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Individuals with Down syndrome (DS), the result of trisomy of human chromosome Hsa21 (Ts21), present with an array of skeletal abnormalities typified by altered craniofacial features, short stature and low bone mineral density (BMD). While bone deficits progress with age in both sexes, low bone mass is more pronounced in DS men than women and osteopenia appears earlier. In the current study, the reproductive hormone status (FSH, LH, testosterone) of 17 DS patients (males, ages range 19–52 years) was measured. Although testosterone was consistently low, the hypothalamic-pituitary-gonadal axis was intact with corresponding rises in FSH and LH. To provide further insight into the heterogeneity of the bone mass in DS, the skeletal phenotypes of three of the most used murine DS models, Ts65Dn (Ts65), TC1, and Dp16(Yey1) (Dp16) were characterized and contrasted. Evaluation of the bone phenotype of both male and female 3-month-old Dp16 mice demonstrated sexual dimorphism, with low bone mass apparent in males, as it is in Ts65, but not in female Dp16. In contrast, male TC1 mice had no apparent bone phenotype. To determine whether low bone mass in DS impacted fracture healing, fractures of the middle phalanx (P2) digits were generated in both male and female Dp16 mice at 15 weeks of age, an age where the sexually dimorphic low BMD persisted. Fracture healing was assessed via in vivo microCT over (13 weeks) 93 days post fracture (DPF). At 93 DPF, 0 % of DS male (n = 12) or female (n = 8) fractures healed, compared to 50 % of the male (n = 28) or female (n = 8) WT littermate fractures. MicroCT revealed periosteal unbridged mineralized callus formation across the fracture gap in Dp16 mice, which was confirmed by subsequent histology. These studies provide the first direct evidence of significantly impaired fracture healing in the setting of DS.

The availability of tools to accurately replicate the clinical phenotype of rare human diseases is a key step toward improved understanding of disease progression and the development of more effective therapeutics. We successfully generated the first large animal model of a rare human bone disease, hypophosphatasia (HPP) using CRISPR/Cas9 to introduce a single point mutation in the tissue nonspecific alkaline phosphatase (TNSALP) gene (ALPL) (1077 C > G) in sheep. HPP is a rare inherited disorder of mineral metabolism that affects bone and tooth development, and is associated with muscle weakness. Compared to wild-type (WT) controls, HPP sheep have reduced serum alkaline phosphatase activity, decreased tail vertebral bone size, and metaphyseal flaring, consistent with the mineralization deficits observed in human HPP patients. Computed tomography revealed short roots and thin dentin in incisors, and reduced mandibular bone in HPP vs. WT sheep, accurately replicating odonto-HPP. Skeletal muscle biopsies revealed aberrant fiber size and disorganized mitochondrial cristae structure in HPP vs. WT sheep. These genetically engineered sheep accurately phenocopy human HPP and provide a novel large animal platform for the longitudinal study of HPP progression, as well as other rare human bone diseases.

Down syndrome (DS), characterized by trisomy of human chromosome 21, is associated with a variety of endocrine disorders as well as profound skeletal abnormalities. The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of antiresorptive agents in people with DS. Sclerostin antibody (SclAb) is a therapeutic candidate currently being evaluated as a bone anabolic agent. Scl, the product of the sclerostin gene (SOST), inhibits bone formation through its inhibition of Wnt signaling. SclAb increases bone mass by suppressing the action of the endogenous inhibitor of bone formation, Scl. To examine the effects of SclAb on the DS bone phenotype, 8‐week‐old male wild‐type (WT) andTs65Dn DS mice were treated with 4 weekly iv injections of 100 mg/kg SclAb. Dual‐energy X‐ray absorptiometry (DXA), microCT, and dynamic histomorphometry analyses revealed that SclAb had a significant anabolic effect on both age‐matched WT littermate controls and Ts65Dn DS mice that was osteoblast mediated, without significant changes in osteoclast parameters. SclAb treatment significantly increased both cortical and trabecular bone mass at multiple sites; SclAb treatment resulted in the normalization of Ts65Dn bone mineral density (BMD) to WT levels in the proximal tibia, distal femur, and whole body. Ex vivo bone marrow cultures demonstrated that SclAb increased the recruitment of the mesenchymal progenitors into the osteoblast lineage, as indicated by increased alkaline phosphatase–positive colonies, with no effect on osteoclast differentiation. Together, in the setting of a murine model of DS and decreased bone turnover, SclAb had a potent anabolic effect. SclAb stimulated bone formation and increased osteoblastogenesis without affecting osteoclastogenesis or bone resorption. These data suggest that SclAb is a promising new therapy to improve bone mass and reduce fracture risk in the face of the low bone mass and turnover prevalent in the DS population. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Down syndrome (DS), characterized by trisomy of human chromosome 21, is associated with a variety of endocrine disorders as well as profound skeletal abnormalities. The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of antiresorptive agents in people with DS. Sclerostin antibody (SclAb) is a therapeutic candidate currently being evaluated as a bone anabolic agent. Scl, the product of the sclerostin gene (SOST), inhibits bone formation through its inhibition of Wnt signaling. SclAb increases bone mass by suppressing the action of the endogenous inhibitor of bone formation, Scl. To examine the effects of SclAb on the DS bone phenotype, 8‐week‐old male wild‐type (WT) andTs65Dn DS mice were treated with 4 weekly iv injections of 100 mg/kg SclAb. Dual‐energy X‐ray absorptiometry (DXA), microCT, and dynamic histomorphometry analyses revealed that SclAb had a significant anabolic effect on both age‐matched WT littermate controls and Ts65Dn DS mice that was osteoblast mediated, without significant changes in osteoclast parameters. SclAb treatment significantly increased both cortical and trabecular bone mass at multiple sites; SclAb treatment resulted in the normalization of Ts65Dn bone mineral density (BMD) to WT levels in the proximal tibia, distal femur, and whole body. Ex vivo bone marrow cultures demonstrated that SclAb increased the recruitment of the mesenchymal progenitors into the osteoblast lineage, as indicated by increased alkaline phosphatase–positive colonies, with no effect on osteoclast differentiation. Together, in the setting of a murine model of DS and decreased bone turnover, SclAb had a potent anabolic effect. SclAb stimulated bone formation and increased osteoblastogenesis without affecting osteoclastogenesis or bone resorption. These data suggest that SclAb is a promising new therapy to improve bone mass and reduce fracture risk in the face of the low bone mass and turnover prevalent in the DS population. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Bone is a common site for metastasis in breast cancer patients and is associated with a series of complications that significantly compromise patient survival, partially due to the advanced stage of disease at the time of detection. Currently, no clinically-approved biomarkers can identify or predict the development of bone metastasis. We recently identified a unique peptide fragment of parathyroid hormone-related protein (PTHrP), PTHrP(12-48), as a validated serum biomarker in breast cancer patients that correlates with and predicts the presence of bone metastases. In this study, the biological activity and mode of action of PTHrP(12-48) was investigated. Sequence-based and structure-based bioinformatics techniques predicted that the PTHrP(12-48) fragment formed an alpha helical core followed by an unstructured region after residue 40 or 42. Thereafter, detailed structure alignment and molecular docking simulations predicted a lack of interaction between PTHrP(12-48) and the cognate PTH1 receptor (PTHR1). The in silico prediction was confirmed by the lack of PTHrP(12-48)-stimulated cAMP accumulation in PTHR1-expressing human SaOS2 cells. Using a specific human PTHrP(12-48) antibody that we developed, PTHrP(12-48) was immunolocalized in primary and bone metastatic human breast cancer cells, as well as within human osteoclasts (OCLs) in bone metastasis biopsies, with little or no localization in other resident bone or bone marrow cells. In vitro, PTHrP(12-48) was internalized into cultured primary human OCLs and their precursors within 60 min. Interestingly, PTHrP(12-48) treatment dose-dependently suppressed osteoclastogenesis, via the induction of apoptosis in both OCL precursors as well as in mature OCLs, as measured by the activation of cleaved caspase 3. Collectively, these data suggest that PTHrP(12-48) is a bioactive breast cancer-derived peptide that locally regulates the differentiation of hematopoietic cells and the activity of osteoclasts within the tumor-bone marrow microenvironment, perhaps to facilitate tumor control of bone. © 2017 American Society for Bone and Mineral Research.

There exists limited understanding about the intersectional nature of needs and inequities among sexual and gender minorities in Macedonia and Eastern Europe. We conducted a qualitative, cross-sectional and national needs assessment among 71 sexual and gender minority community members using semi-structured focus groups and interviews. Thematic analysis was used to better understand their self-identified needs, their concerns about equity and the intersectional nature of their needs. Community members discussed a wide range of health and healthcare needs as well as the social and structural factors that influence those needs, including: cultural norms; victimisation and safety concerns and the role of law, policy and politics; education and democratisation of knowledge; and economic and housing opportunities. Needs were patterned across different sexual and gender minority subgroups such that those experiencing heightened marginalisation (e.g. trans* persons) also experienced compounded forms of inequity. Given that sexual and gender minorities in Macedonia have numerous structurally induced intersectional needs, multilevel and multifaceted strategies are needed to ensure that their rights and needs are respected, protected and fulfilled at structural, community and individual levels.

Dans la zone des Niayes au Sénégal, les sols sont pauvres en matières organiques et en éléments nutritifs nécessaires aux plantes. Les engrais chimiques utilisés pour améliorer les rendements ont engendré une forte pollution des sols et de la nappe phréatique. L’objectif de cette étude est d’évaluer la valeur agronomique du compost fabriqué à base des feuilles de neem et d’anacarde, de fiente de volaille et de la cendre de bois. Le compost obtenu présente un rapport C/N de 15,49 et des teneurs en N - P - K de 9,1, 14,8 et 7,3 mg/kg, respectivement. Les différentes doses du compost testées sur des cultures maraichères ont révélé des performances agronomiques meilleures par rapport aux témoins. La dose T3 (30 t/ha) a induit les meilleurs rendements pour la tomate (27,213 t/ha) et l’oignon (105,263 t/ha). Pour le chou et la pomme de terre, la dose T1 (10 t/ha) a permis d’obtenir les meilleurs rendements (144,533 t/ha et 55,163 t/ha, respectivement). Par contre pour le poivron, la dose T2 (20 t/ha) a favorisé les meilleurs rendements (32,534 t/ha) avec un poids moyen (81,748g) et un nombre de fruits/récolte considérablement plus élevé. Ce compost pourrait constituer une alternative réelle à l’utilisation abusive de l’engrais minéral dans la zone agricole des Niayes.Mots clés : Compost, Neem, Feuilles d’anacarde, Maraichage, Sénégal

It was a retrospective and descriptive study based on the calculation of the frequency, and to describe the clinical epidemiology, anatomopathologics and therapeutics aspects of the vulva cancers recorded between 1st of January 2005 to 31st of December 2014 at the service. We recorded 12 cases with Medium Age of 54 years, with extremity of 22 years and 84 years. We noted 1% of vulva cancer among the 1234 cases of Gynecological cancers diagnosed in the service. Two- third of the patients were elder than 55 years and the multiparous with 75%. The prurition and the tumefaction were the principal motive of consultation among 41.66 %. The tumor had epithelial origin in the clinical stage III in 50% of cases according to FIGO (2009). 3.6% of vulvectomy associated with lymphadenectomy in two-third and one case of radiotherapy. The cancers cases recorded were invasive epithelium type in old age women. These were intended to allow precocious diagnose and adequate taking care of the disease.

Bone is a common site for metastasis in breast cancer patients and is associated with a series of complications that significantly compromise patient survival, partially due to the advanced stage of disease at the time of detection. Currently, no clinically-approved biomarkers can identify or predict the development of bone metastasis. We recently identified a unique peptide fragment of parathyroid hormone-related protein (PTHrP), PTHrP(12-48), as a validated serum biomarker in breast cancer patients that correlates with and predicts the presence of bone metastases. In this study, the biological activity and mode of action of PTHrP(12-48) was investigated. Sequence-based and structure-based bioinformatics techniques predicted that the PTHrP(12-48) fragment formed an alpha helical core followed by an unstructured region after residue 40 or 42. Thereafter, detailed structure alignment and molecular docking simulations predicted a lack of interaction between PTHrP(12-48) and the cognate PTH1 receptor (PTHR1). The in silico prediction was confirmed by the lack of PTHrP(12-48)-stimulated cAMP accumulation in PTHR1-expressing human SaOS2 cells. Using a specific human PTHrP(12-48) antibody that we developed, PTHrP(12-48) was immunolocalized in primary and bone metastatic human breast cancer cells, as well as within human osteoclasts (OCLs) in bone metastasis biopsies, with little or no localization in other resident bone or bone marrow cells. In vitro, PTHrP(12-48) was internalized into cultured primary human OCLs and their precursors within 60 min. Interestingly, PTHrP(12-48) treatment dose-dependently suppressed osteoclastogenesis, via the induction of apoptosis in both OCL precursors as well as in mature OCLs, as measured by the activation of cleaved caspase 3. Collectively, these data suggest that PTHrP(12-48) is a bioactive breast cancer-derived peptide that locally regulates the differentiation of hematopoietic cells and the activity of osteoclasts within the tumor-bone marrow microenvironment, perhaps to facilitate tumor control of bone. © 2017 American Society for Bone and Mineral Research.

Locusts and grasshoppers are the most important economical threat in the sahelian agricultural system. Principal control strategies of these pests are synthetic chemicals which are, however, harmful to the environment and human health. Metarhizium anisopliae based biopesticide Green Muscle IMI330189 has been recently developed for the control of locusts and grasshoppers. In this paper, we assessed the pathogenicity of three local strains of M. anisopliae var. acridum on Locusta migratoria migratorioides and Zonocerus variegatus, in comparison to the commercial product, IMI330189. There was various level of pathogenicity within the strains on the two pests. On L. migratoria, DPV5 caused the highest mortality after three weeks (91.2%). There was a significant difference between DPV5 and IMI330189. However, there were no significant differences between IMI330189 and the other strains. On Z. variegatus there were no significant differences between IMI330189 DPV5 and DPV10. DPV15 had the lowest pathogenic activity. Moreover, the comparison of susceptibility of both insect pests to Metarhizium strains showed that L. migratoria is more susceptible than Z. variegatus. DPV5 had the shortest LT50 on L. migratoria 7.1 days whereas on Z. variegatus, the LT50 value of DPV5 was comparable to IMI330189. Our study suggests that, DPV5 which was isolated from Kraussaria angulifera in Senegal is a promising candidate for future development for locusts and grasshoppers control in the country.Keywords: Green Muscle, African migratory locust, grasshoppers, local strains, biopesticides

The recent detection in Senegal of the tomato leaf miner, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) and its rapid geographic spread, is a real concern for tomato production in Africa south of the Sahara. Deployment of effective biological control in the newly invaded area is urgently needed. The predatory species, Nesidiocoris tenuis (Reuter, 1895) (Heteroptera: Miridae), was collected, for the first time in Senegal, from tomato fields infested with T. absoluta. Laboratory feeding bioassay confirmed a potential of N. tenuis as a biocontrol agent of T. absoluta.

Diamondback moth (DBM), Plutella xylostella (L.), remains a major pest of brassica crops worldwide. Chemical control of this pest remains difficult due to the rapid development of resistance to insecticides and to their effect on natural enemies. The objective of this study was to assess the toxicity of Bacillus thuringiensis (Bt), neem oil and methamidophos on larvae of P. xylostella under laboratory conditions. Leaf-dip bioassay for DBM larvae was used to assess mortality. For each treatment, three doses (low, medium and high) were applied on cabbage leaves and presented to third instar larvae. Larval mortality was performed every 24 hours for a period of eight days. The application of the three dosages of Biobit was more effective against P. xylostella larvae when compared to the other treatments. However, there was no significant difference in larval mortality when all three doses of Biobit were tested compared to the control. Methamidophos was the least toxic treatments with high dosage recording the lowest mortality rate of 52.5%. These results showed that Btbased biopesticides and neem extracts could be of help, but their deployment should be part of an integrated pest management package, which recognizes the constraints of farmers while addressing the requirement to control of P. xylostella populations.Keywords: Diamondback moth, biopesticide, Azadirachta indica, cabbage, bioassay.