Search

International audience; In this paper, a flat hyperbolic lens antenna using Groove Gap Waveguide (GGW) technology is designed at 300 GHz. A GGW horn antenna is used to feed the metamaterial lens placed in a parallel plate waveguide (PPW), in order to increase the directivity in the direction of propagation. The combination of both devices, the metalens and the GGW antenna, achieves excellent radiation performance.

International audience; Nous introduisons la lentille de Luneburg réflective (Reflecting Luneburg lens, RLL), un formateur de faisceau innovant conçu pour surmonter les contraintes plus significatives des lentilles de Luneburg planaires conventionnelles et des autres formateurs, comme le coupleur pillbox. Les RLL offrent de nombreux avantages : balayage total en azimut, possibilité de générer des faisceaux pincés et faible profil. Elles sont également applicables pour une vaste variété de dispositifs fonctionnant en micro-onde, en gamme THz et en optique.

High bone mass (HBM) disorders are a clinically and genetically heterogeneous subgroup of rare skeletal dysplasias. Here we present a case of a previously unreported familial skeletal dysplasia characterized by HBM and lucent bone lesions that we aimed to clinically characterize and genetically investigate. For phenotyping, we reviewed past clinical records and imaging tests, and performed physical examination (PE), bone densitometry, and mineral panels in affected individuals, including a male proband, his son and daughter, in addition to unaffected controls, including the proband's wife and brother. Affected individuals also underwent impact microindentation (IMI). In an effort to elucidate the disorder's molecular etiology, whole exome sequencing (WES) was performed in all individuals to filter for rare variants present only in affected ones. The cases displayed a unique skeletal phenotype with a mix of sclerotic features and lucent bone lesions, and high IMI values. Bone mineral density was very elevated in the proband and his daughter. The proband's daughter also exhibited idiopathic scoliosis (IS), in addition to mild thrombocytopenia and mild structural thyroid abnormalities, which were the only extra-skeletal abnormalities identified. WES analysis yielded 5 rare putative pathogenic variants in affected members in genes that are associated with bone metabolism including: SEM4AD, TBX18, PTCH1, PTK7, and ADGRE5. The PTK7 variant appeared as possibly implicated in the development of IS while the TBX18 and SEMA4D variants stood out as the strongest candidates for the lucent bone lesions and HBM, respectively, given their high predicted pathogenicity and putative role in bone biology. Variant functionality should be addressed in the future to assess their implication in skeletal metabolism as it is the first time that mutations in TBX18 and SEMA4D have been associated to bone developmental lesions and mineral metabolism in a clinical setting.

Atypical femoral fractures (AFF) are rare fragility fractures in the subtrocantheric or diaphysis femoral region associated with long-term bisphosphonate (BP) treatment. The etiology of AFF is still unclear even though a genetic basis is suggested. We performed whole exome sequencing (WES) analysis of 12 patients receiving BPs for at least 5 years who sustained AFFs and 4 controls, also long-term treated with BPs but without any fracture. After filtration and prioritization of rare variants predicted to be damaging and present in genes shared among at least two patients, a total of 272 variants in 132 genes were identified. Twelve of these genes were known to be involved in bone metabolism and/or AFF, highlighting DAAM2 and LRP5, both involved in the Wnt pathway, as the most representative. Afterwards, we intersected all mutated genes with a list of 34 genes obtained from a previous study of three sisters with BP-related AFF, identifying nine genes. One of these (MEX3D) harbored damaging variants in two AFF patients from the present study and one shared among the three sisters. Gene interaction analysis using the AFFNET web suggested a complex network among bone-related genes as well as with other mutated genes. BinGO biological function analysis highlighted cytoskeleton and cilium organization. In conclusion, several genes and their interactions could provide genetic susceptibility to AFF, that along with BPs treatment and in some cases with glucocorticoids may trigger this so feared complication.

Objective: To assess the effect of vitamin D supplementation on musculoskeletal complications related to aromatase inhibitor (AI) treatment in patients with breast cancer. Material and methods: Prospective observational study of women undergoing AI treatment, recruited in the B‐ABLE cohort. Patients with baseline serum 25 (OH) D (25‐hydroxyvitamin D) levels 0 at 3 months, was evaluated using logistic regression. Results: Vitamin D supplementation at the start of AI treatment decreased the risk of both incident arthralgia and its worsening. The effective threshold of 25 (OH) D in serum to reduce joint pain was established at 40 ng/ml. However, this threshold was not significantly related to bone changes at one year of follow‐up. However, vitamin D levels were in‐ versely correlated with lumbar spine bone loss (LS) (β=0.177% [95% CI: 0.014 to 0.340]). Conclusions: Vitamin D supplementation aimed at achieving serum 25(OH)D levels of at least 40 ng/ml is protective for arthralgia. Vitamin D levels at three months could predict the risk of bone loss in LS at one year of AI treatment. The‐ refore, high doses of vitamin D are recommended in these patients, who are more prone to musculoskeletal conditions.

National audience; Une cellule élémentaire contrôlée optiquement à 1,5 µm est proposée pour intégration dans un réseau transmetteur en bande X. Un prototype a été caractérisé dans un guide d'onde avec une différence de phase de 180°±10° entre les deux états de la cellule, dans la bande fréquence de 8.7-10.5GHz avec une bande passante relative à-3dB de 9.8%.

Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF.

Resumen Objetivo: Los inhibidores de la aromatasa (IA) se han asociado con una pérdida de masa ósea acelerada y un mayor riesgo de fracturas osteoporóticas. Con este trabajo se pretendió evaluar los factores de riesgo de fractura incidente en pacientes con cáncer de mama que reciben IA. Material y métodos: Estudio prospectivo-observacional de cohorte de mujeres con cáncer de mama que inician tratamiento con IA (cohorte B-ABLE). Las pacientes realizaron tratamiento durante 5 años o bien 2 ó 3 años si habían recibido previamente tamoxifeno. Se les evaluó la salud ósea desde el inicio del tratamiento hasta un año después de finalizar dicho tratamiento mediante densitometría ósea, marcadores de remodelado óseo, niveles de vitamina D y una radiografía antero-posterior y otra lateral de columna. Se realizó el cálculo de riesgo de fractura mediante la herramienta FRAX® antes de iniciar IA. Se utilizaron modelos de Cox para calcular los ratios de riesgo (HR [IC 95%]) de fractura. Resultados: Un total de 943 pacientes fueron incluidas en el estudio. El 5,4% sufrieron una fractura incidente, la mayoría durante el tratamiento con IA, aunque un 21,5% ocurrieron durante el primer año después de finalizar la terapia. La mayoría de las fracturas incidentes fueron vertebrales clínicas (29,4%) y de Colles (31,4%). El 86,3% de las pacientes tenían un diagnóstico de osteopenia u osteoporosis en el momento de la fractura y el 33% tenían los niveles de β-CTX (isómero β del telopéptido carboxiterminal del colágeno tipo I) por encima de la normalidad. Las pacientes diagnosticadas de osteoporosis o con riesgo de fractura al inicio del estudio fueron tratadas con antirresortivos óseos. No se encontraron diferencias significativas en el riesgo de fractura entre pacientes con y sin tratamiento antirresortivo: HR=1,75 [IC 95%: 0,88 a 3,46]. Tampoco se encontraron diferencias entre las pacientes que habían hecho tratamiento previo con tamoxifeno respecto a las que no (HR=1,00 [IC 95%: 0,39 a 2,56]). La herramienta FRAX® dio valores de media dentro del rango de riesgo intermedio, con 13 pacientes con valores de alto riesgo de fractura principal. Conclusiones: El principal factor de riesgo detectado para fractura incidente en pacientes tratadas con IA es el diagnóstico de osteopenia u osteoporosis. El cálculo de la herramienta FRAX® y la determinación de los niveles de β-CTX son herramientas útiles para identificar a pacientes de alto riesgo. Summary Objetive: Aromatase inhibitors (AI) have been associated with an accelerated loss of bone mass and an increased risk of osteoporosis fractures. This study assesses the risk factors for incident fracture in breast cancer patients receiving AI. Material and methods: Prospective-observational cohort study of women with breast cancer who begin treatment with AI (B-ABLE cohort). Patients were treated for 5 years or 2 or 3 years if they had previously received tamoxifen. Bone health was assessed from the beginning of the treatment until one year post treatment by bone densitometry, bone remodeling markers, vitamin D levels and an anteroposterior and lateral spine radiography. The fracture risk calculation was performed using the FRAX® tool before starting AI. Cox models were used to calculate the risk ratios (HR [95% CI]) of fracture. Results: A total of 943 patients were included in the study. 5.4% suffered an incident fracture, most during AI treatment, although 21.5% occurred during the first year after the end of therapy. Most of the incident fractures were clinical vertebral (29.4%) and Colles (31.4%). 86.3% of the patients had a diagnosis of osteopenia or osteoporosis at the time of the fracture and 33% had the levels of β-CTX (β isomer of the carboxyterminal telopeptide of type I collagen) above normal. Patients diagnosed with osteoporosis or at risk of fracture at the start of the study were treated with bone antiresorptives. No significant differences in fracture risk were found between patients with and without antiresorptive therapy: HR=1.75 [95% CI: 0.88 to 3.46]. Nor were differences found among patients who had previously treated with tamoxifen compared to those who did not (HR=1.00 [95% CI 0.39 to 2.56]). The FRAX® tool gave average values within the intermediate risk range, with 13 patients with high risk of major fracture values. Conclusions: The main risk factor detected for incident fracture in patients treated with AI is the diagnosis of osteopenia or osteoporosis. The calculation of the FRAX® tool and the determination of β-CTX levels are useful tools to identify high-risk patients.

Background To investigate longitudinal associations of maternal glucose/HbA(1c)and insulin dose with birthweight-related outcomes in women with type 1 diabetes. Methods We performed a cohort study including 473 pregnant women with type 1 diabetes with singleton pregnancies. We investigated maternal self-monitored blood glucose (SMBG, mmol/L), HbA(1c)(%, mmol/mol) and insulin dose (IU/kg/day) in the three trimesters as potential independent variables, while adjusting for potential confounders. Outcomes of interest were birthweight, birthweight SD score, neonatal length, weight/length index, ponderal index and placental weight. Multiple linear regression analysis was performed with separate analyses for SMBG and HbA(1c). Results Maternal glucose and insulin dose were independently associated with birthweight-related outcomes. In the main analysis, in the first trimester most associations were positive for insulin dose, in the second the associations were positive for glucose and inverse for insulin while in the third there were no associations. Most sensitivity analyses produced consistent results. In a sensitivity analysis splitting the first trimester in two periods, positive associations of maternal insulin with birthweight-related outcomes were observed in weeks 0+ to 6+. Conclusions Early in pregnancy in women with type 1 diabetes, maternal insulin dose is positively associated with birthweight-related outcomes, whereas in the second trimester, a positive association with SMBG emerges and the association with maternal insulin becomes inverse. If confirmed in other cohorts, these results would have implications in the management of women with type 1 diabetes.

Fibrous dysplasia/McCune–Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.

Genome-wide association studies (GWAS) have repeatedly identified genetic variants associated with bone mineral density (BMD) and osteoporotic fracture in non-coding regions of C7ORF76, a poorly studied gene of unknown function. The aim of the present study was to elucidate the causality and molecular mechanisms underlying the association. We re-sequenced the genomic region in two extreme BMD groups from the BARCOS cohort of postmenopausal women to search for functionally relevant variants. Eight selected variants were tested for association in the complete cohort and 2 of them (rs4342521 and rs10085588) were found significantly associated with lumbar spine BMD and nominally associated with osteoporotic fracture. cis-eQTL analyses of these 2 SNPs, together with SNP rs4727338 (GWAS lead SNP in Estrada et al., Nat Genet. 44:491-501, 2012), performed in human primary osteoblasts, disclosed a statistically significant influence on the expression of the proximal neighbouring gene SLC25A13 and a tendency on the distal SHFM1. We then studied the functionality of a putative upstream regulatory element (UPE), containing rs10085588. Luciferase reporter assays showed transactivation capability with a strong allele-dependent effect. Finally, 4C-seq experiments in osteoblastic cell lines showed that the UPE interacted with different tissue-specific enhancers and a lncRNA (LOC100506136) in the region. In summary, this study is the first one to analyse in depth the functionality of C7ORF76 genomic region. We provide functional regulatory evidence for the rs10085588, which may be a causal SNP within the 7q21.3 GWAS signal for osteoporosis.

Resumen Objetivos: La microindentación de impacto (MII) es una técnica que permite medir in vivo la resistencia tisular mecánica ósea. Se ha demostrado que la MII proporciona información útil sobre la evaluación de enfermedades esqueléticas, pero se desconoce el efecto que la edad puede ejercer sobre la propiedad ósea medida. El objetivo del estudio es analizar la relación entre la edad y la MII. Material y métodos: El índice de Resistencia Mineral Ósea (BMSi), la variable de medición de MII, se midió en 69 mujeres (mediana de edad: 49 años; rango: 30-81 años) y 19 varones (mediana de edad: 34 años; rango: 24-98 años) sanos. La correlación entre BMSi y la edad se analizó mediante regresión lineal. La asociación entre BMSi y edad se evaluó mediante ANOVA tras ajustar por el índice de masa corporal. El posible efecto de depleción estrogénica postmenopáusica sobre el BMSi se estudió comparando el subgrupo de mujeres más jóvenes con las más mayores mediante la prueba t de Student. Resultados: Los análisis de regresión lineal mostraron que la BMSi no se correlaciona con la edad en varones (R2=0,0016, p=0,74) ni en mujeres (R2=0,076, p=0,25). Asimismo, el análisis ajustado de ANOVA no demostró asociación entre la BMSi y la edad ni en varones (p=0,78) ni en mujeres (p=0,73). Finalmente, no se encontraron diferencias entre la BMSi entre las mujeres más jóvenes y las mayores (p=0,8). Conclusiones: La resistencia tisular mecánica ósea en individuos sanos es independiente a la edad y a la depleción estrogénica postmenopáusica. Summary Objective: Impact microindentation (IMI) is a technique that allows the measurement of mechanicalbone tissue resistance in vivo. IMI has proven to provide useful information on the evaluation of skeletal diseases, but the effect of age on the bone property that is measured by this technique is unknown. This study aims to analyzethe relationship between age and MIH. Materials and methods: Bone Material Strength index (BMSi), IMI’s output variable, was measured in 69 healthy women (median age: 49 years, range: 30-81 years) and 19 healthy men (median age: 34 years, range: 24-98 years). The correlation between BMSi and age was analyzed by linear regression. The association between BMSi and age was evaluated by ANOVA after adjusting for body mass index. The potential effect of postmenopausal estrogenic depletion on BMSi was studied by comparing the younger vs the older subset of women through a t-student test. Results: Linear regression analysis showed that BMSi was not correlated with age in either men (R2=0.0016, p=0.74) or women (R2=0.076, p=0.25). Similarly, the BMI-adjusted ANOVA model revealed a lack of association of BMSi with age in men (p=0.78) and women (p=0.73). Finally, there were not significant differences on BMSi detected between the younger and the older subset of women (p=0.8). Conclusions: Bone tissue mechanical resistance in healthy individuals is independent of age and postmenopausal estrogenic depletion.

International audience; Metasurfaces are thin (2D) metamaterials designed for manipulating the dispersion properties of surface-waves (SWs) or the reflection properties of incident plane-waves. Thanks to the sub-wavelength sizes of the patches used in the implementation step, these surfaces can be described by a surface impedance boundary condition (IBC). In this paper, we investigate a 'Method of Moments' (MoM) based analysis of such surface with a family of entire-domain basis functions named 'Fourier-Bessel' functions. The orthogonality property of these functions on a disk allows us to represent any smooth current distribution in an effective manner and thereby to drastically reduce the size of the MoM matrix. © 2017 IEEE.