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Summary:. The coronavirus disease 2019 posed an unprecedented strain to plastic surgery services. The scarcity of validated guidelines—at the beginning of this healthcare crisis—to direct clinical, ethical, transparent decision-making for head and neck cancer patients requiring palliative reconstructive surgery was a difficult situation. We report a 15-year-old girl with an advanced chemoresistant rare radiotherapy-induced mandibular osteosarcoma during the early phase of the pandemic in the United States in mid-March 2020, when official recommendations for triage were still developing. Local guidelines suggested canceling all elective procedures, and allowed operating emergency and/or nonelective cases only. Many surgeons declined surgery due to patient’s poor prognosis and high perioperative risk, but her mother pursued different professional opinions elsewhere. However, upon Beaumont hospital approval, the patient underwent radical en bloc resection of the tumor, hemimandibulectomy, zygomatic resection, maxillectomy, and hemipalate resection followed by reconstruction with free fibula osteocutaneous and anterolateral thigh flaps. The challenging decision to proceed with surgery was based on evidence-based and objective risk-stratifying scores, available at the time, and ethical recommendations from emerging reliable published literature. Despite a favorable postoperative outcome, the patient expired due to cardiac complications of the disease. Our patient taught us that ethical decision-making, sound clinical judgment, and a patient-centered individualized approach remain pivotal aspects of the medical profession. Although the surgery will not provide a cure for the disease, we have found that palliative reconstructive surgery can greatly improve patient’s quality of life, and help family cope with the advancing stages of disease.

Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of nascent viral transcripts. P-TEFb exists in multiple complexes in cells, and its core consists of a kinase, Cdk9, and a regulatory subunit, either Cyclin T1 or Cyclin T2. Tat binds directly to Cyclin T1 and thereby targets the Cyclin T1/P-TEFb complex that phosphorylates the CTD of RNA polymerase II and the negative factors that inhibit elongation, resulting in efficient transcriptional elongation. P-TEFb is tightly regulated in cells infected by HIV-1—CD4+ T lymphocytes and monocytes/macrophages. A number of mechanisms have been identified that inhibit P-TEFb in resting CD4+ T lymphocytes and monocytes, including miRNAs that repress Cyclin T1 protein expression and dephosphorylation of residue Thr186 in the Cdk9 T-loop. These repressive mechanisms are overcome upon T cell activation and macrophage differentiation when the permissivity for HIV-1 replication is greatly increased. This review will summarize what is currently known about mechanisms that regulate P-TEFb and how this regulation impacts HIV-1 replication and latency.

Nasal NK/T cell lymphomas (NKTCL) are a subset of aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin's lymphomas. The role of EBV in pathogenesis of NKTCL is not clear. Intriguingly, EBV encodes more than 40 microRNAs (miRNA) that are differentially expressed and largely conserved in lymphocryptoviruses. While miRNAs play a critical role in the pathogenesis of cancer, especially lymphomas, the expression and function of EBV transcribed miRNAs in NKTCL are not known. To examine the role of EBV miRNAs in NKTCL, we used microarray profiling and qRT-PCR to identify and validate expression of viral miRNAs in SNK6 and SNT16 cells, which are two independently derived NKTCL cell lines that maintain the type II EBV latency program. All EBV BART miRNAs except BHRF-derived miRNAs were expressed and some of these miRNAs are expressed at higher levels than in nasopharyngeal carcinomas. Modulating the expression of BART9 with antisense RNAs consistently reduced SNK6 and SNT16 proliferation, while antisense RNAs to BARTs-7 and -17-5p affected proliferation only in SNK6 cells. Furthermore, the EBV LMP-1 oncoprotein and transcript levels were repressed when an inhibitor of BART9 miRNA was transfected into SNK6 cells, and overexpression of BART9 miRNA increased LMP-1 protein and mRNA expression. Our data indicate that BART9 is involved in NKTCL proliferation, and one of its mechanisms of action appears to be regulating LMP-1 levels. Our findings may have direct application for improving NKTCL diagnosis and for developing possible novel treatment approaches for this tumor, for which current chemotherapeutic drugs have limited effectiveness.

Summary:. Beyond being aesthetically unpleasing, metatarsal defects have been known to lead to several patient concerns such as intermetatarsal malpositioning and metatarsalgia. There are several reconstructive techniques that have been utilized for reconstruction of bony defects in the foot, including the free dorsal toe flap and dorsal metatarsal perforator flap. Our institution has utilized the free fibular flap for surgical management pertaining to tarsal reconstruction. Our study looks to evaluate the work of a single plastic surgeon and identify patient postoperative outcomes. A retrospective chart review was conducted at Beaumont Health System, Royal Oak for patients who underwent first metatarsal reconstruction with a free fibular flap between the years 2015 and 2022. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively gathered and analyzed. A total of two patients were isolated after chart review. Both patients were found to have tolerated the procedure well and had no intraoperative complications. In addition, all patients had clinically viable flaps and were satisfied with their surgical results. The free fibular flap may be used effectively in the management of metatarsal defects that have failed prior therapy. In our study, both patients who underwent surgical management with a free fibular flap were noted to have successful long-term results. With the right expertise and patient population, a free fibular flap can be highly successful in the repair of metatarsal defects.

Vascular closure devices have become more popular in some clinical settings because they allow for quicker hemostasis and earlier ambulation. Although these devices have several benefits compared with manual compression, errors in deployment can result in a multitude of complications. We have presented two cases in which the Celt arterial closure device was maldeployed and caused significant patient morbidity.

Background:. It is predicted that 281,550 new cases of invasive breast cancer and 49,290 new cases of ductal carcinoma in situ will be diagnosed this year. In this study, we will detail our experience with simultaneous contralateral autologous breast augmentation during unilateral breast reconstruction utilizing bilateral deep inferior epigastric perforator (DIEP) flaps. Methods:. A retrospective analysis of patients who underwent simultaneous contralateral autologous breast augmentation during unilateral breast reconstruction utilizing bilateral DIEP flaps by the senior surgeons at Beaumont Health Systems, Royal Oak, was conducted. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively analyzed. Results:. Seven patients who met the inclusion criteria were identified. One patient underwent immediate reconstruction with DIEP flaps, one patient had a history of lumpectomy and underwent delayed partial breast reconstruction, three patients had delayed unilateral DIEP breast reconstruction with contralateral breast augmentation, and two patients had previous augmentations that were revised. All patients examined in this review tolerated the procedures well and had clinically viable flaps along with superior aesthetic outcomes. Conclusions:. This technique can be applied to various clinical conditions, including immediate breast reconstruction, delayed breast reconstruction, and salvage for failed implant-based reconstruction, leading to optimal patient outcomes and satisfaction. Unilateral breast reconstruction with simultaneous contralateral autologous breast augmentation utilizing bilateral DIEP flaps is a surgical technique that more plastic surgeons should utilize.

Background:. Primary options for oromandibular reconstruction with osteocutaneous free flaps are the vascularized fibula and iliac crest. Complications of mandible reconstruction are not uncommon and include osteomyelitis, malunion, and osteoradionecrosis (ORN) after radiation therapy. The medial femoral condyle (MFC) free flap is an established salvage option for carpal reconstruction in hand surgery, frequently used for scaphoid nonunion and avascular necrosis. We hypothesize that the MFC flap can be utilized to restore blood supply and reverse the negative effects of radiotherapy in patients who require mandibular reconstruction due to ORN. Methods:. A retrospective chart review was conducted at Beaumont Health System, Royal Oak, for patients who underwent MFC free flap reconstruction for mandibular ORN between the years 2012 and 2018. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively gathered. Results:. A total of four patients were isolated. Four patients developed ORN after resection of squamous cell carcinoma and adjuvant radiotherapy. No patients experienced donor site deficits. Revisions after MFC reconstruction were dependent on individual aesthetics and involvement of neighboring tissue. All four patients continue to be followed with no current issues to the osseous component of the MFC flap. Conclusion:. Utilization of the MFC periosteal flap is a viable option in selected patients to salvage nonunion/resorption of mandible reconstruction and ORN of the mandible. Our experience found that the MFC is able to provide pain resolution and healing of intraoral soft tissue defects, and may halt the progression of ORN of the mandible.

Background:. The medial canthus represents the medial confluence of the upper and lower eyelid margins and plays an integral role in the lacrimal duct system. Various flaps have been utilized for the reconstruction of the lower eyelid in the medial canthal region. Our institution primarily utilizes the paramedian forehead flap for the reconstruction of medial canthus defects. Our study looked to evaluate the work of a single plastic surgeon and identify their postoperative outcomes. Methods:. A retrospective chart review was conducted at Beaumont Health System, Royal Oak, for patients who underwent medial canthal repair by the lead surgeon between the years 2014 and 2018. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively gathered and analyzed. Results:. A total of five patients were isolated. Patients underwent paramedian forehead flap medial canthal repair by the lead surgeon and were found to tolerate the procedure well. All patients had clinically viable flaps with aesthetically pleasing results. Conclusions:. Utilization of the paramedian forehead flap leads to successful medial canthal repair with adequate coverage. Although the paramedian forehead flap requires three stages to complete, the procedure leaves patients with aesthetically pleasing results. In addition, the paramedian forehead flap has limited cases of ectropion. With the right expertise and patient population, the paramedian forehead flap can be highly successful in the repair of medial canthal defects.

Background:. Ballistic facial injuries are rare, with most trauma centers reporting 1–20 cases annually. These patients present significant management challenges to reconstructive surgeons, not only due to their rarity but also due to the complex decision-making process that is involved. The aim of this study was to review our experience with the application of craniofacial microsurgery in management of facial gunshot wounds. Methods:. A retrospective review of a single-surgeon experience at a level I trauma center from 2011 to 2020 for patients sustaining self-inflicted gunshot wounds to the face requiring microsurgical reconstruction was performed. Outcomes included reconstructive techniques, free flap type and indication, airway evolution, feeding modality, respective timing of interventions, and complications. Results:. Between 2012 and 2021, 13 patients presented for microsurgical reconstruction at our institution for gunshot wounds to the face. The majority (90%) of patients were men, and the average age at time of injury was 26. The median from the time of injury to first free flap was 93 days. Thirteen patients represented 23 free flaps. On average, patients underwent a total of two free flaps. The most common microsurgical flap was the fibula flap (14) followed by the radial forearm flap (6). Conclusions:. Based on our findings, we describe a novel algorithm for function restoration and aesthetic revisions based on injury location. Underlying principles include avoiding early use of reconstruction plates, establishing occlusion early, and aligning bony segments using external fixation. An algorithmic approach to these injuries can improve outcomes.

Background:. May-Thurner syndrome (MTS) is an anatomical variant that results in compression of the left common iliac vein by the right common iliac artery. Although often asymptomatic, lower extremity swelling/edema, deep venous thrombosis, post-thrombotic syndrome, and eventual lymphedema (due to long-standing venous obstruction) can develop. The clinical management of patients presenting for lymphedema surgery with concomitant or undiagnosed MTS is not well described. Methods:. This review investigates two patients who were evaluated for unilateral lower extremity lymphedema, both of whom were subsequently diagnosed with MTS. Standard imaging (including lymphoscintigraphy, indocyanine green lymphangiography, and magnetic resonance venography) were performed to identify proximal venous obstruction. Treatment was accomplished using vascular surgical management, including stenting of the iliac vein before lymphedema reconstruction with vascularized lymph node transfer and multiple lymphovenous bypass. Results:. Both patients we examined in this review had improvement of lymphedema with vascular surgical management. Literature review reveals that MTS has an incidence as high as 20% in the population, although commonly unidentified due to lack of symptomatology. Conclusions:. There are no studies documenting the incidence of MTS in patients referred for lymphedema surgical management. Routine studies should be obtained to screen for proximal venous obstruction in patients presenting for surgical management of lower extremity lymphedema. Additional research is needed regarding the approach to managing patients with both MTS and lymphedema. Careful observational and prospective studies may elucidate the appropriate time interval between venous stenting and lymphedema microsurgical reconstruction.

Summary:. Patients with gunshot wounds to the face have massive soft tissue and bony damage from projectile and blast injuries. They often require multiple, staged reconstructive surgeries with cross-facial nerve grafting and free muscle flap for re-establishment of facial expression. Injury to or total loss of the facial nerve and branches can result in loss of function of the orbicularis oculi muscle, which leads to the loss of protective mechanisms of eyelid function and blink reflex. The purpose of this article is to provide a literature review and discussion of eyelid reanimation after facial paralysis and to discuss our surgical technique with free platysma muscle grafts of the eyelid. The patient is a 45-year-old man with a history of a gunshot wound to the right face. He underwent multiple reconstructive surgeries in the past, and in preparation for eyelid reanimation, he underwent a cross-facial nerve graft from the left temporal branch to the right eyelid. At initial postoperative evaluation, the patient was able to close his right eye with minimal lagophthalmos, and at 3-month follow-up, he exhibited stronger blinking reflex. This case demonstrates that a free platysma graft with direct neurotization with cross-facial nerve graft fascicles can be utilized for restoration of spontaneous eyelid animation. However, there may be failure of neurotization and inability of the spontaneous blink reflex to be present. Despite these limitations, we still recommend the utilization of free platysma graft to provide upper eyelid reanimation through cross-facial nerve graft.

Background:. Crouzon syndrome (CS) is a rare form of craniosynostosis characterized by bicoronal craniosynostosis and facial features including severe midface hypoplasia, exophthalmos, and hypertelorism. Most patients are diagnosed and treated in early childhood; however, there are a few reports of Crouzon patients treated as adults with monobloc facial advancement. To our knowledge, this is the first report of a family affected by CS treated sequentially with monobloc facial advancement using combined internal and external distraction osteogenesis (rigid external distraction). Methods:. We present a family from Jamaica (mother 47 years old, older daughter 17, and younger daughter 9) who were brought to our craniofacial clinic with stigmata of CS and no previous surgical intervention. Patients had bicoronal craniosynostosis and exorbitism, with varying severity, sequelae, and comorbidities. Here, we delineate our technique of monobloc distraction osteogenesis with advancement osteotomies using dual “push–pull” method, elevation of a split anteriorly based tunneled pericranial flap to seal off nasal cavity, and internal and external distraction. Results:. Our patients had favorable outcomes after reconstruction to reduce ocular symptoms and improve midface hypoplasia and aesthetic appearance. No intracranial injury, hardware/soft-tissue infection, hardware failure, or (new) loss of vision were encountered in 10 months follow-up. Conclusions:. Dual “push–pull” monobloc distraction is safe and effective for a range of ages in CS; it allows good vector control, accommodates patient compliance, and allows early rigid external distraction device removal with sufficient time for consolidation. This surgery can be performed with highly satisfactory results.

Nuclear pore complexes (NPCs) are multiprotein channels connecting the nucleus with the cytoplasm. NPCs have been shown to have tissue-specific composition, suggesting that their function can be specialized. However, the physiological roles of NPC composition changes and their impacts on cellular processes remain unclear. Here we show that the addition of the Nup210 nucleoporin to NPCs during myoblast differentiation results in assembly of an Mef2C transcriptional complex required for efficient expression of muscle structural genes and microRNAs. We show that this NPC-localized complex is essential for muscle growth, myofiber maturation, and muscle cell survival and that alterations in its activity result in muscle degeneration. Our findings suggest that NPCs regulate the activity of functional gene groups by acting as scaffolds that promote the local assembly of tissue-specific transcription complexes and show how nuclear pore composition changes can be exploited to regulate gene expression at the nuclear periphery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.

Intracellular iron homeostasis is critical for survival and proliferation. Lipocalin 24p3 is an iron-trafficking protein that binds iron through association with a bacterial siderophore, such as enterobactin, or a postulated mammalian siderophore. Here, we show that the iron-binding moiety of the 24p3-associated mammalian siderophore is 2,5-dihydroxybenzoic acid (2,5-DHBA), which is similar to 2,3-DHBA, the iron-binding component of enterobactin. We find that the murine enzyme responsible for 2,5-DHBA synthesis, BDH2, is the homolog of bacterial EntA, which catalyzes 2,3-DHBA production during enterobactin biosynthesis. RNA interference-mediated knockdown of BDH2 results in siderophore depletion. Mammalian cells lacking the siderophore accumulate abnormally high amounts of cytoplasmic iron, resulting in elevated levels of reactive oxygen species, whereas the mitochondria are iron deficient. Siderophore-depleted mammalian cells and zebrafish embryos fail to synthesize heme, an iron-dependent mitochondrial process. Our results reveal features of intracellular iron homeostasis that are conserved from bacteria through humans., (Copyright 2010 Elsevier Inc. All rights reserved.)

In a recent issue of Molecular Cell, Deato et al. (2008) elucidate the basis by which the muscle-specific activator MyoD recruits the core transcription machinery to the promoter of a key regulatory gene involved in myogenic differentiation.

TATA-box-binding protein (TBP)-related factor 3, TRF3 (also called TBP2), is a vertebrate-specific member of the TBP family that has a conserved carboxy-terminal region and DNA-binding domain virtually identical to that of TBP (ref. 1). TRF3 is highly expressed during embryonic development, and studies in zebrafish and Xenopus have shown that it is required for normal embryogenesis. Here we show that zebrafish embryos depleted of Trf3 exhibit multiple developmental defects and, in particular, fail to undergo haematopoiesis. Expression profiling for Trf3-dependent genes identified mespa, which encodes a transcription factor whose murine orthologue is required for mesoderm specification, and chromatin immunoprecipitation verified that Trf3 binds to the mespa promoter. Depletion of Mespa resulted in developmental and haematopoietic defects markedly similar to those induced by Trf3 depletion. Injection of mespa messenger RNA (mRNA) restored normal development to a Trf3-depleted embryo, indicating mespa is the single Trf3 target gene required for zebrafish embryogenesis. Zebrafish embryos depleted of Trf3 or Mespa also failed to express cdx4, a caudal-related gene required for haematopoiesis. Mespa binds to the cdx4 promoter, and epistasis analysis revealed an ordered trf3-mespa-cdx4 pathway. Thus, in zebrafish, commitment of mesoderm to the haematopoietic lineage occurs through a transcription factor pathway initiated by a TBP-related factor.