Influence of Streptococcus mitis and Streptococcus sanguinis on virulence of Candida albicans : in vitro and in vivo studies

Abstract

The aim was to evaluate in vitro possible interactions, gene expression, and biofilm formation in species of Candida albicans, Streptococcus mitis, and Streptococcus sanguinis and their in vivo pathogenicity. The in vitro analysis evaluated the effects of S. mitis and S. sanguinis on C. albicans's biofilm formation by CFU count, filamentation capacity, and adhesion (ALS1, ALS3, HWP1) and transcriptional regulatory gene (BCR1, CPH1, EFG1) expression. In vivo studies evaluated the pathogenicity of the interaction of the microorganisms on Galleria mellonella, with analyses of the CFU per milliliter count and filamentation. In vitro results indicated that there was an observed decrease in CFU (79.4–71.5%) in multi-species biofilms. The interaction with S. mitis inhibited filamentation, which seems to increase its virulence factor with over-expression of genes ALS1, ALS3, and HWP1 as well the interaction with S. sanguinis as ALS3 and HWP1. S. mitis upregulated BRC1, CPH1, and EFG1. The histological images of in vivo study indicate an increase in the filamentation of C. albicans when in interaction with the other species. It was concluded that S. mitis interaction suggests increased virulence factors of C. albicans, with periods of lower virulence and proto-cooperation in the interaction with S. sanguinis.

Neonatal calf meningitis associated with Streptococcus gallolyticus subsp . gallolyticus

Abstract

Here, we report a case of neonatal calf meningitis due to Streptococcus gallolyticus subsp. gallolyticus (SGG). Clinical, pathological and microbiological findings were evaluated. API Strep, 16S rRNA gene sequencing, rpoB gene sequencing and sodA gene sequencing were used for the complete identification of SGG. This is the first documented report of neonatal calf meningitis due to SGG in veterinary medicine.

Disease Burden and Treatment Patterns of Psoriasis in Russia: A Real-World Patient and Dermatologist Survey

Abstract

Introduction

Data regarding disease burden and quality of life (QoL) for patients with psoriasis from Russia are limited. The objective of this study was to describe the demographic and clinical characteristics, comorbidities, and treatment patterns of systemic therapy eligible psoriasis patients in Russia in order to assess the impact of psoriasis on the QoL and work productivity of the patients and to evaluate patient/dermatologist concordance on disease severity, signs/symptoms, and satisfaction with psoriasis treatment.

Methods

Data were collected by the Growth from Knowledge Disease Atlas global real-world evidence programme from nine countries. The data from the Russian population are presented here. Adult patients who had a current or prior history of moderate-to-severe psoriasis and were receiving prescription treatment at the time of the survey were included. Dermatologist-reported data on disease severity, symptoms, comorbidities, and treatment as well as patient-reported data on QoL and work productivity were collected. Descriptive analysis of the data was conducted. Patient/dermatologist concordance was assessed using Cohen's κ.

Results

A total of 300 patients from Russia were included. The mean Psoriasis Area and Severity Index score was 9.0 and the mean disease duration was 9.9 years. The proportion of patients with itch, skin pain, and comorbidities increased as current psoriasis severity increased. The disease had a negative impact on patients' QoL (mean Dermatology Life Quality Index score: 7.1) and work productivity (33.2% drop in work productivity), which further deteriorated as disease severity increased. A large proportion of the enrolled patients (60%) were treated with topical agents only. Overall, the level of concordance between patients and their dermatologists regarding psoriasis severity and satisfaction with overall disease control achieved was low.

Conclusion

Results demonstrate a substantial disease burden on psoriasis patients in Russia, despite receiving treatment for their psoriasis, as well as low patient/dermatologist concordance of views on treatment outcomes. These findings also highlight a need to further incorporate the patient's views into treatment decision-making in Russia.

Funding

Novartis Pharma AG, Basel, Switzerland.

Acral Melanoma: A Patient’s Experience and Physician’s Commentary

Abstract

This article, co-authored by a patient diagnosed with acral melanoma, discusses the patient's experience of being diagnosed with and treated with surgery for this disease. The physician discusses the epidemiology, genetics, diagnosis, treatment, and prognosis of acral melanoma. Follow-up care plans are also discussed.

Iddo Landau, Finding Meaning in an Imperfect World. Oxford, England: Oxford University Press, 2017. ISBN 9780190657666, $25, Hbk

Growth through Adversity: Exploring Associations between Internal Strengths, Posttraumatic Growth, and Wisdom

Bad Art and Good Taste

Temporal Encoding During Unimodal and Bimodal Odor Processing in the Human Brain

Abstract

Introduction

In daily life, people encounter a wide range of odors, most of which contain multiple chemical substances. So-called bimodal odors stimulate both the olfactory and trigeminal nerve, and the interaction between these two systems shapes the perception of the odor. However, temporal encoding of these sensory systems during bimodal odor processing has received limited scientific attention.

Methods

To investigate this, we recorded the electrophysiological response in 17 participants to relatively unimodal olfactory (strawberry), trigeminal (l-isopulegol) and strongly bimodal (strawberry and l-isopulegol) stimuli.

Results

ERP amplitudes and intensity ratings were significantly bigger for bimodal stimulation, as compared to unimodal stimulations. No significant difference was observed between N1 and P2 response latencies to olfactory and bimodal stimuli while responses to both stimuli showed longer latencies compared to the response of the trigeminal stimulus.

Conclusions

Results provide further evidence of interaction between olfactory and trigeminal systems; additional activation of the olfactory system results in more vigorous electrophysiological responses and the experience of higher intensity. In addition, results indicate that the trigeminal system is faster to react to stimulation.

Implications

The current study offers a view on the temporal processing of bimodal odorants that are most likely to be encountered in the environment. We link the more vigorous electrophysiological response to a more complex odorant with activation of different neural structures.

Characterization and Evaluation of Changes in the Aroma-Active Components in Szechuan Pepper ( Zanthoxylum bungeanum Maxim) Under Different Cooking Temperatures Using Gas Chromatography-Olfactometry

Abstract

Introduction

The flavor of Szechuan pepper plays an important role in Sichuan cuisine, where it is responsible for the tingling and numbing characteristic. The aims of this study were to characterize and identify aroma-active compounds of Szechuan pepper and to evaluate changes in flavor components between room and high temperature (ca. 70–80 °C).

Methods

Solvent-assisted flavor evaporation (SAFE) and headspace solid-phase microextraction (HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-olfactometry (GC-O) were used.

Results

In this study, linalool, linalyl acetate, and limonene were identified as the major components by both SAFE and HS-SPME. Seven compounds, namely myrcene, limonene, 1,8-cineole, linalool, 2-phenylethanol, 4-methylacetophenone, and trans-carveol, were identified as aroma-active compounds using GC-O. The most intense aroma-active compounds were 1,8-cineole and linalool. Moreover, 2-phenylethanol and 4-methylacetophenone were identified as aroma-active components for the first time in Szechuan pepper. The relative contents of 1,8-cineole, linalool, 2-phenylethanol, 4-methylacetophenone, and trans-carveol were significantly increased as simulated cooking temperature increased from 40 to 75 °C, whereas myrcene, limonene, and hexanal were significantly decreased; 1,8-cineole was not detected at 40 °C but was detected at 75 °C.

Conclusions

A total of 83 volatile compounds were identified, including 62 by SAFE and 57 by HS-SPME. Of these, 34 volatile compounds were identified by both SAFE and HS-SPME. For the first time, 2-phenylethanol and 4-methylacetophenone were identified as key aroma-active components in Szechuan pepper. The overall flavor of Szechuan pepper might be influenced by a result of the relative ratios of key aroma-active components. Cooking temperature should be taken into consideration when Szechuan pepper is used as an ingredient in food.

Implications

These results could be beneficial for furthering our understanding of aroma-active compounds in Szechuan pepper and improving dishes prepared with this ingredient.

Keeping Our Eyes on the Prize: Focusing on Parenting Supports Depressed Parents’ Involvement in Home Visiting Services

Abstract

Objectives Improving family retention and engagement is crucial to the success of home visiting programs. Little is known about retaining and engaging depressed parents in services. The purpose of the study is to examine how home visit content moderates the association between depression and retention and engagement. Methods The sample (N = 1322) was served by Healthy Families America (n = 618) and Parents as Teachers (n = 704) between April 1, 2012 and June 30, 2016. Parents averaged 23 years (SD = 6). Nearly half of the parents were White (48%) and the majority was single (71%). Depression was screened with the Patient Health Questionnaire-2. Home visitors reported the percent of time focused on particular content and parent engagement at every home visit. Results Multilevel regression analyses showed the amount of time that home visitors spent supporting parent–child interaction moderated the association between depression and retention at 6 (B = .08, SE = .03, p = .003) and 12 (B = .1, SE = .03, p < .001) months, such that there was a stronger positive association for depressed parents. The main effects of child development focused content and retention at 6 (B = .07, SE = .01, p < .001) and 12 (B = .08, SE = .01, p < .001) months were positive, while effects of case management focused content at 6 (B = − .06, SE = .01, p < .001) and 12 (B = − .07, SE = .01, p < .001) months were negative. Conclusions Families were more likely to be retained when home visitors focused on child development and parent–child interaction, but less likely with more case management focus. Parents with positive depression screens were more likely to remain in services with more time spent focused on supporting parent–child interactions.

Correction to: Triadic Interactions in MIECHV: Relations to Home Visit Quality

The article "Triadic interactions in MIECHV: Relations to home visit quality", written by Carla A. Peterson, Kere Hughes-Belding, Neil Rowe, Liuran Fan, Melissa Walter, Leslie Dooley, Wen Wang and Chloe Steffensmeier, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 12 June 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 9 July 2018 to © The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Correction to: Randomized Trial of a Training Program to Improve Home Visitor Communication around Sensitive Topics

The article "Randomized Trial of a Training Program to Improve Home Visitor Communication around Sensitive Topics", written by Allison West, Laina Gagliardi, Amanda Gatewood, Susan Higman, Jane Daniels, Kay O'Neill and Anne Duggan, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access.

Mother and Home Visitor Emotional Well-Being and Alignment on Goals for Home Visiting as Factors for Program Engagement

Abstract

Objectives Family engagement in home visiting (HV), as indicated by length of enrollment, is a major challenge as most families do not stay enrolled for the intended duration prescribed by HV models. This study examined maternal and visitor emotional well-being as factors for maternal satisfaction with the program in addressing reasons for enrolling in HV and program engagement and the role of their working alliance with the visitor as a mediator of this. Methods Longitudinal data were collected from 148 mothers and 54 visitors in 21 HV programs. Mothers completed surveys shortly after enrolling and 6 months later to assess attributes of the working alliance with their visitor. Visitors completed a survey to assess work-related well-being. HV program data were used to measure engagement. Results Mothers enrolled for multiple, diverse reasons, most often to promote child development and parenting (96%). Mothers' satisfaction with program efforts to address reasons for enrollment was highest for parenting (79%) and lowest for jobs and education (30%). Results of the mediational path model indicated that ratings of the visitor on goal alignment were positively associated with engagement. Maternal emotional availability and visitor work-related emotional exhaustion were negatively associated with engagement. Exploratory analyses suggested that ratings of the visitor on goal alignment were a stronger predictor of engagement for mothers with low emotional availability compared to other mothers. Conclusions for Practice Visitor alignment with mothers on goals and responsiveness to reasons for enrolling appear to be effective in promoting engagement. Individualizing services to reflect maternal goals and emotional capacity may be important strategies to address engagement challenges.

Work-Related Stressors Among Maternal, Infant, and Early Childhood Home Visiting (MIECHV) Home Visitors: A Qualitative Study

Abstract

Background The Florida Maternal, Infant, and Early Childhood Home Visiting (MIECHV) program delivers evidence-based home visiting services to over 1400 families each year. Home visitors are integral in providing resources for families to promote healthy pregnancy, child development, family wellness, and self-sufficiency. Due to the nature of this work, home visitors experience work-related pressures and stressors that can impact staff well-being and retention. Objectives The purpose of this study was to understand primary sources of work-related stress experienced by home visitors, subsequent effects on their engagement with program participants, and to learn of coping mechanisms used to manage stress. Methods In 2015, Florida MIECHV program evaluators conducted ten focus groups with 49 home visitors during which they ranked and discussed their top sources of work-related stress. Qualitative analysis was conducted to identify emergent themes in work-related stressors and coping/supports. Results Across all sites, the burden of paperwork and data entry were the highest ranked work-related stressors perceived as interfering with home visitors' engagement with participants. The second-highest ranked stressors included caseload management, followed by a lack of resources for families, and dangerous environments. Home visitors reported gratification in their helping relationships families, and relied on coworkers or supervisors as primary sources of workplace support along with self-care (e.g. mini-vacations, recreation, and counseling). Conclusions for practice Florida MIECHV home visitors across all ten focus groups shared similar work-related stressors that they felt diminished engagement with program participants and could impact participant and staff retention. In response, Florida MIECHV increased resources to support home visitor compensation and reduce caseloads, and obtained a competitive award from HRSA to implement a mindfulness-based stress reduction training statewide.

Correction to: What’s Happening During Home Visits? Exploring the Relationship of Home Visiting Content and Dosage to Parenting Outcomes

The article "What's Happening During Home Visits? Exploring the Relationship of Home Visiting Content and Dosage to Parenting Outcomes", written by Peggy Nygren, Beth Green, Katie Winters and Anna Rockhill, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 13 June 2018 without open access.

Randomized Controlled Trial of Doula-Home-Visiting Services: Impact on Maternal and Infant Health

Abstract

Introduction Although home-visiting programs typically engage families during pregnancy, few studies have examined maternal and child health outcomes during the antenatal and newborn period and fewer have demonstrated intervention impacts. Illinois has developed an innovative model in which programs utilizing evidence-based home-visiting models incorporate community doulas who focus on childbirth education, breastfeeding, pregnancy health, and newborn care. This randomized controlled trial (RCT) examines the impact of doula-home-visiting on birth outcomes, postpartum maternal and infant health, and newborn care practices. Methods 312 young (M = 18.4 years), pregnant women across four communities were randomly assigned to receive doula-home-visiting services or case management. Women were African American (45%), Latina (38%), white (8%), and multiracial/other (9%). They were interviewed during pregnancy and at 3-weeks and 3-months postpartum. Results Intervention-group mothers were more likely to attend childbirth-preparation classes (50 vs. 10%, OR = 9.82, p < .01), but there were no differences on Caesarean delivery, birthweight, prematurity, or postpartum depression. Intervention-group mothers were less likely to use epidural/pain medication during labor (72 vs. 83%; OR = 0.49, p < .01) and more likely to initiate breastfeeding (81 vs. 74%; OR = 1.72, p < .05), although the breastfeeding impact was not sustained over time. Intervention-group mothers were more likely to put infants on their backs to sleep (70 vs. 61%; OR = 1.64, p < .05) and utilize car-seats at three weeks (97 vs. 93%; OR = 3.16, p < .05). Conclusions for practices The doula-home-visiting intervention was associated with positive infant-care behaviors. Since few evidence-based home-visiting programs have shown health impacts in the postpartum months after birth, incorporating doula services may confer additional health benefits to families.

Correction to: Mother and Home Visitor Emotional Well-Being and Alignment on Goals for Home Visiting as Factors for Program Engagement

The article "Mother and Home Visitor Emotional Well-Being and Alignment on Goals for Home Visiting as Factors for Program Engagement", written by L. Burrell, S. Crowne, K. Ojo, R. Snead, K. O'Neill, F. Cluxton‑Keller and A. Duggan, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access.

Correction to: Getting to the Warm Hand-Off: A Study of Home Visitor Referral Activities

The article "Getting to the Warm Hand-Off: A Study of Home Visitor Referral Activities", written by Jessica Goldberg, Jessica Greenstone Winestone, Rebecca Fauth, Melissa Colón and Maria Verónica Mingo, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 02 June 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 17 July 2018 to © The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (https://ift.tt/1iwynXF), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Correction to: Randomized Controlled Trial of Doula-Home-Visiting Services: Impact on Maternal and Infant Health

The article "Randomized Controlled Trial of Doula-Home-Visiting Services: Impact on Maternal and Infant Health", written by Sydney L. Hans, Renee C. Edwards and Yudong Zhang, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 18 July 2018 to © The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Correction to: The Efficacy of Using Peer Mentors to Improve Maternal and Infant Health Outcomes in Hispanic Families: Findings from a Randomized Clinical Trial

The article "The Efficacy of Using Peer Mentors to Improve Maternal and Infant Health Outcomes in Hispanic Families: Findings from a Randomized Clinical Trial", written by Melanie Lutenbacher, Tonya Elkins, Mary S. Dietrich and Anais Riggs, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 31 May 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 16 July 2018 to © The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Introduction to the Special Issue on Taking Home Visiting to Scale: Findings from the Maternal, Infant, and Early Childhood Home Visiting Program State-Led Evaluations

Abstract

The Maternal, Infant and Early Childhood Home Visiting (MIECHV) Program is a two-generation approach to supporting healthy families through home visits during pregnancy and early childhood. All states and territories receiving MIECHV funding are encouraged to evaluate their programs. This special issue highlights evaluations from 11 awardees—Arkansas, Florida, Illinois, Iowa, Maryland, Massachusetts, Michigan, New Jersey, Oregon, Pennsylvania, and Tennessee. With the wide expansion of home visiting since the onset of MIECHV, the state-led evaluations contribute to the understanding of replication and scale-up of evidence-based home visiting.

Correction to: Introduction to the Special Issue on Taking Home Visiting to Scale: Findings from the Maternal, Infant, and Early Childhood Home Visiting Program State-Led Evaluations

The article "Introduction to the Special Issue on Taking Home Visiting to Scale: Findings from the Maternal, Infant, and Early Childhood Home Visiting Program State-Led Evaluations", written by Nicole Denmark, Kyle Peplinski, Mariel Sparr, Judy Labiner-Wolfe, Susan Zaid, Pooja Gupta and Kassie Mae Miller, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 19 June 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 18 July 2018 to © The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Schmerzhafte Lymphadenopathie nach Insektenstich – ein Fallbericht

Zusammenfassung

Tularämie ist eine bakterielle Zoonose, die meist durch Zecken- und Insektenstiche oder durch Kontakt mit dem Fleisch infizierter Tiere übertragen wird. Wir berichten über einen 36-jährigen Patienten, der nach einem Insektenstich am Abdomen Fieber, Schüttelfrost, Kopfschmerzen und eine einseitige, schmerzhafte, inguinale Lymphadenopathie mit rötlich-livider Verfärbung der umgebenden Haut entwickelte. Die Diagnose einer ulzeroglandulären Tularämie wurde mittels Polymerasekettenreaktion (PCR) und Serologie gestellt. Es wurde eine 21-tägige Therapie mit Doxycyclin durchgeführt, die zur Abheilung führte.

Nerve Injury After Surgical Excision of Mandibular Third Molars Under Local Anesthesia: An Audit

Abstract

Background

Injury of the inferior alveolar nerve (IAN) sustained during surgical removal of an impacted lower third molar may cause paresthesia of the lower lip, chin, lower gingivae and anterior teeth. Lingual nerve (LN) injuries may result in ipsilateral paresthesia of the anterior two thirds of the tongue, mucosa of floor of mouth and lingual gingivae. A close anatomic relationship between the roots of the third molar and mandibular canal places the IAN at risk of damage.

Purpose

The primary aim of this retrospective audit was to ascertain the incidence of IAN and LN damage after mandibular third molar surgery in National Dental Centre Singapore. A secondary aim was to identify the contributory factors for the risk of IAN and LN nerve injury on the basis of the data collected.

Methods

This retrospective audit included 1276 mandibular third molar surgical removals performed in the local anesthesia operating theatre (LAOT) at the National Dental Centre Singapore (NDCS) from April to December 2013. Data included patient details, clinical characteristics, and 1 week postoperative presence/absence of sensory alteration as reported by the patient.

Results

Summary of results- Out of 1276 third molar sites audited, 8 (0.62%) sites had altered sensation of the IAN and 1 (0.078%) had altered sensation of the LN at 1 week postoperative review.

Conclusion

The incidence of IAN injury (0.62%) and lingual Nerve injury (0.08%) after one week from surgery in our audit was low compared to similar studies. This retrospective audit did not show any correlation of nerve injury to age, gender, race, site, angulation of tooth, grade of operator, removal of bone or tooth division. There was no single radiological sign associated with paresthesia, although the most common radiological signs were interruption of the canal line and darkening of the roots.

Influence of fiber connectivity in simulations of cardiac biomechanics

Abstract

Purpose

Personalized computational simulations of the heart could open up new improved approaches to diagnosis and surgery assistance systems. While it is fully recognized that myocardial fiber orientation is central for the construction of realistic computational models of cardiac electromechanics, the role of its overall architecture and connectivity remains unclear. Morphological studies show that the distribution of cardiac muscular fibers at the basal ring connects epicardium and endocardium. However, computational models simplify their distribution and disregard the basal loop. This work explores the influence in computational simulations of fiber distribution at different short-axis cuts.

Methods

We have used a highly parallelized computational solver to test different fiber models of ventricular muscular connectivity. We have considered two rule-based mathematical models and an own-designed method preserving basal connectivity as observed in experimental data. Simulated cardiac functional scores (rotation, torsion and longitudinal shortening) were compared to experimental healthy ranges using generalized models (rotation) and Mahalanobis distances (shortening, torsion).

Results

The probability of rotation was significantly lower for ruled-based models [95% CI (0.13, 0.20)] in comparison with experimental data [95% CI (0.23, 0.31)]. The Mahalanobis distance for experimental data was in the edge of the region enclosing 99% of the healthy population.

Conclusions

Cardiac electromechanical simulations of the heart with fibers extracted from experimental data produce functional scores closer to healthy ranges than rule-based models disregarding architecture connectivity.

Progranulin overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway contributes to the resistance of dermal fibroblasts to the anti-fibrotic effect of tumor necrosis factor-α in localized scleroderma

Dermal fibroblasts derived from patients with systemic sclerosis (SSc) overproduce progranulin (PGRN), an endogenous antagonist of tumor necrosis factor (TNF) receptors, due to the deficiency of transcription factor Fli1. Fli1 expression is also decreased in dermal fibroblasts derived from patients with localized scleroderma (LSc).

Research Techniques Made Simple: CAR T Cell Therapy

Chimeric antigen receptor (CAR) and chimeric autoantibody receptor T cell therapy hold great promise in the treatment of cancer and autoimmune disease, respectively. This powerful technique involves genetically engineering T lymphocytes to enable selective destruction of disease-causing cells. In the current approach, a patient's T cells are genetically engineered to express an antigen-specific antibody fragment fused to activating cytoplasmic T cell signaling domains. Following ex vivo activation and genetic modification of a patient's own T cells, the individually-tailored CAR T cells are then infused into the patient for the selective destruction of cells bearing the targeted antigen.

Advances in Cutaneous Lupus Erythematosus and Dermatomyositis: A report from the 4th International Conference on Cutaneous Lupus Erythematosus An ongoing need for international consensus and collaborations

LB1537 Matrix metalloproteinase 1 deficiency in epidermal keratinocytes makes them susceptible to IFN-γ and impairs their migration

The hyperproliferative human epidermal keratinocytes HaCaT are often used in experimental studies of psoriasis. Recently, we reported that Th1 cytokines TNF, IFN-γ and IL17 exhibited an antiproliferative effect on HaCaT cells. The aim of this paper was to explore how knocking matrix metalloproteinase 1 (MMP1) down in epidermal keratinocytes affected their proliferation, migration and differentiation and be beneficial for psoriasis. MMP1-deficient and control cells were generated by lentiviral transduction.

Platelet rich plasma as an adjunctive treatment in Lichen Plano pilaris

A Provider Global Assessment Quality Measure for Clinical Practice for Inflammatory Skin Disorders

Current quality measures in dermatology have limited feasibility and validity for demonstrating value of care provided. Expert consensus was reached on a global severity metric for incorporation into a quality measure for inflammatory dermatoses. This effort will facilitate standardized data collection and may better demonstrate quality of care in dermatology.

Clinical and dermoscopic features of cutaneous BAP1 inactivated melanocytic tumors: results of a multicenter case-control study by the International Dermoscopy Society (IDS)

Multiple BAP-1 inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer-syndrome involving germline mutations in BAP1. We have identified 5 dermoscopic patterns present in BIMT. Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise suspicion for BIMT associated with BAP1 germline mutations.

Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone

Various factors are linked to poor outcomes in squamous cell carcinoma, but poor differentiation and invasion beyond subcutaneous fat may greater predict risk of locoregional disease and disease-specific death., Mohs surgery alone provides excellent marginal control of high-risk squamous cell carcinoma and may lower rates of measured poor outcomes.

Comment on Okhovat et al “The first 30 years of the American Academy of Dermatology skin cancer screening program: 1985-2014”

Lack of an FDA indication should not limit access to appropriate treatment

Dermoscopy of Pityrosporum Folliculitis

Reflectance confocal microscopy as novel tool for pre-surgical identification of basal cell carcinoma biopsy site

Rethinking the classification of alopecia areata

A population-based registry study on relative survival from melanoma in Germany stratified by tumor thickness for each histological subtype

Melanoma relative survival varies by histology. However, differences were strongly alleviated after adjustment for tumor thickness. Increased 5-year relative survival between the periods 2002-2005 and 2010-2013 is explained by a decrease in tumor thickness. Prevention and awareness should be encouraged as prognosis of thick melanoma is still poor.

Validated Patient-Reported Outcome Measurements for Psoriasis may not Reflect Patients’ Current Preferences

Influence of sex on biomarkers of oxidative stress in the kidney, lungs, and liver of rabbits after exposure to diazinon

Abstract

The present study evaluated the effect of two oral doses of the pesticide diazinon (25 and 125 mg/kg bw) on four biochemical parameters (malondialdehyde and glutathione levels, and catalase and glutathione S-transferase enzymatic activities) in the kidney, lungs, and liver of rabbit after 10 days of exposure. Malondialdehyde levels were significantly greater in exposed animals compared to controls, especially in the animals exposed to the higher dose of the pesticide. This result was reflected in the glutathione levels, which were significantly lower at that same higher dose. Catalase activity was also inhibited by the higher dose of the pesticide in all three organs analysed, whereas inhibition of glutathione S-transferase activity was only significant for the kidney and lungs. There were some slight differences between the sexes: taking the results for all three organs, the higher dose of diazinon resulted in a clearly significant inhibitory effect on the catalase activity and glutathione levels in males, and a significant enhancing effect on the malondialdehyde levels in females. These results help to confirm the interest of considering such endogenous factors in future ecotoxicological studies, and that the four biomarkers considered are suitable for reflecting the toxic effects of diazinon on rabbits, especially the effects related to oxidative stress.

Graphical abstract

Rosacea: 5 Things to Know

These five things include some lesser known, but critically important, facts about rosacea and its management.
Medscape Dermatology

“The Same Thing That Makes You Live Can Kill You in the End”: Exploring the Effects of Growth Rates and Longevity on Cellular Metabolic Rates and Oxidative Stress in Mammals and Birds

Abstract

All aerobic organisms are subjected to metabolic by-products known as reactive species (RS). RS can wreak havoc on macromolecules by structurally altering proteins and inducing mutations in DNA, among other deleterious effects. To combat accumulating damage, organisms have an antioxidant system to sequester RS before they cause cellular damage. The balance between RS production, antioxidant defences, and accumulated cellular damage is termed oxidative stress. Physiological ecologists, gerontologists, and metabolic biochemists have turned their attention to whether oxidative stress is the principal, generalized mechanism that mediates and limits longevity, growth rates, and other life-history trade-offs in animals, as may be the case in mammals and birds. At the crux of this theory lies the regulation and activities of the mitochondria with respect to the organism and its metabolic rate. At the whole-animal level, evolutionary theory suggests that developmental trajectories and growth rates can shape the onset and rate of aging. Mitochondrial function is important for aging since it is the main source of energy in cells, and the main source of RS. Altering oxidative stress levels, either increase in oxidative damage or reduction in antioxidants, has proven to also decrease growth rates, which implies that oxidative stress is a cost of, as well as a constraint on, growth. Yet, in nature, many animals exhibit fast growth rates that lead to higher loads of oxidative stress, which are often linked to shorter lifespans. In this article, I summarize the latest findings on whole-animal life history trade-offs, such as growth rates and longevity, and how these can be affected by mitochondrial cellular metabolism, and oxidative stress.

The subventricular zone concept: ready for therapeutic implications?

For more than 10 years, with reaffirmation of the key role of radiation therapy (RT) in the postoperative management of most gliomas,¹ it has been a frustrating fact that no significant progress can be claimed in our specialty. Neither the "dose-escalation" nor the "dose-painting" concept, even when guided by "high-tech" imaging, permits significantly better local control that translates into longer survival. What we define as the CTV (clinical target volume), which should reflect the microscopic extension of glioma cells, is still a rather rough isotropic expansion of the GTV (gross tumor volume), usually 1.5–2 cm beyond.² Exploring new areas of potential progress in RT, several publications focused on glioblastoma (GBM) suggested that the subventricular zone (SVZ) could be the "niche" of glioma stem cells, which explains at least in part the inevitable recurrence of most gliomas: We would regularly miss the target, ignoring this key zone where the more radioresistant cells would hide.^3,4

Production of gasoline range hydrocarbons from catalytic cracking of linoleic acid over various acidic zeolite catalysts

Abstract

Employment of edible oils as alternative green fuel for vehicles had raised debates on the sustainability of food supply especially in the third-world countries. The non-edible oil obtained from the abundantly available rubber seeds could mitigate this issue and at the same time reduce the environmental impact. Therefore, this paper investigates the catalytic cracking reaction of a model compound named linoleic acid that is enormously present in the rubber seed oil. Batch-scale experiments were conducted using 8.8 mL Inconel batch reactor having a cyclic horizontal swing span of 2 cm with a frequency of 60 cycles per minute at 450 °C under atmospheric condition for 90 min. The performance of HZSM-5, HBeta, HFerrierite, HMordenite and HY catalysts was tested for their efficiency in favouring gasoline range hydrocarbons. The compounds present in the organic liquid product were then analysed using GC-MS and classified based on PIONA which stands for paraffin, isoparaffin, olefin, naphthenes and aromatics respectively. The results obtained show that HZSM-5 catalyst favoured gasoline range hydrocarbons that were rich in aromatics compounds and promoted the production of desired isoparaffin. It also gave a higher cracking activity; however, large gaseous as by-products were produced at the same time.

Remediation of TCE-contaminated groundwater using KMnO 4 oxidation: laboratory and field-scale studies

Abstract

The objectives of this study were to (1) conduct laboratory bench and column experiments to determine the oxidation kinetics and optimal operational parameters for trichloroethene (TCE)-contaminated groundwater remediation using potassium permanganate (KMnO₄) as oxidant and (2) to conduct a pilot-scale study to assess the efficiency of TCE remediation by KMnO₄ oxidation. The controlling factors in laboratory studies included soil oxidant demand (SOD), molar ratios of KMnO₄ to TCE, KMnO₄ decay rate, and molar ratios of Na₂HPO₄ to KMnO₄ for manganese dioxide (MnO₂) production control. Results show that a significant amount of KMnO₄ was depleted when it was added in a soil/water system due to the existence of natural soil organic matters. The presence of natural organic material in soils can exert a significant oxidant demand thereby reducing the amount of KMnO₄ available for the destruction of TCE as well as the overall oxidation rate of TCE. Supplement of higher concentrations of KMnO₄ is required in the soil systems with high SOD values. Higher KMnO₄ application resulted in more significant H⁺ and subsequent pH drop. The addition of Na₂HPO₄ could minimize the amount of produced MnO₂ particles and prevent the clogging of soil pores, and TCE oxidation efficiency would not be affected by Na₂HPO₄. To obtain a complete TCE removal, the amount of KMnO₄ used to oxidize TCE needs to be higher than the theoretical molar ratio of KMnO₄ to TCE based on the stoichiometry equation. Relatively lower oxidation rates are obtained with lower initial TCE concentrations. The half-life of TCE decreased with increased KMnO₄ concentrations. Results from the pilot-scale study indicate that a significant KMnO₄ decay occurs after the injection due to the reaction of KMnO₄ with soil organic matters, and thus, the amount of KMnO₄, which could be transported from the injection point to the downgradient area, would be low. The effective influence zone of the KMnO₄ oxidation was limited to the KMnO₄ injection area (within a 3-m radius zone). Migration of KMnO₄ to farther downgradient area was limited due to the reaction of KMnO₄ to natural organic matters. To retain a higher TCE removal efficiency, continuous supplement of high concentrations of KMnO₄ is required. The findings would be useful in designing an in situ field-scale ISCO system for TCE-contaminated groundwater remediation using KMnO₄ as the oxidant.

Speciation and uptake of antimony and arsenic by two populations of Pteris vittata L. and Holcus lanatus L. from co-contaminated soil

Abstract

This study aimed to investigate the Sb and As co-accumulating processes of Pteris vittata under soil culture condition, including the transformation of Sb and As, and the difference in co-accumulating ability among different plant species/populations. Two populations of P. vittata and one population of As-tolerant species Holcus lanatus L. were grown on soil co-contaminated by Sb and As. Sb and As speciation in plants was assessed by X-ray absorption near-edge structure (XANES) spectroscopy. P. vittata displayed strong As- but limited Sb-accumulating ability, with the highest shoot concentrations of As and Sb reaching 455 and 26 mg kg⁻¹, respectively. After 28 days culture, the concentrations of Sb and As in the soil solution were reduced by up to 22% and 36% in the P. vittata treatments, respectively. Holcus lanatus showed limited uptake for both metalloids. In P. vittata, the reduction of arsenate to arsenite occurred (with As in shoots all existing as arsenite), but limited reduction of antimonate to antimonite (with more than 90% of Sb in shoots existing as antimonate) was observed. In terms of the differences in metalloid uptake between the two P. vittata populations, the population from the habitat with higher soil As concentration showed 35% higher As uptake than the population from the habitat with lower As concentration. This populational difference may partly result from varying As transformation efficiencies. However, no significant difference was observed in Sb accumulation between the two populations.

Nasal and Lacrimal Sac Histopathology in Patients With Systemic Sarcoidosis Undergoing External Lacrimal Drainage Surgery

Purpose: To review the histological findings in the lacrimal sac and nasal mucosa from patients with sarcoidosis undergoing external lacrimal drainage surgery. Methods: All patients undergoing external dacryocystorhinostomy at Moorfields Eye Hospital with a known history of sarcoidosis had biopsies taken from the lacrimal sac and/or nasal mucosa during surgery. These patients were identified from databases at Moorfields Eye Hospital and the Institute of Ophthalmology, and their clinical notes were reviewed retrospectively for intraoperative findings with a view to identifying common trends. The histological findings of each biopsy were reviewed and classified as showing granulomas, nongranulomatous inflammation, or nonspecific fibrosis. Results: Forty patients (29 females; 72%) were known to have systemic sarcoidosis prior to surgery, and they underwent 60 external dacryocystorhinostomies. Paired histological samples were available from 49/60 (82%) procedures, nasal biopsies alone in 3 dacryocystorhinostomies (5%), and solely lacrimal sac biopsies in 8 (13%). The main site of systemic sarcoidosis was pulmonary involvement (19 patients; 48%). Recorded operative findings included 9 large lacrimal sac mucoceles (29%), a "thick" (26%) or "inflamed" (9.7%) lacrimal sac mucosa, and "thick" (36%) or "friable" (32%) nasal mucosa. Noncaseating granulomas were identified in 34/57 (60%) sacs, and 45/52 (87%) nasal tissues—this being in 31/49 (63%) of paired tissues. Chronic inflammation, without granulomas, was present in 20/57 (35%) lacrimal sacs but only in 5/52 (9.6%) of nasal biopsies. Conclusions: In patients with sarcoidosis undergoing external dacryocystorhinostomy, the characteristic histological feature—noncaseating granulomas—is present in most patients' lacrimal sac mucosa and in almost all of their nasal mucosae. The lacrimal sac and nasal mucosa often appears abnormal—thickened or friable—during surgery. Accepted for publication July 14, 2018. G.E.R. receives some funding from the Department of Health's National Institute of Health Research Biomedical Research Centre for Ophthalmology at Moor fields Eye Hospital and University College, London Institute of Ophthalmology. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Geoffrey E. Rose, D.Sc., F.R.C.Ophth., Adnexal Service, Moorfields Eye Hospital NHS Foundation Trust, City Road, London EVC1V 2PD, United Kingdom. E-mail: geoff.rose@moorfields.nhs.uk © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Spontaneous Orbital Hemorrhage Related to the Extraocular Muscles

Purpose: The authors present the largest series of patients to date of spontaneous hemorrhage in relation to extraocular muscles (EOMs). Methods: Observational retrospective case series. Institutional review board approval was obtained. Results: Eighteen patients with a mean age of 71 years presented with 20 episodes of spontaneous orbital hemorrhage closely related to an EOM. Most patients woke with unilateral proptosis, pain, and diplopia. Vision was impaired in 25%. Imaging identified a characteristic well-circumscribed hematoma arising within the muscle sheath or intermuscular septum. Three episodes required surgical drainage. All patients had good recovery of vision. Discussion: The authors describe a distinct clinical entity of idiopathic hemorrhages related to EOMs. No patient had an underlying vascular malformation or other lesion. The authors demonstrate that a proportion of these patients have vascular risk factors, namely, hypertension, hyperlipidemia, and antiplatelet use. This study suggests that inferior rectus is the most commonly affected EOM and shows that it is the muscle sheath or intermuscular septum of inferior rectus that is involved, rather than the muscle belly. Most patients can be managed conservatively with good visual outcomes. However, there were 3 exceptional cases that required surgical intervention. Conclusions: The findings that spontaneous orbital hemorrhages related to EOMs have certain predisposing factors, a characteristic radiological appearance, and a typically benign course will be helpful for clinicians in the management of this condition. Accepted for publication July 25, 2018. The authors have no financial or conflicts of interest to disclose. Presented at the World Ophthalmology Congress on 16–19 June 2018 in Barcelona, Spain. Address correspondence and reprint requests to Helen H. Chan, M.B.B.S., Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne 3002, Victoria, Australia. E-mail: Helen.Chan@eyeandear.org.au © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Angular Vein Varix Congestion From Chronic Glasses Wear

This is a case report of a symptomatic varicose angular vein exacerbated by chronic glasses wear. Compressing the vein in a recumbent position led to increased fullness of the medial canthal region and reproduced his symptoms. Obliteration by cauterization of the vein led to resolution of symptoms. Accepted for publication July 17, 2018. Supported by core grant for vision research National Eye Institute P30 EY001792 and unrestricted Research to Prevent Blindness departmental grant. The authors have no conflicts of interest to disclose. Address correspondence and reprint requests to Daniel J. Oh, M.D., Illinois Eye & Ear Infirmary, University of Illinois at Chicago, 1855 West Taylor Street, Chicago, IL 60612. E-mail: jdanieloh@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Idiopathic Acquired Lacrimal Canalicular Obstruction

Purpose: Acquired lacrimal canalicular obstruction has a variety of causes. In a small proportion of patients, no cause can be identified. This article describes a cohort of 27 patients with idiopathic acquired lacrimal canalicular obstruction encountered over a 28-year period. Methods: The diagnostic database of the senior author was analyzed to identify all cases of idiopathic acquired lacrimal canalicular obstruction seen from 1990 to 2017. Demographic, clinical, and treatment details were analyzed. Patients with primary lacrimal punctal stenosis or closure were excluded from the analysis. Results: The authors encountered 27 patients with idiopathic acquired lacrimal canalicular obstruction (17 female, 63%) aged 34 to 91 years (median: 65 years). The level of canalicular obstruction ranged from 1 to 10 mm from the punctum. Canalicular obstruction involved 1 canaliculus in 4 patients, 2 in 14 (ipsilateral in all except one), 3 in 3, and all 4 in 6. One patient who presented with ipsilateral upper and lower canalicular obstructions developed contralateral upper and lower obstructions several years later, and another patient redeveloped obstructions after initial successful surgical repair. In all cases, there were no features on history or examination to suggest a cause for the canalicular obstruction. Follow up ranged from 1 to 260 months (mean: 39 months). Sixteen patients underwent surgical repair, 11 with a dacryocystorhinostomy and placement of a Lester Jones glass bypass tube, 2 had a canaliculo-dacryocystorhinostomy (anastomosis of the canaliculus to the nose), 2 had dacryocystorhinostomy and trephination of the canalicular obstruction with silicone intubation, and 1 had a dacryocystorhinostomy alone to try and improve drainage through a single patent canaliculus. Conclusion: Idiopathic acquired lacrimal canalicular obstruction is uncommon and occurs more frequently in older women. The condition may be slowly progressive and can affect one or more canaliculi at any level. Treatment is the same as for any other cause of acquired lacrimal canalicular obstruction. Accepted for publication July 31, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Alan A. McNab, D.Med.Sc., F.R.A.N.Z.C.O., Suite 216, 100 Victoria Parade, East Melbourne, 3002 Victoria, Australia. E-mail: amcnab@bigpond.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Age-Related Changes in the Clinical Phenotype of Compressive Optic Neuropathy in Thyroid Eye Disease

Purpose: This study compares the age-related clinical features of thyroid eye disease-compressive optic neuropathy (TED-CON) to those with noncompressive disease (TED-NC). Methods: A retrospective case series review of 165 orbits from 121 patients with TED-CON were compared with an age- and gender-matched cohort of 88 orbits from 44 patients with TED-NC with institutional review board approval. Clinical features including exophthalmos, dyschromatopsia, restricted ocular motility, visual acuity, and mean deviation on 24-2 Humphrey Visual Field were compared in 5 age groups. A previously validated formula, the Columbia TED-CON Diagnostic formula, used to mathematically predict the presence or absence of compressive optic neuropathy was applied, and the sensitivity and specificity of the formula was measured in each age group. Results: Exophthalmos, dyschromatopsia, restricted ocular motility, and mean deviation on 24-2 Humphrey Visual Field vary significantly across age groups in patients with TED-CON. Conversely, only visual acuity and dyschromatopsia vary significantly across age groups in patients with TED-NC. There was a significant difference between the TED-CON and the TED-NC groups when comparing the 2 groups by decade. The Columbia TED-CON Diagnostic formula had high sensitivity and specificity (74–90%) in all age groups. Conclusions: This is the first study to date demonstrating the age-related variability of clinical characteristics in a large series of patients with either TED-CON or TED-NC. The clinical phenotype of TED-CON varies significantly by decade when examining exophthalmos, dyschromatopsia, ocular motility restriction, and mean deviation on 24-2 Humphrey Visual Field. These clinical characteristics are also significantly different when compared with a population of patients with TED-NC. Accepted for publication July 9, 2018. The authors have no financial or conflicts of interest to disclose. Presented at American Society of Ophthalmic Plastic and Reconstructive Surgery 48th Annual Fall Scientific Symposium on November 9, 2017 in New Orleans, LA, U.S.A. Address correspondence and reprint requests to Ashley A. Campbell, M.D., Oculoplastic and Reconstructive Surgery, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Maumenee 505, 600 N. Wolfe Street, Baltimore, MD. E-mail: ashley.campbell@jhmi.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

The Role of Inferior Turbinate Fracture in the Management of Congenital Nasolacrimal Duct Obstruction

Purpose: To evaluate the effect of inferior turbinate fracture in the treatment of congenital nasolacrimal obstruction combined with first attempt probing in children younger than 36 months. Methods: This prospective case–control study was conducted on 230 eyes from 176 children aged 12 to 36 months with congenital nasolacrimal duct obstruction. All patients underwent simple probing under general anesthesia. Inferior turbinate fracture was performed in case group combined with first probing. Patients were followed up 1, 3, and 6 months after surgery. Results: Total success rate was 91.2% for patients with turbinate fracture and 86.4% for patients without turbinate fracture. The difference between success rates was not statistically significant (p = 0.269). The authors did not find significant difference between cases and controls in age subgroups. Success rate in combined case and control groups in patients younger than 24 months (success rate: 91.7%) was significantly higher than those older than 24 months (success rate: 71.9%; p = 0.001). In univariate logistic regression analysis, age ≥24 months showed a negative association with the success rate (odds ratio = 0.232; 95% confidence interval: 0.91–0.59; p = 0.002). Other factors like sex, bilaterality of nasolacrimal duct obstruction, method of probing were not significantly associated with response to treatment. Conclusions: Inferior turbinate fracture does not improve the outcomes of simple probing and is not recommended during the first attempt in treatment of congenital nasolacrimal duct obstruction. Late probing (after 24 months of age) may have a higher failure rate, and increased age is the important factor that predicts failure in probing simple congenital nasolacrimal duct obstruction. Accepted for publication July 27, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Raziyeh Mahmoudzadeh, M.D., Farabi Eye Hospital, Ghazvin square, Tehran, Iran. E-mail: razieh.mah@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Light Perception Vision Recovery After Treatment for Calcium Hydroxylapatite Cosmetic Filler–Induced Blindness

A 51-year-old woman presented with no light perception vision of the right eye 12 hours after another provider injected calcium hydroxylapatite into the glabella and dorsum of the nose. Exam and fluorescein angiography demonstrated optic nerve edema and choroidal hypoperfusion consistent with ischemia of the posterior ciliary circulation. The central retinal circulation appeared intact. One thousand two hundred units of retrobulbar hyaluronidase were injected urgently in several boluses. Oral prednisone and aspirin also were administered. Ocular massage was also initiated. One day later, visual acuity improved to light perception that remained stable at 3 months. Retrobulbar hyaluronidase injection, ocular massage, prednisone, and aspirin were correlated to recovery of light perception vision in this case of calcium hydroxylapatite filler embolization to the choroidal circulation. The mechanism for the recovery of some vision and the role of hyaluronidase and other medications remain uncertain. Further research in treatments for ophthalmic complications of facial fillers is warranted. Accepted for publication August 14, 2018. The authors acknowledge support in part by Research to Prevent Blindness grant to UCI. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Priscilla Q. Vu, M.D., M.S., Gavin Herbert Eye Institute, University of California Irvine, 850 Health Sciences Road, Irvine, CA 92697. E-mail priscilv@uci.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Morphological and Biophysical Determinants of the Intracellular and Extracellular Waveforms in Nigral Dopaminergic Neurons: A Computational Study

Action potentials (APs) in nigral dopaminergic neurons often exhibit two separate components: the first reflecting spike initiation in the dendritically located axon initial segment (AIS) and the second the subsequent dendro-somatic spike. These components are separated by a notch in the ascending phase of the somatic extracellular waveform and in the temporal derivative of the somatic intracellular waveform. Still, considerable variability exists in the presence and magnitude of the notch across neurons. To systematically address the contribution of AIS, dendritic and somatic compartments to shaping the two-component APs, we modeled APs of previously in vivo electrophysiologically characterized and 3D-reconstructed male mouse and rat dopaminergic neurons. A parsimonious two-domain model, with high (AIS) and lower (dendro-somatic) Na⁺ conductance, reproduced the notch in the temporal derivatives, but not in the extracellular APs, regardless of morphology. The notch was only revealed when somatic active currents were reduced, constraining the model to three domains. Thus, an initial AIS spike is followed by an actively generated spike by the axon-bearing dendrite (ABD), in turn followed mostly passively by the soma. The transition from being a source compartment for the AIS spike to a source compartment for the ABD spike satisfactorily explains the extracellular somatic notch. Larger AISs and thinner ABD (but not soma-to-AIS distance) accentuate the AIS component. We conclude that variability in AIS size and ABD caliber explains variability in AP extracellular waveform and separation of AIS and dendro-somatic components, given the presence of at least three functional domains with distinct excitability characteristics.

SIGNIFICANCE STATEMENT Midbrain dopamine neurons make an important contribution to circuits mediating motivation and movement. Understanding the basic rules that govern the electrical activity of single dopaminergic neurons is therefore essential to reveal how they ultimately contribute to movement and motivation as well as what goes wrong in associated disorders. Our computational study focuses on the generation and propagation of action potentials and shows that different morphologies and excitability characteristics of the cell body, dendrites and proximal axon can explain the diversity of action potentials shapes in this population. These compartments likely make differential contributions both to normal dopaminergic signaling and could potentially underlie pathological dopaminergic signaling implicated in addiction, schizophrenia, Parkinson's disease, and other disorders.

The Widespread Network Effects of Focal Epilepsy

Motion Extrapolation for Eye Movements Predicts Perceived Motion-Induced Position Shifts

Transmission delays in the nervous system pose challenges for the accurate localization of moving objects as the brain must rely on outdated information to determine their position in space. Acting effectively in the present requires that the brain compensates not only for the time lost in the transmission and processing of sensory information, but also for the expected time that will be spent preparing and executing motor programs. Failure to account for these delays will result in the mislocalization and mistargeting of moving objects. In the visuomotor system, where sensory and motor processes are tightly coupled, this predicts that the perceived position of an object should be related to the latency of saccadic eye movements aimed at it. Here we use the flash-grab effect, a mislocalization of briefly flashed stimuli in the direction of a reversing moving background, to induce shifts of perceived visual position in human observers (male and female). We find a linear relationship between saccade latency and perceived position shift, challenging the classic dissociation between "vision for action" and "vision for perception" for tasks of this kind and showing that oculomotor position representations are either shared with or tightly coupled to perceptual position representations. Altogether, we show that the visual system uses both the spatial and temporal characteristics of an upcoming saccade to localize visual objects for both action and perception.

SIGNIFICANCE STATEMENT Accurately localizing moving objects is a computational challenge for the brain due to the inevitable delays that result from neural transmission. To solve this, the brain might implement motion extrapolation, predicting where an object ought to be at the present moment. Here, we use the flash-grab effect to induce perceptual position shifts and show that the latency of imminent saccades predicts the perceived position of the objects they target. This counterintuitive finding is important because it not only shows that motion extrapolation mechanisms indeed work to reduce the behavioral impact of neural transmission delays in the human brain, but also that these mechanisms are closely matched in the perceptual and oculomotor systems.

Intrinsic Mechanisms of Frequency Selectivity in the Proximal Dendrites of CA1 Pyramidal Neurons

Gamma oscillations are thought to play a role in learning and memory. Two distinct bands, slow (25–50 Hz) and fast (65–100 Hz) gamma, have been identified in area CA1 of the rodent hippocampus. Slow gamma is phase locked to activity in area CA3 and presumably driven by the Schaffer collaterals (SCs). We used a combination of computational modeling and in vitro electrophysiology in hippocampal slices of male rats to test whether CA1 neurons responded to SC stimulation selectively at slow gamma frequencies and to identify the mechanisms involved. Both approaches demonstrated that, in response to temporally precise input at SCs, CA1 pyramidal neurons fire preferentially in the slow gamma range regardless of whether the input is at fast or slow gamma frequencies, suggesting frequency selectivity in CA1 output with respect to CA3 input. In addition, phase locking, assessed by the vector strength, was more precise for slow gamma than fast gamma input. This frequency selectivity was greatly attenuated when the slow Ca²⁺-dependent K⁺ (SK) current was removed from the model or blocked in vitro with apamin. Perfusion of slices with BaCl₂ to block A-type K⁺ channels tightened this frequency selectivity. Both the broad-spectrum cholinergic agonist carbachol and the muscarinic agonist oxotremorine-M greatly attenuated the selectivity. The more precise firing at slower frequencies persisted throughout all of the pharmacological manipulations conducted. We propose that these intrinsic mechanisms provide a means by which CA1 phase locks to CA3 at different gamma frequencies preferentially in vivo as physiological conditions change with behavioral demands.

SIGNIFICANCE STATEMENT Gamma frequency activity, one of multiple bands of synchronous activity, has been suggested to underlie various aspects of hippocampal function. Multisite recordings within the rat hippocampal formation indicate that different behavioral tasks are associated with synchronized activity between areas CA3 and CA1 at two different gamma bands: slow and fast gamma. In this study, we examine the intrinsic mechanisms that may allow CA1 to selectively "listen" to CA3 at slow compared with fast gamma and suggest mechanisms that gate this selectivity. Identifying the intrinsic mechanisms underlying differential gamma preference may help to explain the distinct types of CA3–CA1 synchronization observed in vivo under different behavioral conditions.

14-3-3 Proteins Reduce Cell-to-Cell Transfer and Propagation of Pathogenic {alpha}-Synuclein

α-Synuclein (αsyn) is the key protein that forms neuronal aggregates in the neurodegenerative disorders Parkinson's disease (PD) and dementia with Lewy bodies. Recent evidence points to the prion-like spread of αsyn from one brain region to another. Propagation of αsyn is likely dependent on release, uptake, and misfolding. Under normal circumstances, this highly expressed brain protein functions normally without promoting pathology, yet the underlying endogenous mechanisms that prevent αsyn spread are not understood. 14-3-3 proteins are highly expressed brain proteins that have chaperone function and regulate protein trafficking. In this study, we investigated the potential role of the 14-3-3 proteins in the regulation of αsyn spread using two models of αsyn spread. In a paracrine αsyn model, 14-3-3 promoted release of αsyn complexed with 14-3-3. Despite higher amounts of released αsyn, extracellular αsyn showed reduced oligomerization and seeding capability, reduced internalization, and reduced toxicity in primary mixed-gender mouse neurons. 14-3-3 inhibition reduced the amount of αsyn released, yet released αsyn was more toxic and demonstrated increased oligomerization, seeding capability, and internalization. In the preformed fibril model, 14-3-3 reduced αsyn aggregation and neuronal death, whereas 14-3-3 inhibition enhanced αsyn aggregation and neuronal death in primary mouse neurons. 14-3-3s blocked αsyn spread to distal chamber neurons not exposed directly to fibrils in multichamber, microfluidic devices. These findings point to 14-3-3s as a direct regulator of αsyn propagation, and suggest that dysfunction of 14-3-3 function may promote αsyn pathology in PD and related synucleinopathies.

SIGNIFICANCE STATEMENT Transfer of misfolded aggregates of α-synuclein from one brain region to another is implicated in the pathogenesis of Parkinson's disease and other synucleinopathies. This process is dependent on active release, internalization, and misfolding of α-synuclein. 14-3-3 proteins are highly expressed chaperone proteins that interact with α-synuclein and regulate protein trafficking. We used two different models in which toxicity is associated with cell-to-cell transfer of α-synuclein to test whether 14-3-3s impact α-synuclein toxicity. We demonstrate that 14-3-3 reduces α-synuclein transfer and toxicity by inhibiting oligomerization, seeding capability, and internalization of α-synuclein, whereas 14-3-3 inhibition accelerates the transfer and toxicity of α-synuclein in these models. Dysfunction of 14-3-3 function may be a critical mechanism by which α-synuclein propagation occurs in disease.

Chemogenetic Isolation Reveals Synaptic Contribution of {delta} GABAA Receptors in Mouse Dentate Granule Neurons

Two major GABA_A receptor classes mediate ionotropic GABA signaling, those containing a subunit and those with a 2 subunit. The classical viewpoint equates 2-containing receptors with IPSCs and -containing receptors with tonic inhibition because of differences in receptor localization, but significant questions remain because the populations cannot be pharmacologically separated. We removed this barrier using gene editing to confer a point mutation on the subunit in mice, rendering receptors containing the subunit picrotoxin resistant. By pharmacologically isolating -containing receptors, our results demonstrate their contribution to IPSCs in dentate granule neurons and weaker contributions to thalamocortical IPSCs. Despite documented extrasynaptic localization, we found that receptor localization does not preclude participation in isolated IPSCs, including mIPSCs. Further, phasic inhibition from subunit-containing receptors strongly inhibited summation of EPSPs, whereas tonic activity had little impact. In addition to any role that -containing receptors may play in canonical tonic inhibition, our results highlight a previously underestimated contribution of -containing receptors to phasic inhibition.

SIGNIFICANCE STATEMENT GABA_A receptors play key roles in transient and tonic inhibition. The prevailing view suggests that synaptic 2-containing GABA_A receptors drive phasic inhibition, whereas extrasynaptic -containing receptors mediate tonic inhibition. To re-evaluate the impact of receptors, we took a chemogenetic approach that offers a sensitive method to probe the synaptic contribution of -containing receptors. Our results reveal that localization does not strongly limit the contribution of receptors to IPSCs and that receptors make an unanticipated robust contribution to phasic inhibition.

Ultrafast Cortical Gain Adaptation in the Human Brain by Trial-To-Trial Changes of Associative Strength in Fear Learning

In fear conditioning, more efficient sensory processing of a stimulus (the conditioned stimulus, CS) that has acquired motivational relevance by being paired with an aversive event (the unconditioned stimulus, US) has been associated with increased cortical gain in early sensory brain areas (Miskovic and Keil, 2012). Further, this sensory gain modulation related to short-term plasticity changes occurs independently of aware cognitive anticipation of the aversive US, pointing toward implicit learning mechanisms (Moratti and Keil, 2009). However, it is unknown how quickly the implicit learning of CS–US associations results in the adaptation of cortical gain. Here, using steady-state visually evoked fields derived from human Magnetoencephalography (MEG) recordings in two experiments (N = 33, 17 females and 16 males), we show that stimulus-driven neuromagnetic oscillatory activity increases and decreases quickly as a function of associative strength within three or four trials, as predicted by a computationally implemented Rescorla–Wagner model with the highest learning rate. These ultrafast cortical gain adaptations are restricted to early visual cortex using a delay fear conditioning procedure. Short interval (500 ms) trace conditioning resulted in the same ultrafast activity modulations by associative strength, but in a complex occipito-parieto-temporo-frontal network. Granger causal analysis revealed that reverberating top-down and bottom-up influences between anterior and posterior brain regions during trace conditioning characterized this network. Critically, in both delay and trace conditioning, ultrafast cortical gain modulations as a function of associative strength occurred independently of conscious US anticipation.

SIGNIFICANCE STATEMENT In ever-changing environments, learned associations between a cue and an aversive consequence must change under new stimulus–consequence contingencies to be adaptive. What predicts potential dangers now might be meaningless in the next situation. Predictive cues are prioritized, as reflected by increased sensory cortex activity for these cues. However, this modulation also must adapt to altered stimulus–consequence contingencies. Here, we show that human visual cortex activity can be modulated quickly according to ultrafast contingency changes within a few learning trials. This finding extends to frontal brain regions when the cue and the aversive event are separated in time. Critically, this ultrafast updating process occurs orthogonally to aware aversive outcome anticipation and therefore relies on unconscious implicit learning mechanisms.

Differentiable Processing of Objects, Associations, and Scenes within the Hippocampus

The hippocampus is known to be important for a range of cognitive functions, including episodic memory, spatial navigation, and thinking about the future. However, researchers have found it difficult to agree on the exact nature of this brain structure's contribution to cognition. Some theories emphasize the role of the hippocampus in associative processes. Another theory proposes that scene construction is its primary role. To directly compare these accounts of hippocampal function in human males and females, we devised a novel mental imagery paradigm where different tasks were closely matched for associative processing and mental construction, but either did or did not evoke scene representations, and we combined this with high-resolution functional MRI. The results were striking in showing that different parts of the hippocampus, along with distinct cortical regions, were recruited for scene construction or nonscene-evoking associative processing. The contrasting patterns of neural engagement could not be accounted for by differences in eye movements, mnemonic processing, or the phenomenology of mental imagery. These results inform conceptual debates in the field by showing that the hippocampus does not seem to favor one type of process over another; it is not a story of exclusivity. Rather, there may be different circuits within the hippocampus, each associated with different cortical inputs, which become engaged depending on the nature of the stimuli and the task at hand. Overall, our findings emphasize the importance of considering the hippocampus as a heterogeneous structure, and that a focus on characterizing how specific portions of the hippocampus interact with other brain regions may promote a better understanding of its role in cognition.

SIGNIFICANCE STATEMENT The hippocampus is known to be important for a range of cognitive functions, including episodic memory, spatial navigation, and thinking about the future. However, researchers have found it difficult to agree on the exact nature of this brain structure's contribution to cognition. Here we used a novel mental imagery paradigm and high-resolution functional MRI to compare accounts of hippocampal function that emphasize associative processes with a theory that proposes scene construction as a primary role. The results were striking in showing that different parts of the hippocampus, along with distinct cortical regions, were recruited for scene construction or nonscene-evoking associative processing. We conclude that a greater emphasis on characterizing how specific portions of the hippocampus interact with other brain regions may promote a better understanding of its role in cognition.

This Week in The Journal

Sphingosine Kinase Regulates Neuropeptide Secretion During the Oxidative Stress-Response Through Intertissue Signaling

The Nrf2 antioxidant transcription factor promotes redox homeostasis in part through reciprocal signaling between neurons and neighboring cells, but the signals involved in intertissue signaling in response to Nrf2 activation are not well defined. In Caenorhabditis elegans, activation of SKN-1/Nrf2 in the intestine negatively regulates neuropeptide secretion from motor neurons. Here, we show that sphingosine kinase (SPHK-1) functions downstream of SKN-1/Nrf2 in the intestine to regulate neuropeptide secretion from motor neurons during the oxidative stress response in C. elegans hermaphrodites. SPHK-1 localizes to mitochondria in the intestine and SPHK-1 mitochondrial localization and kinase activity are essential for its function in regulating motor neuron function. SPHK-1 is recruited to mitochondria from cytosolic pools and its mitochondrial abundance is negatively regulated by acute or chronic SKN-1 activation. Finally, the regulation of motor function by SKN-1 requires the activation of the p38 MAPK cascade in the intestine and occurs through controlling the biogenesis or maturation of dense core vesicles in motor neurons. These findings show that the inhibition of SPHK-1 in the intestine by SKN-1 negatively regulates neuropeptide secretion from motor neurons, revealing a new mechanism by which SPHK-1 signaling mediates its effects on neuronal function in response to oxidative stress.

SIGNIFICANCE STATEMENT Neurons are highly susceptible to damage by oxidative stress, yet have limited capacity to activate the SKN-1/Nrf2 oxidative stress response, relying instead on astrocytes to provide redox homeostasis. In Caenorhabditis elegans, intertissue signaling from the intestine plays a key role in regulating neuronal function during the oxidative stress response. Here, through a combination of genetic, behavioral, and fluorescent imaging approaches, we found that sphingosine kinase functions in the SKN-1/Nrf2 pathway in the intestine to regulate neuropeptide biogenesis and secretion in motor neurons. These results implicate sphingolipid signaling as a new component of the oxidative stress response and suggest that C. elegans may be a genetically tractable model to study non-cell-autonomous oxidative stress signaling to neurons.

AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission

Mitochondrial fission and fusion impact numerous cellular functions and neurons are particularly sensitive to perturbations in mitochondrial dynamics. Here we describe that male mice lacking the mitochondrial A-kinase anchoring protein 1 (AKAP1) exhibit increased sensitivity in the transient middle cerebral artery occlusion model of focal ischemia. At the ultrastructural level, AKAP1^–/– mice have smaller mitochondria and increased contacts between mitochondria and the endoplasmic reticulum in the brain. Mechanistically, deletion of AKAP1 dysregulates complex II of the electron transport chain, increases superoxide production, and impairs Ca²⁺ homeostasis in neurons subjected to excitotoxic glutamate. Ca²⁺ deregulation in neurons lacking AKAP1 can be attributed to loss of inhibitory phosphorylation of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) at the protein kinase A (PKA) site Ser637. Our results indicate that inhibition of Drp1-dependent mitochondrial fission by the outer mitochondrial AKAP1/PKA complex protects neurons from ischemic stroke by maintaining respiratory chain activity, inhibiting superoxide production, and delaying Ca²⁺ deregulation. They also provide the first genetic evidence that Drp1 inhibition may be of therapeutic relevance for the treatment of stroke and neurodegeneration.

SIGNIFICANCE STATEMENT Previous work suggests that activation of dynamin-related protein 1 (Drp1) and mitochondrial fission contribute to ischemic injury in the brain. However, the specificity and efficacy of the pharmacological Drp1 inhibitor mdivi-1 that was used has now been discredited by several high-profile studies. Our report is timely and highly impactful because it provides the first evidence that genetic disinhibition of Drp1 via knock-out of the mitochondrial protein kinase A (PKA) scaffold AKAP1 exacerbates stroke injury in mice. Mechanistically, we show that electron transport deficiency, increased superoxide production, and Ca²⁺ overload result from genetic disinhibition of Drp1. In summary, our work settles current controversies regarding the role of mitochondrial fission in neuronal injury, provides mechanisms, and suggests that fission inhibitors hold promise as future therapeutic agents.

Dissociation of LFP Power and Tuning in the Frontal Cortex during Memory

Working memory, the ability to maintain and manipulate information in the brain, is critical for cognition. During the memory period of spatial memory tasks, neurons in the prefrontal cortex code for memorized locations via persistent, spatially tuned increases in activity. Local field potentials (LFPs) are understood to reflect summed synaptic activity of local neuron populations and may offer a window into network-level processing. We recorded LFPs from areas 8A and 9/46 while two male cynomolgus macaques (Macaca fascicularis) performed a long duration (5.1–15.6 s) memory-guided saccade task. Greater than ~16 Hz, LFP power was contralaterally tuned throughout the memory period. Yet power for both contralateral and ipsilateral targets fell gradually after the first second of the memory period, dropping below baseline after a few seconds. Our results dissociate absolute LFP power from mnemonic tuning and are consistent with modeling work that suggests that decreasing synchronization within a network may improve the stability of memory coding.

SIGNIFICANCE STATEMENT The frontal cortex is an important site for working memory. There, individual neurons reflect memorized information with selective increases in activity, but how collections of neurons work together to achieve memory is not well understood. In this work, we examined rhythmic electrical activity surrounding these neurons, which may reflect the operation of recurrent circuitry that could underlie memory. This rhythmic activity was spatially tuned with respect to memorized locations as long as memory was tested (~7.5 s). Surprisingly, however, the overall magnitude of rhythmic activity decreased steadily over this period, dropping below baseline levels after a few seconds. These findings suggest that collections of neurons may actively desynchronize to promote stability in memory circuitry.

Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.

SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.

Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse

Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. However, the functions of mGluRs in the auditory system under normal and diseased states are not well understood. The medial nucleus of the trapezoid body (MNTB) is a critical nucleus in the auditory brainstem nuclei involved in sound localization. In addition to the classical calyx excitatory inputs, MNTB neurons also receive synaptic inhibition and it remains entirely unknown how this inhibition is regulated. Here, using whole-cell voltage clamp in brain slices, we investigated group I mGluR (mGluR I)-mediated modulation of the glycinergic and GABAergic inputs to MNTB neurons in both WT mice and a fragile X syndrome (FXS) mouse model (both sexes) in which the fragile X mental retardation gene 1 is knocked out (Fmr1 KO), causing exaggerated activity of mGluR I and behavioral phenotypes. Activation of mGluR I by (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) increased the frequency and amplitude of glycinergic spontaneous IPSCs (sIPSCs) in both WT and Fmr1 KO neurons in a voltage-gated sodium channel-dependent fashion, but did not modulate glycinergic evoked IPSCs (eIPSCs). In contrast, 3,5-DHPG did not affect GABAergic sIPSCs, but did suppress eIPSCs in WT neurons via endocannabinoid signaling. In the KO, the effect of 3,5-DHPG on GABAergic eIPSCs was highly variable, which supports the notion of impaired GABAergic signaling in the FXS model. The differential modulation of sIPSC and eIPSC and differential modulation of glycinergic and GABAergic transmission suggest distinct mechanisms responsible for spontaneous and evoked release of inhibitory transmitters and their modulation through the mGluR I signaling pathway.

SIGNIFICANCE STATEMENT Neurons communicate with each other through the release of neurotransmitters, which assumes two basic modes, spontaneous and evoked release. These two release modes are believed to function using the same vesicle pool and machinery. Recent works have challenged this dogma, pointing to distinct vesicle release mechanisms underlying the two release modes. Here, we provide the first evidence in the central auditory system supporting this novel concept. We discovered neural-transmitter- and release-mode-specific neuromodulation of inhibitory transmission by metabotropic glutamate receptors and revealed part of the signaling pathways underlying this differential modulation. The results establish the foundation for a multitude of directions to study physiological significance of different release modes in auditory processing.

{alpha}-Neurexins Together with {alpha}2{delta}-1 Auxiliary Subunits Regulate Ca2+ Influx through Cav2.1 Channels

Action potential-evoked neurotransmitter release is impaired in knock-out neurons lacking synaptic cell-adhesion molecules α-neurexins (αNrxns), the extracellularly longer variants of the three vertebrate Nrxn genes. Ca²⁺ influx through presynaptic high-voltage gated calcium channels like the ubiquitous P/Q-type (Ca_V2.1) triggers release of fusion-ready vesicles at many boutons. α2 Auxiliary subunits regulate trafficking and kinetic properties of Ca_V2.1 pore-forming subunits but it has remained unclear if this involves αNrxns. Using live cell imaging with Ca²⁺ indicators, we report here that the total presynaptic Ca²⁺ influx in primary hippocampal neurons of αNrxn triple knock-out mice of both sexes is reduced and involved lower Ca_V2.1-mediated transients. This defect is accompanied by lower vesicle release, reduced synaptic abundance of Ca_V2.1 pore-forming subunits, and elevated surface mobility of α2-1 on axons. Overexpression of Nrxn1α in αNrxn triple knock-out neurons is sufficient to restore normal presynaptic Ca²⁺ influx and synaptic vesicle release. Moreover, coexpression of Nrxn1α together with α2-1 subunits facilitates Ca²⁺ influx further but causes little augmentation together with a different subunit, α2-3, suggesting remarkable specificity. Expression of defined recombinant Ca_V2.1 channels in heterologous cells validates and extends the findings from neurons. Whole-cell patch-clamp recordings show that Nrxn1α in combination with α2-1, but not with α2-3, facilitates Ca²⁺ currents of recombinant Ca_V2.1 without altering channel kinetics. These results suggest that presynaptic Nrxn1α acts as a positive regulator of Ca²⁺ influx through Ca_V2.1 channels containing α2-1 subunits. We propose that this regulation represents an important way for neurons to adjust synaptic strength.

SIGNIFICANCE STATEMENT Synaptic transmission between neurons depends on the fusion of neurotransmitter-filled vesicles with the presynaptic membrane, which subsequently activates postsynaptic receptors. Influx of calcium ions into the presynaptic terminal is the key step to trigger vesicle release and involves different subtypes of voltage-gated calcium channels. We study the regulation of calcium channels by neurexins, a family of synaptic cell-adhesion molecules that are essential for many synapse properties. Using optical measurements of calcium influx in cultured neurons and electrophysiological recordings of calcium currents from recombinant channels, we show that a major neurexin variant facilitates calcium influx through P/Q-type channels by interacting with their α2-1 auxiliary subunits. These results propose a novel way how neurons can modulate the strength of distinct synapses.

A Novel Alternative Splicing Mechanism That Enhances Human 5-HT1A Receptor RNA Stability Is Altered in Major Depression

The serotonin-1A (5-HT1A) receptor is a key regulator of serotonergic activity and is implicated in mood and emotion. However, its post-transcriptional regulation has never been studied in humans. In the present study, we show that the "intronless" human 5-HT1A gene (HTR1A) is alternatively spliced in its 3'-UTR, yielding two novel splice variants. These variants lack a ~1.6 kb intron, which contains an microRNA-135 (miR135) target site. Unlike the human HTR1A, the mouse HTR1A lacks the splice donor/accepter sites. Thus, in the mouse HTR1A, splicing was not detected. The two spliced mRNAs are extremely stable, are resistant to miR135-induced downregulation, and have greater translational output than the unspliced variant. Moreover, alternative HTR1A RNA splicing is oppositely regulated by the splice factors PTBP1 and nSR100, which inhibit or enhance its splicing, respectively. In postmortem human brain tissue from both sexes, HTR1A mRNA splicing was prevalent and region-specific. Unspliced HTR1A was expressed more strongly in the hippocampus and midbrain versus the prefrontal cortex (PFC), and correlated with reduced levels of nSR100. Importantly, HTR1A RNA splicing and nSR100 levels were reduced in the PFC of individuals with major depression compared with controls. Our unexpected findings uncover a novel mechanism to regulate HTR1A gene expression through alternative splicing of microRNA sites. Altered levels of splice factors could contribute to changes in regional and depression-related gene expression through alternative splicing.

SIGNIFICANCE STATEMENT Alternative splicing, which is prevalent in brain tissue, increases gene diversity. The serotonin-1A receptor gene (HTR1A) is a regulator of serotonin, which is implicated in mood and emotion. Here we show that human HTR1A RNA is alternately spliced. Splicing removes a microRNA site to generate ultrastable RNA and increase HTR1A expression. This splicing varies in different brain regions and is reduced in major depression. We also identify specific splice factors for HTR1A RNA, showing they are also reduced in depression. Thus, we describe a novel mechanism to regulate gene expression through splicing. Altered levels of splice factors could contribute to depression by changing gene expression.

Correction: Marneweck et al., "Neural Representations of Sensorimotor Memory- and Digit Position-Based Load Force Adjustments Before the Onset of Dexterous Manipulation"

Effects of a novel curcumin derivative on the functions of kidney in streptozotocin-induced type 2 diabetic rats

Abstract

Objective

B6, an analog of curcumin, is a compound isolated from a traditional Chinese medicine Turmeric. In this paper, we aimed to explore the efficacy of B6 on diabetic nephropathy and the related mechanisms.

Materials and methods

The effects of B6 were studied on fast-blood glucose, serum creatinine, urea nitrogen, urine albumen/24 h, pathological changes of main organs, the levels of ACE2 and ACE2 mRNA in the rat model of diabetes induced by streptozotocin.

Results

The results showed that B6 treatment could reduce serum creatinine, urea nitrogen, urine albumen/24 h, decrease the level of AngII, improve the renal pathological changes in diabetic rats and increase the levels of ACE2 and ACE2 mRNA.

Conclusion

These results suggested B6 could protect the renal function of diabetic rats. This study provided scientific basis for the further researches and clinical applications of B6.

Interferon-β inhibits inflammatory responses mediators via suppression of iNOS signaling pathway in PBMCs from patients with primary Sjögren’s syndrome

Abstract

Background

Primary Sjögren's syndrome (pSS) represents a chronic, systemic autoimmune disorder, characterized by lymphocytic infiltration of exocrine glands, inducing compromised secretory function and tissue destruction. Increasing evidence had revealed that inflammatory mediators, such as nitric oxide (NO) and pro-inflammatory cytokines, are critical in the development and perpetuation of pSS systemic manifestations. In our current study, we aimed to investigate the ex vivo immunomodulatory effect of interferon (IFN)-β on iNOS expression, as well as on pro-inflammatory (tumor necrosis factor (TNF)-α, interleukin (IL)-6) and immunoregulatory (IL-10) cytokine production. Furthermore, we examined potential associations between the influence of IFN-β treatment on NO production, and pSS clinical and serological manifestations.

Methods

In 41 pSS patients documented for their clinical and serological features, NO and cytokines levels were measured by the Griess method and enzyme-linked immunosorbent assay, respectively. Inducible nitric oxide synthase expression was analyzed by fluorescence immunostaining assay, using peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and pSS patients.

Results

Our results revealed a strong down-modulating effect of IFN-β in the secretion of pro-inflammatory mediators including TNF-α, IL-6, and NO production. Interestingly, IFN-β exerts an increase in IL-10 levels. The most suppressive effect exerted by IFN-β on NO production was importantly reported for patients with neurological manifestation. This immunomodulatory effect of IFN-β on NO production is highly related to the decrease of inducible nitric oxide synthase (iNOS) expression.

Conclusion

Our findings highlight a consistent ex vivo inhibitory effect of IFN-β on pro-inflammatory cytokine production and NO pathway in pSS patients. Our data suggest that IFN-β could represent a potential candidate for targeting inflammation during pSS.

Influence of disease-modifying antirheumatic drugs on oxidative and nitrosative stress in patients with rheumatoid arthritis

Abstract

Background

Nitro-oxidative stress plays a central role in the pathogenesis of rheumatoid arthritis (RA) and several articles show correlation with disease activity. However, the influence and mechanisms by which disease-modifying antirheumatic drugs (DMARDs) may interfere with nitro-oxidative stress are poorly understood.

Objective

To show the available data on the effect of the DMARDs on the nitro-oxidative stress in RA patients.

Methods

A bibliographic search was carried out in the electronic databases PUBMED, Lilacs, Scientific Electronic Library Online (SCIELO), and Science Direct and the research was limited to human studies, independently of the publication date.

Results

Most studies were performed with infliximab (IFX, 4 articles), tocilizumab (TCZ, 3 articles) and methotrexate (MTX, 2 articles). MTX and leflunomide showed similar results with reduction of nitric oxide. The studies with TCZ verified a marked decrease of reactive oxygen and nitrogen species. Most studies with IFX found a reduction of protein oxidation, evaluated by protein carbonyl measurement. In the present review, the most remarkable results were observed with the increase of the antioxidant defenses through several markers and antioxidant systems. The only study with etanercept showed very similar results to those obtained with MTX, with decreased pentosidine and oxidative DNA damage.

Conclusions

The majority of the studies reported in this work showed an improvement in the redox state, which could be related to success of the therapy. Thus, oxidative and nitrosative stress markers may be useful to early evaluate the response of DMARDs in patients with RA.

Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article

Abstract

Little is known about the development of psychosis during hydroxychloroquine (HCQ) treatment, especially in elderly patients affected by rheumatic diseases, with multiple comorbidities and treatments. To summarize the available evidence on HCQ-induced psychosis in elders, we performed a literature review. Additionally, individual case safety reports sent to the European Pharmacovigilance database (EudraVigilance) with HCQ as suspected drug and related to adverse events belonging to the System Organ Class 'Psychiatric disorders' were shown. Over the years, evidence was published about the risk of neuropsychiatric clinical manifestations during HCQ treatment for rheumatic diseases, but few of them were related to elderly patients. These adverse events can include less severe clinical manifestations such as affect lability and nervousness or more severe conditions such as actual psychosis and suicidal tendencies, which frequency are actually unknown. The presence of risk factors in these patients may precipitate HCQ-induced psychosis and their precocious detection could be associated with a risk minimization. Among predisposing risk factors, there are the co-exposure to interacting drugs, alcohol intake, familial history of psychiatric diseases, female gender, and the concomitant use of low-dose glucocorticoids. In some cases it was possible to reverse psychotic behaviour with the antipsychotic treatment or with HCQ suspension.

Diagnostic value of salivary CRP and IL-6 in patients undergoing anti-TNF-alpha therapy for rheumatic disease

Abstract

Introduction

Saliva has been increasingly used as a diagnostic medium for disease detection and monitoring. The aim of this observational, prospective, pilot study was to investigate whether salivary concentrations of CRP and IL-6 correlate with those in serum and with the clinical course of a rheumatic disease.

Materials and methods

Nineteen patients with rheumatic disease newly scheduled for anti-TNFα therapy were included. Patients received anti-TNFα treatment (adalimumab, certolizumab, golimumab or infliximab) as per standard protocols. CRP and IL-6 were measured with high-sensitivity immunoassays before and after 12 weeks of therapy, according to standard regimens. The data were analyzed with nonparametric statistics.

Results

Concentrations of CRP in saliva correlated significantly with those in serum (R = 0.62; p < 0.0001) and decreased markedly after successful response to treatment. In patients with a limited response to treatment salivary CRP levels increased. In contrast to CRP, the salivary concentrations of IL-6 did not change significantly over the course of therapy and they did not correlate with serum IL-6 concentrations. Salivary levels of neither CRP nor IL-6 corresponded to parameters of oral health and hygiene.

Conclusions

Salivary CRP but not IL-6 could be of potential use for monitoring the rheumatic disease activity.

Molecular docking and pharmacological/toxicological assessment of a new compound designed from celecoxib and paracetamol by molecular hybridization

Abstract

Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity—AST, ALT, GSH, urea and creatinine—as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1β levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.