Background: Gorham-Stout disease (GSD) is a rare, underreported and poorly investigated osteolytic condition which may affect bone of different regions of the human body. To our knowledge this is the first case of bone reparation during treatment that was traced carefully clinically and radiographically. Such complex craniomaxillofacial involvement [upper jaw with continuous extension to the base of the pterygoid Case Description: We present a case of a 40-year-old subject with massive resorption of the right upper jaw and the base of the ipsilateral PP which was diagnosed as GSD. He was admitted with a year-long history of uncontrollable midfacial pain. Radiographically osteolysis of the maxilla and the PP was evident. Microscopically the specimen lacked any specific signs and consisted of fibrous tissue mingled with blood vessels and lymphatics. Off-label sirolimus 1 mg once daily; zoledronic acid (ZA) 4 mg every 4 weeks and vitamin D 5,000 IU once daily treatment protocol was employed. The extraordinary prominent restoration of the maxillary anterior wall and the base of the pterygoid was first noted after 9 months of treatment (medication implemented for 3 years) and traced throughout the whole 4-year follow-up period. Conclusions: Medical treatment protocol consisting of the combination of the ZA, sirolimus, and vitamin D has showed its effectiveness in the treatment of GSD of the maxilla and the adjacent base of the PP. Further research of this treatment protocol is needed.

Defects in the prelamin A processing enzyme caused by loss-of-function mutations in the ZMPSTE24 gene are responsible for a spectrum of progeroid disorders characterized by the accumulation of farnesylated prelamin A. Here we report that defective prelamin A processing triggers nuclear RIPK1-dependent signalling that leads to necroptosis and inflammation. We show that accumulated prelamin A recruits RIPK1 to the nucleus to facilitate its activation upon tumour necrosis factor stimulation in ZMPSTE24-deficient cells. Kinase-activated RIPK1 then promotes RIPK3-mediated MLKL activation in the nucleus, leading to nuclear envelope disruption and necroptosis. This signalling relies on prelamin A farnesylation, which anchors prelamin A to nuclear envelope to serve as a nucleation platform for necroptosis. Genetic inactivation of necroptosis ameliorates the progeroid phenotypes in Zmpste24 −/− mice. Our findings identify an unconventional nuclear necroptosis pathway resulting from ZMPSTE24 deficiency with pathogenic consequences in progeroid disorder and suggest RIPK1 as a feasible target for prelamin A-associated progeroid disorders.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN–pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1–pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα–TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN–pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1. Zhang, Xu, Liu, Wang et al. identify an inhibitory mechanism for RIPK1 kinase through EGLN1/pVHL-mediated proline hydroxylation, which is disrupted upon prolonged hypoxia that activates RIPK1 activity to promote cell death and inflammation.

Purpose Metastatic involvement of the lingual lymph nodes (LLNs) in oral cavity squamous cell cancer (SCC) has recently been proven to significantly reduce locoregional control and survival. Despite recent refinements in the detection of these lesions, the understanding of the LLN topographic anatomy among clinicians is limited. A proposition of a topographic division on LLN based on a comprehensive literature search and synthesis may be helpful in this condition. Methods A literature search and election based on contemporary PRISMA guidelines was performed for sources on LLN anatomy with special attention on their subdivision. Results Four topographic LLN subgroups were defined: median-between genioglossal and geniohyoid muscles; intermediate parahyoid-medial to the hyoglossal muscle, at the greater cornu of the hyoid bone; lateral sublingual (paraglandular) LLNs-at the sublingual salivary gland; lateral submandibular (paraglandular) LLNs -lateral to the hyoglossal muscle, at the deep surface of the submandibular salivary gland. Conclusion The development and implementation of a unified anatomical topographic classification of LLN subgroups may be among the important conditions for improving the detection and treatment of LLN lesions.

Adenosine monophosphate–activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser 415 to suppress energy stress–induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1 -deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

Objective:To explore the method and clinical effect of repairing neck radiation ulcer with superficial cervical artery flap.Methods:January 2016 to June 2019, 11 cases of neck radiation ulcer were repaired with superficial cervical artery flap. The ulcer occurred 13.4 years after radiotherapy on average, with an area between 1 cm×2 cm and 3 cm×7 cm, extensive fibrosis.After pathological examination, surgical removal of ulcer and surrounding fibrotic tissue, and avoid injuring the neck’s main blood vessels. Wound size after debridement: 6 cm×9 cm-8 cm×13 cm. The flap rotation point is 4-5 cm beside the spine on the acromion level.The flaps were designed along the skin branch of the superficial cervical artery which located by the Doppler blood flow detector.The distance from the rotation point to the flap’s proximal edge is about 2 cm longer than that of the wound’s proximal edge.The size of the flap is about 2 cm larger than the wound.Then the flaps were excised from far to near after exposing the pedicle. The flap was then transferred to the neck to repair the defect formed by the radiation ulcer’s excision. If the tension is low, the donor sites were dissociated about 2-3 cm, then sutureddirectly after reducing tension.If the tension is high, part of the donor site was sutured to reduce the area and then grafted with medium-thickness skin.The postoperative changes of the patient were carefully observed.Among them, 7 cases underwent one-stage operation, 4 cases underwent two-stage operation after the donor area’s pre-expansion.Results:All patients with radiation ulcers were healed completely.The appearance and function of the operation area were good.Followed up for 6-24 months, no recurrences of radiation ulcer were observed. Among them, the flaps of 10 cases survived completely, and the wound healed in one stage.The distal area of the flap necrosed in one case, and repaired by dressing change and skin grafting.Conclusions:Radiation ulcer of the neck is a serious long-term complication after radiotherapy. Once it occurs, it is difficult to heal by conservative treatment. Skin grafting is difficult to survive as well. The superficial cervical artery flap has a constant and abundant blood supply and a hidden donor area, which is a feasible method for the treatment of radiation ulcer of the neck and reconstruction of the function.

目的:介绍在虚拟手术计划辅助下行经口内入路下颌骨切除和血管化骨重建的经验,评价术后重建效果.方法:对9例下颌骨良性肿瘤患者术前行虚拟手术计划,设计、制作适用于口内操作的预设钉孔的导板.然后经口内入路利用截骨导板行下颌骨切除,预弯钛板及血管化骨瓣的植入和固定.术中实时导航验证新下颌骨的空间位置.术后半年,通过临床及影像学检查评价患者外形和功能;通过术后CT与术前STL模型拟合,评估下颌骨重建的精确性.采用SPSS 15.0软件包对数据进行统计学分析.结果:在虚拟手术计划辅助下,9例患者均顺利完成经口内入路下颌骨切除及血管化下颌骨重建,术中导航证实重建下颌骨位置准确.术后半年复查见患者面部对称,无面瘫及开口受限.患者对手术效果满意.图像拟合显示,截骨线位置精确,误差<1 mm[(0.72±0.15)mm],下颌骨重建位置与术前设计高度一致,误差为(1.76±1.99)mm.结论:在虚拟手术计划辅助下,利用预设钉孔的导板和预弯钛板,可以精确实施口内下颌骨切除及血管化骨重建,避免了口外切口,显著提高了下颌骨重建的精确性.

Background Observational studies have indicated an association between polycystic ovary syndrome (PCOS) and periodontitis, but it is unclear whether the association is cofounded or causal. We conducted a two-sample Mendelian randomization (MR) study to investigate the bidirectional relationship between genetically predicted PCOS and periodontitis. Methods From two genome-wide association studies we selected 13 and 7 single nucleotide polymorphisms associated with PCOS and periodontitis, respectively, as instrumental variables. We utilized publicly shared summary-level statistics from European-ancestry cohorts. To explore the causal effect of PCOS on periodontitis, 12,289 cases of periodontitis and 22,326 controls were incorporated, while 4,890 cases of PCOS and 20,405 controls in the reverse MR. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented. Results Genetically determined PCOS was not causally associated with risk of periodontitis (odds ratio 0.97; 95% confidence interval 0.88–1.06; P = 0.50) per one-unit increase in the log-odds ratio of periodontitis. Similarly, no causal effect of periodontitis on PCOS was shown with the odds ratio for PCOS was 1.17 (95% confidence interval 0.91–1.49; P = 0.21) per one-unit increase in the log-odds ratio of periodontitis. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity. Conclusion The bidirectional MR study couldn’t provide convincing evidence for the causal relationship between genetic liability to PCOS and periodontitis in the Europeans. Triangulating evidence across further observational and genetic-epidemiological studies is necessary.

OBJECTIVES:The aim of this article is to introduce and share our experience in the sequential use of a novel guiding plate system for accurate mandibular reconstruction via transoral approach and evaluate its clinical effects. METHODS:Ten patients were operated with transoral mandibulectomy and simultaneous mandibular reconstruction using a novel guiding plate system. Postoperatively, aesthetic assessment and quantitative evaluation were analyzed by measuring the parameters like discrepancy in osteotomy lines, mandibular similarity and symmetry. The independent samples t-test was used and P < 0.05 was considered as significant. RESULTS:All patients underwent planned transoral surgical procedure successfully. The postoperative aesthetic assessment was rated as excellent. The discrepancy between virtual and actual osteotomy lines, at anterior and posterior regions was 0.80 ± 0.08 and 0.98 ± 0.37 mm, respectively. The postoperative evaluation revealed that mandibular similarity was 0.85 ± 0.03, coronal mandibular angle (CMA) 0.66 ± 0.40, axial mandibular angle (AMA) 1.97 ± 1.25, and sagittal mandibular angle (SMA) 1.97 ± 1.05. There was statistically significant difference in the mean values of osteotomy line discrepancy, mandibular similarity and symmetry, among novel guiding plate and traditional plate groups. CONCLUSIONS:The novel guiding plate system is a viable and easy-to-use technology for improving the surgical outcomes in patients requiring transoral mandibulectomy and simultaneous mandibular reconstruction by overcoming the problem of limited access due to the presence of lips and cheeks. This can highly improve the precision in osteotomy, fixation of the prebent titanium reconstruction plate, spatial relation transfer, and achieving better symmetry and similarity of mandibular contour.

Objectives: To evaluate the oncological safety and reliability of the submental island flap (SIF) technique in patients with pathologically node-negative (pN0) and node-positive (pN + ) T1-2 oral squamous cell carcinoma (OSCC) undergoing surgical tumor resection and concurrent SIF reconstruction. Patients and methods: Retrospectively, we reviewed patients with pN0 and pN+ T1-2 OSCC who underwent tumor resection and defect reconstruction with SIF from April 2008 to September 2016, focusing on flap viability, patterns and predictors of locoregional failure, salvage treatments, and oncologic prognosis. Results: Of 160 patients with primary T1-2 OSCC, 33 were pN+ and 127 were pN0. All SIFs beside two were successful (98.75%). During follow-up, 18 patients experienced locoregional tumor relapse, of which 14 were pN0 and four were pN + . The 5-year recurrence-free survival was 88.73% vs. 86.93% for the pN0 and pN + groups, respectively (p = .847). The pN + patients had poorer prognosis than pN0 patients (5-year overall survival, 66.35% vs. 91.10% respectively [p = .005]; disease-specific survival, 74.87% vs. 91.88% respectively [p = .016]). Multivariate analyses indicated there was no independent predictor for locoregional recurrence, but pN + was predictive for poor prognosis (p = .03). Conclusion: SIF is a reliable flap for the reconstruction of OSCC-related small- and medium-sized soft tissue defect. With careful neck dissection and appropriate postoperative adjuvant treatment, the application of SIF did not increase the risk of locoregional tumor recurrence in patients with pN+ T1-2 OSCC compared with those with pN0 T1-2 OSCC.

Familial florid osseous dysplasia (FFOD) is an autosomal dominant disorder of connective tissue, characterized by lobulated cementum-like masses scattered throughout the jaws and the alveolar process. This study aimed to identify the genetic etiology of a three-generation Chinese family affected with FFOD. A novel missense mutation p.C356W in anoctamin 5 (ANO5) gene was successfully identified as the pathogenic mutation by whole-exome sequencing (WES). The p.C356W mutation is located in the first loop between the first and second transmembrane domain of ANO5 protein. Sequence alignment of ANO5 protein among many different species revealed that this position is highly conserved. The p.C356W mutation may damage the predicted protein stability of ANO5 by altering the structure of several extracellular loops of ANO5 and affecting the formation of the disulfide bond, thereby disrupting the correct folding of ANO5 protein. Thus, the amino acid at position 356 appears to play a key role in the protein structural stability and function of ANO5 protein. Our results may also provide new insights into the cause and diagnosis of FFOD and may have implications for genetic counseling and clinical management.

PURPOSE: To introduce our experience in transoral segmental mandibulectomy of benign tumor and intraoral microvascular anastomosis for mandibular reconstruction with vascularized fibula osseous flap. METHODS: Between January and March 2018, transoral segmental mandibulectomy of benign tumor and intraoral microvascular anastomosis for mandibular reconstruction with vascularized fibula osseous flap were performed in 4 patients in our department. Preoperative virtual surgical planning, prebending of reconstruction plate and intraoperative navigation for confirmation of neomandibular site were performed in 3 patients. Facial artery and vein were exposed to protect at intraoral buccal region prior to segmental mandibulectomy and shaping of grafted fibula. Intraoral microvascular anastomosis of facial artery and peroneal artery in an end -to -end fashion, whereas facial vein and peroneal vein in an end -to -end fashion with the Coupler. Conventional postoperative monitoring of blood flow signal was conducted with hand -held ultrasound doppler. Panoramic radiographs were taken to assess the neomandible on day 7 postoperatively. RESULTS: Successful transoral segmental mandibulectomy was completed in 4 patients and intraoral microvascular anastomosis for mandibular reconstruction with vascularized fibula osseous flap was completed in 3 patients. Microvascular anastomosis at submandibular region was done in another patient because intraoral facial vein was not suitable. Normal blood flow signal was displayed on hand -held ultrasound Doppler. Intraoral and donor site wounds were healed uneventfully. Ideal neomandible and good occlusion were observed in postoperative panoramic radiographs. Symmetric facial appearance and no restriction of mouth opening were achieved in all patients. All patients were satisfied with the surgical results. CONCLUSIONS: It is feasible to avoid extraoral incision by transoral segmental mandibulectomy of benign tumor and intraoral microvascular anastomosis for mandibular reconstruction with vascularized fibula osseous flap. The same postoperative results of transoral approach as that of extraoral approach can be achieved.

Background: Treatment of large bone defects represents a major clinical problem worldwide. Suitable bone substitute materials are commonly required to achieve successful bone regeneration, and much effort has been spent to optimize their chemical compositions, 3D architecture and mechanical properties. However, material-immune system interactions are increasingly being recognized as a crucial factor influencing regeneration. Here, we envisioned an accurate and proactive immunomodulation strategy via delivery of IL-4 (key regulator of macrophage polarization) to promote bone substitute material-mediated regeneration. Methods: Four different IL-4 doses (0 ng, 10 ng, 50 ng and 100 ng) were delivered into rat large cranial bone defects at day 3 post-operation of decellularized bone matrix (DBM) material implantation, and the osteogenesis, angiogenesis and macrophage polarization were meticulously evaluated. Results: Micro-CT analysis showed that immunomodulation with 10 ng IL-4 significantly outperformed the other groups in terms of new bone formation (1.23-5.05 fold) and vascularization (1.29-6.08 fold), achieving successful defect bridging and good vascularization at 12 weeks. Histological analysis at 7 and 14 days showed that the 10 ng group generated the most preferable M1/M2 macrophage polarization profile, resulting in a pro-healing microenvironment with more IL-10 and less TNF-α secretion, a reduced apoptosis level in tissues around the materials, and enhanced mesenchymal stem cell migration and osteogenic differentiation. Moreover, in vitro studies revealed that M1 macrophages facilitated mesenchymal stem cell migration, while M2 macrophages significantly increased cell survival, proliferation and osteogenic differentiation, explaining the in vivo findings. Conclusions: Accurate immunomodulation via IL4 delivery significantly enhanced DBM-mediated osteogenesis and angiogenesis via the coordinated involvement of M1 and M2 macrophages, revealing the promise of this accurate and proactive immunomodulatory strategy for developing new bone substitute materials.

Surgical interventions for malignant neoplasms of the head and neck region bear a risk of general medical complications. Venous thromboembolism and pulmonary embolism is closely tied to patients suffering from carcinoma who are exposed to thrombotic events. These comprise the most common medical complications in patients undergoing head neck surgery. In patients with pulmonary embolism, the incidence of acute renal failure ranges is not rare. Rhabdomyolysis is an unusual and probably often overlooked clinical syndrome which may lead to acute renal failure and permanent myoglobinuric renal damage. Clinical case which is outlined here represents an example of pulmonary embolism combined with acute renal failure in a patient with no obvious risk factors after bilateral neck dissection. Rhabdomyolysis in such conditions may be an overlooked and underdiagnosed reason of acute renal failure development.

Background: We conducted a retrospective analysis of the clinical outcomes and evaluated the reconstructive strategies in patients who underwent secondary maxillary reconstruction with a vascularized fibula osteomyocutaneous flap (VFOF).Methods: From May of 2001 to June of 2014, 34 patients who underwent secondary maxillary reconstruction with VFOF, with or without titanium mesh, were reviewed. The patients were divided into two groups of maxillary reconstruction, according to different planning and treatment strategies. In Group 1, presurgical planning was achieved using three-dimensional stereomodeling (n = 12). In Group 2, virtual surgical planning was performed and guided templates were produced (n = 22). The differences in the preoperative planning, intraoperative technique, postoperative complications, and long-term results between the two groups were analyzed. Statistical analysis was performed to determine the differences between the two groups and the risk factors for prognosis.Results: Similar and accurate secondary maxillary reconstructions were successfully performed in Group 1 and 2. Postoperative complications were reported in 8 patients in Group 1 and 11 patients in Group 2. Complications were reported in patients who underwent radiotherapy. The incidence of postoperative complications in Group 2 were lower than that in Group 1 with the exception of midfacial collapse (P > 0.05). The long-term results of some patients with class 3 defects were not satisfactory because of midfacial collapse and lower eyelid ectropion. Stepwise regression analysis showed radiotherapy to be a risk factor for prognosis.Conclusions: The long-term results of secondary maxillary reconstruction were reported to be acceptable in our study. Radiotherapy was the risk factor for prognosis in secondary maxillary reconstruction. On the basis of these results, we highly recommend our strategy for secondary maxillary reconstruction. Good functional results could be achieved after the accurate restoration of maxillary alveolar ridge with several fibular segments using virtual surgical planning and dental restoration. (C) 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Since diabetes lead to alterations in bone metabolism with reductions in bone mineral content and delayed bone formation, the most effective method for bone regeneration in diabetes remains to be determined. In this study, type 2 diabetes were successfully induced via a high-fat diet and low-dose streptozotocin intraperitoneal injection. Excess reactive oxygen species (ROS) has been implicated in diabetes mellitus. Overexpression of ROS can lead to oxidative stress and subsequently to H2O2-mediated impaired proliferation and delayed cellular differentiation. As a result, antioxidant alpha-lipoic acid (ALA)-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres were fabricated using the emulsion solvent evaporation method, and a sustained and controlled release of ALA was observed up to 27 days. It was demonstrated that biodegradable PLGA microspheres loaded with ALA acted as ROS scavengers and partially recover the mesenchymal stem cell proliferation and differentiation. The bone formation of ALA loaded scaffolds in rat cranial bone defects were greater than the prime three-dimensional collagen scaffold. These results suggest the application of ALA loaded PLGA microsphere exhibit good bioactivity and bone forming ability in diabetes.

In oral and oropharyngeal cancer, the presence of regional neck metastasis strongly influences treatment planning and survival prognosis. A number of imaging techniques can be utilized in the clinic for diagnosis and staging. A patient with oropharyngeal cancer was staged T2 cN1 after clinical examination, computed tomography, and F-18-fluorodeoxyglucose positron emission tomography with computed tomography. Contrast-enhanced microbubble imaging was applied for diagnosis of a lymph node suspected of harboring a metastasis. The result of the microbubble procedure showed the suspicious node to be tumor negative, and this was later confirmed by frozen section and serial step section of the harvested node. Contrast-enhanced ultrasonography with introduction of intravenous microbubble contrast may be of benefit in staging oropharyngeal cancer in patients with enlarged neck lymph nodes.

Effective penetration through the blood-brain barrier (BBB) remains a challenge for the treatment of many brain diseases. In this study, a small molecule, sinapic acid (SA), extracted from mustard, was selected as a novel bioinspired BBB-permeable ligand for efficient drug delivery in glioma treatment. SA was conjugated on the surface of zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-encapsulated bovine serum albumin (BSA)-based nanoparticles, yielding nBSA-SA. The PMPC shell serves as a protective layer to prolong the in vivo blood circulation time with a better chance to cross the BBB. Furthermore, temozolomide (TMZ), which can be loaded onto the nanoparticles via electrostatic interactions with acrylic acid (AA) to generate AA-nBSA-SA-TMZ, was applied as an excellent chemotherapeutic drug for glioma therapy. The obtained nanoparticles with a distinct size show great BBB permeability. Through the mechanism study, it was found that the cell internalization of the SA-conjugated nanoparticles is an energy-dependent process with only transient disruption of the BBB. The biological evaluation results unambiguously suggest that drug-loaded nanoparticles can lead to strong apoptosis on the tumor site and increase the median survival time of glioma-bearing mice. Overall, this novel BBB-permeable ligand SA paves the way for the delivery of cargo into the brain and provides a powerful nanoplatform for glioma therapy via intravenous administration.