Non-coding RNAs and neuroinflammation: implications for neurological disorders.

Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.

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.

Late Bleeding Following Cleft Palate Repair: An Under-Reported Finding?

ABSTRACT: The objective of this article is to assess the incidence of late bleeding following cleft palate repair (palatoplasty) in children. This is a retrospective review of a prospectively maintained database of patients treated for Cleft Lip and Palate in a tertiary academic pediatric hospital setting over 2 hospitals (Middlemore and Starship Hospitals) under the same multidisciplinary team of the Auckland Regional Cleft and Craniofacial Service, New Zealand. All patients with a diagnosis of Cleft Lip and/or Palate undergoing primary cleft palate repair over an 11 year period until March 2020 were included in the study. Our results found there were 482 patients with a new diagnosis of Cleft Lip and/or Palate from Jan 2009 through to March 2020. Three hundred sixty-six of those patients underwent primary palatoplasty at an average age of 10.5 months (range 8-18 months). The sub-types of cleft palate diagnoses were one-third Veau I, one-third Veau II, and the remaining one-third were Veau III, IV, and submucous cleft palate. One-third were syndromic. A total of 6 patients were re-admitted to hospital after discharge from their primary admission with bleeding from the cleft palate surgical site. Of the 6 patients re-admitted, 5 needed blood transfusions and 4 required an urgent return to the operating room. The authors found the rate of late bleeding following primary cleft palate repair in our unit is 1:61 operations or 1.6%. Late bleeding following cleft palate surgery is not well reported in the literature.

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.

Temporoparietal Fascial Flap for Soft Tissue Reconstruction of Pediatric and Young Adult Foot Defects: A Case Series.

Soft tissue defects of the foot due to trauma, infection, or malignancy are common and present a reconstructive challenge, as the foot requires specialized tissue that is thin, supple, yet durable enough to support the high demand of its function. The temporoparietal fascial flap, based on the superficial temporal artery and vein, is a reliable and versatile flap that possesses all these advantages. We present a case series detailing our experience with this flap for reconstruction of post-traumatic soft tissue defects of the foot in 4 patients (3 children and 1 young adult) with 5-year follow-up data. All patients were able to use the foot normally again to full capacity and wear normal footwear. They were also satisfied with the aesthetic outcome of the reconstruction and well-concealed donor site. This series highlights the success of this flap in providing excellent functional and aesthetic coverage for soft tissue foot defects in children and young adults, with minimal donor site morbidity.

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.

Iliac Crest Donor Site for Children With Cleft Lip and Palate Undergoing Alveolar Bone Grafting: A Long-term Assessment.

The authors aimed to accurately assess the donor site morbidity from iliac crest bone grafts for secondary bone grafting in patients with cleft lip and palate alveolar defects. Fifty patients between 3 months and 10 years following alveolar bone grafting for cleft lip and palate were entered into the study. Two-thirds of patients had no significant concerns about the donor site. The remaining third had some concerns about the appearance of their hips and less than 10% of patients expressing strong agreement with statements about concerns with shape, appearance, and self-consciousness about the iliac crest donor site. Examination findings showed the average length of scar being 5.4 cm and a third of patients having some minor palpable boney irregularities of the iliac crest. The authors found that the alveolar crest donor site is well tolerated by patients long term but has a measurable morbidity long term.

OK-432 and lymphatic malformations in children: the Starship Children's Hospital experience.

BACKGROUND: Surgery has previously been the mainstay of treatment for lymphatic malformations but has attendant problems of marked scarring, high chance of recurrence and potential nerve damage. Alternative management for these lesions involves the intralesional injection of OK-432. The present paper reviews OK-432 use in lymphatic malformations in children. METHODS: A retrospective chart review was carried out of children undergoing intralesional OK-432 therapy from the Departments of Paediatric Surgery, Paediatric Otolaryngology and Plastic Surgery at Starship Children's Hospital, Auckland. RESULTS: Over the past 4 years, seven children under the age of 5 years underwent OK-432 therapy as day-case procedures requiring between one and seven procedures each. Four children had lesions involving the axilla/chest wall, two involved extra-mylohyoid tissues in the neck and one child had lymphatic malformation involving tongue, floor of mouth and an extra-mylohyoid component. Spontaneous haemorrhage into a cystic space may be the cause of the observed partial resolution of the lymphangiomas in two. A predictor of a successful outcome was the ability to aspirate fluid prior to injection. Ultrasound guidance was useful to localize the lesions for aspiration and injection. Macrocystic lesions respond well to OK-432 therapy but the response of microcystic or cavernous lesions to OK-432 is disappointing and surgery remains the definitive treatment for these microcystic lesions. CONCLUSION: OK-432 appears to be a safe and effective treatment for the macrocystic component of lymphatic malformations.

Surgical interventions in children with meningococcal purpura fulminans--a review of 117 procedures in 21 children.

BACKGROUND/PURPOSE: There are few reports describing the surgical management and outcome of children suffering purpura fulminans secondary to meningococcal sepsis. New Zealand is in the grips of a meningococcal epidemic, and, with the attendant sequalae of the disease process, the authors sought to formally review the children who have required surgical involvement. METHODS: A retrospective case review of children with the sequalae of meningococcal disease presenting to the Orthopedic and Plastic Surgical Units in a university teaching hospital was undertaken. RESULTS: There were 117 procedures in 21 children performed over a 12-year period. Surgical management was separated into 2 phases-early and late. The mean delay from admission with acute sepsis to the first surgical procedure (ie, early intervention) was 15.9 days. Debridement and autologous skin grafting was the mainstay of managing the necrotic defects; however, allograft skin proved a useful adjunct as a physiologic dressing. Local flaps were used with deep defects down to bone, but in the extremities amputation to viable tissue was required once gangrene was demarcated. Amputations were carried out in 9 of 21 children. Late interventions were related to relief of contractures or fibula overgrowth causing stump ulceration. Clinical follow-up showed that all children interviewed over 5 years of age (9 children) attend ordinary regular school classes and were physically active within the context of their physical disabilities. CONCLUSIONS: The data would suggest that children requiring surgery for purpura fulminans achieve age-appropriate milestones and are primarily limited by their physical disability related to amputations, scarring, and abnormal bone growth.