Low Dose of Bisphosphonate Enhances Sclerostin Antibody‐Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model

Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures that are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BPs) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models. In this study, the effects of the concurrent use of BP and SclAb were evaluated during bone growth in a mouse harboring an OI‐causing Gly→Cys mutation on col1a1. A single dose of antiresorptive BP facilitated the anabolic action of SclAb by increasing availability of surfaces for new bone formation via retention of primary trabeculae that would otherwise be remodeled. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined. Cortical gains in mass and strength occurred through SclAb alone, independent of presence of BP. In conclusion, these preclinical results support the scientific hypothesis that minimal antiresorptive treatment can amplify the effects of SclAb during early stages of skeletal growth to further improve bone structure and rigidity, a beneficial outcome for children with OI. © 2018 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144688/1/jbmr3421.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144688/2/jbmr3421_am.pd

Pamidronate Administration During Pregnancy and Lactation Induces Temporal Preservation of Maternal Bone Mass in a Mouse Model of Osteogenesis Imperfecta

During pregnancy and lactation, the maternal skeleton undergoes significant bone loss through increased resorption to provide the necessary calcium supply to the developing fetus and suckling neonate. This period of skeletal vulnerability has not been clearly associated with increased maternal fracture risk, but these physiological conditions can exacerbate an underlying metabolic bone condition like osteogenesis imperfecta. Although bisphosphonates (BPs) are commonly used in postmenopausal women, there are cases where premenopausal women taking BPs become pregnant. Given BPs’ long half‐life, there is a need to establish how BPs affect the maternal skeleton during periods of demanding metabolic bone changes that are critical for the skeletal development of their offspring. In the present study, pamidronate‐ (PAM‐) amplified pregnancy‐induced bone mass gains and lactation‐induced bone loss were prevented. This preservation of bone mass was less robust when PAM was administered at late stages of lactation compared with early pregnancy and first day of lactation. Pregnancy‐induced osteocyte osteolysis was also observed and was unaffected with PAM treatment. No negative skeletal effects were observed in offspring from PAM‐treated dams despite lactation‐induced bone loss prevention. These findings provide important insight into (1) a treatment window for when PAM is most effective in preserving maternal bone mass, and (2) the maternal changes in bone metabolism that maintain calcium homeostasis crucial for fetal and neonatal bone development. © 2019 American Society for Bone and Mineral ResearchPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153136/1/jbmr3831.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153136/2/jbmr3831_am.pd

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non‐OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low‐dose SclAb (TRL, 2.5 μg/mL), or high‐dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt‐related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone‐forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients’ genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision‐making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/2/jbm410377_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/1/jbm410377.pd

Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice

Neorealism and the Organization of American States (OAS): an examination of CARICOM rationality toward Venezuela and the United States

Since 2017, CARICOM member states have been divided in the positions they take on Organization of American States (OAS) resolutions addressing political instability in Venezuela. This article uses a neorealism framework to determine whether or not the provision of energy investments by Venezuela and the United States to CARICOM member countries is an attempt on their part to skew the OAS voting mechanism in their national interests. The article also examines the extent to which CARICOM member states’ response to Venezuela’s and United States’ interest in the OAS demonstrates a pattern of rationality. The findings suggest that though the OAS provides a medium for states to negotiate mutually beneficial solutions, states are rational actors and even where they do corporate, dominant states may try to manifest their self-interest

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Proteoglycan‐4 ( Prg4 ) protects synovial joints from arthropathic changes by mechanisms that are incompletely understood. Parathyroid hormone (PTH), known for its anabolic actions in bone, increases Prg4 expression and has been reported to inhibit articular cartilage degeneration in arthropathic joints. To investigate the effect of Prg4 and PTH on articular cartilage, 16‐week‐old Prg4 mutant and wild‐type mice were treated with intermittent PTH (1–34) or vehicle control daily for six weeks. Analyses included histology of the knee joint, micro‐CT of the distal femur, and serum biochemical analysis of type II collagen fragments (CTX‐II). Compared to wild‐type littermates, Prg4 mutant mice had an acellular layer of material lining the surfaces of the articular cartilage and menisci, increased articular cartilage degradation, increased serum CTX‐II concentrations, decreased articular chondrocyte apoptosis, increased synovium SDF‐1 expression, and irregularly contoured subchondral bone. PTH‐treated Prg4 mutant mice developed a secondary deposit overlaying the acellular layer of material lining the joint surfaces, but PTH‐treatment did not alter signs of articular cartilage degeneration in Prg4 mutant mice. The increased joint SDF‐1 levels and irregular subchondral bone found in Prg4 mutant mice introduce novel candidate mechanisms by which Prg4 protects articular cartilage. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 183–190, 2013Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94686/1/22207_ftp.pd

Translational treatment paradigm for managing non‐unions secondary to radiation injury utilizing adipose derived stem cells and angiogenic therapy

BackgroundBony non‐unions arising in the aftermath of collateral radiation injury are commonly managed with vascularized free tissue transfers. Unfortunately, these procedures are invasive and fraught with attendant morbidities. This study investigated a novel, alternative treatment paradigm utilizing adipose‐derived stem cells (ASCs) combined with angiogenic deferoxamine (DFO) in the rat mandible.MethodsRats were exposed to a bioequivalent dose of radiation and mandibular osteotomy. Those exhibiting non‐unions were subsequently treated with surgical debridement alone or debridement plus combination therapy. Radiographic and biomechanical outcomes were assessed after healing.ResultsSignificant increases in biomechanical strength and radiographic metrics were observed in response to combination therapy (p < .05). Importantly, combined therapy enabled a 65% reduction in persisting non‐unions when compared to debridement alone.ConclusionWe support the continued investigation of this promising combination therapy in its potential translation for the management of radiation‐induced bony pathology. © 2015 Wiley Periodicals, Inc. Head Neck 38: E837–E843, 2016Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137613/1/hed24110.pd

Lifeworld Inc. : and what to do about it

Can we detect changes in the way that the world turns up as they turn up? This paper makes such an attempt. The first part of the paper argues that a wide-ranging change is occurring in the ontological preconditions of Euro-American cultures, based in reworking what and how an event is produced. Driven by the security – entertainment complex, the aim is to mass produce phenomenological encounter: Lifeworld Inc as I call it. Swimming in a sea of data, such an aim requires the construction of just enough authenticity over and over again. In the second part of the paper, I go on to argue that this new world requires a different kind of social science, one that is experimental in its orientation—just as Lifeworld Inc is—but with a mission to provoke awareness in untoward ways in order to produce new means of association. Only thus, or so I argue, can social science add to the world we are now beginning to live in

Lisht as a New Kingdom glass-making site with its own chemical signature

Lisht is one of a few New Kingdom sites with known glass-working debris. Here, we present evidence for the primary production of glass at Lisht, including crucible fragments and semi-finished glass. We also provide 12 new chemical analyses of glass from Lisht, including trace elements. We argue that the glass made at Lisht has a specific chemical signature within the broader range of Late Bronze Age glass compositions from Egypt, further underlining the former existence of primary glass production there and offering the possibility of identifying Lisht-made glass elsewhere in Egypt and beyond

Bisphosphonate-Associated Osteonecrosis of the Jaw: Are We Dealing with a Localized Non-Traditional Calciphylaxis?

The bisphosphonate (BP) family of drugs has been used as a vital component in cancer therapy and many other diseases. One of the main adverse effects related to (BP) is BP-associated osteonecrosis of the jaw (ONJ). Although this condition was first recognized in 2003, the pathophysiologic mechanism remains undefined. Our hypothesis is that ONJs clinical course and delayed wound healing is in part correlated to a localized non-traditional calciphylaxis. This effect is identified by the evidence of calcium deposition in the connective tissue and around small blood vessels in the soft tissues immediately adjacent to ONJ lesions. This phenomenon helps to fill gaps in the cascade of events which leads to soft tissue ischemia, necrosis, and non-healing ONJ lesions. Our finding adds to the current knowledge of the potential pathophysiologic mechanisms related to ONJ