Resilient anatomy and local plasticity of naive and stress haematopoiesis.

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.

Mathematical Simulation and Numerical Computation of the Temperature Profiles in the Peripherals of Human Brain during the Tepid Sponge Treatment to Fever.

BACKGROUND: Fever is one of the frequently occurring diseases in human beings, and the body is said to have befallen in fever if the arterial or internal body temperature rises to 38°C. The patient who suffers from fever is either given paracetamol or tepid sponging or both. OBJECTIVE: This paper is aimed at studying the effects of the tepid sponge in normalizing the high temperature of the human body during fever. Among the various available methods for tepid sponging, the impact of holding a cool wet cloth on the forehead for reducing the fever is analyzed and pictured graphically. METHOD: For analyzing the effects of tepid sponge on the temperature distribution of the domain consisting of scalp, skull, and cerebrospinal fluid (CSF), a cool wet cloth is brought in contact with the skin allowing the heat to transfer from the brain to the wet cloth through these layers. The heat transfer in living biological tissues is different from ordinary heat transfer in other nonliving materials. Therefore, a model based on the bioheat equation has been constructed. The model has been solved by numerical methods for both steady- and unsteady-state cases. The domain, which consists of the scalp, skull, and CSF layers of the human head, has been discretized into four equal parts along the axes of the three-dimensional coordinate system. The forward difference and forward time centered space approximations were employed for numerical temperature distribution results at the nodal points. RESULTS: The effects of tepid sponge in reducing the body temperature with fever at 38°C, 39.5°C, and 41°C have been numerically calculated, and the results were pictured graphically. For transient cases, the corresponding calculations have been carried out at times t = 2 minutes, 4 minutes, and 6 minutes. CONCLUSION: Among all the available remedies to fever, tepid sponging has shown a significant effect in controlling fever.

Orthopedic and neurosurgical care of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is due to mutations in the PHEX gene leading to unregulated production of FGF23 and uncontrollable hypophosphatemia. XLH is characterized in children by rickets, short stature, waddling gait, and leg bowing of variable morphology and severity. Phosphate supplements and oral vitamin D analogs partially or, in some cases, fully restore the limb straightness. XLH patients may also be affected by premature, complete, or partial ossification of sutures between cranial bone, which could eventually result in cranial dysmorphia, decreased intracranial volume, and secondary abnormally high intracranial pressure with a cerebral compression. Our goal is to address the criteria and the management of the skeletal complications associated with XLH, mainly orthopedic and neurosurgical care, and reflect on decision-making and follow-up complexities.

3D-printed external cranial protection following decompressive craniectomy after brain injury: A pilot feasibility cohort study.

OBJECTIVES: 3D-printed (3DP) customized temporary cranial protection solutions following decompressive craniectomy (DC) are currently not widely practiced. A pilot trial of a 3DP customized head protection prototype device (HPPD) on 10 subjects was conducted during the subacute rehabilitation phase. MATERIALS AND METHODS: Subjects > 30 days post-DC with stable cranial flaps and healed wounds were enrolled. HPPD were uniquely designed based on individuals' CT scan, where the base conformed to the surface of the individual's skin covering the cranial defect, and the lateral surface three-dimensionally mirrored, the contralateral healthy head. Each HPPD was fabricated using the fused deposition modeling method. These HPPD were then fitted on subjects using a progressive wearing schedule and monitored over 1, 2, 4, 6 and 8 follow-up (FU) weeks. Outcomes during FU included; reported wearing time/day (hours), subjective pain, discomfort, pruritus, dislodgment, cosmesis ratings; and observed wound changes. The primary outcome was safety and tolerability without pain or wound changes within 30 minutes of HPPD fitting. RESULTS: In all, 10 enrolled subjects received 12 HPPDs [5/10 male, mean (SD) age 46 (14) years, mean (SD) duration post-DC 110 days (76)] and all subjects tolerated 30 minutes of initial HPPD fitting without wound changes. The mean (SD) HPPD mass was 61.2 g (SD 19.88). During 8 weeks of FU, no HPPD-related skin dehiscence was observed, while 20% (2/10) had transient skin imprints, and 80% (8/10) reported self-limiting pressure and pruritis. DISCUSSION: Findings from this exploratory study demonstrated preliminary feasibility and safety for a customized 3DP HPPD for temporary post-DC head protection over 8 weeks of follow-up. Monitoring and regular rest breaks during HPPD wear were important to prevent skin complications. CONCLUSION: This study suggests the potential for wider 3DP technology applications to provide cranial protection for this vulnerable population.

Effect of Amelotin on Bone Growth in the Murine Calvarial Defect Model.

Amelotin (AMTN) is a protein that is expressed during the maturation of dental enamel and has important role in enamel hydroxyapatite mineralization. However, it is not well understood whether AMTN has a strong mineral-promoting ability in bone. In this study, the effect of AMTN on bone healing was investigated using mice calvarial defect model in vivo, and the expression of bone marker genes and cell proliferation were investigated to clarify the role of AMTN in bone mineralization using mouse osteogenic cells (MC3T3-E1) in vitro. Collagen membranes, with or without recombinant human (rh) AMTN, were applied to calvarial defects created on the parietal bones of C57BL/6N mice. Microcomputed tomography and histological observation revealed that the defect largely filled with mineralized tissue by the rhAMTN-containing membrane in eight weeks. Moreover, CD31 positive cells were observed in the newly formed mineralized tissue and around the rhAMTN-containing membrane. In the presence of rhAMTN, the expression of the Spp1 gene in MC3T3-E1 cells significantly increased within ten days in an osteoinductive medium. Moreover, rhAMTN significantly enhanced MC3T3-E1 cell proliferation. These findings indicate that AMTN positively influences bone repair by promoting hydroxyapatite mineralization.

Assessment of novel surgical procedures using decellularised muscle and bioactive ceramic: a histological analysis.

Tissue regeneration and neovascularisation in cases of major bone loss is a challenge in maxillofacial surgery. The hypothesis of the present study is that the addition of resorbable bioactive ceramic Silica Calcium Phosphate Cement (SCPC) to Declluraized Muscle Scaffold (DSM) can expedite bone formation and maturation. Two surgical defect models were created in 18 nude transgenic mice. Group 1(n = 6), with a 2-mm decortication calvarial defect, was treated with a DSM/SCPC sheet over the corticated bone as an onlay then seeded with human Mesenchymal Stromal Cells hMSC in situ. In Group 2 (n = 6), a critical size (4 mm) calvarial defect was made and grafted with DSM/SCPC/in situ human bone marrow stromal cells (hMSCs). The control groups included Group 3 (n = 3) animals, with a 2-mm decortication defect treated with an onlay DSM sheet, and Group 4 (n = 3) animals, treated with critical size defect grafted with plain DSM. After 8 weeks, bone regeneration in various groups was evaluated using histology, immunohistochemistry and histomorphometry. New bone formation and maturation was superior in groups treated with DSM/SCPC/hMSC. The DMS/SCPC scaffold has the ability to augment and induce bone regeneration and neovascularisation in cases of major bone resorption and critical size defects.

From head micro-motions towards CSF dynamics and non-invasive intracranial pressure monitoring.

Continuous monitoring of the intracranial pressure (ICP) is essential in neurocritical care. There are a variety of ICP monitoring systems currently available, with the intraventricular fluid filled catheter transducer currently representing the "gold standard". As the placement of catheters is associated with the attendant risk of infection, hematoma formation, and seizures, there is a need for a reliable, non-invasive alternative. In the present study we suggest a unique theoretical framework based on differential geometry invariants of cranial micro-motions with the potential for continuous non-invasive ICP monitoring in conservative traumatic brain injury (TBI) treatment. As a proof of this concept, we have developed a pillow with embedded mechanical sensors and collected an extensive dataset (> 550 h on 24 TBI coma patients) of cranial micro-motions and the reference intraparenchymal ICP. From the multidimensional pulsatile curve we calculated the first Cartan curvature and constructed a "fingerprint" image (Cartan map) associated with the cerebrospinal fluid (CSF) dynamics. The Cartan map features maxima bands corresponding to a pressure wave reflection corresponding to a detectable skull tremble. We give evidence for a statistically significant and patient-independent correlation between skull micro-motions and ICP time derivative. Our unique differential geometry-based method yields a broader and global perspective on intracranial CSF dynamics compared to rather local catheter-based measurement and has the potential for wider applications.

Spread of segmental/multifocal idiopathic adult-onset dystonia to a third body site.

BACKGROUND: Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized. MATERIALS AND METHODS: We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part. RESULTS: We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site. DISCUSSION AND CONCLUSION: Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.

Metal-induced delayed type hypersensitivity responses potentiate particle induced osteolysis in a sex and age dependent manner.

It is widely recognized that innate macrophage immune reactions to implant debris are central to the inflammatory responses that drive biologic implant failure over the long term. Less common, adaptive lymphocyte immune reactions to implant debris, such as delayed type hypersensitivity (DTH), can also affect implant performance. It is unknown which key patient factors, if any, mediate these adaptive immune responses that potentiate particle/macrophage mediated osteolysis. The objective of this investigation was to determine to what degree known adaptive immune responses to metal implant debris can affect particle-induced osteolysis (PIO); and if this pathomechanism is dependent on: 1) innate immune danger signaling, i.e., NLRP3 inflammasome activity, 2) sex, and/or 3) age. We used an established murine calvaria model of PIO using male and female wild-type C57BL/6 vs. Caspase-1 deficient mice as well as young (12-16 weeks old) vs. aged (18-24 months old) female and male C57BL/6 mice. After induction of metal-DTH, and Cobalt-alloy particle (ASTM F-75, 0.4um median diameter) calvaria challenge, bone resorption was assessed using quantitative micro-computed tomography (micro-CT) analysis and immune responses were assessed by measuring paw inflammation, lymphocyte transformation test (LTT) reactivity and adaptive immune cytokines IFN-gamma and IL-17 (ELISA). Younger aged C57BL/6 female mice exhibited the highest rate and severity of metal sensitivity lymphocyte responses that also translated into higher PIO compared to any other experimental group. The absence of inflammasome/caspase-1 activity significantly suppressed DTH metal-reactivity and osteolysis in both male and female Caspase-1 deficient mice. These murine model results indicate that young female mice are more predisposed to metal-DTH augmented inflammatory responses to wear debris, which is highly influenced by active NLRP3 inflammasome/caspase-1 danger signaling. If these results are clinically meaningful for orthopedic patients, then younger female individuals should be appropriately assessed and followed for DTH derived peri-implant complications.

A landmark-free morphometrics pipeline for high-resolution phenotyping: application to a mouse model of Down syndrome.

Characterising phenotypes often requires quantification of anatomical shape. Quantitative shape comparison (morphometrics) traditionally uses manually located landmarks and is limited by landmark number and operator accuracy. Here, we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome and a population of the Diversity Outbred (DO) mouse model, comparing it with a landmark-based approach. We identified cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening), homologous to the human phenotype. Shape variation in the DO mice was partly attributable to allometry (size-dependent shape variation) and sexual dimorphism. The landmark-free method performed as well as, or better than, the landmark-based method but was less labour-intensive, required less user training and, uniquely, enabled fine mapping of local differences as planar expansion or shrinkage. Its higher resolution pinpointed reductions in interior mid-snout structures and occipital bones in both the models that were not otherwise apparent. We propose that this landmark-free pipeline could make morphometrics widely accessible beyond its traditional niches in zoology and palaeontology, especially in characterising developmental mutant phenotypes.

Cranial Suture Regeneration Mitigates Skull and Neurocognitive Defects in Craniosynostosis.

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.

The effects of morin on bone regeneration to accelerate healing in bone defects in mice.

Restoring bone defects are the major challenge facing clinical trial therapy, particularly skull related problems. Morin, a naturally occurring compound, has pro-osteogenesis. This research focuses on assessing the role of morin for its pro-osteogenesis activities. We utilized in vivo and in vitro models to investigate the molecular-level mechanisms of morin's osteoblastic biological activity. The effectiveness of morin on pro-osteogenesis (100 mg/kg/day) was assessed by monitoring modifications in the bone histomorphometry score, the development of immature osteoblasts from mesenchymal stems cells and improvements in the expression of pro-osteogenic cytokines in skull defected (SD) mice. Quantitative-PCR, Western blot analysis, and immunofluorescence were studied to investigate the signaling pathways. Morin has a substantial in vivo pro-osteogenesis effect which can facilitate the development of osteoblasts, the production of osteoblast related marker genes, and in vitro protein markers for osteoblasts. From a molecular biology standpoint, morin contributes to the development of osteoblasts and stimulation of the Wnt pathway with the activation and translocation of ß-catenin nuclei. Our findings from the study revealed that morin may be a beneficial substitute for helping regenerate bone defects.

Orthotopic Bone Formation by Streamlined Engineering and Devitalization of Human Hypertrophic Cartilage.

Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation. In this study, we aimed at engineering and devitalizing upscaled quantities of HyC ECM within a perfusion bioreactor, followed by in vivo assessment in an orthotopic bone repair model. We hypothesized that the devitalized HyC ECM would outperform a clinical product currently used for bone reconstructive surgery. Human MSC were genetically engineered with a gene cassette enabling apoptosis induction upon addition of an adjuvant. Engineered hMSC were seeded, differentiated, and devitalized within a perfusion bioreactor. The resulting HyC ECM was subsequently implanted in a 10-mm rabbit calvarial defect model, with processed human bone (Maxgraft®) as control. Human MSC cultured in the perfusion bioreactor generated a homogenous HyC ECM and were efficiently induced towards apoptosis. Following six weeks of in vivo implantation, microcomputed tomography and histological analyses of the defects revealed an increased bone formation in the defects filled with HyC ECM as compared to Maxgraft®. This work demonstrates the suitability of engineered devitalized HyC ECM as a bone substitute material, with a performance superior to a state-of-the-art commercial graft. Streamlined generation of the devitalized tissue transplant within a perfusion bioreactor is relevant towards standardized and automated manufacturing of a clinical product.

Pneumocephalus and air travel: an experimental investigation on the effects of aircraft cabin pressure on intracranial pressure.

This study investigates the effects of aircraft cabin pressure on intracranial pressure (ICP) elevation of a pneumocephalus patient. We propose an experimental setup that simulates the intracranial hydrodynamics of a pneumocephalus patient during flight. It consists of an acrylic box (skull), air-filled balloon [intracranial air (ICA)], water-filled balloon (cerebrospinal fluid and blood) and agarose gel (brain). The cabin was replicated using a custom-made pressure chamber. The setup can measure the rise in ICP during depressurization to levels similar to that inside the cabin at cruising altitude. ΔICP, i.e. the difference between mean cruising ICP and initial ICP, was found to increase with ICA volume and ROC. However, ΔICP was independent of the initial ICP. The largest ΔICP was 5 mmHg; obtained when ICA volume and ROC were 20 ml and 1,600 ft/min, respectively. The postulated ICA expansion and the subsequent increase in ICP in pneumocephalus patients during flight were successfully quantified in a laboratory setting. Based on the quantitative and qualitative analyses of the results, an ICA volume of 20 ml and initial ICP of 15 mmHg were recommended as conservative thresholds that are required for safe air travel among pneumocephalus patients. This study provides laboratory data that may be used by doctors to advise post-neurosurgical patients if they can safely fly.

Difficult Intubation due to Penetrating Trauma from a Crossbow Bolt.

We present the case of a patient with penetrating neck and craniofacial trauma from a self-inflicted crossbow bolt injury. This case highlights the challenges involved in prehospital airway management related to an in situ foreign object penetrating the oral cavity. We review the complications associated with such injuries and considerations for effective prehospital airway management.

Complicación por inyección de silicona en estética facial: migración a tejido adenoideo / Silicone injection complication in facial aesthetics: Migration to adenoids

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Phosphorylated chitin increased bone formation when implanted into rat calvaria with the Ti-device.

BACKGROUND: Previously we found that a group of phosphorylated proteins (SIBLINGs) in bone binds with the Ti-device, and increases the early bone formation around the Ti-implants remarkably. From these results, we explained the biochemical mechanism of a strong bond between living bone and Ti, which was discovered by Brånemark and colleagues. For the clinical application of our findings, we need a large amount of these proteins or their substitutes. OBJECTIVE: We aimed to create a new molecule that equips with essential functions of SIBLINGs, Ti-binding, and bone enhancement around the Ti implant. METHODS: We chemically phosphorylated chitin and obtained a soluble form of phosphorylated chitin (P-chitin). In this solution, we immersed the Ti-devices of web-form (TW) which we previously developed and obtained the P-chitin coated TWs. Then we tested the P-chitin coated TWs for their calcification ability in vitro, and bone enhancing ability in vivo, by implanting them into rat calvaria. We compared the P-chitin coated TW and the non-coated TW in regard to their calcification and bone enhancing abilities. RESULTS: Ti-devices coated with phosphorylated-chitin induced a ten times higher calcification in vitro at 20 days, and four times more elevated amount of bone formation in vivo at two weeks than the uncoated Ti-device. CONCLUSIONS: Phosphorylated chitin could be a partial substitute of bone SIBLING proteins and are clinically applicable to accelerate bone formation around the Ti implants, thereby achieving the strong bond between living bone and Ti.

Cranial burr holes in the emergency department: to drill or not to drill?

The practice of trepanning (referred to today as a craniotomy) dates back to the Neolithic period. Reasons for drilling a hole through the skull evolved from releasing evil spirits and curing insanity to practical management of head injuries in ancient Greece and Rome. Today, craniotomy or drilling a burr hole through the skull is very much the purview of the neurosurgeon. Yet one could argue that the procedure itself is more 'bone surgery' than 'brain surgery'. Nevertheless, despite the fact that head injury is a common presentation at district general hospitals and traumatic extra-axial haemorrhages are encountered often, the straightforward skillset required to drill a burr hole as a pretransfer, temporising, life-saving measure is seldom taught and has never gained traction. What we advocate in this article is the adaptation and novel application of an old, tried and tested technique in new hands. The critical pathophysiological turning point of any expanding extra-axial haemorrhage is the inflection point on the volume/Intracranial pressure (ICP) curve beyond which compensation is impossible. The subsequent rising ICP initiates a predictable continuum of clinical signs signalling progressive herniation. There are few emergencies as time-critical as a patient with an isolated, expanding extradural haemorrhage embarking on a trajectory of rostrocaudal deterioration and inevitable death. In many cases, the tragedy is compounded by the knowledge that such a patient probably has a healthy underlying brain, often evidenced by a lucid period after trauma. Our emergency department is attached to a small 300-bed District General Hospital (DGH) on the rural North West coast of Ireland. We are 262 km distant by road from a national neurosciences department that can, at best, be reached in 2 hours and 30 min. Quality improvement review of years of dismal outcomes in patients such as those described earlier with potentially remediable pathology prompted research and development of the skillset we are now able to offer, an old technique in new hands.

Bioactive Pore-Forming Bone Adhesives Facilitating Cell Ingrowth for Fracture Healing.

The effectiveness of commercial bone adhesives is known to be hampered by the weak efficacy of cell ingrowth. The strategy of macropore-forming, especially bioactive macropores, holds considerable promise to circumvent this problem, thereby promoting fracture healing. Herein, a class of bioactive glass-involved macropore-embedded bone adhesives is developed, which is capable of facilitating the migration of bone-derived mesenchymal stromal cells into the adhesive layer and differentiation into osteocytes. The integration of bioactive glass-particle-encapsulated porogens in the bone adhesives is key to this approach. A robust instant bonding on the bone adhesive and a high efficiency of bone regeneration on a mouse skull are observed, both of which are vital for clinical applications and personalized surgical procedures. This work represents a general strategy to design biomaterials with high cell-ingrowth efficacy.