Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases.

Denosumab has been used successfully to treat disease-associated osteoclast overactivity, including giant cell tumor of bone. Given its mechanism of action, denosumab is a potent potential treatment of other osteoclast bone dysplasias including central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), and cherubism. Relatively little is known about the safety and efficacy of denosumab in patients with these conditions, especially in children. We report on 3 pediatric patients treated with denosumab over a 3-year period at UCLA Medical Center (Los Angeles and Santa Monica, CA, USA): a 12-year-old with recurrent ABC of the pelvis, a 14-year-old with CGCG of the mandible, and a 12-year-old with cherubism. All were started on a 1-year course of 15 doses 120 mg s.c., given monthly with two loading doses on day 8 and 15. All patients demonstrated rapid and pronounced clinical improvement while on denosumab, including a significant reduction in pain and sclerosis of lytic lesions on radiographs. Within 1 month of initiating therapy, 2 patients experienced hypocalcemia (Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and hypophosphatemia, with 1 patient experiencing symptoms. One patient went on to experience symptomatic rebound hypercalcemia (CTCAE grade 4) 5 months after completing therapy, requiring bisphosphonates and calcitonin. For the second patient, we developed a schedule to wean denosumab involving the progressive lengthening of time between doses from 1 to 4 months in 1-month increments before cessation. We found that denosumab therapy results in significant clinical and radiographic improvement for pediatric patients with nonresectable ABC, CGCG, and cherubism. Problems with serum calcium may be more common in younger patients, with symptomatic and protracted rebound hypercalcemia after cessation of therapy the most significant. We present a potential solution to this problem with progressive spacing of doses. Potential serious adverse events from alterations in calcium homeostasis should be explored in prospective clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Changes in vitamin biomarkers during a 2-year intervention trial involving increased fruit and vegetable consumption by free-living volunteers

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Anatomic brain asymmetry in vervet monkeys.

Asymmetry is a prominent feature of human brains with important functional consequences. Many asymmetric traits show population bias, but little is known about the genetic and environmental sources contributing to inter-individual variance. Anatomic asymmetry has been observed in Old World monkeys, but the evidence for the direction and extent of asymmetry is equivocal and only one study has estimated the genetic contributions to inter-individual variance. In this study we characterize a range of qualitative and quantitative asymmetry measures in structural brain MRIs acquired from an extended pedigree of Old World vervet monkeys (n = 357), and implement variance component methods to estimate the proportion of trait variance attributable to genetic and environmental sources. Four of six asymmetry measures show pedigree-level bias and one of the traits has a significant heritability estimate of about 30%. We also found that environmental variables more significantly influence the width of the right compared to the left prefrontal lobe

Establishment of a Murine Pro-acinar Cell Line to Characterize Roles for FGF2 and α3β1 Integrins in Regulating Pro-acinar Characteristics

Radiation therapy for head and neck cancers results in permanent damage to the saliva producing acinar compartment of the salivary gland. To date, a pure pro-acinar cell line to study underlying mechanisms of acinar cell diferentiation in culture has not been described. Here, we report the establishment of a pro-acinar (mSG-PAC1) and ductal (mSG-DUC1) cell line, from the murine submandibular salivary gland (SMG), which recapitulate developmental milestones in diferentiation. mSG-DUC1 cells express the ductal markers, keratin-7 and keratin-19, and form lumenized spheroids. mSG-PAC1 cells express the pro-acinar markers SOX10 and aquaporin-5. Using the mSG-PAC1 cell line, we demonstrate that FGF2 regulates specifc steps during acinar cell maturation. FGF2 up-regulates aquaporin-5 and the expression of the α3 and α6 subunits of the α3β1 and α6β1 integrins that are known to promote SMG morphogenesis and diferentiation. mSG-DUC1 and mSG-PAC1 cells were derived from genetically modifed mice, homozygous for foxed alleles of the integrin α3 subunit. Similar to SMGs from α3-null mice, deletion of α3 alleles in mSG-PAC1 cells results in the up-regulation of E-cadherin and the downregulation of CDC42. Our data indicate that mSG-DUC1 and mSG-PAC1 cells will serve as important tools to gain mechanistic insight into salivary gland morphogenesis and diferentiation

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

The Straight Talk Campaign in Uganda: Impact of mass media initiatives—Summary report

This Horizons study in Uganda found that exposure by adolescents to Straight Talk, a mass media initiative focused on adolescent sexual and reproductive health (ASRH), was associated with greater ASRH knowledge, a greater likelihood of having been tested for HIV, and more communication with parents about ASRH issues

Prevalence of Posterior Shoulder Subluxation in Children With Neonatal Brachial Plexus Palsy After Early Full Passive Range of Motion Exercises

BackgroundChildren with neonatal brachial plexus palsy (NBPP) are often prescribed shoulder range of motion (ROM) exercises; however, the extent and timing of exercise implementation remains controversial in the context of shoulder joint integrity. The association of ROM exercises to delayed posterior shoulder subluxation (PSS) is unknown.ObjectiveTo determine prevalence of PSS in children with NBPP who began full passive ROM exercises before 6 months of age, and characteristics associated with development or absence of PSS in children.DesignCrossâ sectional study.SettingTertiary care NBPP referral center.ParticipantsFortyâ six children with NBPP, aged 24â 57 months, who began full ROM exercises before 6 months of age.MethodsOne radiologist conducted bilateral shoulder ultrasound (US) on each child to evaluate for PSS. One occupational therapist evaluated each child clinically for PSS using defined parameters without knowledge of US results.Main Outcome MeasuresBy US, 20% of children had PSS; 46% had PSS by clinical examination. Shoulder active ROM limitations and history of shoulder surgery were associated with presence of PSS. Extent of NBPP was not associated with PSS.ResultsNine of 46 children (20%) met US criteria for PSS; α angle was 58° ± 21° (mean ± standard deviation [SD]). Twentyâ one children (46%) met clinical criteria. Mean age at examination was 35 ± 10 months. Shoulder active ROM (P â ¤ .004) was associated with PSS, whereas passive ROM was not (P â ¥ .08). History of secondary shoulder surgery and primary nerve graft repair were associated with PSS (P = .04). Extent of NBPP by Narakas classification was not associated with PSS (P = .48).ConclusionsEarly use of fullâ arc passive ROM home exercise program is not associated with increased prevalence of PSS in children with NBPP compared to prevalence of PSS in published literature. We suggest careful clinical examination, based on defined criteria, provides a reasonable screening examination for evaluating PSS that can be confirmed by noninvasive US.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147125/1/pmr21235.pd