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With the growth of contrast-enhanced ultrasound (CEUS) clinically, there are concerns about histologic bioeffects in regards to the implementation of high mechanical index (MI) imaging, such as the imaging sequence used for a specific CEUS technique known as flash-replenishment. The data presented are results from a pilot study, which explored flash-replenishment with high and moderate MI imaging sequences at time points of 24 hours and 2 weeks post imaging. This pilot study was followed by a larger study, which can be found in a journal article entitled "Histological and Blood Chemistry Examination of the Rodent Kidney After Exposure to Flash-Replenishment Ultrasound Contrast Imaging" Nyankima et al., 2019.

Mutations in myelin protein zero (MPZ) cause inherited peripheral neuropathies, including Charcot‑Marie‑Tooth disease (CMT) and Dejerine‑Sottas neuropathy. Mutant MPZ proteins have previously been reported to cause CMT via enhanced endoplasmic reticulum (ER) stress and Schwann cell (SC) death, although the pathological mechanisms have not yet been elucidated. In this study, we generated an in vitro model of rat SCs expressing mutant MPZ (MPZ V169fs or R98C) proteins and validated the increase in cell death and ER stress induced by the overexpression of the MPZ mutants. Using this model, we examined the efficacy of 3 different aminosalicylic acids (ASAs; 4‑ASA, sodium 4‑ASA and 5‑ASA) in alleviating pathological phenotypes. FACS analysis indicated that the number of apoptotic rat SCs, RT4 cells, induced by mutant MPZ overexpression was significantly reduced following treatment with each ASA. In particular, treatment with 4‑ASA reduced the levels of ER stress markers in RT4 cells induced by V169fs MPZ mutant overexpression and relieved the retention of V169fs mutant proteins in the ER. Additionally, the level of an apoptotic signal mediator (p‑JNK) was only decreased in the RT4 cells expressing R98C MPZ mutant protein following treatment with 4‑ASA. Although 4‑ASA is known as a free radical scavenger, treatment with 4‑ASA in the in vitro model did not moderate the level of reactive oxygen species, which was elevated by the expression of mutant MPZ proteins. On the whole, the findings of this study indicate that treatment with 4‑ASA reduced the ER stress and SC death caused by 2 different MPZ mutants and suggest that ASA may be a potential therapeutic agent for CMT.

Background: Glutamatergic neurons represent the largest neuronal class in the brain and are responsible for the bulk of excitatory synaptic transmission and plasticity. Abnormalities in glutamatergic neurons are linked to several brain disorders and their modulation represents a potential opportunity for emerging bioelectronic medicine (BEM) approaches. Here, we have used a set of electrophysiological assays to identify the effect of the pyrimidine nucleoside uridine on glutamatergic systems in ex vivo brain slices. An improved understanding of glutamatergic synaptic transmission and plasticity, through this type of examination, is critical to the development of potential neuromodulation strategies., Methods: Ex vivo hippocampal slices (400 μm thick) were prepared from mouse brain. We recorded field excitatory postsynaptic potentials (fEPSP) in the CA1's stratum radiatum by stimulation of the CA3 Schaeffer collateral/commissural axons. Uridine was applied at concentrations (3, 30, 300 μM) representing the physiological range present in brain tissue. Synaptic function was studied with input-output (I-O) functions, as well as paired-pulse facilitation (PPF). Synaptic plasticity was studied by applying tetanic stimulation to induce post-tetanic potentiation (PTP), short-term potentiation (STP) and long-term potentiation (LTP). Additionally, we determined whether uridine affected synaptic responses carried solely by n-methyl-d-aspartate receptors (NMDARs), particularly during the oxygen-glucose deprivation (OGD) paradigm., Results: The presence of uridine altered glutamatergic synaptic transmission and plasticity. We found that uridine affected STP and LTP in a concentration-dependent manner. Low-dose uridine (3 μM) had no effect, but higher doses (30 and 300 μM) impaired STP and LTP. Moreover, uridine (300 μM) decreased NMDAR-mediated synaptic responses. Conversely, uridine (at all concentrations tested) had a negligible effect on PPF and basal synaptic transmission, which is mediated primarily by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In addition, uridine (100 μM) exerted a protective effect when the hippocampal slices were challenged with OGD, a widely used model of cerebral ischemia., Conclusions: Using a wide set of electrophysiological assays, we identify that uridine interacts with glutamatergic neurons to alter NMDAR-mediated responses, impair synaptic STP and LTP in a dose-dependent manner, and has a protective effect against OGD insult. This work outlines a strategy to identify deficits in glutamatergic mechanisms for signaling and plasticity that may be critical for targeting these same systems with BEM device-based approaches. To improve the efficacy of potential neuromodulation approaches for treating brain dysfunction, we need to improve our understanding of glutamatergic systems in the brain, including the effects of modulators such as uridine., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Purpose: To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC)., Experimental Design: We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen., Results: We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro . We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro . Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo . Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA ( P = 0.002) and validation ( P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset., Conclusions: We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy., (©2019 American Association for Cancer Research.)

We present results from a large ( n = 3,016) field experiment at a global organization testing whether a brief science-based online diversity training can change attitudes and behaviors toward women in the workplace. Our preregistered field experiment included an active placebo control and measured participants' attitudes and real workplace decisions up to 20 weeks postintervention. Among groups whose average untreated attitudes-whereas still supportive of women-were relatively less supportive of women than other groups, our diversity training successfully produced attitude change but not behavior change. On the other hand, our diversity training successfully generated some behavior change among groups whose average untreated attitudes were already strongly supportive of women before training. This paper extends our knowledge about the pathways to attitude and behavior change in the context of bias reduction. However, the results suggest that the one-off diversity trainings that are commonplace in organizations are unlikely to be stand-alone solutions for promoting equality in the workplace, particularly given their limited efficacy among those groups whose behaviors policymakers are most eager to influence., Competing Interests: Conflict of interest statement: This research was made possible, in part, by a donation by the field partner to Wharton People Analytics and by a grant from the Russell Sage Foundation. In addition, A.M.G. has a financial relationship with the field partner in which he has been paid for consulting unrelated to this research., (Copyright © 2019 the Author(s). Published by PNAS.)

Obesity and obesity-associated disorders have become world-wide epidemics, substantially increasing the risk of debilitating morbidity and mortality. A characteristic feature of these disorders, which include the metabolic syndrome (MetS) and type 2 diabetes, is chronic low-grade inflammation stemming from metabolic and immune dysregulation. Inflammation in the CNS (neuroinflammation) and cognitive impairment have also been associated with obesity-driven disorders. The nervous system has a documented role in the regulation of metabolic homeostasis and immune function, and recent studies have indicated the important role of vagus nerve and brain cholinergic signaling in this context. In this review, we outline relevant aspects of this regulation with a specific focus on obesity-associated conditions. We outline accumulating preclinical evidence for the therapeutic efficacy of cholinergic stimulation in alleviating obesity-associated inflammation, neuroinflammation, and metabolic derangements. Recently demonstrated beneficial effects of galantamine, a centrally acting cholinergic drug and cognitive enhancer, in patients with MetS are also summarized. These studies provide a rationale for further therapeutic developments using pharmacological and bioelectronic cholinergic modulation for clinical benefit in obesity-associated disorders.

Background: With the advent of minimally invasive techniques, the standard approaches to many surgeries have changed. We compared the financial costs and health care outcomes between standard thymectomy via sternotomy and video assisted thoracoscopic surgery (VATS)., Methods: A 3-year review [2010-2012] of the National Inpatient Sample (NIS) was performed. All patients undergoing thymectomy were included. Patients undergoing VATS thymectomy were identified. Outcomes measured were hospital length of stay (LOS), hospital charges, and mortality. Univariate and multivariate analyses were performed to control for demographics and comorbidities., Results: The results of 2,065 patients who underwent thymectomy were analyzed, of which 373 (18.1%) had VATS thymectomy and 1,692 (81.9%) had standard thymectomy. Mean age was 52.8±16, 42.5% were male, and 65.5% were Caucasian. There was a significant interval increase in number of patients undergoing VATS thymectomy (10% in 2010 vs . 19.2% in 2012, P<0.001). Patients undergoing standard thymectomy had longer hospital LOS (6.8±6.6 vs . 3.3d±3.4 d, P<0.001), hospital charges $88,838±$120,892 vs . $57,251±$54,929) and hospital mortality (0.9% vs . 0%, P=0.01). In multivariate analysis, thymectomy via sternotomy was independently associated with increased hospital LOS B =1.6 d, P<0.001) and charges (B = $13,041, P=0.041)., Conclusions: Our study demonstrates decreased hospital length of stay and reduced hospital charges in patients undergoing VATS thymectomy compared to standard thymectomy. Our data demonstrates that the prevalence of VATS thymectomies is increasing, likely related to improved healthcare and financial outcomes., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The effects of biogeographical separation and parent material differences in soil bacterial structure and diversity in offshore islands remain poorly understood. In the current study, we used next-generation sequencing to characterize the differences in soil bacterial communities in five offshore subtropical granite islands (Matsu Islets, MI) of mainland China and two offshore tropical andesite islands (Orchid [OI] and Green Islands [GI]) of Taiwan. The soils of OI and GI were more acidic and had higher organic carbon and total nitrogen content than MI soils. The bacterial communities were dominated by Acidobacteria and Proteobacteria but had different relative abundance because soils were derived from different parent material and because of geographic distance. Non-metric multi-dimensional scaling revealed that the communities formed different clusters among different parent material and geographically distributed soils. The alpha-diversity in bacterial communities was higher in tropical than subtropical soils. Mantel test and redundancy analysis indicated that bacterial diversity and compositions of OI and GI soils, respectively, were positively correlated with soil pH, organic carbon, total nitrogen, microbial biomass carbon and nitrogen. These results suggest that variations in soil properties of offshore islands could result from differences in soil parent material. Distinct soils derived from different parent material and geographic distance could in turn alter the bacterial communities.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of mechanical anisotropy in the kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate the clinical feasibility of acoustic radiation force (ARF)-induced peak displacement (PD) measures for both exploiting and obviating mechanical anisotropy in the cortex of human kidney allografts, in vivo. Validation of the imaging methods is provided by preclinical studies in pig kidneys, in which ARF-induced PD values were significantly higher ( , Wilcoxon) when the transducer executing asymmetric ARF was oriented across versus along the nephrons. The ratio of these PD values obtained with the transducer oriented across versus along the nephrons strongly linearly correlated ( R 2 = 0.95 ) to the ratio of shear moduli measured by shear wave elasticity imaging. On the contrary, when a symmetric ARF was implemented, no significant difference in PD was observed ( p > 0.01 ). Similar results were demonstrated in vivo in the kidney allografts of 14 patients. The symmetric ARF produced PD measures with no significant difference ( p > 0.01 ) between along versus across alignments, but the asymmetric ARF yielded PD ratios that remained constant over a six-month observation period post-transplantation, consistent with stable serum creatinine level and urine protein-to-creatinine ratio in the same patient population ( p > 0.01 ). The results of this pilot in vivo clinical study suggest the feasibility of 1) implementing symmetrical ARF to obviate mechanical anisotropy in the kidney cortex when anisotropy is a confounding factor and 2) implementing asymmetric ARF to exploit mechanical anisotropy when mechanical anisotropy is a potentially relevant biomarker.

Purpose of Review: Surfactant protein-A (SP-A) is a collectin protein expressed in airway epithelia that is critical in the modulation of both innate and adaptive immunity against inhaled pathogens. In this review, we highlight associations of altered SP-A function in asthma and chronic rhinosinusitis, and its potential role as a targeted therapy for sinusitis., Recent Findings: SP-A has been shown to bind and opsonize inhaled pathogens, thereby clearing bacteria through phagocytosis. We have recently identified that SP-A levels are increased in response to Pseudomonas aeruginosa, a common bacterial pathogen in chronic rhinosinusitis. Moreover, SP-A has also been shown to modulate epithelial inflammatory mediators and play a role in eosinophil-mediated airway disease. The development of a transgenic murine model expressing human genetic variants of SP-A2 have suggested that the human surfactant protein-A2 223K variant significantly increases eosinophil degranulation, suggesting a genotype-phenotype correlation in human airway disease., Summary: SP-A is important in both the innate and adaptive host defense mechanisms in the upper and lower airways. Although research in this field in sinusitis is nascent, initial work suggests that aberrant SP-A regulation may be one etiologic factor in the development of bacterial and eosinophilic-associated sinusitis.

Background: Catechins, polyphenols derived from tea leaves, have been shown to have antibacterial properties, through direct killing of bacteria as well as through inhibition of bacterial toxin activity. In particular, certain catechins have been shown to have bactericidal effects on the oral bacterium, Aggregatibacter actinomycetemcomitans, as well as the ability to inhibit a key virulence factor of this organism, leukotoxin (LtxA). The mechanism of catechin-mediated inhibition of LtxA has not been shown., Methods: In this work, we studied the ability of six catechins to inhibit LtxA-mediated cytotoxicity in human white blood cells, using Trypan blue staining, and investigated the mechanism of action using a combination of techniques, including fluorescence and circular dichroism spectroscopy, confocal microscopy, and surface plasmon resonance., Results: We found that all the catechins except (-)-catechin inhibited the activity of this protein, with the galloylated catechins having the strongest effect. Pre-incubation of the toxin with the catechins increased the inhibitory action, indicating that the catechins act on the protein, rather than the cell. The secondary structure of LtxA was dramatically altered in the presence of catechin, which resulted in an inhibition of toxin binding to cholesterol, an important initial step in the cytotoxic mechanism of the toxin., Conclusions: These results demonstrate that the catechins inhibit LtxA activity by altering its structure to prevent interaction with specific molecules present on the host cell surface., General Significance: Galloylated catechins modify protein toxin structure, inhibiting the toxin from binding to the requisite molecules on the host cell surface., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The optimal maxillary antrostomy size to surgically treat sinusitis is not well known. In this study, we examined clinical metrics of disease severity and symptom scores, measured secreted inflammatory markers, and characterized the sinus microbiome to determine if there were significant differences in outcome between different maxillary ostial sizes., Methods: Prospective randomized, single-blinded clinical trial enrolling 12 individuals diagnosed with recurrent acute or chronic rhinosinusitis. Each patient was blinded and randomized to receive minimal maxillary ostial dilation via balloon sinuplasty on 1 side vs a mega-antrostomy on the contralateral side. Data collected included symptom scores (20-item Sino-Nasal Outcome Test [SNOT-20]), endoscopy, and radiologic Lund-Mackay scores. During surgery and at their postoperative visit swabs were obtained from each maxillary sinus, and 16S DNA and inflammatory cytokine levels analyzed. The use of each patient as their own control allowed us to minimize confounding variables., Results: There was statistically significant improvement in SNOT-20 symptom scores postoperatively in all patients. There were no significant differences between maxillary ostial size in postoperative endoscopy scores, cytokine profile, or bacterial burden. There were statistically significant differences in relative postoperative abundance of Staphylococcus, Lactococcus, and Cyanobacteria between the mega-antrostomy and mini-antrostomy., Conclusions: The method used in surgical maxillary antrostomies had no effect on endoscopy scores or cytokine profiles. Microbiome analysis determined significant differences between the different antrostomy sizes in postoperative Staphylococcus, Lactococcus, and Cyanobacteria abundance. The clinical significance of these changes in the sinus microbiome are not known but may be a result of increased access to postoperative sinonasal irrigations., (© 2018 ARS-AAOA, LLC.)

Kingella kingae is a member of the commensal oropharyngeal flora of young children. Improvements in detection methods have led to the recognition of K. kingae as an emerging pathogen that frequently causes osteoarticular infections in children and a severe form of infective endocarditis in children and adults. Kingella kingae secretes a membrane-damaging RTX (Repeat in ToXin) toxin, RtxA, which is implicated in the development of clinical infections. However, the mechanism by which RtxA recognizes and kills host cells is largely unexplored. To facilitate structure-function studies of RtxA, we have developed a procedure for the overproduction and purification of milligram amounts of biologically active recombinant RtxA. Mass spectrometry analysis revealed the activation of RtxA by post-translational fatty acyl modification on the lysine residues 558 and/or 689 by the fatty-acyltransferase RtxC. Acylated RtxA was toxic to various human cells in a calcium-dependent manner and possessed pore-forming activity in planar lipid bilayers. Using various biochemical and biophysical approaches, we demonstrated that cholesterol facilitates the interaction of RtxA with artificial and cell membranes. The results of analyses using RtxA mutant variants suggested that the interaction between the toxin and cholesterol occurs via two cholesterol recognition/interaction amino acid consensus motifs located in the C-terminal portion of the pore-forming domain of the toxin. Based on our observations, we conclude that the cytotoxic activity of RtxA depends on post-translational acylation of the K558 and/or K689 residues and on the toxin binding to cholesterol in the membrane.

Background: Most thoracic surgical procedures in the United States are being performed by general surgeons (GSs) without any advanced training. With the recent approval of computed tomography screening for lung malignancy in high-risk populations, the number of thoracic oncologic resections is expected to rise. Previous literature has demonstrated consistently worsened outcomes for patients undergoing thoracic surgical procedure when done by nonthoracic fellowship-trained surgeons. Using the American College of Surgeons National Surgical Quality Improvement Project database, we examined short-term outcomes in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for malignancy., Materials and Methods: Data were obtained from the American College of Surgeons National Surgical Quality Improvement Project from 2010-2015. We identified patients who had an International Classification of Disease 9 diagnosis of lung cancer (162) who underwent VATS lobectomy (current procedural terminology 32663). We included only adults (≥18y) and elective cases. We excluded patients who had preoperative diagnosis of sepsis, contaminated wound class, or those patients with missing American Society of Anesthesiologists classification, morbid obesity, functional status, length of stay (LOS), or sex, and race information. We identified two groups by specialty: GS versus cardiothoracic (CT) surgeon. We then performed univariate analysis. We then performed propensity score analysis using a 1:3 ratio of general surgery patients to CT patients. Outcomes of interest included 30-d postoperative mortality, 30-d postoperative morbidity, and LOS., Results: A total of 4105 patients were identified, 607 performed by GSs, 3508 performed by CT surgeons. The mean age for patients who underwent lobectomies by GSs was 68.6 versus 67.8 in the CT surgeon group (P < 0.05). The majority were female (58.09% GS versus 57.74% CT surgeon). There was a statistically significant difference in race between groups; patients were more likely to be African American in the CT surgeon group. Operative time was lower in the GS group as opposed to the CT surgeon group 179 min versus 196 (P < 0.01). Univariate analysis (mortality <0.1 CT surgeon and GS) and 1:3 propensity score matched analysis (0.08 GS% versus 0.08% CT surgeon) failed to demonstrate a significant difference in mortality. There was a statistically significant difference in median LOS between groups (6.2 GS versus 5.1 CT surgeon). Univariate and propensity matched analyses of pneumonia, sepsis, wound infection, deep vein thrombosis, transfusion requirement, myocardial infarction stroke, postoperative renal insufficiency, failure to wean, pulmonary embolism, reintubation, and deep organ space infection all failed to demonstrate a statistically significant difference between our groups of interest. Urinary tract infection was noted to be higher in the GS group operating room 2.29 as compared to the CT surgeon group (P value 0.02)., Conclusions: In this large observational study, we found that VATS lobectomies performed by GS compared to the matched CT surgeon cohort had shorter operative time, and there was no difference in major postoperative morbidity or mortality. However, LOS was higher and there was increased risk of urinary tract infection in the GS compared to matched CT surgeon cohort., (Published by Elsevier Inc.)

The surgeon's knowledge of a patient's individual anatomy is critical in skull base surgery. Trainees and experienced surgeons can benefit from surgical simulation; however, current models are expensive and impractical for widespread use. In this study, we report a next-generation mixed-reality surgical simulator. We segmented critical anatomic structures for 3-dimensional (3D) models to develop a modular teaching tool. We then developed a navigation tracking system utilizing a 3D-printed endoscope as a trackable virtual-reality (VR) controller and validated the accuracy on VR and 3D-printed skull models within 1 cm. We combined VR and augmented-reality visual cues with our 3D physical model to simulate sinus endoscopy and highlight segmented structures in real time. This report provides evidence that a mixed-reality simulator combining VR and 3D-printed models is feasible and may prove useful as an educational tool that is low cost and customizable.

Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Aβ was dramatically increased in PS1-E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC-derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery.

The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

The Gram-negative bacterium Aggregatibacter actinomycetemcomitans, commonly associated with localized aggressive periodontitis (LAP), secretes an RTX (repeats-in-toxin) protein leukotoxin (LtxA) that targets human white blood cells, an interaction that is driven by its recognition of the lymphocyte function-associated antigen-1 (LFA-1) integrin. In this study, we report on the inhibition of LtxA-LFA-1 binding as an antivirulence strategy to inhibit LtxA-mediated cytotoxicity. Specifically, we designed and synthesized peptides corresponding to the reported LtxA binding domain on LFA-1 and characterized their capability to inhibit LtxA binding to LFA-1 and subsequent cytotoxic activity in human immune cells. We found that several of these peptides, corresponding to sequential β-strands in the LtxA-binding domain of LFA-1, inhibit LtxA activity, demonstrating the effectiveness of this approach. Further investigations into the mechanism by which these peptides inhibit LtxA binding to LFA-1 reveal a correlation between toxin-peptide affinity and LtxA-mediated cytotoxicity, leading to a diminished association between LtxA and LFA-1 on the cell membrane. Our results demonstrate the possibility of using target-based peptides to inhibit LtxA activity, and we expect that a similar approach could be used to hinder the activity of other RTX toxins.

The dystrobrevin-binding protein 1 (DTNBP1) gene is a candidate risk factor for schizophrenia and has been associated with cognitive ability in both patient populations and healthy controls. DTNBP1 encodes dysbindin protein, which is localized to synaptic sites and is reduced in the prefrontal cortex and hippocampus of patients with schizophrenia, indicating a potential role in schizophrenia etiology. Most studies of dysbindin function have focused on the sandy (sdy) mice that lack dysbindin protein and have a wide range of abnormalities. In this study, we examined dysbindin salt and pepper (spp) mice that possess a single point mutation on the Dtnbp1 gene predicted to reduce, but not eliminate, dysbindin expression. By western blot analysis, we found that spp homozygous (spp -/-) mutants had reduced dysbindin and synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex, but unaltered levels in hippocampus. Behaviorally, spp mutants performed comparably to controls on a wide range of tasks assessing locomotion, anxiety, spatial recognition and working memory. However, spp -/- mice had selective deficits in tasks measuring novel object recognition and social novelty recognition. Our results indicate that reduced dysbindin and SNAP-25 protein in the prefrontal cortex of spp -/- is associated with selective impairments in recognition processing. These spp mice may prove useful as a novel mouse model to study cognitive deficits linked to dysbindin alterations. Our findings also suggest that aspects of recognition memory may be specifically influenced by DTNBP1 single nucleotide polymorphisms or risk haplotypes in humans and this connection should be further investigated., (© 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Loss or mutation of TP53 has been linked to alterations in anti-tumor immunity as well as dysregulation of cell cycle and apoptosis. We explored immunologic effects and mechanisms following restoration of wild-type human TP53 cDNA in murine oral cancer cells using the therapeutic nanocomplex scL-53. We demonstrated scL-53 induces dose-dependent expression of TP53 and induction of apoptosis and immunogenic cell death. We further demonstrated both TP53-dependent and independent induction of tumor cell immunogenicity through the use of blocking mAbs, nanocomplex loaded with DNA plasmid with or without TP53 cDNA, empty nanocomplex and siRNA knockdown techniques. TP53-independent immune modulation was observed following treatment with nanocomplex loaded with DNA plasmid lacking TP53 cDNA and abrogated in STING-deficient tumor cells, supporting the presence of a cytoplasmic DNA sensing, STING-dependent type-I IFN response. Cooperatively, TP53- and STING-dependent alterations sensitized tumor cells to CTL-mediated lysis, which was further enhanced following reversal of adaptive immune resistance with PD-1 mAb. In vivo , combination scL-53 and PD-1 mAb resulted in growth control or rejection of established tumors that was abrogated in mice depleted of CD8+ cells or in STING deficient mice. Cumulatively, this work demonstrates 1) a direct anti-tumor effects of functional TP53; 2) non-redundant TP53- and STING-dependent induction of tumor cell immunogenicity following scL-53 treatment; and 3) that adaptive immune resistance following scL-53 treatment can be reversed with PD-based immune checkpoint blockade, resulting in the rejection or control of syngeneic murine tumors. These data strongly support the clinical combination of scL-53 and immune checkpoint blockade.

Background and Objective: Objective Structured Clinical Examination (OSCE) has been used in many areas of healthcare training over the years. However, it constantly needs to be upgraded and enhanced due to technological and teaching changes. We aim at implementing an integrative OSCE method which employs informatics via the virtual patient within the pharmacy education curriculum at Taipei Medical University to enhance the pharmacy students' competence for using and disseminating information and to also improve critical thinking and clinical reasoning., Methods: We propose an integrated pharmacy OSCE which uses standardized patients and virtual patients (DxR Clinician). To evaluate this method, we designed four simulated stations and pilot tested with 19 students in the first year of the Master in Clinical Pharmacy program. Three stations were simulated as the inpatient pharmacy: 1) History and lab data collection; 2) Prescription review; 3) Calling physician to discuss potential prescription problems. The fourth was simulated as the patient ward station to provide patient education. A satisfaction questionnaire was administered at the end of the study., Results: Students rated their ability of 2.84, 2.37, 2.37, and 3.63 of 5 for each of the four stations, with the second and third being the most difficult stations. The method obtained an average rating of 4.32 of 5 for relevance, 4.16 for improving clinical ability, 4.32 for practicality in future healthcare work, and 4.28 for willing to have another similar learning experience., Conclusion: The integration of Virtual Patient in this study reveals that this assessment method is efficient and practical in many aspects. Most importantly, it provides the test taker with a much closer real-life clinical encounter. Although it is in many ways more difficult, it also provides for better "learning from mistakes" opportunities for test-takers., (Copyright © 2017. Published by Elsevier B.V.)

Objectives Cigarette smoking and passive smoke exposure have been associated with chronic rhinosinusitis (CRS). Our goal in this systematic review was to (1) determine if there was a strong correlative effect in large population studies between cigarette smoke exposure and the prevalence of CRS, (2) investigate pathogenic mechanisms of cigarette smoke in the upper airway, and (3) determine if a history of cigarette smoking affects the medical and surgical outcomes of CRS. Data Sources MEDLINE, Embase, Cochrane CENTRAL, Web of Science SCI and CPCI-S, and websites. Methods A comprehensive literature review and quantitative meta-analysis of studies based on the PRISMA protocol and examining the relationship between cigarette smoke exposure and CRS was performed. A search strategy was developed using various terms such as sinusitis, rhinitis, rhinosinusitis, and smoking. The articles were categorized by (1) epidemiology, (2) pathophysiology, and (3) outcomes. Data regarding study design, population/setting, methods, and bias were collected. Results The initial search generated 2621 titles/abstracts with 309 articles undergoing secondary review and 112 articles for final review. We determined that there is a strong correlation between active and passive cigarette smoke with the prevalence of CRS. Cigarette smoke challenge to sinonasal epithelia results in the release of inflammatory mediators and altered ciliary beat frequency. Pediatric patients exposed to secondhand smoke appear to have particularly poor outcomes. Conclusion There is clear evidence that cigarette smoke is related to CRS, but longitudinal and mechanistic studies are required to determine a causative effect. This information is critical for greater understanding of CRS health outcomes.

In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S- cis diene conformer. This is the first example where a fluorescent dye adopts the stable S- cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S- cis diene conformation can lead to new strategies for the design of near-IR dyes.

Background: Chronic sinusitis is a commonly diagnosed condition in adults who frequently present with late-stage disease and irreversible changes to the sinus mucosa. Understanding the natural history of chronic sinusitis is critical in developing therapies designed to prevent or slow the progression of disease., Objective: We sought to determine early life risk factors for adult sinusitis in a longitudinal cohort study (Tucson Children's Respiratory Study)., Methods: Physician-diagnosed sinusitis was reported at age 6. Adult sinusitis between 22 and 32 years was defined as self-reported sinusitis plus physician-ordered sinus radiologic films. Atopy was assessed by skin prick test. Individuals were grouped into 4 phenotypes: no sinusitis (n = 621), transient childhood sinusitis only (n = 57), late-onset adult sinusitis only (n = 68), and early onset chronic sinusitis (childhood and adult sinusitis, n = 26)., Results: Sinusitis was present in 10.8% of children and 12.2% of adults. Childhood sinusitis was the strongest independent risk factor for adult sinusitis (odds ratio = 4.2; 95% CI: 2.5-7.1; P < .0001; n = 772). Early onset chronic sinusitis was associated with increased serum IgE levels as early as at 9 months of age, atopy (assessed by skin prick test reactivity), childhood eczema and allergic rhinitis, frequent childhood colds, maternal asthma, and with increased prevalence of concurrent asthma. No association was found between late-onset adult sinusitis and any of the early life risk factors studied., Conclusions: We identified an early onset chronic sinusitis phenotype associated with a predisposition to viral infections/colds in early life, allergies, and asthma. Elucidation of the molecular mechanisms for this phenotype may lead to future therapies to prevent the progression of the disease into adult sinusitis., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Intrinsic therapeutic resistance especially in cancer stem cells (CSCs) together with extensive tumor cell infiltration and restricted permeation of the blood-brain barrier (BBB) by drugs may all contribute to the treatment failure in patients with glioblastoma multiforme (GBM). Accumulating evidence suggests that long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a role in tumor cell infiltration and therapeutic resistance of GBM. Using our tumor-targeted nanocomplex, we have modulated the expression of MALAT1 and investigated its impact on GBM cells. Importantly, our nanocomplex is able to target CSCs that are considered to be the prime culprits in therapeutic resistance and recurrence of GBM. Attenuation of MALAT1 by RNA interference significantly lowered the growth, motility and stemness of GBM cells. In addition, silencing of MALAT1 clearly improved the sensitivity of GBM cells to chemotherapeutic agents including the current first-line therapy of GBM [temozolomide (TMZ)]. In animal models of GBM, tumor involution with a modest but statistically significant survival benefit was achieved with concurrent treatment of TMZ and nanocomplex-mediated silencing of MALAT1. These results suggest that combining standard TMZ treatment with lncRNA-targeting therapies using our nanocomplex could substantially enhance the very poor prognosis for GBM patients.

The failure of therapeutic agents to cross the blood-brain barrier (BBB) has been a major impediment in the treatment of neurological disorders and brain tumors. We have addressed this issue using an immunoliposome nanocomplex (designated scL) that delivers therapeutic nucleic acids across the BBB into the deep brain via transcytosis mediated by transferrin receptors. We validated brain delivery of payloads after systemic administration by monitoring uptake of fluorescently labeled payloads and by confirming up- or down-modulation of specific target gene expression in the brain, mainly in neuronal cells. As proof of concept for the therapeutic potential of our delivery system, we employed scL delivering an siRNA targeting tumor necrosis factor alpha to suppress neuroinflammation and neuronal apoptosis and to protect mice in lethal endotoxemia triggered by bacterial lipopolysaccharide. Brain delivery of therapeutic payloads via scL has major implications for the development of treatments for neurological disorders and brain tumors., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Contrast-enhanced ultrasound (CEUS) is an emerging technology with no known nephrotoxicity. CEUS has been utilized in cardiac and abdominal imaging for decades in Asia and Europe and has recently received greater attention in the United States with its approval for characterization of indeterminate liver lesions. Emerging data suggest that CEUS has potential as a diagnostic imaging tool among individuals who have contraindications to CT and MRI. Few nephrologists are aware of CEUS and even fewer are aware of its potential applications among individuals with kidney disease. This review introduces CEUS to the nephrology community and provides a basic overview of CEUS technology. Knowledge of the applications, advantages, and disadvantages of CEUS provides the framework for nephrologists to make informed decisions regarding this emerging imaging test in appropriate circumstances. This review focuses on the use of CEUS for the characterization of indeterminate kidney lesions and summarizes the most recent data, some of which specifically includes patients with chronic kidney disease (CKD). The results demonstrate that CEUS has high sensitivity and moderate specificity for detecting malignancy in indeterminate kidney lesions among individuals with and without CKD. In conclusion, CEUS is an emerging imaging technique that may have clinically useful applications for detecting malignant kidney lesions, specifically in patients with CKD. However, most of the current data come from small, single-center studies, and larger, multicenter studies are needed., (© 2017 S. Karger AG, Basel.)

Background: Despite the impact of medication literacy (ML) on patients' safe use of medications, existing instruments are mostly for general health literacy measurement or designed for specific disease populations, with few specifically designed for ML., Objective: To develop and validate the first Chinese medication literacy measure (ChMLM)., Methods: The ChMLM was developed by a multidisciplinary and bilingual expert panel and subsequently pilot-tested. The final version had 17 questions in four sections: vocabulary, non-prescription drug, prescription drug and drug advertisement. Face-to-face interviews were administered in a convenience sample of adults with diverse sociodemographic characteristics. Internal consistency was assessed by Cronbach's alpha. Content validity was confirmed by the expert panel, and hypothesis testing was performed to assess construct validity., Results: A total of 634 adults were interviewed. The mean (SD) total ChMLM score was 13.0 (2.8). The internal validity was acceptable (Cronbach's alpha=0.72). Nine of the ten a priori hypotheses were fulfilled. Younger age, higher income and higher education levels were significantly associated with a higher ChMLM score. Furthermore, higher scores on the ChMLM were associated with higher confidence or less difficulty in writing, reading, speaking and listening abilities in a health-care encounter. No association was found between ChMLM total scores and frequency of doctor's visits., Conclusion: The ChMLM is a valid and reliable ML measure. It may help pharmacists and other health-care providers to target patients and problem areas that need interventions with the ultimate goal of preventing medication errors and harm., (© 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.)

Target-activated chemical probes are important tools in basic biological research and medical diagnosis for monitoring enzyme activities and reactive small molecules. Based on the fluorescence turn-on mechanism, they can be divided into two classes: dye-based fluorescent probes and caged-luciferin. In this paper, we introduce a new type of chemical probe in which the fluorescence turn-on is based on controlled streptavidin-biotin binding. Compared to conventional probes, the streptavidin-biotin controlled binding probe has several advantages, such as minimal background at its "OFF" state, multiple signal amplification steps, and unlimited selection of the optimal dyes for detection. To expand the scope, a new synthetic method was developed, through which a wider range of analyte recognition groups can be easily introduced to construct the binding probe. This probe design was successfully applied to image and study secreted peroxynitrite (ONOO - ) at the cell surface of macrophages where information on ONOO - is difficult to obtain. As the signals are generated upon the binding of streptavidin to the biotin probe, this highly versatile design can not only be used in fluorescence detection but can also be applied in various other detection modes, such as electrochemical and enzyme-amplified luminescence detection.

Background: Innovation represents a core value of the American Rhinologic Society (ARS), with multiple efforts to promote research in the advancement rhinologic care. We therefore sought to identify trends in extramural sinusitis funding and underutilized sources of support to facilitate future efforts., Methods: A systematic review of the National Institutes of Health (NIH) Research Portfolio Online Tools (RePORTER) database (fiscal year 1993 to 2017) was completed with the search strategy: ("chronic sinusitis" OR rhinosinusitis). All identified studies were accepted for review, with comparison to ARS membership rolls to identify studies supported by ARS investigators. Foundation awards were surveyed to identify and characterize additional sources of support., Results: The systematic review identified 958 projects receiving NIH funding, of which 120 remain active. The percentage of sinusitis-related awards and total funding relative to all NIH awards increased over the past 10 years (2006 to 2016) from 0.06% (8 / 9128) and 0.09% ($2,151,152 / $3,358,338,602) to 0.87% (86 / 9540) and 0.90% ($37,201,095 / $4,300,145,614). Among active studies, 9 investigators maintain membership in the ARS and serve as principal investigator or project leader in 12 (10%) studies. ARS investigators received the greatest number of awards from the National Institute on Deafness and Other Communication Disrders (n = 8,66.7%), while only receiving 2.2% of awarded funding from the National Institute of Allergy and Infectious Diseases ($607,500/$26,873,022), the largest source of awards for sinusitis research., Conclusion: Support for sinusitis research is significantly growing, with the largest source of active funding not being fully utilized by members of the ARS. Further efforts to promote funding priorities among extramural sources is necessary to facilitate increased funding for ARS member initiatives., (© 2017 ARS-AAOA, LLC.)

Background: The PharmaCloud system, a cloud-based medication system, was launched by the Taiwan National Health Insurance Administration (NHIA) in 2013 to integrate patients' medication lists among different medical institutions. The aim of the preliminary study was to evaluate satisfaction with this system among physicians and pharmacists at the early stage of system implementation., Methods: A questionnaire was developed through a review of the literature and discussion in 6 focus groups to understand the level of satisfaction, attitudes, and intentions of physicians and pharmacists using the PharmaCloud system. It was then administered nationally in Taiwan in July to September 2015. Descriptive statistics and multiple regression were performed to identify variables influencing satisfaction and intention to use the system., Results: In total, 895 pharmacist and 105 physician questionnaires were valid for analysis. The results showed that satisfaction with system quality warranted improvement. Positive attitudes toward medication reconciliation among physicians and pharmacists, which were significant predictors of the intention to use the system (β= 0.223, p < 0.001). Most physicians and pharmacists agreed that obtaining signed patient consent was needed but preferred that it be conducted by the NHIA rather than by individual medical institutions (4.02 ± 1.19 vs. 3.49 ± 1.40, p < 0.01)., Conclusions: The preliminary study results indicated a moderate satisfaction toward the PharmaCloud system. Hospital pharmacists had a high satisfaction rate, but neither are physicians and community pharmacists. Continuously improvement on system quality has been performing based on the results of this preliminary survey. Policies and standardization processes, including privacy protection, are still warranted further actions to make the Taiwan PharmaCloud system a convenient platform for medication reconciliation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) is a common inflammatory disorder of the upper airway characterized by chronic inflammation and significant sinonasal remodeling. CRS is comprised of 2 major subgroups, based on whether polyps are present or absent. In some cases, it is characterized by colonization with opportunistic pathogens such as Pseudomonas aeruginosa (PA), Staphylococcus aureus, and other bacteria. The innate immune system of the sinonasal epithelium is the first line of defense against inhaled pathogens. Surfactant protein A (SP-A) is a member of the collectin family secreted by the airway epithelia and plays a critical role in airway innate immunity, as it can aggregate bacteria. We hypothesized that SP-A plays a role in bacterial CRS., Methods: Air-liquid interface (ALI) cultures of nasal epithelial cells were derived from human ex-vivo healthy and CRS sinus tissues (n = 26) and challenged with PA. SP-A levels were measured with western blot and quantitative reverse transcript-polymerase chain reaction (qRT-PCR) in ALI and sinus tissues., Results: We determined that SP-A: (i) mRNA and protein levels are increased significantly in CRS tissues compared with healthy sinuses; (ii) although primarily expressed in the lung, it is also synthesized and expressed in sinonasal epithelia; (ii) is expressed in the sinuses of an SP-A humanized transgenic mouse but not in SP-A knockout mice; (iv) mRNA levels are upregulated significantly during PA challenge, but protein levels are downregulated 4 hours postchallenge and upregulated at 12 hours., Conclusion: Our data suggest that SP-A is expressed in the sinuses and that it plays a role in the sinus innate immune responses during bacterial infections., (© 2017 ARS-AAOA, LLC.)

Background: Patients with chronic kidney disease are at increased risk of cystic kidney disease that requires imaging monitoring in many cases. However, these same patients often have contraindications to contrast-enhanced computed tomography and magnetic resonance imaging. This study evaluates the accuracy of contrast-enhanced ultrasound (CEUS), which is safe for patients with chronic kidney disease, for the characterization of kidney lesions in patients with and without chronic kidney disease., Methods: We performed CEUS on 44 patients, both with and without chronic kidney disease, with indeterminate or suspicious kidney lesions (both cystic and solid). Two masked radiologists categorized lesions using CEUS images according to contrast-enhanced ultrasound adapted criteria. CEUS designation was compared to histology or follow-up imaging in cases without available tissue in all patients and the subset with chronic kidney disease to determine sensitivity, specificity and overall accuracy., Results: Across all patients, CEUS had a sensitivity of 96% (95% CI: 84%, 99%) and specificity of 50% (95% CI: 32%, 68%) for detecting malignancy. Among patients with chronic kidney disease, CEUS sensitivity was 90% (95% CI: 56%, 98%), and specificity was 55% (95% CI: 36%, 73%)., Conclusions: CEUS has high sensitivity for identifying malignancy of kidney lesions. However, because specificity is low, modifications to the classification scheme for contrast-enhanced ultrasound could be considered as a way to improve contrast-enhanced ultrasound specificity and thus overall performance. Due to its sensitivity, among patients with chronic kidney disease or other contrast contraindications, CEUS has potential as an imaging test to rule out malignancy., Trial Registration: This trial was registered in clinicaltrials.gov, NCT01751529 .

Objective: We evaluated the learning curve for external cephalic version (ECV) using learning curve-cumulative sum (LC-CUSUM) analysis., Methods: This was a retrospective study involving 290 consecutive cases between October 2013 and March 2017. We evaluated the learning curve for ECV on nulli and over para 1 group using LC-CUSUM analysis on the assumption that 50% and 70% of ECV procedures succeeded by description a trend-line of quadratic function with reliable R 2 values., Results: The overall success rate for ECV was 64.8% (188/290), while the success rate for nullipara and over para 1 groups was 56.2% (100/178) and 78.6% (88/112), respectively. 'H' value, that the actual failure rate does not differ from the acceptable failure rate, was -3.27 and -1.635 when considering ECV success rates of 50% and 70%, respectively. Consequently, in order to obtain a consistent 50% success rate, we would require 57 nullipara cases, and in order to obtain a consistent 70% success rate, we would require 130 nullipara cases. In contrast, 8 to 10 over para 1 cases would be required for an expected success rate of 50% and 70% on over para 1 group., Conclusion: Even a relatively inexperienced physician can experience success with multipara and after accumulating experience, they will manage nullipara cases. Further research is required for LC-CUSUM involving several practitioners instead of a single practitioner. This will lead to the gradual implementation of standard learning curve guidelines for ECV., Competing Interests: Conflict of interest: No potential conflict of interest relevant to this article was reported.

Charcot-Marie-Tooth disease (CMT) is a genetic disorder that can be caused by aberrations in >80 genes. CMT has heterogeneous modes of inheritance, including autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Over 95% of cases are dominantly inherited. In this study, we investigated whether regulation of a mutant allele by an allele-specific small interfering RNA (siRNA) can alleviate the demyelinating neuropathic phenotype of CMT. We designed 19 different allele-specific siRNAs for Trembler J (Tr-J) mice harboring a naturally occurring mutation (Leu16Pro) in Pmp22. Using a luciferase assay, we identified an siRNA that specifically and selectively reduced the expression level of the mutant allele and reversed the low viability of Schwann cells caused by mutant Pmp22 over-expression in vitro. The in vivo efficacy of the allele-specific siRNA was assessed by its intraperitoneal injection to postnatal day 6 of Tr-J mice. Administration of the allele-specific siRNA to Tr-J mice significantly enhanced motor function and muscle volume, as assessed by the rotarod test and magnetic resonance imaging analysis, respectively. Increases in motor nerve conduction velocity and compound muscle action potentials were also observed in the treated mice. In addition, myelination, as evidenced by toluidine blue staining and electron microscopy, was augmented in the sciatic nerves of the mice after allele-specific siRNA treatment. After validating suppression of the Pmp22 mutant allele at the mRNA level in the Schwann cells of Tr-J mice, we observed increased expression levels of myelinating proteins such as myelin basic protein and myelin protein zero. These data indicate that selective suppression of the Pmp22 mutant allele by non-viral delivery of siRNA alleviates the demyelinating neuropathic phenotypes of CMT in vivo, implicating allele-specific siRNA treatment as a potent therapeutic strategy for dominantly inherited peripheral neuropathies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity ( p = 0.001) and time-to-80% on wash-out ( p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes.

Background: Cystic fibrosis (CF) heterozygotes with a single mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are at significantly higher risk to develop chronic rhinosinusitis (CRS). However the reasons why remain unknown. We tested the hypothesis that CFTR heterozygotes would have smaller sinus volumes than healthy controls. To exclude sinus disease as a confounding factor we also assessed paranasal sinus volume in those with CRS, but without known CFTR mutations., Methods: A total of 131 adults of white Northern European and Latino origin were recruited: 81 diagnosed with CRS and 50 healthy controls. Subjects were genotyped for 9 common CFTR mutations covering >80% of mutation prevalence. Those with CRS were separated by CFTR mutational status and matched demographically to healthy controls. Three-dimensional sinus volume, mucosal opacification, and skull volume were quantified to obtain the percentage of pneumatization and extent of mucosal disease in each sinus. Twenty-item Sino-Nasal Outcome Test (SNOT-20) and endoscopy scores were also analyzed., Results: In individuals diagnosed with CRS we identified 7 CFTR heterozygotes (8.64%); no CFTR mutations were identified in our healthy controls. There were no significant differences between the 3 matched groups other than sinus pneumatization. The frontal and maxillary sinuses were significantly smaller in CFTR heterozygotes with CRS compared to CFTR wild-type subjects with or without disease., Conclusion: CFTR heterozygotes with CRS have significantly smaller frontal and maxillary sinus size compared to those without mutations, irrespective of disease state. This sinus hypoplasia may contribute to impaired mucus clearance and chronic sinus disease development., (© 2016 ARS-AAOA, LLC.)

Diffusion tensor imaging (DTI) is used extensively in neuroscience to noninvasively estimate white matter (WM) microarchitecture. However, the diffusion signal is inherently ambiguous because it infers WM structure from the orientation of water diffusion and cannot identify the biological sources of diffusion changes. To compare inferred WM estimates to directly labeled axonal elements, we performed a novel within-subjects combination of high-resolution ex vivo DTI with two-photon laser microscopy of intact mouse brains rendered optically transparent by Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY). We found that myelin basic protein (MBP) immunofluorescence significantly correlated with fractional anisotropy (FA), especially in WM regions with coherent fiber orientations and low fiber dispersion. Our results provide evidence that FA is particularly sensitive to myelination in WM regions with these characteristics. Furthermore, we found that radial diffusivity (RD) was only sensitive to myelination in a subset of WM tracts, suggesting that the association of RD with myelin should be used cautiously. This combined DTI-CLARITY approach illustrates, for the first time, a framework for using brain-wide immunolabeling of WM targets to elucidate the relationship between the diffusion signal and its biological underpinnings. This study also demonstrates the feasibility of a within-subject combination of noninvasive neuroimaging and tissue clearing techniques that has broader implications for neuroscience research., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Minimal-change glomerulopathy is defined histologically by the presence of normal glomeruli on light microscopy and diffuse podocyte effacement on electron microscopy. Although effective in children, corticosteroid treatment in adults is more variable and time to response can be prolonged. Data to support rituximab use in adults with corticosteroid-dependent or resistant minimal-change glomerulopathy are limited. Here, we describe the clinical course of adults with corticosteroid-dependent or -resistant minimal-change glomerulopathy who received rituximab., Methods: Demographic and clinical data were collected and analyzed from all adult patients with native kidney, biopsy-proven, minimal-change glomerulopathy who were administered rituximab between 2009 and 2014 and cared for at the UNC Kidney Center., Results: Ten patients with corticosteroid-resistant (n = 5) or corticosteroid-dependent (n = 5) idiopathic minimal-change glomerulopathy were treated with rituximab between 2009 and 2014. Rituximab treatment induced remission in all 10 patients with a median time to remission of 2 months. The median time from rituximab to corticosteroid discontinuation was 3.5 months. The median remission time was 29 months and follow-up time was 39.5 months. No serious adverse events attributable to rituximab were observed., Conclusion: Rituximab induced remission in all patients with corticosteroid-dependent or -resistant minimal-change glomerulopathy, and may hold great therapeutic potential with good efficacy and minimal toxicity. Mounting evidence implies that a well-conducted randomized controlled clinical trial using rituximab in adults with minimal-change glomerulopathy in both corticosteroid-resistant and corticosteroid-dependent patients is warranted., (© 2017 S. Karger AG, Basel.)

We provide datasets from combined ex vivo diffusion tensor imaging (DTI) and Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY) performed on intact mouse brains. DTI-derived measures of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were compared to antibody-based labeling of myelin basic protein (MBP), as measured by fluorescence microscopy. We used a customized CLARITY hydrogel solution to facilitate whole brain tissue clearing and subsequent immunolabeling. We describe how CLARITY was made compatible with magnetic resonance imaging with the intention of facilitating future multimodal imaging studies that may combine noninvasive imaging with 3D immunohistochemistry. These data and methods are related to the accompanying research article entitled, 'The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains' (E.H. Chang, M. Argyelan, M. Aggarwal, T-S. Chandon, K.H. Karlsgodt, S. Mori, A.K. Malhotra, 2016) [1].

Objectives/hypothesis: Surgery and postoperative radiation therapy are commonly used in the treatment of advanced sinonasal cancer. However, post-treatment radiation changes to the brain often mimic radiologic findings suggestive of tumor recurrence, leading to potential unnecessary intracranial biopsies. The objective of this study was to determine clinical factors that predict signs of tumor recurrence versus radiation necrosis in post-therapy sinonasal malignancies with intracranial extension., Study Design: Retrospective study., Methods: Twenty-six patients with sinonasal malignancy with intracranial extension underwent surgery and radiation ± chemotherapy between 2010 and 2014 at the University of Arizona. We analyzed sinonasal cancer type, stage, total radiation dosimetry, time until imaging changes, surgical pathology, associated imaging, and patient demographics., Results: Thirteen of 26 patients had postoperative imaging changes seen on surveillance magnetic resonance imaging (MRI). Five were deemed to have tumor recurrence due to new metastasis seen on positron emission tomography/computed tomography scan. Four patients were observed with serial imaging that confirmed pseudoprogression. In four patients, there was sufficient concern due to persistent MRI changes, which prompted surgical biopsy, and only one of them was positive for tumor recurrence. Factors that favored tumor recurrence included faster onset of imaging changes on MRI (55 vs. 186 days, P < .05)., Conclusions: Intracranial tumor recurrence can be difficult to distinguish between radiation necrosis in sinonasal cancers treated with surgery and postoperative radiation ± chemotherapy. Patients with sub-total resection and rapid onset of MRI changes in postsurveillance scans are more likely to have tumor recurrence versus radiation necrosis. Future imaging techniques or tests that investigate tumor biomarkers are necessary to prevent unnecessary biopsies., Level of Evidence: 4 Laryngoscope, 126:2445-2450, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Sinonasal schwannomas with intracranial extension are exceedingly rare, with only 7 cases reported in the literature. Schwannomas can be isolated or multiple and are commonly associated with familial disorders such as neurofibromatosis 2 (NF 2) or familial schwannomatosis or in sporadic cases seen in sporadic schwannomatosis. Nearly all people with NF2 older than 30 years of age will have the hallmark of bilateral vestibular schwannomas (VS). This case highlights a reported case of an adult with separate primary intracranial tumors. We review the diagnostic criteria of NF2 and schwannomatosis, a recently described third variant of neurofibromatosis. In this case, we incorporate family history, histopathology, and the pathophysiology of both disorders to help determine a diagnosis for this patient., (© The Author(s) 2016.)

Introduction: Accountable care organizations (ACO) and alternative payment models are a sign of the change in reimbursement from fee-for-service to value-based reimbursement. The focus of health care under ACOs is represented by the Triple Aim: to improve the experience of health care, improve the health of populations, and reduce the per capita costs. Individuals with chronic rhinosinusitis (CRS) are heavy consumers of health care services. Results of recent studies have indicated that there is the potential for improved outcomes and cost savings from early surgical intervention. Adhering to the principles of the Triple Aim may signal a paradigm shift in regard to timing of intervention for CRS in certain patients., Methods: A scoping review was performed to analyze the current literature related to management of CRS and the impact on cost, population health outcomes, and the patient's experience of health care., Results: A growing body of literature indicates that, in appropriately selected patients, when compared with medical management, endoscopic sinus surgery has the potential to improve patient outcomes and reduce the long-term cost burden of CRS., Conclusion: With the advent of ACOs, a paradigm shift in the treatment of CRS is inevitable to better conform to the goals of the Triple Aim. Future treatment algorithms will need to account for the heterogeneity within CRS and seek to identify appropriate timing and interventions for patients on an individual basis if the value of health care is to be improved.

Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m(2)/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of -47%, -51%, and -79%. Two others had stable disease with significant shrinkage (-25% and -16%). These results support phase 2 testing of SGT-53 in combination with docetaxel.

Recognition of and binding to cholesterol on the host cell membrane is an initial step in the mechanism of numerous pathogens, including viruses, bacteria, and bacterial toxins; however, a viable method of inhibiting this interaction has not yet been uncovered. Here, we describe the mechanism by which a cholesterol recognition amino acid consensus peptide interacts with cholesterol and inhibits the activity of a cholesterol-binding bacterial leukotoxin (LtxA). Using a series of biophysical techniques, we have shown that the peptide recognizes the hydroxyl group of cholesterol with nanomolar affinity and does not disrupt membrane packing, suggesting that it sits primarily near the membrane surface. As a result, LtxA is unable to bind to cholesterol or subsequently become internalized in host cells. Additionally, because cholesterol is not being removed from the cell membrane, the peptide-treated target cells remain viable over extended periods of time. We have demonstrated the use of this peptide in the inhibition of toxin activity for an antivirulence approach to the treatment of bacterial disease, and we anticipate that this approach might have broad utility in the inhibition of viral and bacterial pathogenesis.

Traumatic brain injury (TBI) is common in both civilian and military life, placing a large burden on survivors and society. However, with the recognition of neural stem cells in adult mammals, including humans, came the possibility to harness these cells for repair of damaged brain, whereas previously this was thought to be impossible. In this review, we focus on the rodent adult subventricular zone (SVZ), an important neurogenic niche within the mature brain in which neural stem cells continue to reside. We review how the SVZ is perturbed following various animal TBI models with regards to cell proliferation, emigration, survival, and differentiation, and we review specific molecules involved in these processes. Together, this information suggests next steps in attempting to translate knowledge from TBI animal models into human therapies for TBI.

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.