International Consensus (ICON): allergic reactions to vaccines

Routine immunization, one of the most effective public health interventions, has effectively reduced death and morbidity due to a variety of infectious diseases. However, allergic reactions to vaccines occur v...

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Selection and characterization of single domain antibodies against human CD20

Publication date: October 2016
Source:Molecular Immunology, Volume 78
Author(s): Jinny L. Liu, Dan Zabetakis, Ellen R. Goldman, George P. Anderson
CD20 is a membrane protein with four integral membrane regions and a large extracellular loop between residues 142 and 187, which serves as a target binding region for rituximab (RTX) and most other anti-CD20 monoclonal antibodies. It is highly expressed in B-lymphoma cells and B lymphocytes and often serves as a target for immunotherapy. In this study, we developed single domain antibodies (sdAbs) for the sensitive detection of CD20. To achieve this, an immune sdAb library was prepared from llamas immunized with a fusion between the large loop from CD20 and Hoc, a highly antigenic protein from the T4 bacteriophage, (CD20-Hoc). By subtracting binders to recombinant Hoc during the biopanning, potential anti-CD20 sdAbs were selected, sequenced, and characterized for their binding affinity to CD20-Hoc fusion versus Hoc. Twenty five clones grouped into three different families based on CDR3 sequence were identified as potential CD20 binders. The binding kinetics of representative sdAbs from each class and RTX were evaluated by surface plasmon resonance (SPR). Most of the sdAbs that were evaluated show binding affinities to CD20-Hoc in the nM range, and class A sdAbs, exhibited ≥40-fold increase in affinity for CD20-Hoc versus Hoc. When the binding of the sdAbs to CD20 on SU-DHL-4 cells was evaluated by flow cytometry, only class A sdAbs displayed strong binding to CD20 and recognized DHL cells in a concentration dependent manner.



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IL-27 suppresses SKOV3 cells proliferation by enhancing STAT3 and inhibiting the Akt signal pathway

Publication date: October 2016
Source:Molecular Immunology, Volume 78
Author(s): Zhu Zhang, Bin Zhou, Kui Zhang, Yaping Song, Lin Zhang, Mingrong Xi
Ovarian cancer continues to be the most lethal gynecologic malignancy worldwide. IL-27 is a novel member of the IL-12 cytokine family. The aim of this study was to investigate the effects of IL-27 on the ovarian cystadenocarcinoma cell line SKOV3 and determine possible mechanisms underlying its effect. We stably transfected an IL-27 plasmid, empty vector, IL-27 shRNA or negative control into SKOV3 cells. Cell proliferative activity was evaluated using a WST-1 cell proliferation assay kit. Cell viability was quantified by measurements of lactate dehydrogenase release. The mRNA levels of nine genes were tested by q-PCR. Western blotting was used to verify apoptosis and signal pathways. We found that the IL-27 plasmid significantly enhanced cytotoxicity and inhibited the proliferation of SKOV3 cells. Caspase-3 protein was augmented by IL-27 plasmid and abated by IL-27 shRNA. The incremental expression of IL-27 activated the STAT3 pathway and attenuated the Akt pathway. The over-expression of IL-27 could significantly upregulate a series of antitumor cytokines including IL-6, IL-12 and interferon-γ and down-regulate protumor factors such as TLR4 and NF-κB1. Our data show that IL-27 has direct antitumor capacity in ovarian cancer cells via enhancing apoptosis by inducing the STAT3 pathway and restraining the Akt pathway.Précis: IL-27 enhanced the cytotoxicity and suppressed the proliferation of ovarian cancer cells by activating STAT3 and inhibiting the Akt signal pathway. IL-27 plays an important role in antitumor activity against epithelial ovarian cancer.



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Heralding a new paradigm in 3D tumor modeling

Publication date: November 2016
Source:Biomaterials, Volume 108
Author(s): Eliza L.S. Fong, Daniel A. Harrington, Mary C. Farach-Carson, Hanry Yu
Numerous studies to date have contributed to a paradigm shift in modeling cancer, moving from the traditional two-dimensional culture system to three-dimensional (3D) culture systems for cancer cell culture. This led to the inception of tumor engineering, which has undergone rapid advances over the years. In line with the recognition that tumors are not merely masses of proliferating cancer cells but rather, highly complex tissues consisting of a dynamic extracellular matrix together with stromal, immune and endothelial cells, significant efforts have been made to better recapitulate the tumor microenvironment in 3D. These approaches include the development of engineered matrices and co-cultures to replicate the complexity of tumor-stroma interactions in vitro. However, the tumor engineering and cancer biology fields have traditionally relied heavily on the use of cancer cell lines as a cell source in tumor modeling. While cancer cell lines have contributed to a wealth of knowledge in cancer biology, the use of this cell source is increasingly perceived as a major contributing factor to the dismal failure rate of oncology drugs in drug development. Backing this notion is the increasing evidence that tumors possess intrinsic heterogeneity, which predominantly homogeneous cancer cell lines poorly reflect. Tumor heterogeneity contributes to therapeutic resistance in patients. To overcome this limitation, cancer cell lines are beginning to be replaced by primary tumor cell sources, in the form of patient-derived xenografts and organoids cultures. Moving forward, we propose that further advances in tumor engineering would require that tumor heterogeneity (tumor variants) be taken into consideration together with tumor complexity (tumor-stroma interactions). In this review, we provide a comprehensive overview of what has been achieved in recapitulating tumor complexity, and discuss the importance of incorporating tumor heterogeneity into 3D in vitro tumor models. This work carves out the roadmap for 3D tumor engineering and highlights some of the challenges that need to be addressed as we move forward into the next chapter.



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The influence of titanium surface characteristics on macrophage phenotype polarization during osseous healing in type I diabetic rats: a pilot study

Abstract

Objectives

This study assessed the effect of titanium surface modification on macrophage phenotype polarization and osseous healing under diabetic conditions.

Materials and methods

Critical-sized calvarial defects were created in healthy and streptozotocin-induced type I diabetic Sprague-Dawley rats. Titanium (Ti) discs with either large-grit sandblasted and acid-etched micro-rough (SLA) or hydrophilic-modified SLA (modSLA) surfaces were used to cover the healing defect for a period of up to 28 days. Samples of the exudate within the calvarial defect and beneath the titanium discs were collected 1, 4 and 7 days post-surgery for inflammatory cytokine analysis using an ELISA. The macrophage phenotype(s) on the Ti disc surfaces were determined by CD11c+ (M1) and CD163+ (M2) immunofluorescent staining. Samples of the healing defects at days 14 and 28 were also prepared for histomorphometric analysis.

Results

Cytokine levels in the diabetic animals were higher than those of the healthy group throughout the observation period. The modSLA surface significantly reduced MIP-2 levels at day 1 in both diabetic and healthy animals, and MCP-1 levels at day 4 in the diabetic animals. Immuno-fluorescent staining showed that an M2-like macrophage phenotype was more frequently found on the modSLA surface at day 1 in healthy and day 4 in both healthy and diabetic animals. Histomorphometric analysis showed more new bone formation on the modSLA surface at days 14 and 28 in both groups, although statistically significant differences were only found in the healthy group.

Conclusion

Diabetic conditions greatly increased the expression of proinflammatory cytokines during osseous healing. The modSLA surface was shown to promote an M2-like macrophage phenotypic response in titanium adherent macrophages despite the significantly elevated inflammatory environment induced by uncontrolled type I diabetes. Modulation of the macrophage phenotype by the modSLA surface in the early healing period was associated with osseous healing under both healthy and uncontrolled diabetic conditions.

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Narratives of children with high-functioning autism spectrum disorder: A meta-analysis

Publication date: December 2016
Source:Research in Developmental Disabilities, Volume 59
Author(s): Inmaculada Baixauli, Carla Colomer, Belén Roselló, Ana Miranda
BackgroundThe aim of this meta-analysis was to analyze the narrative performance of children and adolescents with high-functioning Autism Spectrum Disorders (ASD) in terms of microstructure, macrostructure and internal state language.MethodA systematic literature search yielded 24 studies that met the predetermined inclusion criteria. Effect sizes for each study were calculated for eight variables and analyzed using a random effects model. Intellectual ability, age and type of narrative were considered as potential moderators.ResultsResults revealed that the children with ASD performed significantly worse than their peers on all the variables considered.ConclusionsFindings are discussed taking into account the main explanatory psychological autism theories. Implications for intervention and orientations for future research are suggested.



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p16 expression as a prognostic and predictive marker in high-grade localized osteosarcoma of the extremities: an analysis of 357 cases

Publication date: December 2016
Source:Human Pathology, Volume 58
Author(s): Alberto Righi, Marco Gambarotti, Marta Sbaraglia, Andrea Sisto, Stefano Ferrari, Angelo P. Dei Tos, Piero Picci
The potential prognostic and predictive value of p16 in high-grade localized osteosarcoma of the extremities has been recently investigated in small series of cases, and the results from different studies were somewhat controversial. A retrospective immunohistochemical analysis of p16 expression was performed in a series of 357 patients, included in different neoadjuvant chemotherapy protocols from 1986 to 2010, to explore its potential prognostic and predictive value. Immunohistochemistry was performed with a commercially available p16 monoclonal mouse antibody. Follow-up data were available in all cases with a median of 120 months. Positivity for p16 was detected in 70.6% (252/357) of cases. The p16 expression did not differ by age, sex, tumor site, histologic subtype, tumor volume, surgical margin, serum alkaline phosphatase levels, and lactate dehydrogenase levels. In the different chemotherapy protocols included, the incidence of p16 expression was similar. The absence of p16 expression was significantly associated with an adverse disease-free survival (P=.04) and overall survival (P=.05) when compared with the presence of p16 expression. At the multivariate Cox regression analysis, p16 expression lost its prognostic significance. Multivariate logistic regression analysis showed that as p16 expression was the only statistically significant parameter to predict the pathological response to neoadjuvant chemotherapy treatment with an odds ratio of 3.025 (P<.001) for "good" chemotherapy response. Our data indicate that the negative expression of p16 is associated with a reduced rate of good response to primary chemotherapy and to a worse probability of survival, although it was not confirmed as an independent prognostic biomarker after multivariate analysis.



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Renomedullary Interstitial Cell Tumors: Pathologic Features and Clinical Correlations.

Renomedullary interstitial cell tumors are common incidental findings in kidney specimens. Despite their frequency, little is known about their morphology and pathogenesis. Kidneys from 402 unselected autopsies were sectioned at 1 to 2 mm intervals, and all lesions were examined histologically. A total of 421 renomedullary interstitial cell tumors were present in 150 patients (37%), ranging from 1 to 23 tumors per patient (mean=3). There was no statistically significant difference in age, sex, hypertension, heart weight, tobacco smoking, diabetes mellitus, and renal function between patients with renomedullary interstitial cell tumors and those without. Almost half the patients with renomedullary interstitial cell tumors (41%) had bilateral tumors, and they were older than patients with unilateral tumors (P=0.0007). The tumors ranged in size from 0.5 to 6 mm (mean 1.7 mm). The lesions varied in cellularity: fibrous stroma was found in older patients, whereas cellular and hypocellular stroma predominated in younger patients (P=0.001 and P

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Myolipoma of Soft Tissue: Clinicopathologic Analysis of 34 Cases.

Myolipoma of soft tissue, which was first described by Meis and Enzinger (1991), is a rare benign neoplasm characterized by the admixture of mature adipocytes and well-differentiated smooth muscle cells. Recently, cytogenetic alteration of the HMGA2 gene has been reported in 2 myolipomas. We present the clinicopathologic features of 34 cases of myolipoma of soft tissue, study immunoreactivity for HMGA2, and review the previous literature. In our series, there were 32 women and 2 men, with age at presentation ranging from 35 to 94 years (median, 55 y). The most frequently affected site was retroperitoneum (47%), followed by pelvis (15%), abdominal wall (12%), and intra-abdominal sites (9%). Follow-up information was available for 17 patients (50%), ranging from 1 to 202 months (mean, 41 mo). None has developed local recurrence or metastasis. Grossly, tumors were well circumscribed, and the cut surface showed an admixture of yellowish adipose tissue and tan-whitish nodules. The size ranged from 2.4 to 60 cm (median 10.5 cm). Histologically, the tumors were composed of an intimate admixture of mature fat cells and bland spindle-shaped cells with brightly eosinophilic cytoplasm, arranged in fascicles. Some cases showed the following unusual features focally: hypercellular fascicular pattern (N=2), degenerative nuclear atypia (N=1), round cell morphology (N=1), hemosiderin deposition (N=1), metaplastic cartilage (N=1), metaplastic bone (N=1), and eosinophil infiltrates (N=1). Immunohistochemically, spindle cells showed strong and diffuse positivity for desmin (26/26 cases), SMA (20/21), and ER (13/15). Nuclear positivity for HMGA2 was identified in 15 of 25 cases (60%). MDM2 and CDK4 were usually negative (14/15, 8/9, respectively). In summary, myolipoma of soft tissue is a distinctive benign tumor composed of mature fat cells and smooth muscle cells and arises most commonly in deep-seated locations of middle-aged women. In our study, 60% of cases showed nuclear staining for HMGA2 by immunohistochemistry, which supports the possibility that these tumors harbor aberration of the HMGA2 gene, as seen in lipomas and leiomyomas elsewhere. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci: A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma.

An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes-including FH-performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH+/- positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH+/-/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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NRASQ61R Mutation-specific Immunohistochemistry Also Identifies the HRASQ61R Mutation in Medullary Thyroid Cancer and May Have a Role in Triaging Genetic Testing for MEN2.

A quarter of patients with medullary thyroid carcinoma (MTC) have germline mutations in the RET proto-oncogene indicating MEN2. Therefore genetic testing is recommended for all patients presenting with MTC. Approximately 40% of MTCs have somatic RET mutations. Somatic mutations in the RAS genes are the next most common driver mutations and appear to be mutually exclusive with germline RET mutation. The single most common somatic RAS mutation is HRASQ61R (c.182A>G), reported in 4.6% to 11% of all MTCs. Mutation-specific immunohistochemistry (IHC) initially developed to identify the NRASQ61R mutation in melanoma (clone SP174) has proven highly sensitive and specific. Because the amino acid sequences for the HRAS and NRAS proteins at codon 61 are identical, we postulated that SP174 IHC would also identify the somatic HRASQ61R mutation. IHC with SP174 was performed on a tissue microarray of 68 patients with MTC including 13 (22.8%) with molecularly confirmed MEN2. Seven (10.3%) MTCs demonstrated positive staining. Six of these patients had already undergone germline RET mutation testing as part of clinical care and were all confirmed to be wild type, excluding the diagnosis of MEN2. All SP174 immunohistochemically positive MTCs were proven to have HRASQ61R mutation (and lack KRASQ61R and NRASQ61R) by Sanger sequencing. All MEN2 patients showed negative staining. We conclude that IHC with SP174 is highly specific for the HRASQ61R mutation in MTC. Because current data suggest that this mutation is mutually exclusive with germline RET mutation, IHC may also have a role in triaging formal genetic testing for MEN2. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1hexVwJ Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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SMARCB1/INI1 Involvement in Pediatric Chordoma: A Mutational and Immunohistochemical Analysis.

Chordomas arise in the skull base and spine and usually occur in adults and are rare in the pediatric population. Cases of chordoma in pediatric age are often poorly differentiated, showing cytologic atypia, increased cellularity, and mitosis, and their aggressive behavior is associated with a high incidence of metastatic spread and a short patient survival. Recent studies have described loss of SMARCB1/INI1 protein in poorly differentiated chordomas associated not with point mutations but with SMARCB1/INI1 gene deletions instead. In this study, we considered immunohistochemistry and SMARCB1/INI1 mutational status to examine SMARCB1 status in a series of pediatric chordomas (7 classic and 1 poorly differentiated). We performed immunohistochemical tests for INI1, brachyury, S100, and cytokeratins and conducted a genetic analysis on the SMARCB1 coding sequence (NM_003073) using the Sanger method and multiplex ligation-dependent probe amplification to detect abnormal copy numbers of the gene locus. All 8 cases were positive for brachyury, whereas there was no nuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly differentiated chordoma. Genetic analysis identified a missense mutation in 2 cases and a nonsense mutation associated with loss of SMARCB1/INI1 protein and features of poorly differentiated tumor in 1. These mutations were novel variants occurring in heterozygosity, and they were judged to be pathogenic by 3 different bioinformatic tools. In 7 of 8 cases we performed multiplex ligation-dependent probe amplification, and 3 cases showed deletions at the SMARCB1 locus. Our results confirm the pathogenic involvement of SMARCB1/INI1 in childhood chordoma. We also describe 3 novel pathogenic mutations. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Histologic Grading of Prostatic Adenocarcinoma Can Be Further Optimized: Analysis of the Relative Prognostic Strength of Individual Architectural Patterns in 1275 Patients From the Canary Retrospective Cohort.

Histologic grading remains the gold standard for prognosis in prostate cancer, and assessment of Gleason score plays a critical role in active surveillance management. We sought to optimize the prognostic stratification of grading and developed a method of recording and studying individual architectural patterns by light microscopic evaluation that is independent of standard Gleason grade. Some of the evaluated patterns are not assessed by current Gleason grading (eg, reactive stromal response). Individual histologic patterns were correlated with recurrence-free survival in a retrospective postradical prostatectomy cohort of 1275 patients represented by the highest-grade foci of carcinoma in tissue microarrays. In univariable analysis, fibromucinous rupture with varied epithelial complexity had a significantly lower relative risk of recurrence-free survival in cases graded as 3+4=7. Cases having focal "poorly formed glands," which could be designated as pattern 3+4=7, had lower risk than cribriform patterns with either small cribriform glands or expansile cribriform growth. In separate multivariable Cox proportional hazard analyses of both Gleason score 3+3=6 and 3+4=7 carcinomas, reactive stromal patterns were associated with worse recurrence-free survival. Decision tree models demonstrate potential regrouping of architectural patterns into categories with similar risk. In summary, we argue that Gleason score assignment by current consensus guidelines are not entirely optimized for clinical use, including active surveillance. Our data suggest that focal poorly formed gland and cribriform patterns, currently classified as Gleason pattern 4, should be in separate prognostic groups, as the latter is associated with worse outcome. Patterns with extravasated mucin are likely overgraded in a subset of cases with more complex epithelial bridges, whereas stromogenic cancers have a worse outcome than conveyed by Gleason grade alone. These findings serve as a foundation to facilitate optimization of histologic grading and strongly support incorporating reactive stroma into routine assessment. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Mixed Epithelial and Stromal Tumor of the Kidney: A Clinicopathologic Study of 53 Cases.

Mixed epithelial and stromal tumor of the kidney is an uncommon complex neoplasm, and previous studies have included only a modest number of cases and have left gaps in our understanding of its morphology. We analyzed 53 tumors (46 F, median age: 49 y), collecting data on gross, histologic, and immunohistochemical features. The most common gross appearance was solid and cystic (47%). Hypocellular fibrous and cellular spindle cell stroma were the most common stromal types, followed by smooth muscle differentiation, edematous stroma, and adipose tissue. Hypocellular fibrous stroma and adipose tissue were more common in larger tumors (P=0.003 and 0.04, respectively) and cellular spindle cell stroma in smaller tumors (P=0.0009). Combinations of diverse stromal elements were common: roughly 50% of tumors contained >4 types of stroma. With regard to epithelium, tiny crowded and branching glands were present in 60% of tumors. Round glands lined by tall cuboidal epithelium, reminiscent of thyroid follicles, spatulate papillae reminiscent of phyllodes tumor, glands reminiscent of nephrogenic adenoma, and complex papillae were also frequently found. Combinations of diverse epithelial elements were common: 64% of tumors contained >4 types of epithelium. All of the tumors except 1 were positive for smooth muscle actin in the stroma. Desmin and caldesmon expression were more variable. Stains for progesterone and estrogen receptors showed positivity in the stromal component in 85% and 73% of tumors, respectively. CD10 and CD34 immunolabeling were restricted to pericystic spindle cells. No tumor expressed inhibin. In summary, this study demonstrates a strong tendency for mixed epithelial and stromal tumors to contain multiple types of stroma and epithelium and comprehensively analyzes the immunohistochemical profile. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Adaptation and Compensation of Vestibular Responses Following Superior Canal Dehiscence Surgery

Objective: To describe vestibulo-ocular function and compensatory mechanisms in the immediate postoperative period after superior canal dehiscence surgery. Study Design: Prospective longitudinal study. Setting: Tertiary medical center. Patients: Five patients who underwent plugging of superior semicircular canal via middle cranial fossa approach. Interventions: Bedside quantitative video head impulse testing (vHIT). Main Outcome Measures: Dynamic measures of vestibulo-ocular reflex (VOR) function including VOR gain and compensatory saccades during vHIT. Results: Mean VOR gain of the ipsilateral superior semicircular canal (SC) decreased from 0.71 ± 0.1 preoperatively to 0.28 ± 0.07 on postoperative day (POD) 2–4 (p = 0.0031), consistent with plugging. There was also a significant immediate postoperative decrease of VOR gain for the other ipsilateral canals (posterior canal (PC) from gain 0.91 ± 0.33 down to 0.55 ± 0.14, p = 0.040; horizontal canal (HC) from 0.81 ± 0.08 down to 0.54 ± 0.19, p = 0.038). On PODs 1–2, compensatory saccades after testing the plugged SC occurred exclusively after the head stopped moving (overt) with latency of 186.2 ms ± 19.9 ms. By POD 7 saccade latency decreased to 141.0 ± 17.5 ms (p = 0.032), and saccades were occurring during the vertical head rotation (covert saccades). Follow-up >40 days was consistent with previous findings in that mean SC gain remained low. HC gain recovered fully, but some cases did not have full recovery of PC gain. Conclusion: When the SC is plugged surgically, early quantitative vHIT demonstrates significantly reduced VOR gain for all of the ipsilateral canals. Possible mechanisms include labyrinthine inflammation and loss of perilymph at the time of surgery. Full recovery is typical for the horizontal canal but not always for the PC. Evidence of central compensation occurred by the elicitation of compensatory saccades and by reducing their latencies within the first week after surgery.

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Letter From the New Editor-in-Chief

No abstract available

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What Could Posturography Tell Us About Balance Problems in Parkinson's Disease?

Objective: Impaired balance in patients with Parkinson's disease (PD) leads to loss of balance and frequent falls. Computerized dynamic posturography allows the assessment of stance tasks whereas mobile posturography analyzes the balance in free-field conditions, where falls among PD patients commonly occur (e.g. sitting down or standing up). The aim of the present study is to assess postural stability in PD patients with both techniques. Study Design: Prospective study. Setting: University Hospitals, ambulatory care (outpatient clinic). Patients: Thirty-three patients diagnosed with idiopathic PD. Intervention: Balance assessment. Main Outcome Measures: Dizziness handicap inventory (DHI), activities-specific balance confidence scale (ABC), composite score of sensory organization test (SOT), results of free-field body sway analysis (standard balance deficit test (SBDT)), or geriatric SBDT. Results: PD patients showed a significantly higher sway in the roll direction in almost all of the SBDT conditions. Also, pathological sway compared with normative values was more prominent in complex tasks. There is a significant correlation between the different objective variables of the postural study (SOT and SBDT) and the ABC, but not with the DHI. Finally, the percentage of PD patients with a pathological score in SOT-composite score was 54.5% whereas in SBDT-composite score it was significantly higher (93.9%). Conclusion: Mobile posturography is more accurate in depicting the reality of balance impairment in PD patients than platform posturography. Also, ABC relates better than DHI to the significant psychological consequences of balance impairments. An increased lateral trunk sway seems to be a key factor of postural instability in PD patients.

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The Chronic Ear: John L. Dornhoffer and Michael B. Gluth, eds.; New York: Thieme, 2016.

No abstract available

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Role of STAT1 and Oxidative Stress in Gentamicin-Induced Hair Cell Death in Organ of Corti

Rationale: Oxidative stress plays a critical role in gentamicin-induced hair cell death. Previous work has implicated the cytoplasmic transcription factor signal transducer and activator of transcription 1 (STAT1) as a potential mediator of drug-induced ototoxicity, but role in aminoglycosides is largely unknown. This study investigated aminoglycosides-induced cell death, exploring contributions of reactive oxygen species and STAT1 pathway in injury and protection. Methods: Neonatal murine organ of Corti explants from 2 to 3 day postnatal pups (n = 96) were treated with gentamicin at (4 μM, 50 μM) for 4 to 72 hours, with/without protectants. Effects on STAT1 pathway and gentamicin-induced hair cell death were measured with 50 μM Epigallocatechin gallate (EGCG, a STAT1 inhibitor) and all-trans retinoic acid (atRA, a STAT1 activator). Hair cell morphology was evaluated and hair cell loss was quantified with cytocochleograms. Mitochondrial membrane potential was assayed and superoxide generation and suppression was measured with dihydroethidium (DHE) staining. Results: Co-administration of 50 μM EGCG conferred protection from 4 μM gentamicin toxicity (p 

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Music-induced Hearing Loss in Children, Adolescents, and Young Adults: A Systematic Review and Meta-analysis

Objective: Exposure to loud music has increased significantly because of the current development of personal music players and mobile phones. The aim of this study was to provide an overview of music-induced hearing loss and its symptoms in children. Data Sources: The search was performed in the databases Embase, Medline (OvidSP), Web-of-science, Scopus, Cinahl, Cochrane, PubMed publisher, and Google Scholar. Only articles written in English were included. Study Selection: Articles describing hearing levels and music exposure in children were used, published from 1990 until April 2015. Data Extraction: The quality of the studies was assessed on reporting, validity, power, and the quality of audiometric testing. Data Synthesis: Data of each publication was extracted into spreadsheet software and analyzed using best evidence synthesis. Conclusion: The prevalence of increased hearing levels (>15 dB HL) was 9.6%, and high-frequency hearing loss was found in 9.3%. The average hearing thresholds were 4.79 dB HL at low frequencies (0.5, 1, and 2 kHz) and 9.54 dB HL at high frequencies (3, 4, and 6 kHz). Most studies reported no significant association between pure-tone air thresholds and exposure to loud music. However, significant changes in hearing thresholds and otoacoustic emissions, and a high tinnitus prevalence suggest an association between music exposure and hearing loss in children.

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Intracranial Pressure and Promontory Vibration With Soft Tissue Stimulation in Cadaveric Human Whole Heads

Hypothesis: Intracranial pressure and skull vibrations are correlated and depend on the stimulation position and frequency. Background: A hearing sensation can be elicited by vibratory stimulation on the skin covered skull, or by stimulation on soft tissue such as the neck. It is not fully understood whether different stimulation sites induce the skull vibrations responsible for the perception or whether other transmission pathways are dominant. The aim of this study was to assess the correlation between intracranial pressure and skull vibration measured on the promontory for stimulation to different sites on the head. Methods: Measurements were performed on four human cadaver heads. A bone conduction hearing aid was held in place with a 5-Newton steel headband at four locations (mastoid, forehead, eye, and neck). While stimulating in the frequency range of 0.3 to 10 kHz, acceleration of the cochlear promontory was measured with a Laser Doppler Vibrometer, and intracranial pressure at the center of the head with a hydrophone. Results: Promontory acceleration and intracranial pressure was measurable for all stimulation sites. The ratios were comparable between all stimulation sites for frequencies below 2 kHz. Conclusion: These findings indicate that both promontory acceleration and intracranial pressure are involved for stimulation on the sites investigated. The transmission pathway of sound energy is comparable for the four stimulation sites.

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Outer Hair Cell Molecular Protein, Prestin, as a Serum Biomarker for Hearing Loss: Proof of Concept

Hypothesis: At present there are no serum biomarkers available to monitor cochlear health in those at risk of hearing loss. Outer hair cells (OHCs) play an important role in cochlear function and are one of the cellular elements most vulnerable to damage, such as acoustic trauma. We hypothesized that an OHC-specific protein can serve as a biomarker for OHC damage in circulation. Methods: After assessing auditory function, rats were exposed to intense octave band noise for 2 to 3 hours. Auditory function was assessed 14 days after trauma. Blood samples were collected and prestin concentration was measured using enzyme-linked immunosorbent assay. Results: Circulating prestin was detectable in all control and noise-exposed animals. At 14 days after trauma, however, noise-exposed rats demonstrated statistically significant decrease in prestin concentrations compared with control animals. Conclusion: This work, for the first time, provides proof of concept that an otologic serum biomarker level can change after acoustic trauma and hearing loss. Our approach represents an entirely novel strategy in hearing diagnostics and has both research and clinical potential. Further work is needed to map out the temporal course of change in serum prestin concentrations after inner ear trauma, better define the relationship of serological and functional changes, and explore application to other etiologies of hearing loss (e.g., ototoxins).

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Postoperative Complications and Readmission Rates Following Surgery for Cerebellopontine Angle Schwannomas

Objective: To investigate the 30-day postoperative complication, readmission, and reoperation rates following surgery for cerebellopontine angle (CPA) schwannomas. Study Design: Cross-sectional analysis. Setting: National surgical quality improvement program dataset (NSQIP) 2009 through 2013. Patients: All surgical cases with an International Classification of Diseases, 9th edition, Clinical Modification (ICD-9-CM) diagnosis code of 225.1, benign neoplasms of cranial nerves, and one of the following current procedural terminology (CPT) codes, were included: 61616, 61526, 61530, and 61520. Intervention(s): Surgical resection as indicated by the CPT codes above. Main Outcome Measure(s): Demographics, comorbidities, 30-day postoperative complications, readmission rate, and reoperation rate. Results: Overall, 404 cases were identified, of which 42.6% were men. The average age was 51 years. Comorbidities were present in 45.3%. NSQIP-tracked complications occurred in 9.7% of patients. Most common complications were wound infections including surgical-site infection and wound dehiscence (11 patients, 2.7%), sepsis (10 patients, 2.5%), blood loss (nine patients, 2.2%), and deep vein thrombosis (DVT; seven patients, 1.7%). Mortality occurred in four patients (1.0%). The complication rate was statistically higher in patients with comorbidities versus those without (10.2% versus 4.1%, p = 0.04). Patients with complications were more likely to undergo reoperation (2.5% with versus 4.1% without, p = 0.001). Unplanned readmissions occurred in 41 cases (10.1%) and reoperations occurred in 23 patients (5.7%). Conclusions: Most common NSQIP-tracked complications in excision of CPA neoplasms are infections, sepsis, blood loss, and deep vein thrombosis (DVT). Further, investigation of patients with unplanned readmission and reoperation are warranted. Neurotologists need to take an active role in the data to be gathered in the NSQIP database as it relates to vestibular schwannomas.

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Applying Neurotrophins to the Round Window Rescues Auditory Function and Reduces Inner Hair Cell Synaptopathy After Noise-induced Hearing Loss

Hypothesis: Applying neurotrophins to the round window immediately after a single noise exposure will prevent noise-induced hidden hearing loss. Background: Loud noise can eliminate neural connections between inner hair cells and their afferent neurons (thereby diminishing sound perception) without causing a detectable change on audiogram. This phenomenon is termed hidden hearing loss. Methods: Guinea pigs were exposed for 2 hours to 4 to 8 kHz noise at either 95 or 105 dB SPL. Immediately afterward a 4 μl bolus of neurotrophins (brain-derived neurotrophic factor 1 μg/μl, and neurotrophin-3 1 μg/μl) was delivered to the round window of one ear, and saline to the other. Auditory brainstem responses to pure-tone pips were acquired preoperatively, and at 1 and 2 weeks' postexposure. Cochleae were removed and whole mounted for immunohistochemical analysis, with presynaptic ribbons of inner hair cells and associated postsynaptic glutamatergic AMPA receptors identified using CtBP2 and GluA2 antibodies respectively. Results: After exposure to 105 dB noise, threshold did not change, but the amplitude growth of the auditory brainstem response was significantly reduced in control ears in response to 16 and 32 kHz tones. The amplitude growth was also reduced neurotrophin ears, but to a lesser degree and the reduction was not significant. Similar results were obtained from control ears exposed to 95 dB, but amplitude growth recovered in neurotrophin-treated ears, this reaching statistical significance in response to 16 kHz tones. There were significantly more presynaptic ribbons, postsynaptic glutamate receptors, and colocalized ribbons after neurotrophin treatment. Conclusion: A single dose of neurotrophins delivered to the round window reduced synaptopathy and recovered high-frequency hearing in ears exposed to 95 dB noise. These findings suggest that hidden hearing loss may be reduced by providing trophic support to the cochlea after injury.

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Hyperostotic En Plaque Meningioma Mimicking Fibrous Dysplasia of the Temporal Bone

No abstract available

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The Underlying Mechanism of Preventing Facial Nerve Stimulation by Triphasic Pulse Stimulation in Cochlear Implant Users Assessed With Objective Measure

Hypothesis: Triphasic pulse stimulation prevents from facial nerve stimulation (FNS) because of a different electromyographic input–output function compared with biphasic pulse stimulation. Background: FNS is sometimes observed in cochlear implant users as an unwanted side effect of electrical stimulation of the auditory nerve. The common stimulation applied in current cochlear implant consists of biphasic pulse patterns. Two common clinical remedies to prevent unpleasant FNS caused by activation of certain electrodes are to expand their pulse phase duration or simply deactivate them. Unfortunately, in some patients these methods do not provide sufficient FNS prevention. In these patients triphasic pulse can prevent from FNS. The underlying mechanism is yet unclear. Methods: Electromyographic (EMG) recordings of muscles innervated by the facial nerve (musculi orbicularis ori and oculi) were applied to quantitatively assess the effects on FNS. Triphasic and biphasic fitting maps were compared in four subjects with severe FNS. Based on the recordings, a model is presented which intends to explain the beneficial effects of triphasic pulse application. Results: Triphasic stimulation provided by fitting of an OPUS 2 speech processor device. For three patients, EMG was successfully recorded depending on stimulation level up to uncomfortable and intolerable FNS stimulation as upper boarder. The obtained EMG recordings demonstrated high individual variability. However, a difference between the input–output function for biphasic and triphasic pulse stimulation was visually observable. Compared with standard biphasic stimulation, triphasic pulses require higher stimulation levels to elicit an equal amount of FNS, as reflected by EMG amplitudes. In addition, we assume a steeper slope of the input–output function for biphasic pulse stimulation compared with triphasic pulse stimulation. Conclusion: Triphasic pulse stimulation prevents from FNS because of a smaller gradient of EMG input–output function compared with biphasic pulse stimulation. The underlying mechanism can be modeled by differences in spatiotemporal spread of the electrical field.

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Long-term Hearing Preservation Outcomes After Cochlear Implantation for Electric-Acoustic Stimulation

Objective: This study reviewed outcomes of hearing preservation (HP) surgery in a cochlear implant patient population, with clinical follow-up results up to 11 years after implantation. Study Design: Retrospective case review. Setting: Tertiary referral university hospital. Patients: Ninety six patients (103 ears) with partial deafness who underwent HP surgery at the University Hospital Frankfurt since 1999 were included. Electrode carriers were Cochlear Slim Straight, MED-EL Standard, Medium, Flex20, and Flex24. Intervention: Cochlear implantation using the HP surgery technique with either the cochleostomy or round window approach. Main Outcome Measures: Pure-tone averages for low frequencies (125 Hz, 250 Hz, 500 Hz, PTAlow) and speech perception scores of the Freiburg monosyllable and number tests in quiet. PTAlow shifts were used to evaluate HP as complete for ≤10 dB, partial between 10 and 30 dB, and minimal for ≥30 dB. Time intervals were: preoperative, postoperative, after 12 months, and long-term (>24 months, mean 51.4 months, range 2–11 years). Impacts of electrode design and surgical approach were analyzed. Results: Postoperatively (n = 103), HP was complete in 32 (31.1%), partial in 49 (47.6%), minimal in 14 (13.6%), and loss of hearing occurred in 8 cases (7.8%). After 12 months (n = 81), HP was complete in 22 (27.2%), partial in 33 (40.7%), minimal in 11 (13.6%), and loss of hearing occurred in 7 additional cases. For long-term outcomes (n = 62) HP was complete in 7 (11.3%), partial in 24 (38.7%), minimal in 9 (14.5%), and loss of hearing occurred in 7 additional cases (total 22/103, 21.4%). Cases with residual hearing who could utilize acoustic amplification (i.e., PTAlow 

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Cochlear Implants in Adults: Effects of Age and Duration of Deafness on Speech Recognition

Objective: Unexplained outcome variability exists among adults with cochlear implants (CIs). Two significant predictors are age and duration of deafness, with older patients and those with longer durations of deafness generally demonstrating poorer speech recognition. However, these factors are often highly correlated. Thus, it is unclear whether poorer outcomes should be attributed primarily to age-related declines or to the experience of auditory deprivation. Our aim was to examine the effects of aging and duration of hearing loss on outcomes for postlingually deaf adults with CIs. Study Design: Retrospective review of adults who received CIs from 1983 to 2014. Setting: Tertiary adult CI program. Patients: Sixty-four adult patients with postlingual hearing loss beginning after age 12 years, full electrode insertion, normal cochlear anatomy, and availability of postoperative outcome measures. Intervention: Cochlear implantation with 12 months or greater of device use. Main Outcome Measures: Postoperative pure-tone averages (0.5, 1, 2, and 3 kHz) and recognition of words in sentences (Hearing in Noise Test and AzBio). Results: Age at postoperative testing had a negative partial correlation with AzBio scores, when controlling for duration of deafness, whereas duration of deafness had a positive partial correlation with AzBio scores, when controlling for age. No other effects were identified. Conclusion: Older age at testing was associated with poorer recognition of words in difficult sentences, suggesting that cognitive aging may negatively impact CI outcomes. Further studies are needed to examine how a long duration of auditory deprivation affects CI outcomes.

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Calcium Homeostasis During Attack and Remission in Patients With Idiopathic Benign Paroxysmal Positional Vertigo

Objective: To evaluate changes in calcium metabolism in patients with idiopathic benign paroxysmal positional vertigo (BPPV) on initial presentation and at the follow-up visit. Subjects and Methods: The study comprised a total of 31 patients aged greater than 18 years who presented at the otorhinolaryngology outpatient clinic of our hospital, newly diagnosed as idiopathic BPPV based on the history compatible with BPPV and positive provocative maneuver (either Dix-Hallpike or Roll test). The first blood sample was obtained on the day of initial presentation when the patient was found to have active unilateral BPPV. After 6 months, a blood sample was again drawn in accordance with the procedure. Blood samples were analyzed for data on 25-hydroxyvitamin D (25(OH)-D), total calcium, parathormone and ionized calcium on initial presentation, and at the follow-up visit. Results: The patients comprised 20 (64.5%) women and 11 (35.5%) men with a mean age of 49.78 years (range, 23–75 years). During an attack a higher prevalence of decreased serum Vitamin D is less than 20 ng/ml, was determined (93.5% versus 38.7%). There were statistical differences between the Vitamin D values, parathormone, and corrected by pH ionized calcium in both periods (p 

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Cone Beam CT Versus Multislice CT: Radiologic Diagnostic Agreement in the Postoperative Assessment of Cochlear Implantation

Objective: To evaluate the diagnostic concordance between multislice computed tomography (MSCT) and cone beam computed tomography (CBCT) in the early postoperative assessment of patients after cochlear implantation. Study Design: Prospective, randomized, single-center, interventional, pilot study on the diagnostic performance of a medical device. Setting: Tertiary referral center. Patients: Patients aged over 18 years requiring a computed tomographic (CT) scan after cochlear implant surgery. Interventions: Nine patients were implanted with electrode arrays from three different manufacturers, including one bilateral. High-resolution MSCT and CBCT were then performed, and two experienced radiologists blinded to the imaging modality evaluated the randomized images, twice. Main Outcome Measures: Concordance between MSCT and CBCT for assessing the scalar position (tympani or vestibuli) of the electrodes. Secondary outcome measures were also studied: length of the intracochlear electrode array, percentage of implanted cochlea, number of intracochlear electrodes, and radiation doses. Results: There was a good agreement between both CT scanners in determining the scalar position and estimating the number of implanted electrodes and percentage of implanted cochlea. CBCT had a lower radiation exposure. Conclusions: The CBCT appears to be a useful tool for postoperative assessment of cochlear implanted adult patients and is comparable to the conventional scanner in determining the scalar position, with lower radiation exposure.

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Real Incidence of Vestibular Schwannoma? Estimations From a National Registry

Objective: To identify incidence of vestibular schwannoma (VS) in The Netherlands. Determining incidence of VS poses considerable challenges given the lack of complete epidemiologic data. Study Design: Retrospective patient review. Setting: Tertiary referral center. Patients: Patients with VS in The Netherlands. Data on patients with VS during 2001 to 2012 were obtained from The Netherlands Cancer Registry (NCR). Notification to the NCR is primarily pathology-based, but additional sources are used, including databases from hospital registrations and radiology departments. In addition, VS incidence estimations for the Leiden region were made; since these data are considered most complete, it was anticipated that estimates calculated from this region approximated the true incidence of VS in The Netherlands. Intervention(s): Magnetic resonance imaging (MRI). Main Outcome Measure(s): Incidence of VS. Results: From 2001 to 2012, a total of 3,663 patients of VS were registered. One thousand forty patients (28.4%) were pathologically confirmed, the majority only had a clinical diagnosis (n = 2623, 71.6%). Incidence increased from 10.3 per one million inhabitants (European Standardized Rate, ESR) to 15.5. Considerable variation in incidence rates was observed across regions, ranging from 12.0 to 24.9 per million over the total period. In the Leiden region, incidence was estimated at 25.5 per million during 2005 to 2007, and 33.2 per million during 2009 to 2012. In this region, the ratio of clinical versus histopathological diagnoses rose from 1.4 to 6.7. Conclusions: Completeness of the registration of VS varies across regions in The Netherlands. Incidence estimates obtained from regions with the highest rates are higher than those reported by previous studies.

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Air-Bone Gaps Contribute to Functional Hearing Preservation in Cochlear Implantation

Objective: To examine the incidence and effect of postoperative air-bone gaps in subjects who received cochlear implants for the purpose of hearing preservation. Study Design: Prospective, multicenter, nonrandomized, repeated measures within subject design. Setting: Ten tertiary care institutions. Patients: Fifty adults participating in a multicenter clinical trial of the Cochlear Nucleus Hybrid implant system. Intervention(s): Cochlear implantation with Hybrid L24 electrode. Audiometric testing including air and bone conductive thresholds and tympanometry preoperatively and at multiple time points postoperatively for 1 year. Main Outcome Measure(s): Average air-bone gaps (ABG) and percentage of patients with ABGs (≥15 dB HL) measured for each time point for 1 year postoperatively at 250, 500, and 1000 Hz. Correlation of tympanograms and ABGs. Results: The mean ABGs at 250, 500, and 1000 Hz increased postoperatively (p 60% of patients at 250 Hz, in >38% at 500 Hz, and in >50% at 1000 Hz in those with residual hearing. No significant relationships were found between abnormal tympanograms and ABG. Conclusion: The incidence of ABGs postoperatively is higher than previously expected and does not correlate to abnormalities on tympanometry. ABGs can adversely affect the fitting of postoperative residual hearing and associated functional benefit. Additionally, intraoperative strategies should be used to potentially reduce ABGs, and bone conduction thresholds should be measured postoperatively.

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The Clinical Behavior of Asymptomatic Incidental Vestibular Schwannomas Is Similar to That of Symptomatic Tumors

Background: The clinical behavior of asymptomatic incidentally diagnosed vestibular schwannoma (VS) remains undefined. Specifically, it is unknown whether these tumors represent a more indolent biological variant. Such information would be beneficial toward patient counseling regarding treatment strategy and surveillance intervals during observation. Study Design: Case series with matched cohort. Setting: Single tertiary academic referral center. Patients: All patients with asymptomatic incidentally diagnosed VS who were evaluated between January 2000 and December 2015 were analyzed. Only cases where imaging was obtained for unrelated indications in patients with symmetrical or normal hearing and lack of any attributable symptoms were included. A separate VS reference cohort composed of patients with typical symptomatology, matched according to tumor size, age and sex, was used for comparison. Main Outcome Measures: Growth, symptom progression, treatment. Results: A total of 38 incidental VS were evaluated, representing approximately 1.6% of all VS evaluated during this time. There was a statistically significant increase in the rate of incidental tumor diagnosis over time. Estimated survival free of tumor growth or treatment (95% CI; number still at risk) at 1, 3, and 5 years after diagnosis was 89% (77–100; 22), 74% (57–95; 13), and 54% (35–84; 4), respectively. The median growth rate for the 11 patients with tumor growth was 1.3 mm/year. Time to growth or treatment (p = 0.18), growth rate (p = 0.60), and rate of audiometric decline was not statistically significantly different between incidentally discovered and symptomatic reference groups. Conclusion: The frequency of asymptomatic, incidentally diagnosed VS is rising. These data demonstrate that the clinical behavior of asymptomatic incidental VS is not different than that of age-, sex-, and size-matched symptomatic VS. Thus, if initial observation is undertaken, patients with asymptomatic incidental tumors still require long-term magnetic resonance imaging surveillance performed at regular time intervals.

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Massive Tension Pneumocephalus Following Cochlear Implant Surgery

Objective: To report clinical presentation, management and outcomes of a rare complication of cochlear implant surgery. Patient: A 68-year-old man, affected by profound bilateral deafness because of superficial cerebral hemosiderosis, presented to Authors' Department 8 days after cochlear implant surgery with vomiting, fever, and mental confusion. Brain computed tomographic (CT) scan showed a massive collection of intracranial air from an osteodural defect in the right tegmen mastoideum because of repeated nose blowing in the postoperative period. Intervention: A multilayer reconstruction of the tegmen with obliteration of the mastoid cavity using abdominal subcutaneous adipose tissue was performed, preserving the cochlear implant in place. Main Outcome and Results: Following surgery the patient showed rapid neurological improvement and CT scan performed 2 days later showed complete resolution of the intracranial air collection. He is currently using the cochlear implant with open set performances. Conclusion: Pneumocephalus is a rare complication of cochlear implant surgery. In patients with severe neurological signs following cochlear implantation (CI), pneumocephalus should be suspected. Drilling of mastoid air cells may expose dura mater and positive high pressure events may break meningeal layers and force air into the cranial cavity.

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Ebola virus: A gap in drug design and discovery - experimental and computational perspective

Abstract

The Ebola virus (EboV), formally known as the Ebola hemorrhagic fever (EHF) is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the EboV been developed, including Zmapp and peptides. In addition existing drugs which have been repurposed towards anti-EboV activity have been re-examined and are seen to be promising candidates towards combating Ebola. Drug development involving computational tools have been widely employed towards target-based drug design. Screening large libraries have greatly stimulated research toward effective anti-EboV drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of EboV inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites and mechanism of action of the virus. This review focuses on EboV inhibitors, drugs which could be repurposed to combat EboV, computational methods which study drug-target interactions as well as providing further insight into the mode of action of the EboV.

This article is protected by copyright. All rights reserved.

There is a huge gap in literature with regard to the guidelines towards the discovery of anti-Ebola inhibitors. This review focuses on inhibitors of the EboV, drug repurposing to combat Ebola, as well as in silico methods which study drug-target interactions. This report will be immensely valuable toward the design of EboV inhibitors.

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Preparation, Characterization and In Vitro Evaluation of Bleomycin-Containing Nanoliposomes

Abstract

Bleomycin is an anticancer drug used against various types of cancers. The aim of this study was to prepare a new PEGylated and non-PEGylated nanoliposomal formulation of bleomycin (PEG-nLip-BLM and nLip-BLM) and evaluate their anticancer activity in different tumor cell lines. The liposomes were prepared by thin film-hydration method and then bleomycin (BLM) was loaded to the prepared vesicles. The size, zeta potential, entrapment efficiency, loading rate, release profile and cytotoxicity of liposomal formulations in TC-1, LLC1 and HFLF-PI5 cell lines were investigated. Mean particle size and zeta potential of the PEG-nLip-BLM and nLip-BLM were found to be 99.4±4.6 nm, -34.83±4.7 mV; and 112.2±7.2 nm and -27.5±3.2 mV, respectively which were stable for at least two months. Encapsulation and loading efficiency of BLM for PEG-nLip-BLM and nLip-BLM were obtained about 83.1±4.2 %, 14.3±2.5 %; and 78.3±8.6 %, 11.1±3.3 %, respectively. Drug release study showed a slow release pattern without considerable burst effect. The liposomal formulations indicated lower toxicity compared to free drug in case of TC-1 and HFLF-PI5 cells; but their cytotoxicity against LLC1 cells were significantly higher than free drug. The results of current study indicated that PEG-nLip-BLM can be a suitable candidate for drug delivery to solid tumors.

This article is protected by copyright. All rights reserved.

Bleomycin-containing nanoliposomes were successfully prepared and characterized. PEG-nLip-BLM showed excellent stability, high loading efficacy and improved cytotoxicity against LLC1 cells and good retention capability compare to nLip-BLM and free drug. These findings will facilitate the production of a new formulation of BLM with long-acting action and more efficient anticancer activity for testing on human subjects

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Characterization of Parotid Tumors With Dynamic Susceptibility Contrast Perfusion-Weighted Magnetic Resonance Imaging and Diffusion-Weighted Mr Imaging.

Purpose: To characterize parotid tumors with dynamic susceptibility contrast perfusion-weighted magnetic resonance (MR) imaging and diffusion-weighted MR imaging. Material and Methods: Prospective study was conducted upon 48 consecutive patients (27 men, 21 women; aged 15-75 years; mean, 45 years) with parotid tumors that underwent dynamic susceptibility contrast perfusion-weighted MR imaging was performed after bolus injection of gadopentate dimeglumine and diffusion-weighted MR imaging. The dynamic susceptibility contrast percentage (DSC%) and apparent diffusion coefficient (ADC) values of parotid tumors were calculated and correlated with histopathological findings. Results: The DSC% of malignant parotid tumors (33.53% +/- 3.99%) was significantly different (P = 0.001) from that of benign parotid tumors (22.29% +/- 4.13%). The threshold values of DSC% and ADC used in differentiating malignant from benign parotid tumors were 26.5% and 1.07 x 10-3 mm2/s, respectively, with area under the curve (AUC) of 0.96 and 0.81, respectively. The DSC% of malignant parotid tumors was significantly different from that of Warthin tumors (P = 0.001). The cutoff DSC% used to differentiate malignancy from Warthin tumors was 26.9% with an AUC of 0.99. There was a significant difference in DSC% and ADC values between pleomorphic adenomas and Warthin tumors (P = 0.001). The threshold values of DSC% and ADC used in differentiating pleomorphic adenomas from Warthin tumors was 22.5% and 0.99 x 10-3 mm2/s, respectively, with AUC of 0.88 and 0.98, respectively. Conclusions: Dynamic susceptibility contrast-enhanced perfusion-weighted MR imaging and diffusion-weighted MR imaging are noninvasive promising methods that are used for differentiation of malignant from benign parotid tumors and for characterization of some benign parotid tumors. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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CT Differentiation of Female Peritoneal Tuberculosis and Peritoneal Carcinomatosis From Normal-Sized Ovarian Cancer.

Objective: The purpose of this study was to analyze the computed tomography (CT) features of female peritoneal tuberculosis and peritoneal carcinomatosis from normal-sized ovarian cancer for their differentiation. Materials and Methods: We analyzed the CT features of 18 female peritoneal tuberculosis and 17 peritoneal carcinomatosis with proven normal-sized ovarian carcinomas. Omental change, mesenteric change, parietal peritoneal thickening, lymph node enlargement, ascites, ovarian CT attenuation, and ovarian capsular change were analyzed. Results: Heterogeneous parenchymal hyperattenuation and capsular change of the ovary were more frequently seen in cases of peritoneal carcinomatosis than in cases of female peritoneal tuberculosis (P = 0.002, P

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Arterial and Venous Pulmonary Vascular Morphology and Their Relationship to Findings in Cardiac Magnetic Resonance Imaging in Smokers.

Objective: Prior work has described the relationship between pulmonary vascular pruning on computed tomography (CT) scans and metrics of right-sided heart dysfunction in smokers. In this analysis, we sought to look at pruning on a lobar level, as well as examine the effect of the arterial and venous circulation on this association. Methods: Automated vessel segmentation applied to noncontrast CT scans from the COPDGene Study in 24 subjects with cardiac magnetic resonance imaging scans was used to create a blood volume distribution profile. These vessels were then manually tracked to their origin and characterized as artery or vein. Results: Assessment of pruning on a lobar level revealed associations between pruning and right ventricular function previously not observed on a global level. The right ventricular mass index, the right ventricular end-systolic volume index, and pulmonary arterial-to-aorta ratio were associated with both arterial and venous pruning, whereas right ventricular ejection fraction was associated with only arterial pruning. Conclusions: Lobar assessment and segmentation of the parenchymal vasculature into arterial and venous components provide additional information about the relationship between loss of vasculature on CT scans and right ventricular dysfunction. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Submillisievert Computed Tomography of the Chest Using Model-Based Iterative Algorithm: Optimization of Tube Voltage With Regard to Patient Size.

Objective: The aim of this study was to define optimal tube potential for soft tissue and vessel visualization in dose-reduced chest CT protocols using model-based iterative algorithm in average and overweight patients. Methods: Thirty-six patients receiving chest CT according to 3 protocols (120 kVp/noise index [NI], 60; 100 kVp/NI, 65; 80 kVp/NI, 70) were included in this prospective study, approved by the ethics committee. Patients' physical parameters and dose descriptors were recorded. Images were reconstructed with model-based algorithm. Two radiologists evaluated image quality and lesion conspicuity; the protocols were intraindividually compared with preceding control CT reconstructed with statistical algorithm (120 kVp/NI, 20). Mean and standard deviation of attenuation of the muscle and fat tissues and signal-to-noise ratio of the aorta were measured. Results: Diagnostic images (lesion conspicuity, 95%-100%) were acquired in average and overweight patients at 1.34, 1.02, and 1.08 mGy and at 3.41, 3.20, and 2.88 mGy at 120, 100, and 80 kVp, respectively. Data are given as CT dose index volume values. Conclusions: Model-based algorithm allows for submillisievert chest CT in average patients; the use of 100 kVp is recommended. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of early surgical decompression on functional and histological outcomes after severe experimental thoracic spinal cord injury

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECTIVE In acute traumatic brain injury, decompressive craniectomy is a common treatment that involves the removal of bone from the cranium to relieve intracranial pressure. The present study investigated whether neurological function following a severe spinal cord injury improves after utilizing either a durotomy to decompress the intradural space and/or a duraplasty to maintain proper flow of cerebrospinal fluid. METHODS Sixty-four adult female rats (n = 64) were randomly assigned to receive either a 3- or 5-level decompressive laminectomy (Groups A and B), laminectomy + durotomy (Groups C and D), or laminectomy + duraplasty with graft (Group E and F) at 24 hours following a severe thoracic contusion injury (200 kilodynes). Duraplasty involved the use of DuraSeal, a hydrogel dural sealant. Uninjured and injured control groups were included (Groups G, H). Hindlimb locomotor function was assessed by open field locomotor testing (BBB) and CatWalk gait analysis at 35 days postinjury. Bladder function was analyzed and bladder wall thickness was assessed histologically. At 35 days postinjury, mechanical and thermal allodynia were assessed by the Von Frey hair filament and hotplate paw withdrawal tests, respectively. Thereafter, the spinal cords were dissected, examined for gross anomalies at the injury site, and harvested for histological analyses to assess lesion volumes and white matter sparing. ANOVA was used for statistical analyses. RESULTS There was no significant improvement in motor function recovery in any treatment groups compared with injured controls. CatWalk gait analysis indicated a significant decrease in interlimb coordination in Groups B, C, and D (p < 0.05) and swing speed in Groups A, B, and D. Increased mechanical pain sensitivity was observed in Groups A, C, and F (p < 0.05). Rats in Group C also developed thermal pain hypersensitivity. Examination of spinal cords demonstrated increased lesion volumes in Groups C and F and increased white matter sparing in Group E (p < 0.05). The return of bladder automaticity was similar in all groups. Examination of the injury site during tissue harvest revealed that, in some instances, expansion of the hydrogel dural sealant caused compression of the spinal cord. CONCLUSIONS Surgical decompression provided no benefit in terms of neurological improvement in the setting of a severe thoracic spinal cord contusion injury in rats at 24 hours postinjury. Decompressive laminectomy and durotomy did not improve motor function recovery, and rats in both of these treatment modalities developed neuropathic pain. Performing a durotomy also led to increased lesion volumes. Placement of DuraSeal was shown to cause compression in some rats in the duraplasty treatment groups. Decompressive duraplasty of 3 levels does not affect functional outcomes after injury but did increase white matter sparing. Decompressive duraplasty of 5 levels led to neuropathic pain development and increased lesion volumes. Further comparison of dural repair techniques is necessary.

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Incidence and risk factors for failed medical management of spinal epidural abscess: a systematic review and meta-analysis

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECTIVE Spinal epidural abscess (SEA) is a life-threatening infection. It is uncertain whether medical versus surgical treatment is the ideal initial approach for neurologically intact patients with SEA. Recent evidence demonstrates that initial medical management is increasingly common; however, patients who ultimately require surgery after failed medical management may have a worse prognosis than those whose treatment was initially surgical. The primary objective of this study was to establish the current incidence of failed medical management for SEA. The secondary aim was to identify risk factors associated with the failure of medical management. METHODS The authors conducted a systematic review and meta-analysis by searching electronic databases (MEDLINE, Embase, CINAHL, and PubMed), recent conference proceedings, and reference lists of relevant articles. Studies that reported original data on consecutive adult patients with SEA treated medically were eligible for inclusion. RESULTS Twelve studies met the inclusion criteria, which included a total of 489 medically treated patients with SEA. Agreement on articles for study inclusion was very high between the reviewers (kappa 0.86). In a meta-analysis, the overall pooled risk of failed medical management was 29.3% (95% CI 21.4%–37.2%) and when medical to surgical crossover was used to define failure the rate was 26.3% (95% CI 13.0%–39.7%). Only 6 studies provided data for analysis by intended treatment, with a pooled estimate of 35.1% (95% CI 15.7%–54.4%) of failed medical management. Two studies reported predictors of the failure of medical management. CONCLUSIONS Although the incidence of failed medical management of SEA was relatively common in published reports, estimates were highly heterogeneous between studies, thus introducing uncertainty about the frequency of this risk. A consensus definition of failure is required to facilitate comparison of failure rates across studies.

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Is less always better? Keyhole and standard subtemporal approaches: evaluation of temporal lobe retraction and surgical volume with and without zygomatic osteotomy in a cadaveric model

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE The subtemporal approach is one of the surgical routes used to reach the interpeduncular fossa. Keyhole subtemporal approaches and zygomatic arch osteotomy have been proposed in an effort to decrease the amount of temporal lobe retraction. However, the effects of these modified subtemporal approaches on temporal lobe retraction have never been objectively validated. METHODS A keyhole and a classic subtemporal craniotomy were executed in 4 fresh-frozen silicone-injected cadaver heads. The target was defined as the area bordered by the superior cerebellar artery, the anterior clinoid process, supraclinoid internal carotid artery, and the posterior cerebral artery. Once the target was fully visualized, the authors evaluated the amount of temporal lobe retraction by measuring the distance between the base of the middle fossa and the temporal lobe. In addition, the volume of the surgical and anatomical corridors was assessed as well as the surgical maneuverability using navigation and 3D moldings. The same evaluation was conducted after a zygomatic osteotomy was added to the two approaches. RESULTS Temporal lobe retraction was the same in the two approaches evaluated while the surgical corridor and the maneuverability were all greater in the classic subtemporal approach. CONCLUSIONS The zygomatic arch osteotomy facilitates the maneuverability and the surgical volume in both approaches, but the temporal lobe retraction benefit is confined to the lateral part of the middle fossa skull base and does not result in the retraction necessary to expose the selected target.

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Aneurysms with persistent patency after treatment with the Pipeline Embolization Device

Journal of Neurosurgery, Ahead of Print.
The Pipeline Embolization Device (PED) was approved for the treatment of intracranial aneurysms from the petrous to the superior hypophyseal segment of the internal carotid artery. However, since its approval, its use for treatment of intracranial aneurysms in other locations and non-sidewall aneurysms has grown tremendously. The authors report on a cohort of 15 patients with 16 cerebral aneurysms that incorporated an end vessel with no significant distal collaterals, which were treated with the PED. The cohort includes 7 posterior communicating artery aneurysms, 5 ophthalmic artery aneurysms, 1 superior cerebellar artery aneurysm, 1 anterior inferior cerebellar artery aneurysm, and 2 middle cerebral artery aneurysms. None of the aneurysms achieved significant occlusion at the last follow-up evaluation (mean 24 months). Based on these observations, the authors do not recommend the use of flow diverters for the treatment of this subset of cerebral aneurysms.

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Image-guided endoscopic surgery for spontaneous supratentorial intracerebral hematoma

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE Endoscopic removal of intracerebral hematomas is becoming increasingly common, but there is no standard technique. The authors explored the use of a simple image-guided endoscopic method for removal of spontaneous supratentorial hematomas. METHODS Virtual reality technology based on a hospital picture archiving and communications systems (PACS) was used in 3D hematoma visualization and surgical planning. Augmented reality based on an Android smartphone app, Sina neurosurgical assist, allowed a projection of the hematoma to be seen on the patient's scalp to facilitate selection of the best trajectory to the center of the hematoma. A obturator and transparent sheath were used to establish a working channel, and an endoscope and a metal suction apparatus were used to remove the hematoma. RESULTS A total of 25 patients were included in the study, including 18 with putamen hemorrhages and 7 with lobar cerebral hemorrhages. Virtual reality combined with augmented reality helped in achieving the desired position with the obturator and sheath. The median time from the initial surgical incision to completion of closure was 50 minutes (range 40–70 minutes). The actual endoscopic operating time was 30 (range 15–50) minutes. The median blood loss was 80 (range 40–150) ml. No patient experienced postoperative rebleeding. The average hematoma evacuation rate was 97%. The mean (± SD) preoperative Glasgow Coma Scale (GCS) score was 6.7 ± 3.2; 1 week after hematoma evacuation the mean GCS score had improved to 11.9 ± 3.1 (p < 0.01). CONCLUSIONS Virtual reality using hospital PACS and augmented reality with a smartphone app helped precisely localize hematomas and plan the appropriate endoscopic approach. A transparent sheath helped establish a surgical channel, and an endoscope enabled observation of the hematoma's location to achieve satisfactory hematoma removal.

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A method for safely resecting anterior butterfly gliomas: the surgical anatomy of the default mode network and the relevance of its preservation

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE Gliomas invading the anterior corpus callosum are commonly deemed unresectable due to an unacceptable risk/benefit ratio, including the risk of abulia. In this study, the authors investigated the anatomy of the cingulum and its connectivity within the default mode network (DMN). A technique is described involving awake subcortical mapping with higher attention tasks to preserve the cingulum and reduce the incidence of postoperative abulia for patients with so-called butterfly gliomas. METHODS The authors reviewed clinical data on all patients undergoing glioma surgery performed by the senior author during a 4-year period at the University of Oklahoma Health Sciences Center. Forty patients were identified who underwent surgery for butterfly gliomas. Each patient was designated as having undergone surgery either with or without the use of awake subcortical mapping and preservation of the cingulum. Data recorded on these patients included the incidence of abulia/akinetic mutism. In the context of the study findings, the authors conducted a detailed anatomical study of the cingulum and its role within the DMN using postmortem fiber tract dissections of 10 cerebral hemispheres and in vivo diffusion tractography of 10 healthy subjects. RESULTS Forty patients with butterfly gliomas were treated, 25 (62%) with standard surgical methods and 15 (38%) with awake subcortical mapping and preservation of the cingulum. One patient (1/15, 7%) experienced postoperative abulia following surgery with the cingulum-sparing technique. Greater than 90% resection was achieved in 13/15 (87%) of these patients. CONCLUSIONS This study presents evidence that anterior butterfly gliomas can be safely removed using a novel, attention-task based, awake brain surgery technique that focuses on preserving the anatomical connectivity of the cingulum and relevant aspects of the cingulate gyrus.

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A brief history of carotid-cavernous fistula

Journal of Neurosurgery, Ahead of Print.
Carotid-cavernous fistula was one of the first intracranial vascular lesions to be recognized. This paper focuses on the historical progression of our understanding of the condition and its symptomatology—from the initial hypothesis of ophthalmic artery aneurysm as the cause of pulsating exophthalmos to the recognition and acceptance of fistulas between the carotid arterial system and cavernous sinus as the true etiology. The authors also discuss the advancements in treatment from Benjamin Travers' early common carotid ligation and wooden compression methods to today's endovascular approaches.

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Modification of electrophysiological activity pattern after anterior thalamic deep brain stimulation for intractable epilepsy: report of 3 cases

Journal of Neurosurgery, Ahead of Print.
OBJECTIVE Thalamic stimulation can provoke electroencephalography (EEG) synchronization or desynchronization, which can help to reduce the occurrence of seizures in intractable epilepsy, though the underlying mechanism is not fully understood. Therefore, the authors investigated changes in EEG electrical activity to better understand the seizure-reducing effects of deep brain stimulation (DBS) in patients with intractable epilepsy. METHODS Electrical activation patterns in the epileptogenic brains of 3 patients were analyzed using classical low-resolution electromagnetic tomography analysis recursively applied (CLARA). Electrical activity recorded during thalamic stimulation was compared with that recorded during the preoperative and postoperative off-stimulation states in patients who underwent anterior thalamic nucleus DBS for intractable epilepsy. RESULTS Interictal EEG was fully synchronized to the β frequency in the postoperative on-stimulation period. The CLARA showed that electrical activity during preoperative and postoperative off-stimulation states was localized in cortical and subcortical areas, including the insular, middle frontal, mesial temporal, and precentral areas. No electrical activity was localized in deep nucleus structures. However, with CLARA, electrical activity in the postoperative on-stimulation period was localized in the anterior cingulate area, basal ganglia, and midbrain. CONCLUSIONS Anterior thalamic stimulation could spread electrical current to the underlying neuronal networks that connect with the thalamus, which functions as a cortical pacemaker. Consequently, the thalamus could modify electrical activity within these neuronal networks and influence cortical EEG activity by inducing neuronal synchronization between the thalamus and cortical structures.

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Recurrent giant cranial desmoid tumor in a 3-year-old boy with familial adenomatous polyposis requiring bifrontoparietal cranioplasty: case report

Journal of Neurosurgery: Pediatrics, Ahead of Print.
Desmoid tumors, also known as aggressive fibromatosis, are locally infiltrating musculoaponeurotic neoplasms arising in connective tissues. Desmoid tumors may be associated with familial adenomatous polyposis (FAP), a genetic disorder that presents with hundreds to thousands of precancerous colorectal polyps. The authors report the case of an 18-month-old boy who underwent resection of a right temporal desmoid tumor (initially diagnosed as cranial fasciitis) and developed a bilateral frontoparietal calvarial desmoid tumor 2 years later. The patient underwent gross-total resection of the tumor that required a large cranioplasty. He was subsequently diagnosed with FAP. The patient has been without tumor recurrence for 9 years afterwards and has not required revision of his cranioplasty. This is the first report describing a recurrent cranial desmoid tumor in a pediatric patient with FAP. The authors believe, however, that some of the cases previously reported as cranial fasciitis are likely desmoid tumors pathobiologically and genetically.

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Mature salivary gland rests within sonic hedgehog–positive medulloblastoma: case report and insights into the molecular genetics and embryopathology of ectopic intracranial salivary gland analogs

Journal of Neurosurgery: Pediatrics, Ahead of Print.
Intracranial ectopic salivary gland rests within dural-based lesions are reported very infrequently in the literature. The authors report the unique case of a 12-year-old boy with a cerebellar medulloblastoma positive for sonic hedgehog (Shh) that contained intraaxial mature ectopic salivary gland rests. The patient underwent clinical and radiological monitoring postoperatively, until he died of disseminated disease. An autopsy showed no evidence of salivary glands within disseminated lesions. The intraaxial presence of salivary gland rests and concomitant Shh positivity of the described tumor point to a disorder in differentiation as opposed to ectopic developmental foci, which are uniformly dural based in the described literature. The authors demonstrate the characteristic "papilionaceous" appearance of the salivary glands with mucicarmine stain and highlight the role of Shh signaling in explaining the intraaxial presence of seromucous gland analogs. This article reports the first intraaxial posterior fossa tumor with heterotopic salivary gland rests, and it provides molecular and embryopathological insights into the development of these lesions.

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