British Association of Dermatologists guidelines for the management of lichen sclerosus 2018

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of lichen sclerosus (LS) in adults (18+ years), children (0-12 years) and young people (13-17 years). The document aims to.

offer an appraisal of all relevant literature up to July 2017, focusing on any key developments.

address important, practical clinical questions relating to the primary guideline objective.

provide guideline recommendations and if appropriate research recommendations.

The guideline is presented as a detailed review with highlighted recommendations for practical use in primary care and in secondary care clinics, in addition to an updated Patient Information Leaflet (PIL; available on the BAD website, http://ift.tt/1tltLhk).

This article is protected by copyright. All rights reserved.

The efficacy of probiotic supplementation in rheumatoid arthritis: a meta-analysis of randomized, controlled trials

Abstract

Probiotics are considered as -immunomodulatory agents; their efficacy as an adjunct therapy option for rheumatoid arthritis (RA), however, remains controversial. The main aim of the present meta-analysis, therefore, was to compare available data from the published randomized, controlled trials (RCTs) recruiting adults with RA which compared probiotics with placebo. The English literature search was performed using Ovid version of Medline, EmBase, Web of Science, and the Central Cochrane library through October 2016 and supplemented by hand searching reference lists. Among 240 citations identified, 4 RCTs (153 participants; 89% female) were included. All data were pooled using a standardized mean difference (SMD) with a 95% CI. Compared to the placebo, probiotics did not change the inflammatory parameters (erythrocyte sedimentation rate, tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6, IL-10, and IL-12) and oxidative stress indices (total antioxidant capacity and malondialdehyde) significantly. The borderline significant reduction as a result of probiotic administration was only determined in C-reactive protein [SDM − 0.32 (95% CI − 0.65 to 0.00)]. Among disease activity indices (disease activity score [DAS], tender joint count, and swollen joint count), DAS showed a significant improvement following probiotic treatment with a SMD (95% CI) of − 0.58 (− 0.97 to − 0.19). The number of trials was too small to determine if a strain-, dose-, or duration-response effect was present. Probiotics seem to be less effective in RA; however, to reach a firm conclusion, we need further evidence.

Transcription factors early growth response gene (Egr) 2 and 3 control inflammatory responses of tolerant T cells

Abstract

Introduction

Impaired proliferation and production of IL2 are the hallmarks of experimental T cell tolerance. However, in most autoimmune diseases, auto-reactive T cells do not display hyper proliferation, but inflammatory phenotypes.

Methods

We have now demonstrated that the transcription factors Egr2 and 3 are important for the control of inflammatory cytokine production by tolerant T cells, but not for tolerance induction.

Results

In the absence of Egr2 and 3, T cell tolerance, as measured by impaired proliferation and production of IL2, can still be induced, but tolerant T cells produced high levels of inflammatory cytokines. Egr2 and 3 regulate expression of differentiation repressors and directly inhibit T-bet function in T cells. Indeed, decreased expression of differentiation repressors, such as Id3 and Tcf1, and increased expression of inflammatory transcription factors, such as RORγt and Bhlhe40 were found in Egr2/3 deficient T cells under tolerogenic conditions. In addition, T-bet was co-expressed with Egr2 in tolerant T cells and Egr2/3 defects leads to production of high levels of IFNγ in tolerant T cells.

Conclusions

Our findings demonstrated that despite impaired proliferation and IL2 production, tolerant T cells can display inflammatory responses in response to antigen stimulation and this is controlled at least partly by Egr2 and 3.

Impaired proliferation and production of IL2 are the hallmarks of experimental T cell tolerance. However, in most autoimmune diseases, auto-reactive T cells do not display hyperproliferation, but inflammatory phenotypes. We have now demonstrated that the transcription factors Egr2 and 3 are important for the control of inflammatory cytokine production by tolerant T cells, but not for tolerance induction.

Effectiveness of using a new polyurethane foam multi-layer dressing in the sacral area to prevent the onset of pressure ulcer in the elderly with hip fractures: A pragmatic randomised controlled trial

Hip fractures in the elderly are a serious problem for the health service due to the high rate of complications. One of these complications is pressure ulcers that, according to the literature, occur in 8.8% to 55% of patients and mainly arise in the sacral area. The present randomised controlled trial tests whether applying a new innovative multi-layer polyurethane foam dressing (ALLEVYN LIFE™), reduces the onset of pressure ulcers in the sacral area. From March to December 2016, 359 fragility hip fracture patients were randomly divided into 2 groups: 182 in the control group and 177 in the experimental group. Pressure ulcers occurred overall in 36 patients (10%): 8 patients (4.5%) in the experimental group compared to 28 (15.4%) in the control group: P = 0.001, relative risk 0.29 (95% CI 0.14-0.61) with NNT of 9 (95% CI 6-21). In the experimental group the onset of pressure ulcers occurred on average on the 6th day compared to the 4th day in the control group (HR 4.4). Using polyurethane foam is effective at reducing the rate of pressure ulcers in the sacrum in elderly patients with hip fracture. The adhesiveness of this device also enables costs to be kept down.

No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project

Abstract

Background

Despite successful antiretroviral therapy people living with HIV (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function and cognitive impairment. This has raised concerns that PLWH may experience accelerated ageing-related brain pathology.

Methods

We performed a multi-centre longitudinal study of 134 virologically-suppressed PLWH (median age = 56.0 years) and 79 demographically-similar HIV-negative controls (median age = 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multi-modality neuroimaging (T1-weighted, T2-weighted, diffusion-MRI, resting-state functional-MRI, spectroscopy, arterial spin labelling) at baseline and after two-year follow-up. Group differences in rates of change were assessed using linear mixed effects models.

Results

123 PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval = 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking, alcohol use, recreational drug use, blood pressure, body-mass index or cholesterol levels.At baseline, PLWH had poorer global cognitive performance (P<0.01), lower grey matter volume (P=0.04), higher white matter hyperintensity load (P=0.02), abnormal white-matter microstructure (P<0.005) and greater 'brain-predicted age difference' (P=0.01). Longitudinally, there were no significant differences in rates of change in any neuroimaging measure between PLWH and HIV-negative controls (P>0.1). Cognitive performance was stable across the study period in both groups.

Conclusions

Our finding indicate that when receiving successful treatment, middle-aged PLWH are not at increased risk of accelerated ageing-related brain changes or cognitive decline over two years, when compared to closely-matched HIV-negative controls.

Intimate Partner Violence Among Transgender Youth: Associations with Intrapersonal and Structural Factors

Violence and Gender , Vol. 0, No. 0.

“We Do Not Matter”: Transgender Migrants/Refugees in the Dutch Asylum System

Violence and Gender , Vol. 0, No. 0.

Lacrimoplasty: a new bone fixation technique for recurrent lacrimal gland prolapse

Abstract

Lacrimal gland prolapse is an often ignored and undiagnosed condition in patients seeking blepharoplasty. Recognition and correct treatment can avoid poor outcomes in such cases. Traditional techniques of treating the prolapsed lacrimal gland include light cautery, partial excision, and periosteal suture fixation. A few series of lacrimal gland prolapse have been published in the literature. But a literature search failed to reveal any reports on the recurrence of surgically treated lacrimal gland prolapse. We report the incidence of lacrimal gland prolapse purely based on the external deformity and also report a case of recurrence following surgical lacrimal gland periosteal hitching, in a patient with blepharochalasis syndrome 4 years post the original correction. A new technique of true bony fixation of the recurrent prolapsed lacrimal gland to the lacrimal fossa is described. We call the new technique 'lacrimoplasty'. An operative video is also included to demonstrate the technique step by step.

Level of Evidence: level V, therapeutic study.

Systemic treatments for melasma: adjuvant therapy with a novel topical agent

Oral lichen sclerosus: a systematic review of reported cases and two new cases

Abstract

Lichen sclerosus (LS) is a chronic inflammatory mucocutaneous disease with uncertain etiology. It occurs as white plaque-like lesions mostly in the anogenital skin. Oral mucosal involvement is extremely rare. This study aims to summarize the features of published oral lichen sclerosus (OLS) and two new cases.

A systematic search of the English literature from 1955 to 2016 was performed in MEDLINE, Scopus, and Web of Science, and cross-references were searched manually. Search phrases included "lichen sclerosus," "mouth," "oral," "lip," "palate," "floor of mouth," "tongue," "gingiva," "buccal mucosa," and "mouth diseases." Cases with clinical and histopathological confirmation of diagnosis of OLS were included.

A total of 41 (39 published and 2 new) histologically confirmed OLS cases were available. The median age of OLS patients was 31 years, and 66% of the patients were female. Most of the OLS lesions were asymptomatic. They were located in the labial mucosa (n = 20), lip (n = 15), buccal mucosa (n = 14), gingiva (n = 12), tongue (n = 12), and palate (n = 7).

OLS is rare and typically presents as asymptomatic, white, plaque-like lesions. Malignant transformation of preexisting OLS has not been reported.

Atypical clinical presentations of Malassezia folliculitis: a retrospective analysis of 94 biopsy-proven cases

Clinical study of fibrosing alopecia in a pattern distribution in a Latin American population

Isotretinoin treatment for folliculitis decalvans: a retrospective case-series study

Abstract

Background

The literature includes only a few reports of oral isotretinoin for the treatment of folliculitis decalvans (FD). This study aimed to determine the most effective dose and duration of oral isotretinoin monotherapy for achieving remission in FD patients.

Methods

This retrospective case series study included FD patients that were treated with oral isotretinoin. Patient demographics, clinical characteristics, and treatment details were obtained from the patients' medical records. Patients were contacted via telephone after treatment was completed and asked about any relapses, time period of relapses, and the long-term effects of the treatment.

Results

The study included 39 male patients with a mean age of 37.9 ± 15.5 years. All of the patients received oral isotretinoin 0.1–1.02 mg/kg/day (10–90 mg/day) for a median duration of 2.5 months (range: 1–8 months). In all, 82.0% of patients healed after the treatment. Patients that received oral isotretinoin ≥0.4 mg/kg/day for ≥3 months responded better, and 66% of them never relapsed.

Conclusion

Contrary to general belief, oral isotretinoin monotherapy resulted in complete response in the majority of patients in this study. Based on this finding, we think oral isotretinoin ≥0.4 mg/kg/day should be given for ≥3 months to minimize the likelihood of relapse. In addition, we think oral isotretinoin monotherapy should be considered a promising treatment alternative for FD that warrants further research.

Issue Information

Issue Information

Case of primary cutaneous anaplastic large cell lymphoma misdiagnosed as squamous cell carcinoma by pseudocarcinomatous hyperplasia

Case of deep dissecting hematoma resulting in sepsis due to Pseudomonas aeruginosa infection

Increased interleukin-36γ expression in skin and sera of patients with atopic dermatitis and mycosis fungoides/Sézary syndrome

Abstract

Interleukin (IL)-36γ is expressed by keratinocytes and functions as a key initiator of inflammation in the skin. IL-36γ expression is enhanced by tumor necrosis factor-α and IL-17A, having a strong association with psoriasis. In this study, we examined the role of IL-36γ in atopic dermatitis (AD) and mycosis fungoides (MF)/Sézary syndrome (SS). Serum levels of IL-36γ in AD patients and MF/SS patients were elevated compared with those of healthy controls. Importantly, serum IL-36γ levels in AD patients positively correlated with Eczema Area and Severity Index and those of MF/SS patients positively correlated with serum soluble IL-2 receptor levels. IL-36γ mRNA levels in AD skin and MF/SS skin were significantly higher than those of normal skin. IL-36γ mRNA levels in MF/SS skin positively correlated with IL-17A mRNA levels. Immunohistochemical staining revealed that IL-36γ was highly expressed in keratinocytes in lesional skin of AD and MF/SS. Taken together, our study demonstrated that IL-36γ expression was increased in sera and skin of patients with AD and MF/SS as was reported in psoriatic patients.

Vogt–Koyanagi–Harada disease-like uveitis induced by vemurafenib for metastatic cutaneous malignant melanoma

Fibroblastic rheumatism: A case of multiple nodules of fingers and hands, contractures of fingers and polyarthritis

A novel WO 3 sonocatalyst for treatment of rhodamine B under ultrasonic irradiation

Abstract

Pure WO₃ powder was prepared from a simple method and applied into sonocatalytic degradation of rhodamine B (RhB), the model compound. The structure and properties of samples were characterized by X-ray diffractometry (XRD), transmission electron microscopy (TEM), ultraviolet–visible (UV–vis) absorption spectroscopy, and photoluminescence (PL) spectroscopy. We studied the effects of WO₃ on the sonocatalytic degradation of RhB and the operational parameters such as catalyst dosage and RhB concentration. The experimental results showed that the best sonocatalytic degradation ratio (59.39%) of organic dyes could be obtained when the optimal conditions of 10.00-mg/L initial concentration, 3.00-g/L prepared WO₃ powder added amount, 99-W ultrasound output power, and 270-min ultrasonic irradiation were adopted. Under ultrasonic conditions, the degradation rate after addition of WO₃ reached the highest activity of 57.9%, and about three times the rate of degradation was not added. Abundant ·OH was induced by WO₃ powder under ultrasonic irradiation, which may be the main contributor to the high sonodegradation rate.

Investigating the effects of environmental factors on autism spectrum disorder in the USA using remotely sensed data

Abstract

This study aimed to assess the association between exposures to outdoor environmental factors and autism spectrum disorder (ASD) prevalence in a diverse and spatially distributed population of 8-year-old children from the USA (n = 2,097,188) using the air quality index (AQI) of the US Environmental Protection Agency as well as satellite-derived data of PM_2.5 concentrations, sunlight, and maximum heat index. Multivariable logistic regression analyses were performed to determine whether the unhealthy AQI, PM_2.5, sunlight, and maximum heat index were related to the odds of ASD prevalence based on gender and race and taking into consideration the confounding factors of smoking and socioeconomic status. The logistic regression odds ratios for ASD per 10% increase in the unhealthy AQI were greater than 1 for all categories, indicating that unhealthy AQI is related to the odds of ASD prevalence. The odds ratio of ASD due to the exposure to the unhealthy AQI was higher for Asians (OR = 2.96, 95% CI = 1.11–7.88) than that for Hispanics (OR = 1.308, 95% CI = 0.607–2.820), and it was higher for Blacks (OR = 1.398, 95% CI = 0.827–2.364) than that for Whites (OR = 1.219, 95% CI = 0.760–1.954). The odds ratio of ASD due to the unhealthy AQI was slightly higher for males (OR = 1.123, 95% CI = 0.771–1.635) than that for females (OR = 1.117, 95% CI = 0.789–1.581). The effects of the unhealthy environmental exposures on the odds ratios of ASD of this study were inconclusive (i.e., statically insignificant; p value > 0.05) for all categories except for Asians. The odds ratios of ASD for Asians were increased by 5, 12, and 14% with increased levels of the environmental exposures of 10 μg/m³ of PM_2.5, 1000 kJ/m² of sunlight, and 1 °F of maximum heat index, respectively. The odds ratios of ASD prevalence for all categories, except for Asians, were increased with the inclusion of the smoking covariate, reflecting the effect of smoking on ASD prevalence besides the unhealthy environmental factors.

Cultural Sensitivity: Response to Review of Cutaneous Flushing

Slit2/Robo1 signaling is involved in angiogenesis of glomerular endothelial cells exposed to a diabetic-like environment

Abstract

Abnormal angiogenesis plays a pathological role in diabetic nephropathy (DN), contributing to glomerular hypertrophy and microalbuminuria. Slit2/Robo1 signaling participates in angiogenesis in some pathological contexts, but whether it is involved in glomerular abnormal angiogenesis of early DN is unclear. The present study evaluated the effects of Slit2/Robo1 signaling pathway on angiogenesis of human renal glomerular endothelial cells (HRGECs) exposed to a diabetic-like environment or recombinant Slit2-N. To remove the effect of Slit2 derived from mesangial cells, human renal mesangial cells (HRMCs) grown in high glucose (HG) medium (33 mM) were transfected with Slit2 siRNA and then the HG-HRMCs-CM with Slit2 depletion was collected after 48 h. HRGECs were cultured in the HG-HRMCs-CM or recombinant Slit2-N for 0, 6, 12, 24, or 48 h. The mRNA and protein expressions of Slit2/Robo1, PI3K/Akt and HIF-1α/VEGF signaling pathways were detected by quantitative real-time PCR, western blotting, and ELISA, respectively. The CCK-8 cell proliferation assay, flow cytometry and the scratch wound-healing assay were used to assess cell proliferation, cycles, and migration, respectively. Matrigel was used to perform a tubule formation assay. Our results showed that the HG-HRMCs-CM with Slit2 depletion enhanced the activation of Slit2/Robo1, PI3K/Akt, and HIF-1α/VEGF signaling in HRGECs in time-dependent manner (0–24 h post-treatment). In addition, the HG-HRMCs-CM with Slit2 depletion significantly promoted HRGECs proliferation, migration, and tube formation. Pretreatment of HRGECs with Robo1 siRNA suppressed the activation of PI3K/Akt and HIF-1α/VEGF signaling and inhibited angiogenesis, whereas PI3K inhibitor suppressed HIF-1α/VEGF signaling, without influencing Robo1 expression. In the HRGECs treated with Slit2-N, Slit2-N time-dependently enhanced the activation of Robo1/PI3K/Akt/VEGF pathway but not HIF-1α activity, and promoted HRGECs proliferation, migration, and tube formation. The effects induced by Slit2 were also abolished by Robo1 siRNA and PI3K inhibitor. Taken together, our findings indicate that in a diabetic-like environment, in addition to mesangial cells, autocrine activation of Slit2/Robo1 signaling of HRGECs may contribute to angiogenesis of HRGECs through PI3K/Akt/VEGF pathway; therefore, Slit2/Robo1 signaling may be a potent therapeutic target for the treatment of abnormal angiogenesis in early DN and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis.

Chronic mild hypoxia promotes profound vascular remodeling in spinal cord blood vessels, preferentially in white matter, via an α5β1 integrin-mediated mechanism

Abstract

Spinal cord injury (SCI) leads to rapid destruction of neuronal tissue, resulting in devastating motor and sensory deficits. This is exacerbated by damage to spinal cord blood vessels and loss of vascular integrity. Thus, approaches that protect existing blood vessels or stimulate the growth of new blood vessels might present a novel approach to minimize loss or promote regeneration of spinal cord tissue following SCI. In light of the remarkable power of chronic mild hypoxia (CMH) to stimulate vascular remodeling in the brain, the goal of this study was to examine how CMH (8% O₂ for up to 7 days) affects blood vessel remodeling in the spinal cord. We found that CMH promoted the following: (1) endothelial proliferation and increased vascularity as a result of angiogenesis and arteriogenesis, (2) increased vascular expression of the angiogenic extracellular matrix protein fibronectin as well as concomitant increases in endothelial expression of the fibronectin receptor α5β1 integrin, (3) strongly upregulated endothelial expression of the tight junction proteins claudin-5, ZO-1 and occludin and (4) astrocyte activation. Of note, the vascular remodeling changes induced by CMH were more extensive in white matter. Interestingly, hypoxic-induced vascular remodeling in spinal cord blood vessels was markedly attenuated in mice lacking endothelial α5 integrin expression (α5-EC-KO mice). Taken together, these studies demonstrate the considerable remodeling potential of spinal cord blood vessels and highlight an important angiogenic role for the α5β1 integrin in promoting endothelial proliferation. They also imply that stimulation of the α5β1 integrin or controlled use of mild hypoxia might provide new approaches for promoting angiogenesis and improving vascular integrity in spinal cord blood vessels.

Signs of physical abuse and neglect in the mature patient

Publication date: Available online 5 October 2017
Source:Clinics in Dermatology
Author(s): Karlijn Clarysse, Coleen Kivlahan, Ingo Beyer, Jan Gutermuth
Neglect and physical abuse of elderly is a worrisome health problem, which is expected to grow even further, considering the 'aging of the population.' By 2060, the number of people over 65 is expected to double, whereas birth rates are low. This trend will cause a significant imbalance between different age groups and put more senior adults at risk for abuse. Risk factors, associated with abuse and neglect, are well established and can be categorized in socio-demographic, victim or perpetrator related risk factors. The impacts of these risk factors depend mainly on the setting, which can be community-dwelling or institutionalized older adults. In community-based settings, 90% of perpetrators are family members. In each setting, suspicious physical injuries should be recognized and addressed promptly. This can be very challenging in elderly, amongst others due to the age-related skin changes, which can mimic abuse; however, there are some cutaneous clues that should always raise suspicion of abuse, such as patterned shape or distribution, different healing stages of wounds, parallel injuries, signs of blunt trauma, and irregular patches of alopecia. General awareness is needed, and the advice of dermatologists, who are best trained to differentiate between those lesions, should be systematically sought, in order to reduce false positive and negative interpretations.

Erratum

Integrative and Comparative Biology; doi:10.1093/icb/icx073.

Editorial

Issue Information

Photodermatology and Photomedicine: Meeting Calendar

Self-Perception Theory, Radical Behaviourism, and the Publicity/Privacy Issue

Abstract

According to Bem's self-perception theory, people know their own minds in the same way that they know those of others: they infer their own minds by observing their own behavior and the circumstances in which this behavior takes place. Although Bem's theory seems anti-introspectionistic, it claims that people infer their minds by observing their own behavior only when internal cues are weak, ambiguous, or un-interpretable. This has led some to argue that Bem does not rule out a priori introspective access to the mind and thus introspection as a research method. This paper will discuss self-perception theory and its influence over recent research and will argue that introspection is not an autonomous research method. This is so because of its radical behavioristic outlook, according to which all methods and data of psychology must be public and not private. Then, the paper will discuss the epistemological implications of this behavioristic attitude on psychology. Finally, it will argue in favor of introspection as an autonomous research method and an independent source of data for psychology.

Accuracy and reliability of a hand-held in vivo skin indentation device to assess skin elasticity

Abstract

Objective

The aim of this study was to evaluate the performance of a hand-held indentation device for fast and reliable determination of skin stiffness.

Methods

Device accuracy to indentation depths of 0.6 and 1.3 mm was first evaluated on plastic foam materials with mechanical properties verified by a laboratory material testing device. Subsequently, the device's sensitivity to detect age related changes in skin stiffness was evaluated among 46 healthy women (18-79 years). Finally, the reproducibility of the method was tested with 6 healthy subjects.

Results

High correlation was detected between indentation stiffness of reference material and Young's modulus determined with mechanical testing device (0.6 mm indenter: r=0.97, p=0.05; 1.3 mm indenter: r=0.98, p=0.04). Age-related decrease of 38% in skin stiffness was observed in healthy volunteers (p<0.05). The coefficient of variation for 0.6 and 1.3 mm indenters were 7.4% and 8.5%, respectively. No trend related to hysteresis effect was observed from repeated measurements.

Conclusions

The presented indentation technique was accurate against the laboratory material testing device. Furthermore, skin changes related to aging could be detected with the indentation technique. The new device was found to be feasible for monitoring skin stiffness in cosmetics and clinical conditions.

This article is protected by copyright. All rights reserved.

Discrimination and Interpersonal Violence: Reported Experiences of Trans* Undergraduate Students

Violence and Gender , Vol. 0, No. 0.

Optimal Cut-Off Points for the Short-Negative Act Questionnaire and Their Association with Depressive Symptoms and Diagnosis of Depression

Abstract

Objectives

The behavioural experience method has been extensively used in the literature for the measurement of potential bullying behaviours at work. However, this approach presents limitations when used to classify respondents as targets or non-targets of workplace bullying. Therefore, the present study aimed to: (i) identify optimal cut-off points, reflecting a possible subjectively experienced exposure to occasional and frequent workplace bullying, for the 9-item Short Negative Act Questionnaire (S-NAQ), and (ii) examine the criterion validity of these cut-off points in relation to depressive symptoms and diagnosis of depression.

Methods

The study was based on a sample of 4882 participants from the Danish MODENA cohort study (year 2011), which included both the S-NAQ (score range 9–45) and a one-item measure applying the self-labelling method with a definition to assess occasional and frequent workplace bullying. We employed receiver operating characteristic (ROC) curve analyses to derive the cut-off points for the S-NAQ. Based on these cut-off points, we created a new S-NAQ variable with three levels of exposure (i.e. 'not exposed', 'first threshold', and 'second threshold') and tested its criterion validity in relation to depressive symptoms (N = 4071) and diagnosis of depression (N = 4844).

Results

The S-NAQ cut-off points obtained were ≥12 and ≥16 when using occasional and frequent bullying as reference standards, respectively. Both cut-off points showed high classification accuracy (area under the curve = 0.89 and 0.93) as well as good sensitivity (84.8% and 88.0%) and specificity (77.4% and 94.7%). In the adjusted linear regression analyses, both the first (B = 0.78, 95% confidence interval [CI] = 0.66–0.90) and the second threshold of exposure (B = 1.65, 95% CI = 1.44–1.86) were significantly associated with depressive symptoms. In the adjusted logistic regression analyses, both the first (odds ratio [OR] = 3.55, 95% CI = 1.98–6.38) and the second threshold of exposure (OR = 5.90, 95% CI = 2.93–11.88) were significantly associated with diagnosis of depression.

Conclusions

The two cut-off points for the S-NAQ identified in this study showed a significant association with both depressive symptoms and diagnosis of depression. However, future prospective studies are needed to establish the predictive validity of the proposed cut-off points.

Combining Environmental Investigation and a Dual-Analytical Strategy to Isolate the Legionella longbeachae Strain Linked to Two Occupational Cases of Legionellosis

Abstract

Legionella has a global distribution, mainly in aquatic and man-made environments. Under the right conditions, this bacterium is a notorious human pathogen responsible for severe pulmonary illnesses. Legionellosis outbreaks are reported around the world, and exposure to water droplet aerosols containing Legionella pneumophila is usually the mechanism of its transmission. Even if L. pneumophila causes most outbreaks, Legionella longbeachae also accounts for some cases. Unlike most other Legionella strains, L. longbeachae is typically found in soil. Given the wide diversity and high concentration of microorganisms found in soil, isolating L. longbeachae by culture can be challenging. Because the chances of successfully isolating the strain are low, it is often not even attempted. This study reports the strategies used to successfully isolate L. longbeachae strain that was responsible of the two occupational legionellosis in Quebec. Fifteen random samples were collected from the soil of the metal recycling plant where the diagnosed workers were employed, covering 1.5% of the accessible surface of the plant. All samples were analyzed with both the quantitative polymerase chain reaction (qPCR) and culture methods. Four qPCR detection systems targeting Legionella spp, L. pneumophila, L. pneumophila serogroup 1, and L. longbeachae were used. Acid, heat, and acid/heat treatments were used for the culture method. For the qPCR method, all samples were positives for Legionella spp but only four were positives for L. longbeachae. For the culture method, only one isolate could be confirmed to be L. longbeachae. However, that strain proves to be the same one that caused the occupational legionellosis. Detecting the presence of L. longbeachae using the qPCR method made it possible to target the right samples to enable the cultivable strain of L. longbeachae to be isolated from the soil of the metal recycling plant. The complementarity of the two methods was established. This paper demonstrated the advantages of selecting the proper sampling and analytical strategies to achieve the isolation of the strain responsible for the infections. It also highlights for the first time in Quebec the potential occupational risks associated with L. longbeachae from soil and should motivate questioning soil exposures when all sources of water contamination have been eliminated from the causal analysis of legionellosis.

Identification of Sources of Endotoxin Exposure as Input for Effective Exposure Control Strategies

Abstract

Objective

Aim of the present study is to investigate the levels of endotoxins on product samples from potatoes, onions, and seeds, representing a relevant part of the agro-food industry in the Netherlands, to gather valuable insights in possibilities for exposure control measures early in the process of industrial processing of these products.

Methods

Endotoxin levels on 330 products samples from companies representing the potato, onion, and seed (processing) industry (four potato-packaging companies, five potato-processing companies, five onion-packaging companies, and four seed-processing companies) were assessed using the Limulus Amboecyte Lysate (LAL) assay. As variation in growth conditions (type of soil, growth type) and product characteristics (surface roughness, dustiness, size, species) are assumed to influence the level of endotoxin on products, different types, and growth conditions were considered when collecting the samples. Additionally, waste material, rotten products, felt material (used for drying), and process water were collected.

Results

A large variation in the endotoxin levels was found on samples of potatoes, onions, and seeds (overall geometric standard deviation 17), in the range between 0.7 EU g⁻¹ to 16400000 EU g⁻¹. The highest geometric mean endotoxin levels were found in plant material (319600 EU g⁻¹), followed by soil material (49100 EU g⁻¹) and the outer side of products (9300 EU g⁻¹), indicating that removal of plant and soil material early in the process would be an effective exposure control strategy. The high levels of endotoxins found in the limited number of samples from rotten onions indicate that these rotten onions should also be removed early in the process. Mean endotoxin levels found in waste material (only available for seed processing) is similar to the level found in soil material, although the range is much larger. On uncleaned seeds, higher endotoxin levels were found than on cleaned seeds, indicating that cleaning processes are important control measures and also that the waste material should be handled with care.

Conclusions

Although endotoxin levels in batches of to–be-processed potatoes, onions, and seeds vary quite dramatically, it could be concluded that rotten products, plant material, and waste material contain particularly high endotoxin levels. This information was used to propose control measures to reduce exposure to endotoxins of workers during the production process.

Association of Facial Exercise With the Appearance of Aging

This pilot study assesses the association of a 20-week facial exercise program with the facial appearance of middle-aged women.

Bullous Pemphigoid Without IgG Autoantibodies to the BP180 NC16A Domain

This case series examines the association of nonreactivity of IgG to the noncollagenous 16A domain using the enzyme-linked immunosorbent assay and the chemiluminescent enzyme immunoassay and severity of disease course in 14 patients with bullous pemphigoid.

Facial Papules in a Patient With Lichen Planopilaris

A woman in her 50s with biopsy-proven scalp lichen planopilaris presented with slightly pruritic facial papules that coincided with the start of her hair loss condition; she denied a history of severe acne or other inflammatory skin disorders and had no health problems. What is your diagnosis?

Rituximab as Single Long-term Maintenance Therapy in Difficult-to-Treat Pemphigus

This case-series study of 11 patients with severe, difficult-to-treat pemphigus examines whether rituximab alone can be used long-term as maintenance therapy for prevention of relapse.

Fluorouracil for Prevention of Keratinocyte Carcinoma

This randomized, double-blind, placebo-controlled trial examined the use of topical fluorouracil, 5%, to prevent keratinocyte carcinoma.

A hybrid optimization strategy for registering images with large local deformations and intensity variations

Abstract

Purpose

To develop a method for intra-patient registration of pre- and post-contrast abdominal MR images with large local deformations and large intensity variations.

Method

A hybrid method is proposed to deal with this problem. It consists of two coupled techniques: (1) descriptor matching (DM) at the original resolution using a discrete optimization strategy to avoid getting trapped in a local minimum; (2) continuous optimization to refine the registration outcome based on autocorrelation of local image structure (ALOST). Our method—called DM-ALOST—has become insensitive to the local uptake of contrast agent by exploiting the mean phase and the phase congruency extracted from the multi-scale monogenic signal. The method was extensively tested on abdominal MR data of 30 patients with Crohn's disease.

Results

DM-ALOST produced significantly larger mean Dice coefficients than two state-of-the-art methods \(({p}<0.05)\) .

Conclusion

Both qualitative and quantitative tests demonstrated improved registration using the proposed method compared to the state-of-the-art. The DM-ALOST method facilitates measurement of corresponding features from different abdominal MR images, which can aid to assess certain diseases, particularly Crohn's disease.

A Simple Method for International Standardization of Photographic Documentation for Aesthetic Plastic Surgery

Proposal of a Classification System for the Assessment and Treatment of Prominent Ear Deformity

Abstract

Background

Prominent ear is the most common external ear deformity. To comprehensively treat prominent ear deformity, adequate comprehension of its pathophysiology is crucial. In this article, we analyze cases of prominent ear and suggest a simple classification system and treatment algorithm according to pathophysiology.

Methods

We retrospectively reviewed a total of 205 Northeast Asian patients' clinical data who underwent an operation for prominent ear deformity. Follow-up assessments were conducted 3, 6, and 12 months after surgery. Prominent ear deformities were classified by diagnostic checkpoints. Class I (simple prominent ear) includes prominent ear that developed with the absence of the antihelix without conchal hypertrophy. Class II (mixed-type prominent ear) is defined as having not only a flat antihelix, but also conchal excess. Class III (conchal-type prominent ear) has an enlarged conchal bowl with a well-developed antihelix.

Results

Among the three types of prominent ear, class I was most frequent (162 patients, 81.6%). Class II was observed in 28 patients (13.6%) and class III in 10 patients (4.8%). We used the scaphomastoid suture method for correction of antihelical effacement, the anterior approach conchal resection for correction of conchal hypertrophy, and Bauer's squid incision for lobule prominence. The complication rate was 9.2% including early hematoma, hypersensitivity, and suture extrusion. Unfavorable results occurred in 4% including partial recurrence, overcorrection, and undercorrection.

Conclusions

To reduce unfavorable results and avoid recurrence, we propose the use of a classification and treatment algorithm in preoperative evaluation of prominent ear.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

Attention Priority Map of Face Images in Human Early Visual Cortex

Attention priority maps are topographic representations that are used for attention selection and guidance of task-related behavior during visual processing. Previous studies have identified attention priority maps of simple artificial stimuli in multiple cortical and subcortical areas, but investigating neural correlates of priority maps of natural stimuli is complicated by the complexity of their spatial structure and the difficulty of behaviorally characterizing their priority map. To overcome these challenges, we reconstructed the topographic representations of upright/inverted face images from fMRI BOLD signals in human early visual areas primary visual cortex (V1) and the extrastriate cortex (V2 and V3) based on a voxelwise population receptive field model. We characterized the priority map behaviorally as the first saccadic eye movement pattern when subjects performed a face-matching task relative to the condition in which subjects performed a phase-scrambled face-matching task. We found that the differential first saccadic eye movement pattern between upright/inverted and scrambled faces could be predicted from the reconstructed topographic representations in V1–V3 in humans of either sex. The coupling between the reconstructed representation and the eye movement pattern increased from V1 to V2/3 for the upright faces, whereas no such effect was found for the inverted faces. Moreover, face inversion modulated the coupling in V2/3, but not in V1. Our findings provide new evidence for priority maps of natural stimuli in early visual areas and extend traditional attention priority map theories by revealing another critical factor that affects priority maps in extrastriate cortex in addition to physical salience and task goal relevance: image configuration.

SIGNIFICANCE STATEMENT Prominent theories of attention posit that attention sampling of visual information is mediated by a series of interacting topographic representations of visual space known as attention priority maps. Until now, neural evidence of attention priority maps has been limited to studies involving simple artificial stimuli and much remains unknown about the neural correlates of priority maps of natural stimuli. Here, we show that attention priority maps of face stimuli could be found in primary visual cortex (V1) and the extrastriate cortex (V2 and V3). Moreover, representations in extrastriate visual areas are strongly modulated by image configuration. These findings extend our understanding of attention priority maps significantly by showing that they are modulated, not only by physical salience and task–goal relevance, but also by the configuration of stimuli images.

This Week in The Journal

Why Editorial Rejection?

Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of Ctcf in Camk2a-Cre-Expressing Neurons

CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations in CTCF cause intellectual disability and autistic features. Knocking out Ctcf in mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked out Ctcf postnatally in glutamatergic forebrain neurons under the control of Camk2a-Cre. Ctcf^loxP/loxP;Camk2a-Cre⁺ (Ctcf CKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age. Ctcf CKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA from Ctcf CKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically from Ctcf CKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia in Ctcf CKO hippocampus. Finally, we found that microglia in Ctcf CKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immunostaining for CD68, a marker of microglial activation. Our findings confirm that Ctcf KO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction.

SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a DNA-binding protein that organizes nuclear chromatin topology. Mutations in CTCF cause intellectual disability and autistic features in humans. CTCF deficiency in embryonic neurons is lethal in mice, but mice with postnatal CTCF depletion are less well studied. We find that mice lacking Ctcf in Camk2a-expressing neurons (Ctcf CKO mice) have spatial learning/memory deficits, impaired fine motor skills, subtly altered social interactions, and decreased dendritic spine density. We demonstrate that Ctcf CKO mice overexpress inflammation-related genes in the brain and have microglia with abnormal morphology that label positive for CD68, a marker of microglial activation. Our findings suggest that inflammation and dysfunctional neuron–microglia interactions are factors in the pathology of CTCF deficiency.

Multiple Lines of Evidence Indicate That Gliotransmission Does Not Occur under Physiological Conditions

A major controversy persists within the field of glial biology concerning whether or not, under physiological conditions, neuronal activity leads to Ca²⁺-dependent release of neurotransmitters from astrocytes, a phenomenon known as gliotransmission. Our perspective is that, while we and others can apply techniques to cause gliotransmission, there is considerable evidence gathered using astrocyte-specific and more physiological approaches which suggests that gliotransmission is a pharmacological phenomenon rather than a physiological process. Approaches providing evidence against gliotransmission include stimulation of Gq-GPCRs expressed only in astrocytes, as well as removal of the primary proposed source of astrocyte Ca²⁺ responsible for gliotransmission. These approaches contrast with those supportive of gliotransmission, which include mechanical stimulation, strong astrocytic depolarization using whole-cell patch-clamp or optogenetics, uncaging Ca²⁺ or IP3, chelating Ca²⁺ using BAPTA, and nonspecific bath application of agonists to receptors expressed by a multitude of cell types. These techniques are not subtle and therefore are not supportive of recent suggestions that gliotransmission requires very specific and delicate temporal and spatial requirements. Other evidence, including lack of propagating Ca²⁺ waves between astrocytes in healthy tissue, lack of expression of vesicular release machinery, and the demise of the d-serine gliotransmission hypothesis, provides additional evidence against gliotransmission. Overall, the data suggest that Ca²⁺-dependent release of neurotransmitters is the province of neurons, not astrocytes, in the intact brain under physiological conditions.

Dual Perspectives Companion Paper: Gliotransmission: Beyond Black-and-White, by Iaroslav Savtchouk and Andrea Volterra

Restoration of Dendritic Complexity, Functional Connectivity, and Diversity of Regenerated Retinal Bipolar Neurons in Adult Zebrafish

Adult zebrafish (Danio rerio) are capable of regenerating retinal neurons that have been lost due to mechanical, chemical, or light damage. In the case of chemical damage, there is evidence that visually mediated behaviors are restored after regeneration, consistent with recovery of retinal function. However, the extent to which regenerated retinal neurons attain appropriate morphologies and circuitry after such tissue-disrupting lesions has not been investigated. Adult zebrafish of both sexes were subjected to intravitreal injections of ouabain, which destroys the inner retina. After retinal regeneration, cell-selective markers, confocal microscopy, morphometrics, and electrophysiology were used to examine dendritic and axonal morphologies, connectivities, and the diversities of each, as well as retinal function, for a subpopulation of regenerated bipolar neurons (BPs). Although regenerated BPs were reduced in numbers, BP dendritic spreads, dendritic tree morphologies, and cone–bipolar connectivity patterns were restored in regenerated retinas, suggesting that regenerated BPs recover accurate input pathways from surviving cone photoreceptors. Morphological measurements of bipolar axons found that numbers and types of stratifications were also restored; however, the thickness of the inner plexiform layer and one measure of axon branching were slightly reduced after regeneration, suggesting some minor differences in the recovery of output pathways to downstream partners. Furthermore, ERG traces from regenerated retinas displayed waveforms matching those of controls, but with reduced b-wave amplitudes. These results support the hypothesis that regenerated neurons of the adult zebrafish retina are capable of restoring complex morphologies and circuitry, suggesting that complex visual functions may also be restored.

SIGNIFICANCE STATEMENT Adult zebrafish generate new retinal neurons after a tissue-disrupting lesion. Existing research does not address whether regenerated neurons of adults successfully reconnect with surrounding neurons and establish complex morphologies and functions. We report that, after a chemical lesion that ablates inner retinal neurons, regenerated retinal bipolar neurons (BPs), although reduced in numbers, reconnected to undamaged cone photoreceptors with correct wiring patterns. Regenerated BPs had complex morphologies similar to those within undamaged retina and a physiological measure of photoreceptor–BP connectivity, the ERG, was restored to a normal waveform. This new understanding of neural connectivity, morphology, and physiology suggests that complex functional processing is possible within regenerated adult retina and offers a system for the future study of synaptogenesis during adult retinal regeneration.

Gliotransmission: Beyond Black-and-White

Astrocytes are highly complex cells with many emerging putative roles in brain function. Of these, gliotransmission (active information transfer from glia to neurons) has probably the widest implications on our understanding of how the brain works: do astrocytes really contribute to information processing within the neural circuitry? "Positive evidence" for this stems from work of multiple laboratories reporting many examples of modulatory chemical signaling from astrocytes to neurons in the timeframe of hundreds of milliseconds to several minutes. This signaling involves, but is not limited to, Ca²⁺-dependent vesicular transmitter release, and results in a variety of regulatory effects at synapses in many circuits that are abolished by preventing Ca²⁺ elevations or blocking exocytosis selectively in astrocytes. In striking contradiction, methodologically advanced studies by a few laboratories produced "negative evidence," triggering a heated debate on the actual existence and properties of gliotransmission. In this context, a skeptics' camp arose, eager to dismiss the whole positive evidence based on a number of assumptions behind the negative data, such as the following: (1) deleting a single Ca²⁺ release pathway (IP3R2) removes all the sources for Ca²⁺-dependent gliotransmission; (2) stimulating a transgenically expressed Gq-GPCR (MrgA1) mimics the physiological Ca²⁺ signaling underlying gliotransmitter release; (3) age-dependent downregulation of an endogenous GPCR (mGluR5) questions gliotransmitter release in adulthood; and (4) failure by transcriptome analysis to detect vGluts or canonical synaptic SNAREs in astrocytes proves inexistence/functional irrelevance of vesicular gliotransmitter release. We here discuss how the above assumptions are likely wrong and oversimplistic. In light of the most recent literature, we argue that gliotransmission is a more complex phenomenon than originally thought, possibly consisting of multiple forms and signaling processes, whose correct study and understanding require more sophisticated tools and finer scientific experiments than done until today. Under this perspective, the opposing camps can be reconciled and the field moved forward. Along the path, a more cautious mindset and an attitude to open discussion and mutual respect between opponent laboratories will be good companions.

Dual Perspectives Companion Paper: Multiple Lines of Evidence Indicate That Gliotransmission Does Not Occur under Physiological Conditions, by Todd A. Fiacco and Ken D. McCarthy

Normal Topography and Binocularity of the Superior Colliculus in Strabismus

In subjects with alternating strabismus, either eye can be used to saccade to visual targets. The brain must calculate the correct vector for each saccade, which will depend on the eye chosen to make it. The superior colliculus, a major midbrain center for saccade generation, was examined to determine whether the maps serving each eye were shifted to compensate for strabismus. Alternating exotropia was induced in two male macaques at age 1 month by sectioning the tendons of the medial recti. Once the animals grew to maturity, they were trained to fixate targets with either eye. Receptive fields were mapped in the superior colliculus using a sparse noise stimulus while the monkeys alternated fixation. For some neurons, sparse noise was presented dichoptically to probe for anomalous retinal correspondence. After recordings, microstimulation was applied to compare sensory and motor maps. The data showed that receptive fields were offset in position by the ocular deviation, but otherwise remained aligned. In one animal, the left eye's coordinates were rotated ~20° clockwise with respect to those of the right eye. This was explained by a corresponding cyclorotation of the ocular fundi, which produced an A-pattern deviation. Microstimulation drove the eyes accurately to the site of receptive fields, as in normal animals. Single-cell recordings uncovered no evidence for anomalous retinal correspondence. Despite strabismus, neurons remained responsive to stimulation of either eye. Misalignment of the eyes early in life does not alter the organization of topographic maps or disrupt binocular convergence in the superior colliculus.

SIGNIFICANCE STATEMENT Patients with strabismus are able to make rapid eye movements, known as saccades, toward visual targets almost as gracefully as subjects with normal binocular alignment. They can even exercise the option of using the right eye or the left eye. It is unknown how the brain measures the degree of ocular misalignment and uses it to compute the appropriate saccade for either eye. The obvious place to investigate is the superior colliculus, a midbrain oculomotor center responsible for the generation of saccades. Here, we report the first experiments in the superior colliculus of awake primates with strabismus using a combination of single-cell recordings and microstimulation to explore the organization of its topographic maps.

Distinct Neurobehavioral Mechanisms for Expectancy Violation and Value Updating

CaMKII{alpha} Mediates the Effect of IL-17 To Promote Ongoing Spontaneous and Evoked Pain in Multiple Sclerosis

Pain is a common and severe symptom in multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the CNS. The neurobiological mechanism underlying MS pain is poorly understood. In this study, we investigated the role of Ca²⁺/calmodulin-dependent protein kinase IIα (CaMKIIα) in driving chronic pain in MS using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that spinal CaMKIIα activity was enhanced in EAE, correlating with the development of ongoing spontaneous pain and evoked hypersensitivity to mechanical and thermal stimuli. Prophylactic or acute administration of KN93, a CaMKIIα inhibitor, significantly reduced the clinical scores of EAE and attenuated mechanical allodynia and thermal hyperalgesia in EAE. siRNA targeting CaMKIIα reversed established mechanical and thermal hypersensitivity in EAE mice. Furthermore, CaMKIIαT286A point mutation mice showed significantly reduced EAE clinical scores, an absence of evoked pain, and ongoing spontaneous pain when compared with littermate wild-type mice. We found that IL-17 is responsible for inducing but not maintaining mechanical and thermal hyperalgesia that is mediated by CaMKIIα signaling in EAE. Together, these data implicate a critical role of CaMKIIα as a cellular mechanism for pain and neuropathy in multiple sclerosis and IL-17 may act upstream of CaMKIIα in the generation of pain.

SIGNIFICANCE STATEMENT Pain is highly prevalent in patients with multiple sclerosis (MS), significantly reducing patients' quality of life. Using the experimental autoimmune encephalomyelitis (EAE) model, we were able to study not only evoked hyperalgesia, but also for the first time to demonstrate spontaneous pain that is also experienced by patients. Our study identified a role of spinal CaMKIIα in promoting and maintaining persistent ongoing spontaneous pain and evoked hyperalgesia pain in EAE. We further demonstrated that IL-17 contributes to persistent pain in EAE and functions as an upstream regulator of CaMKIIα signaling. These data for the first time implicated CaMKIIα and IL-17 as critical regulators of persistent pain in EAE, which may ultimately offer new therapeutic targets for mitigating pain in multiple sclerosis.

A Therapeutic Link between Astrogliosis and Remyelination in a Mouse Model of Multiple Sclerosis

A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo

The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. In vitro, FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo. We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-directed insertion strategy to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an in vivo setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.

SIGNIFICANCE STATEMENT The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease. The tau protein is thus widely felt to play a key role in promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. Here we capitalize on an "experiment of nature" in which rare missense mutations in tau cause familial neurodegeneration and neurofibrillary tangle formation. By comparing the biochemical activities of different tau mutations with their in vivo toxicity in a well controlled Drosophila model system, we find that all mutations tested increase phosphorylation of tau and trigger a cascade of neurotoxicity critically impinging on the integrity of the actin cytoskeleton.

Circular RNA DLGAP4 Ameliorates Ischemic Stroke Outcomes by Targeting miR-143 to Regulate Endothelial-Mesenchymal Transition Associated with Blood-Brain Barrier Integrity

Circular RNAs (circRNAs) are highly expressed in the CNS and regulate physiological and pathophysiological processes. However, the potential role of circRNAs in stroke remains largely unknown. Here, we show that the circRNA DLGAP4 (circDLGAP4) functions as an endogenous microRNA-143 (miR-143) sponge to inhibit miR-143 activity, resulting in the inhibition of homologous to the E6-AP C-terminal domain E3 ubiquitin protein ligase 1 expression. circDLGAP4 levels were significantly decreased in the plasma of acute ischemic stroke patients (13 females and 13 males) and in a mouse stroke model. Upregulation of circDLGAP4 expression significantly attenuated neurological deficits and decreased infarct areas and blood–brain barrier damage in the transient middle cerebral artery occlusion mouse stroke model. Endothelial-mesenchymal transition contributes to blood–brain barrier disruption and circDLGAP4 overexpression significantly inhibited endothelial-mesenchymal transition by regulating tight junction protein and mesenchymal cell marker expression. Together, the results of our study are illustrative of the involvement of circDLGAP4 and its coupling mechanism in cerebral ischemia, providing translational evidence that circDLGAP4 serves as a novel therapeutic target for acute cerebrovascular protection.

SIGNIFICANCE STATEMENT Circular RNAs (circRNAs) are involved in the regulation of physiological and pathophysiological processes. However, whether circRNAs are involved in ischemic injury, particularly cerebrovascular disorders, remains largely unknown. Here, we demonstrate a critical role for circular RNA DLGAP4 (circDLGAP4), a novel circular RNA originally identified as a sponge for microRNA-143 (miR-143), in ischemic stroke outcomes. Overexpression of circDLGAP4 significantly attenuated neurological deficits and decreased infarct areas and blood–brain barrier damage in the transient middle cerebral artery occlusion mouse stroke model. To our knowledge, this is the first report describing the efficacy of circRNA injection in an ischemic stroke model. Our investigation suggests that circDLGAP4 may serve as a novel therapeutic target for acute ischemic injury.

Trajectory Analysis Unveils Reelin's Role in the Directed Migration of Granule Cells in the Dentate Gyrus

Reelin controls neuronal migration and layer formation. Previous studies in reeler mice deficient in Reelin focused on the result of the developmental process in fixed tissue sections. It has remained unclear whether Reelin affects the migratory process, migration directionality, or migrating neurons guided by the radial glial scaffold. Moreover, Reelin has been regarded as an attractive signal because newly generated neurons migrate toward the Reelin-containing marginal zone. Conversely, Reelin might be a stop signal because migrating neurons in reeler, but not in wild-type mice, invade the marginal zone. Here, we monitored the migration of newly generated proopiomelanocortin-EGFP-expressing dentate granule cells in slice cultures from reeler, reeler-like mutants and wild-type mice of either sex using real-time microscopy. We discovered that not the actual migratory process and migratory speed, but migration directionality of the granule cells is controlled by Reelin. While wild-type granule cells migrated toward the marginal zone of the dentate gyrus, neurons in cultures from reeler and reeler-like mutants migrated randomly in all directions as revealed by vector analyses of migratory trajectories. Moreover, live imaging of granule cells in reeler slices cocultured to wild-type dentate gyrus showed that the reeler neurons changed their directions and migrated toward the Reelin-containing marginal zone of the wild-type culture, thus forming a compact granule cell layer. In contrast, directed migration was not observed when Reelin was ubiquitously present in the medium of reeler slices. These results indicate that topographically administered Reelin controls the formation of a granule cell layer.

SIGNIFICANCE STATEMENT Neuronal migration and the various factors controlling its onset, speed, directionality, and arrest are poorly understood. Slice cultures offer a unique model to study the migration of individual neurons in an almost natural environment. In the present study, we took advantage of the expression of proopiomelanocortin-EGFP by newly generated, migrating granule cells to analyze their migratory trajectories in hippocampal slice cultures from wild-type mice and mutants deficient in Reelin signaling. We show that the compartmentalized presence of Reelin is essential for the directionality, but not the actual migratory process or speed, of migrating granule cells leading to their characteristic lamination in the dentate gyrus.

Opposite Effects of Basolateral Amygdala Inactivation on Context-Induced Relapse to Cocaine Seeking after Extinction versus Punishment

Studies using the renewal procedure showed that basolateral amygdala (BLA) inactivation inhibits context-induced relapse to cocaine-seeking after extinction. Here, we determined whether BLA inactivation would also inhibit context-induced relapse after drug-reinforced responding is suppressed by punishment, an animal model of human relapse after self-imposed abstinence due to adverse consequences of drug use. We also determined the effect of central amygdala (CeA) inactivation on context-induced relapse.

We trained rats to self-administer cocaine for 12 d (6 h/d) in Context A and then exposed them to either extinction or punishment training for 8 d in Context B. During punishment, 50% of cocaine-reinforced lever-presses produced an aversive footshock of increasing intensity (0.1–0.5 or 0.7 mA). We then tested the rats for relapse to cocaine seeking in the absence of cocaine or shock in Contexts A and B after BLA or CeA injections of vehicle or GABA agonists (muscimol-baclofen). We then retrained the rats for cocaine self-administration in Context A, repunished or re-extinguished lever pressing in Context B, and retested for relapse after BLA or CeA inactivation.

BLA or CeA inactivation decreased context-induced relapse in Context A after extinction in Context B. BLA, but not CeA, inactivation increased context-induced relapse in Context A after punishment in Context B. BLA or CeA inactivation provoked relapse in Context B after punishment but not extinction. Results demonstrate that amygdala's role in relapse depends on the method used to achieve abstinence and highlights the importance of studying relapse under abstinence conditions that more closely mimic the human condition.

SIGNIFICANCE STATEMENT Relapse to drug use during abstinence is often provoked by re-exposure to the drug self-administration environment or context. Studies using the established extinction-reinstatement rodent model of drug relapse have shown that inactivation of the basolateral amygdala inhibits context-induced drug relapse after extinction of the drug-reinforced responding. Here, we determined whether basolateral amygdala inactivation would also inhibit relapse after drug-reinforced responding is suppressed by punishment, a model of human relapse after self-imposed abstinence. Unexpectedly, we found that basolateral amygdala inactivation had opposite effects on relapse provoked by re-exposure to the drug self-administration environment after extinction versus punishment. Our results demonstrate that depending on the historical conditions that lead to abstinence, amygdala activity can either promote or inhibit relapse.

Ventral Midline Thalamus Is Necessary for Hippocampal Place Field Stability and Cell Firing Modulation

The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip–mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields.

SIGNIFICANCE STATEMENT Growing evidence suggest that the ventral midline thalamic nuclei (reuniens and rhomboid) might play a substantial role in various cognitive tasks including spatial memory. In the present article, we show that the lesions of these nuclei impair the spatial representations encoded by CA1 place cells of both familiar and novel environments. First, reduced variability of place cell firing appears to indicate an impairment of attentional processes. Second, impaired stability of place cell representations could explain the long-term memory deficits observed in previous behavioral studies.

Are Cocaine-Seeking "Habits" Necessary for the Development of Addiction-Like Behavior in Rats?

Drug self-administration models of addiction typically require animals to make the same response (e.g., a lever-press or nose-poke) over and over to procure and take drugs. By their design, such procedures often produce behavior controlled by stimulus–response (S-R) habits. This has supported the notion of addiction as a "drug habit," and has led to considerable advances in our understanding of the neurobiological basis of such behavior. However, to procure such drugs as cocaine, addicts often require considerable ingenuity and flexibility in seeking behavior, which, by definition, precludes the development of habits. To better model drug-seeking behavior in addicts, we first developed a novel cocaine self-administration procedure [puzzle self-administration procedure (PSAP)] that required rats to solve a new puzzle every day to gain access to cocaine, which they then self-administered on an intermittent access (IntA) schedule. Such daily problem-solving precluded the development of S-R seeking habits. We then asked whether prolonged PSAP/IntA experience would nevertheless produce "symptoms of addiction." It did, including escalation of intake, sensitized motivation for drug, continued drug use in the face of adverse consequences, and very robust cue-induced reinstatement of drug seeking, especially in a subset of "addiction-prone" rats. Furthermore, drug-seeking behavior continued to require dopamine neurotransmission in the core of the nucleus accumbens (but not the dorsolateral striatum). We conclude that the development of S-R seeking habits is not necessary for the development of cocaine addiction-like behavior in rats.

SIGNIFICANCE STATEMENT Substance-use disorders are often characterized as "habitual" behaviors aimed at obtaining and administering drugs. Although the actions involved in consuming drugs may involve a rigid repertoire of habitual behaviors, evidence suggests that addicts must be very creative and flexible when trying to procure drugs, and thus drug seeking cannot be governed by habit alone. We modeled flexible drug-seeking behavior in rats by requiring animals to solve daily puzzles to gain access to cocaine. We find that habitual drug-seeking isn't necessary for the development of addiction-like behavior, and that our procedure doesn't result in transfer of dopaminergic control from the ventral to dorsal striatum. This approach may prove useful in studying changes in neuropsychological function that promote the transition to addiction.

PKD1 Promotes Functional Synapse Formation Coordinated with N-Cadherin in Hippocampus

Functional synapse formation is critical for the wiring of neural circuits in the developing brain. The cell adhesion molecule N-cadherin plays important roles in target recognition and synaptogenesis. However, the molecular mechanisms that regulate the localization of N-cadherin and the subsequent effects remain poorly understood. Here, we show that protein kinase D1 (PKD1) directly binds to N-cadherin at amino acid residues 836–871 and phosphorylates it at Ser 869, 871, and 872, thereby increasing the surface localization of N-cadherin and promoting functional synapse formation in primary cultured hippocampal neurons obtained from embryonic day 18 rat embryos of either sex. Intriguingly, neuronal activity enhances the interactions between N-cadherin and PKD1, which are critical for the activity-dependent growth of dendritic spines. Accordingly, either disruption the binding between N-cadherin and PKD1 or preventing the phosphorylation of N-cadherin by PKD1 in the hippocampal CA1 region of male rat leads to the reduction in synapse number and impairment of LTP. Together, this study demonstrates a novel mechanism of PKD1 regulating the surface localization of N-cadherin and suggests that the PKD1-N-cadherin interaction is critical for synapse formation and function.

SIGNIFICANCE STATEMENT Defects in synapse formation and function lead to various neurological diseases, although the mechanisms underlying the regulation of synapse development are far from clear. Our results suggest that protein kinase D1 (PKD1) functions upstream of N-cadherin, a classical synaptic adhesion molecule, to promote functional synapse formation. Notably, we identified a crucial binding fragment to PKD1 at C terminus of N-cadherin, and this fragment also contains PKD1 phosphorylation sites. Through this interaction, PKD1 enhances the stability of N-cadherin on cell membrane and promotes synapse morphogenesis and synaptic plasticity in an activity-dependent manner. Our study reveals the role of PKD1 and the potential downstream mechanism in synapse development, and contributes to the research for neurodevelopment and the therapy for neurological diseases.

Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice

The brainstem locus coeruleus (LC) supplies norepinephrine to the forebrain and degenerates in Alzheimer's disease (AD). Loss of LC neurons is correlated with increased severity of other AD hallmarks, including β-amyloid (Aβ) plaques, tau neurofibrillary tangles, and cognitive deficits, suggesting that it contributes to the disease progression. Lesions of the LC in amyloid-based transgenic mouse models of AD exacerbate Aβ pathology, neuroinflammation, and cognitive deficits, but it is unknown how the loss of LC neurons affects tau-mediated pathology or behavioral abnormalities. Here we investigate the impact of LC degeneration in a mouse model of tauopathy by lesioning the LC of male and female P301S tau transgenic mice with the neurotoxin N-(2-chloroethyl)-N-ethyl-bromobenzylamine (DSP-4) starting at 2 months of age. By 6 months, deficits in hippocampal-dependent spatial (Morris water maze) and associative (contextual fear conditioning) memory were observed in lesioned P301S mice while performance remained intact in all other genotype and treatment groups, indicating that tau and LC degeneration act synergistically to impair cognition. By 10 months, the hippocampal neuroinflammation and neurodegeneration typically observed in unlesioned P301S mice were exacerbated by DSP-4, and mortality was also accelerated. These DSP-4-induced changes were accompanied by only a mild aggravation of tau pathology, suggesting that increased tau burden cannot fully account for the effects of LC degeneration. Combined, these experiments demonstrate that loss of LC noradrenergic neurons exacerbates multiple phenotypes caused by pathogenic tau, and provides complementary data to highlight the dual role LC degeneration has on both tau and Aβ pathologies in AD.

SIGNIFICANCE STATEMENT Elucidating the mechanisms underlying AD is crucial to developing effective diagnostics and therapeutics. The degeneration of the LC and loss of noradrenergic transmission have been recognized as ubiquitous events in AD pathology, and previous studies demonstrated that LC lesions exacerbate pathology and cognitive deficits in amyloid-based mouse models. Here, we reveal a complementary role of LC degeneration on tau-mediated aspects of the disease by using selective lesions of the LC and the noradrenergic system to demonstrate an exacerbation of cognitive deficits, neuroinflammation, neurodegeneration in a transgenic mouse model of tauopathy. Our data support an integral role for the LC in modulating the severity of both canonical AD-associated pathologies, as well as the detrimental consequences of LC degeneration during disease progression.

The Dual Function of the Polybasic Juxtamembrane Region of Syntaxin 1A in Clamping Spontaneous Release and Stimulating Ca2+-Triggered Release in Neuroendocrine Cells

The exact function of the polybasic juxtamembrane region (5RK) of the plasma membrane neuronal SNARE, syntaxin 1A (Syx), in vesicle exocytosis, although widely studied, is currently not clear. Here, we addressed the role of 5RK in Ca²⁺-triggered release, using our Syx-based intramolecular fluorescence resonance energy transfer (FRET) probe, which previously allowed us to resolve a depolarization-induced Ca²⁺-dependent close-to-open transition (CDO) of Syx that occurs concomitant with evoked release, both in PC12 cells and hippocampal neurons and was abolished upon charge neutralization of 5RK. First, using dynamic FRET analysis in PC12 cells, we show that CDO occurs following assembly of SNARE complexes that include the vesicular SNARE, synaptobrevin 2, and that the participation of 5RK in CDO goes beyond its participation in the final zippering of the complex, because mutations of residues adjacent to 5RK, believed to be crucial for final zippering, do not abolish this transition. In addition, we show that CDO is contingent on membrane phosphatidylinositol 4,5-bisphosphate (PIP2), which is fundamental for maintaining regulated exocytosis, as depletion of membranal PIP2 abolishes CDO. Prompted by these results, which underscore a potentially significant role of 5RK in exocytosis, we next amperometrically analyzed catecholamine release from PC12 cells, revealing that charge neutralization of 5RK promotes spontaneous and inhibits Ca²⁺-triggered release events. Namely, 5RK acts as a fusion clamp, making release dependent on stimulation by Ca²⁺.

SIGNIFICANCE STATEMENT Syntaxin 1A (Syx) is a central protein component of the SNARE complex, which underlies neurotransmitter release. Although widely studied in relation to its participation in SNARE complex formation and its interaction with phosphoinositides, the function of Syx's polybasic juxtamembrane region (5RK) remains unclear. Previously, we showed that a conformational transition of Syx, related to calcium-triggered release, reported by a Syx-based FRET probe, is abolished upon charge neutralization of 5RK (5RK/A). Here we show that this conformational transition is dependent on phosphatidylinositol 4,5-bisphosphate (PIP2) and is related to SNARE complex formation. Subsequently, we show that the 5RK/A mutation enhances spontaneous release and inhibits calcium-triggered release in neuroendocrine cells, indicating a previously unrecognized role of 5RK in neurotransmitter release.

Corrigendum

Corrigendum to Jones et al. Pediatric low-grade gliomas: next biologically driven steps. Neuro-Oncology, (http://ift.tt/2lPEC2h) first published online August 02, 2017.

Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma

Abstract

Background

Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is an ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small molecule inhibitor of PP2A designed to sensitize cancer cells to DNA damage from irradiation and chemotherapy. A recently completed phase I trial of LB100 in solid tumors demonstrated its safety. Here, we show the therapeutic potential of LB100 in chordoma.

Methods

Three patient-derived chordoma cell lines, U-CH1, JHC7 and UM-Chor1 were used. Cell proliferation was determined with LB100 alone and in combination with irradiation. Cell cycle progression was assessed by flow cytometry. Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear damage was investigated using Raman imaging and transmission electron microscopy. A xenograft model was established to determine potential clinical utility of adding LB100 to irradiation.

Results

PP2A inhibition in concert with irradiation demonstrated in vitro growth inhibition. The combination of LB100 and radiation also induced accumulation at the G₂/M phase of the cell cycle, the stage most sensitive to radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand breaks. Animals implanted with chordoma cells and treated with the combination of LB100 and radiation demonstrated tumor growth delay.

Conclusions

Combining LB100 and radiation enhanced DNA damage-induced cell death and delayed tumor growth in an animal model of chordoma. PP2A inhibition by LB100 treatment may improve the effectiveness of radiation therapy for chordoma.

The FDA NIH Biomarkers, EndpointS, and other Tools (BEST) Resource in Neuro-Oncology

Abstract

In early 2016, the US Food and Drug Administration (FDA) and National Institutes of Health (NIH) published the first version of the glossary included in the Biomarkers, EndpointS, and other Tools (BEST) Resource¹. The BEST glossary was constructed to harmonize and clarify terms used in translational science and medical product development and to provide a common language used for communication by those agencies. It is considered a "living" document that will be updated in the future. This review will discuss the main biomarker and clinical outcome categories contained in the BEST glossary as they apply to neuro-oncology, as well as the overlapping and hierarchical relationships among them.

308 nm-Excimerlaser zur Therapie von Psoriasis und entzündlichen Hauterkrankungen

Zusammenfassung

Der 308 nm-Excimerlaser ermöglicht eine wirkungsvollere und sicherere UVB-Therapie als die klassische UV-Phototherapie: eine gezielte Bestrahlung in höherer Dosis bei niedrigerer kumulativer Belastung mit dem Ergebnis rascherer Abheilung v. a. umschriebener Hautveränderungen. Das gilt auch für therapieresistente Restherde, die trotz Systemtherapie nicht abklingen. Kombinationstherapien verbessern meist das Ergebnis und ermöglichen, die Dosis des UVB sowie systemischer Medikation zu reduzieren. Excimerlasertherapien können bei einer zunehmenden Zahl von Hauterkrankungen angewendet werden, v. a. bei jenen, die auf Phototherapie oder Photochemotherapie ansprechen.

Nitrobenzene reduction using nanoscale zero-valent iron supported by polystyrene microspheres with different surface functional groups

Abstract

Three polystyrene (PS) resin microspheres supported nanoscale zero-valent iron (nZVI), i.e., nZVI@PS, nZVI@PS-Cl, and nZVI@PS-N, were prepared and characterized by FT-IR, XPS, SEM, EDS, and weighing method. The functional groups on the carriers showed obvious influence on the loading quantity, the micro morphology, and the reduction efficiency of these supported nZVI. The best hybrid reducer was nZVI@PS-N. The load quantity of nZVI was 0.2476 g/g, and some of them were dispersed and the others remained as particles (≤ 50 nm). At optimal reaction conditions, i.e., initial solution pH = 3, 25 °C, 100 r/min stirring, 99% nitrobenzene (NB) in 250 mL 123.1 mg/L NB solution could be totally reduced into AN by 1.31 g fresh nZVI@PS-N within 20 min. The excellent reduction efficiency and fast degradation rate of nZVI@PS-N were mainly attributed to the synergistic effects between the good adsorption property of its carrier and the high reduction activity of nZVI particles. NZVI@PS-N was reproducible and recycled, and 90.6% degradation ratio of NB was till obtained at its seventh recycle. The results showed that nZVI@PS-N had high potential practical application value in the reductive degradation and emergency rescue of nitrobenzene pollutant.

The adaptability of a wetland plant species Myriophyllum aquaticum to different nitrogen forms and nitrogen removal efficiency in constructed wetlands

Abstract

Constructed wetlands (CWs) cultivated with Myriophyllum aquaticum showed great potential for total nitrogen (TN) removal from aquatic ecosystems in previous studies. To evaluate the growth characteristics, photosynthetic pigment content, and antioxidative responses of M. aquaticum, as well as its TN removal efficiency in CWs, M. aquaticum was treated with different levels of ammonium (NH₄⁺) and nitrate (NO₃⁻) for 28 days. The results indicated that M. aquaticum had strong nitrogen stress tolerance and was more likely to be suppressed by high levels of NH₄⁺ than NO₃⁻. High levels of NH₄⁺ also led to inhibition of synthesis of photosynthetic pigments and increased peroxidase activity in plant leaves, which was not found in the NO₃⁻ treatments. High levels of both NH₄⁺ and NO₃⁻ generated obvious oxidative stress through elevation of malondialdehyde content while decreasing superoxide dismutase activity in the early stage. A sustainable increase of TN removal efficiency in most of the CWs indicated that M. aquaticum was a candidate species for treating wastewater with high levels of nitrogen because of its higher tolerance for NH₄⁺ and NO₃⁻ stress. However, the increase of TN removal efficiency was hindered in the late stage when treated with high levels of NH₄⁺ of 26 and 36 mmol/L, indicating that its tolerance to NH₄⁺ stress might have a threshold. The results of this study will enrich the studies on detoxification of high ammonium ion content in NH₄⁺-tolerant submerged plants and supply valuable reference data for proper vegetation of M. aquaticum in CWs.

Experimentation in Institutions: Ethics, Creativity, and Existential Competence

Abstract

The existential, experiential, ethical, pathic and pre-pathic dimensions of education are essential for the creative composition of subjectivities in institutional spaces, yet educational research and policy tend increasingly to privilege technical discourses and prescriptive approaches both when evaluating 'what is effective in education' and when determining educational policy. This essay explores those aspects of the educational experience and educational institutions that are often felt and sensed pre-cognitively by students, parents and teachers, but are seldom given further elaboration or articulation in educational research. We will reflect on what is meant by the experience of education and experience in education, including the struggles to make sense of or understand something, the surprises that strike pre-reflectively, and the ways in which such moments are noticed, pursued, and explored rather than reflexively 'evaluated'. We then explore the idea of experimentation in institutions, in particular in relation to the range of concepts that Jean Oury introduces in order to move our attention and awareness to questions of experience, existence, atmosphere, and the pathic—the way in which we undergo, sense and participate in the world prior to cognition and the desire for mastery and control of our encounters. Finally, we address the question of the ethics of institutions.

(Un)Fixing Education

Abstract

In this article we consider the material dimensions of schooling as constitutive of the possibilities inherent in "fixing" education. We begin by mapping out the problem of "fixing education," pointing to the necrophilic tendencies of contemporary education—a desire to kill what otherwise might be life-giving. In this sense, to "fix" education is to make otherwise fluid processes-of-living static. We next point to the material realities of this move to fix. After establishing the material consequences of perpetually fixing schools, we provide a brief overview of two critical perspectives that might be shown as attempts to "unfix" education: critical pedagogy and unschooling. Though both offer critiques of normative education, these approaches are also bound by their failure to fully engage with the material dimensions of schooling. As such, both critical pedagogy and unschooling inadvertently cut off key possibilities for human flourishing within educational environments. In their rush to "unfix"—to counter the necrophilic tendencies of contemporary education—these approaches exclude or otherwise foreclose upon resistive challenges to the normative order that extend from the margins. In response, we turn to the possibilities for unschooling within the materially public spaces of schools. These are the spaces where fixity fails—possibility extends from unschooling in schools, from unfixing the process of fixing education. We end by considering the possibilities inherent in Community Service Learning as a valuable means to engage in a radically public, and unfixed, educational system.

A New Version of Optimism for Education

Abstract

The primary purpose of this paper is to outline the conceptual means by which it is possible to be optimistic about education. To provide this outline I turn to Ian Hunter and David Blacker, after a brief introduction to Nietzsche's conceptions of optimism and pessimism, to show why certain forms of optimism in education are either intellectually unhelpful or dispositionally helpless in the face of current educational issues. The alternative form of optimism—which I argue is both intellectually and practically helpful—is drawn from a reading of Friedrich Nietzsche. This reading of Nietzsche is not a simple exercise representing his views. As Nietzsche never explicitly advocated for any form of optimism—and frequently advocated against many of its manifestations—drawing what I call 'a new version of optimism' from his writings is no straightforward task, and certainly not without risk. As such, I have extended my readings of Nietzsche across his entire oeuvre, including his writings unintended for publication from his Nachlass. At the core of my argument is the claim that when Nietzsche was sketching out what he called 'a new version of pessimism' (Nietzsche in Writings from the late notebooks, Cambridge University Press, Cambridge, 2003: 173), it was actually quite close to what we might now call 'a new version of optimism.' This first claim precipitates a second, which is that this new version of optimism is not only especially suited to contemporary educational thought and practice but is itself a description of an educational experience and disposition.

From Critical Education to An Embodied Pedagogy of Hope: Seeking a Liberatory Praxis with Black, Working Class Girls in the Neoliberal 16–19 College

Abstract

In this article I present a discussion about the purpose of education of, for and with black, working class, young women within an inner-London, twenty-first century college, and explore the complex and imperfect ways that educational purpose translates into educational practice. I discuss the respective value of two contrasting discourses of education that operate in this college: firstly, a neoliberal discourse of education and educational success; secondly, a critical tradition of education, as traced through the work of Paulo Freire, feminist critics of his work and, ultimately, the work of bell hooks. I argue that a neoliberal rhetoric surrounding education, and the ways it translates into the practice of educating, plays a particular role in Black British, working class girls' continuing educational marginalization. I thus articulate a more liberatory approach to teaching and learning with young, black women, drawing specifically on a hooksian vision of education as it emerges primarily through the work of, Ruth Nicole Brown and Stephanie D. Sears. Within these discussions, I explore dance as a potentially liberatory pedagogic practice, and articulate a possible approach here as an, always imperfect, embodied pedagogy of hope.

A New Rootedness? Education in the Technological Age

Abstract

This paper explores the challenges facing educators in a time when modern technology, and especially modern social technology, has an increasingly powerful hold on our lives. The educational challenge does not primarily concern questions concerning the use of technology in the classroom, or as part of the learning environment, but a changeover in the whole social environment that marks our time. Taking guidance from Heidegger, Wittgenstein, Dewey and Nietzsche, the essay explores what we want the education of children to achieve, and how, if at all, this can be achieved in an age of modern social technology. The central argument is that the most basic educational goal of human flourishing cannot be achieved today as long as the main criteria of "best practice" in the classroom foreground pupil enjoyment rather than endurance of suffering. The paradox is that any call for the latter is now largely heard in a way cultivated by the culture of the former: namely, poorly and vulgarly, associated only with bullying authoritarianism, rather than the devoted care of teachers who want to awaken their pupils to self-responsibility.

Teaching, in Spite of Excellence: Recovering a Practice of Teaching-Led Research

Abstract

Although, as a result of the introduction of the Teaching Excellence Framework, the principle of teaching excellence is receiving renewed attention in English higher education, the idea has been left largely undefined. The cynic might argue, in agreement with Bill Readings, that this lack of a precise definition is deliberate, since teaching excellence is not designed to observe teaching but to permit an integrated system of accounting. This article, however, develops a different line of criticism. Following Readings's characterization of "excellence" as symptomatic of the "Americanization" of higher education, it traces the principle of teaching excellence in English educational discourse back to the influence of debates, led by Ernest Boyer in the US, concerning the teaching-research nexus. Contextualizing these debates in relation to ideas about the learning society influenced by theories of human capital and investment in national productivity, it takes issue with descriptions of recent policy that overemphasize the corporate structure of the university and its vision of the student as consumer at the expense of recognizing the continuation of the nation-state organization of the student as producer. Reconnecting this broader framework back to the teaching-research nexus, the article examines how this intersects with the dominant agenda of research-led teaching excellence, centred on the idea of the productivity of research, and outlines an alternative notion of teaching-led research, developed out of the work of Boyer and Walter Benjamin, within which teaching might continue, in spite of excellence.

Correlation of APRIL with production of inflammatory cytokines during acute malaria in the Brazilian Amazon

Abstract

Introduction

A proliferation-inducing ligand (APRIL) and B cell activation factor (BAFF) are known to play a significant role in the pathogenesis of several diseases, including BAFF in malaria. The aim of this study was to investigate whether APRIL and BAFF plasma concentrations could be part of inflammatory responses associated with P. vivax and P. falciparum malaria in patients from the Brazilian Amazon.

Methods

Blood samples were obtained from P. vivax and P. falciparum malaria patients (n = 52) resident in Porto Velho before and 15 days after the beginning of treatment and from uninfected individuals (n = 12). We investigated APRIL and BAFF circulating levels and their association with parasitaemia, WBC counts, and cytokine/chemokine plasma levels. The expression levels of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) on PBMC from a subset of 5 P. vivax-infected patients were analyzed by flow cytometry.

Results

APRIL plasma levels were transiently increased during acute P. vivax and P. falciparum infections whereas BAFF levels were only increased during acute P. falciparum malaria. Although P. vivax and P. falciparum malaria patients have similar cytokine profiles during infection, in P. vivax acute phase malaria, APRIL but not BAFF levels correlated positively with IL-1, IL-2, IL-4, IL-6, and IL-13 levels. We did not find any association between P. vivax parasitaemia and APRIL levels, while an inverse correlation was found between P. falciparum parasitaemia and APRIL levels. The percentage of TACI positive CD4+ and CD8+ T cells were increased in the acute phase P. vivax malaria.

Conclusion

These findings suggest that the APRIL and BAFF inductions reflect different host strategies for controlling infection with each malaria species.

APRIL and BAFF levels in P. vivax and P. falciparum malaria.

Vitiligo und Psoriasis

Zusammenfassung

Berichtet wird der Fall einer 59-jährigen Patientin, bei der zum Vorstellungszeitpunkt sowohl eine Psoriasis vulgaris als auch eine Vitiligo bestanden. Die depigmentierten Areale beschränkten sich dabei nicht ausschließlich auf die psoriatischen Plaques. Bekannt sind zahlreiche Gemeinsamkeiten im Pathomechanismus dieser beiden häufigen Erkrankungen. So handelt es sich jeweils um T‑Zell-vermittelte Autoimmunerkrankungen, bei denen u. a. das Köbner-Phänomen vorkommt. Letztlich nicht geklärt ist bislang jedoch, ob es sich um eine überzufällige oder beliebige Koinzidenz handelt. Abzuwarten bleibt diesbezüglich die weitere klinische und epidemiologische Forschung.

Studies in the logic of K -onfirmation

Abstract

This research article revisits Hempel's logic of confirmation in light of recent developments in categorical proof theory. While Hempel advocated several logical conditions in favor of a purely syntactical definition of a general non-quantitative concept of confirmation, we show how these criteria can be associated to specific logical properties of monoidal modal deductive systems. In addition, we show that many problems in confirmation logic, such as the tacked disjunction, the problem of weakening with background knowledge and the problem of irrelevant conjunction, are also associated with specific logical properties and, incidentally, with some of Hempel's logical conditions of adequacy. We discuss the raven paradox together with further objections against Hempel's approach, showing how our analysis enables a clear understanding of the relationships between Hempel's conditions, the problems in confirmation logic, and the properties of deductive systems.

Adsorption kinetics and mechanisms of copper ions on activated carbons derived from pinewood sawdust by fast H 3 PO 4 activation

Abstract

Two kinds of pinewood sawdust activated carbon adsorbents were prepared by fast activation with H₃PO₄ in a spouted bed, and the application in adsorption of copper ions was investigated. With only 3 min of activation time, the BET surface area of activated carbons reached 1537.5 m²/g for impregnation mass ratio of H₃PO₄ to sawdust at 1:1 and activation temperature of 500 °C (IR1-500), whereas it was 1750.7 m²/g for the impregnation ratio at 4:1 and activation temperature of 800 °C (IR4-800). The pseudo second-order reaction kinetics well describes the experimental adsorption of copper ion in this study, indicating chemisorption dominated in the process. By the C_1s spectrum, activated carbons from IR1-500 contained more carboxyl groups (-COOH) and carbonyl groups (C=O), which played an important role in copper ions adsorption. In addition, it was found that the P-containing groups (metaphosphates) also involved in the adsorption of copper ion.