Low bone mass and impaired fracture healing in mouse models of Trisomy21 (Down syndrome).

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.

'Until we have laws everything is useless!': intersectionality, self-identified needs and inequity among sexual and gender minorities in Macedonia.

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.

Genetic engineering a large animal model of human hypophosphatasia in sheep.

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.

Sclerostin Antibody Treatment Stimulates Bone Formation to Normalize Bone Mass in Male Down Syndrome Mice.

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.

PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan.

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.

[Scanning electron microscope sudy of the morphology of fungi isolated from patients at the Aristide La Dantec Hospital in Dakar, Senegal]. / Etude en microscopie electronique à balayage de la morphologie des champignons isoles chez des malades a l'Hôpital Aristide Le Dantec de Dakar (Sénégal).

In order to improve the identification of fungi usually isolated among some patients at Dantec Hospital, a study by scanning electron microscopy has been carried out. It deals with four species of yeasts (Candida albicans, Candida parapsilosis, Rhodotorula rubra Sacharomyces cerevisiae) six species of dermatophytes (Trichophyton rubrum, Trichophyton soudanense, Trichophyton interdigitale, Microsporum canis, Trichophyton violaceum, Microsporum audouinii); two species of mildew, (Aspergullus flavus, Aspergillus niger) and one species of dimorphic fungi (Histoplasma duboisii). The yeasts get a smooth surface with, often, a mark of but on it. Microsporum canis presents some echinulate macroconidia. Trichophyton violaceum is characterized by the appearance of echinulate chlamydoconidium with a twofold bulge and Microsporum audouinii by a echinulate chlamydoconidium with a bulge only. Trichophyton rubrum presents macroconidia with smooth surface and in "sausage" form, as for Trichophyton soudanense it presents some arthroconidia that are cells which get more or less rectangular form and with smooth surface. Aspergillus flavus is characterized by the presence of a conidiophore with a verrucosis surface and an aspergillary head of about 36 microns having some spores with almost smooth inner surface. On the other hand, Aspergillus niger gets a conidiophore with smooth surface. As for Histoplasma duboisii, the surface of the chlamydoconidium presents some verrucosis that are real conidia in formation. The scanning electron microscopy enables use to discover the existence of characters that are likely to be used for the identification of fungi.

On the development cycle and ultrastructure of Vavraia culicis Weiser, 1947 (microsporida, pleistophoridae) with comments on the taxonomy of the genus Vavraia Weiser, 1977.

Vavraia culicis was studied using light and electron microscopy. The hosts were larvae of Anopheles gambiae collected in Senegal. Merogonial and sporogonial plasmodia had isolated nuclei. A thick amorphous coat was formed externally to the plasma membrane of the merogonial plasmodium, which developed into the envelope of the sporophorous vesicle. Division of merogonial and sporogonial plasmodia occurred by plasmotomy. Only one type of spores was produced. The polar filament was anisofilar. Meiosis was not observed.

Enquete sur les hopitaux nationaux du Mali: rapport

Nombre de pays en voie de developpement sont a la recherche de systeme de sante adequat; ou de strategies efficaces et efficientes pour assurer une application correcte de leur politique de sante. Les organismes internationaux comme l'OMS; l'UNICEF et particulierement les ONG contribuent a ces recherches en menant des essais communautaires sur le terrain. C'est dans ce cadre que se situe l'intervention du plan international dans l'arrondissement de Sanankoroba. Par la presente etude nous avons voulu apprehender l'impact qu'un comite de sante de village pouvait avoir sur la sante d'une population en terme de couverture sanitaire. [Abstract terminated]