Hemarthrosis in a Pediatric Patient With Immune Thrombocytopenia and Lyme Arthritis.

The presentation of immune thrombocytopenia is dependent on the degree of thrombocytopenia, with no to mild bleeding symptoms, primarily mucocutaneous bleeding. Severe bleeding in other organ systems is a rare complication. Spontaneous hemarthrosis is rare in patients without hemophilia. We report a child presenting with oral and cutaneous petechial lesions and left knee hemarthrosis without trauma. Laboratory findings showed severe thrombocytopenia consistent with immune thrombocytopenia. Serologic tests were consistent with Lyme disease. Hemarthrosis was presumed secondary to Lyme disease monoarticular joint inflammation with bleeding exacerbated by severe thrombocytopenia. Hemarthrosis resolved and platelet counts normalized following immunoglobulin infusion, steroid course, and antibiotics.

Proximal tibia fracture dislocations: Management and outcomes of a severe and under-recognized injury.

INTRODUCTION: Proximal tibia fracture dislocations (PTFDs) are a subset of plateau fractures with little in the literature since description by Hohl (1967) and classification by Moore (1981). We sought to evaluate reliability in diagnosis of fracture-dislocations by traumatologists and to compare their outcomes with bicondylar tibial plateau fractures (BTPFs). METHODS: This was a retrospective cohort study at 14 level 1 trauma centers throughout North America. In all, 4771 proximal tibia fractures were reviewed by all sites and 278 possible PTFDs were identified using the Moore classification. These were reviewed by an adjudication board of three traumatologists to obtain consensus. Outcomes included inter-rater reliability of PTFD diagnosis, wound complications, malunion, range of motion (ROM), and knee pain limiting function. These were compared to BTPF data from a previous study. RESULTS: Of 278 submitted cases, 187 were deemed PTFDs representing 4% of all proximal tibia fractures reviewed and 67% of those submitted. Inter-rater agreement by the adjudication board was good (83%). Sixty-one PTFDs (33%) were unicondylar. Eleven (6%) had ligamentous repair and 72 (39%) had meniscal repair. Two required vascular repair. Infection was more common among PTFDs than BTPFs (14% vs 9%, p = 0.038). Malunion occurred in 25% of PTFDs. ROM was worse among PTFDs, although likely not clinically significant. Knee pain limited function at final follow-up in 24% of both cohorts. CONCLUSIONS: PTFDs represent 4% of proximal tibia fractures. They are often unicondylar and may go unrecognized. Malunion is common, and PTFD outcomes may be worse than bicondylar fractures.

Generation of two multipotent mesenchymal progenitor cell lines capable of osteogenic, mature osteocyte, adipogenic, and chondrogenic differentiation.

Mesenchymal progenitors differentiate into several tissues including bone, cartilage, and adipose. Targeting these cells in vivo is challenging, making mesenchymal progenitor cell lines valuable tools to study tissue development. Mesenchymal stem cells (MSCs) can be isolated from humans and animals; however, obtaining homogenous, responsive cells in a reproducible fashion is challenging. As such, we developed two mesenchymal progenitor cell (MPC) lines, MPC1 and MPC2, generated from bone marrow of male C57BL/6 mice. These cells were immortalized using the temperature sensitive large T-antigen, allowing for thermal control of proliferation and differentiation. Both MPC1 and MPC2 cells are capable of osteogenic, adipogenic, and chondrogenic differentiation. Under osteogenic conditions, both lines formed mineralized nodules, and stained for alizarin red and alkaline phosphatase, while expressing osteogenic genes including Sost, Fgf23, and Dmp1. Sost and Dmp1 mRNA levels were drastically reduced with addition of parathyroid hormone, thus recapitulating in vivo responses. MPC cells secreted intact (iFGF23) and C-terminal (cFGF23) forms of the endocrine hormone FGF23, which was upregulated by 1,25 dihydroxy vitamin D (1,25D). Both lines also rapidly entered the adipogenic lineage, expressing adipose markers after 4 days in adipogenic media. MPC cells were also capable of chondrogenic differentiation, displaying increased expression of cartilaginous genes including aggrecan, Sox9, and Comp. With the ability to differentiate into multiple mesenchymal lineages and mimic in vivo responses of key regulatory genes/proteins, MPC cells are a valuable model to study factors that regulate mesenchymal lineage allocation as well as the mechanisms that dictate transcription, protein modification, and secretion of these factors.

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model.

Fibroblast growth factor-23 (FGF23) is a critical factor in chronic kidney disease (CKD), with elevated levels causing alterations in mineral metabolism and increased odds for mortality. Patients with CKD develop anemia as the kidneys progressively lose the ability to produce erythropoietin (EPO). Anemia is a potent driver of FGF23 secretion; therefore, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in clinical trials to elevate endogenous EPO to resolve anemia was tested for effects on iron utilization and FGF23-related parameters in a CKD mouse model. Mice were fed either a casein control diet or an adenine-containing diet to induce CKD. The CKD mice had markedly elevated iFGF23 and blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Cohorts of mice were then treated with a patient-equivalent dose of BAY 85-3934 (BAY; Molidustat), which elevated EPO and completely resolved aberrant complete blood counts (CBCs) in the CKD mice. iFGF23 was elevated in vehicle-treated CKD mice (120-fold), whereas circulating iFGF23 was significantly attenuated (>60%) in the BAY-treated CKD mice. The BAY-treated mice with CKD also had reduced BUN, but there was no effect on renal vitamin D metabolic enzyme expression. Consistent with increased EPO, bone marrow Erfe, Transferrin receptor (Tfrc), and EpoR mRNAs were increased in BAY-treated CKD mice, and in vitro hypoxic marrow cultures increased FGF23 with direct EPO treatment. Liver Bmp-6 and hepcidin expression were downregulated in all BAY-treated groups. Femur trabecular parameters and cortical porosity were not worsened with BAY administration. In vitro, differentiated osteocyte-like cells exposed to an iron chelator to simulate iron depletion/hypoxia increased FGF23; repletion with holo-transferrin completely suppressed FGF23 and normalized Tfrc1. Collectively, these results support that resolving anemia using a HIF-PHI during CKD was associated with lower BUN and reduced FGF23, potentially through direct restoration of iron utilization, thus providing modifiable outcomes beyond improving anemia for this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).

Heart failure is not a determinant of central sleep apnea in the pediatric population.

BACKGROUND/OBJECTIVES: Adults with heart failure (HF) have high prevalence of central sleep apnea (CSA). While this has been repeatedly investigated in adults, there is a deficiency of similar research in pediatric populations. The goal of this study was to compare prevalence of CSA in children with and without HF and correlate central apneic events with heart function. METHODS: Retrospective analysis of data from children with and without HF was conducted. Eligible children were less than 18 years old with echocardiogram and polysomnogram within 6 months of each other. Children were separated into groups with and without HF based on left ventricular ejection fraction (LVEF). Defining CSA as central apnea-hypopnea index (CAHI) more than 1/hour, the cohort was also classified into children with and without CSA for comparative study. RESULTS: A total of 120 children (+HF: 19, -HF: 101) were included. The +HF group was younger, with higher prevalence of trisomy 21, muscular dystrophy, oromotor incoordination, and structural heart disease. The +HF group had lower apnea-hypopnea index (median: 3/hour vs. 8.6/hour) and lower central apnea index (CAI) (median: 0.2/hour vs. 0.55/hour). Prevalence of CSA was similar in both groups (p = .195). LogCAHI was inversely correlated to age (Pearson correlation coefficient: -0.245, p = .022). Children with CSA were younger and had higher prevalence of prematurity (40% vs. 5.3%). There was no significant difference in LVEF between children with and without CSA. After excluding children with prematurity, relationship between CAHI and age was no longer sustained. CONCLUSIONS: In contrast to adults, there is no difference in prevalence of CSA in children with and without HF. Unlike in adults, LVEF does not correlate with CAI in children. Overall, it appears that central apneic events may be more a function of age and prematurity rather than of heart function.

Regulation of Fibroblast Growth Factor 23 by Iron, EPO, and HIF.

PURPOSE OF REVIEW: Fibroblast growth factor-23 (FGF23) is the key hormone produced in bone critical for phosphate homeostasis. Elevated serum phosphorus and 1,25dihydroxyvitaminD stimulates FGF23 production to promote renal phosphate excretion and decrease 1,25dihydroxyvitaminD synthesis. Thus completing the feedback loop and suppressing FGF23. Unexpectedly, studies of common and rare heritable disorders of phosphate handling identified links between iron and FGF23 demonstrating novel regulation outside the phosphate pathway. RECENT FINDINGS: Iron deficiency combined with an FGF23 cleavage mutation was found to induce the autosomal dominant hypophosphatemic rickets phenotype. Physiological responses to iron deficiency, such as erythropoietin production as well as hypoxia inducible factor activation, have been indicated in regulating FGF23. Additionally, specific iron formulations, used to treat iron deficiency, alter post-translational processing thereby shifting FGF23 protein secretion. SUMMARY: Molecular and clinical studies revealed that iron deficiency, through several mechanisms, alters FGF23 at the transcriptional and post-translational level. This review will focus upon the novel discoveries elucidated between iron, its regulators, and their influence on FGF23 bioactivity.