Contemporary Indications in Breast Reconstruction

CLINICS IN PLASTIC SURGERY

Copyright

ELSEVIER

Preface

Breast reconstruction has evolved immensely over the past decades. The initial satisfaction of just being able to create a resemblance of a breast mound has evolved into the current possibilities to re-create a virtually normal-appearing and -feeling breast. Advances in management of breast cancer as well as surgical techniques and materials have greatly contributed to these improvements in outcomes. Now, it seems we have come to a crossroads in breast reconstruction. The field has evolved in such an exponential way that the possibilities of performing breast reconstruction are manifold.

Contents

Jian Farhadi, Stefan O.P. Hofer, and Jaume Masia

Contributors

JIAN FARHADI, MD, FMH (Plast), EBOPRAS

Forthcoming Issues

Gluteal Augmentation

Neoadjuvant Chemotherapy for Breast Cancer Treatment and the Evidence-Based Interaction with Immediate Autologous and Implant-Based Breast Reconstruction

This article aims to determine the impact of neoadjuvant chemotherapy on immediate breast reconstruction by assessing their compatibility for oncological safety and the incidence and management of postoperative complications. A review of scientific publications published between 2009 and 2017 was undertaken. The relationship between neoadjuvant chemotherapy and immediate breast reconstruction was analyzed to compile and assess the potential interaction between the procedures. The search was limited to English language publications, but there were no limiting factors at the level of study typology. Full-text articles, including the references leading to other relevant studies, were evaluated.

Daylight photodynamic therapy versus cryosurgery for the treatment and prophylaxis of actinic keratoses of the face − protocol of a multicenter, prospective, randomized, controlled, two-armed study

Abstract

Background

Photodynamic therapy with daylight (DL-PDT) is efficacious in treating actinic keratosis (AK), but the efficacy of field-directed, repetitive DL-PDT for the treatment and prophylaxis of AK in photodamaged facial skin has not yet been investigated.

Methods/design

In this multicenter, prospective, randomized, controlled, two-armed, observer-blinded trial, patients with a minimum of 5 mild-to-moderate AK lesions on photodamaged facial skin are randomly allocated to two treatment groups: DL-PDT with methyl aminolevulinate (MAL) and cryosurgery. In the DL-PDT group (experimental group), 5 treatments of the entire face are conducted over the course of 18 months. After preparation of the lesion and within 30 min after MAL application, patients expose themselves to daylight for 2 h. In the control group, lesion-directed cryosurgery is conducted at the first visit and, in the case of uncleared or new AK lesions, also at visits 2 to 5. The efficacy of the treatment is evaluated at visits 2 to 6 by documenting all existing and new AK lesions in the face. Cosmetic results and improvement of photoaging parameters are evaluated by means of a modified Dover scale.

Primary outcome parameter is the cumulative number of AK lesions observed between visits 2 and 6.

Secondary outcome parameters are complete clearance of AK, new AK lesions since the previous visit, cosmetic results independently evaluated by both patient and physician, patient-reported pain (visual analogue scale), patient and physician satisfaction scores with cosmetic results, and patient-reported quality of life (Dermatology Life Quality Index). Safety parameters are also documented (adverse events and serious adverse events).

Discussion

This clinical trial will assess the efficacy of repetitive DL-PDT in preventing AK and investigate possible rejuvenating effects of this treatment. (Trial registration: ClinicalTrials.gov Identifier: NCT02736760).

Trial registration

ClinicalTrials.gov Identifier: NCT02736760. Study Code Daylight_01. EudraCT 2014–005121-13.

T cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate to severe psoriasis during tofacitinib treatment

Psoriasis is often treated with immunomodulatory therapies that may affect immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor.

Thermal Acclimation Ability Varies in Temperate and Tropical Aquatic Insects from Different Elevations

Synopsis

It has long been recognized that populations and species occupying different environments vary in their thermal tolerance traits. However, far less attention has been given to the impact of different environments on the capacity for plastic adjustments in thermal sensitivity, i.e., acclimation ability. One hypothesis is that environments characterized by greater thermal variability and seasonality should favor the evolution of increased acclimation ability compared with environments that are aseasonal or thermally stable. Additionally, organisms under selection for high heat tolerance may experience a trade-off and lose acclimation ability. Few studies have tested these non-mutually exclusive hypotheses at both broad latitudinal and local elevation scales in phylogenetically paired taxa. Here, we measure short-term acclimation ability of the critical thermal maximum (CT_MAX) in closely related temperate and tropical mayflies (Ephemeroptera) and stoneflies (Plecoptera) from mountain streams at different elevations. We found that stream temperature was a good predictor of acclimation ability in mayflies, but not in stoneflies. Specifically, tropical mayflies showed reduced acclimation ability compared with their temperate counterparts. High elevation tropical mayflies had greater acclimation ability than low elevation mayflies, which reflected the wider temperature variation experienced in high elevation streams. In contrast, temperate and tropical stoneflies exhibited similar acclimation responses. We found no evidence for a trade-off between heat tolerance and acclimation ability in either taxonomic order. The acclimation response in stoneflies may reflect their temperate origin or foraging mode. In combination with previous studies showing tropical taxa have narrower thermal breadths, these results demonstrate that many lower elevation tropical aquatic insects are more vulnerable to climate warming than their temperate relatives.

Stranger than Fiction: Costs and Benefits of Everyday Confabulation

Abstract

In this paper I discuss the costs and benefits of confabulation, focusing on the type of confabulation people engage in when they offer explanations for their attitudes and choices. What makes confabulation costly? In the philosophical literature confabulation is thought to undermine claims to self-knowledge. I argue that when people confabulate they do not necessarily fail at mental-state self-attributions, but offer ill-grounded explanations which often lead to the adoption of other ill-grounded beliefs. What, if anything, makes confabulation beneficial? As people are unaware of the information that would make their explanations accurate, they are not typically in a position to acknowledge their ignorance or provide better-grounded explanations for their attitudes and choices. In such cases, confabulating can have some advantages over offering no explanation because it makes a distinctive contribution to people's sense of themselves as competent and largely coherent agents. This role of ill-grounded explanations could not be as easily played by better-grounded explanations should these be available. In the end, I speculate about the implications of this conclusion for attempting to eliminate or reduce confabulation.

Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR)

Patients with psoriasis are at an increased risk for depression. However, the impact of treatment on this risk is unclear.

Correction to: Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review

The article "Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review", written by Antonia Dimitrakopoulou-Strauss, Ulrich Ronellenfitsch, Caixia Cheng, Leyun Pan, Christos Sachpekidis, Peter Hohenberger, and Thomas Henzler, was originally published Online First without open access. After publication in volume 5, issue 3, pages 183‒197, the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://ift.tt/1iwynXF), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as appropriate credit is given to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Thighplasty: improving aesthetics through revival of the medial, horizontal procedure: a safe and scar saving option

Publication date: Available online 25 October 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Karl Schwaiger, Elisabeth Russe, Klemens Heinrich, Florian Ensat, Gernot Steiner, Gottfried Wechselberger, Michaela Hladik
IntroductionThighplasty is a common bodycontouring procedure, but also associated with a high complication rate. The purpose of this study was to access the outcome of the medial horizontal thigh lift as it is a common surgical technique regarding thigh deformity correction performed at the authors' department. Surgical keysteps, clinical applications, advantages and disadvantages of the procedure are shown. Postoperative evaluation took place with special focus on individual patient satisfaction.MethodsRetrospective analysis of 25 bilateral thigh lifts with single medial horizontal incision line was performed. Evaluated data include patient age, sex, body mass index, combined procedures, additional liposuction, weight loss, former bariatric surgery, comorbidities, smoking status and surgical complications. Follow-up was performed with a standardized protocol and the scar was accessed according to the Vancouver-Scare-Scale. Additionally the patients were asked to complete a questionnaire divided into the sections 'scars', 'postoperative result' and 'sexuality'.ResultsAverage patient-age was 43 years. Average follow-up was 2 years and 8 months. Average weight loss before surgery was 57 kg. 28% of the patients were smoker. 64% had a combined procedure. 36% of all patients additionally received a liposuction of the medial thigh. During follow up we observed in six cases (24%) complications, which were designated as 'minor complications' in five times (conservative management without problems) and 'major complication' in one time (surgical revision). Overall postoperative patient satisfaction was high.Discussion and ConclusionCompared to the horizontal and vertical combined thigh lift with the classic T-shaped incision lines we observed fewer complications and a reduction of postoperative morbidity. Additionally patient satisfaction was very high. We estimate that the main reason therefore is the avoidance of the vertical scar and its associated short- and longterm problems. The evaluated data confirm the medial horizontal thighplasty as a good and valuable surgical option for the management of thigh deformities with moderate skin and tissue excess, localized in the upper part of the thigh.

Fabricating biomedical origami: a state-of-the-art review

Abstract

Purpose

Origami-based biomedical device design is an emerging technology due to its ability to be deployed from a minimal foldable pattern to a larger volume. This paper aims to review state-of-the-art origami structures applied in the medical device field.

Methods

Publications and reports of origami structure related to medical device design from the past 10 years are reviewed and categorized according to engineering specifications, including the application field, fabrication material, size/volume, deployment method, manufacturability, and advantages.

Results

This paper presents an overview of the biomedical applications of devices based on origami structures, including disposable sterilization covers, cardiac catheterization, stent grafts, encapsulation and microsurgery, gastrointestinal microsurgery, laparoscopic surgical grippers, microgrippers, microfluidic devices, and drug delivery. Challenges in terms of materials and fabrication, assembly, modeling and computation design, and clinical adoptability are discussed at the end of this paper to provide guidance for future origami-based design in the medical device field.

Conclusion

Concepts from origami can be used to design and develop novel medical devices. Origami-based medical device design is currently progressing, with researchers improving design methods, materials, fabrication techniques, and folding efficiency.

Validation workflow for a clinical Bayesian network model in multidisciplinary decision making in head and neck oncology treatment

Abstract

Purpose

Oncological treatment is being increasingly complex, and therefore, decision making in multidisciplinary teams is becoming the key activity in the clinical pathways. The increased complexity is related to the number and variability of possible treatment decisions that may be relevant to a patient. In this paper, we describe validation of a multidisciplinary cancer treatment decision in the clinical domain of head and neck oncology.

Method

Probabilistic graphical models and corresponding inference algorithms, in the form of Bayesian networks, can support complex decision-making processes by providing a mathematically reproducible and transparent advice. The quality of BN-based advice depends on the quality of the model. Therefore, it is vital to validate the model before it is applied in practice.

Results

For an example BN subnetwork of laryngeal cancer with 303 variables, we evaluated 66 patient records. To validate the model on this dataset, a validation workflow was applied in combination with quantitative and qualitative analyses. In the subsequent analyses, we observed four sources of imprecise predictions: incorrect data, incomplete patient data, outvoting relevant observations, and incorrect model. Finally, the four problems were solved by modifying the data and the model.

Conclusion

The presented validation effort is related to the model complexity. For simpler models, the validation workflow is the same, although it may require fewer validation methods. The validation success is related to the model's well-founded knowledge base. The remaining laryngeal cancer model may disclose additional sources of imprecise predictions.

Developing Control Algorithms of a Voluntary Cough for an Artificial Bioengineered Larynx Using Surface Electromyography of Chest Muscles: A Prospective Cohort Study

Abstract

Objective

This prospective cohort study investigates the prediction of a voluntary cough using surface electromyography (EMG) of intercostal and diaphragm muscles, in order to develop control algorithms for an EMG controlled artificial larynx.

Setting

The Ear Institute, London.

Main outcome measures

EMG onset compared to voluntary cough exhalation onset and to 100ms (to give the artificial larynx the time to close the bioengineered vocal cords) before voluntary cough exhalation onset, in twelve healthy participants.

Results

In the 189 EMG of intercostal muscle detected voluntary coughs, 172 coughs (91% CI 70-112) were detected before onset of cough exhalation and 128 coughs (67.6% CI 33.7-101.7) 100ms before onset of cough exhalation. In the 158 EMG of diaphragm muscle detected voluntary coughs, 149 coughs (94.3% CI 76.3-112.3) were detected before onset of cough exhalation and 102 coughs (64.6% CI 26.6-102.6) 100ms before onset of cough exhalation. More coughs were detected before onset of cough exhalation when combining EMG activity of intercostal and diaphragm muscles and comparing this to intercostal muscle activity alone (183 coughs [96.8% CI 83.8-109.8] v 172 coughs, p=0.0294). When comparing the mentioned combination to diaphragm muscle activity alone, the higher percentage detected coughs before cough exhalation onset was not found to be significant (183 coughs v 149 coughs, p=0.295). In addition, more coughs were detected 100ms before onset of cough exhalation with the mentioned combination of EMG activity and comparing this to intercostal muscles alone (149 coughs [78.8% CI 48.8-108.8] v 128 coughs, p=0.0198) and to diaphragm muscles alone (149 coughs v 102 coughs, p=0.0038).

Conclusions

Most voluntary coughs can be predicted based on combined EMG signals of intercostal and diaphragm muscles and therefore these two muscle groups will be useful in controlling the bioengineered vocal cords within the artificial larynx during a voluntary cough.

This article is protected by copyright. All rights reserved.

Needs and preferences of patients with head and neck cancer in integrated care

Abstract

Objectives

Incorporation of patients' perspectives in daily practice is necessary to adapt care to users' needs. However, information on patients' needs and preferences for integrated care is lacking. The aim was to explore these needs and preferences, taking patients with head and neck cancer (HNC) as example, to adapt current integrated care to be more patient-centered.

Design

Semi-structured interviews were held with current and former patients and chairmen of patient associations. Relevant needs and preferences were identified and categorized using the eight-dimension Picker model of patient-centered care.

Setting

Integrated HNC in the Netherlands.

Participants

HNC-patients and chairmen of two Dutch HNC-patient associations.

Main outcome measures

Patients' needs and preferences of integrated HNC care categorized according the Picker model.

Results

A total of 34 themes of needs and preferences were identified, by 14 HNC-patients or their delegates, using the Picker dimensions. Themes often emerged were: personalization of healthcare regarding patients values, clear insight into the healthcare process at organizational level, use of personalized communication, education and information that meets patients requirements, adequate involvement of allied health professionals for physical support, more attention to the impact of HNC and its treatment, adequate involvement of family and friends, adequate general practitioner involvement in the after care, and waiting time reduction.

Conclusions

Monitoring the identified themes in integrated HNC care, fitting in the Picker model, will enable us to respond better to the needs and preferences of patients and patient-centered care in oncological care can be enhanced.

This article is protected by copyright. All rights reserved.

Penile Chancres in a Man Who Has Sex With Men

This case report describes the clinical and serologic evolution of multiple penile chancres in a man who has sex with men.

Sun Protection Policies in Elementary Schools in California

This study examines sun safety policies and deviation from a 2005-disseminated sample policy among member districts of the California School Boards Association.

Tanning Salon Compliance in States With Legislation to Protect Youth Access

This cross-sectional telephone survey investigates compliance rates in the 42 states and the District of Columbia with legislation restricting tanning bed use in minors.

An Annular Eruption on the Trunk and Limbs

An otherwise healthy man in his 20s presented with a 2-month history of itchy skin lesions on his trunk, arms, and groin with no associated extracutaneous symptoms. What is your diagnosis?

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT_2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT_2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT_2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT_2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT_2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT_2B-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT_2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.

SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT_2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT_2B receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting in vivo properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to ex vivo dopamine neurons were found in mice lacking 5-HT_2B receptors. These data support the idea that the chronic 5-HT_2B-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.

MicroRNA-1906, a Novel Regulator of Toll-Like Receptor 4, Ameliorates Ischemic Injury after Experimental Stroke in Mice

Toll-like receptor 4 (TLR4) is a proinflammatory cascade initiator in poststroke inflammation. In this study, miR-1906, a novel regulator of TLR4, was identified via in silico analysis and microRNA profiling in male adult mice and its expression was then quantitated in the ischemic hemisphere. We found miR-1906 to be significantly brain enriched in the ischemic hemisphere and even more drastically enriched in the peri-infarct regions. Furthermore, in vitro experiments demonstrated that, during oxygen–glucose deprivation, miR-1906 expression was increased in glial cells but decreased in neurons. Surprisingly, despite the augmentation of intracellular abundance, miR-1906 expression in extracellular vesicles was decreased in astrocyte cell culture supernatants, suggesting reduced sources of miR-1906 from glia to neurons. When exogenous miR-1906 was administered, decreased TLR4 protein expression was observed both in vitro and in vivo. Using Cy3 labeling, exogenous miR-1906 uptake by astrocytes, microglia, and neurons was visualized directly in vivo. Reduced infarct volumes and improved functional outcomes were observed in middle cerebral artery occlusion mice receiving miR-1906. However, the protective effects of miR-1906 disappeared with the genetic knock-out of TLR4, suggesting that TLR4 is a major target of miR-1906 through which the microRNA exerts its therapeutic effects.

SIGNIFICANCE STATEMENT The current study identified miR-1906 as a novel specific regulator of Toll-like receptor 4 (TLR4) and depicted its distinct expression patterns in different cerebral regions and cell types during ischemic attack. Therefore, the therapeutic supplementation of miR-1906 can be beneficial in the modulation of poststroke inflammation. Using Cy3 labeling, exogenous miR-1906 expression was visualized and shown to enter astrocytes, microglia, and neurons successfully in vivo. Supplemental therapeutic miR-1906 resulted in reduced TLR4 expression and improved outcomes after middle cerebral artery occlusion in a mouse model, but its neuroprotective function was TLR4 dependent, suggesting that TLR4 is a major target of miR-1906.

Weak Higher-Order Interactions in Macroscopic Functional Networks of the Resting Brain

Interactions among different brain regions are usually examined through functional connectivity (FC) analysis, which is exclusively based on measuring pairwise correlations in activities. However, interactions beyond the pairwise level, that is, higher-order interactions (HOIs), are vital in understanding the behavior of many complex systems. So far, whether HOIs exist among brain regions and how they can affect the brain's activities remains largely elusive. To address these issues, here, we analyzed blood oxygenation level-dependent (BOLD) signals recorded from six typical macroscopic functional networks of the brain in 100 human subjects (46 males and 54 females) during the resting state. Through examining the binarized BOLD signals, we found that HOIs within and across individual networks were both very weak regardless of the network size, topology, degree of spatial proximity, spatial scales, and whether the global signal was regressed. To investigate the potential mechanisms underlying the weak HOIs, we analyzed the dynamics of a network model and also found that HOIs were generally weak within a wide range of key parameters provided that the overall dynamic feature of the model was similar to the empirical data and it was operating close to a linear fluctuation regime. Our results suggest that weak HOI may be a general property of brain's macroscopic functional networks, which implies the dominance of pairwise interactions in shaping brain activities at such a scale and warrants the validity of widely used pairwise-based FC approaches.

SIGNIFICANCE STATEMENT To explain how activities of different brain areas are coordinated through interactions is essential to revealing the mechanisms underlying various brain functions. Traditionally, such an interaction structure is commonly studied using pairwise-based functional network analyses. It is unclear whether the interactions beyond the pairwise level (higher-order interactions or HOIs) play any role in this process. Here, we show that HOIs are generally weak in macroscopic brain networks. We also suggest a possible dynamical mechanism that may underlie this phenomenon. These results provide plausible explanation for the effectiveness of widely used pairwise-based approaches in analyzing brain networks. More importantly, it reveals a previously unknown, simple organization of the brain's macroscopic functional systems.

The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A

Transcription factor 4 (TCF4 also known as ITF2 or E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt–Hopkins syndrome, intellectual disability, and schizophrenia (SCZ). Here, we show that TCF4-dependent transcription in cortical neurons cultured from embryonic rats of both sexes is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signaling. PKA phosphorylates TCF4 directly and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons and in the developing brain in vivo. We also demonstrate that Gadd45g (growth arrest and DNA damage inducible gamma) is a direct target of neuronal-activity-induced, TCF4-dependent transcriptional regulation and that TCF4 missense variations identified in SCZ patients alter the transcriptional activity of TCF4 in neurons. This study identifies a new role for TCF4 as a neuronal-activity-regulated transcription factor, offering a novel perspective on the association of TCF4 with cognitive disorders.

SIGNIFICANCE STATEMENT The importance of the basic helix-loop-helix transcription factor transcription factor 4 (TCF4) in the nervous system is underlined by its association with common and rare cognitive disorders. In the current study, we show that TCF4-controlled transcription in primary cortical neurons is induced by neuronal activity and protein kinase A. Our results support the hypotheses that dysregulation of neuronal-activity-dependent signaling plays a significant part in the etiology of neuropsychiatric and neurodevelopmental disorders.

Signatures of Somatic Inhibition and Dendritic Excitation in Auditory Brainstem Field Potentials

Extracellular voltage recordings (V_e; field potentials) provide an accessible view of in vivo neural activity, but proper interpretation of field potentials is a long-standing challenge. Computational modeling can aid in identifying neural generators of field potentials. In the auditory brainstem of cats, spatial patterns of sound-evoked V_e can resemble, strikingly, V_e generated by current dipoles. Previously, we developed a biophysically-based model of a binaural brainstem nucleus, the medial superior olive (MSO), that accounts qualitatively for observed dipole-like V_e patterns in sustained responses to monaural tones with frequencies >~1000 Hz (Goldwyn et al., 2014). We have observed, however, that V_e patterns in cats of both sexes appear more monopole-like for lower-frequency tones. Here, we enhance our theory to accurately reproduce dipole and non-dipole features of V_e responses to monaural tones with frequencies ranging from 600 to 1800 Hz. By applying our model to data, we estimate time courses of paired input currents to MSO neurons. We interpret these inputs as dendrite-targeting excitation and soma-targeting inhibition (the latter contributes non-dipole-like features to V_e responses). Aspects of inferred inputs are consistent with synaptic inputs to MSO neurons including the tendencies of inhibitory inputs to attenuate in response to high-frequency tones and to precede excitatory inputs. Importantly, our updated theory can be tested experimentally by blocking synaptic inputs. MSO neurons perform a critical role in sound localization and binaural hearing. By solving an inverse problem to uncover synaptic inputs from V_e patterns we provide a new perspective on MSO physiology.

SIGNIFICANCE STATEMENT Extracellular voltages (field potentials) are a common measure of brain activity. Ideally, one could infer from these data the activity of neurons and synapses that generate field potentials, but this "inverse problem" is not easily solved. We study brainstem field potentials in the region of the medial superior olive (MSO); a critical center in the auditory pathway. These field potentials exhibit distinctive spatial and temporal patterns in response to pure tone sounds. We use mathematical modeling in combination with physiological and anatomical knowledge of MSO neurons to plausibly explain how dendrite-targeting excitation and soma-targeting inhibition generate these field potentials. Inferring putative synaptic currents from field potentials advances our ability to study neural processing of sound in the MSO.

Valence, Not Utility, Underlies Reward-Driven Prioritization in Human Vision

Objects associated with reward draw attention and evoke enhanced activity in visual cortex. What is the underlying mechanism? One possibility is that reward's impact on vision is mediated by unique circuitry that modulates sensory processing, selectively increasing the salience of reward-associated stimuli. Alternatively, effects of reward may be part of a more general mechanism that prioritizes the processing of any beneficial object, importantly including stimuli that are associated with the evasion of loss. Here, we test these competing hypotheses by having male and female humans detect naturalistic objects associated with monetary reward, the evasion of equivalent loss, or neither of these. If vision is economically normative, processing of objects associated with reward and evasion of loss should be prioritized relative to neutral stimuli. Results from fMRI and behavioral experiments show that this is not the case: whereas objects associated with reward were better detected and represented in ventral visual cortex, detection and representation of stimuli associated with the evasion of loss were degraded. Representations in parietal cortex reveal a notable exception to this pattern, showing enhanced encoding of both reward- and loss-associated stimuli. Experience-driven visual prioritization can thus be economically irrational, driven by valence rather than objective utility.

SIGNIFICANCE STATEMENT Normative economic models propose that gain should have the same value as evasion of equivalent loss. Is human vision rational in this way? Objects associated with reward draw attention and are well represented in visual cortex. This is thought to have evolutionary origins, highlighting objects likely to provide benefit in the future. But benefit can be conferred not only through gain, but also through evasion of loss. Here we demonstrate that the visual system prioritizes real-world objects presented in images of natural scenes only when these objects have been associated with reward, not when they have provided the opportunity to evade financial loss. Visual selection is thus non-normative and economically irrational, driven by valence rather than objective utility.

Spatial Structure of Synchronized Inhibition in the Olfactory Bulb

Olfactory sensory input is detected by receptor neurons in the nose, which then send information to the olfactory bulb (OB), the first brain region for processing olfactory information. Within the OB, many local circuit interneurons, including axonless granule cells, function to facilitate fine odor discrimination. How interneurons interact with principal cells to affect bulbar processing is not known, but the mechanism is likely to be different from that in sensory cortical regions because the OB lacks an obvious topographical organization. Neighboring glomerular columns, representing inputs from different receptor neuron subtypes, typically have different odor tuning. Determining the spatial scale over which interneurons such as granule cells can affect principal cells is a critical step toward understanding how the OB operates. We addressed this question by assaying inhibitory synchrony using intracellular recordings from pairs of principal cells with different intersomatic spacing. We found, in acute rat OB slices from both sexes, that inhibitory synchrony is evident in the spontaneous synaptic input in mitral cells (MCs) separated up to 220 μm (300 μm with elevated K⁺). At all intersomatic spacing assayed, inhibitory synchrony was dependent on Na⁺ channels, suggesting that action potentials in granule cells function to coordinate GABA release at relatively distant dendrodendritic synapses formed throughout the dendritic arbor. Our results suggest that individual granule cells are able to influence relatively large groups of MCs and tufted cells belonging to clusters of at least 15 glomerular modules, providing a potential mechanism to integrate signals reflecting a wide variety of odorants.

SIGNIFICANCE STATEMENT Inhibitory circuits in the olfactory bulb (OB) play a major role in odor processing, especially during fine odor discrimination. However, how inhibitory networks enhance olfactory function, and over what spatial scale they operate, is not known. Interneurons are potentially able to function on both a highly localized, synapse-specific level and on a larger, spatial scale that encompasses many different glomerular channels. Although recent indirect evidence has suggested a relatively localized functional role for most inhibition in the OB, in the present study, we used paired intracellular recordings to demonstrate directly that inhibitory local circuits operate over large spatial scales by using fast action potentials to link GABA release at many different synaptic contacts formed with principal cells.

The Timing of Reward-Seeking Action Tracks Visually Cued Theta Oscillations in Primary Visual Cortex

An emerging body of work challenges the view that primary visual cortex (V1) represents the visual world faithfully. Theta oscillations in the local field potential (LFP) of V1 have been found to convey temporal expectations and, specifically, to express the delay between a visual stimulus and the reward that it portends. We extend this work by showing how these oscillatory states in male, wild-type rats can even relate to the timing of a visually cued reward-seeking behavior. In particular, we show that, with training, high precision and accuracy in behavioral timing tracks the power of these oscillations and the time of action execution covaries with their duration. These LFP oscillations are also intimately related to spiking responses at the single-unit level, which themselves carry predictive timing information. Together, these observations extend our understanding of the role of cortical oscillations in timing generally and the role of V1 in the timing of visually cued behaviors specifically.

SIGNIFICANCE STATEMENT Traditionally, primary visual cortex (V1) has been regarded as playing a purely perceptual role in stimulus-driven behaviors. Recent work has challenged that view by showing that theta oscillations in rodent V1 may come to convey timed expectations. Here, we show that these theta oscillations carry predictive information about timed reward-seeking actions, thus elucidating a behavioral role for theta oscillations in V1 and extending our understanding of the role of V1 in decision making.

Interneuronal Network Activity at the Onset of Seizure-Like Events in Entorhinal Cortex Slices

The onset of focal seizures in humans and in different animal models of focal epilepsy correlates with reduction of neuronal firing and enhanced interneuronal network activity. Whether this phenomenon contributes to seizure generation is still unclear. We used the in vitro entorhinal cortex slices bathed in 4-aminopirydine (4-AP) as an experimental paradigm model to evaluate the correlation between interneuronal GABAergic network activity and seizure-like events. Epileptiform discharges were recorded in layer V–VI pyramidal neurons and fast-spiking interneurons in slices from male and female mice and in the isolated female guinea pig brain preparation during perfusion with 4-AP. We observed that 90% of seizure-like events recorded in principal cells were preceded by outward currents coupled with extracellular potassium shifts, abolished by pharmacological blockade of GABA_A receptors. Potassium elevations associated to GABA_A receptor-mediated population events were confirmed in the entorhinal cortex of the in vitro isolated whole guinea pig brain. Fast-rising and sustained extracellular potassium increases associated to interneuronal network activity consistently preceded the initiation of seizure-like events. We conclude that in the 4-AP seizure model, interneuronal network activity occurs before 4-AP-induced seizures and therefore supports a role of interneuron activity in focal seizure generation.

SIGNIFICANCE STATEMENT The paper focuses on the mechanisms of ictogenesis, a topic that requires a step beyond the simplistic view that seizures, and epilepsy, are due to an increase of excitatory network activity. Focal temporal lobe seizures in humans and in several experimental epilepsies likely correlate with a prevalent activation of interneurons. The potassium channel blocker 4-aminopyridine reliably induces seizure-like events in temporal lobe structures. Herein, we show that a majority of seizures in the entorhinal cortex starts with interneuronal network activity accompanied by a fast and sustained increase in extracellular potassium. Our new findings reinforce and add a new piece of evidence to the proposal that limbic seizures can be supported by GABAergic hyperactivity.

MEG Insight into the Spectral Dynamics Underlying Steady Isometric Muscle Contraction

To gain fundamental knowledge on how the brain controls motor actions, we studied in detail the interplay between MEG signals from the primary sensorimotor (SM1) cortex and the contraction force of 17 healthy adult humans (7 females, 10 males). SM1 activity was coherent at ~20 Hz with surface electromyogram (as already extensively reported) but also with contraction force. In both cases, the effective coupling was dominant in the efferent direction. Across subjects, the level of ~20 Hz coherence between cortex and periphery positively correlated with the "burstiness" of ~20 Hz SM1 (Pearson r 0.65) and peripheral fluctuations (r 0.9). Thus, ~20 Hz coherence between cortex and periphery is tightly linked to the presence of ~20 Hz bursts in SM1 and peripheral activity. However, the very high correlation with peripheral fluctuations suggests that the periphery is the limiting factor. At frequencies <3 Hz, both SM1 signals and ~20 Hz SM1 envelope were coherent with both force and its absolute change rate. The effective coupling dominated in the efferent direction between (1) force and the ~20 Hz SM1 envelope and (2) the absolute change rate of the force and SM1 signals. Together, our data favor the view that ~20 Hz coherence between cortex and periphery during isometric contraction builds on the presence of ~20 Hz SM1 oscillations and needs not rely on feedback from the periphery. They also suggest that effective cortical proprioceptive processing operates at <3 Hz frequencies, even during steady isometric contractions.

SIGNIFICANCE STATEMENT Accurate motor actions are made possible by continuous communication between the cortex and spinal motoneurons, but the neurophysiological basis of this communication is poorly understood. Using MEG recordings in humans maintaining steady isometric muscle contractions, we found evidence that the cortex sends population-level motor commands that tend to structure according to the ~20 Hz sensorimotor rhythm, and that it dynamically adapts these commands based on the <3 Hz fluctuations of proprioceptive feedback. To our knowledge, this is the first report to give a comprehensive account of how the human brain dynamically handles the flow of proprioceptive information and converts it into appropriate motor command to keep the contraction force steady.

A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala–ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal–limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.

SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal–limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Attention to Color Sharpens Neural Population Tuning via Feedback Processing in the Human Visual Cortex Hierarchy

Attention can facilitate the selection of elementary object features such as color, orientation, or motion. This is referred to as feature-based attention and it is commonly attributed to a modulation of the gain and tuning of feature-selective units in visual cortex. Although gain mechanisms are well characterized, little is known about the cortical processes underlying the sharpening of feature selectivity. Here, we show with high-resolution magnetoencephalography in human observers (men and women) that sharpened selectivity for a particular color arises from feedback processing in the human visual cortex hierarchy. To assess color selectivity, we analyze the response to a color probe that varies in color distance from an attended color target. We find that attention causes an initial gain enhancement in anterior ventral extrastriate cortex that is coarsely selective for the target color and transitions within ~100 ms into a sharper tuned profile in more posterior ventral occipital cortex. We conclude that attention sharpens selectivity over time by attenuating the response at lower levels of the cortical hierarchy to color values neighboring the target in color space. These observations support computational models proposing that attention tunes feature selectivity in visual cortex through backward-propagating attenuation of units less tuned to the target.

SIGNIFICANCE STATEMENT Whether searching for your car, a particular item of clothing, or just obeying traffic lights, in everyday life, we must select items based on color. But how does attention allow us to select a specific color? Here, we use high spatiotemporal resolution neuromagnetic recordings to examine how color selectivity emerges in the human brain. We find that color selectivity evolves as a coarse to fine process from higher to lower levels within the visual cortex hierarchy. Our observations support computational models proposing that feature selectivity increases over time by attenuating the responses of less-selective cells in lower-level brain areas. These data emphasize that color perception involves multiple areas across a hierarchy of regions, interacting with each other in a complex, recursive manner.

A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain

Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin on the cell surface. Our previous studies indicate that uPA and uPAR expression increase in the ischemic brain during the recovery phase from an acute ischemic injury and that uPA binding to uPAR promotes neurological recovery after an acute ischemic stroke. Here, we used male mice genetically deficient on either uPA (uPA^–/–) or uPAR (uPAR^–/–) or with a four-amino acid substitution into the growth factor domain of uPA that abrogates its binding to uPAR (Plat^GFDhu/GFDhu) to investigate the mechanism whereby uPA promotes neurorepair in the ischemic brain. We found that neurons release uPA and astrocytes recruit uPAR to their plasma membrane during the recovery phase from a hypoxic injury and that binding of neuronal uPA to astrocytic uPAR induces astrocytic activation by a mechanism that does not require plasmin generation, but instead is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-regulated phosphorylation of the signal transducer and activator of transcription 3 (STAT3). We report that uPA/uPAR binding is necessary and sufficient to induce astrocytic activation in the ischemic brain and that astrocytes activated by neuronal uPA promote synaptic recovery in neurons that have suffered an acute hypoxic injury via a mechanism mediated by astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). In summary, we show that uPA/uPAR-induced astrocytic activation mediates a cross talk between astrocytes and injured neurons that promotes synaptic recovery in the ischemic brain.

SIGNIFICANCE STATEMENT To date, there is no therapeutic strategy to promote synaptic recovery in the injured brain. Here, we show that neurons release urokinase-type plasminogen activator (uPA) and astrocytes recruit the uPA receptor (uPAR) to their plasma membrane during the recovery phase from a hypoxic injury. We found that binding of neuronal uPA to astrocytic uPAR promotes astrocytic activation and that astrocytes activated by uPA–uPAR binding promote synaptic recovery in neurons that have suffered a hypoxic injury by a mechanism that does not require plasmin generation, but instead is mediated by ERK1/2-regulated STAT3 phosphorylation, astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). Our work unveils a new biological function for uPA–uPAR as mediator of a neuron–astrocyte cross talk that promotes synaptic recovery in the ischemic brain.

Drosophila Neprilysin 1 Rescues Memory Deficits Caused by Amyloid-{beta} Peptide

Neprilysins are Type II metalloproteinases known to degrade and inactivate a number of small peptides, in particular the mammalian amyloid-β peptide (Aβ). In Drosophila, several neprilysins expressed in the brain are required for middle-term (MTM) and long-term memory (LTM) in the dorsal paired medial (DPM) neurons, a pair of large neurons that broadly innervate the mushroom bodies (MB), the center of olfactory memory. These data indicate that one or several peptides need to be degraded for MTM and LTM. We have previously shown that the fly amyloid precursor protein (APPL) is required for memory in the MB. We show here that APPL is also required in adult DPM neurons for MTM and LTM formation. This finding prompted us to search for an interaction between neprilysins and Drosophila Aβ (dAβ), a cleavage product of APPL. To find out whether dAβ was a neprilysin's target, we used inducible drivers to modulate neprilysin 1 (Nep1) and dAβ expression in adult DPM neurons. Experiments were conducted either in both sexes or in females. We show that Nep1 inhibition makes dAβ expression detrimental to both MTM and LTM. Conversely, memory deficits displayed by dAβ-expressing flies are rescued by Nep1 overexpression. Consistent with behavioral data, biochemical analyses confirmed that Nep1 degrades dAβ. Together, our findings establish that Nep1 and dAβ expressed in DPM neurons are functionally linked for memory processes, suggesting that dAβ is a physiological target for Nep1.

SIGNIFICANCE STATEMENT Neprilysins are endopeptidases known to degrade a number of small peptides and in particular the amyloid peptide. We previously showed that all four neprilysins expressed in the Drosophila brain are involved in specific phases of olfactory memory. Here we show that an increase in the level of the neprilysin 1 peptidase overcomes memory deficits induced by amyloid peptide in young flies. Together, the data reveal a functional interaction between neprilysin 1 and amyloid peptide, suggesting that neprilysin 1 degrades amyloid peptide. These findings raise the possibility that, under nonpathological conditions, mammalian neprilysins degrade amyloid peptide to ensure memory formation.

Top-Down Modulation of Auditory-Motor Integration during Speech Production: The Role of Working Memory

Although working memory (WM) is considered as an emergent property of the speech perception and production systems, the role of WM in sensorimotor integration during speech processing is largely unknown. We conducted two event-related potential experiments with female and male young adults to investigate the contribution of WM to the neurobehavioural processing of altered auditory feedback during vocal production. A delayed match-to-sample task that required participants to indicate whether the pitch feedback perturbations they heard during vocalizations in test and sample sequences matched, elicited significantly larger vocal compensations, larger N1 responses in the left middle and superior temporal gyrus, and smaller P2 responses in the left middle and superior temporal gyrus, inferior parietal lobule, somatosensory cortex, right inferior frontal gyrus, and insula compared with a control task that did not require memory retention of the sequence of pitch perturbations. On the other hand, participants who underwent extensive auditory WM training produced suppressed vocal compensations that were correlated with improved auditory WM capacity, and enhanced P2 responses in the left middle frontal gyrus, inferior parietal lobule, right inferior frontal gyrus, and insula that were predicted by pretraining auditory WM capacity. These findings indicate that WM can enhance the perception of voice auditory feedback errors while inhibiting compensatory vocal behavior to prevent voice control from being excessively influenced by auditory feedback. This study provides the first evidence that auditory-motor integration for voice control can be modulated by top-down influences arising from WM, rather than modulated exclusively by bottom-up and automatic processes.

SIGNIFICANCE STATEMENT One outstanding question that remains unsolved in speech motor control is how the mismatch between predicted and actual voice auditory feedback is detected and corrected. The present study provides two lines of converging evidence, for the first time, that working memory cannot only enhance the perception of vocal feedback errors but also exert inhibitory control over vocal motor behavior. These findings represent a major advance in our understanding of the top-down modulatory mechanisms that support the detection and correction of prediction-feedback mismatches during sensorimotor control of speech production driven by working memory. Rather than being an exclusively bottom-up and automatic process, auditory-motor integration for voice control can be modulated by top-down influences arising from working memory.

Neutrophils Are Critical for Myelin Removal in a Peripheral Nerve Injury Model of Wallerian Degeneration

Wallerian degeneration (WD) is considered an essential preparatory stage to the process of axonal regeneration. In the peripheral nervous system, infiltrating monocyte-derived macrophages, which use the chemokine receptor CCR2 to gain entry to injured tissues from the bloodstream, are purportedly necessary for efficient WD. However, our laboratory has previously reported that myelin clearance in the injured sciatic nerve proceeds unhindered in the Ccr2^–/– mouse model. Here, we extensively characterize WD in male Ccr2^–/– mice and identify a compensatory mechanism of WD that is facilitated primarily by neutrophils. In response to the loss of CCR2, injured Ccr2^–/– sciatic nerves demonstrate prolonged expression of neutrophil chemokines, a concomitant extended increase in the accumulation of neutrophils in the nerve, and elevated phagocytosis by neutrophils. Neutrophil depletion substantially inhibits myelin clearance after nerve injury in both male WT and Ccr2^–/– mice, highlighting a novel role for these cells in peripheral nerve degeneration that spans genotypes.

SIGNIFICANCE STATEMENT The accepted view in the basic and clinical neurosciences is that the clearance of axonal and myelin debris after a nerve injury is directed primarily by inflammatory CCR2⁺ macrophages. However, we demonstrate that this clearance is nearly identical in WT and Ccr2^–/– mice, and that neutrophils replace CCR2⁺ macrophages as the primary phagocytic cell. We find that neutrophils play a major role in myelin clearance not only in Ccr2^–/– mice but also in WT mice, highlighting their necessity during nerve degeneration in the peripheral nervous system. These degeneration studies may propel improvements in nerve regeneration and draw critical parallels to mechanisms of nerve degeneration and regeneration in the CNS and in the context of peripheral neuropathies.

Chd7 Collaborates with Sox2 to Regulate Activation of Oligodendrocyte Precursor Cells after Spinal Cord Injury

Oligodendrocyte precursor cells (OPCs) act as a reservoir of new oligodendrocytes (OLs) in homeostatic and pathological conditions. OPCs are activated in response to injury to generate myelinating OLs, but the underlying mechanisms remain poorly understood. Here, we show that chromodomain helicase DNA binding protein 7 (Chd7) regulates OPC activation after spinal cord injury (SCI). Chd7 is expressed in OPCs in the adult spinal cord and its expression is upregulated with a concomitant increase in Sox2 expression after SCI. OPC-specific ablation of Chd7 in injured mice leads to reduced OPC proliferation, the loss of OPC identity, and impaired OPC differentiation. Ablation of Chd7 or Sox2 in cultured OPCs shows similar phenotypes to those observed in Chd7 knock-out mice. Chd7 and Sox2 form a complex in OPCs and bind to the promoters or enhancers of the regulator of cell cycle (Rgcc) and protein kinase C (PKC) genes, thereby inducing their expression. The expression of Rgcc and PKC is reduced in the OPCs of the injured Chd7 knock-out mice. In cultured OPCs, overexpression and knock-down of Rgcc or PKC promote and suppress OPC proliferation, respectively. Furthermore, overexpression of both Rgcc and PKC rescues the Chd7 deletion phenotypes. Chd7 is thus a key regulator of OPC activation, in which it cooperates with Sox2 and acts via direct induction of Rgcc and PKC expression.

SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to oligodendrocyte (OL) loss and demyelination, along with neuronal death, resulting in impairment of motor or sensory functions. Oligodendrocyte precursor cells (OPCs) activated in response to injury are potential sources of OL replacement and are thought to contribute to remyelination and functional recovery after SCI. However, the molecular mechanisms underlying OPC activation, especially its epigenetic regulation, remain largely unclear. We demonstrate here that the chromatin remodeler chromodomain helicase DNA binding protein 7 (Chd7) regulates the proliferation and identity of OPCs after SCI. We have further identified regulator of cell cycle (Rgcc) and protein kinase C (PKC) as novel targets of Chd7 for OPC activation.

Inhibition of IL-1{beta} Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease

Creutzfeldt–Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral–commissural synapses in the CA1 area of ~100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ~300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1β-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1β plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1β signaling may offer a novel symptomatic treatment for CJD.

SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt–Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high brain levels of the inflammatory cytokine IL-1β. Here we show that blocking IL-1β receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and reduces seizure susceptibility in a CJD mouse model. These results link neuroinflammation to defective neurotransmission and the enhanced susceptibility to seizures in CJD and raise the possibility that targeting IL-1β with clinically available drugs may be beneficial for symptomatic treatment of the disease.

Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus

Glycoprotein-deleted rabies virus-mediated monosynaptic tracing has become a standard method for neuronal circuit mapping, and is applied to virtually all parts of the rodent nervous system, including the spinal cord and primary sensory neurons. Here we identified two classes of unmyelinated sensory neurons (nonpeptidergic and C-fiber low-threshold mechanoreceptor neurons) resistant to direct and trans-synaptic infection from the spinal cord with rabies viruses that carry glycoproteins in their envelopes and that are routinely used for infection of CNS neurons (SAD-G and N2C-G). However, the same neurons were susceptible to infection with EnvA-pseudotyped rabies virus in tumor virus A receptor transgenic mice, indicating that resistance to retrograde infection was due to impaired virus adsorption rather than to deficits in subsequent steps of infection. These results demonstrate an important limitation of rabies virus-based retrograde tracing of sensory neurons in adult mice, and may help to better understand the molecular machinery required for rabies virus spread in the nervous system. In this study, mice of both sexes were used.

SIGNIFICANCE STATEMENT To understand the neuronal bases of behavior, it is important to identify the underlying neural circuitry. Rabies virus-based monosynaptic tracing has been used to identify neuronal circuits in various parts of the nervous system. This has included connections between peripheral sensory neurons and their spinal targets. These connections form the first synapse in the somatosensory pathway. Here we demonstrate that two classes of unmyelinated sensory neurons, which account for >40% of dorsal root ganglia neurons, display resistance to rabies infection. Our results are therefore critical for interpreting monosynaptic rabies-based tracing in the sensory system. In addition, identification of rabies-resistant neurons might provide a means for future studies addressing rabies pathobiology.

Unique Maturation Trajectories of Basket and Chandelier Cells in the Neocortex

Some Reflections on the Term Sautrāntika in Vinaya Context: vinayadharaḥ sautrāntikaḥ in the Mahāparinirvāṇa-mahāsūtra

Abstract

The word sautrāntika is known to designate one of the philosophical schools in later documents, but its earlier phase remains uncertain. The discovery of this term in the Mahāparinirvāṇa-mahāsūtra thus brings forward new evidence essential for solving the problem of sautrāntika. In this paper, I will attempt to establish the interpretation of the context, in which the phrase vinayadharaḥ sautrāntikaḥ appears.

IgE autoantibodies and their association with the disease activity and phenotype in bullous pemphigoid: a systematic review

Abstract

Bullous pemphigoid (BP) is the most common autoimmune skin disease of blistering character. The underlying pathophysiological mechanism involves an immune attack, usually by IgG class autoantibodies, on the autoantigen BP 180/BPAg2, which is a type XVII collagen (COL17) protein acting as the adhesion molecule between the epidermis and the basement membrane of the dermis. About 40 years ago, following consistent findings of elevated total serum IgE levels in BP patients, it was hypothesized that IgE may be involved in the pathophysiology of BP. Our objective was to determine whether there is strong evidence for an association between IgE class autoantibodies and the clinical severity or phenotype of BP. Three databases were searched for relevant studies and appropriate exclusion and inclusion criteria were applied. Data was extracted and assessed in relation to the study questions concerning the clinical significance of IgE autoantibodies in BP. Nine studies found that anti-BP180 autoantibodies of IgE class are associated with increased severity of BP, whereas two studies did not find such an association. The number of studies which found an association between higher IgE autoantibody levels and the erythematous urticarial phenotype of BP (5) was equal in number to the studies which found no such association (5). In conclusion, higher serum IgE autoantibody levels are associated with more severe clinical manifestations of BP. There is insufficient evidence to support higher IgE autoantibody levels being associated with specific clinical phenotypes of BP.

Vacuum sealing with a ‘flipper’ for the treatment of plantar excision defects

Lymphangiosarcoma of the hip arising in a congenital non-irradiated lymphangioma

Clinicopathological analysis of myxoid proximal-type epithelioid sarcoma

Abstract

Proximal-type epithelioid sarcoma (ES) with a diffuse myxoid stroma is rare. Here, we report the case of a 33-year-old man with a perineal mass. Imaging demonstrated the presence of a poorly demarcated 6.9 × 5.3-cm mass in the subcutaneous perineal region. Macroscopic examination showed that the resected tissues were partially necrotic. Histological examination showed that the tumor comprised numerous large or pleomorphic epithelioid cells with large vesicular nuclei and prominent nucleoli. A clear background of necrosis and inflammatory exudates was also present. Immunohistochemical examination showed that the tumor cells were positive for vimentin and CD34—both of which were expressed throughout the cytoplasm—but typically did not express nuclear INI1 (SMARCB1). HE staining demonstrated that the mucus content of the tumor was approximately 80%. The patient was diagnosed with proximal-type ES with myxoid features. The patient died due to disease progression after 2 months of follow up and without undergoing further treatment in our department. To our knowledge, only two cases of proximal-type ES with diffuse myxoid stroma have been reported (Table 1). Proximal-type ES is rare, and this is the first case report of proximal ES with myxoid features in the perineal area.

Cover Image

The cover image, by Genki Kimura et al., is based on the Original Article Effects of intranasally dosed posaconazole on fungal load and biomarkers in Aspergillus fumigatus infected immunocompromised mice, DOI: 10.1111/myc.12653.

Issue Information

Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: A Retrospective International Study of Invasive/advanced cancer of the urothelium (RISC).

Abstract

BackgroundCisplatin-based combination chemotherapy is the standard treatment for advanced urinary tract cancer (aUTC) but 50% of patients are ineligible for cisplatin according to recently published criteria. We used a multinational database to study patterns of chemotherapy utilization in patients with aUTC and determine their impact on survival.Patients and MethodsThis was a retrospective study of patients with: UTC (bladder, renal pelvis, ureter or urethra); advanced disease (stages T4b and/or N+ and/or M+); urothelial, squamous or adenocarcinoma histology. Primary objective was overall survival (OS). Eligibility-for-cisplatin was defined by: Eastern Cooperative Oncology group (ECOG) performance status (PS)≤1, creatinine clearance (CrCl)≥60 ml/min, no hearing loss, no neuropathy, no heart failure. Cox regression multivariate analyses were used to establish independent associations of cisplatin vs. non-cisplatin-based chemotherapy on OS.Results1794 patients treated between 2000 and 2013 at 29 centers were analyzed. Median follow-up was 29.1 months. 1333 patients (74%) received 1^st-line chemotherapy: Use of 1^st-line chemotherapy was associated with longer OS: (Hazard ratio [HR]: 1.91, 95% confidence interval [CI]: 1.67-2.20). Type of 1st-line chemotherapy received was: cisplatin-based 669 (50%), carboplatin-based 399 (30%), other 265 (20%). Cisplatin use was an independent favorable prognostic factor (HR: 1.54, 95% CI: 1.35-1.77). This benefit was independent of baseline characteristics or co-morbidities but was associated with eligibility-for-cisplatin: eligible patients treated with cisplatin lived longer than those who were not (HR: 1.74, 95% CI: 1.36-2.21), while such benefit was not observed among ineligible patients. 26% of patients who did not receive cisplatin were eligible for this agent. Median OS of ineligible patients was poor irrespective of the chemotherapy used.ConclusionsThe importance of applying published criteria of eligibility-for-cisplatin was confirmed in a multinational, real-world setting in aUTC. The reasons for deviations from these criteria set targets to improve adherence. Effective therapies for cisplatin-ineligible patients are needed.

A gene signature to predict high tumour-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple negative breast cancer

Abstract

Introduction: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival.Patients and Methods: Using 99 pre-treatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115).Results: A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS (HR: 0.28 for a one-unit increase in the value of the four-gene signature, 95%CI: 0.13-0.63). In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95%CI: 0.06-0.43). The four-gene signature added significant prognostic information when compared to the clinicopathologic pre-treatment model (likelihood ratio test in the training set p = 0.004 and in the validation set p = 0.002).Conclusion: A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.

Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain

Abstract

Background

Cebranopadol (a.k.a. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain. It also showed analgesic properties in various rat models of pain and had a better safety profile as compared to equi-analgesic doses of morphine. Since antinociceptive properties of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of subcutaneous cebranopadol (10 mg/kg) in various mouse pain models.

Methods

We used models of acute, tonic, and chronic pain induced by thermal and chemical stimuli, with a particular emphasis on pharmacoresistant chronic neuropathic pain evoked by oxaliplatin in which cebranopadol was used alone or in combination with simvastatin.

Key results

As shown in the hot plate test, the analgesic activity of cebranopadol developed more slowly as compared to morphine (90–120 min vs. 60 min). Cebranopadol displayed a significant antinociceptive activity in acute pain models, i.e., the hot plate, writhing, and capsaicin tests. It attenuated nocifensive responses in both phases of the formalin test and reduced cold allodynia in oxaliplatin-induced neuropathic pain model. Its efficacy was similar to that of morphine. Used in combination and administered simultaneously, 4 or 6 h after simvastatin, cebranopadol did not potentiate antiallodynic activity of this cholesterol-lowering drug. Cebranopadol did not induce any motor deficits in the rotarod test.

Conclusion

Cebranopadol may have significant potential for the treatment of various pain types, including inflammatory and chemotherapy-induced neuropathic pain.

Running INTERFERONce on Immunotherapy

Abstract

A new wave of immunotherapies has considerably expanded treatment options for cutaneous melanoma patients. One strategy for boosting the anti-tumor immune response is to block inhibitory immune checkpoint proteins that restrain immune cells. Utilizing this strategy, FDA-approved immune checkpoint inhibitors targeting CTLA-4 (ipilimumab) and PD-1/PD-L1 (nivolumab, pembrolizumab) alone or in combination enhance existing immune responses and have increased patient survival and response durability.

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“Chondroblastoma-like” Epithelioid Fibrous Histiocytoma: A Previously Undescribed and Potentially Confusing Variant

Abstract

Background

Epithelioid benign fibrous histiocytoma has been considered a variant of fibrous histiocytoma, but is now considered a distinct entity, typically showing ALK expression. Most show typical morphological features, including an epidermal collarette and large, bland, epithelioid cells. We have recently encountered two examples of showing an unusual pattern of pericellular calcification, a previously unreported finding.

Methods

Available slides were reviewed and clinical follow-up was obtained.

Results

These lesions occurred on the chin of a 16-year-old and 19-year-old female and showed prominent pericellular calcification in addition to otherwise-typical features of epithelioid fibrous histiocytoma. By immunohistochemistry, both lesions were intensely positive for ALK protein. Clinical follow up (available for one case) showed the patient to be disease free 5 months after excision.

Conclusions

To the best of our knowledge, epithelioid fibrous histiocytomas showing "chondroblastoma-like" calcification have not been previously reported. The chief significance of this finding seems to be in its potential for confusion with other calcifying tumors of the skin and subcutis. Awareness that epithelioid fibrous histiocytomas may show this unusual morphological finding, careful morphological evaluation, and ancillary immunohistochemical studies, including ALK protein, should allow for their confident diagnosis in essentially all instances.

Primary Chondro-osseous melanoma (Chondrosarcomatous & Osteosarcomatous Melanoma)

Abstract

Melanoma can rarely show malignant chondro-osseous differentiation and can cause diagnostic confusion. We report three cases of primary melanoma with extensive bone and cartilage matrix. The first case arose in the nasal mucosa of a 72-year old woman, the second case in the left index finger of a 26-year old woman and the third case in the left cheek of a 68-year old woman. In tumors where osseous and chondroid differentiation appear in mucosa and skin, primary melanoma with chondro-osteosarcomatous differentiation should be considered in the differential. Careful histological examination together with clinical correlation and ancillary immunohistochemical studies can ensure the correct diagnosis is made.

Late-stage nodular erythema elevatum diutinum mimicking sclerotic fibroma

Abstract

Erythema elevatum diutinum (EED) is a rare, cutaneous vasculitis of uncertain origins. EED can present clinically as chronic bilateral, symmetrical, periarticular papules, plaques, and nodules. We report here an unusual case of EED presenting as multiple, densely fibrosing nodules on the feet of a 60 year-old HIV positive woman. The initial evaluation of the patient was complicated by the strong histologic resemblance of multiple lesions to sclerotic fibroma (SF), a cutaneous manifestation of Cowden disease. Our case highlights the important features that distinguish these two pathologic entities.

Cryptococcal cellulitis: A rare entity histologically mimicking a neutrophilic dermatosis

Abstract

Cutaneous Cryptococcus infection presents classically with granulomatous and gelatinous reactive patterns. Cases mimicking neutrophilic dermatoses have not been described. Conversely, neutrophilic dermatoses with degrading cells mimicking cryptococcal organisms have been reported. We report a case of cryptococcal cellulitis in an immunocompromised male with a robust neutrophilic infiltrate raising histologic consideration for a neutrophilic dermatosis.

Histomorphometric approach to differentiate skin lesions of tuberculoid leprosy from sarcoidosis

ABSTRACT

Background

More than 200,000 new cases of leprosy are detected worldwide annually. Physicians commonly have difficulty in differentiating tuberculoid form of leprosy (TL) from sarcoidosis' cutaneous manifestation.

Methods

Skin biopsies of 33 patients with TL and 24 with sarcoidosis were reviewed on hematoxylin and eosin and Gomori stained sections, in order to find reliable criteria for distinguishing one disease from another.

Results

Nine of the 24 features analyzed presented significant predictive value for diagnosis (p < 0.05). Predominance of tuberculoid granulomas in adnexal and neural distribution, and granulomas replacing the nerves localized within sweat gland glomeruli were predictive to TL diagnosis. For sarcoidosis, dermal fibrosis, back-to-back distribution of the granulomas, presence of atypical giant cells and plasma cells, greater number of conventional giant cells, and spared nerves beside the granuloma were predictive criteria. The median surface density of reticulin fibers was significantly higher in sarcoidosis (3.44) than in TL (2.99). Nonetheless, using logistic regression, this variable did not discriminate the diseases (p = 0.096).

Conclusions

Isolated histological features are not fully predictive to differentiate the two diseases. However, those with statistical value can assist this distinction in diagnostic practice. Although the results of the analysis of the reticulin fibers density did not tell apart TL from sarcoidosis, they corroborate the idea of fibers fragmentation within tuberculoid leprosy granulomas, reiterating the importance of morphometry in the histological examination.

Leiomyosarcoma of the great saphenous vein (vena saphena magna) with granular cell change. Report of a superficial neoplasm

Abstract

The great saphenous vein (GSV) corresponds to the main superficial large caliber vessel affected by leiomyosarcoma (LMS). Given its superficial location and because signs of vascular origin may not be clinically apparent, LMS of the GSV may be misinterpreted clinically as superficial non-vascular soft tissue mass. Herein we report a case on the distal portion of the right GSV of a 57year-old man. The histopathological recognition of a large caliber vein-associated LMS (with granular cell change) in an incisional biopsy specimen was crucial to guide radiological evaluation and confirmation of a superficial vascular LMS before surgical treatment. Recognizing this entity in small biopsies is important as its surgical treatment and prognosis differ substantially from non-vascular superficial soft tissue (i.e. subcutaneous and dermal) LMSs. In addition, because vascular LMSs can involve long vessel segments, underestimation of extent of disease is a risk. To the best of our knowledge, granular cell change has not been documented in LMS of the GSV.

Reduction of groin wound complications in vascular surgery patients using closed incision negative pressure therapy (ciNPT): a prospective, randomised, single-institution study

Abstract

Groin wound infections in patients undergoing vascular procedures often cause a lengthy process of wound healing. Several clinical studies and case reports show a reduction of surgical site infections (SSIs) in various wound types after using closed incision negative pressure therapy (ciNPT). The aim of this prospective, randomised, single-institution study was to investigate the effectiveness of ciNPT (PREVENA™ Therapy) compared to conventional therapy on groin incisions after vascular surgery. From 1 February to 30 October 2015, 100 patients with 129 groin incisions were analysed. Patients were randomised and treated with either ciNPT (n = 58 groins) or the control dressing (n = 71 groins). ciNPT was applied intraoperatively and removed on days 5–7 postoperatively. The control group received a conventional adhesive plaster. Wound evaluation based on the Szilagyi classification took place postoperatively on days 5–7 and 30. Compared to the control group, the ciNPT group showed a significant reduction in wound complications (P < 0·0005) after both wound evaluation periods and in revision surgeries (P = 0·022) until 30 days postoperatively. Subgroup analysis revealed that ciNPT had a significant effect on almost all examined risk factors for wound healing. ciNPT significantly reduced the incidence of incision complications and revision procedures after vascular surgery.

Corrigenda: Omission of the Description of Informed Consent on the Identifiable Photos and the Description on Ethical Treatment of Experimental Animals.

Related Articles

Corrigenda: Omission of the Description of Informed Consent on the Identifiable Photos and the Description on Ethical Treatment of Experimental Animals.

Arch Plast Surg. 2017 Oct 24;:

Authors: Editorial office, Archives of Plastic Surgery

PMID: 29063742 [PubMed - as supplied by publisher]

A Technique for Reduction of Edentulous Fractures Using Dentures and SMARTLock Hybrid Fixation System.

Related Articles

A Technique for Reduction of Edentulous Fractures Using Dentures and SMARTLock Hybrid Fixation System.

Plast Reconstr Surg Glob Open. 2017 Sep;5(9):e1473

Authors: Carlson AR, Shammas RL, Allori AC, Powers DB

Abstract
Establishing anatomic reduction of an edentulous mandible fracture is a frequently acknowledged challenge in craniomaxillofacial trauma surgery. In this study, we report a novel method for the reduction of the edentulous mandible fracture, via fabrication of modified Gunning splints using existing dentures and SMARTLock hybrid arch bars. This technique dramatically simplifies the application of an arch bar to dentures, obviates the need for the fabrication of impressions and custom splints, and eliminates the lag time associated with the creation of splints. Furthermore, this method may be used with or without adjunctive rigid internal fixation. The technique described herein of creating Gunning splints with SMARTLock hybrid arch bars provides surgeons with a simple, rapid, single-stage solution for reduction of mandibular fractures in the edentulous patient.

PMID: 29062645 [PubMed]

Detachment and Deontic Language in Law

Abstract

Some legal philosophers regard the use of deontic language to describe the law as philosophically significant. Joseph Raz argues that it gives rise to 'the problem of normativity of law'. He develops an account of what he calls 'detached' legal statements to resolve the problem. Unfortunately, Raz's account is difficult to reconcile with the orthodox semantics of deontic language. The article offers a revised account of the distinction between committed and detached legal statements. It argues that deontic statements carry a Gricean generalized conversational implicature to the effect that the rules in question reflect the speaker's own commitments. Detached legal statements are made when this implicature is either explicitly cancelled or when the conversational context is sufficient to defeat the implicature. I conclude by offering some tentative reflections on the theoretical significance of deontic language in the law.

Expression Profiles of Long Noncoding RNA in UVA-Induced Human Skin Fibroblasts

Background: Long noncoding RNA (lncRNA) are differentially expressed across stages of differentiation and development, but the role of lncRNA in human skin photoaging mechanisms remains poorly understood. Objective: This study aimed to determine lncRNA expression changes in human dermal fibroblasts (HDF) induced by repeated UVA irradiation and to explore correlations between lncRNA and skin photoaging prognosis. Methods: In the UVA-HDF group, HDF were subjected to repeated UVA irradiation (10 J/cm² UVA twice daily for 7 days); in the control group, HDF received no irradiation. High-throughput sequencing was used to detect lncRNA expression profiles. Functional annotation analysis and pathway enrichment were preformed via Gene Ontology and KEGG. Predicted lncRNA target genes were identified by bioinformatic analysis. Results: In the UVA-HDF group, 1,730 lncRNA exhibited over 2-fold expression changes compared with the control group: 1,494 were upregulated, and 236 downregulated. Predicted lncRNA targets were associated with matrix metalloproteinases, cathepsin D, mitogen-activated protein kinase and TGF-β signaling pathways, and collagen fiber metabolism following repeated UVA damaging mechanisms. Conclusions: lncRNA profiles were aberrantly expressed in UVA-HDF and might play a key role in skin photoaging. This study provides novel insights into the repeated UVA-damaging pathology and potential targets for treatment of human skin photoaging.
Skin Pharmacol Physiol 2017;30:315-323

Neurokinin-1 Receptor Antagonists: Promising Agents in the Treatment of Chronic Pruritus

Abstract

Purpose of Review

Chronic pruritus (CP) is often refractory to conventional therapies leading to a substantial quality of life impairment. Better understanding of the underlying pathophysiological mechanisms allowed the development of novel drugs targeting specific mechanisms, such as neurokinin-1 receptor (NK1R) antagonists. This review aims to provide an overview of the mechanisms of action of NK1R antagonists and the evidence of its efficacy in the treatment of CP of various origins.

Recent Findings

NK1R and its endogenous ligand substance P mediate itch at peripheral and central levels. Novel NK1R antagonists have shown promising antipruritic properties in open-label studies and case series including patients with CP due to chronic prurigo, cutaneous T cell lymphoma, solid tumors, and biological antitumoral therapies.

Summary

NK1R antagonists are promising agents in the treatment of CP of different origins. First evidence from randomized controlled trials supports the potency of these agents as a therapeutic option for CP.

Familial acanthosis nigricans with p.K650T FGFR3 mutation

Abstract

Acanthosis nigricans (AN) is a pigmentary skin disorder, which may present in association with clinical disorders such as obesity and malignancy. Occasionally, this unique skin manifestation is seen in alliance with several skeletal disorders, such Crouzon syndrome, achondroplasia and hypochondroplasia (HCH). These orthopedic disorders are known to have genetic changes in FGFR3. Recently, AN was reported in HCH with p.K650T mutation in FGFR3, and to date, there are only three reports, comprising 18 cases, describing AN harboring this specific gene mutation. Herein, we detail three new cases of AN with p.K650T FGFR3 mutation, and review the 21 known cases.

Regional incidences of adult T-cell leukemia/lymphoma with cutaneous involvement in Japan

Abstract

Between 2008 and 2015, 462 newly-diagnosed adult T-cell leukemia/lymphoma (ATLL) patients with cutaneous involvement were found from the nationwide registry for Japanese patients with cutaneous lymphoma, of which 391 were selected for the study. They ranged in age from 28 to 93 years (median, 69 years), and included 215 men and 176 women (male : female ratio = 1.2). The 391 patients comprised 193 (50%) with smoldering type, 52 (13%) with chronic type, 44 (11%) with lymphoma type and 102 (26%) with acute type. The total number of patients in Kyushu/Okinawa was 8.8-times higher than that in Kanto, which was set as the reference value, while the estimated prevalence of human T-lymphotropic virus 1 (HTLV-1) carriers in Kyushu/Okinawa has been reported to be only 2.5-times higher than that in Kanto. In this study, the annual incidence of ATLL per 100 000 residents in Kyushu/Okinawa was 32-times higher than that in Kanto. Our results indicated the higher incidence rate of ATLL in the endemic area than those in the non-endemic areas in Japan, compared with the regional differences of HTLV-1 prevalence determined by serological HTLV-1 screening for blood donors. In addition, this analysis revealed that regional differences of mycosis fungoides/Sézary syndrome incidence rates were very small compared with those of ATLL.

Novel KRT9 missense mutation in a Japanese case of epidermolytic palmoplantar keratoderma

Dramatic effect of hydroxychloroquine on lupus alopecia

Abstract

Lupus alopecia is usually difficult to treat. We report a case of a 40-year-old woman with Sjögren's syndrome and atopic dermatitis who presented with discoid lupus erythematosus on the forearms and lupus erythematosus profundus with alopecia involving the scalp. A biopsy specimen taken from the discoid lupus erythematosus lesion on the forearm further exhibited a xanthomatous reaction, which however was not detected in another specimen from the lupus erythematosus profundus on the scalp. Treatment with oral hydroxychloroquine showed dramatic effects and complete hair regrowth was obtained 3 months later.

Successful treatment of relapsed folliculotropic mycosis fungoides with mogamulizumab followed by intensity-modulated radiotherapy

Correction to: Abstracts of the 12th German Allergy Congress

Correction to:

Allergo J Int 2017

http://ift.tt/2zO7Zaq

The original article has been corrected. Erroneously, in the online html article "abstract" was given as article …

Corrigenda: Omission of the Description of Informed Consent on the Identifiable Photos and the Description on Ethical Treatment of Experimental Animals.

Related Articles

Corrigenda: Omission of the Description of Informed Consent on the Identifiable Photos and the Description on Ethical Treatment of Experimental Animals.

Arch Plast Surg. 2017 Oct 24;:

Authors: Editorial office, Archives of Plastic Surgery

PMID: 29063742 [PubMed - as supplied by publisher]

Thighplasty: improving aesthetics through revival of the medial, horizontal procedure: a safe and scar saving option

Thighplasty is a common bodycontouring procedure, but also associated with a high complication rate. The purpose of this study was to access the outcome of the medial horizontal thigh lift as it is a common surgical technique regarding thigh deformity correction performed at the authors' department. Surgical keysteps, clinical applications, advantages and disadvantages of the procedure are shown. Postoperative evaluation took place with special focus on individual patient satisfaction.

Introduction, Festschrift in Honor of Prof. Volker Buβ

We are very pleased to present this Festschrift in honor of our colleague, mentor and friend Prof. Volker Buß, which was initiated to celebrate his 75^th birthday. The aim of this special issue is to recollect his substantial contributions and achievements of his career in the field of Theoretical/Computational Photochemistry.

This article is protected by copyright. All rights reserved.

Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients

Immune checkpoint inhibitors play an important role in the current management of advanced melanoma [1–3]. Ipilimumab, a monoclonal antibody that binds the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) molecule on the surface of T cells and blocks CTLA-4 mediated signaling, was the first checkpoint inhibitor approved for melanoma treatment [1]. However, anti-programmed death-1 (PD-1) monoclonal antibodies (αPD-1mAbs: nivolumab [4,5] and pembrolizumab [6,7]) were shown to be more effective than αCTLA-4mAb, and the current melanoma guideline recommends αPD-1mAbs as the first-line treatment for patients without BRAF mutation (NCCN melanoma guideline, version 1.2017).

Association Between Maternal and Child Health Handbook and Quality of Antenatal Care Services in Palestine

Abstract

Objectives The Maternal and Child Health (MCH) handbook is an integrated home-based record allowing clients to keep records on the continuum of care for mothers and children. This study aimed to assess associations between MCH handbook ownership and receipt of selected content of antenatal care services in Palestine. Methods Distribution of the MCH handbook in Palestine was launched in 2008. We used an anonymous data set of the Palestinian Family Survey 2010 and analyzed the data of 2026 women who had live births within the past 12 months. Descriptive statistical analysis was conducted to assess differences between MCH handbook holders and non-holders. Multivariable logistic regression models were used to estimate adjusted odds ratios of the effects of MCH handbook use according to proxy indicators of antenatal care quality. Results Accounting for about 60% (n = 1202) of study participants, handbook holders were more likely to be primipara, live in the Gaza Strip, live in refugee camps, and live within a 30-min distance to antenatal care facilities; however, household wealth levels for handbook holders were lower compared with non-holders. Handbook users had significantly higher odds of receiving all three kinds of medical tests and receiving information on five or more health education topics as part of antenatal care. The higher odds remained after adjusting for possible confounding variables, such as household wealth, region, residential area, birth order of the child, frequency of antenatal care, and time required to reach antenatal care facilities. Conclusions for Practice Use of the handbook as a portable checklist possibly promoted providers' higher adherence to the national guideline.

Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas

Abstract

Background

Rare multicentric lower-grade gliomas (LGG) represent a unique opportunity to study the heterogeneity between distinct tumor foci in a single patient, and to infer their origins and parallel patterns of evolution.

Methods

In this study, we integrate clinical features, histology and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the two lesions.

Results

One patient was diagnosed with multicentric IDH1 mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with TCGA data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and chromosomes 1p/19q-codeleted oligodendroglioma and IDH1 mutated and 1p/19q intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second.

Conclusions

Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Corrigendum

Corrigendum to Zhang et al. HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro Oncol (doi: 10.1093/neuonc/not131) first published online November 7, 2013.

Antioxidant status of serum bilirubin, uric acid and albumin in pemphigus vulgaris

Summary

Background

Oxidative stress and low antioxidant status are implicated in the pathogenesis of inflammatory and autoimmune diseases. Pemphigus vulgaris (PV) is an extremely severe autoimmune bullous dermatosis characterized by intraepithelial bullae on the skin and mucosa, and its antioxidant status is not fully understood.

Aim

To assess correlations between PV and serum antioxidant levels of bilirubin, uric acid (UA) and albumin.

Methods

We enrolled 116 patients newly diagnosed with PV who were admitted to the First Affiliated Hospital of Guangxi Medical University (Guangxi, China), and 108 healthy controls (HCs). Clinical characteristics and laboratory parameters of patients were retrospectively analysed.

Results

Our survey shows that compared with the HC groups, serum levels of bilirubin [total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil)], UA and albumin were significantly lower in patients with PV, regardless of sex. In all groups, serum Tbil, Dbil, Ibil, UA and albumin levels were lower for women than for men. Severity of pemphigus was slightly negatively associated with Tbil, Dbil and Ibil, but was not associated with UA or albumin. Moreover, when the data were adjusted for the covariances of age and sex separately, Tbil, Dbil, Ibil, UA and albumin were all relevant to PV.

Conclusions

Our findings demonstrate that serum levels of bilirubin (Tbil, Dbil and Ibil), UA and albumin are reduced in patients with PV supporting the hypothesis that oxidative stress and antioxidant status are important in the pathogenic mechanism of PV.

Excellent Beauty: The Naturalness of Religion and the Unnaturalness of the World

Excellent Beauty: The Naturalness of Religion and the Unnaturalness of the World

Respiratory Symptoms in Hospital Cleaning Staff Exposed to a Product Containing Hydrogen Peroxide, Peracetic Acid, and Acetic Acid

Abstract

Cleaning and disinfecting products consisting of a mixture of hydrogen peroxide (HP), peracetic acid (PAA), and acetic acid (AA) are widely used as sporicidal agents in health care, childcare, agricultural, food service, and food production industries. HP and PAA are strong oxidants and their mixture is a recognized asthmagen. However, few exposure assessment studies to date have measured HP, PAA, and AA in a health care setting. In 2015, we performed a health and exposure assessment at a hospital where a new sporicidal product, consisting of HP, PAA, and AA was introduced 16 months prior. We collected 49 full-shift time-weighted average (TWA) air samples and analyzed samples for HP, AA, and PAA content. Study participants were observed while they performed cleaning duties, and duration and frequency of cleaning product use was recorded. Acute upper airway, eye, and lower airway symptoms were recorded in a post-shift survey (n = 50). A subset of 35 cleaning staff also completed an extended questionnaire that assessed symptoms reported by workers as regularly occurring or as having occurred in the previous 12 months. Air samples for HP (range: 5.5 to 511.4 ppb) and AA (range: 6.7 to 530.3 ppb) were all below established US occupational exposure limits (OEL). To date, no full-shift TWA OEL for PAA has been established in the United States, however an OEL of 0.2 ppm has been suggested by several research groups. Air samples for PAA ranged from 1.1 to 48.0 ppb and were well below the suggested OEL of 0.2 ppm. Hospital cleaning staff using a sporicidal product containing HP, PAA, and AA reported work-shift eye (44%), upper airway (58%), and lower airway (34%) symptoms. Acute nasal and eye irritation were significantly positively associated with increased exposure to the mixture of the two oxidants: HP and PAA, as well as the total mixture (TM)of HP, PAA, and AA. Shortness of breath when hurrying on level ground or walking up a slight hill was significantly associated with increased exposure to the oxidant mixture (P = 0.017), as well as the TM (P = 0.026). Our results suggest that exposure to a product containing HP, PAA, and AA contributed to eye and respiratory symptoms reported by hospital cleaning staff at low levels of measured exposure.