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Transgender (trans) individuals experience disproportionately high rates of discrimination and social exclusion which negatively impacts their health and well-being. However, a recent focus on social inclusion has revealed the protective effect that community engagement can have on trans individuals’ well-being. The purpose of this study was to investigate the sources and perceptions of community inclusion among trans people and to better understand how a feeling of connectedness can lead to elevated well-being. Thirty-three trans individuals living in a mid-sized urban and rural region of Southern Ontario, Canada were interviewed for a larger study focused on experiences of discrimination. Using NVivo 12, a thematic analysis on perceptions of community inclusion was conducted involving 22 participants from the larger study. Primary sources of community inclusion among trans individuals were in-person trans events, trans groups, and online forums. All three sources led to enhanced well-being by fostering feelings of acceptance, belonging, and safety. Our study supports a need to prioritize these sources as supportive outlets to promote the positive well-being of trans individuals.

Osteopathia striata with cranial sclerosis (OS–CS) is a rare skeletal dysplasia characterized by linear striations of the long bones, osteosclerosis of the cranium, and extra‐skeletal anomalies. We provide a comprehensive description of the skeletal phenotype in a French‐Canadian girl with a moderate to severe form of sporadic OS–CS. Multiple medical problems, including anal stenosis and the Pierre–Robin sequence, were evident in the first few years of life. At 14 years, she was fully mobile, with normal intellect and stature. She suffered chronic lower extremity pain in the absence of fractures, as well as severe headaches, unilateral facial paralysis, and bilateral mixed hearing loss. Biochemical indices of bone and mineral metabolism were within normal limits. Bone densitometry showed increased areal bone mineral density in the skull, trunk, and pelvis, but not in the upper and lower extremities. An iliac bone biopsy specimen revealed an increased amount of trabecular bone. Trabeculae were abnormally thick, but there was no evidence of disturbed bone remodeling. In a cranial bone specimen, multiple layers of periosteal bone were found that covered a compact cortical compartment containing tightly packed haversian canals. Bone lamellation was normal in both the iliac and skull samples. Osteoclast differentiation studies showed that peripheral blood osteoclast precursors from this patient formed functional osteoclasts in vitro. Thus, studies of bone metabolism did not explain why bone mass is increased in most skeletal areas of this patient. Cranial histology points to exuberant periosteal bone formation as a potential cause of the cranial sclerosis. © 2004 Wiley‐Liss, Inc.

Abstract.: We studied iliac crest biopsy cores taken from young individuals with osteogenesis imperfecta of several types, and from age-matched normals; the same samples had been used in prior studies using conventional light microscopic histomorphometric procedures. The PMMA blocks were micro-milled to a fine finish, carbon coated, and imaged using backscattered electrons (BSE) in an automated digital scanning electron microscope (SEM). For comparison of BSE signal levels between samples, microscope operation parameters were standardized by reference to halogenated dimethacrylate standards, and recording data from stereological arrays of 512*512 nonoverlapping pixels at 3.5 μm separation. All OI types showed higher average mineralization densities than age- and site-matched normals. This is interpreted as the result of the failure in matrix assembly, such that it has a higher water volume fraction available for mineral deposition. Added to the net deficit in bone quantity, the predicted higher stiffness of the more mineralized bone will account for much of the observed `brittleness' that characterizes this class of genetic disease. The mean mineralization density, which was higher in types III, IV, and V than in type I, appears to be correlated with disease severity.

The microstructure of iliac crest biopsies from normal children or from those afflicted with osteogenesis imperfecta (OI) has not previously been studied to determine the tissue histology in the context of the degree of mineralization. The material in this study comprised 112 iliac crest biopsies from children aged 1.9–22.9 years. Fifty-eight were reference biopsies taken from children with no bone disease and the remainder were biopsies from children diagnosed as having OI (23 were Type I, 8 Type III, 18 Type IV, and 5 Type V). The specimens, which had been embedded in polymethylmethacrylate (PMMA), were micromilled and carbon coated to permit backscattered electron imaging. Reference biopsies from very young children often contained densely mineralized cartilage, and evidence of rapid cortical drift. Circumferential lamellae became a prominent feature after the toddler stage, and active remodeling and slower cortical drift continued through childhood. The biopsies from older teenagers and young adults were indistinguishable. Occasional mineralized osteocyte lacunae were detected in even the youngest children. Bone from children with OI Type I often appeared normal in microstructure and amount, but in some there was a dearth of bone and an abundance of osteocytes. Compared with age-matched controls, cortical and trabecular bone from children with OI Types III and IV were markedly sparse and very cellular, and primary osteonal systems continued to be formed later than expected. A distinguishing feature of the bone from OI Type V patients was the failure of patches of bone to mineralize, especially adjoining a reversal line. Packets of bone tissue exhibiting either considerably higher than normal or deficient mineralization would contribute to the characteristic trait of mechanical weakness.

Critical-sized defects (CSDs) were introduced into rat calvaria to test the hypothesis that absorption of surrounding blood, marrow, and fluid from the osseous wound into a bioabsorbable polymer matrix with unique microarchitecture can induce bone formation via hematoma stabilization. Scaffolds with 90% porosity, specific surface areas of approximately 10 m2/g, and median pore sizes of 16 and 32 µm, respectively, were fabricated using an emulsion freeze-drying process. Contact radiography and radiomorphometry revealed the size of the initial defects (50 mm2) were reduced to 27 ± 11 mm2 and 34 ± 17 mm2 for CSDs treated with poly(D,L-lactide-co-glycolide). Histology and histomorphometry revealed scaffolds filled with significantly more de novo bone than negative controls (p < 0.007), more osteoid than both the negative and autograft controls (p < 0.002), and small masses of mineralized tissue (<15 µm in diameter) observed within the scaffolds. Based on these findings, we propose a change in the current paradigm regarding the microarchitecture of scaffolds for in vivo bone regeneration to include mechanisms based on hematoma stabilization.

The hypophosphatemic (Hyp) mouse is the murine homolog for human hypophosphatemic vitamin D‐resistant rickets. We previously reported that bone cells isolated from normal and Hypmice produced abnormal bone when transplanted intramuscularly into mutant mice. To assess the role of hypophosphatemia on bone formation in transplants, normal and Hypmouse periostea were pair transplanted into control or phosphate (P)‐supplemented Hypmice and into control or P‐deprived normal mice. The bone nodules formed in transplants after 2 weeks were characterized by measuring the thickness of the surrounding osteoid seams and the relative osteoid volume. P restriction in normal recipient mice impaired bone formation by transplanted normal cells and aggravated the defective bone formation by Hypcells. The osteoid thickness and volume remained significantly higher in Hyptransplants than in normal cotransplants, however. P supplementation of Hyprecipient mice normalized bone formation by transplanted normal cells but not by Hypcells. However, a marked decrease in osteoid thickness and volume was observed in Hyptransplants down to values observed in normal recipient mice. These results indicate that hypophosphatemia is not the only cause of abnormal bone formation in the Hypmouse but that an osteoblast dysfunction contributes to the bone disease. These observations further support the concept that the osteoblast may be an important target for the Hypmutation.

Aims: A study was designed to assess the effects of a standardized instructional videotape on reducing interobserver variability for several commonly used observer-dependent outcome measures. Methods: During a single day, six rheumatologists independently examined six patients with rheumatoid arthritis (RA) in a predetermined order using a Latin square design, before and after viewing a standardized videotape demonstrating 13 examination techniques. Reliability coefficients were calculated based on the variance components of the analysis of variance (ANOVA) table. Results: Prestandardization reliability coefficients were >0.80 for all measures and remained above 0.80 following standardization. Conclusions: It is usually assumed that serial measurement in clinical trials should be performed by the same assessor because of concern regarding interobserver variability. However, the high levels of prestandardization interobserver reliability observed in this study indicate that, for these variables, serial measurements in a clinical trial could be made by different assessors, assuming they were equally skilled. This observation has important implications for outcome measurement in RA clinical trials. Although high levels of prestandardization reliability precluded the demonstration of any significant effect, we speculate that the videotape might be effective in training less-experienced assessors. Reductions in observer variability have the potential to diminish sample size requirements for RA antirheumatic drug studies. The use of a videotape to achieve this goal offers cost and convenience advantages over one-on-one training procedures, and this method should be further assessed in less-experienced assessors.

Bone cells isolated from the Hyp mouse, the murine homologue for hypophosphatemic vitamin D‐resistant rickets, produce abnormal bone when transplanted to either normal or phosphate‐supplemented Hyp mice. To assess whether correction of the bone formation by mutant cells transplanted into either normal or Hyp mice could be achieved in the presence of supraphysiologic serum concentrations of 1,25‐dihydroxyvitamin D3(1,25‐(OH)2D3), recipient mice of both genotypes were infused continuously with 1,25‐(OH)2D3(0.2 μg/kg/day). Bone nodules present in transplants recovered after 14 days were characterized by measuring the osteoid thickness and volume. Administration of 1,25‐(OH)2D3to Hyp mice corrected the defective bone formation by normal cells but not by pair‐transplanted Hyp cells, despite normalization of serum phosphate levels and 3‐fold increases in serum 1,25‐(OH)2D3. The osteoid thickness and volume in Hyp transplants into 1,25‐(OH)2D3‐treated Hyp mice were, however, markedly reduced down to values observed for Hyp transplants into recipient normal mice. Administration of 1,25‐(OH)2D3to normal mice improved further bone formation by mutant cells without affecting that by pair‐transplanted normal cells. Administration of 24,25‐(OH)2D3(1 μg/kg/day) combined with 1,25‐(OH)2D3to recipient mice of both genotypes prevented the sharp fall in serum 24,25‐(OH)2D3but was not more beneficial than 1,25‐(OH)2D3alone for improving bone formation by transplanted Hyp cells. These observations demonstrate an abnormal response of the mutant cells to the extracellular environment and support the concept of an intrinsic osteoblast defect in the Hyp mouse.

The hypophosphatemic (Hyp) mouse is an animal model for human hypophosphatemic vitamin D‐resistant rickets. We have reported that bone cells isolated from Hyp mice born to homozygous mutant females produce abnormal bone when transplanted into normal mice. To test whether an environmentally acquired defect of the mutant cells contributed to the impaired bone formation observed in transplants, periostea and osteoblasts from normal and Hyp littermates were transplanted intramuscularly into normal animals. To test more specifically for an hypophosphatemia‐induced cell alteration before transplantation, bone cells isolated from phosphate‐depleted normal mice were transplanted into normal animals. The bone nodules formed in 2 week transplants were characterized by measuring their osteoid thickness and volume. Impaired bone formation was evidenced in Hyp transplants compared to normal littermate transplants by increased osteoid thickness and volume. In contrast to cells from mutant mice, cells isolated from normal mice with comparable hypophosphatemia produced normal bone. These results indicate that the inability of Hyp osteoblasts to produce normal bone when placed in a normal environment is not the consequence of prior exposure to an altered environment but likely of an intrinsic cellular abnormality. These observations add further support to the concept that the osteoblast is an important target for the Hyp mutation.

Abstract: A technique for determining a set of weights for the linear combination of a number of measures is applied to a concrete problem. The set of weights meets the criterion of maximum separation of the total scores of two different occupational groups.

C57BL/6J Hyp/Y male mice, and X-linked hypophosphatemic human males are dwarfed and have rickets responsive to orthophosphate (Pi). Serum Pi in mature Hyp/Y mice is low (4.6±0.9mg/dl) vs normal +/Y male littermates (7.6±1.Omg/dl, p<0.001). Serum calcium is low normal in Hyp/Y. The renal “excretion index” (mg Pi in urine/mg creat.)/(mg Pi/ml serum) is 103±25 vs 65±16 in +/Y mice (p<0.01). Endogenous kidney cortex Pi is 314μg/g wet wt. in Hyp/Y despite hypophosphatemia, & 307μg/g in +/Y mice. Concentration-dependent uptake of 32Pi into organic and inorganic pools in renal cortex slices is normal in Hyp/Y kidney, under initial-rate and steady-state conditions. The mutant gene product in Hyp/Y is apparently limited to the luminal surface in the kidney tubule since net reabsorption in vivo (luminal membrane) is depressed, while in vitro uptake by slices (basilar membrane) is normal. Preliminary evidence for a luminal membrane defect is also present in Hyp/Y intestine. These findings offer the first in vitro evidence to support the hypothesis that the XLH gene affects Pi luminal back-flux during transepithelial absorption.

Renal inorganic phosphate (Pi) transport is impaired in familial hypophosphatemic rickets (FHR). Short et al. (Science,179, 700, 1973) have reported that the mutation was also expressed in the gut. We have examined Pi uptake in vitro by jejunal mucosa from 7 (4 female, 3 male) FHR mutants (from 5 pedigrees) and 6 controls. Peroral samples were incubated for 5 to 40 minutes in TRIS buffer, pH 7.4 with substrate concentrations from 0.003 to 3 mM. Pi uptake was concentrative and energy dependent reaching mean distribution ratios for 32P of 4.2±0.9 in controls and 5.0±0.5 in patients after incubation with 0.003 mM 32Pi for 40 minutes. Incorporation of Pi in the organic pool was rapid and equilibrated after 10 minutes at a 32Pi/32P total ratio of 0.5, at all substrate concentrations, in both groups. Only one mediated transport system for Pi was present in control subjects, with a Michaelis constant ≃ 0.2 mM and a maximum velocity ≃0.7 mmoles per liter per 40 minutes. Similar kinetic values were obtained in the group of FHR patients. These observations do not support the thesis that a significant defect for Pi uptake is present in the jejunal mucosa of FHR mutants.

Serum Pi in dwarfed, rachitic C57BL/6J Hyp/Y mice is low (4.6±0.9mg/dl) vs normal +/Y male littermates (7.6±1.0mg/ dl,p<0.001). Serum calcium is low normal in Hyp/Y. The Hyp/Y renal “excretion index” (mg Pi in urine/mg creat.)/ (mg Pi/ml serum) is 103±25, vs 65±16 in +A mice (p<0.001). The trait is X-linked and is thus a model of X-linked hypophosphatemia in man. Kidney cortex Pi is 290µg/g wet wt in +/Y and 288 in Hyp/Y despite hypophosphatemia. Concentration-dependent uptake of 32Pi into organic and ingrganic pools in kidney cortex slices iS normal in Hyp/Y under initial-rate and steady-state conditions. The mutant gene product in Hyp/Y is apparently limited to the luminal surface in the kidney tubule, since net reabsorption in vivo at the luminal membrane is depressed, while in vitro uptake by slices at the basilar membrane is normal. These findings offer the first evidence for our hypothesis that the X-linked hypophosphatemia gene permits excess back-flux of Pi into urine from renal epithelium during tubular absorption.

Renal inorganic phosphate (Pi) transport is impaired in familial hypophosphatemic rickets (FHR). Short et al. (Science, 179, 700, 1973) have reported that the mutation was also expressed in the gut. We have examined Pi uptake in vitro by jejunal mucosa from 7 (4 female, 3 male) FHR mutants (from 5 pedigrees) and 6 controls. Peroral samples were incubated for 5 to 40 minutes in TRIS buffer, pH 7.4 with substrate concentrations from 0.003 to 3 mM. Pi uptake was concentrative and energy dependent reaching mean distribution ratios (intracellular/extracellular 32P) of 4.2 ± 0.9 in controls and 5.0 ± 0.5 in patients after incubation with 0.003 mM 32Pi for 40 minutes. Incorporation of Pi in the organic pool was rapid and equilbrated after 10 minutes at a 32Pi/total 32P ratio of 0.5, at old substrate concentrations, in both groups. Only one mediated transport system for Pi was present in control subjects, with a Michael is constant ?0.2 mM and a maximum velocity ?0.7 mmoles per liter per 40 minutes. Similar kinetic values were obtained in the group of FHR patients. These observations do not support the thesis that a significant defect for Pi uptake is present in the jejunal mucosa of FHR mutants.