Faculty Bibliography

OBJECTIVES: Vitiligo commonly presents in children, with half of all cases developing before 20 years of age. Although studies have characterized differences between pediatric and adult vitiligo, little is known about vitiligo presenting in early childhood. The purpose of this study was to compare clinical features of early-onset (<3 years old) and later-onset (3-18 years old) childhood vitiligo. METHODS: This retrospective case series examined patients given a diagnosis of vitiligo in a pediatric dermatology practice at an academic medical center from 1990 to 2014. Characteristics of the early- and later-onset groups were compared by chi2 and t test for categorical and continuous variables, respectively. RESULTS: Of the 208 children in the study, 31 had early-onset and 177 had later-onset disease. Early-onset vitiligo was associated with higher percentages of body surface area involvement and increased rates of disease progression during an average 1.9 years of follow-up. There were no significant differences between the 2 groups in repigmentation, vitiligo type, halo nevi, gender ratio, or personal and family history of autoimmune diseases. LIMITATIONS: This was a retrospective, single-institution study. CONCLUSION: Patients given a diagnosis of vitiligo at younger ages tend to have more extensive and progressive disease.

Traumatic brain injury (TBI) remains one of the most prevalent forms of morbidity among Veterans and Service Members, particularly for those engaged in the conflicts in Iraq and Afghanistan. Neuroimaging has been considered a potentially useful diagnostic and prognostic tool across the spectrum of TBI generally, but may have particular importance in military populations where the diagnosis of mild TBI is particularly challenging, given the frequent lack of documentation on the nature of the injuries and mixed etiologies, and highly comorbid with other disorders such as post-traumatic stress disorder, depression, and substance misuse. Imaging has also been employed in attempts to understand better the potential late effects of trauma and to evaluate the effects of promising therapeutic interventions. This review surveys the use of structural and functional neuroimaging techniques utilized in military studies published to date, including the utilization of quantitative fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), volumetric analysis, diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), positron emission tomography (PET), magnetoencephalography (MEG), task-based and resting state functional MRI (fMRI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). The importance of quality assurance testing in current and future research is also highlighted. Current challenges and limitations of each technique are outlined, and future directions are discussed.

Reconstruction of large maxillary and mandibular defects following ablative surgery has posed a challenge to the head and neck surgeon due to the high functional and esthetic demands requiring precise three-dimensional reconstruction. Previous issues with maxillofacial reconstruction have included poor facial contour, unfavorable orthognathic relationships, and inability to provide adequate dental rehabilitation. The advent of the fibula flap along with (3D) facial analysis and virtual surgical simulation has revolutionized surgical interventions of the head and neck. Recent reports on the long-term success of dental implants in fibula reconstructions have made dental rehabilitation a reality. However, the loading and restoration of these implants are usually delayed prior to final prosthodontic rehabilitation leading to adverse functional, esthetic and psychological effects. Rohner et al. has documented the success of a two-stage surgery of fibula harvest and dental implant placement (Stage 1) followed by ablative surgery, inset and immediate loading with a dental prosthesis (Stage 2)⁽²⁾; this procedure is a two stage process that involves a 10-week delay between each surgery and will leave the patient edentulous. At our institution, computer-aided surgery and CAD/CAM technologies have enabled us to virtually plan complex surgery and have afforded our group the opportunity of providing a "Jaw in a Day '¹ This technique is a one-stage complete surgery including ablation, free flap, implant, and prosthetic reconstruction. A retrospective chart review was conducted for all patients who received immediate dental implants with a dental prosthesis in a fibular free flap following mandibular resection due to benign tumors. "Jaw in a Day 'procedures were completed at two of our affiliated hospitals (Bellevue Hospital Center and NYU Langone Medical Center) from January 2011 to January 2015. We looked at success rate of flaps, implants, and prostheses. We also looked at primary and long-term complications. Of the 8 patients who underwent the above procedure, a total of 35 immediate implants were placed along with a fixed prosthesis. Patients received maxillary/mandibular resection, fibula free flap reconstruction with immediate implant and dental prosthesis placement. All patients treated were diagnosed with benign mandibular (7) and maxillary (1) tumors, including ameloblastoma (6), odontogenic myxoma (1), and AV malformation (1). Of the 35 implants placed, 1 implant failed and was removed. The cumulative survival of fibular-free flaps was 100%. The cumulative implant success rate was 97%. Complications included soft tissue perimplantitis (2), plate exposure (2), and (1) prosthesis that did not adequately fit. The followup of the 8 patients was from January 2011 to January 2015. Single-stage maxillofacial reconstruction with virtual surgical planning has greatly impacted the field of maxillofacial reconstruction allowing for precision and accuracy while improving patient's function and quality of life. The above study shows its feasibility and low complication rates. Immediate implant and dental prosthesis placement has helped reduce the time for dental prosthetic rehabilitation and avoid the traditional 3- to 6-month delay period. Reconstruction with a MVFFF and immediate dental rehabilitation has revolutionized the treatment of benign tumor following ablative surgery

BACKGROUND: Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention (PCI) is not well defined. We aimed to analyze the prevalence and characteristics of patients undergoing PCI with previously unrecognized prediabetes, diabetes and metabolic syndrome. METHODS: Data were collected from 740 patients undergoing elective PCI between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Hemoglobin A1c (A1c >/= 6.5% for DM, A1c 5.7-6.4% for prediabetes). A modified definition was used for metabolic syndrome [3 or more of the following criteria: body mass index (BMI) >/=30 kg/m2; triglycerides >/= 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure >/= 130 mmHg and/or diastolic >/= 85 mmHg; A1c >/= 5.7% or on therapy]. RESULTS: Mean age was 67 years, median BMI was 28.2 kg/m2 , and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of PCI. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM). CONCLUSION: Among patients undergoing elective PCI, a substantial number were identified with new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors

SCOPE: The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long-chain n-3 polyunsaturated fatty acids (PUFAs) have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabolic pathways whose deregulation has been associated with CVD risk. In this work we investigated whether miRNA expression was regulated by docosahexanoic acid, conjugated linoleic acid and cholesterol in Caco-2 cells. RESULTS: Among the modulated miRNAs, miR-107 was differentially expressed by all treatments and this modulation was independent of its hosting gene, panthothenate kinase 1, possibly through its own promoter, which contains binding sites for metabolically relevant transcription factors. Among the putative target genes of miR-107, we found some genes with key roles in circadian rhythm. Specifically, we demonstrated that binding of miR-107 to the circadian locomotor output cycles kaput gene results in the deregulation of the circadian rhythm of the cells. CONCLUSION: Since chronodisruption has been linked to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and CVD, our findings suggest that miR-107 could represent a new approach for pharmacological treatment of these diseases.

With the advent of the microvascular fibula free flap (MVFFF), maxillofacial reconstruction following ablative surgery has been a viable solution for patients with large maxillary or mandibular defects. Furthermore, total maxillofacial reconstruction in a two-stage process, where the fibula is harvested and dental implants placed (Stage I) followed by ablative surgery, inset and immediate loading with a dental prosthesis (Stage 2) has been well documented.1 This procedure, however, requires two separate surgical procedures and a delay of at least 10 weeks between each stage where the patient is often left partially or completely edentulous. The incorporation of computer-aided surgical simulation (CASS) and computer-aided design/computer-aided manufacturing (CAD/CAM) has made it possible to not only complete total maxillofacial reconstruction from tumor ablationto immediate insertion of an implant-retained dental prosthesis in a single OR procedure, butithas also increased the predictability and accuracy of maxillofacial reconstruction and decreased intraoperative time.2 Patients requiring more complex maxillofacial reconstruction heavily benefit from increased precision of the final surgical outcome as the accuracy of each osteotomy influences subsequent steps. The aim of our study is to assess the predictability and accuracy of virtually planned, single-stage total maxillofacial reconstruction, also known as 'Jaw in a Day'.³ We conducted a retrospective chart review of all patients who underwent maxillofacial tumor ablation, MVFFF reconstruction, implant placement and immediate implant loading with a dental prosthesis in a single OR procedure. These procedures were completed at Bellevue Hospital Center and NYU Langone Medical Center from January 2011 to January 2015. All cases were virtually planned with Medical Modeling (Golden, CO), and stereolithographic models, osteotomy guides, implant guides, and dental prosthesis were fabricated via CAD/CAM technology. To determine the precision and accuracy of the post-surgical outcomes, we compared the final positions of the implants and fibula on postoperative CT imaging with the planned positions of the implants and fibula based on preoperative virtual planning with Medical Modeling. A total of 8 patients underwent tumor ablation, MVFFF reconstruction, implant placement and immediateimplant loading with a dental prosthesis in a single OR procedure. All patients were diagnosed with benign mandibular (7) and maxillary (1) tumors, including ameloblastoma (6), odontogenic myxoma (1), and AVmalformation (1).Atotal of 35implants were placed with satisfactory primary stability at the time of surgery. On average, the final positions of the implants placed were within 2mm of the virtually treatment planned positions within the fibula. To date, there have been no flap failures and only one implant has failed osseointegration into the MVFFF. Total maxillofacial reconstruction via CASS and CAD/CAM technology has made it possible for surgeons to complete these procedures with high precision and accuracy while minimizing intraoperative time. Additionally, immediate dental rehabilitation is possible at the time of ablation, eliminating the period of edentulism for these patients. Given the highly predictable and accurate postoperative outcomes and low complications rates of virtually planned total maxillofacial reconstruction with a MVFFF and immediate dental rehabilitation, this technique is quickly becoming the standard of care for patients requiring complex maxillofacial reconstruction

There is an increasing need in biology and clinical medicine to robustly and reliably measure tens-to-hundreds of peptides and proteins in clinical and biological samples with high sensitivity, specificity, reproducibility and repeatability. Previously, we demonstrated that LC-MRM-MS with isotope dilution has suitable performance for quantitative measurements of small numbers of relatively abundant proteins in human plasma, and that the resulting assays can be transferred across laboratories while maintaining high reproducibility and quantitative precision. Here we significantly extend that earlier work, demonstrating that 11 laboratories using 14 LC-MS systems can develop, determine analytical figures of merit, and apply highly multiplexed MRM-MS assays targeting 125 peptides derived from 27 cancer-relevant proteins and 7 control proteins to precisely and reproducibly measure the analytes in human plasma. To ensure consistent generation of high quality data we incorporated a system suitability protocol (SSP) into our experimental design. The SSP enabled real-time monitoring of LC-MRM-MS performance during assay development and implementation, facilitating early detection and correction of chromatographic and instrumental problems. Low to sub-nanogram/mL sensitivity for proteins in plasma was achieved by one-step immunoaffinity depletion of 14 abundant plasma proteins prior to analysis. Median intra- and inter-laboratory reproducibility was <20%, sufficient for most biological studies and candidate protein biomarker verification. Digestion recovery of peptides was assessed and quantitative accuracy improved using heavy isotope labeled versions of the proteins as internal standards. Using the highly multiplexed assay, participating laboratories were able to precisely and reproducibly determine the levels of a series of analytes in blinded samples used to simulate an inter-laboratory clinical study of patient samples. Our study further establishes that LC-MRM-MS using stable isotope dilution, with appropriate attention to analytical validation and appropriate quality c`ontrol measures, enables sensitive, specific, reproducible and quantitative measurements of proteins and peptides in complex biological matrices such as plasma.

The LTBPs (or latent transforming growth factor beta binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, -2, -3, and -4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here. The LTBPs were first identified as forming latent complexes with TGFbeta by covalently binding the TGFbeta propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFbeta precursor in the trans-golgi network but LAP and TGFbeta remain strongly bound through non-covalent interactions. LAP, TGFbeta, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFbeta latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFbeta activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFbeta regulation, TGFbeta-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly.

Toll-like receptors (TLRs) play critical roles in innate immunity in many animal species. The sole TLR of C. elegans-TOL-1-is required for a pathogen-avoidance behavior, yet how it promotes this behavior is unknown. We show that for pathogen avoidance TOL-1 signaling is required in the chemosensory BAG neurons, where it regulates gene expression and is necessary for their chemosensory function. Genetic studies revealed that TOL-1 acts together with many conserved components of TLR signaling. BAG neurons are activated by carbon dioxide (CO2), and we found that this modality is required for pathogen avoidance. TLR signaling can therefore mediate host responses to microbes through an unexpected mechanism: by promoting the development and function of chemosensory neurons that surveil the metabolic activity of environmental microbes.

The p75 neurotrophin receptor (p75(NTR)) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75(NTR) interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75(NTR) signaling are trimeric (i.e., TNFR-associated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75(NTR) is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75(NTR) activation in a growth cone retraction functional assay. However, monomers are capable of inducing acute morphological effects in neurons. We propose that p75(NTR) activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75(NTR) confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system. SIGNIFICANCE STATEMENT: The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including apoptosis, neuronal processes remodeling, and synaptic plasticity. The goal of our work was to inquire whether oligomers of the receptor are required for function. Here we report that p75(NTR) predominantly assembles as a trimer, similar to other tumor necrosis factor receptors. Interestingly, monomers and trimers coexist at the cell surface, but trimers are not required for p75(NTR) activation in a functional assay. However, monomers are capable of inducing acute morphological effects in neurons. Identification of the oligomerization state of p75(NTR) begins to provide insights to the mechanisms of signal initiation of this noncatalytic receptor, as well as to develop therapeutic interventions to diminish its activity.