Network-Based Transcriptome Analysis Reveals FAM3C as a Novel Potential Biomarker for Glioblastoma.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencing and scRNA-sequencing), which were obtained from TCGA and GEO databases. By using the STRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next, Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3C­coregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patients but also gave a new insight into a potential resource for future GBM studies.

Shifts in Reduction Mammaplasty Surgical Volumes With the Emergence of a Global Pandemic.

INTRODUCTION: The onset of the COVID-19 pandemic resulted in significant changes to the surgical caseload for various surgery departments across the United States. As medical institutions prioritized resources for the expected increase in patient volumes due to the SARS-CoV-2 viral infection, surgical departments saw a decrease in nonemergent and elective surgical procedures. Reduction mammoplasties, which are largely covered by insurance, are among the elective procedures that provide significant revenue to the hospital. This expected decline in procedures suggests a potential decline in revenue provided by the plastic surgery department of a hospital. The purpose of this study was to analyze the loss of revenue experienced by a single academic medical institution due to changes in breast reduction mammoplasty volumes during the COVID-19 pandemic. METHODS: Upon institutional review board approval, using the Augusta University Medical Center's Financial Billing Data, 373 patients who underwent bilateral reduction mammoplasty were queried. A time horizon of March 2019 to February 2022 was used to determine the pre- and post-COVID case load and charges that were incurred. Statistical analysis to compare the prior 12 months and after 24 months of COVID was conducted using 2 samples of equal variance t test and F test confirming equal variance. RESULTS: There was a statistically significant increase in the number of reduction mammoplasties performed per month from the year before the onset of COVID-19 (March 2020) to the 2 years after (6.6-11.4 per month, P = 0.0024). There was a statistically significant increase in the per-month charges from the AU Health system for reduction mammoplasties for the same period ($31,780.92-$52,113.34 per month, P = 0.0054). Although there was an increase in per-month revenue from reduction mammoplasties, this increase failed to reach statistical significance ($7,059.95-$10,423.51 per month, P = 0.064). CONCLUSIONS: The plastic surgery department saw a statistically significant increase in reduction mammoplasty cases and subsequent charges in the post-COVID cohort. These findings suggest that the emergence of a nationwide pandemic did not necessarily lead to a decrease in the volume of nonemergent surgical cases despite an expected decrease in caseload due to the need to reallocate hospital resources. On the contrary, there was an increase in caseload suggesting that there may be other factors contributing to patients' pursuance of reduction mammoplasty post-COVID including convenience, resulting from time off due to pandemic, meeting insurance-covered reduction criteria, and projected recovery time.

Cutaneous Wound Healing and the Effects of Cannabidiol.

Cutaneous wounds, both acute and chronic, begin with loss of the integrity, and thus barrier function, of the skin. Surgery and trauma produce acute wounds. There are 22 million surgical procedures per year in the United States alone, based on data from the American College of Surgeons, resulting in a prevalence of 6.67%. Acute traumatic wounds requiring repair total 8 million per year, 2.42% or 24.2 per 1000. The cost of wound care is increasing; it approached USD 100 billion for just Medicare in 2018. This burden for wound care will continue to rise with population aging, the increase in metabolic syndrome, and more elective surgeries. To heal a wound, an orchestrated, evolutionarily conserved, and complex series of events involving cellular and molecular agents at the local and systemic levels are necessary. The principal factors of this important function include elements from the neurological, cardiovascular, immune, nutritional, and endocrine systems. The objectives of this review are to provide clinicians engaged in wound care and basic science researchers interested in wound healing with an updated synopsis from recent publications. We also present data from our primary investigations, testing the hypothesis that cannabidiol can alter cutaneous wound healing and documenting their effects in wild type (C57/BL6) and db/db mice (Type 2 Diabetes Mellitus, T2DM). The focus is on the potential roles of the endocannabinoid system, cannabidiol, and the important immune-regulatory wound cytokine IL-33, a member of the IL-1 family, and connective tissue growth factor, CTGF, due to their roles in both normal and abnormal wound healing. We found an initial delay in the rate of wound closure in B6 mice with CBD, but this difference disappeared with time. CBD decreased IL-33 + cells in B6 by 70% while nearly increasing CTGF + cells in db/db mice by two folds from 18.6% to 38.8% (p < 0.05) using a dorsal wound model. We review the current literature on normal and abnormal wound healing, and document effects of CBD in B6 and db/db dorsal cutaneous wounds. CBD may have some beneficial effects in diabetic wounds. We applied 6-mm circular punch to create standard size full-thickness dorsal wounds in B6 and db/db mice. The experimental group received CBD while the control group got only vehicle. The outcome measures were rate of wound closure, wound cells expressing IL-33 and CTGF, and ILC profiles. In B6, the initial rate of wound closure was slower but there was no delay in the time to final closure, and cells expressing IL-33 was significantly reduced. CTGF + cells were higher in db/bd wounds treated with CBD. These data support the potential use of CBD to improve diabetic cutaneous wound healing.

Herpes Simplex Virus 1 Small Noncoding RNAs 1 and 2 Activate the Herpesvirus Entry Mediator Promoter.

Herpes simplex virus 1 (HSV-1) latency-associated transcript (LAT) plays a significant role in efficient establishment of latency and reactivation. LAT has antiapoptotic activity and downregulates expression of components of the type I interferon pathway. LAT also specifically activates expression of the herpesvirus entry mediator (HVEM), one of seven known receptors used by HSV-1 for cell entry that is crucial for latency and reactivation. However, the mechanism by which LAT regulates HVEM expression is not known. LAT has two small noncoding RNAs (sncRNAs) that are not microRNAs (miRNAs), within its 1.5-kb stable transcript, which also have antiapoptotic activity. These sncRNAs may encode short peptides, but experimental evidence is lacking. Here, we demonstrate that these two sncRNAs control HVEM expression by activating its promoter. Both sncRNAs are required for wild-type (WT) levels of activation of HVEM, and sncRNA1 is more important in HVEM activation than sncRNA2. Disruption of a putative start codon in sncRNA1 and sncRNA2 sequences reduced HVEM promoter activity, suggesting that sncRNAs encode a protein. However, we did not detect peptide binding using two chromatin immunoprecipitation (ChIP) approaches, and a web-based algorithm predicts low probability that the putative peptides bind to DNA. In addition, computational modeling predicts that sncRNA molecules bind with high affinity to the HVEM promoter, and deletion of these binding sites to sncRNA1, sncRNA2, or both reduced HVEM promoter activity. Together, our data suggest that sncRNAs exert their function as RNA molecules, not as proteins, and we provide a model for the predicted binding affinities and binding sites of sncRNA1 and sncRNA2 in the HVEM promoter. IMPORTANCE HSV-1 causes recurrent ocular infections, which is the leading cause of corneal scarring and blindness. Corneal scarring is caused by the host immune response to repeated reactivation events. LAT functions by regulating latency and reactivation, in part by inhibiting apoptosis and activating HVEM expression. However, the mechanism used by LAT to control HVEM expression is unclear. Here, we demonstrate that two sncRNAs within the 1.5-kb LAT transcript activate HVEM expression by binding to two regions of its promoter. Interfering with these interactions may reduce latency and thereby eye disease associated with reactivation.

Blocking HSV-1 glycoprotein K binding to signal peptide peptidase reduces virus infectivity in vitro and in vivo.

HSV glycoprotein K (gK) is an essential herpes protein that contributes to enhancement of eye disease. We previously reported that gK binds to signal peptide peptidase (SPP) and that depletion of SPP reduces HSV-1 infectivity in vivo. To determine the therapeutic potential of blocking gK binding to SPP on virus infectivity and pathogenicity, we mapped the gK binding site for SPP to a 15mer peptide within the amino-terminus of gK. This 15mer peptide reduced infectivity of three different virus strains in vitro as determined by plaque assay, FACS, and RT-PCR. Similarly, the 15mer peptide reduced ocular virus replication in both BALB/c and C57BL/6 mice and also reduced levels of latency and exhaustion markers in infected mice when compared with control treated mice. Addition of the gK-15mer peptide also increased the survival of infected mice when compared with control mice. These results suggest that blocking gK binding to SPP using gK peptide may have therapeutic potential in treating HSV-1-associated infection.

Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection.

Ocular HSV-1 infection is a major cause of eye disease and innate and adaptive immunity both play a role in protection and pathology associated with ocular infection. Previously we have shown that M1-type macrophages are the major and earliest infiltrates into the cornea of infected mice. We also showed that HSV-1 infectivity in the presence and absence of M2-macrophages was similar to wild-type (WT) control mice. However, it is not clear whether the absence of M1 macrophages plays a role in protection and disease in HSV-1 infected mice. To explore the role of M1 macrophages in HSV-1 infection, we used mice lacking M1 activation (M1-/- mice). Our results showed that macrophages from M1-/- mice were more susceptible to HSV-1 infection in vitro than were macrophages from WT mice. M1-/- mice were highly susceptible to ocular infection with virulent HSV-1 strain McKrae, while WT mice were refractory to infection. In addition, M1-/- mice had higher virus titers in the eyes than did WT mice. Adoptive transfer of M1 macrophages from WT mice to M1-/- mice reduced death and rescued virus replication in the eyes of infected mice. Infection of M1-/- mice with avirulent HSV-1 strain KOS also increased ocular virus replication and eye disease but did not affect latency-reactivation seen in WT control mice. Severity of virus replication and eye disease correlated with significantly higher inflammatory responses leading to a cytokine storm in the eyes of M1-/- infected mice that was not seen in WT mice. Thus, for the first time, our study illustrates the importance of M1 macrophages specifically in primary HSV-1 infection, eye disease, and survival but not in latency-reactivation.

Sexual Dimorphism in the Polarization of Cardiac ILCs through Elabela.

Elabela is a component of the apelinergic system and may exert a cardioprotective role by regulating the innate immune responses. Innate lymphoid cells (ILCs) have a significant role in initiating and progressing immune-inflammatory responses. While ILCs have been intensively investigated during the last decade, little is known about their relationship with the apelinergic system and their cardiac diversity in a gender-based paradigm. In this study, we investigated the polarization of cardiac ILCs by Elabela in males versus females in a mouse model. Using flow cytometry and immunohistochemistry analyses, we showed a potential interplay between Elabela and cardiac ILCs and whether such interactions depend on sexual dimorphism. Our findings showed, for the first time, that Elabela is expressed by cardiac ILCs, and its expression is higher in females' ILC class 3 (ILC3s) compared to males. Females had higher frequencies of ILC1s, and Elabela was able to suppress T-cell activation and the expression of co-stimulatory CD28 in a mixed lymphocyte reaction assay (MLR). In conclusion, our results suggest, for the first time, a protective role for Elabela through its interplay with ILCs and that it can be used as an immunotherapeutic target in the treatment of cardiovascular disorders in a gender-based fashion.

Suppression of CD80 Expression by ICP22 Affects Herpes Simplex Virus Type 1 Replication and CD8+IFN-γ+ Infiltrates in the Eyes of Infected Mice but Not Latency Reactivation.

Previously, we reported that herpes simplex virus type 1 (HSV-1) ICP22 binds to the CD80 promoter and suppresses its expression in vitro and in vivo. To better understand the impact of ICP22 binding to CD80 on HSV-1 infectivity and pathogenicity, we mapped the region of ICP22 required to bind the CD80 promoter to a 40-amino-acid (aa) region of ICP22. We constructed a recombinant HSV-1 expressing a truncated form of ICP22 that lacks these 40 aa, which does not bind to the CD80 promoter (KOS-ICP22Δ40) and retains the ability to replicate efficiently in rabbit skin cells, in contrast to ICP22-null virus. The replication of this recombinant virus in vitro and in vivo was higher than that of the ICP22-null virus, but virus replication kinetics were lower than those of the wild-type (WT) control virus. Similar to ICP22-null virus, the KOS-ICP22Δ40 mutant virus increased CD80 expression in dendritic cells (DCs) and interferon gamma (IFN-γ) expression in CD8+ T cells but not CD4+ T cells in infected mouse corneas. In contrast to the significantly reduced virus replication in the eyes of ocularly infected mice, the levels of latency reactivation were similar between KOS-ICP22Δ40 virus and WT virus. Thus, blocking ICP22 binding to the CD80 promoter using a recombinant virus expressing a truncated ICP22 that lacks CD80 promoter binding appears to reduce virus replication and enhance CD8+IFN-γ+ infiltrates in corneas of infected mice, with no effect on latency reactivation. IMPORTANCE Direct binding of HSV-1 ICP22 to the CD80 promoter downregulates the expression of the costimulatory molecule CD80 but not CD86. In this study, we fine mapped the region of ICP22 required for binding to the CD80 promoter and constructed a recombinant virus containing a deletion in ICP22 that failed to bind to the CD80 promoter. This recombinant virus replicated less efficiently in vitro and in vivo than did the WT control virus, although CD80-expressing CD11c+ cells and IFN-γ-expressing CD8+ T cells were increased. Interestingly, the levels of latency and reactivation in the two viruses were similar despite lower virus replication in the eyes of infected mice. Therefore, blocking the interaction of ICP22 with the CD80 promoter could be used to temper the immune response.

White-Eyed Orbital Blowout Fracture With Oculocardiac Reflex Secondary to Extraocular Entrapment in a Pediatric Patient.

White-eyed orbital blowout fractures in the pediatric population can present with acute onset diplopia, ophthalmalgia, and abnormal duction. These findings are attributed to the tendency of younger bone to break and reapproximate owing to greater elasticity. This phenomenon, commonly referred to as the greenstick fracture, increases the risk of entrapment of surrounding soft tissue structures in orbital floor fractures. Further concern arises in the presence of an oculocardiac reflex, which requires urgent intervention to prevent serious bradycardia. Prolonged entrapment can go unnoticed and result in irreversible ischemic damage to entrapped tissues. This case discusses the presentation 16-year-old female who sustained a left sided, white-eyed blowout fracture from a face-first ground level fall. On admission, she displayed restrictive strabismus and mild periorbital edema around the left eye. Vertical gaze was restricted when looking inferiorly on the affected side. With sustained upward gaze, her heart rate decreased from 99 to 81 beats per minute. High-resolution non-contrast computed tomography scans of the head showed entrapment of the inferior rectus muscle and periorbital fat. Liberation of entrapped tissues with reduction of bony segments was performed urgently, utilizing a MEDPOR® Titan 3D orbital floor plate and secured with two screws. The patient had an uneventful postoperative period and showed considerable improvements in periorbital edema, duction, and ophthalmalgia on the affected side. In addition, the oculocardiac reflex could no longer be elicited on prolonged upward gaze. Mild and improving paresthesia was noted in the maxillary distribution of the left trigeminal nerve. Sensory deficits like this are the result of fracture communication with the infraorbital canal, which may cause irritation of the infraorbital nerve responsible for sensation by the maxillary division. By postoperative week 7, she had complete resolution of periorbital edema, indiscernible duction abnormalities, and complete healing of surgical incision sites, and an oculocardiac reflex could not be elicited.

Expression of Murine CD80 by Herpes Simplex Virus 1 in Place of Latency-Associated Transcript (LAT) Can Compensate for Latency Reactivation and Anti-apoptotic Functions of LAT.

High rates of wild-type (WT) herpes simplex virus 1 (HSV-1) latency reactivation depend on the anti-apoptotic activities of latency-associated transcript (LAT). Replacing LAT with the baculovirus inhibitor of apoptosis protein (cpIAP) or cellular FLIP (FLICE-like inhibitory protein) gene restored the WT latency reactivation phenotype to that of a LAT-minus [LAT(-)] virus, while similar recombinant viruses expressing interleukin-4 (IL-4) or interferon gamma (IFN-γ) did not. However, HSV-1 recombinant virus expressing cpIAP did not restore all LAT functions. Recently, we reported that a similar recombinant virus expressing CD80 in place of LAT had higher latency reactivation than a LAT-null virus. The present study was designed to determine if this CD80-expressing recombinant virus can restore all LAT functions as observed with WT virus. Our results suggest that overexpression of CD80 fully rescues LAT function in latency reactivation, apoptosis, and immune exhaustion, suggesting that LAT and CD80 have multiple overlapping functions.IMPORTANCE Recurring ocular infections caused by HSV-1 can cause corneal scarring and blindness. A major function of the HSV-1 latency-associated transcript (LAT) is to establish high levels of latency and reactivation, thus contributing to the development of eye disease. Here, we show that the host CD80 T cell costimulatory molecule functions similarly to LAT and can restore the ability of LAT to establish latency, reactivation, and immune exhaustion as well as induce the expression of caspase 3, caspase 8, caspase 9, and Bcl2. Our results suggest that, in contrast to several other previously tested genes, CD80-expressing virus can completely compensate for all known and tested LAT functions.

Aesthetic Concepts and Interdisciplinary Approach in a Patient With Bilateral Cleft Lip and Palate and Missing Premaxilla: A Case Report.

The smile is an important part of the individual's facial expression, it allows the communication of emotions and ideas. However, its aesthetics can be severely compromised in patients with cleft lip and palate due to multiple missing, malformed and malposed teeth, abnormal soft tissue morphology, upper lip scar tissue, and altered anatomy in the lower third of the face. This clinical case reports the interdisciplinary treatment approach of a young male patient with complete bilateral cleft lip and palate and missing premaxilla. Prosthodontic rehabilitation included a zirconia-based fixed dental prosthesis, with pink porcelain to camouflage the bony defect and restore the facial and dental aesthetics. Maxillary second premolars received lithium disilicate crowns to obtain a more harmonious smile line and adequate occlusion. A resin-bonded fixed partial denture restored a missing mandibular central incisor. Tooth proportions, gingival contours and facial ratios routinely used in noncleft patients, were used to achieve a consonant smile. The final restorations satisfied the patient's expectations, restored an aesthetically pleasant smile, and provided an adequate occlusion.

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.

Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.

Cannabinoids as a Potential New and Novel Treatment for Melanoma: A Pilot Study in a Murine Model.

BACKGROUND: Malignant melanoma is a complex malignancy with significant morbidity and mortality. The incidence continues to rise, and despite advances in treatment, the prognosis is poor. Thus, it is necessary to develop novel strategies to treat this aggressive cancer. Synthetic cannabinoids have been implicated in inhibiting cancer cell proliferation, reducing tumor growth, and reducing metastasis. We developed a unique study focusing on the effects of treatment with a cannabinoid derivative on malignant melanoma tumors in a murine model. METHODS: Murine B16F10 melanoma tumors were established subcutaneously in C57BL/6 mice. Mice were then treated with intraperitoneal injections of vehicle twice per week (control-group 1, n = 6), Cisplatin 5 mg/kg/wk (group 2; n = 6), and Cannabidiol (CBD) 5 mg/kg twice per week (group 3; n = 6). Tumors were measured and volume calculated as (4π/3) × (width/2)2 × (length/2). Tumor size and survival curves were measured. Results were compared using a one-way ANOVA with multiple comparison test. RESULTS: A significant decrease in tumor size was detected in mice treated with CBD when compared with the control group (P = 0.01). The survival curve of melanoma tumors treated with CBD increased when compared with the control group and was statistically significant (P = 0.04). The growth curve and survival curve of melanoma tumors treated with Cisplatin were significantly decreased and increased, respectively, when compared with the control and CBD-treated groups. Mice treated with Cisplatin demonstrated the longest survival time, but the quality of life and movement of CBD-treated mice were observed to be better. CONCLUSIONS: We demonstrate a potential beneficial therapeutic effect of cannabinoids, which could influence the course of melanoma in a murine model. Increased survival and less tumorgenicity are novel findings that should guide research to better understand the mechanisms by which cannabinoids could be utilized as adjunctive treatment of cancer, specifically melanoma. Further studies are necessary to evaluate this potentially new and novel treatment of malignant melanoma.

Whole Body Vibration-Induced Omental Macrophage Polarization and Fecal Microbiome Modification in a Murine Model.

Human nutrient metabolism, developed millions of years ago, is anachronistic. Adaptive features that offered survival advantages are now great liabilities. The current dietary pattern, coupled with massively reduced physical activities, causes an epidemic of obesity and chronic metabolic diseases, such as type 2 diabetes mellitus. Chronic inflammation is a major contributing factor to the initiation and progression of most metabolic and cardiovascular diseases. Among all components of an innate immune system, due to their dual roles as phagocytic as well as antigen-presenting cells, macrophages play an important role in the regulation of inflammatory responses, affecting the body's microenvironment and homeostasis. Earlier studies have established the beneficial, anti-inflammatory effects of whole body vibration (WBV) as a partial exercise mimetic, including reversing the effects of glucose intolerance and hepatic steatosis. Here for the first time, we describe potential mechanisms by which WBV may improve metabolic status and ameliorate the adverse consequences through macrophage polarization and altering the fecal microbiome.

Venous Thromboembolism Incidence After Craniofacial Surgery.

INTRODUCTION: Current protocols for venous thromboembolism (VTE) prophylaxis after craniofacial surgery (CFS) vary widely with substantial disagreements in both indications and managements. An evidence-based approach to this issue requires the following: the incidence of postoperative VTE, comorbidities associated with coagulopathy, risk reduction after VTE prophylaxis, and complications attributable to prophylaxis. This study addresses the first two. DESIGN: Retrospective cross-sectional study. METHODS: Discharge data from 64,170 patients undergoing CFS between 2008 and 2013 extracted from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample were analyzed. The outcome measures extracted were: deep venous thrombosis, pulmonary embolism, demographic data, common comorbidities, length of stay, total cost, and discharge outcome. RESULTS: Diagnoses of deep venous thrombosis or pulmonary embolism, collectively classified as VTE, were observed in 355 (0.55%) of 64,170 patients discharged after CFS. Other surgeries exhibited a VTE rate of 1.17%. Men exhibited nearly double the incidence of VTE relative to women (0.69% compared with 0.37% respectively, P < 0.001), and the risk factors of adulthood, advanced age, cardiovascular disease, obesity, and malignancy were associated with increased VTE incidence with odds ratios of 9.93, 3.66, 1.80, 2.02, and 2.02, respectively (P < 0.005). Tobacco use did not exhibit any significant association (odds ratio, 0.94; P = 0.679). Afflicted patients experienced 4.60 times longer hospital stays averaging 23.8 days (95% confidence interval, 21.4-26.2; P < 0.001) compared the average of 5.2 days experienced by CFS patients without VTE. They incurred an average cost of US $298,228 (95% confidence interval, 262,726 to 333,731; P < 0.001) which was 4.17 times the US $72,376 expense of treating other CFS patients. The likelihood for a CFS patient to experience a poor outcome at the time of discharge was 54.6% higher after VTE. CONCLUSIONS: The risk of postoperative VTE after CFS is significantly increased in adults, patients with advanced age, cardiovascular disease, obesity, and malignancy. However even in those high-risk cases, postoperative VTE incidence remains relatively low after CFS. These findings in conjunction with further study regarding the risk associated with the addition of VTE chemoprophylaxis compared against mechanical VTE prophylaxis, such as sequential pneumatic compression stockings, may determine whether routine use of VTE chemoprophylaxis is appropriate.

Aesthetic Unit Boundary Approach to Large Fibroadenoma Resection.

BACKGROUND: Fibroadenomas are the most common benign breast tumors in adolescents. Surgical excision is indicated when the tumor becomes large or symptomatic. Multiple approaches have been described. However, unsightly scars, excess skin, and breast asymmetry are common challenges after tumor resection. The aims of our study were to describe a concentric circumareolar approach combining the round-block technique and geometric principles in the management of large benign breast tumors. METHODS: This was a retrospective review of pediatric patients who have undergone excision of large fibroadenoma with concentric circumareolar approach from June 2007 to May 2017. Preoperatively, the excess skin that needed to be resected was marked based on geometric principles. Under general anesthesia, circumareolar deepithelialization of the excess skin and tumor resection were performed. Purse-string suture technique was used to achieve the proper nipple-areola complex size. RESULTS: Satisfactory breast symmetry and minimal scarring were achieved in all 6 patients. One patient developed a small seroma, which resolved spontaneously without intervention. CONCLUSIONS: Concentric circumareolar approach can be used to resect large benign breast tumors while concealing the scar along the aesthetic unit boundary of the breast. The cosmetic outcome and recovery were promising. The approach is simple to execute, highly reproducible, and less dependent on intuition.

Thyroxine Exposure Effects on the Cranial Base.

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine, in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to micro-computed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.

Effects of thyroxine exposure on the Twist 1 +/- phenotype: A test of gene-environment interaction modeling for craniosynostosis.

BACKGROUND: Craniosynostosis, the premature fusion of one or more of the cranial sutures, is estimated to occur in 1:1800 to 2500 births. Genetic murine models of craniosynostosis exist, but often imperfectly model human patients. Case, cohort, and surveillance studies have identified excess thyroid hormone as an agent that can either cause or exacerbate human cases of craniosynostosis. METHODS: Here we investigate the influence of in utero and in vitro exogenous thyroid hormone exposure on a murine model of craniosynostosis, Twist 1 +/-. RESULTS: By 15 days post-natal, there was evidence of coronal suture fusion in the Twist 1 +/- model, regardless of exposure. With the exception of craniofacial width, there were no significant effects of exposure; however, the Twist 1 +/- phenotype was significantly different from the wild-type control. Twist 1 +/- cranial suture cells did not respond to thyroxine treatment as measured by proliferation, osteogenic differentiation, and gene expression of osteogenic markers. However, treatment of these cells did result in modulation of thyroid associated gene expression. CONCLUSION: Our findings suggest the phenotypic effects of the genetic mutation largely outweighed the effects of thyroxine exposure in the Twist 1 +/- model. These results highlight difficultly in experimentally modeling gene-environment interactions for craniosynostotic phenotypes. Birth Defects Research (Part A) 106:803-813, 2016. © 2016 Wiley Periodicals, Inc.

Innate lymphoid cells: a paradigm for low SSI in cleft lip repair.

BACKGROUND: Cleft lip and palate reconstructions demonstrate significantly lower surgical site infection rates compared with clean-contaminated cases, prompting investigation into the pathophysiology causing this discrepancy. Recent studies have identified a new group of innate lymphocytes called innate lymphoid cells (ILCs), located in barrier surfaces of the skin, airways, and intestine. Our objectives were to explore for the first time the presence of ILCs in the vermillion of neonates and young children undergoing cleft lip reconstruction and characterize their composition by measuring the three classes of ILCs. MATERIALS AND METHODS: Lip tissue samples were collected from 13 subjects undergoing vermillion resection during cleft lip reconstructive surgery. Preparative, transmission electron microscopy, and analytical flow cytometry were performed. The functionality of ILCs was tested in terms of their capacity to produce type 1 (IFN-γ/TNF-α), type 2 (IL-5/IL-13), and type 3 (IL-17/IL-22) cytokines. Data were analyzed using Student t test or the analysis of variance to establish significance (P < 0.05) among groups for all other data. RESULTS: All three classes of ILCs were detected and visualized in the tissue samples. In all samples, the level of ILC2 subset was significantly higher than the other two ILC subsets (P < 0.01), followed by the ILC1 subset, which was present in significantly higher levels than the ILC3 subset (P < 0.05). CONCLUSIONS: Our data place ILCs for the first time in the interface of oral mucosal immunity, tissue microenvironment, and homeostasis during and after tissue development, possibly explaining lower infection rates in cleft lip or palate reconstructions.

Tissue Dynamics: Lessons Learned From Sutural Morphogenesis and Cancer Growth.

UNLABELLED: Why are cranial sutures the way they are? How do cancers grow? Merging physics and mathematics with biology, we develop equations describing these complex adaptive systems, to which all biological entities belong, calling them laws of tissue dynamics:Where t is time, E is energy, M is body mass, X is the biological characteristic of interest, C is a constant, a is an exponent.(1) is based on conservation of matter: for any given tissue, materials in must equal to materials out +/- assimilated or degraded. (2) is based on energy conservation. All living systems require energy, without which life becomes impossible. Equation (2) is a power spectrum. OBJECTIVES: This study aimed to introduce the laws of tissue dynamics and to illustrate them using observations from craniofacial and cancer growth. METHODS: We use cranial sutures as a model system to test Equation (1), we also measure the in vitro growth rate of normal murine liver and spleen cells, comparing them to B16F10 melanoma cells. We show the increase in compound growth rate and energetic requirement of malignant versus normal cells as partial proof of Equation (2). RESULTS: The constant width and wavy form of cranial sutures are the inevitable results of repeated iteration from coupling of growth and stress. The compound growth rate of B10F16 melanoma cells exceeds that of normal cells by 1.0 to 1.5%, whereas their glucose uptake is equal to 3.6 billion glucose molecules/cell per minute. SUMMARY: Living things are complex adaptive systems, thus a different way of thinking and investigating, going beyond the current reductive approach, is required.