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

Effects of Strontium Ranelate on Spinal Osteoarthritis Progression

OBJECTIVE: The aim of this study was to determine whether a 3-year treatment with strontium ranelate could delay the progression of spinal osteoarthritis (OA). METHODS: This study was a post-hoc analysis of pooled data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and TReatment Of Peripheral OSteoporosis (TROPOS) trials performed on 1105 women with osteoporosis and concomitant radiological spinal OA at baseline, and for whom lumbar x-rays were available at baseline and over the 3-year treatment period. The presence and severity of osteophytes, disc space narrowing and sclerosis in the lumbar intervertebral spaces was graded according to a validated method, and an overall OA score was calculated for each intervertebral space. Back pain (measured on a five-point Likert scale only in SOTI) and health-related quality of life (SF-36 questionnaire) were assessed at baseline and after 3 years. Patients who suffered an incident or progressive vertebral fracture during the study were excluded from the analysis. RESULTS: The proportion of patients with worsening overall spinal OA score was reduced by 42% in the strontium ranelate group, compared with placebo (RR, 0.58; 95% CI, 0.42 to 0.79; p = 0.0005). Significantly more patients in the strontium ranelate group experienced an improvement in back pain after 3 years, compared with placebo (p = 0.03), while no significant difference was observed in terms of health-related quality of life between these patient groups. CONCLUSIONS: The results of this post-hoc analysis suggest that strontium ranelate could reduce the progression of the radiographic features of spinal OA and back pain in women with osteoporosis and prevalent spinal OA

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

Benefit of burosumab in adults with X-linked hypophosphataemia (XLH) is maintained with long-term treatment

Objectives To report the impact of continued burosumab treatment on clinical laboratory tests of efficacy, patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia who continued from a 96-week phase 3 study into a 48-week open-label extension. Methods Eligible participants from the phase 3 study continued on the burosumab regimen received at the end of the phase 3 study for a further 48 weeks (n=31). Some (not all) received compassionate burosumab treatment between the two studies (a period of 6–18 months). The primary efficacy outcome was fasting serum phosphate concentration; secondary outcomes were serum 1,25 dihydroxyvitamin D concentration, renal phosphate reabsorption, PROs and ambulatory function. Results Improvements in fasting serum phosphate, serum 1,25 dihydroxyvitamin D and renal phosphate reabsorption at 96 weeks were maintained through the 48-week extension. Improvements were also maintained in stiffness and physical function measured using the Western Ontario and McMaster Universities Osteoarthritis Index, pain and fatigue endpoints measuring using the Brief Pain Inventory short-form and Brief Pain Inventory, respectively, and in ambulatory function (6-Minute Walk Test). A post-hoc exploratory analysis exploring outcomes in participants who discontinued burosumab treatment between the studies (n=7) and those who received at least one dose (n=23) indicated that the benefits of burosumab on clinical laboratory tests of efficacy, PROs and ambulatory function may be lost when treatment is interrupted but recover over time when treatment is reinstated. Conclusion Continued treatment with burosumab appears necessary for sustained clinical benefit