The Benefits and Burdens of Pediatric Palliative Care and End-of-Life Research: A Systematic Review

Objective: The aim of this study is to report the benefits and burdens of palliative research participation on children, siblings, parents, clinicians, and researchers. Background: Pediatric palliative care requires research to mature the science and improve interventions. A tension exists between the desire to enhance palliative and end-of-life care for children and their families and the need to protect these potentially vulnerable populations from untoward burdens. Methods: Systematic review followed PRISMA guidelines with prepared protocol registered as PROSPERO #CRD42018087304. MEDLINE, CINAHL, PsycINFO, EMBASE, Scopus, and The Cochrane Library were searched (2000–2017). English-language studies depicting the benefits or burdens of palliative care or end-of-life research participation on either pediatric patients and/or their family members, clinicians, or study teams were eligible for inclusion. Study quality was appraised using the Mixed Methods Appraisal Tool (MMAT). Results: Twenty-four studies met final inclusion criteria. The benefit or burden of palliative care research participation was reported for the child in 6 papers; siblings in 2; parents in 19; clinicians in 3; and researchers in 5 papers. Benefits were more heavily emphasized by patients and family members, whereas burdens were more prominently emphasized by researchers and clinicians. No paper utilized a validated benefit/burden scale. Discussion: The lack of published exploration into the benefits and burdens of those asked to take part in pediatric palliative care research and those conducting the research is striking. There is a need for implementation of a validated benefit/burden instrument or interview measure as part of pediatric palliative and end-of-life research design and reporting

Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model

Osteogenesis imperfecta (OI) is a heritable form of bone fragility typically associated with a dominant COL1A1 or COL1A2 mutation. Variable phenotype for OI patients with identical collagen mutations is well established, but phenotype variability is described using the qualitative Sillence classification. Patterning a new OI mouse model on a specific collagen mutation therefore has been hindered by the absence of an appropriate kindred with extensive quantitative phenotype data. We benefited from the large sibships of the Old Order Amish (OOA) to define a wide range of OI phenotypes in 64 individuals with the identical COL1A2 mutation. Stratification of carrier spine (L1–4) areal bone mineral density (aBMD) Z -scores demonstrated that 73% had moderate to severe disease (less than −2), 23% had mild disease (−1 to −2), and 4% were in the unaffected range (greater than −1). A line of knock-in mice was patterned on the OOA mutation. Bone phenotype was evaluated in four F 1 lines of knock-in mice that each shared approximately 50% of their genetic background. Consistent with the human pedigree, these mice had reduced body mass, aBMD, and bone strength. Whole-bone fracture susceptibility was influenced by individual genomic factors that were reflected in size, shape, and possibly bone metabolic regulation. The results indicate that the G610C OI (Amish) knock-in mouse is a novel translational model to identify modifying genes that influence phenotype and for testing potential therapies for OI. © 2010 American Society for Bone and Mineral ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65040/1/90720_ftp.pd

Deficiency of Cartilage-Associated Protein in Recessive Lethal Osteogenesis Imperfecta

Classic osteogenesis imperfecta, an autosomal dominant disorder associated with osteoporosis and bone fragility, is caused by mutations in the genes for type I collagen. A recessive form of the disorder has long been suspected. Since the loss of cartilage-associated protein (CRTAP), which is required for post-translational prolyl 3-hydroxylation of collagen, causes severe osteoporosis in mice, we investigated whether CRTAP deficiency is associated with recessive osteogenesis imperfecta. Three of 10 children with lethal or severe osteogenesis imperfecta, who did not have a primary collagen defect yet had excess post-translational modification of collagen, were found to have a recessive condition resulting in CRTAP deficiency, suggesting that prolyl 3-hydroxylation of type I collagen is important for bone formation

Brittle IV Mouse Model for Osteogenesis imperfecta IV Demonstrates Postpubertal Adaptations to Improve Whole Bone Strength.

Introduction: The Brittle IV (Brtl) mouse was developed as a knock-in model for osteogenesis imperfecta (OI) type IV. A Gly349Cys substitution was introduced into one col1a1 allele, resulting in a phenotype representative of the disease. In this study, we investigate the effect of the Brtl mutation on whole bone architecture, strength, and composition across a range of age groups. Materials and Methods: One-, 2-, 6-, and 12-month-old Brtl and wildtype (WT) mice were analyzed. Femurs were assessed at the central diaphysis for cortical geometric parameters using _CT and were subsequently mechanically tested to failure by four-point bending. Matrix material properties were predicted using _CT data to normalize data from mechanical tests. Raman spectroscopy and DXA were used to assess matrix composition. Results: Our findings show a postpubertal adaptation in which Brtl femoral strength and stiffness increase through a mechanism independent of changes in whole bone geometry. These findings suggest an improvement in the material properties of the bone matrix itself, rather than improvements in whole bone geometry, as seen in previous mouse models of OI. Raman spectroscopic results suggest these findings may be caused by changes in mineral/matrix balance rather than improvements in mineral crystallinity. Conclusions: Our findings parallel the currently unexplained clinical observation of decreased fractures in human OI patients after puberty. The Brtl mouse remains an important tool for investigating therapeutic interventions for OI

Generation of a homology model of the human histamine H₃ receptor for ligand docking and pharmacophore-based screening

The human histamine H₃ receptor (hH₃R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH3R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH₃R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH₃R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH₃R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [³H]Nα-methylhistamine binding assay. The compounds tested showed affinities at hH₃R with Ki values ranging from 0.079 to 6.3 lM