Alterted SLIT2/ROBO1 signalling is linked to impaired placentation of missed and threatened miscarriage in early pregnancy.

AIMS: Two-thirds of early pregnancy failures present with reduced trophoblast invasion, and SLIT2/ROBO1 signalling is considered to play an important role in trophoblast function during pregnancy. We investigated SLIT2/ROBO1 signalling associated with missed and threatened miscarriage during early gestation. METHODS AND RESULTS: Human placenta samples were collected from women with missed miscarriage (n = 25), threatened miscarriage (n = 22) and termination of pregnancy controls (n = 32). Corresponding decreases in beta human chorionic gonadotrophin (ß-hCG) levels and shallow trophoblast invasion were observed in patients with missed and threatened miscarriage, immunohistological staining revealed abnormal Slit2 and Robo1, as well as E-cadherin and activating protein-2 alpha (AP-2α) expression in villi and extravillous trophoblasts, and the expression of these proteins were confirmed in villi and decidua of miscarriage material by Western blotting. Using HTR8/SVneo cells, blocking SLIT2/ROBO1 signalling promoted cell migration, proliferation and suppressed differentiation. Moreover, blocking SLIT2/ROBO1 signalling in HTR8/SVneo cells altered trophoblast differentiation-related and angiogenesis-related gene mRNA expression, which also occurred in the tissues of missed and threatened miscarriage. CONCLUSIONS: SLIT2/ROBO1 signalling may regulate trophoblast differentiation and invasion causing restricting ß-hCG production, shallow trophoblast invasion and inhibiting placental angiogenesis in missed and threatened miscarriage during the first trimester.

Angiogenesis-related immune response may be the prelude to the syndesmophyte formation in Ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic autoimmune arthritis that mainly affects spine joints. To date, the pathogenesis of AS remains unclear, although immune cells and innate immune response cytokines have been suggested to be crucial players. METHODS: By adopting a single-cell RNA sequencing approach in the AS cynomolgus model, we profiled and characterized PBMC proportions along disease progression. RESULTS: Here, our primary focus was on the activation of an immune cascade-initiating lymphocyte subtype known as CD4+CXCR5+ T follicular helper (Tfh) cells. These Tfhs demonstrated a localized residence in AS bone lesion as an ectopic lymphoid structure. Moreover, Tfhs would serve as an upstream initiator for a pro-angiogenic cascade. Then, an expansion in CD14+ monocytes and DC cells subsets resulted in enhanced expression of angiogenesis genes in these AS cynomolgus monkeys. With a confirmed higher abundance of TNF-α accompanying H-type vascular invasion in the osteophytic region, pronounced expansion of Tfhs at such lesion site signaling for monocytes and DCs intrusion is considered as the prelude to the characteristic angiogenic bony outgrowth in AS known as syndesmophytes. CONCLUSIONS: We explored the intimate relationship between local inflammation and bone formation in AS from the perspective of nascent vascularisation. Hence, our study lays the foundation for elucidating a unified AS pathogenesis through the immune-angiogenesis-osteogenesis axis.

A new and spontaneous animal model for ankylosing spondylitis is found in cynomolgus monkeys.

BACKGROUND: Ankylosing spondylitis is a progressive, disabling joint disease that affects millions worldwide. Given its unclear etiology, studies of ankylosing spondylitis relied heavily on drug-induced or transgenic rodent models which retain only partial clinical features. There is obviously a lack of a useful disease model to conduct comprehensive mechanistic studies. METHODS: We followed a group of cynomolgus monkeys having joint lesions reported of spinal stiffness for 2 years by conducting hematological testing, radiographic examination, family aggregation analysis, pathological analysis, and genetic testing. RESULTS: The results confirmed that these diseased animals suffered from spontaneous ankylosing spondylitis with clinical features recapitulating human ankylosing spondylitis disease progression, manifested by pathological changes and biochemical indicators similar to that of ankylosing spondylitis patients. CONCLUSION: The study offers a promising non-human primate model for spontaneous ankylosing spondylitis which may serve as an excellent substitute for its pre-clinical research.

A Core Omnigenic Non-coding Trait Governing Dex-Induced Osteoporotic Effects Identified Without DEXA.

Iatrogenic glucocorticoid (GC)-induced osteoporosis (GIO) is an idiosyncratic form of secondary osteoporosis. Genetic predisposition among individuals may give rise to variant degree of phenotypic changes but there has yet been a documented unified pathway to explain the idiosyncrasy. In this study, we argue that the susceptibility to epigenetic changes governing molecular cross talks along the BMP and PI3K/Akt pathway may underline how genetic background dictate GC-induced bone loss. Concordantly, osteoblasts from BALB/c or C57BL/6 neonatal mice were treated with dexamethasone for transcriptome profiling. Furthermore, we also confirmed that GC-pre-conditioned mesenchymal stem cells (MSCs) would give rise to defective osteogenesis by instigating epigenetic changes which affected the accessibility of enhancer marks. In line with these epigenetic changes, we propose that GC modulates a key regulatory network involving the scavenger receptor Cd36 in osteoblasts pre-conditioning pharmacological idiosyncrasy in GIO.

Recommendation of the best site based on the distribution pattern of extramuscular and intramusular nerves for gluteal muscle injection / Recomendación del mejor sitio para la inyección del músculo glúteo basado en el patrón de distribución de los nervios extramusculares e intramusculares

To reveal the extra- and intramuscular nerve distribution patterns of the gluteus maximus, medius, and minimus, and to provide guidance for gluteal muscle injection in order to avoid nerve injury. Ten adult and 10 child cadavers were used. The superior and inferior gluteal nerves innervating the gluteus maximus, medius, and minimus were dissected, exposed, and sutured in-situ on the muscle. The three gluteal muscles were removed, and the distribution patterns of the intramuscular nerves were revealed by modified Sihler's nerve staining. The nerve distribution pattern was returned to the corresponding position in the body, and the patterns in the four quadrants of the buttock were analyzed. There were 3-12 extramuscular nerve branches of the gluteus maximus, medius, and minimus. After entering the muscle, these nerve branches arborized and anastomosed to form an arc-shaped, nerve-dense zone. The nerve distribution was most dense in the inferomedial region of the superolateral quadrant and the inferolateral region of the superomedial quadrant of the buttocks. The nerve distribution was relatively dense in the inferolateral region of the superolateral quadrant, and the medial region of the inferomedial quadrant. An arc-shaped, nerve-sparse zone in the superolateral and superomedial quadrants near the lower iliac crest accounted for about two-fifths of the two quadrants' limits. The arc-shaped, nerve-sparse zone in the superolateral quadrant is the preferred injection site, and the superomedial quadrant near the lower iliac crest is also recommended as a gluteal intramuscular injection region, free from nerve injury.

El objetivo de este trabajo fue revelar los patrones de distribución nerviosa extramusculat e intramuscular de los músculos glúteo máximo, medio y mínimo y proporcionar orientación para la inyección en la región glútea con el propósito de evitar lesiones nerviosas. Se utilizaron diez cadáveres adultos y diez niños. Los nervios glúteos superior e inferior que inervan a los músculos glúteo máximo, medio y mínimo fueron disecados, expuestos y suturados in situ en el músculo. Se extirparon los tres músculos glúteos y se revelaron los patrones de distribución de los nervios intramusculares mediante la tinción nerviosa de Sihler modificada. El patrón de distribución nerviosa se devolvió a la posición correspondiente en el cuerpo y se analizaron los patrones en los cuatro cuadrantes de la región glútea. Se encontraron 3 a 12 ramos nerviosos extramusculares de los músculos glúteo máximo, medio y mínimo. Después de ingresar al músculo, estas ramas nerviosas se arborizaron y anastomizaron para formar una zona densamente nerviosa en forma de arco. La distribución nerviosa fue de mayor densidad en la región inferomedial del cuadrante superolateral y en la región inferolateral del cuadrante superomedial de la región glútea. La distribución nerviosa era relativamente densa en la región inferolateral del cuadrante superolateral y en la región medial del cuadrante inferomedial. Una zona en forma de arco en los cuadrantes superolateral y superomedial y con escasa inervación, cerca de la cresta ilíaca representaba una parte de los límites de los dos cuadrantes. La zona de poca inervación en forma de arco en el cuadrante superolateral es el sitio de inyección preferido, y el cuadrante superomedial próximo a la cresta ilíaca también se recomienda como una región de inyección intramuscular glútea, libre de lesión nerviosa.