High-grade Mullerian Adenosarcoma: Genomic and Clinicopathologic Characterization of a Distinct Neoplasm With Prevalent TP53 Pathway Alterations and Aggressive Behavior.

Mullerian adenosarcoma harbors low malignant potential, except in cases with myometrial invasion or sarcomatous overgrowth. The presence of a high-grade stromal component has been proposed as an important pathologic predictor of outcome. We hypothesized that high-grade adenosarcoma has distinct clinical and molecular features, distinct from low-grade adenosarcoma. We analyzed the clinicopathologic features and follow-up of 9 high-grade adenosarcomas and a control group of 9 low-grade adenosarcomas. Comprehensive genomic analysis of the high-grade group was performed targeting exons of 409 oncogenes and tumor suppressor genes. In 1 case, the high-grade and low-grade components were separately sequenced. High-grade and low-grade adenosarcomas were comparable in patient age, myometrial invasion, and stage at presentation. Sarcomatous overgrowth was observed in 2/9 (22%) low-grade and 8/9 (89%) high-grade adenosarcomas. Six of 9 (67%) patients with high-grade adenosarcoma developed rapid recurrence; 1 died of her disease. Conversely, no low-grade tumors recurred or metastasized. Sequencing of high-grade adenosarcomas revealed frequent TP53 pathway alterations, identified in 7/9 (78%) cases. p53 expression by immunohistochemistry highly correlated with mutation status. Copy number variations occurred at a mean of 28.8 per tumor; most frequently involved genes included CDK4, MDM2, GNAS, SGK1, and DICER1. High-grade adenosarcoma is an aggressive neoplasm with propensity for short-interval recurrence and metastasis. The proportion of copy number alterations is similar to that reported for adenosarcoma with sarcomatous overgrowth. However, the high frequency of TP53 abnormalities is a novel finding, indicating that high-grade adenosarcoma is a distinct subset with driver TP53 pathway alterations. p53 immunohistochemistry can be used to confirm the presence of a high-grade component. Given its aggressive potential, the presence of any high-grade component in an adenosarcoma should be reported, even in the absence of sarcomatous overgrowth. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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BRAF V600E Mutations Occur in a Subset of Glomus Tumors, and are Associated With Malignant Histologic Characteristics.

Glomus tumors are rare mesenchymal neoplasms with a phenotype akin to the modified smooth muscle cells of the glomus body. Most are benign, but rare examples show malignant histologic characteristics and aggressive behavior. We recently encountered a malignant glomus tumor with BRAF V600E mutation. We sought to study a large cohort for this mutation, with particular attention to associated malignant histologic characteristics. Tumors were classified based on WHO criteria as benign, uncertain malignant potential (glomus tumors of uncertain malignant potential-GT-UMP), or malignant. Tumors were screened for BRAF V600E by immunohistochemistry, and positive staining was evaluated further by Sanger sequencing. A total of 102 glomus tumors were included and classified as benign (57, 56%), GT-UMP (15, 15%) and malignant (30, 29%). Tumors occurred in patients aged 8 to 89.9 years (median: 50.2), without sex predilection (55% men). Most occurred in the superficial soft tissue (84%) and upper extremities (55%). Six of 95 tested cases had BRAF V600E mutation (6%), including 0 of 57 benign tumors, 3 of 14 GT-UMP (21%), and 3 of 24 malignant tumors (12%). Follow-up was obtained for 59 cases (median: 75.7 mo, range: 7.8 to 268.5). Three of 11 malignant tumors (27%) had progressive disease: 1 with metastasis to brain and heart, 1 with enlarging residual disease, and 1 with recurrence. Two of 4 GT-UMP (50%) had progressive disease: 1 with metastasis to lung, and 1 with local recurrence (50%). Three of 44 benign tumors (7%) had local recurrence. Two of 5 patients with BRAF V600E had progression, including 1 GT-UMP with local recurrence and 1 malignant tumor with enlarging residual disease. In summary, BRAF V600E mutation was detected in 6% of glomus tumors, all of which were malignant or GT-UMP. This mutation may be associated with a malignant phenotype, although study of additional cases is needed. In patients with progressive disease, BRAF could be a promising therapeutic target. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Analysis of Orbital Volume Measurements Following Reduction and Internal Fixation Using Absorbable Mesh Plates and Screws for Patients With Orbital Floor Blowout Fractures.

Introduction: Hinge-shaped fractures are common type of orbital floor blowout fractures, for which reduction and internal fixation is ideal. Nonetheless, orbital floor reconstruction using alloplastic materials without reducing the number of bone fragments is the most frequently used procedure. Therefore, this study analyzed and compared the outcomes between open reduction and internal fixation using absorbable mesh plates and screws, and orbital floor reconstruction, by measuring the orbital volume before and after surgery. Method: Among patients with orbital floor blowout fractures, this study was conducted on 28 patients who underwent open reduction and internal fixation, and 27 patients who underwent orbital floor reconstruction from December 2008 to September 2015. The mechanism of injury, ophthalmic symptoms before and after surgery, and the degree of enophthalmos were examined; subsequently, the volumes of the affected and unaffected sides were measured before and after surgery based on computed tomography images. This study compared the degree of recovery in the correction rate of the orbital volume, ophthalmic symptoms, and enophthalmos between the 2 groups. Result: The patients who underwent open reduction and internal fixation, and the patients who underwent orbital floor reconstruction showed average correction rates of 100.36% and 105.24%, respectively. Open reduction and internal fixation showed statistically, significantly superior treatment outcomes compared with orbital floor reconstruction. The ophthalmic symptoms and incidence of enophthalmos completely resolved in both groups. Conclusion: For orbital floor blowout fractures, open reduction and internal fixation using absorbable mesh plates and screws was a feasible alternative to orbital floor reconstruction. (C) 2017 by Mutaz B. Habal, MD.

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The New Anatomical Classification System for Orbital Exenteration Defect.

Background: The unique anatomy of the orbita and the different behavior of each malignant tumor cause us to perform the various types of orbital exenteration that yields to varying defect each of which has own specific demands in terms of the reconstruction. Current classification of orbital exenteration defects seems not to be adequate to provide detailed description. This study reviews 50 exenteration defects to offer a more effective anatomical classification system. Methods: Over a 15 years period, 50 orbital exenteration defects in 47 patients were reconstructed. Defects were categorized according to the resected orbital wall, dura, and ethmoid resection. If the maxillectomy was performed, A or B was added to define the type of maxillectomy as partial (intact palate) or total maxillectomy, respectively. According to these criteria, 4 types of defect patterns were determined including Type 0 (n = 5) with intact orbital wall, Type I (n = 9) with sino-orbital fistula, Type II (n = 4) with crania-orbital fistula with intact dura, Type III (n = 6) with crania-orbital fistula associated with dura defect, and Type IV (n = 8) with cranio-nasal-orbital fistula. There were 12 partial (A) and 6 total maxillectomy (B) defects along with the orbital exenteration. Results: There was no major complication except one. The minor wound-healing problems occurred in 7 patients. Nine patients (19%) used prosthesis. Twenty-two (46.8%) patients chose a patch to cover the area. The remaining 16 patients were not able to use any type of prosthesis because of the reconstruction methods. Conclusion: The authors believe that the authors' anatomical classification system provides more precise description of the defect which eventually enhances the success rate of both reconstruction and resection. (C) 2017 by Mutaz B. Habal, MD.

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An Epithelioid Hemangioendothelioma of the Head and Neck.

An epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of the head and neck region, which carries a risk of recurrence and metastasis. Its etiology is still unclear. It frequently involves the lungs, liver, and bones. Rarely, it may manifest in other parts of the body. Pathologic immunohistochemical investigations are essential to make the definite diagnosis. As it is uncommon, there is no standardized protocol for the treatment of EHE. Herein, the authors report a rare patient with of an EHE localized in the head and neck region. (C) 2017 by Mutaz B. Habal, MD.

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Differential Diagnosis Between Nasal Septal Schwannoma and Nasal Septal Neurofibroma.

Recently, as the authors experienced nasal septal schwannoma and nasal septal neurofibroma with similar clinical symptoms but different endoscopic findings, the authors tried to review all the literatures previously reported on the "Nasal septal schwannoma and Nasal septal neurofibroma." The aim of this study is to thoroughly review previously reported patients with nasal septal schwannomas and neurofibromas and to describe similar and different features focusing on the differential diagnosis between the 2 entities. On the basis of our review, the authors made some important conclusions. First, benign peripheral nerve tumors originating from the nasal septum are uncommon. Especially, nasal septal neurofibroma is extremely rare that only 5 patients were reported. So, more clinical reports of benign peripheral nerve tumors are necessary to elucidate the differences between nasal septal schwannoma and nasal septal neurofibroma. Second, there are some similar features between nasal septal schwannoma and nasal septal neurofibroma such as clinical symptoms, endoscopic findings, and treatment strategy. However, since there seem to be some differences in nasal endoscopic findings, they may be helpful for the provisional diagnosis, and so more patients should be reported to verify that point. Third, image study, especially magnetic resonance imaging (MRI), is considered to be a useful tool for differential diagnosis of benign peripheral nerve tumors originating from the nasal septum. So, more clinical reports reporting MRI findings are needed to verify the differences. Last, because of distinctive histologic appearances of benign peripheral nerve tumors, it is usually not difficult to make the distinction between nasal septal schwannoma and nasal septal neurofibroma. However, immunohistochemical stains including S-100 protein, calretinin, CD 34, factor XIIIa, and CD56 are necessary when it is difficult to differentiate between 2 disease entities. (C) 2017 by Mutaz B. Habal, MD.

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Three-Dimensional Analysis of Midfacial Soft Tissue Changes After Maxillary Posterior Impaction and Intraoral Vertical Ramus Osteotomy for Mandibular Setback in Class III Patients.

This study investigated the correlation between the 3-dimensional changes in midfacial soft tissues, including the parasagittal area and maxilla-mandible complex, after Le Fort I maxillary posterior impaction and bilateral intraoral vertical ramus osteotomy (B-IVRO), using cone-beam computed tomography (CBCT). This retrospective study included 22 skeletal Class III patients (6 men and 16 women; mean age 21.6 years) who underwent orthognathic surgery. Three-dimensional CBCT images taken before and 1 year after surgery were superimposed based on the cranial base. Midfacial soft tissues, including those in the parasagittal area (paranasal area, anterior cheek area, lateral cheek area) and midsagittal areas of the face, were evaluated using reconstructed CBCT images. Correlations and the ratios between soft tissue and hard tissue movement were calculated. After surgery, both paranasal areas showed significant forward movement (about 2.0 mm) and the largest upward movement (about 0.15 mm) among the 3 areas. The paranasal areas moved forward with a ratio of 0.5, according to vertical movement of B. Orthognathic surgery using Le Fort I maxillary posterior impaction with B-IVRO mandibular setback results in forward movement of midfacial soft tissues, even though sagittal movement of the maxilla is limited because facial muscles and retaining ligaments pull the redundant soft tissues, which are caused by vertical movement of the maxilla-mandible. This midfacial soft tissue change with maxillary posterior impaction could be advantageous to patients who have paranasal depression and protrusion of the upper lip owing to proclined upper incisors, which are prevalent among Asian Class III patients. (C) 2017 by Mutaz B. Habal, MD.

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Esophageal Stricture in a Child With Habit of Acidic Drinks.

A 12-year-old boy with Down syndrome referred to the authors' department with dysphagia and growth retardation. Dysphagia was especially with solid foods and had a 12-month history. When he was 7, he had started to drink Coke and from that time he had a Coke drinking habit. Every day he was drinking more than 2 L Coke and was eating meals in small amounts. Investigations of the patient revealed esophageal stricture related to acidic drink habit and gastro-oesephageal reflux. The patient was treated with recurrent bouginage, antireflux medication, and nutrional support. The patient became symptom free from 13 months and gained weight. The clinicians should take the nutrition habits into consideration when evaluating the esophageal stricture patients. (C) 2017 by Mutaz B. Habal, MD.

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Prediction of Late Enophthalmos Using Preoperative Orbital Volume and Fracture Area Measurements in Blowout Fracture.

Enophthalmos caused by orbital volume expansion is the traditional indication for blowout fracture operation, but it may not appear immediately after orbital trauma due to periorbital swelling. The purpose of this study was to investigate the correlations of the orbital volume ratio (OVR) and, orbital fracture area (OFA) with the late enophthalmos measurement in unilateral pure blowout fracture. Seventy-two patients who had experienced a blowout fracture were divided into 2 groups, the conservative treatment group (n = 40) and the operative treatment group (n = 32). The authors measured the preoperative OVR and OFA using three-dimensional facial bone computed tomography and investigated their relationship with late enophthalmos that obtained 6 months after orbital trauma. In both conservative and operative groups, there were significant positive correlations between the OVR and OFA (P

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Anatomical Relationship of the Inferior Bundle of the Incisivus Labii Inferioris With the Depressor Labii Inferioris and the Platysma.

The current study examined the inferior bundle of the incisivus labii inferioris muscle (ILI) and its morphologic and spatial relationships with regard to the depressor labii inferioris muscle (DLI) and the platysma. Incisivus labii inferioris muscles and their inferior bundles were investigated in 50 specimens from embalmed Korean adult cadavers. The inferior bundle of the ILI was divided from the originating fibers of the ILI, and it was present in all specimens (100%). The inferior bundle of the ILI could be distinguished into the transverse and inferolateral slips according to their courses and locations. The inferior bundle of the ILI was classified into 3 types according to the presence of the transverse and inferolateral slips. In Type I (44%), the inferior bundle of the ILI had both the transverse and inferolateral slips. In Type II (48%), the inferior bundle of the ILI had only the transverse slip. In Type III (8%), the inferior bundle of the ILI had only the inferolateral slip. The transverse and inferolateral slips were usually attached to the deep fibers of both the platysma lateral to the DLI and the lateral portion of the DLI via aponeurosis, just below the ILI and above the inferior margin of the mandible, respectively. The new anatomical findings of the present study might contribute to the understanding of the detailed movements required to raise the lower lip. This knowledge will be useful for botulinum toxin type A therapies, various facial surgeries, orthodontic treatment, and electromyographic analyses in this area. (C) 2017 by Mutaz B. Habal, MD.

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Line Laser as an Assistance for Facial and Dental Midlines Evaluation in Single-Splint Orthognathic Surgery.

Coincidence of facial and dental midlines is one of the important goals in orthognathic-orthodontic treatment to achieve optimum facial aesthetics and good occlusal functions. Tools assisting diagnosis of facial midline are usually ruler or dental floss. These tools are usually hand held and hinder the global sight required in facial evaluation. Line laser device projects a steady narrow laser line and is commonly used in construction and carpentry to replace traditional chalk line tool. The authors take the advantages of line laser and incorporate it into facial evaluation in the authors' practice of single-splint orthognathic surgery. During June 2013 to May 2015, the authors used line laser device to evaluate facial and dental midlines in 28 patients of facial asymmetry requiring orthognathic surgery during consultation in office and intraoperative evaluation. The details of integrating this device to practice are described. All the patients showed improved facial symmetry and coincidence of facial and dental midlines after operation. Postoperative orthodontics were finished smoothly. Line laser is available from general utility stores and is safe to use according to laser safety regulation. From the authors' experiences, it is burden free to apply in facial and dental midlines evaluation and improves the practice. (C) 2017 by Mutaz B. Habal, MD.

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Use of Acellular Allogenic Dermal Matrix (MegaDerm) in Orbital Wall Reconstruction: A Comparison With Absorbable Mesh Plate and Porous Polyethylene.

The selection of materials for orbital wall reconstruction has been a matter of debate. This study aimed to evaluate the effectiveness of an acellular allogenic dermal matrix (ADM) as an orbital wall reconstruction material and to compare the results of orbital wall reconstruction with the ADM to those of reconstruction with the more widely used absorbable mesh plate and porous polyethylene. We retrospectively reviewed the clinical charts and computed tomography images of 73 patients who underwent orbital reconstruction at 1 institution between March 2013 and February 2014. In the ADM group, the mean defect size of 29 patients was 2.89 cm2. After orbital wall reconstruction with ADM, patients with preoperative enophthalmos (7 patients), limited range of eyeball movement (6 patients), and diplopia (12 patients) showed improvements. In the comparative study, the 3 groups showed no significant differences with respect to age distribution (P = 0.522), defect size (P = 0.455), and preoperative findings such as enophthalmos (P = 0.811), diplopia (P = 0.357), and limited range of eyeball movement (P = 0.795). All the preoperative symptoms improved in every group, and in the ADM group, no complication was observed during the postoperative follow-up. ADM is a biocompatible material that combines the flexibility and rigidity required to support the orbital soft tissue. Therefore, it could be an excellent alternative material for orbital wall reconstruction. (C) 2017 by Mutaz B. Habal, MD.

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Osseous Flap of Galea and Periosteum Filled With Mesenchymal Stem Cells, Platelet-Rich Plasma, Bone Dust, and Hyaluronic Acid.

Reconstructive surgery to craniofacial deformities caused by tumor ressections, traumas or congenital malformation are frequent in medicine practice. It aims to provide the patients with better quality of life and functional improvement of speech, breathing, chewing, and swallowing. Many are the techniques described in the literature to recover bone defects. This study evaluated a vascularized galeal and periosteum flap in rabbits, which could possibly substitute the bone graft in reconstructive surgery, especially for facial defects. It involved rabbits, divided into 12 groups, submitted to a surgical procedure to construct the galea and periosteum cranial flap filled with fragments of cranial bone, platelet-rich plasma, mesenchimal stem cells, and hyaluronic acid. The evaluation methods included image examinations and histological analysis. The results demonstrated bone formation with the use of platelet-rich plasma, mesenchimal stem cells, and bone fragments. The use of several enrichment materials of osseous cellular stimulation improved the quality and bone tissue organization. The more enrichment factor used, the better the tissue quality result was. Much research should be done to improve the methods and to analyze if results in human have the same bone formation as it happened in rabbits. (C) 2017 by Mutaz B. Habal, MD.

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Early Post-treatment Assessment of MRI Perfusion Biomarkers Can Predict Long-term Response of Lung Cancer Brain Metastases to Stereotactic Radiosurgery

Abstract

Background

Imaging criteria to evaluate the response of brain metastases to stereotactic radiosurgery (SRS) in the early post-treatment period remains a crucial unmet need. The aim of this study is to correlate early (within 12 weeks) post-treatment perfusion MRI changes with long-term outcomes after treatment of lung cancer brain metastases with SRS.

Methods

Pre- and post-treatment perfusion MRI scans were obtained in patients treated with SRS for intact non-small cell lung cancer brain metastases. Time-dependent leakage (K ^trans), blood plasma volume (Vp), and extracellular extravascular volume (Ve) were calculated for each lesion. Patients were followed longitudinally with serial MRI until death, progression, or intervention (whole brain radiation or surgery).

Results

We included 53 lesions treated with SRS from 41 total patients. Median follow-up after treatment was 11 months. Actuarial local control at one year was 85%. Univariate analysis demonstrated a significant difference (p=0.032) in post-treatment K ^trans SD between patients with progressive disease (mean=0.0317) and without progressive disease (mean=0.0219). A post-treatment K ^trans SD cutoff value of 0.017 was highly sensitive (89%) for predicting progressive disease and no progressive disease. Early post-treatment volume change was not associated with outcome (p=0.941).

Conclusions

Post-treatment K^trans SD may be used as an early post-treatment imaging biomarker to help predict long-term response of lung cancer brain metastases to SRS. This can help identify patients who will ultimately fail SRS and allow for timelier adjustment in treatment approach. These data should be prospectively validated in larger patient cohorts and other histologies.

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Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation

Abstract

Background

O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma. We investigated whether this marker furthermore defines a molecularly distinct tumor subtype with clinically different outcome.

Methods

We analyzed copy number alteration (CNV) and methylation profiles of 1095 primary and 92 progressive Isocitrate dehydrogenase (IDH) wildtype glioblastomas, including paired samples from 49 patients. DNA mutation data from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA and 55 Chinese Glioma Genome Atlas samples were analyzed.

Results

Among untreated glioblastomas, MGMT promoter methylated (mMGMT) and unmethylated (uMGMT) tumors did not show different CNV or specific gene mutations, but a higher mutation count in mMGMT tumors. We identified three methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including GBX2 were found to be hypermethylated and downregulated on mRNA level in mMGMT tumors.In progressive glioblastomas, PDGFRA and GLI2 amplifications were enriched in mMGMT tumors. mMGMT tumors gain PDGFRA amplification whereas uMGMT tumors with PDGFRA amplifications frequently lose this amplification upon progression. Glioblastoma patients surviving < 6 months and mMGMT harbored less frequent EGFR amplifications, more frequent TP53 mutations and a higher TNF-NFκB pathway activation compared to patients surviving longer than 12 months.

Conclusions

MGMT promoter methylation status does not define a molecularly distinct glioblastoma subpopulation among untreated tumors. Progressive mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have more unfavorable molecular profiles.

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Perioperative management of rare coagulation factor deficiency states in cardiac surgery

Abstract

Rare bleeding disorders (RBDs) include the hereditary deficiency of fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI or FXIII. RBDs do not confer a protective effect against atheromatous plaque formation, and thus the need for cardiovascular (CV) surgery in RBD patients is expected to increase with improved healthcare access (diagnosis and management) and longevity of the population. Clinical data regarding the management of RBDs in this setting are sparse, but the perioperative care team is obliged to gain a better understanding on available biological and pharmacological hemostatic agents. Perioperative management of RBDs in CV surgery is further complicated by heparin anticoagulation, haemodilution, and consumption of procoagulant and anticoagulant proteins associated with cardiopulmonary bypass (CPB). The aims of this review are to summarize pathophysiology of RBDs and laboratory monitoring pertinent to CV surgery, available factor replacement agents, and to provide the framework for perioperative coagulation management of RBD patients.

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Modeling the mammalian sleep cycle

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Franz Weber
During sleep, the mammalian brain transitions through repeated cycles of non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. The physiological implementation of this slow ultradian brain rhythm is largely unknown. Two differing dynamical mechanisms have been proposed to underlie the NREM–REM cycle. The first model type relies on reciprocal interactions between inhibitory and excitatory neural populations resulting in stable limit cycle oscillations. Recent experimental findings instead favor a model, in which mutually inhibitory interactions between REM sleep-promoting (REM-on) and REM sleep-suppressing (REM-off) neural populations stabilize the brain state. Sow modulations in the neural excitability, that are hypothesized to reflect the homeostatic need for REM sleep, abruptly switch the brain in and out of REM sleep.

Graphical abstract

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Characterizing and interpreting the influence of internal variables on sensory activity

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Richard D Lange, Ralf M Haefner
The concept of a tuning curve has been central for our understanding of how the responses of cortical neurons depend on external stimuli. Here, we describe how the influence of unobserved internal variables on sensory responses, in particular correlated neural variability, can be understood in a similar framework. We suggest that this will lead to deeper insights into the relationship between stimulus, sensory responses, and behavior. We review related recent work and discuss its implication for distinguishing feedforward from feedback influences on sensory responses, and for the information contained in those responses.



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Multimodal management for acute invasive fungal rhinosinusitis

Acute invasive fungal rhinosinusitis (IFRS) is an aggressive sinonasal infection that is associated with a high risk of morbidity and mortality. Acute IFRS typically affects individuals with a deficient immune system and is characterized by a fulminant proliferation of tissue invasion by opportunistic fungal species. The early diagnosis and management of acute IFRS play important roles in improving the disease prognosis. The management of acute IFRS requires a multimodal approach that relies on both medical and surgical interventions.

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Bleeding After Tonsillectomy

Oropharyngeal hemorrhage after tonsillectomy is one of the most common post-procedural ENT emergencies which require immediate attention. Management choices depend on the severity of bleeding, underlying platelet/coagulation disorders, and the patient′s maturity and age. Treatment range from simple observation to an emergent need to both secure the airway and stop the hemorrhage. The work up of the hemorrhagic patient will be discussed from the pre-operative to post-operative time period. Surgical techniques in response to various acuity will be discussed to fully elucidate options to control the hemorrhage.

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Emergency Operative Airway Techniques

The Otolaryngologist-Head and Neck surgeon must be adept at providing assistance and intervening surgically in airway management when adequate ventilation becomes challenging. A step-wise and logical approach to airway emergencies can prevent poor outcomes. It is therefore important to have both a strong understanding of airway anatomy as well as an armamentarium of strategies or techniques in securing the airway if ones initial approach is problematic. The present article discusses several surgical approaches to the patient with a difficult airway.

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Management of Parapharyngeal and Retropharyngeal Space Infections

Deep neck space infection is a relatively common condition with potentially catastrophic, life-threatening complications. A detailed understanding of the topography of the neck, relationships between compartments of the neck, and the propagation of infection is essential for accurate assessment and formulation of a propitious and timely treatment plan. This chapter focuses on approaches to the deepest spaces in the anterior neck – the parapharyngeal space (PPS) and retropharyngeal space (RPS). Treatment starts with assessment and assurance of a safe, stable airway, broad spectrum intravenous antibiotics, and contrasted imaging to formulate a surgical plan.

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Cervical and craniofacial necrotizing fasciitis

Cervical and craniofacial necrotizing fasciitis is an aggressive disease process that at times has subtle etiologies and physical findings. Involvement in the head and neck is rare; however, when present it can have extensive morbidity and mortality. High index of suspicion is paramount for early treatment and survival. We describe the presentation, diagnosis and treatment of cervical and craniofacial necrotizing fasciitis. We detail the typical physical exam findings as well as diagnosis based on imaging.

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Pediatric Airway Foreign Body

Foreign body aspiration in the pediatric population is a potentially life-threatening emergency that carries both diagnostic and management challenges. Children often present after a witnessed aspiration or choking event. For those children who are asymptomatic or have nonspecific findings, clinical symptoms, chest radiography and a thorough physical examination are critical for diagnosis. A reasonable suspicion of foreign body aspiration warrants a bronchoscopy. This article focuses on the management of pediatric airway foreign bodies, including the initial evaluation, preparation and treatment approach.

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Orbital complications of acute sinusitis

In the pre-antibiotic era, orbital complications of acute sinusitis were not infrequent, often leading to severe patient morbidity, including blindness. Today, treatment of orbital complications consists primarily of systemic antibiotic therapy with surgical intervention reserved for large or medically unresponsive orbital or subperiosteal abscesses. Staging systems have been created to assist physicians in management and prognosis of such complications, but do not replace clinical acumen. While powerful antibiotics have decreased the morbidity associated with orbital complications of acute sinusitis, the physician should remain aware of potential complications and ready to escalate treatment when necessary.

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Urticaria by thiamine (vitamin B1)

Publication date: Available online 23 August 2017
Source:Allergology International
Author(s): Ana Rodríguez-Fernández, Marcos Sánchez-Domínguez, Blanca Noguerado-Mellado, Patricia Rojas-Pérez-Ezquerra




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High quality of evidence is uncommon in Cochrane systematic reviews in Anaesthesia, Critical Care and Emergency Medicine.

BACKGROUND: The association between the quality of evidence in systematic reviews and authors' conclusions regarding the effectiveness of interventions relevant to anaesthesia has not been examined. OBJECTIVE: The objectives of this study were: to determine the proportion of systematic reviews in which the authors made a conclusive statement about the effect of an intervention; to describe the quality of evidence derived from outcomes in reviews that used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) working group system for grading the quality of evidence; and to identify review characteristics associated with conclusiveness. DESIGN: Cross-sectional analysis of Cochrane systematic reviews from the Anaesthesia, Critical Care and Emergency Review Group was undertaken. DATA SOURCES: The Cochrane webpage was used to identify reviews for inclusion ( http://.ace.cochrane.org/). ELIGIBILITY CRITERIA: New and updated versions of systematic reviews published up to 17 September 2015 were eligible. Protocols for systematic reviews were excluded. RESULTS: A total of 159 reviews were included. GRADE was used in 103 reviews (65%). Of these, high-level evidence for the primary outcome was identified in 11 reviews (10%). The main reasons that quality of evidence for the primary outcome was downgraded were risk of bias (n = 44; 43%) and imprecision (n = 36; 35%). Authors of 47% (n = 75) of the total number of reviews made conclusive statements about the effects of interventions. Independent predictors of conclusiveness in the subgroup of reviews with GRADE assessments were quality of evidence for the primary outcome (odds ratio 2.03; 95% confidence interval: [1.18 to 3.52] and an increasing number of studies included in reviews (OR 1.05; 95% CI: [1.01 to 1.09]). CONCLUSION: It was common for conclusive statements to be made about the effects of interventions despite evidence for the primary outcome being rated less than high quality. Improving methodological quality of trials would have the greatest impact on improving the quality of evidence. 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 without permission from the journal. http://ift.tt/OBJ4xP (C) 2017 European Society of Anaesthesiology

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Repetitive Mild Closed Head Injury Alters Protein Expression and Dendritic Complexity in a Mouse Model

Journal of Neurotrauma , Vol. 0, No. 0.


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Sacral anatomy of the phytosaur Smilosuchus adamanensis, with implications for pelvic girdle evolution among Archosauriformes

Abstract

The sacrum – consisting of those vertebrae that articulate with the ilia – is the exclusive skeletal connection between the hindlimbs and axial skeleton in tetrapods. Therefore, the morphology of this portion of the vertebral column plays a major role in the evolution of terrestrial locomotion. Whereas most extant reptiles only possess the two plesiomorphic sacral vertebrae, additional vertebrae have been incorporated into the sacrum multiple times independently among early-diverging archosaurian (crocodylians + birds) clades. Phytosauria was a diverse, abundant, and cosmopolitan clade of archosauriforms throughout the Late Triassic, but postcrania of this clade are rarely described and few species-level taxonomic placements of phytosaurian postcranial material are available, potentially hampering knowledge of morphological disparity in the postcranial skeleton among phytosaurs. Here, we describe the sacrum of Smilosuchus adamanensis, a phytosaur recovered from the Upper Triassic Chinle Formation of Arizona. This sacrum consists of the two primordial sacral vertebrae, but has a vertebra incorporated from the trunk into the sacrum (= a dorsosacral) and is therefore the first Late Triassic phytosaur and one of the first non-archosaurian archosauromorphs to be described with more than two sacral vertebrae. Our interpretation of this element as a dorsosacral is justified by the lateral extent of the dorsosacral ribs, clear surfaces of articulation between the distal ends of the dorsosacral ribs and the first primordial sacral ribs, and the scar on the medial surface of each ilium for articulation with each dorsosacral rib. Additionally, we provide the first detailed description of the vertebral junction formed by two anteriorly projecting flanges on the first primordial sacral ribs and their corresponding facets on the centrum of the dorsosacral. Computed tomographic (CT) imaging reveals that the two primordial sacrals are not co-ossified and that the dorsosacral morphology of this specimen is not the result of obvious pathology. We place this incorporation of a trunk vertebra into the phytosaurian sacrum in a broader evolutionary context, with this shift in vertebral identity occurring at least seven times independently among Triassic archosauriforms, including at least three times in early crocodylian-line archosaurs and at least four times among bird-line archosaurs. Additionally, anteriorly projecting flanges of sacral ribs which articulate with the anterior-adjacent centrum have evolved several times in archosauriforms, and we interpret 'shared' sacral ribs (= a sacral rib that articulates with two adjacent sacral centra more or less equally) present in some archosaurian clades as a more extreme example of this morphology. In extant taxa the highly conserved Hox gene family plays a central role in the patterning of the axial skeleton, especially vertebral identity; therefore, the independent incorporation of a trunk vertebra into the sacrum across multiple archosauriform lineages may suggest a homologous underlying developmental mechanism for this evolutionary trend.

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The impact of treatment for head and neck cancer on positive psychological change within a year of completing treatment

Head and neck cancer carries a high level of morbidity and mortality. So why could anyone find having such a disease a positive event? The adversity hypothesis of "what doesn't kill you makes you stronger" suggests that people can use adversity to develop as human beings. This positive psychological change has received little attention in relation to head and neck cancer. Responses to the Silver Lining Questionnaire, University of Washington Quality of Life Questionnaire, and Short-Form 12 were collected from a postal survey, 3 to 12 months after the completion of treatment for head and neck cancer.

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Relatively low invasive capacity of Porphyromonas gingivalis strains into human gingival fibroblasts in vitro

Publication date: November 2017
Source:Archives of Oral Biology, Volume 83
Author(s): Ju Young Jang, Keum Jin Baek, Youngnim Choi, Suk Ji
ObjectiveBacterial invasion into host cells is a common strategy to escape the host immune system. Gingival fibroblasts (GFs) are the most predominant non-phagocytic cell type in gingival connective tissue. Therefore, invasion into GFs was thought to be the first strategy for the survival of Porphyromonas gingivalis. The present study compared the invasive ability of P. gingivalis into GFs with those of other red-complex and relatively less pathogenic bacterial strains, especially Fusobacterium nucleatum.Materials and methodsInvasive ability of bacterial strains into GFs was measured using a flow cytometric invasion assay at a multiplicity of infection of 1000. The effect of dual infection with F. nucleatum CCUG 37843T on P. gingivalis ATCC 49417 invasion was investigated. The invasive ability of F. nucleatum and P. gingivalis was confirmed using confocal microscopy.ResultsThe invasive ability of red-complex bacteria was markedly lower than that of F. nucleatum or Campylobacter gracilis. The invasive ability of 4 types and 10 clinical strains of P. gingivalis was less than 6%, and that of F. nucleatum strains was greater than 45%. Confocal analysis revealed that the percentage of bacteria invading GFs in the cell-treated P. gingivalis and F. nucleatum were 0.0068% and 1.22%, respectively. Dual infection with F. nucleatum increased the invasive ability of P. gingivalis.ConclusionThe invasive capacities of P. gingivalis into GFs were comparatively lower than those of relatively less pathogenic bacteria. Invasion into GFs cannot be the first strategy for survival of P. gingivalis in gingival connective tissue.



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“Metabolism of Odontoblast-like cells submitted to transdentinal irradiation with blue and red LED”

Publication date: November 2017
Source:Archives of Oral Biology, Volume 83
Author(s): Leopoldina de Fátima Dantas de Almeida, Fernanda Gonçalves Basso, Ana Paula Silveira Turrioni, Carlos Alberto de-Souza-Costa, Josimeri Hebling
ObjectivesThe present study evaluated the trans-dentinal effect of light emitting diodes (LEDs) irradiation on the metabolism of odontoblast-like cells.MethodsSeventy-two dentin discs (0.2mm thick) were obtained from human molar teeth. MDPC-23 cells (20,000 cells/disc) were seeded on the pulpal side of the discs using DMEM, supplemented with 10% fetal bovine serum (FBS). After 12h, the culture medium was replaced with DMEM containing 0.5% FBS. After additional 12h, blue (455±10nm) or red (630±10nm) LEDs were used at irradiances of 80 and 40mW/cm², respectively, to irradiate the occlusal side of the discs. The energy doses were fixed at 2 or 4J/cm². Cell viability, alkaline phosphatase activity (ALP), total protein production and collagen synthesis were evaluated 72h after irradiation. Data were submitted to Kruskal-Wallis and Mann-Whitney tests (α=0.05).ResultsRed light promoted proliferative effects at the energy dose of 4J/cm². Conversely, cell cultures irradiated with 2J/cm² emitted by the blue light showed reduced viability. ALP production was stimulated by red light in comparison with blue light at 4J/cm². Total protein production was reduced after exposure to blue light at 4J/cm², while no effect was observed on collagen production.ConclusionsIrradiation with red LED at 4J/cm² bio-stimulated the viability of odontoblast-like cells, whilst blue light had unfavorable effects on the cellular metabolism.



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Enlighting the Shadow for Advanced Hepatocellular Carcinoma: Immunotherapy with Immune Checkpoint Inhibitors

Abstract

Hepatocellular carcinoma has still been one of the cancer with increasing incidence and highest mortality rate in the world. Although many new promising developments have been defined in hepatocarcinogenesis, with a short survival the treatment of patients with advanced hepatocellular carcinoma is an emerging issue. On the recent decade, only one anti-angiogenic agent sorafenib improved overall survival with costing a hardly manageable toxicity. Novel immunotherapeutic agents, especially immune checkpoint inhibitors are on the edge of more effective but less toxic treatments for these patients. In this article the activity of immune checkpoint inhibitors, anti-CTLA-4 and anti-PD1 antibodies for the treatment of patients with advanced hepatocellular cancer will be reviewed.

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Anatomical topography of the inferior lumbar triangle for transversus abdominis block

Abstract

Background

Rapid development of anesthetic techniques of thoracic paravertebral block required to redefine anatomical landmarks of the inferior lumbar (Petit) triangle (ILT). Anesthesiologists are mainly interested in the ILT to perform the transversus abdominis plane (TAP) block. The aim of this study was to provide comprehensive information of the ILT to improve the success of TAP block.

Methods

Descriptional anatomy of ILTs such as dimensions, space, area, and types was analyzed in 25 preserved adult male cadavers.

Results

The ILT was identified in 100% out of all explored cadavers' lumbar regions. The predominant triangle was the acute-angled shaped (46%). The ILT in terms of the surface area was classified into four distinct types: Type I with a surface area <8 cm² was identified in 50%. Type II or intermediate triangles with a surface area of 8–12 cm² were detected in 36%. Type III or large triangles with a surface area >12 cm² were found in 14%. Type 0 or no triangle did not exhibit a triangle. For the orientation zone over the posterior lumbar region, it was measured with the distances from the posterior median line (M) to the apex (A), medial point (B), and lateral point (C) of the triangle. MA; as M1A transverse line: 103.3 ± 21.3 mm (left) and 106.4 ± 18.4 mm (right), MB; as M2B transverse line; 102.4 ± 21.8 mm (left) and 105 ± 17.9 mm (right), MC; as M3C transverse line; 119 ± 20.5 mm (left) and 120 ± 19.2 mm (right) were measured. In addition, the measurements of the vertical lines were measured. M1A–M2B and M1A–M3C vertical lines were 20.1–22.8 mm (left–right) and 30–29 mm (left–right), respectively.

Conclusions

The shape, the size, useful points, geometry, and topography of the ILT are important to determine the orientation points during block procedures. It is possible to visualize the needle pathway in different shape of ILT to ultrasound-guided TAP block. Anesthetic intervention needs to be individualized, depending upon the size of the triangle. The findings may be useful in establishing the area with the highest probability of localization of the ILT which can improve both the safety and efficiency of TAP block.

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Interpretation of thyroid scintigraphy is inconsistent among endocrinologists

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Characteristics of Real-World Signal to Noise Ratios and Speech Listening Situations of Older Adults With Mild to Moderate Hearing Loss.

Objectives: The first objective was to determine the relationship between speech level, noise level, and signal to noise ratio (SNR), as well as the distribution of SNR, in real-world situations wherein older adults with hearing loss are listening to speech. The second objective was to develop a set of prototype listening situations (PLSs) that describe the speech level, noise level, SNR, availability of visual cues, and locations of speech and noise sources of typical speech listening situations experienced by these individuals. Design: Twenty older adults with mild to moderate hearing loss carried digital recorders for 5 to 6 weeks to record sounds for 10 hours per day. They also repeatedly completed in situ surveys on smartphones several times per day to report the characteristics of their current environments, including the locations of the primary talker (if they were listening to speech) and noise source (if it was noisy) and the availability of visual cues. For surveys where speech listening was indicated, the corresponding audio recording was examined. Speech-plus-noise and noise-only segments were extracted, and the SNR was estimated using a power subtraction technique. SNRs and the associated survey data were subjected to cluster analysis to develop PLSs. Results: The speech level, noise level, and SNR of 894 listening situations were analyzed to address the first objective. Results suggested that as noise levels increased from 40 to 74 dBA, speech levels systematically increased from 60 to 74 dBA, and SNR decreased from 20 to 0 dB. Most SNRs (62.9%) of the collected recordings were between 2 and 14 dB. Very noisy situations that had SNRs below 0 dB comprised 7.5% of the listening situations. To address the second objective, recordings and survey data from 718 observations were analyzed. Cluster analysis suggested that the participants' daily listening situations could be grouped into 12 clusters (i.e., 12 PLSs). The most frequently occurring PLSs were characterized as having the talker in front of the listener with visual cues available, either in quiet or in diffuse noise. The mean speech level of the PLSs that described quiet situations was 62.8 dBA, and the mean SNR of the PLSs that represented noisy environments was 7.4 dB (speech = 67.9 dBA). A subset of observations (n = 280), which was obtained by excluding the data collected from quiet environments, was further used to develop PLSs that represent noisier situations. From this subset, two PLSs were identified. These two PLSs had lower SNRs (mean = 4.2 dB), but the most frequent situations still involved speech from in front of the listener in diffuse noise with visual cues available. Conclusions: The present study indicated that visual cues and diffuse noise were exceedingly common in real-world speech listening situations, while environments with negative SNRs were relatively rare. The characteristics of speech level, noise level, and SNR, together with the PLS information reported by the present study, can be useful for researchers aiming to design ecologically valid assessment procedures to estimate real-world speech communicative functions for older adults with hearing loss. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of High Sound Exposure During Air-Conducted Vestibular Evoked Myogenic Potential Testing in Children and Young Adults.

Objectives: Vestibular evoked myogenic potential (VEMP) testing is increasingly utilized in pediatric vestibular evaluations due to its diagnostic capability to identify otolith dysfunction and feasibility of testing. However, there is evidence demonstrating that the high-intensity stimulation level required to elicit a reliable VEMP response causes acoustic trauma in adults. Despite utility of VEMP testing in children, similar findings are unknown. It is hypothesized that increased sound exposure may exist in children because differences in ear-canal volume (ECV) compared with adults, and the effect of stimulus parameters (e.g., signal duration and intensity) will alter exposure levels delivered to a child's ear. The objectives of this study are to (1) measure peak to peak equivalent sound pressure levels (peSPL) in children with normal hearing (CNH) and young adults with normal hearing (ANH) using high-intensity VEMP stimuli, (2) determine the effect of ECV on peSPL and calculate a safe exposure level for VEMP, and (3) assess whether cochlear changes exist after VEMP exposure. Design: This was a 2-phase approach. Fifteen CNH and 12 ANH participated in phase I. Equivalent ECV was measured. In 1 ear, peSPL was recorded for 5 seconds at 105 to 125 dB SPL, in 5-dB increments for 500- and 750-Hz tone bursts. Recorded peSPL values (accounting for stimulus duration) were then used to calculate safe sound energy exposure values for VEMP testing using the 132-dB recommended energy allowance from the 2003 European Union Guidelines. Fifteen CNH and 10 ANH received cervical and ocular VEMP testing in 1 ear in phase II. Subjects completed tympanometry, pre- and postaudiometric threshold testing, distortion product otoacoustic emissions, and questionnaire addressing subjective otologic symptoms to study the effect of VEMP exposure on cochlear function. Results: (1) In response to high-intensity stimulation levels (e.g., 125 dB SPL), CNH had significantly higher peSPL measurements and smaller ECVs compared with ANH. (2) A significant linear relationship between equivalent ECV (as measured by diagnostic tympanometry) and peSPL exists and has an effect on total sound energy exposure level; based on data from phase I, 120 dB SPL was determined to be an acoustically safe stimulation level for testing in children. (3) Using calculated safe stimulation level for VEMP testing, there were no significant effect of VEMP exposure on cochlear function (as measured by audiometric thresholds, distortion product otoacoustic emission amplitude levels, or subjective symptoms) in CNH and ANH. Conclusions: peSPL sound recordings in children's ears are significantly higher (~3 dB) than that in adults in response to high-intensity VEMP stimuli that are commonly practiced. Equivalent ECV contributes to peSPL delivered to the ear during VEMP testing and should be considered to determine safe acoustic VEMP stimulus parameters; children with smaller ECVs are at risk for unsafe sound exposure during routine VEMP testing, and stimuli should not exceed 120 dB SPL. Using 120 dB SPL stimulus level for children during VEMP testing yields no change to cochlear function and reliable VEMP responses. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Biomarkers, imaging and multifocality in intraductal papillary mucinous neoplasms: relevant for decision making?

Future Oncology, Ahead of Print.


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Do all aromatase inhibitors have similar efficacy and safety?

Future Oncology, Ahead of Print.


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Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-Oncology Research

Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1) and anti-PD-L1 (PD-ligand 1) drugs by the United States Food & Drug Administration (FDA) for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this paper, we describe a novel use of sequential multiple assignment randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART.  SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity.

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Repetitive Mild Closed Head Injury Alters Protein Expression and Dendritic Complexity in a Mouse Model

Journal of Neurotrauma , Vol. 0, No. 0.


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Biomarkers, imaging and multifocality in intraductal papillary mucinous neoplasms: relevant for decision making?

Future Oncology, Ahead of Print.


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PDL-1/PD1 inhibitors: antibody or antinobody?

Future Oncology, Ahead of Print.


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Do all aromatase inhibitors have similar efficacy and safety?

Future Oncology, Ahead of Print.


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Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics

Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefor...

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Anatomical topography of the inferior lumbar triangle for transversus abdominis block

Abstract

Background

Rapid development of anesthetic techniques of thoracic paravertebral block required to redefine anatomical landmarks of the inferior lumbar (Petit) triangle (ILT). Anesthesiologists are mainly interested in the ILT to perform the transversus abdominis plane (TAP) block. The aim of this study was to provide comprehensive information of the ILT to improve the success of TAP block.

Methods

Descriptional anatomy of ILTs such as dimensions, space, area, and types was analyzed in 25 preserved adult male cadavers.

Results

The ILT was identified in 100% out of all explored cadavers' lumbar regions. The predominant triangle was the acute-angled shaped (46%). The ILT in terms of the surface area was classified into four distinct types: Type I with a surface area <8 cm² was identified in 50%. Type II or intermediate triangles with a surface area of 8–12 cm² were detected in 36%. Type III or large triangles with a surface area >12 cm² were found in 14%. Type 0 or no triangle did not exhibit a triangle. For the orientation zone over the posterior lumbar region, it was measured with the distances from the posterior median line (M) to the apex (A), medial point (B), and lateral point (C) of the triangle. MA; as M1A transverse line: 103.3 ± 21.3 mm (left) and 106.4 ± 18.4 mm (right), MB; as M2B transverse line; 102.4 ± 21.8 mm (left) and 105 ± 17.9 mm (right), MC; as M3C transverse line; 119 ± 20.5 mm (left) and 120 ± 19.2 mm (right) were measured. In addition, the measurements of the vertical lines were measured. M1A–M2B and M1A–M3C vertical lines were 20.1–22.8 mm (left–right) and 30–29 mm (left–right), respectively.

Conclusions

The shape, the size, useful points, geometry, and topography of the ILT are important to determine the orientation points during block procedures. It is possible to visualize the needle pathway in different shape of ILT to ultrasound-guided TAP block. Anesthetic intervention needs to be individualized, depending upon the size of the triangle. The findings may be useful in establishing the area with the highest probability of localization of the ILT which can improve both the safety and efficiency of TAP block.

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How the mind shapes action: Offline contexts modulate involuntary episodic retrieval

Abstract

Involuntary retrieval of previous stimulus–response episodes is a centerpiece of many theories of priming, episodic binding, and action control. Typically it is assumed that by repeating a stimulus from trial n–1 to trial n, involuntary retrieval is triggered in a nearly automatic fashion, facilitating (or interfering with) the to-be-executed action. Here we argue that changes in the offline context weaken the involuntary retrieval of previous episodes (the offline context is defined to be the information presented before or after the focal stimulus). In four conditions differing in cue modality and target modality, retrieval was diminished if participants changed the target selection criterion (as indicated by a cue presented before the selection took place) while they still performed the same task. Thus, solely through changes in the offline context (cue or selection criterion), involuntary retrieval can be weakened in an effective way.

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Interactions between visual working memory representations

Abstract

We investigated whether the representations of different objects are maintained independently in working memory or interact with each other. Observers were shown two sequentially presented orientations and required to reproduce each orientation after a delay. The sequential presentation minimized perceptual interactions so that we could isolate interactions between memory representations per se. We found that similar orientations were repelled from each other whereas dissimilar orientations were attracted to each other. In addition, when one of the items was given greater attentional priority by means of a cue, the representation of the high-priority item was not influenced very much by the orientation of the low-priority item, but the representation of the low-priority item was strongly influenced by the orientation of the high-priority item. This indicates that attention modulates the interactions between working memory representations. In addition, errors in the reported orientations of the two objects were positively correlated under some conditions, suggesting that representations of distinct objects may become grouped together in memory. Together, these results demonstrate that working-memory representations are not independent but instead interact with each other in a manner that depends on attentional priority.

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Split internal jugular vein: surgical and radiological implications

Publication date: Available online 23 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): Satheesha B. Nayak




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Fasting and surgical performance: potential source of harm?

Publication date: Available online 23 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): M.T. Brands, P. Hockey, A. Sced, P.A. Brennan




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Hard neck lumps: a review of uncommon and sometimes overlooked causes of these worrying presentations

Publication date: Available online 23 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): M.I. Ammar, R.S. Oeppen, C. Bowles, P.A. Brennan
While a neck lump is a common presentation that can raise suspicion of a potentially serious underlying disease, a hard lump, though less common, may be even more concerning for the patient, and prompt urgent investigation. Metastatic squamous cell carcinoma is the commonest underlying diagnosis that must be excluded, but other diseases or even normal anatomy of the neck can be associated with lumps that are hard or bony. Many of these presentations are relatively rare and may not be familiar to oral and maxillofacial surgeons (OMFS) (particularly more junior clinicians) as a differential diagnosis of a hard neck mass. We have reviewed these lesions to raise awareness of possible unusual causes, particularly when patients are not initially examined in a specialist neck lump clinic where ultrasound is readily available.



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Scarless total maxillectomy: midfacial degloving with extended transconjunctival retrocaruncular approach

Publication date: Available online 23 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): K. Muscat, R. Cobb, L. Vassiliou, A. Fry, L. Cascarini




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If trainers regularly validate trainees’ eLogbook records, they will spot a trainee who is not keeping theirs up-to-date

Publication date: Available online 23 August 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): P. Magennis, A. Begley




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Targeting phosphatidylinositol 3-kinase signaling pathway for therapeutic enhancement of vascular-targeted photodynamic therapy

Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with phosphatidylinositol 3-kinase (PI3K) signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here three clinically relevant small molecule inhibitors (BYL719, BKM120 and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110α isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of anti-apoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement.

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Estrogen receptor {beta} is a novel target in acute myeloid leukemia

Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive whereas cells with low ERβ were insensitive to diosmetin. Knockdown of ERβ confirmed resistance whereas overexpression enhanced sensitivity to diosmetin; which was demonstrated to be mediated by ROS signaling.  In summary, these studies highlight targeting of ERβ with diosmetin as a potential novel therapeutic strategy for the treatment of AML.

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EZH2 inhibition by tazemetostat results in altered dependency on B-cell activation signaling in DLBCL

The EZH2 small molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin's Lymphoma (NHL).  We have previously shown that EZH2 inhibitors display an anti-proliferative effect in multiple pre-clinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model.  Previous work has demonstrated that co-treatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic anti-proliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models.  Multiple agents that inhibit the B-cell receptor pathway (e.g. ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT- EZH2 backgrounds of diffuse large B-Cell Lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation.  To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1 and gene signatures corresponding to more advanced stages of maturation.  These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased B-cell maturation and a greater dependence on B-cell activation signaling.

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Liver Transplantation for the Treatment of Complicated Iatrogenic Biliary Injuries: A National Review from the UNOS Dataset.

Background: Liver transplantation (LT) is rarely indicated in the management of iatrogenic bile duct injuries (IBDI), but occasionally it becomes the only remaining therapy. The purpose of this study is to evaluate potential complications of IBDI and their impact on perioperative mortality, graft and patient survival after LT. Methods: The UNOS database was queried for all LT performed in the United States between 1994 and 2014. Of the 101 238 liver transplants performed, 61 were related to IBDI. We performed a case matched analysis in a 5:1 ratio. Results: The median age for patients with IBDI was 50.16+11.7 years with a mean MELD score of 22.6 + 9.8. Patients receiving liver transplantation for IBDI were more likely women (54.1%, p 0.001), had lower incidence of hepatitis C virus infection (4.9%, p 0.001) and longer cold ischemic time (p 0.001). The mean BMI was 25.5+ 5.2) in patients transplanted for IBDI. IBDI was recognized as the strongest independent predictor associated with 8-fold increased risk of early graft loss (p 0.001, OR 8.4) and a 2.9-fold increased risk of 30-day mortality after LT in a case matched analysis (p 0.03). Conclusions: IBDI is an uncommon but challenging indication for liver transplantation. These patients have significantly increased rates of early graft loss. IBDI is an independent factor related to increased risk of perioperative death after LT. Further studies are needed to determine the causes of perioperative complications and identify potential modifiable factors to improve outcomes in patients undergoing transplantation for IBDI. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Interpretation of thyroid scintigraphy is inconsistent among endocrinologists

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The Effects of Low Concentrations of Silver Nanoparticles on Wheat Growth, Seed Quality, and Soil Microbial Communities

Abstract

The growing demand for and production of commercial silver nanoparticles (AgNPs) inevitably increases the risk for their environmental release and soil accumulation, which could have deleterious effects on plant growth and soil microorganism communities. However, to date, little is known about how AgNPs impact plant growth, seed quality, and soil microbial communities. We therefore evaluated wheat growth and seed quality after exposure to low concentration of AgNPs while characterizing the composition of the associated soil microbial community by high-throughput sequencing of 16S rRNA genes. Our results showed that low concentration of AgNPs (1 mg/kg in fresh soil) neither inhibited wheat seedling growth nor changed the amino acid content in wheat seeds. Interestingly, the soil microorganisms in the wheat-planted group had more diversity and richness than those in the bulk-soil group. The structure of the bacterial community was affected by AgNP exposure, most significantly during the transition from the seedling to the vegetative stage of the wheat, but recovered to normal level after 49 days of treatment. In conclusion, the results from this study highlight that the environmental risks associated with low concentration of AgNPs, which have clear bioeffects on soil microorganisms, warrant further investigation.

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Adjuvant radiotherapy after radical cystectomy and ileal orthotopic neobladder

Publication date: Available online 23 August 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Mohmed S. Zaghloul, Tarek M. Zaghloul




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Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress

This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (33±12 yrs), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during i) functional residual capacity apnea (FRC_Apnea) and ii) continued RBR. Data from RBR were analyzed at matched (i.e., to FRC_Apnea) hemoglobin saturation (HbSat) levels (RBR_Matched) or more severe levels (RBR_End). A third protocol compared alternating periods (30s) of FRC and RBR (FRC-RBR_ALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71±6%; P=NS), RBR_Matched was associated with reduced AP frequency and APs per burst compared to FRC_Apnea (both P<0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRC_Apnea (+10±2; P<0.001), but not RBR_Matched (+1±2; P=NS). Second, despite more severe chemoreflex stress during RBR_End (HbSat: 56±13 vs. 71±6%; P<0.001), RBR_End was associated with a restrained increase in the APs per burst (FRC_Apnea: +18±7; RBR_End: +11±5) and total AP clusters (FRC_Apnea: +10±2; RBR_End: +6±4) (both P<0.01). During FRC-RBR_ALT, all periods of FRC elicited sympathetic AP recruitment (all P<0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P=NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even, extreme, chemoreflex stress.

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Anatomy and Physiology of Phrenic Afferent Neurons

Large diameter myelinated phrenic afferents discharge in phase with diaphragm contraction and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that 1) activation of both myelinated and non-myelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; 2) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; 3) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and 4) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and non-myelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity.

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Role of digit placement control on sensorimotor transformations for dexterous manipulation

Dexterous manipulation relies on the ability to modulate grasp forces to variable digit position. However, the sensorimotor mechanisms underlying such critical ability are not well understood. The present study addressed whether digit force-to-position modulation relies entirely on feedback of digit placement and force, or on the integration of such feedback with motor commands responsible for digit positioning. In two experiments, we asked 25 subjects to estimate the index fingertip position relative to the thumb (Perception test), or grasp and lift an object with an asymmetrical mass distribution while preventing object roll (Action test). Both tests were performed after subjects' digits were placed actively or passively at different distances (Active and Passive condition, respectively) and without visual feedback. As motor commands for digit positioning would be integrated with position and force feedback in the Active condition, we hypothesized this condition to be characterized by greater accuracy of digit position estimation and digit force-to-position modulation. Surprisingly, discrimination of digit position and force-to-position modulation were statistically indistinguishable in the Active and Passive conditions. However, the Active condition of the Action test was characterized by larger peak load force rate and shorter load phase duration (p < 0.05 and 0.001, respectively). We conclude that voluntary commands for digit positioning are not essential for accurate digit force-to-position modulation. Thus, digit force-to-position modulation can be implemented by integrating sensory feedback of digit position and voluntary commands of digit force production following contact.

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Vowel generalization and its relation to adaptation during perturbations of auditory feedback

Repeated perturbations of auditory feedback during vowel production elicit changes not only in the production of the perturbed vowel (adaptation) but also in the production of nearby vowels that were not perturbed (generalization). The finding that adaptation generalizes to other, non-perturbed vowels suggest that sensorimotor representations for vowels are not independent; instead the goals for producing any one vowel may depend in part on the goals for other vowels. The present study investigated the dependence or independence of vowel representations by evaluating adaptation and generalization in two groups of speakers exposed to auditory perturbations of their first formant (F1) during different vowels. The speakers in both groups who adapted to the perturbation exhibited generalization in two non-perturbed vowels that were produced under masking noise. Correlation testing was performed to evaluate the relations between adaptation and generalization as well as between the generalization in the two non-perturbed vowels. These tests identified significant coupling between the F1 changes of adjacent vowels but not non-adjacent vowels. The pattern of correlation findings indicates that generalization was due in part to feedforward representations that are partly shared across adjacent vowels, possibly to maintain their acoustic contrast.

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A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl- from acidic organelles in amacrine cells

Gamma-amino butyric acid (GABA) and glycine typically mediate synaptic inhibition because their ligand-gated ion channels support the influx of Cl^-. However, the electrochemical gradient for Cl^- across the postsynaptic plasma membrane determines the voltage response of the postsynaptic cell. Typically low cytosolic Cl^- supports inhibition while higher levels of cytosolic Cl^- can suppress inhibition or promotes depolarization. We previously reported that nitric oxide (NO) releases Cl^- from acidic organelles and transiently elevates cytosolic Cl^- making the response to GABA and glycine excitatory. Here, we test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the NO-dependent efflux of organellar Cl^-. We first establish the mRNA and protein expression of CFTR in our model system, cultured chick retinal amacrine cells. Using whole cell voltage clamp recordings of currents through GABA-gated Cl^- channels, we examine the effects of pharmacological inhibition of CFTR on the NO-dependent release of internal Cl-. To interfere with the expression of CFTR, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing. We find that both pharmacological inhibition and CRISPR/Cas9-mediated knockdown of CFTR blocks the ability of NO to release Cl^- from internal stores. These results demonstrate that CFTR is required for the NO-dependent efflux of Cl^- from acidic organelles.

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Functional and molecular plasticity of gamma and alpha-1 GABAA receptor subunits in the dorsal motor nucleus of the vagus after experimentally-induced diabetes

Chronic experimentally-induced hyperglycemia augments subunit specific gamma-aminobutyric acid A (GABA_A) receptor-mediated inhibition of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). However, the contribution of α1 or GABA_A receptor subunits, which are ubiquitously expressed on central nervous system neurons, to this elevation in inhibitory tone have not been determined. This study investigated the effect of chronic hyperglycemia/hypoinsulinemia on α1- and -subunit specific GABA_A receptor-mediated inhibition using electrophysiological recordings in vitro and quantitative (q)RT-PCR. DMV neurons from streptozotocin-treated mice demonstrated enhancement of both phasic and tonic inhibitory currents in response to application of the α1-subunit selective GABA_A receptor positive allosteric modulator, zolpidem. Responses to low concentrations of the GABA_A receptor antagonist, gabazine suggested an additional increased contribution of -subunit-containing receptors to tonic currents in DMV neurons. Consistent with the functional elevation in α1- and -subunit-dependent activity, transcription of both the α1- and 2-subunits was increased in the dorsal vagal complex of streptozotocin-treated mice. Overall these findings suggest an increased sensitivity to both zolpidem and gabazine after several days of hyperglycemia/hypoinsulinemia, which could contribute to altered parasympathetic output from DMV neurons in diabetes.

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Microglia-mediated synaptic elimination in neuronal development and disease

It has recently become clear that microglia, the immune cells of the central nervous system, are far more active in the healthy brain than previously thought. Microglia facilitate many stages of brain development by shaping neuronal connectivity via synaptic elimination. Dysfunction of these same processes likely underlies a wide range of neurological and neurodevelopmental disorders.

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Intrinsic frequency biases and profiles across human cortex

Recent findings in monkeys suggest that intrinsic periodic spiking activity in selective cortical areas occurs at timescales that follow a sensory or lower-order to higher-order processing hierarchy (Murray et al. 2014). It has not yet been fully explored if a similar timescale hierarchy is present in humans. Additionally, these measures in the monkey studies have not addressed findings that rhythmic activity within a brain area can occur at multiple frequencies. Here we investigate in humans if regions may be biased towards particular frequencies of intrinsic activity and if a full cortical mapping still reveals an organization that follows this hierarchy. We examined the spectral power in multiple frequency bands (0.5-150Hz) from task-independent data using magnetoencephalography (MEG). We compared standardized power across bands to find regional frequency biases. Our results demonstrate a mix of lower and higher frequency biases across sensory and higher-order regions. Thus they suggest a more complex cortical organization that does not simply follow this hierarchy. Additionally, some regions do not display a bias for a single band, and a data-driven clustering analysis reveals a regional organization with high standardized power in multiple bands. Specifically, theta and beta are both high in dorsal frontal cortex while delta and gamma are high in ventral frontal cortex and temporal cortex. Occipital and parietal regions are biased more narrowly towards alpha power and ventral temporal lobe displays specific biases towards gamma. Thus intrinsic rhythmic neural activity displays a regional organization but one that is not necessarily hierarchical.

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Impact of prior errors on visuomotor adaptation and savings: experimental considerations and clinical implications

The motor system retains learning from visuomotor adaptation tasks in the form of "savings" to enable faster readaptation to similar perturbations in the future. Leow et al. (J Neurophysiol 116: 1603-1614, 2016) suggest that the experience of prior errors during relearning is necessary for savings while repetition of prior actions may not be sufficient. These findings provide novel insight into factors that contribute to visuomotor adaptation and can be applied to future experimental and clinical research.

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The Divisive-Normalization Model of V1 Neurons: A Comprehensive Comparison of Physiological Data and Model Predictions

The physiological responses of simple and complex cells in the primary visual cortex (V1) have been studied extensively and modeled at different levels. At the functional level, the divisive normalization model (DNM, Heeger, 1992) has accounted for a wide range of single-cell recordings in terms of a combination of linear filtering, nonlinear rectification, and divisive normalization. We propose standardizing the formulation of the DNM and implementing it in software that takes static grayscale images as inputs and produces firing-rate responses as outputs. We also review a comprehensive suite of 30 empirical phenomena and report a series of simulation experiments that qualitatively replicate dozens of key experiments with a standard parameter set consistent with physiological measurements. This systematic approach identifies novel falsifiable predictions of the DNM. We show how the model simultaneously satisfies the conflicting desiderata of flexibility and falsifiability. Our key idea is that, while adjustable parameters are needed to accommodate the diversity across neurons, they must be fixed for a given individual neuron. This requirement introduces falsifiable constraints when this single neuron is probed with multiple stimuli. We also present mathematical analyses and simulation experiments that explicate some of these constraints.

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White-nose syndrome increases torpid metabolic rate and evaporative water loss in hibernating bats

Fungal diseases of wildlife typically manifest as superficial skin infections but can have devastating consequences for host physiology and survival. White-nose syndrome (WNS) is a fungal skin disease that has killed millions of hibernating bats in North America since 2007. Infection with the fungus Pseudogymnoascus destructans causes bats to rewarm too often during hibernation, but the cause of increased arousal rates remains unknown. Based on data from studies of captive and free-living bats, two mechanistic models have been proposed to explain disease processes in WNS. Key predictions of both models are that WNS-affected bats will show (1) higher metabolic rates during torpor (TMR), and (2) higher rates of evaporative water loss (EWL). We collected bats from a WNS-negative hibernaculum, inoculated one group with P. destructans and sham-inoculated a second group as controls. After four months of hibernation, we used respirometry to measure TMR and EWL. Both predictions were supported and our data suggest that infected bats were more affected by variation in ambient humidity than controls. Furthermore, disease severity, as indicated by the area of the wing with UV fluorescence, was positively correlated with EWL but not TMR. Our results provide the first direct evidence that heightened energy expenditure during torpor, and higher EWL, independently contribute to WNS pathophysiology with implications for the design of potential treatments for the disease.

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Fluorescence quenching by metal centered porphyrins and poryphyrin enzymes

Fluorescence spectroscopy and microscopy has been used extensively to monitor biomolecules, especially reactive oxygen species (ROS) and more recently reactive sulfide (RSS) species. Nearly all fluorophores are either excited by or emit light between 450 and 550 nm which is similar to the absorbance of heme proteins and metal-centered porphyrins. Here we examined the effects of catalase (Cat), reduced and oxidized hemoglobin (Hb and metHb), albumin (alb), manganese (III) Tetrakis (4-Benzoic Acid) porphyrin chloride (MnTBAP), iron proto-porphyrin IX (hemin) and copper proto-porphyrin IX (CuPPIX) on the fluorescence properties of fluorescein. We also examined the effects of catalase and MnTBAP on fluorophores for ROS (dichlorofluorescein, DCF), polysulfides (3',6'-Di(O-thiosalicyl)fluorescein, SSP4) and H₂S (7-azido-4-methylcoumarin, AzMC) previously activated by H₂O₂, a mixed polysulfide (H₂S_n, n=1-7) and H₂S, respectively. All except albumin concentration-dependently inhibited fluorophore fluorescence and absorbed light between 450 and 550 nm suggesting that the inhibitory effect was physical not catalytic. Catalase inhibition of fluorescein fluorescence was unaffected by sodium azide, dithiothreitol, diamide, TCEP or iodoacetate, supporting a physical inhibitory mechanism. Catalase and TBAP augmented then inhibited DCF fluorescence, but only inhibited SSP4 and AzMC fluorescence indicative of a substrate-specific catalytic oxidation of DCF and nonspecific fluorescence inhibition of all three fluorophores. These results suggest caution must be exercised when using any fluorescent tracers in the vicinity of metal-centered porphyrins.

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Cyclical Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Remote ischemic preconditioning (RIPC) is characterized by the cyclical application of limb blood flow restriction and reperfusion, and has been shown to protect vital organs during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) similarly combines bouts of blood flow restriction with low-intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with BFRE, however, is the potential for an augmented rise in sympathetic outflow, due to greater activation of the exercise pressor reflex. Due to the use of lower workloads, however, we hypothesized that BFRE would elicit an attenuated increase in sympathetic outflow (assessed via plasma norepinephrine (NE) and mean arterial pressure (MAP)), and middle cerebral artery velocity (MCAv) when compared with conventional exercise (CE). Fifteen subjects underwent two leg-press exercise interventions: 1.BFRE-220 mmHg bilateral thigh occlusion at 20% 1 rep-max (1RM), and; 2.CE-65% 1RM without occlusion. Each condition consisted of 4 x 5-min cycles of exercise, with 3 x 10-reps in each cycle. 5-min of rest and reperfusion (for BFRE) followed each cycle. MAP increased with exercise (P<0.001), and was 4-5 mmHg higher with CE vs. BFRE (P≤0.09). Mean MCAv also increased with exercise (P<0.001) and was higher with CE compared to BFRE during the first bout of exercise only (P=0.07). Plasma [NE] increased with CE only (P<0.001), and was higher than BFRE throughout exercise (P≤0.02). The attenuated sympathetic response combined with similar cerebrovascular responses suggest that cyclical BFRE could be explored as an alternative to CE in the clinical setting.

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Obesity-induced vascular inflammation involves elevated arginase activity

Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (EC) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high fat/high sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular EC and increased expression of tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and EC. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor ABH (2-(S)-amino-6-boronohexanoic acid). In mouse aortic EC, exposure to high glucose (25 mM) and Na palmitate (200 μM) reduced NO production, increased A1, TNFα, VCAM-1, ICAM-1 and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. Summary- HFHS diet-induced VAT inflammation is mediated by EC A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation.

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Combining Remote Ischemic Preconditioning and Aerobic Exercise: A Novel Adaptation of Blood Flow Restriction Exercise

Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE), performed at the same relative intensity. We also assessed the cerebrovascular responses, due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65-70% HR_max with and without intermittent BFR (4x5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher [NE] compared to CE (1249±170 vs 962±114 pg/ml; P=0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P=0.33), and MAP was 4-5 mmHg lower with BFRE vs. CE during the reperfusion periods (P≤0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials (P≥0.22), suggesting equivalent cerebro-metabolic demand. The exaggerated sympatho-excitatory response with BFRE was not accompanied by higher MAP, likely due to the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac- or stroke-rehabilitation, where exercising patients could benefit from the cardio- and cerebro-protection associated with RIPC.

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Optimizing success and avoiding mishaps in the most difficult image guided breast biopsies

Breast cancer is an increasing challenge in developed and limited resource areas of the world. Early detection of breast cancer offers the best chance for optimal care and best outcomes. A critical step in early detection is to obtain efficient and accurate tissue diagnoses. While image-guided core needle breast biopsies are usually straightforward for experienced breast imagers, there are some not uncommon scenarios which present particular challenges. In this review article we will discuss these difficult situations and offer our tried and true methods to ensure safe and successful biopsies, while using stereotactic, ultrasound, and MRI guidance.

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Contrast Enhanced Spectral Mammography: A Review

Contrast-enhanced spectral mammography (CESM) provides low-energy 2D mammographic images comparable to standard digital mammography and a post-contrast recombined image to assess tumor neovascularity similar to MRI. The utilization of CESM in the United States is currently low but could increase rapidly given many potential indications for clinical use. This article discusses historical background and literature review of indications and diagnostic accuracy of CESM to date. CESM is a growing technique for breast cancer detection and diagnosis that has levels of sensitivity and specificity on par with contrast-enhanced breast MRI.

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Mediastinal (Epipericardial) Fat Necrosis – an Overlooked and Little Known Cause of Acute Chest Pain Mimicking Acute Coronary Syndrome

Necrosis of the fat adjacent to the heart, referred to as pericardial fat necrosis, epipericardial fat necrosis, and mediastinal fat necrosis, is a rare, self-limited condition. It presents as the sudden onset of severe chest pain that mimics symptoms of pulmonary embolism and acute coronary syndrome. CT findings are quite typical and consist of a round or oval shaped mass-like lesion containing soft tissue and fat density components in the cardiophrenic space.Lack of familiarity with this condition has led in the past to surgical interventions in order to remove the mass-like mediastinal fat necrosis.

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