Augmented and Virtual Reality Navigation for Interventions in the Musculoskeletal System

Abstract

Purpose of Review

Augmented reality (AR) and virtual reality (VR) are cutting-edge technologies that offer advanced navigational solutions. These systems are just starting to be used in interventional radiology and the literature has been limited to pre-clinical and translational experiments. In this paper, we present a review of AR and VR for musculoskeletal interventions.

Recent Findings

Mixed reality systems have evolved from costly research systems to fully commercialized clinical instruments designed to facilitate operators in navigating complex anatomy. Studies within interventional radiology have demonstrated safety, improved accuracy, and decreased exposure to ionizing radiation.

Summary

We review the progression of mixed reality systems from their early origins in computer science through their current day surgical applications, with a special focus on landmark studies within radiologic interventions for the musculoskeletal system. We highlight the instrumentation, clinical workflow, benefits and drawbacks, and suggested future directions for the two main AR systems: head-mounted display and image-overlay.

The wrongs of racist beliefs

Abstract

We care not only about how people treat us, but also what they believe of us. If I believe that you're a bad tipper given your race, I've wronged you. But, what if you are a bad tipper? It is commonly argued that the way racist beliefs wrong is that the racist believer either misrepresents reality, organizes facts in a misleading way that distorts the truth, or engages in fallacious reasoning. In this paper, I present a case that challenges this orthodoxy: the case of the supposedly rational racist. We live in a world that has been, and continues to be, structured by racist attitudes and institutions. As a result, the evidence might be stacked in favour of racist beliefs. But, if there are racist beliefs that reflect reality and are rationally justified, what could be wrong with them? Moreover, how do I wrong you by believing what I epistemically ought believe given the evidence? To address this challenge, we must recognize that there are not only epistemic norms governing belief, but moral ones as well. This view, however, is at odds with the assumption that moral obligation requires a kind of voluntary control that we lack with regard to our beliefs. This background assumption motivates many philosophers to try to explain away the appearance that beliefs can wrong by locating the wrong elsewhere, e.g., in an agent's actions. Further, even accounts that accept the thesis that racist beliefs can wrong restrict the class of beliefs that wrong to beliefs that are either false or the result of hot irrationality, e.g., the racist belief is a result of ill-will. In this paper I argue that although these accounts will capture many of the wrongs associated with racist beliefs, they will be only partial explanations because they cannot explain the wrong committed by the supposedly rational racist. The challenge posed by the supposedly rational racist concerns our epistemic practices in a non-ideal world. The world is an unjust place, and there may be many morally objectionable beliefs it justifies. To address this challenge, we must seriously consider the thesis that people wrong others in virtue of what they believe about them, and not just in virtue of what they do.

Occurrence and distribution of antibiotic resistance genes in the sediments of drinking water sources, urban rivers, and coastal areas in Zhuhai, China

Abstract

Antibiotic resistance genes (ARGs) are regarded as emerging contaminants related with human activities. Aquatic environments of an urban city are apt for the persistence and prevalence of ARGs. In this study, we investigated the occurrence and distribution of ARGs and integrase genes in the sediment samples collected from drinking water sources, urban rivers, and coastal areas of Zhuhai, China, in the dry and wet seasons of 2016. The results show that sulfonamide resistance gene of sulII was present at the highest detection frequency (85.71%); and its average concentrations were also the highest in both dry and wet seasons (3.78 × 10⁷ and 9.04 × 10⁷ copies/g sediment, respectively), followed by tetC, tetO, tetA, ermB, dfrA1, and bla_PSE-1. Temporally, the concentrations of total ARGs in the wet season were likely higher than those in the dry season; and spatially, the concentrations of total ARGs in the drinking water sources were substantially lower than those in the urban rivers and nearby coastal areas, indicating the different degrees of anthropogenic impact and consequent health risks. Positive correlations were found between intI1 and each quantitative ARG in all wet season samples rather than dry season samples, which suggested higher temperature and more rain in summer might have positive influences on ARG dissemination, especially that mediated by intI1 gene and class I integrons.

Tratamiento sistémico de la psoriasis moderada-grave en edad pediátrica en Galicia: estudio descriptivo

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): A. Batalla, R. Fernández-Torres, L. Rodríguez-Pazos, B. Monteagudo, R. Pardavila-Riveiro, R. Rodríguez-Lojo, Á. Zulaica, M. Cabanillas, E. Fonseca, Á. León, L. Fernández-Díaz, T. Abalde, L. Salgado-Boquete, F. Valdés, M.J. Seoane-Pose, H. Vázquez-Veiga, I. Suárez-Conde, J. Álvarez-López, Á. Flórez
Antecedentes y objetivoLos trabajos sobre el tratamiento sistémico de la psoriasis en edad pediátrica son escasos. El objetivo principal de este trabajo consistió en describir qué tratamientos sistémicos se emplean en práctica clínica en psoriasis moderada-grave en edad pediátrica. Secundariamente se describió la efectividad y perfil de seguridad de dichos tratamientos.Materiales y métodosEstudio descriptivo transversal multicéntrico, de los pacientes con psoriasis moderada-grave, que siendo menores de 18 años estuviesen recibiendo o hubieran recibido tratamiento sistémico (clásico o biológico) o fototerapia. Se recogieron datos clínico-demográficos, tipo de tratamiento recibido, y tolerancia, efectos indeseables y respuesta al mismo.ResultadosSe obtuvieron datos de 40 pacientes (60% sexo femenino, edad media 13 años), que realizaron 63 ciclos de tratamiento. Teniendo en cuenta el primer tratamiento (n=40), la fototerapia fue la opción más frecuente (68%), seguida de acitretino (15%). Considerando el total de ciclos de tratamiento (n=63), el tratamiento más frecuentemente empleado fue la fototerapia (57%), seguida de metotrexato (16%). En la semana 12 (incluye evaluación de fototerapia), el 66% y el 22% fueron buenos respondedores o respondedores parciales, respectivamente. En la semana 24 (datos exclusivos sobre fármacos sistémicos), el 36% y el 32% continuaron con respuestas buenas y parciales. Los tratamientos fueron bien tolerados (97%) y los efectos indeseables escasos (11%), sin que en ningún caso motivasen la suspensión del fármaco.ConclusionesEn la población menor de 18 años con psoriasis moderada-grave evaluada la fototerapia fue el tratamiento más utilizado, seguida de metotrexato. Los tratamientos consiguieron porcentajes de buenos respondedores del 66% en la semana 12 (incluida fototerapia), y del 36% en la semana 24 (fármacos sistémicos sin fototerapia), presentando un buen perfil de seguridad.Background and objectiveStudies on the use of systemic therapy for psoriasis in pediatric patients are scarce. The main aim of this study was to describe the systemic treatments used for moderate to severe psoriasis in pediatric clinical settings. The second aim was to describe the effectiveness and safety of these treatments.Material and methodsDescriptive, cross-sectional, multicenter study of patients under 18 years of age with moderate to severe psoriasis who were being treated or had been treated with a systemic drug (conventional or biologic) or phototherapy. We recorded demographic and clinical information, treatments received, tolerance, adverse effects, and response to treatment.ResultsData were collected for 40 patients (60% female; mean age, 13 years) who had received 63 treatments in total. The most common first treatment (n=40) was phototherapy (administered to 68% of patients), followed by acitretin (15%). The most common treatments overall (n=63) were phototherapy (57%) and methotrexate (16%). At week 12 (evaluation of systemic treatment and phototherapy), 66% of the patients were classified as good responders and 22% as partial responders. The respective rates for week 24 (evaluation of systemic treatment only) were 36% and 32%. The treatments were well tolerated (97%) and adverse effects were reported in just 11% of cases. There were no treatment discontinuations because of adverse effects.ConclusionsPhototherapy, followed by methotrexate, was the most common treatment for moderate to severe psoriasis in this series of patients under 18 years. The treatments showed a favorable safety profile and were associated with a good response rate of 66% at week 12 (systemic treatment and phototherapy) and 36% at week 24 (systemic treatment only).

Graphical abstract

Sarcomas cutáneos: directrices para el diagnóstico y tratamiento. Dermatofibrosarcoma protuberans

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): B. Llombart, C. Serra, C. Requena, M. Alsina, D. Morgado-Carrasco, V. Través, O. Sanmartín
Los sarcomas constituyen un grupo amplio de tumores, muchos de ellos con comportamiento biológico y agresividad diferentes entre sí, que habitualmente requieren un tratamiento multidisciplinario, frecuentemente complejo. El desarrollo en las últimas décadas de la dermatología quirúrgica y oncológica ha permitido que los dermatólogos se conviertan en los especialistas responsables del diagnóstico y tratamiento del cáncer cutáneo. El propósito de este artículo es revisar los principales sarcomas de partes blandas de localización típicamente cutánea.El dermatofibrosarcoma protuberans es un sarcoma de bajo grado de malignidad, con un crecimiento lento e infiltrativo localmente y escasa capacidad metastásica (<3%). El tratamiento de elección es la cirugía micrográfica de Mohs. Es recomendable solicitar el estudio de la translocación COL1A1-PDGFB cuando existen dudas diagnósticas, y para determinar qué pacientes pueden responder a los fármacos inhibidores de la tirosina quinasa. El imatinib está indicado en el dermatofibrosarcoma protuberans localmente avanzado y metastásico.Sarcomas comprise a broad group of tumors, many of whose biological behavior and aggressiveness differ from one type to another. The therapeutic approach is generally multidisciplinary and often complex. Developments in surgical and oncological dermatology during the last few decades have positioned dermatologists as specialists in the diagnosis and treatment of skin cancer. The aim of this article is to review the main soft tissue sarcomas that typically affect the skin. Dermatofibrosarcoma protuberans is a low-grade malignant sarcoma. It exhibits slow-growth, is locally invasive, and has low metastatic potential (<3%). Mohs micrographic surgery is the treatment of choice. The COL1A1-PDGFB translocation should be analyzed in cases of unclear diagnosis and when it is necessary to identify candidates for tyrosine kinase inhibitors. Imatinib is indicated for the treatment of locally advanced and metastatic dermatofibrosarcoma protuberans.

Graphical abstract

Experiencia de un investigador y un dermatólogo sobre el conocimiento del curso clínico del vitiligo no segmentario

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): M.L. Peralta-Pedrero, F. Jurado Santa-Cruz

Estudio ecográfico de metástasis cutáneas de origen visceral

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): C. Cuenca-Barrales, P. Aguayo-Carreras, A. Bueno-Rodriguez, R. Ruiz-Villaverde

Cirugía funcional en tumores malignos subungueales. Serie de casos y revisión de la literatura

Publication date: Available online 4 July 2018
Source:Actas Dermo-Sifiliográficas
Author(s): M. Flores-Terry, G. Romero-Aguilera, C. Mendoza, M. Franco, P. Cortina, M. Garcia-Arpa, L. Gonzalez-Ruiz, J.A. Garrido
Antecedentes y objetivosEl tratamiento clásico de los tumores malignos subungueales (TMSU), carcinoma epidermoide (CESU) y melanoma (MSU), es la amputación. La cirugía funcional del aparato ungueal (CFAU) puede preservar la función sin modificar el pronóstico. Presentamos nuestra serie de TMSU manejados con CFAU, describimos la técnica y revisamos sus indicaciones.Material y métodosEstudio observacional retrospectivo de TMSU tratados con CFAU entre 2008 y 2017, con exéresis supraperióstica en bloque del aparato ungueal, margen a 5mm, y cierre con injerto de piel total.ResultadosSe trataron 11 TMSU, de los cuales 7 fueron MSU (4 in situ, espesor medio: 1,17mm; rango: 0-4mm) y 4 CESU (espesor medio: 3,4mm; rango: 1,6-6mm). Se realizó CFAU en 9 casos y 2 amputaciones en sendos MSU invasivos. El seguimiento medio fue 39 meses, con un rango de 12-96 meses. No hubo recidivas locales ni regionales. Solo un caso —una de las 2 amputaciones— tuvo metástasis (cerebrales) y muerte.La revisión de la literatura de CFAU en TMSU mostró 5 series (103 pacientes en total) con CESU y 14 series (243 pacientes en total) con MSU. El análisis de nuestros casos y de los casos publicados muestra muy escasas recurrencias locales (<7%), y mejores resultados funcionales y estéticos frente a la amputación.ConclusionesLa CFAU es de elección en CESU sin afectación ósea y MSU no invasivo o delgado (Breslow <1mm). Es factible en MSU de grosores intermedios siempre con detallado estudio histológico de márgenes que asegure una resección completa. Por el contrario, en CESU con afectación ósea, MSU muy grueso (>4mm) o recurrencias, la amputación debe ser habitualmente de elección.Background and objectivesAmputation is the conventional treatment for malignant subungual tumors (MSUTs), namely, subungual squamous cell carcinoma (SUSCC) and subungual melanoma (SUM). Functional surgery consisting of wide local excision (WLE) of the nail unit can preserve function without modifying prognosis in such cases. We present a series of MSUTs treated with WLE of the nail unit, describe the technique, and review its indications.Material and methodsRetrospective observational study of MSUTs treated with WLE of the nail unit between 2008 and 2017. The technique consisted of en bloc supraperiosteal excision of the nail unit with a margin of 5mm followed by repair with a full-thickness graft.ResultsEleven MSUTs were treated in the study period: 7 SUMs (4 in situ; mean thickness, 1.17mm; range, 0-4mm) and 4 SUSCCs (mean thickness, 3.4mm; range, 1.6-6mm). WLE of the nail unit was performed in 9 patients and amputation in 2 patients with invasive SUM. Mean follow-up was 39 months (range, 12-96 months) and no local or regional recurrences were detected. One of the 2 patients who underwent amputation developed metastasis to the brain and died. In our review of the literature, we identified 5 series of patients with SUSCC treated with WLE of the nail unit (105 patients) and 14 series of patients with SUM (243 patients). Based on an analysis of these cases and ours, it would appear that WLE of the nail unit is associated with a very low rate of local recurrence (<7%) and offers better functional and cosmetic outcomes than amputation.ConclusionsWLE of the nail unit is the treatment of choice for SUSCC without bone involvement and for thin noninvasive SUM (Breslow depth <1mm). It is also feasible in intermediate-thickness SUMs when detailed histologic examination of the margins confirms complete resection. Amputation, by contrast, is the treatment of choice for SUSCCs with bone involvement, very thick SUMs (>4mm), and recurrent tumors.

Graphical abstract

A new decentralized biological treatment process based on activated carbon targeting organic micropollutant removal from hospital wastewaters

Abstract

Although hospital wastewaters (HWWs) are usually discharged in urban sewage systems, their separate treatment has several benefits, such as the specific treatment of potential toxics as well as avoidance of further dilutions. In this work, an integrated industrial pilot plant (2200 L) corresponding to the technology SeMPAC^® is proposed and validated for such purpose. The process consists of a sequential batch reactor (SBR) connected to an external submerged microfiltration membrane, in which powdered activated carbon (PAC) is directly added into the biological reactor to enhance the removal of the organic micropollutants (OMPs). The combination of different redox conditions in the SBR, as well as the operation at long sludge retention times (SRTs) and high biomass concentrations favored OMP biotransformation in the SBR, being their final removal efficiencies enhanced clearly after PAC addition, especially for the recalcitrant compounds. A periodical renewal of the adsorbent is necessary to overcome its gradual saturation. The main operational conditions were influenced by (i) the recalcitrant OMP carbamazepine, which defines the PAC dosage; (ii) the easily degradable OMP ibuprofen, which can be used to optimize the duration of the aerobic cycle; and (iii) the denitrification efficiency, which defines the correct time length of the anoxic period.

A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening

Clinical Pearls: Fluorescent tattoos as anatomic markers to track trichologic responses

Drug Utilization Patterns and Adherence in Patients on Systemic Medications for the Treatment of Psoriasis: A Retrospective Comparative Cohort Study

There is limited data on adherence to systemic medications for psoriasis in real-world practice. Using a large US health insurance claims database, we found significantly increased odds of adherence to biologics compared to methotrexate. Dermatologists should consider adherence when choosing systemic treatments for psoriasis patients.

Apremilast for moderate hidradenitis suppurativa: results of a randomized controlled trial

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Allard R.J.V. Vossen, M.B.A. van Doorn, Hessel H. van der Zee, Errol P. Prens
BackgroundEffective anti-inflammatory treatments for hidradenitis suppurativa (HS) are limited.ObjectiveTo evaluate the efficacy and short-term safety of apremilast in patients with moderate HS.MethodsTwenty patients with moderate HS were randomised in a 3 : 1 ratio, to receive blinded treatment with apremilast 30 mg twice daily or placebo for 16 weeks. The primary outcome was the Hidradenitis Suppurativa Clinical Response (HiSCR) at week 16. Linear mixed effects modeling (ANCOVA) was used to assess secondary clinical outcomes between treatment groups.ResultsThe HiSCR was met in 8 of 15 (53.3%) patients in the apremilast group and none of 5 patients (0%) in the placebo group (P=0.055) at week 16. Moreover, apremilast-treated patients showed a significantly lower abscess and nodule count (mean difference -2.6; 95% confidence interval -6.0, -0.9; P=0.011), NRS for pain (-2.7; -4.5, -0.9; P=0.009) and itch (-2.8; -5.0, -0.6; P=0.015) over 16 weeks compared with placebo-treated patients. There was no significant difference in the DLQI over time between the two treatment groups (-3.4; -9.0, 2.3; P=0.230). The most frequently reported adverse events in the apremilast-treated patients were mild to moderate headache and gastro-intestinal symptoms, which have not resulted in drop-outs.LimitationsSmall number of patients, relatively short study duration.ConclusionApremilast at a dose of 30 mg twice daily demonstrated clinically meaningful efficacy and was generally well tolerated in patients with moderate HS.

A Phase 2, Randomized Dose-Finding Study of Tapinarof (GSK2894512 Cream) for the Treatment of Atopic Dermatitis

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Johnny Peppers, Amy S. Paller, Tomoko Maeda-Chubachi, Sterling Wu, Kevin Robbins, Kelly Gallagher, John E. Kraus
BackgroundSafe and efficacious topical treatments are needed for atopic dermatitis (AD).ObjectiveWe assessed the safety and efficacy of tapinarof cream (2 concentrations; 2 application frequencies) in patients with AD.MethodsDouble-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients aged 12-65 years, with body surface area (BSA) involvement ≥5% and ≤35% and Investigator Global Assessment (IGA) ≥3 (moderate-severe) at Baseline. Primary endpoint included IGA score of clear or almost clear (0 or 1), and minimum 2-grade improvement ("treatment success") at Week 12. Secondary analyses: ≥ 75% improvement in Eczema Area Severity Index (EASI 75), reduction of numeric rating scale (NRS) Itch from Baseline, and other prespecified endpoints.ResultsTreatment success rates at Week 12 were: 53% [1% BID]; 46% [1% QD]; 37% [0.5% BID]; 34% [0.5% QD]; 24% [vehicle BID]; 28% [vehicle QD]. The rate (53%) of 1% BID was statistically significantly higher than (24%) vehicle BID. Treatment success was maintained for 4 weeks after end of tapinarof treatment. Treatment-emergent adverse events (TEAE) were higher with tapinarof (93/165; 56%) vs. vehicle (34/82; 41%) and mild-to-moderate in intensity.LimitationsLarge confirmation trials are needed.ConclusionsTapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.

A Comparison of Skin Cancer Screening and Treatment Costs at a Massachusetts Cancer Center, 2008 versus 2013

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Frederick C. Morgan, Juanita Duran, Belen Fraile, Pritesh S. Karia, Jennifer Y. Lin, Patrick A. Ott, Emily Stamell Ruiz, David M. Wang, Yichen Zhang, Chrysalyne D. Schmults
BackgroundTemporal analyses of skin cancer costs are needed to examine how expenditure differences between diagnoses are changing.ObjectiveTo tabulate the costs of skin cancer-related care (SCRC), including both screening and treatment, at an academic cancer center at two time points.MethodsCost data (insurance and patient payments) at an academic cancer center from 2008 and 2013 were queried for International Classification of Diseases, Ninth Revision (ICD-9) codes pertaining to skin cancer. Screening costs were separated from treatment costs through associated Current Procedure Terminology (CPT) codes.ResultsThe total annual cost of SCRC increased by 64%, the number of patients receiving SCRC increased by 45%, and the mean cost per patient treated increased by 13%. Screening accounted for 17% and 16% of total annual costs in 2008 and 2013, respectively. The mean cost per melanoma patient increased by 84%, which was the largest increase among skin cancer diagnoses. In 2013, the few melanoma patients treated with ipilimumab (n=48, 4% of melanoma patients) accounted for 42% of melanoma treatment costs and 20% of SCRC costs.LimitationsPrescription costs were unavailableConclusionMelanoma costs increased due to the introduction of ipilimumab. Ongoing studies are needed to monitor SCRC cost-effectiveness at a national level.

Chronic Non-Melanoma Skin Cancers and Health Related Impairment: A Case-Control Study

Publication date: Available online 3 July 2018
Source:Journal of the American Academy of Dermatology
Author(s): Adam Sutton, Ashley Crew, Shauna Higgins, Andrew Kwong, Ashley Wysong

Comparative health risk of inhaled exposure to organic solvents, toxic metals, and hexavalent chromium from the use of spray paints in Taiwan

Abstract

The study investigated the exposure of spray painters to organic solvents, toxic metals, and hexavalent chromium over 21 working days in 2017. The results found these concentrations of 12 VOCs to be below the short-term exposure limit (STEL) established by the US Occupational Safety and Health Administration (OSHA). The mass concentration of total particulate matter (PM) exposure to workers was 20.01 ± 10.78 mg/m³, which exceeds OSHA's permissible exposure level of 15 mg/m³. The mean concentration of the total metals for all particle sizes was 109.1 ± 12.0 μg/m³, and those for lead (496,017.0 ng/m³) and iron (252,123.8 ng/m³) were the highest of metal elements. Significantly, the mean concentrations of Pb and As exceeded OSHA's permissible exposure limits (PELs) of 0.05 and 0.01 mg/m³, respectively. The total hexavalent chromium concentration was 1163.01 ng/m³, and the individual particle sizes (PM_1−2.5, PM₁, and PM_0.25) were strongly and positively correlated with the Cr(VI) concentrations for PM_2.5. The study determined that approximately 56.14% of the hexavalent chromium inhaled during the spray-painting process was deposited in the upper respiratory system of the head airway region, followed by the alveolar and tracheobronchial regions, with fractions of 11.93 and 0.05%, respectively. Although the mean ratio of hexavalent chromium to total chromium was only 3.6% for all particle sizes, the cancer risk of the total particles in Cr(VI) (1.6 × 10⁻³) exceeded the acceptable risk value (10⁻⁶). The cancer risks of As and Cr(VI) associated with quasi-ultrafine particles, PM_0.5–1, PM_1–2.5, and PM_> 2.5, also exceeded 10⁻⁶. Comparison of the carcinogenicity risk of VOCs and metals suggests that the adverse health effect of inhaled particles on spray-painting workers is more serious than that from VOC exposure.

Industry mimetic isomorphism and sustainable development based on the X-STATIS and HJ-biplot methods

Abstract

Based on both neo-institutional theory and comparative institutional analysis, this paper studies the role that mimetic forces play in the patterns and evolution of behavior concerning company sustainability. The panel data is composed of 6600 observations of 600 international large listed companies belonging to 39 different activity sectors for the period 2004–2014. Through employing the multivariate statistical methods HJ-biplot and X-STATIS, which provide a useful visualization of a complex data structure in a low-dimensional space, it can be observed that mimetic forces indicate that firms operating in high-impact sectors—sectors that operate under greater pressure from interest groups—face greater social and environmental risks and have higher corporate social responsibility (CSR) scores than companies from other sectors. The adoption or development of CSR practices depends largely on the type of industry in which the company operates, as stakeholder engagement in different industry sectors has different areas of concern. Therefore, companies operating in more polluting sectors, such as mining, paper, chemicals, or oil, give higher priority to environmental protection and defense of human rights, while other, less polluting companies involved in the communication sector are concerned to a greater extent by social issues, such as business ethics or the rights of their employees. Finally, this paper evidences that firms operating in similar contexts, in industries that face analogous risks and challenges, probably develop common policies and regulations with the aim of mitigating the pressures applied by their major stakeholder groups.

Alcohol Consumption during Adolescence in a Mouse Model of Binge Drinking Alters the Intrinsic Excitability and Function of the Prefrontal Cortex through a Reduction in the Hyperpolarization-Activated Cation Current

Periodic episodes of excessive alcohol consumption ("binge drinking") occur frequently among adolescents, and early binge drinking is associated with an increased risk of alcohol use disorders later in life. The PFC undergoes significant development during adolescence and hence may be especially susceptible to the effects of binge drinking. In humans and in animal models, adolescent alcohol exposure is known to alter PFC neuronal activity and produce deficits in PFC-dependent behaviors, such as decision making, response inhibition, and working memory. Using a voluntary intermittent access to alcohol (IA EtOH) procedure in male mice, we demonstrate that binge-level alcohol consumption during adolescence leads to altered drinking patterns and working memory deficits in young adulthood, two outcomes that suggest medial PFC dysfunction. We recorded from pyramidal neurons (PNs) in the prelimbic subregion of the medial PFC in slices obtained from mice that had IA EtOH and found that they display altered excitability, including a hyperpolarization of the resting membrane potential and reductions in the hyperpolarization-activated cation current (I_h) and in intrinsic persistent activity (a mode of neuronal firing that is dependent on I_h). Many of these effects on intrinsic excitability were sustained following abstinence and observed in mice that showed working memory deficits. In addition, we found that resting membrane potential and the I_h-dependent voltage "sag" in prelimbic PFC PNs are developmentally regulated during adolescence, suggesting that adolescent alcohol exposure may compromise PFC function by arresting the normal developmental trajectory of PN intrinsic excitability.

SIGNIFICANCE STATEMENT Binge alcohol drinking during adolescence has negative consequences for the function of the developing PFC. Using a mouse model of voluntary binge drinking during adolescence, we found that this behavior leads to working memory deficits and altered drinking behavior in adulthood. In addition, we found that adolescent drinking is associated with specific changes to the intrinsic excitability of pyramidal neurons in the PFC, reducing the ability of these neurons to generate intrinsic persistent activity, a phenomenon thought to be important for working memory. These findings may help explain why human adolescent binge drinkers show performance deficits on tasks mediated by the PFC.

{alpha}2{delta}-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses

α₂-4 is an auxiliary subunit of voltage-gated Ca_v1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α₂-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α₂-4, we used genome editing to generate an α₂-4 knock-out (α₂-4 KO) mouse. In male and female α₂-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α₂-4 KO retina. In reconstructions of α₂-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α₂-4 KO mice correlates with a progressive loss of Ca_v1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α₂-4 KO mice and better under photopic than scotopic conditions. We conclude that α₂-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.

SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α₂-4, a subunit of voltage-gated Ca²⁺ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca²⁺ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α₂-4. Our results suggest that alterations in presynaptic Ca²⁺ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α₂-4.

Insights into the Contribution of Voltage-Gated Sodium Channel 1.7 to Paclitaxel-Induced Neuropathy

Loss of CaMKI Function Disrupts Salt Aversive Learning in C. elegans

The ability to adapt behavior to environmental fluctuations is critical for survival of organisms ranging from invertebrates to mammals. Caenorhabditis elegans can learn to avoid sodium chloride when it is paired with starvation. This behavior may help animals avoid areas without food. Although some genes have been implicated in this salt-aversive learning behavior, critical genetic components, and the neural circuit in which they act, remain elusive. Here, we show that the sole worm ortholog of mammalian CaMKI/IV, CMK-1, is essential for salt-aversive learning behavior in C. elegans hermaphrodites. We find that CMK-1 acts in the primary salt-sensing ASE neurons to regulate this behavior. By characterizing the intracellular calcium dynamics in ASE neurons using microfluidics, we find that loss of cmk-1 has subtle effects on sensory-evoked calcium responses in ASE axons and their modulation by salt conditioning. Our study implicates the expression of the conserved CaMKI/CMK-1 in chemosensory neurons as a regulator of behavioral plasticity to environmental salt in C. elegans.

SIGNIFICANCE STATEMENT Like other animals, the nematode Caenorhabditis elegans depends on salt for survival and navigates toward high concentrations of this essential mineral. In addition to its role as an essential nutrient, salt also causes osmotic stress at high concentrations. A growing body of evidence indicates that C. elegans balances the requirement for salt with the danger it presents through a process called salt-aversive learning. We show that this behavior depends on expression of a calcium/calmodulin-dependent kinase, CMK-1, in the ASE salt-sensing neurons. Our study identifies CMK-1 and salt-sensitive chemosensory neurons as key factors in this form of behavioral plasticity.

Deep Neural Networks for Modeling Visual Perceptual Learning

Understanding visual perceptual learning (VPL) has become increasingly more challenging as new phenomena are discovered with novel stimuli and training paradigms. Although existing models aid our knowledge of critical aspects of VPL, the connections shown by these models between behavioral learning and plasticity across different brain areas are typically superficial. Most models explain VPL as readout from simple perceptual representations to decision areas and are not easily adaptable to explain new findings. Here, we show that a well -known instance of deep neural network (DNN), whereas not designed specifically for VPL, provides a computational model of VPL with enough complexity to be studied at many levels of analyses. After learning a Gabor orientation discrimination task, the DNN model reproduced key behavioral results, including increasing specificity with higher task precision, and also suggested that learning precise discriminations could transfer asymmetrically to coarse discriminations when the stimulus conditions varied. Consistent with the behavioral findings, the distribution of plasticity moved toward lower layers when task precision increased and this distribution was also modulated by tasks with different stimulus types. Furthermore, learning in the network units demonstrated close resemblance to extant electrophysiological recordings in monkey visual areas. Altogether, the DNN fulfilled predictions of existing theories regarding specificity and plasticity and reproduced findings of tuning changes in neurons of the primate visual areas. Although the comparisons were mostly qualitative, the DNN provides a new method of studying VPL, can serve as a test bed for theories, and assists in generating predictions for physiological investigations.

SIGNIFICANCE STATEMENT Visual perceptual learning (VPL) has been found to cause changes at multiple stages of the visual hierarchy. We found that training a deep neural network (DNN) on an orientation discrimination task produced behavioral and physiological patterns similar to those found in human and monkey experiments. Unlike existing VPL models, the DNN was pre-trained on natural images to reach high performance in object recognition, but was not designed specifically for VPL; however, it fulfilled predictions of existing theories regarding specificity and plasticity and reproduced findings of tuning changes in neurons of the primate visual areas. When used with care, this unbiased and deep-hierarchical model can provide new ways of studying VPL from behavior to physiology.

Neural Coding of Whisker-Mediated Touch in Primary Somatosensory Cortex Is Altered Following Early Blindness

Sensory systems do not develop and function independently of one another, yet they are typically studied in isolation. Effects of multisensory interactions on the developing neocortex can be revealed by altering the ratios of incoming sensory inputs associated with different modalities. We investigated neural responses in primary somatosensory cortex (S1) of short-tailed opossums (Monodelphis domestica; either sex) after the elimination of visual input through bilateral enucleation very early in development. To assess the influence of tactile experience after vision loss, we also examined naturally occurring patterns of exploratory behavior. In early blind (EB) animals, overall levels of tactile experience were similar to those of sighted controls (SC); locomotor activity was unimpaired and accompanied by whisking. Using extracellular single-unit recording techniques under anesthesia, we found that EB animals exhibited a reduction in the magnitude of neural responses to whisker stimuli in S1, coupled with spatial sharpening of receptive fields, in comparison to SC animals. These alterations manifested as two different effects on sensory processing in S1 of EB animals: the ability of neurons to detect single whisker stimulation was decreased, whereas their ability to discriminate between stimulation of neighboring whiskers was enhanced. The increased selectivity of S1 neurons in EB animals was reflected in improved population decoding performance for whisker stimulus position, particularly along the rostrocaudal axis of the snout, which aligns with the primary axis of natural whisker motion. These findings suggest that a functionally distinct form of somatosensory plasticity occurs when vision is lost early in development.

SIGNIFICANCE STATEMENT After sensory loss, compensatory behavior mediated through the spared senses could be generated entirely through the recruitment of brain areas associated with the deprived sense. Alternatively, functional compensation in spared modalities may be achieved through a combination of plasticity in brain areas corresponding to both spared and deprived sensory modalities. Although activation of neurons in cortex associated with a deprived sense has been described frequently, it is unclear whether this is the only substrate available for compensation or if plasticity within cortical fields corresponding to spared modalities, particularly primary sensory cortices, may also contribute. Here, we demonstrate empirically that early loss of vision alters coding of sensory inputs in primary somatosensory cortex in a manner that supports enhanced tactile discrimination.

Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.

SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, because FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease.

This Week in The Journal

Glial {beta}II Spectrin Contributes to Paranode Formation and Maintenance

Action potential conduction along myelinated axons depends on high densities of voltage-gated Na⁺ channels at the nodes of Ranvier. Flanking each node, paranodal junctions (paranodes) are formed between axons and Schwann cells in the peripheral nervous system (PNS) or oligodendrocytes in the CNS. Paranodal junctions contribute to both node assembly and maintenance. Despite their importance, the molecular mechanisms responsible for paranode assembly and maintenance remain poorly understood. βII spectrin is expressed in diverse cells and is an essential part of the submembranous cytoskeleton. Here, we show that Schwann cell βII spectrin is highly enriched at paranodes. To elucidate the roles of glial βII spectrin, we generated mutant mice lacking βII spectrin in myelinating glial cells by crossing mice with a floxed allele of Sptbn1 with Cnp-Cre mice, and analyzed both male and female mice. Juvenile (4 weeks) and middle-aged (60 weeks) mutant mice showed reduced grip strength and sciatic nerve conduction slowing, whereas no phenotype was observed between 8 and 24 weeks of age. Consistent with these findings, immunofluorescence microscopy revealed disorganized paranodes in the PNS and CNS of both postnatal day 13 and middle-aged mutant mice, but not in young adult mutant mice. Electron microscopy confirmed partial loss of transverse bands at the paranodal axoglial junction in the middle-aged mutant mice in both the PNS and CNS. These findings demonstrate that a spectrin-based cytoskeleton in myelinating glia contributes to formation and maintenance of paranodal junctions.

SIGNIFICANCE STATEMENT Myelinating glia form paranodal axoglial junctions that flank both sides of the nodes of Ranvier. These junctions contribute to node formation and maintenance and are essential for proper nervous system function. We found that a submembranous spectrin cytoskeleton is highly enriched at paranodes in Schwann cells. Ablation of βII spectrin in myelinating glial cells disrupted the paranodal cell adhesion complex in both peripheral and CNSs, resulting in muscle weakness and sciatic nerve conduction slowing in juvenile and middle-aged mice. Our data show that a spectrin-based submembranous cytoskeleton in myelinating glia plays important roles in paranode formation and maintenance.

Perineuronal Nets in the Deep Cerebellar Nuclei Regulate GABAergic Transmission and Delay Eyeblink Conditioning

Perineuronal nets (PNNs), composed mainly of chondroitin sulfate proteoglycans, are the extracellular matrix that surrounds cell bodies, proximal dendrites, and axon initial segments of adult CNS neurons. PNNs are known to regulate neuronal plasticity, although their physiological roles in cerebellar functions have yet to be elucidated. Here, we investigated the contribution of PNNs to GABAergic transmission from cerebellar Purkinje cells (PCs) to large glutamatergic neurons in the deep cerebellar nuclei (DCN) in male mice by recording IPSCs from cerebellar slices, in which PNNs were depleted with chondroitinase ABC (ChABC). We found that PNN depletion increased the amplitude of evoked IPSCs and enhanced the paired-pulse depression. ChABC treatment also facilitated spontaneous IPSCs and increased the miniature IPSC frequency without changing not only the amplitude but also the density of PC terminals, suggesting that PNN depletion enhances presynaptic GABA release. We also demonstrated that the enhanced GABAergic transmission facilitated rebound firing in large glutamatergic DCN neurons, which is expected to result in the efficient induction of synaptic plasticity at synapses onto DCN neurons. Furthermore, we tested whether PNN depletion affects cerebellar motor learning. Mice having received the enzyme into the interpositus nuclei, which are responsible for delay eyeblink conditioning, exhibited the conditioned response at a significantly higher rate than control mice. Therefore, our results suggest that PNNs of the DCN suppress GABAergic transmission between PCs and large glutamatergic DCN neurons and restrict synaptic plasticity associated with motor learning in the adult cerebellum.

SIGNIFICANCE STATEMENT Perineuronal nets (PNNs) are one of the extracellular matrices of adult CNS neurons and implicated in regulating various brain functions. Here we found that enzymatic PNN depletion in the mouse deep cerebellar nuclei (DCN) reduced the paired-pulse ratio of IPSCs and increased the miniature IPSC frequency without changing the amplitude, suggesting that PNN depletion enhances GABA release from the presynaptic Purkinje cell (PC) terminals. Mice having received the enzyme in the interpositus nuclei exhibited a higher conditioned response rate in delay eyeblink conditioning than control mice. These results suggest that PNNs regulate presynaptic functions of PC terminals in the DCN and functional plasticity of synapses on DCN neurons, which influences the flexibility of adult cerebellar functions.

Neural Prediction Errors Distinguish Perception and Misperception of Speech

Humans use prior expectations to improve perception, especially of sensory signals that are degraded or ambiguous. However, if sensory input deviates from prior expectations, then correct perception depends on adjusting or rejecting prior expectations. Failure to adjust or reject the prior leads to perceptual illusions, especially if there is partial overlap (and thus partial mismatch) between expectations and input. With speech, "slips of the ear" occur when expectations lead to misperception. For instance, an entomologist might be more susceptible to hear "The ants are my friends" for "The answer, my friend" (in the Bob Dylan song Blowing in the Wind). Here, we contrast two mechanisms by which prior expectations may lead to misperception of degraded speech. First, clear representations of the common sounds in the prior and input (i.e., expected sounds) may lead to incorrect confirmation of the prior. Second, insufficient representations of sounds that deviate between prior and input (i.e., prediction errors) could lead to deception. We used crossmodal predictions from written words that partially match degraded speech to compare neural responses when male and female human listeners were deceived into accepting the prior or correctly reject it. Combined behavioral and multivariate representational similarity analysis of fMRI data show that veridical perception of degraded speech is signaled by representations of prediction error in the left superior temporal sulcus. Instead of using top-down processes to support perception of expected sensory input, our findings suggest that the strength of neural prediction error representations distinguishes correct perception and misperception.

SIGNIFICANCE STATEMENT Misperceiving spoken words is an everyday experience, with outcomes that range from shared amusement to serious miscommunication. For hearing-impaired individuals, frequent misperception can lead to social withdrawal and isolation, with severe consequences for wellbeing. In this work, we specify the neural mechanisms by which prior expectations, which are so often helpful for perception, can lead to misperception of degraded sensory signals. Most descriptive theories of illusory perception explain misperception as arising from a clear sensory representation of features or sounds that are in common between prior expectations and sensory input. Our work instead provides support for a complementary proposal: that misperception occurs when there is an insufficient sensory representations of the deviation between expectations and sensory signals.

Neural Network Interactions Modulate CRY-Dependent Photoresponses in Drosophila

Light is one of the chief environmental cues that reset circadian clocks. In Drosophila, CRYPTOCHROME (CRY) mediates acute photic resetting of circadian clocks by promoting the degradation of TIMELESS in a cell-autonomous manner. Thus, even circadian oscillators in peripheral organs can independently perceive light in Drosophila. However, there is substantial evidence for nonautonomous mechanisms of circadian photoreception in the brain. We have previously shown that the morning (M) and evening (E) oscillators are critical light-sensing neurons that cooperate to shift the phase of circadian behavior in response to light input. We show here that light can efficiently phase delay or phase advance circadian locomotor behavior in male Drosophila even when either the M- or the E-oscillators are ablated, suggesting that behavioral phase shifts and their directionality are largely a consequence of the cell-autonomous nature of CRY-dependent photoreception. Our observation that the phase response curves of brain and peripheral oscillators are remarkably similar further supports this idea. Nevertheless, the neural network modulates circadian photoresponses. We show that the M-oscillator neurotransmitter pigment dispersing factor plays a critical role in the coordination between M- and E-oscillators after light exposure, and we uncover a potential role for a subset of dorsal neurons in the control of phase advances. Thus, neural modulation of autonomous light detection might play an important role in the plasticity of circadian behavior.

SIGNIFICANCE STATEMENT Input pathways provide circadian rhythms with the flexibility needed to harmonize their phase with environmental cycles. Light is the chief environmental cue that synchronizes circadian clocks. In Drosophila, the photoreceptor CRYPTOCHROME resets circadian clocks cell-autonomously. However, recent studies indicate that, in the brain, interactions between clock neurons are critical to reset circadian locomotor behavior. We present evidence supporting the idea that the ability of flies to advance or delay their rhythmic behavior in response to light input essentially results from cell-autonomous photoreception. However, because of their networked organization, we find that circadian neurons have to cooperate to reset the phase of circadian behavior in response to photic cues. Our work thus helps to reconcile cell-autonomous and non-cell-autonomous models of circadian entrainment.

Nerve Injury-Induced Chronic Pain Is Associated with Persistent DNA Methylation Reprogramming in Dorsal Root Ganglion

Nerve injury-induced hyperactivity of primary sensory neurons in the dorsal root ganglion (DRG) contributes to chronic pain development, but the underlying epigenetic mechanisms remain poorly understood. Here we determined genome-wide changes in DNA methylation in the nervous system in neuropathic pain. Spinal nerve ligation (SNL), but not paclitaxel treatment, in male Sprague Dawley rats induced a consistent low-level hypomethylation in the CpG sites in the DRG during the acute and chronic phases of neuropathic pain. DNA methylation remodeling in the DRG occurred early after SNL and persisted for at least 3 weeks. SNL caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands, in introns, intergenic regions, and repetitive sequences. In contrast, SNL caused more gains of methylation in the spinal cord and prefrontal cortex. The DNA methylation changes in the injured DRGs recapitulated developmental reprogramming at the neonatal stage. Methylation reprogramming was correlated with increased gene expression variability. A diet deficient in methyl donors induced hypomethylation and pain hypersensitivity. Intrathecal administration of the DNA methyltransferase inhibitor RG108 caused long-lasting pain hypersensitivity. DNA methylation reprogramming in the DRG thus contributes to nerve injury-induced chronic pain. Restoring DNA methylation may represent a new therapeutic approach to treat neuropathic pain.

SIGNIFICANCE STATEMENT Epigenetic mechanisms are critically involved in the transition from acute to chronic pain after nerve injury. However, genome-wide changes in DNA methylation in the nervous system and their roles in neuropathic pain development remain unclear. Here we used digital restriction enzyme analysis of methylation to quantitatively determine genome-wide DNA methylation changes caused by nerve injury. We showed that nerve injury caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands in the dorsal root ganglion. Reducing DNA methylation induced pain hypersensitivity, whereas increasing DNA methylation attenuated neuropathic pain. These findings extend our understanding of the epigenetic mechanism of chronic neuropathic pain and suggest new strategies to treat nerve injury-induced chronic pain.

Classification of Neurons in the Primate Reticular Formation and Changes after Recovery from Pyramidal Tract Lesion

The reticular formation is important in primate motor control, both in health and during recovery after brain damage. Little is known about the different neurons present in the reticular nuclei. Here we recorded extracellular spikes from the reticular formation in five healthy female awake behaving monkeys (193 cells), and in two female monkeys 1 year after recovery from a unilateral pyramidal tract lesion (125 cells). Analysis of spike shape and four measures derived from the interspike interval distribution identified four clusters of neurons in control animals. Cluster 1 cells had a slow firing rate. Cluster 2 cells had narrow spikes and irregular firing, which often included high-frequency bursts. Cluster 3 cells were highly rhythmic and fast firing. Cluster 4 cells showed negative spikes. A separate population of 42 cells was antidromically identified as reticulospinal neurons in five anesthetized female monkeys. The distribution of spike width in these cells closely overlaid the distribution for cluster 2, leading us tentatively to suggest that cluster 2 included neurons with reticulospinal projections. In animals after corticospinal lesion, cells could be identified in all four clusters. The firing rate of cells in clusters 1 and 2 was increased in lesioned animals relative to control animals (by 52% and 60%, respectively); cells in cluster 2 were also more regular and more bursting in the lesioned animals. We suggest that changes in both membrane properties and local circuits within the reticular formation occur following lesioning, potentially increasing reticulospinal output to help compensate for lost corticospinal descending drive.

SIGNIFICANCE STATEMENT This work is the first to subclassify neurons in the reticular formation, providing insights into the local circuitry of this important but little understood structure. The approach developed can be applied to any extracellular recording from this region, allowing future studies to place their data within our current framework of four neural types. Changes in reticular neurons may be important to subserve functional recovery after damage in human patients, such as after stroke or spinal cord injury.

Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

Activating Transcription Factor 4 (ATF4) has been postulated as a key regulator of learning and memory. We previously reported that specific hippocampal ATF4 downregulation causes deficits in synaptic plasticity and memory and reduction of glutamatergic functionality. Here we extend our studies to address ATF4's role in neuronal excitability. We find that long-term ATF4 knockdown in cultured rat hippocampal neurons significantly increases the frequency of spontaneous action potentials. This effect is associated with decreased functionality of metabotropic GABA_B receptors (GABA_BRs). Knocking down ATF4 results in significant reduction of GABA_BR-induced GIRK currents and increased mIPSC frequency. Furthermore, reducing ATF4 significantly decreases expression of membrane-exposed, but not total, GABA_BR 1a and 1b subunits, indicating that ATF4 regulates GABA_BR trafficking. In contrast, ATF4 knockdown has no effect on surface expression of GABA_BR2s, several GABA_BR-coupled ion channels or β2 and 2 GABA_ARs. Pharmacologic manipulations confirmed the relationship between GABA_BR functionality and action potential frequency in our cultures. Specifically, the effects of ATF4 downregulation cited above are fully rescued by transcriptionally active, but not by transcriptionally inactive, shRNA-resistant, ATF4. We previously reported that ATF4 promotes stabilization of the actin-regulatory protein Cdc42 by a transcription-dependent mechanism. To test the hypothesis that this action underlies the mechanism by which ATF4 loss affects neuronal firing rates and GABA_BR trafficking, we downregulated Cdc42 and found that this phenocopies the effects of ATF4 knockdown on these properties. In conclusion, our data favor a model in which ATF4, by regulating Cdc42 expression, affects trafficking of GABA_BRs, which in turn modulates the excitability properties of neurons.

SIGNIFICANCE STATEMENT GABA_B receptors (GABA_BRs), the metabotropic receptors for the inhibitory neurotransmitter GABA, have crucial roles in controlling the firing rate of neurons. Deficits in trafficking/functionality of GABA_BRs have been linked to a variety of neurological and psychiatric conditions, including epilepsy, anxiety, depression, schizophrenia, addiction, and pain. Here we show that GABA_BRs trafficking is influenced by Activating Transcription Factor 4 (ATF4), a protein that has a pivotal role in hippocampal memory processes. We found that ATF4 downregulation in hippocampal neurons reduces membrane-bound GABA_BR levels and thereby increases intrinsic excitability. These effects are mediated by loss of the small GTPase Cdc42 following ATF4 downregulation. These findings reveal a critical role for ATF4 in regulating the modulation of neuronal excitability by GABA_BRs.

Oscillatory Encoding of Visual Stimulus Familiarity

Familiarity of the environment changes the way we perceive and encode incoming information. However, the neural substrates underlying this phenomenon are poorly understood. Here we describe a new form of experience-dependent low-frequency oscillations in the primary visual cortex (V1) of awake adult male mice. The oscillations emerged in visually evoked potentials and single-unit activity following repeated visual stimulation. The oscillations were sensitive to the spatial frequency content of a visual stimulus and required the mAChRs for their induction and expression. Finally, ongoing visually evoked (4–8 Hz) oscillations boost the visually evoked potential amplitude of incoming visual stimuli if the stimuli are presented at the high excitability phase of the oscillations. Our results demonstrate that an oscillatory code can be used to encode familiarity and serves as a gate for oncoming sensory inputs.

SIGNIFICANCE STATEMENT Previous experience can influence the processing of incoming sensory information by the brain and alter perception. However, the mechanistic understanding of how this process takes place is lacking. We have discovered that persistent low-frequency oscillations in the primary visual cortex encode information about familiarity and the spatial frequency of the stimulus. These familiarity evoked oscillations influence neuronal responses to the oncoming stimuli in a way that depends on the oscillation phase. Our work demonstrates a new mechanism of visual stimulus feature detection and learning.

Eosinophilic Esophagitis and the Eosinophilic Gastrointestinal Diseases: Approach to diagnosis and management

Publication date: Available online 3 July 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Erin Steinbach, Michelle Hernandez, Evan S. Dellon
The eosinophilic gastrointestinal diseases (EGID) represent disorders of the GI tract that result from the local infiltration and aberrant activity of eosinophils and other immune cells. Eosinophilic esophagitis is the most well-characterized EGID and is defined by the presence of intraepithelial eosinophils in the esophagus (≥15 eosinophils per high powered field) and clinical symptoms associated with esophageal dysfunction. The other EGID are rare and lack strong data regarding pathogenesis and management. The incidence and prevalence of EoE are increasing, and EoE is now a major cause of upper GI morbidity. Management is multidisciplinary, with collaboration between gastroenterologists, allergists, pathologists, and dieticians, and is aimed at amelioration of symptoms and prevention of long-term complications such as esophageal stricture. Treatment options for EoE include proton pump inhibitors, swallowed topical corticosteroids, and elimination diets. Esophageal dilation is used when esophageal strictures or fibrostenotic changes are present. Additional therapies targeting eosinophils and other mediators of Th2 inflammation are under development and are promising. Treatment options for other EGIDs typically involve corticosteroids or dietary elimination.

Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society

Publication date: Available online 4 July 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Stephan Ehl, Itziar Astigarraga, Tatiana von Bahr Greenwood, Melissa Hines, AnnaCarin Horne, Eiichi Ishii, Gritta Janka, Michael B. Jordan, Paul La Rosée, Kai Lehmberg, Rafal Machowicz, Kim E. Nichols, Elena Sieni, Zhao Wang, Jan-Inge Henter
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.

The LIFE PERSUADED project approach on phthalates and bisphenol A biomonitoring in Italian mother-child pairs linking exposure and juvenile diseases

Abstract

Phthalates and bisphenol A (BPA), plasticizers used in several products of daily life, are considered as endocrine disrupters, therefore children exposure is particularly relevant. The LIFE PERSUADED project aims to define the following: (a) the evaluation of internal levels of DEHP's metabolites and BPA in Italian children and their mothers, (b) the association of the exposure with puberty development and obesity diseases, and (c) the effects of exposure in juvenile in vivo model. The cross-sectional study has involved 2160 mother-child pairs, including males and females, children and adolescents, from urban and rural areas of North, Center, and South Italy. A structured questionnaire and a food diary are designed to evaluate the association between lifestyle variables potentially related to DEHP/BPA exposure and internal levels, through univariate and multivariate analyses. Two pilot case-control studies are carried out on idiopathic premature thelarche and precocious puberty (30 girls each group, aged 2–7 years) and idiopathic obesity (30 boys and 30 girls, aged 6–10 years), matched to healthy controls. BPA and DEHP's metabolites are analyzed in urine samples from all recruited subjects. Clinical and toxicological biomarkers are evaluated in serum of case-control subjects. Moreover, the toxicity study is carried out in a juvenile rodent model exposed to mixtures of BPA and DEHP at dose levels recorded in children population. The scientific results of LIFE PERSUADED will contribute to risk assessment of BPA and DEHP.

The Hog1 positive regulated YCT1 Gene Expression under Cadmium tolerance of budding yeast

Abstract

Cadmium is a heavy metal that cause irreversible hazard to the living organisms. Cadmium ion can induces the phosphorylation of MAPKs pathway molecules, such as Hog1 and Slt2, but downstream effectors and potential activation pathway were still unclear. In this study, the RNA-seq data analysis in cadmium-stressed yeast was performed to predict and screen the signal transduction pathway and the potential effect molecules regulated by MAPKs. Based on DEGs and Venn diagram, 31 genes regulated by Hog1p and 2 genes induced by Slt2p, which related to carbohydrate metabolism, oxidative damage, DNA replication stress and detoxification were characterized under Cd exposure yeast. A cysteine-specific transporter (Yct1) modulated by Hog1 was confirmed via RNA-seq result. Meanwhile, we tested the cadmium sensitivity, intracellular cadmium concentrations and β-galactosidase assay, the results indicated that the hypersensitivity of the hog1 mutant to Cd was partly abrogated in YCT1 gene deletion, and induction of YCT1 was dependent on Hog1 and its transcription factors. Yct1p would be epistatic to the Hog1p in Cd tolerance, The investigation of the transcriptome of MAPKs under Cd stress provided valuable information for future molecular studies of cadmium tolerance.

pH level has a strong impact on population dynamics of the yeast Yarrowia lipolytica and oil micro-droplets in multiphasic bioreactor

Abstract

The oleaginous yeast Yarrowia lipolytica has the ability to use oils and fats as carbon source, making it a promising cell factory for the design of alternative bioprocesses based on renewable substrates. However, such a multiphasic bioreactor design is rather complex and leads to several constraints when considering emulsification of the oil-in-water mixture, foaming and cell growth/physiology on hydrophobic substrate. This study aims to shed light on the effect of pH changes on the physico-chemical properties of the cultivation medium and on cell physiology. It was indeed observed that at a pH value of 6, cell growth rate and intracellular lipid accumulation were optimized. Additionally, foaming was significantly reduced. In order to avoid over foaming in bioreactor, without impairing cell physiology, the use of alternative processes that can only act on the physical structure of culture medium, seems to be an effective alternative to usual chemical antifoam agents.

E. coli strain engineering for the production of advanced biopharmaceutical products

Abstract

Since the emergence of the biopharmaceutical industry in the 1980's, Escherichia coli, has played an important role in the industrial production of recombinant proteins and plasmid DNA for therapeutic use. Currently, advanced biopharmaceutical products, including rationally-designed recombinant proteins and viral-vector gene therapies, offer unprecedented promise for the long-term management, and even cure of disease. As such, E. coli remains an important production host for the biopharmaceutical industry. This review provides insight into the industrially-relevant strain engineering approaches used to enhance both the quantity and quality of these therapeutic products.

Effects of solid-state fermentation with three higher fungi on the total phenol contents and antioxidant properties of diverse cereal grains

Abstract

Three culinary-medicinal fungi and mushrooms (Agaricus bisporus AS2796, Helvella lacunosa X1 and Fomitiporia yanbeiensis S.Guo & L.Zhou) were individually inoculated into different cereal grains (wheat, rice, oat, corn, millet, quinoa, buckwheat, soybean, pea and sorghum) and the antioxidant properties of fungus-fermented products after solid-state fermentation (SSF) (0, 7, 14, 21, 28 and 35 days; 25°C) were studied.The results showed that the total phenol contents (TPCs) of the fermented cereals varied with fermentation time and the starter organisms. According to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity, reducing power, ferrous ion chelating ability and superoxide anion radical scavenging ability of ethanolic extracts from the fungus-fermented products (35 days), it was shown that the antioxidant properties of all the products were significantly stronger than uninoculated grains. It revealed that solid-state fermentation (SSF) on cereal grains by dietary fungi is a biotechnological strategy, which may enhance the antioxidant properties of the substrate. The three medicinal mushroom and fungi-fermented products were relatively effective in the antioxidant properties assayed and might be potential antioxidants for application in food products.

Increased sharing and collaboration can decrease barriers to progress in Microbiology

Identifying patients who may benefit from oxaliplatin-containing perioperative chemo(radio)therapy for rectal cancer

Selecting patients with triple negative breast cancer for platinum-based therapy: we still haven't found what we're looking for

Le portfolio de l’interne de chirurgie plastique : un outil d’aide à la formation des internes de chirurgie plastique en France ?

Publication date: Available online 3 July 2018
Source:Annales de Chirurgie Plastique Esthétique
Author(s): A. Bout-Roumazeilles, S. Dast, N. Assaf, C. Herlin, R. Sinna
La réforme du troisième cycle des études médicales a modifié le modèle d'apprentissage des internes de chirurgie plastique, en lui amputant une année de formation. La réforme précise qu'un portfolio devra suivre l'interne au cours de sa formation. Jusqu'à présent la formation pratique des internes de chirurgie plastique était exclusivement dévolue au coordonnateur local de la spécialité et aucun contrôle officiel des connaissances n'avait lieu avant l'examen national du DESC. Prenant en compte ces faits nous avons imaginé le portfolio de l'interne de chirurgie plastique qui permettrait de guider l'interne dans sa progression pratique et dans l'acquisition de ses connaissances théoriques. Il permettrait aussi d'homogénéiser la formation nationale de la spécialité et pourrait, à terme, servir de support à une évaluation formelle des compétences pratiques des internes de chirurgie plastique. Dans un premier temps nous faisons un état des lieux de la formation avant l'apparition de la réforme. Puis nous détaillons les changements qui seront apportés par la réforme. Enfin nous décrivons le portfolio en détail, son contenu, son utilisation et son intérêt.A recent reform of the French government has shortened the plastic surgery residency from 5 to 4 years. Until today, the evaluation and validation of the residency was shared between the local coordinator for practical skills and, after the residency, by the French College of Plastic Surgery for theorical knowledges. The new reform suggests to add a portfolio that will follow the resident during his surgical training. Based on the French reform and syllabus of others medical specialities, we designed a surgical portfolio that will help the resident both with his practical progression and his knowledges acquisition. The aim of the portfolio is to get a national unity of the plastic surgery training. As a first step we will describe the actual plastic surgery residency. Then, we will detail what the reform is going to change. At last, we will introduce the surgical portfolio, its content, its use and its goals.

Secondary bladder exstrophy repair with a bilateral gracilis muscle flap in an adult female patient: Case report of an original procedure

Publication date: Available online 3 July 2018
Source:Annales de Chirurgie Plastique Esthétique
Author(s): J.-B. Schaff, E. Fontaine, C. Dariane, A. Mejean, L. Lantieri, M. Hivelin
Classical bladder exstrophy (CBE), affecting 1 birth out of 30,000, is characterized by an evaginated bladder plate through a defect in the lower abdominal wall, multiple abdominal wall anomalies including a pubic bone arch dehiscence. Numerous approaches from childhood to adulthood are thus required, depending on the severity of the deformity, including the associated genital anomalies. We report the case of a 19-year-old woman with CBE with a history of three-failed primary closure. We performed a secondary neck closure with a concomitant suspension of the bladder neck and reconstruction of the lower abdominal wall using a bilateral gracilis muscle flap transposition. The early postoperative course was uneventful. The patient was discharged at day ten postoperatively. The upper part of the genital sutures (labia minora) secondary healed in three weeks. Assessment at 2, 6 and 16 months postoperatively, respectively noticed a complete healing with successful sexual intercourses, perceived gracilis contraction by the patient, and finally, recent attempts to get pregnant. Neither urinary infection nor urinary leaks occurred. Bilateral crossed gracilis muscles transfer linking both rectus abdominis muscle in front of the reconstructed bladder neck might benefit to bladder exstrophy patients.

Removal of vanadium from wastewater using surface-modified lignocellulosic material

Abstract

Palm fruit husk, a lignocellulosic material, is an agricultural solid waste. Since raw palm fruit husk does not adsorb V (V), it was subjected to surface modification with a cationic surfactant cetyl trimethyl ammonium bromide (CTAB). The surface-modified palm fruit husk showed adsorption capability for V (V). The maximum adsorption of V (V) takes place at pH 4. Adsorption equilibrium data were fitted to Langmuir, Freundlich, and Dubinin Radushkevich (D-R) isotherm models. Kinetic studies showed that the adsorption data fit second-order kinetic model better than first order. Desorption of V (V) proved that it is feasible to recover V (V) from the spent adsorbent. Effect of coexisting anions like Molybdate, sulfate, nitrate, phosphate, and thiocyanate on the adsorption of V (V) was also studied and the foreign ions compete for the adsorption sites with V (V) anionic species. Quantitative removal of V (V) was achieved from synthetic wastewater.

Predictors for Increased and Reduced Rat and Mouse Allergen Exposure in Laboratory Animal Facilities

Abstract

Introduction

Exposure to rat and mouse allergens during work in laboratory animal facilities represents a risk for being sensitized and developing allergic diseases, and it is important to keep the exposure level as low as possible. The objective of this study was to characterize the personal Mus m 1 and Rat n 1 exposure during work in laboratory animal facilities, and to investigate the effect of identified predictors of increased and reduced exposure.

Methods

Mus m 1 and Rat n 1 were analysed in whole day or task-based personal air samples by enhanced sensitivity sandwich enzyme-linked immunosorbent assay. Information about cage-and-rack systems, tasks, and other conditions known to influence the allergen exposure was registered. Predictors for allergen exposure were identified by multiple linear regression analyses.

Results

The median allergen exposure was 3.0 ng m⁻³ Mus m 1 and 0.5 ng m⁻³ Rat n 1, with large task-dependent variations among the samples. The highest exposed job group were animal technicians. Cage emptying and cage washing in the cage washroom represented the highest exposure, whereas animal experiments in the lab/operation room represented the lowest exposure, with laminar airflow bench being an exposure-reducing determinant. Cage changing was the highest exposed task in the animal room, where individually ventilated cages (IVCs) were predictors of reduced exposure for both Mus m 1 and Rat n 1, whereas cage-rack systems with open shelves and sliding doors were predictors of increased Rat n 1 exposure. Cages of IVC type with positive air pressure (IVC+) as well as open shelves and sliding doors were strong predictors of increased exposure during cage emptying and cage washing.

Conclusions

Significant different exposure levels depending on type of work and task imply different risks of sensitization and allergy development. The fact that IVC+ cages have opposite impact on Mus m 1 and Rat n 1 exposure during different tasks may have positive clinical implications when taken into account.

Assessment of Infraorbital Hypesthesia Following Orbital Floor and Zygomaticomaxillary Complex Fractures Using a Novel Sensory Grading System

Purpose: Introduction of a novel sensory grading system to assess the incidence and long-term recovery of infraorbital hypesthesia following orbital floor and inferior orbital rim fractures. Methods: Patients who presented for evaluation of orbital floor and/or zygomaticomaxillary complex (ZMC) fractures between January 2015 and April 2016 were analyzed. Two-point subjective infraorbital sensory grading in 5 discrete anatomic areas was performed. Fractures were repaired based on traditional criteria; hypesthesia was not an indication for surgery. The sensory grading system was repeated a mean 21.7 months (range 18–28) after initial fracture. Results: Sixty-two patients (mean 41.8 years) participated in the initial symptom grading, and 42 patients (67.7%) completed the 2-year follow-up. Overall, 20 of 42 patients (47.6%) had some infraorbital hypesthesia. There were fewer with isolated orbital floor fractures versus ZMC fractures (31.8% vs. 68.4%; p = 0.019). Two years postinjury, 9.1% and 40.0% with isolated floor and ZMC fractures, respectively, had persistent sensory disturbance (p = 0.0188). Of patients with sensory disturbance on presentation, 71.4% with isolated floor fractures and 38.5% with ZMC fractures experienced complete sensory recovery (p = 0.1596). Patients with isolated floor fractures had improved recovery after surgery (100% vs. 33.3% recovery; p = 0.0410). Patients with ZMC fractures showed no difference in sensory prognosis between those repaired and observed. Conclusions: In this pilot study, isolated orbital floor fractures carried a good infraorbital sensory prognosis, further improved by surgical repair. Zygomaticomaxillary complex fractures portended a worse long-term sensory outcome, unaffected by management strategy. This study validates the novel sensory grading system in post-fracture analysis. Accepted for publication May 1, 2018. Podium presentation at the American Society of Ophthalmic Plastic and Reconstructive Surgery Fall 2017 Symposium, New Orleans, Louisiana. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Michael K. Yoon, M.D., Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. E-mail: Michael_Yoon@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Influence of nano-additive on performance and emission characteristics of a diesel engine running on neat neem oil biodiesel

Abstract

This work investigates the experimental study to examine the operation characteristics of a neat neem oil methyl ester (BD100) along with silver oxide nano-particles as a metal-based additive in various mass fractions. Silver oxide nano-particle is mixed into 100% of BD100 at 5 and 10 ppm. The experimental investigation on diesel engine reveals that the addition of silver oxide nano-particles to BD100 resulted in enhancement of brake thermal efficiency (BTE) with a reduction in brake specific fuel consumption (BSFC). The tested emission parameters such as CO, HC, NOx, and smoke were decreased by 12.22, 10.89, 4.24, and 6.61% for BD100+ Ag₂O (5 ppm) and 16.47, 14.21, 6.66, and 8.34% for BD100 respectively when compared to BD100. Overall, improvement in ignition characteristics of the engine was finer by adding 5 and 10 ppm of silver oxide nano-particle to BD100 on account of the enhanced surface area to volume ratio.

Maize shoot cell walls under cadmium stress

Abstract

The composition of shoot cell walls of two maize hybrids (Zea mays L.), the sensitive Novania and the tolerant Almansa, both after cadmium treatment was studied. Previous results showed a smaller effect of cadmium on shoot physiological parameters (e.g., elongation, dry mass, photosynthetic pigments content) in both hybrids compared to their roots. Changes in the composition of shoot cell walls were observed. It was ascertained that the amount of hemicelluloses in shoot cell walls decreased and the amount of lignocellulose complex increased in the sensitive hybrid; the opposite was observed in the tolerant Almansa. Dissimilarities in the cell wall structure of shoots, compared to the roots, in both hybrids were observed mainly in higher quantities of total lignin, in hemicelluloses fractions. The lignocellulose complex remained unchanged in the shoots in comparison to the roots. Nevertheless, in both hybrids, the highest Cd²⁺ amount was found in hemicelluloses. Such modification of the cell walls might affect the amount of binding sites resulting in lower cell wall permeability and subsequently in a lower pollutant influx into the protoplast.