUC=0.72); (ii) the demonstration of a significant association between increased Ct.Po and vertebral and wrist fractures when these fractures were not associated with any measured aBMD variables; (iii) the association between increased Ct.Po and all non-traumatic fractures combined independently of aBMD neck; and (iv) the association between decreased Ct.Th and hip fractures independently of aBMD femur. BDAT variables showed comparable performance to that of aBMD neck with all types of fractures (OR=1.48; AUC=0.72) and that of aBMD femur with hip fractures (OR=2.21; AUC=0.70). If these results are confirmed in prospective studies, cortical BDAT measurements may be considered useful for assessing fracture risk in postmenopausal women

The effect of PL on caspase-3 activation.

<p>PL caused caspase-3 activation in both MM-231 and MM-468 cell lysates after cell treatment with PL for 24 h in concentration ranges of 0–20 μM for MM-231 cells (A) or 0–5 μM for MM-468 cells (B). The data represent two independent studies with n = 3 and are expressed as a fold-increase compared to the control. **** p <i><</i> 0.0001 indicate the highly significant difference between the control vs. treated cells. Likewise, ^#### p <i><</i> 0.0001 between the PL concentration-induced highest caspase level and caspase levels at further increasing PL concentrations in both cell lines.</p

Gene expression quantification in MM-468 cells.

<p>Normalized data show a significant increase in four genes in TNF-α-stimulated cells. On the other side, significant gene repression was observed in cotreated cells. The data points are expressed as the mean ± SEM of two independent experiments. The significant difference between resting and TNF-α-activated groups was determined by an unpaired t-test (*), as the same for TNF-α-treated vs. TNF-α + PL-treated cells (^#). Significance is considered at *p < 0.05, **p < 0.01, and #p < 0.05.</p