Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

GCN5 contributes to intracellular lipid accumulation in human primary cardiac stromal cells from patients affected by Arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease associated with sudden cardiac death and cardiac fibro-fatty replacement. Over the last years, several works have demonstrated that different epigenetic enzymes can affect not only gene expression changes in cardiac diseases but also cellular metabolism. Specifically, the histone acetyltransferase GCN5 is known to facilitate adipogenesis and modulate cardiac metabolism in heart failure. Our group previously demonstrated that human primary cardiac stromal cells (CStCs) contribute to adipogenesis in the ACM pathology. Thus, this study aims to evaluate the role of GCN5 in ACM intracellular lipid accumulation. To do so, CStCs were obtained from right ventricle biopsies of ACM patients and from samples of healthy cadaveric donors (CTR). GCN5 expression was increased both in ex vivo and in vitro ACM samples compared to CTR. When GCN5 expression was silenced or pharmacologically inhibited by the administration of MB-3, we observed a reduction in lipid accumulation and a mitigation of reactive oxygen species (ROS) production in ACM CStCs. In agreement, transcriptome analysis revealed that the presence of MB-3 modified the expression of pathways related to cellular redox balance. Altogether, our findings suggest that GCN5 inhibition reduces fat accumulation in ACM CStCs, partially by modulating intracellular redox balance pathways.

Surgical Outcomes of Orbital Fracture Reconstruction Using Patient-Specific Implants.

PURPOSE: Patient-specific implants (PSIs) are known to yield reliable outcomes in orbital wall fracture reconstruction (high precision, smoother operating techniques, and shorter surgical duration). This study analyzed the surgical error and clinical and esthetic outcomes of orbital reconstructions with PSIs. METHODS: This ambispective cohort study enrolled patients who underwent orbital reconstruction using PSIs between October 2016 and January 2018. The study end points were surgical error, indication and duration of surgery, long-term sequelae, revision surgeries, and surgical complications. Surgical error was analyzed by superimposing the postoperative implant position onto the preoperative virtual plan. Both qualitative (heat map) and quantitative (distance) measurements were obtained. RESULTS: Three patients were enrolled prospectively, and 23 were enrolled retrospectively. Indications for surgery were defect size (25 patients), diplopia (10 patients), impaired eye motility (4 patients), and significant enophthalmos (6 patients). At the last patient visit, there were 5 cases of diplopia, 1 case of exophthalmos, and 6 cases of slight enophthalmos of incremental degree. In terms of surgical error, a mean distance of 0.6 mm (95% confidence interval, 0.49 to 0.76), with a mean maximal distance of 3.4 mm (95% confidence interval, 2.79 to 4.02), was noted. No revision surgery was necessary. Lid malposition complications were not observed. However, 1 case each of symblepharon and scleral show were observed. No time-saving component was observed. CONCLUSIONS: PSI use in orbital reconstruction guarantees a preplanned 3-dimensional anatomical shape with a mean surgical error of just 0.6 mm. Our clinical results were similar to those of other protocols; however, warranting a complex 3-dimensional anatomical shape also in large orbital fractures with a low mean surgical error is feasible by using PSIs.

Volumetric Evaluated Bone Resorption After Open Reduction and Internal Fixation of Condylar Head Fractures of the Mandible.

PURPOSE: Decision making in the management of condylar head fractures remains difficult due to its dependency on multiple factors like fracture type, degree of dislocation, patient`s age and dental condition. As open reduction and internal fixation (ORIF) of condylar head fractures (CHFs) becomes more popular, the question of osteosynthesis removal is controversial. So far, information on volumetric changes after ORIF are available for a short-term period (<6 months) only. This study, therefore, was performed to assess bone resorption after condylar head fractures and to follow-up intermediate-term (>1 year) remodelling after removal of metallic osteosynthesis material. Furthermore clinical outcome was measured using Helkimo Index and put in relation with bone resorption. MATERIALS AND METHODS: A retrospective analysis of 19 patients who underwent open reduction and internal fixation of condylar head fractures at the University Hospital of Zürich between January 2016 and April 2018 using intraoperative cone-beam computed tomography repositioning control was conducted. The bone resorption on the condylar head was measured in the course after removal of osteosynthesis material by segmenting and superimposing of the postoperative 3D radiologic follow-up exam (T2) over the initial intraoperative cone-beam computed tomography (T1) using iPlan-CMF software. Complementary Helkimo index was assessed to put resorption rate in relation to clinical outcome. RESULTS: A total of 19 patients fulfilled the inclusion criteria. The mean follow-up time was 15.6 months and the mean bone resorption on the condylar head was -0.348cm3 or -15.29% of segmented condylar head. There was no correlation of clinical outcome and bone resorption. CONCLUSIONS: Helkimo index showed satisfying results; therefore, ORIF of condylar head fracture proves as a feasible treatment option. The mean bone resorption rate of -15.29% in the intermediate-term follow-up time (mean 15.6 months) is comparable to findings of other studies with short-term follow-up time (< 6 months). Thus, postinterventional remodeling activity and resorption seems highest in the first 4 to 6 postoperative months with little further resorption. In prevention of negative sequelae of protruding implants, timing of osteosynthesis material removal after this period of high bone remodeling activity is recommended. The resorption rate showed no correlation to clinical outcome.

Customized Titanium Reconstruction of Orbital Fractures Using a Mirroring Technique for Virtual Reconstruction and 3D Model Printing.

PURPOSE: Early operative reconstruction using titanium mesh is a technique often used for preventing sequelae after an orbital fracture. We sought to examine the utility of patient-specific molding of the mesh with a biomodel via virtual mirroring of the nonaffected side. METHODS: We retrospectively assessed the clinical and radiological outcomes of orbital fracture reconstruction using a customized titanium mesh shaped on 3D-printed biomodels in 34 unilateral orbital fracture cases. Preoperative virtual orbital reconstruction images, using the mirroring technique, were superimposed on postoperative 3D images, and clinical data from patient charts were analyzed. Orbital reconstructions were rated, and the intention to revise results intraoperatively, or during inpatient or outpatient phases, was assessed by 2 consultants and 2 residents. RESULTS: We found that most fractures arose from falls of <3 meters or from interpersonal violence. Ophthalmic injuries included subconjunctival bleeding, ocular contusion, enophthalmos, and diplopia. Long-term sequelae at last followup were diplopia (8.8%) and mild enophthalmos (11.8%). CONCLUSION: Interrater reliabilities regarding consultants' intention to revise results were substantial to almost perfect at any time point. Therefore, using the mirroring technique for the virtual reconstruction of a fractured orbit and a 3D-printed biomodel to customize commercial titanium implants yields good and reliable results, enhances surgical precision, and decreases the need for intraoperative revision, as well as long-term sequelae of orbital fractures.

ß-Secretase BACE1 Is Required for Normal Cochlear Function.

Cleavage of amyloid precursor protein (APP) by ß-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-ß peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1-/- mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1-/- mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1-/- mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1-/- mice. Together, these data strongly suggest that the hearing loss of BACE1 knock-out mice represents a developmental phenotype.SIGNIFICANCE STATEMENT Given its crucial role in the pathogenesis of Alzheimer's disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild-type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice.

Radiologic Analysis of Surgically Treated Fractures of the Condylar Process by an Endoscopic-Assisted Transoral Approach.

PURPOSE: This study analyzed the radiologic outcomes of patients with unilateral mandibular condylar fractures treated with open reduction-internal fixation (ORIF) through a transoral approach. PATIENTS AND METHODS: In this retrospective study, the radiologic images of 40 patients who underwent open reduction-internal fixation through a transoral approach were presented to 2 independent examiners. All patients underwent the surgical procedure between January 2015 and December 2016 at the Department of Cranio-Maxillofacial Surgery at UniversitätsSpital Zürich and were included in a previous functional outcome study. The surgical results were analyzed and graded as poor, acceptable, or good. The examiners declared whether they would have made any intraoperative revisions if the radiologic information had been available. Finally, the examiners estimated the required duration of elastic intermaxillary fixation (IMF) from the radiologic images, which was compared with the actual duration. RESULTS: Fracture reduction was classified as good in 33 cases (82.5%), acceptable in 5 cases, and poor in 2 cases by one examiner and as good in 32 cases (80%), acceptable in 6 cases, and poor in 2 cases by the other examiner. The inter-rater reliability was determined to be good (Cohen κ = 0.92). Correct osteosynthesis placement was found in 19 cases by one examiner and in 21 cases by the other examiner, with good inter-rater reliability (κ = 0.8). Moderate inter-rater reliability (κ = 0.4) was found for the required duration of elastic IMF. Furthermore, the estimated elastic IMF duration matched the actual duration in fewer than half of the cases. CONCLUSIONS: It is feasible to achieve reliably good radiologic results when operating on condylar process fractures by a transoral approach with endoscopic assistance and angled instruments. Intraoperative 3-dimensional imaging enables instant quality control and prompts surgical revision if needed.

Does Zygomatic Complex Symmetry Differ Between Healthy Individuals and Surgically Treated Patients Using Intraoperative 3-Dimensional Cone Beam Computed Tomographic Imaging?

PURPOSE: Reconstruction of symmetry after zygomaticomaxillary complex (ZMC) fractures is essential for esthetic appearance as well as function. Therefore, this study aimed to analyze whether bony facial symmetry in patients surgically treated for unilateral ZMC fractures via intraoperative imaging differs from that of healthy individuals. PATIENTS AND METHODS: Retrospective and cross-sectional radiographic measurements of patients treated for unilateral ZMC fractures via intraoperative cone beam computed tomography (CBCT) were performed to evaluate the postoperative ZMC symmetry. The same number of healthy individuals without any history of midfacial trauma matched for age and gender served as the control group. Asymmetry of the ZMC was determined by measuring bilateral differences in the malar eminence position on CBCT. In addition, demographic statistics, etiology, and fracture type were analyzed. RESULTS: Analysis of 57 surgically treated patients and 57 healthy individuals with a mean age of 29 years was performed. No significant difference in the symmetry of the malar eminence position was observed between healthy individuals and patients treated for a unilateral ZMC fracture (P = .890). In one third of patients, corrections were needed after intraoperative CBCT control. CONCLUSIONS: The results of this study indicate that, on average, a ZMC asymmetry of 1.6 mm is observed in healthy individuals. Furthermore, the use of intraoperative CBCT for the treatment of dislocated ZMC fractures helps to achieve precise anatomic, symmetrical repositioning and is suggested to improve the quality of care.

Improved Results in Closed Reduction of Zygomatic Arch Fractures by the Use of Intraoperative Cone-Beam Computed Tomography Imaging.

PURPOSE: The use of intraoperative imaging could help overcome the insufficiency of closed reduction that can result from the absence of visible feedback to evaluate the accuracy of the reduction in isolated zygomatic arch fractures. The aim of the present study was to evaluate the use of intraoperative 3-dimensional cone-beam computed tomography (CBCT) to improve the accuracy of reduction, by measuring the remaining cortical step and dislocation angle. We also evaluated the effect of CBCT on the need for repeat surgery. PATIENTS AND METHODS: We performed a retrospective cohort study of patients who had undergone zygomatic arch reduction surgery from January 2008 to May 2018. The patients were grouped according to the predictor variables into group A (postoperative radiologic follow-up studies) and group B (intraoperative CBCT imaging studies). The primary outcome variables were the remaining cortical step and dislocation angle compared with the ideal virtually mirrored position. These were assessed as measures of reduction accuracy. The secondary variables included age, gender, surgery duration, and fracture type. Statistical analysis was performed using a robust multiple regression analysis. RESULTS: The 45 patients were divided into 2 subgroups with 18 patients in the no intraoperative imaging (control) group and 27 patients in the intraoperative imaging group. Insufficient reduction occurred in 1 patient in the group without intraoperative imaging, leading to repeat surgery. No repeat surgery was necessary in the intraoperative imaging group. The remaining cortical step of the intraoperative imaging group was significantly lower than that of the control group (0.18 vs 2.03 mm; P < .001). For the remaining dislocation angle, similar findings were observed but without statistical significance (3.93° vs 7.75°; P = .58). CONCLUSIONS: The use of intraoperative CBCT significantly increased the accuracy of the reduction. Furthermore, the need for repeat surgery was not required for any patient in the intraoperative imaging group with CBCT-guided reduction.

Outcome of Surgically Treated Fractures of the Condylar Process by an Endoscopic Assisted Transoral Approach.

PURPOSE: Fractures of the condylar process are frequent. Ideal management of these fractures, as discussed in the literature, is controversial. Some recent meta-analyses have favored open reduction and internal fixation using various approaches. A strictly transoral approach has been described to minimize scarring and risk of facial nerve injury but has restricted visibility. This retrospective study analyzed outcomes of patients with unilateral mandibular condyle fractures who were treated by open reduction and internal fixation through an endoscopic-assisted transoral approach. MATERIALS AND METHODS: This study included 40 patients who were operated on from January 2015 through December 2016. All patients underwent surgery for a condylar process fracture using an endoscopic-assisted transoral approach. Fracture classification, demographic, and outcome data were collected. RESULTS: Most condylar process fractures were caused by falls from a height less than 3 m. Most were condylar base fractures and classified according to Spiessl and Schroll as Classes I and II. Sixteen patients showed a preoperative malocclusion, whereas 2 patients showed a slight postoperative malocclusion. In cases in which only 1 plate could be placed, the proximal fragment was shorter. A higher Spiessl and Schroll class showed a tendency toward longer operation times. For postoperative outcomes, 1 case of temporary facial palsy was the worst complication (2.5%), 2 cases exhibited minimal occlusal interference (5%), and 1 case exhibited a deviated mouth opening (2.5%). Ramus height was restored in all cases. No chronic pain was found in any cases. CONCLUSIONS: It is feasible to treat condylar process fractures in a safe manner using a transoral approach with endoscopic assistance and angled instruments without facial scarring and at a low complication rate. The endoscope improves the restricted visibility of the transoral approach, although a learning curve is necessary. This applies especially to dislocated fractures or to fractures with a short proximal fragment.

Accuracy of Computer-Guided Template-Based Implant Surgery: A Computed Tomography-Based Clinical Follow-Up Study.

OBJECTIVE: The aim of this clinical study was to analyze the accuracy of computer-guided implant surgery. MATERIALS AND METHODS: Assisted by computed tomography (CT)-based planning software and navigational templates, 16 patients successfully received 26 dental implants. Each implant parameter (a-d) was calculated based on superimposed preoperative and postoperative cone beam CT scans: (a) deviation at entry point; (b) deviation at apex; (c) angular deviation; and (d) depth deviation. RESULTS: Mean central deviation at implant entry point and apex was 0.91 mm (standard error [SE] = 0.11 mm; 95% confidence interval [CI]: 0.69-1.13) and 1.22 mm (SE = 0.11 mm; 95% CI: 0.99-1.45), respectively. Mean angulation deviation was 4.11 degrees (SE = 0.52 degrees; 95% CI: 3.04-5.17) and the average depth deviation was 0.65 mm (SE = 0.11 mm; 95% CI: 0.42-0.87). For the total number of implants placed, the maximum error was 2.34 mm at entry point, 2.71 mm at apex, 9.44 degrees in angular deviation, and 2.00 mm in depth deviation. CONCLUSION: Great accuracy was reached even in advanced cases with prior bone augmentation and complex traumas. This leads to the conclusion that particularly in advanced cases, computer-guided implantation can be beneficial.

Subcutaneous administration of a neutralizing IL-1ß antibody prolongs limb allograft survival.

Cytokine-expression profiles revealed IL-1ß highly upregulated in rejecting skin of limb allografts. We investigate the effect of intragraft treatment with a neutralizing IL-1ß antibody in limb transplantation. Following allogenic hind-limb transplantation, Lewis rats were either left untreated or treated with anti-lymphocyte serum + tacrolimus (baseline); baseline immunosuppression + anti-IL-1ß (1 mg/kg once/week, 6-8 subcutaneous injections) into the transplanted or contralateral limb. Endpoint was rejection grade III or day 100. Graft rejection was assessed by histology, immunohistochemistry, flow cytometry phenotyping of immune cells, and monitoring cytokine expression. Anti-IL-1ß injections into the allograft or contralateral limb resulted in a significant delay of rejection onset (controls: 58.60 ± 0.60; group 3: 75.80 ± 10.87, P = .044; group 4: 73.00 ± 6.49, P = .008) and prolongation of graft survival (controls: 64.60 ± 0.87; group 3: 86.60 ± 5.33, P = .002; group 4: 93.20 ± 3.82, P = .002), compared to controls. Although the phenotype of the graft infiltrating immune cells did not differ between groups, significantly decreased skin protein levels of IL-1ß, IL-4, IL-13, IP-10, MCP-1, and MCP-3 in long-term-survivors indicate an overall decrease of chemoattraction and infiltration of immune cells as the immunosuppressive mechanism of anti-IL-1ß. Inhibition of IL-1ß with short-term systemic immunosuppression prolongs limb allograft survival and represents a promising target for immunosuppression in extremity transplantation.

Cone Beam Computed Tomography Evaluation of the Artery in the Lateral Wall of the Maxillary Sinus: Retrospective Analysis of 602 Sinuses.

PURPOSE: This retrospective study evaluates the location of the arteries in the maxillary sinus, particularly in the middle portion, using cone beam computed tomography (CBCT) scans that can detect the lateral arteries with high reliability. METHODS: In this retrospective study, 2 experienced independent examiners evaluated 602 sinuses on CBCT scans. DISCUSSION: No significant correlation was found between the location of arteries and the patient's age, sex, or dentition. In 92.0% (P ≤ 0.001) of the sinuses, at least 1 arterial branch was detectable. CONCLUSION: Based on the CBCT scans, we found that a very high proportion of patients have the maxillary artery in their lateral sinus wall, which is important information for sinus augmentation or sinus surgery.

Calcified cartilage or bone? Collagens in the tessellated endoskeletons of cartilaginous fish (sharks and rays).

The primary skeletal tissue in elasmobranchs -sharks, rays and relatives- is cartilage, forming both embryonic and adult endoskeletons. Only the skeletal surface calcifies, exhibiting mineralized tiles (tesserae) sandwiched between a cartilage core and overlying fibrous perichondrium. These two tissues are based on different collagens (Coll II and I, respectively), fueling a long-standing debate as to whether tesserae are more like calcified cartilage or bone (Coll 1-based) in their matrix composition. We demonstrate that stingray (Urobatis halleri) tesserae are bipartite, having an upper Coll I-based 'cap' that merges into a lower Coll II-based 'body' zone, although tesserae are surrounded by cartilage. We identify a 'supratesseral' unmineralized cartilage layer, between tesserae and perichondrium, distinguished from the cartilage core in containing Coll I and X (a common marker for mammalian mineralization), in addition to Coll II. Chondrocytes within tesserae appear intact and sit in lacunae filled with Coll II-based matrix, suggesting tesserae originate in cartilage, despite comprising a diversity of collagens. Intertesseral joints are also complex in their collagenous composition, being similar to supratesseral cartilage closer to the perichondrium, but containing unidentified fibrils nearer the cartilage core. Our results indicate a unique potential for tessellated cartilage in skeletal biology research, since it lacks features believed diagnostic for vertebrate cartilage mineralization (e.g. hypertrophic and apoptotic chondrocytes), while offering morphologies amenable for investigating the regulation of complex mineralized ultrastructure and tissues patterned on multiple collagens.

Ultrastructural, material and crystallographic description of endophytic masses - A possible damage response in shark and ray tessellated calcified cartilage.

The cartilaginous endoskeletons of elasmobranchs (sharks and rays) are reinforced superficially by minute, mineralized tiles, called tesserae. Unlike the bony skeletons of other vertebrates, elasmobranch skeletons have limited healing capability and their tissues' mechanisms for avoiding damage or managing it when it does occur are largely unknown. Here we describe an aberrant type of mineralized elasmobranch skeletal tissue called endophytic masses (EPMs), which grow into the uncalcified cartilage of the skeleton, but exhibit a strikingly different morphology compared to tesserae and other elasmobranch calcified tissues. We use materials and biological tissue characterization techniques, including computed tomography, electron and light microscopy, X-ray and Raman spectroscopy and histology to characterize the morphology, ultrastructure and chemical composition of tesserae-associated EPMs in different elasmobranch species. EPMs appear to develop between and in intimate association with tesserae, but lack the lines of periodic growth and varying mineral density characteristic of tesserae. EPMs are mineral-dominated (high mineral and low organic content), comprised of birefringent bundles of large calcium phosphate crystals (likely brushite) aligned end to end in long strings. Both tesserae and EPMs appear to develop in a type-2 collagen-based matrix, but in contrast to tesserae, all chondrocytes embedded or in contact with EPMs are dead and mineralized. The differences outlined between EPMs and tesserae demonstrate them to be distinct tissues. We discuss several possible reasons for EPM development, including tissue reinforcement, repair, and disruptions of mineralization processes, within the context of elasmobranch skeletal biology as well as damage responses of other vertebrate mineralized tissues.

Ultrastructural and developmental features of the tessellated endoskeleton of elasmobranchs (sharks and rays).

The endoskeleton of elasmobranchs (sharks and rays) is comprised largely of unmineralized cartilage, differing fundamentally from the bony skeletons of other vertebrates. Elasmobranch skeletons are further distinguished by a tessellated surface mineralization, a layer of minute, polygonal, mineralized tiles called tesserae. This 'tessellation' has defined the elasmobranch group for more than 400 million years, yet the limited data on development and ultrastructure of elasmobranch skeletons (e.g. how tesserae change in shape and mineral density with age) have restricted our abilities to develop hypotheses for tessellated cartilage growth. Using high-resolution, two-dimensional and three-dimensional materials and structural characterization techniques, we investigate an ontogenetic series of tessellated cartilage from round stingray Urobatis halleri, allowing us to define a series of distinct phases for skeletal mineralization and previously unrecognized features of tesseral anatomy. We show that the distinct tiled morphology of elasmobranch calcified cartilage is established early in U. halleri development, with tesserae forming first in histotroph embryos as isolated, globular islets of mineralized tissue. By the sub-adult stage, tesserae have increased in size and grown into contact with one another. The intertesseral contact results in the formation of more geometric (straight-edged) tesseral shapes and the development of two important features of tesseral anatomy, which we describe here for the first time. The first, the intertesseral joint, where neighboring tesserae abut without appreciable overlapping or interlocking, is far more complex than previously realized, comprised of a convoluted bearing surface surrounded by areas of fibrous attachment. The second, tesseral spokes, are lamellated, high-mineral density features radiating outward, like spokes on a wheel, from the center of each tessera to its joints with its neighbors, likely acting as structural reinforcements of the articulations between tesserae. As tesserae increase in size during ontogeny, spokes are lengthened via the addition of new lamellae, resulting in a visually striking mineralization pattern in the larger tesserae of older adult skeletons when viewed with scanning electron microscopy (SEM) in backscatter mode. Backscatter SEM also revealed that the cell lacunae in the center of larger tesserae are often filled with high mineral density material, suggesting that when intratesseral cells die, cell-regulated inhibition of mineralization is interrupted. Many of the defining ultrastructural details we describe relate to local variation in tissue mineral density and support previously proposed accretive growth mechanisms for tesserae. High-resolution micro-computed tomography data indicate that some tesseral anatomical features we describe for U. halleri are common among species of all major elasmobranch groups despite large variation in tesseral shape and size. We discuss hypotheses about how these features develop, and compare them with other vertebrate skeletal tissue types and their growth mechanisms.

Influence of Mirrored Computed Tomograms on Decision-Making for Revising Surgically Treated Orbital Floor Fractures.

PURPOSE: This study evaluated whether intraoperative imaging with computer-assisted virtual reconstruction would be advantageous in reconstructions of orbital floor fractures. The surgeon's intention to revise a reconstructed primary orbital floor fracture by evaluating a postoperative mirrored computed tomographic (CT) scan was analyzed intraoperatively before wound closure, during inpatient hospitalization, and after hospitalization. The inter-rater agreement and the match of intention to revise and actual revision were analyzed. MATERIALS AND METHODS: Fifty-one anonymized postoperative CT scans of patients with a unilateral orbital floor fracture were mirrored using software. These computer-assisted virtual reconstructions were consecutively examined by 4 examiners. Seven of these patients underwent a revision. In the first part, the inter-rater agreements for all 3 times were analyzed. In the second part, the examiners' intentions to revise were compared with the actual performed revisions. RESULTS: The overall inter-rater agreements were 0.69 for the intraoperative phase, 0.55 for the in-hospital phase, and 0.39 for the post-hospital phase. The intraoperative inter-rater agreement for each examiner was 0.58 to 0.80. The Fleiss κ value for the in-hospital and post-hospital phases was lower. The comparison of the examiners' intention to revise and the actual revisions showed that 15 to 24 additional would have been revised. In contrast, 6 of 7 actual revisions would have been revised intraoperatively. The missed actual revision was the same case by all 4 examiners. The accordance of intention to revise with the actual revisions decreased during hospitalization and even more after hospitalization. This study showed strong agreement among examiners for revising anatomically incorrectly reduced orbital floor fractures intraoperatively by evaluating postoperative mirrored CT scans. During the in-hospital and post-hospital phases, the restraints against revision seemed to increase, thus leading to poorer inter-rater agreement. This analysis of postoperative CT scans with computer-assisted virtual reconstructions of the orbit would have led to considerably more revisions intraoperatively, but all actual revisions were detected except for 1 case. This case was the same for all 4 examiners. Operation time would have been prolonged in the additional revised cases, but a better anatomic reconstruction would have been achieved. Furthermore, the intraoperative result of the reconstruction would have been controlled instantly and corrected immediately, if needed. CONCLUSION: This study showed that of 6 of 7 actual revisions, implant placement would have been revised intraoperatively by all 4 examiners, if intraoperative imaging with computer-assisted virtual reconstruction of the orbit would have been applied. Therefore, the authors suggest that intraoperative imaging with computer-assisted virtual reconstruction could be advantageous in the prevention of later revisions of orbital floor fractures. In this study, the threshold to revise implant placement intraoperatively seemed to be lower when using intraoperative imaging with virtual reconstructions, because considerably more cases would have been revised intraoperatively by the examiners. In the in-hospital and post-hospital phases, this threshold increased, suggesting the more important role of clinical findings. It is uncertain whether the actual surgeons would have revised the same cases as the examiners if they had used intraoperative imaging with virtual reconstructions for their deliberation. However, the intraoperative inter-rater agreement was good and cost-intensive postoperative revisions might be prevented.

Possible role of gap junction intercellular channels and connexin 43 in satellite glial cells (SGCs) for preservation of human spiral ganglion neurons : A comparative study with clinical implications.

Human spiral ganglion (SG) neurons show remarkable survival properties and maintain electric excitability for a long time after complete deafness and even separation from the organ of Corti, features essential for cochlear implantation. Here, we analyze and compare the localization and distribution of gap junction (GJ) intercellular channels and connexin 43 (Cx43) in cells surrounding SG cell bodies in man and guinea pig by using transmission electron microscopy and confocal immunohistochemistry. GJs and Cx43 expression has been recognized in satellite glial cells (SGCs) in non-myelinating sensory ganglia including the human SG. In man, SG neurons can survive as mono-polar or "amputated" cells with unbroken central projections following dendrite degeneration and consolidation of the dendrite pole. Cx43-mediated GJ signaling between SGCs is believed to play a key role in this "healing" process and could explain the unique preservation of human SG neurons and the persistence of cochlear implant function.

Surgical treatment of nasal fractures may benefit from intraoperative 3D imaging.

This retrospective study aimed to assess the effects of the use of intraoperative three-dimensional (3D) imaging on outcomes in surgical treatment of nasal fractures. Furthermore, we investigated whether the use of intraoperative imaging improves outcomes and decreases the frequency of corrective surgeries compared to published literature. This retrospective descriptive study included patients who underwent operative treatment for nasal fractures with the use of intraoperative 3D imaging between January 2015 and January 2020 at a University Hospital. The primary outcome measure was patient satisfaction, which was assessed through patient charts about subjective esthetic problems and nasal obstruction. The secondary outcome measures were the number of intraoperative images and necessity of intra- and postoperative revisions. All the outcomes were evaluated using regression analysis. Of the 172 patients, secondary rhinoplasty and intraoperative revision were performed in 10 (6 %) and 93 (54 %) patients, respectively. Postoperatively, 19 (11 %) and 12 (7 %) patients complained of subjective esthetic problems and nasal obstruction, respectively. The intraoperative revision rate in patients undergoing surgical treatment of nasal fractures with intraoperative 3D imaging was >50 %. However, the incidence of postoperative secondary revision, nasal obstruction, and subjective esthetic problems was lower than that reported in the literature not having an intraoperative imaging. Our findings suggest that prompt quality control of the operative result enables immediate correction and prevents postoperative revision.

Two-screw osteosynthesis of the mandibular condylar head with different screw materials: a finite element analysis.

This study compared the biomechanical behavior of titanium, magnesium, and polylactic acid screws for two-screw osteosynthesis of mandibular condylar head fractures using finite element analysis. Von Mises stress distribution, fracture displacement, and fragment deformation were evaluated. Titanium screws performed the best in terms of carrying the highest load, resulting in the least fracture displacement and fragment deformation. Magnesium screws showed intermediate results, while PLA screws were found to be unsuitable with stress values exceeding their tensile strength. These findings suggest that magnesium alloys could be considered a suitable alternative to titanium screws in mandibular condylar head osteosynthesis.