Impact of Adverse Event Solicitation on the Safety Profile of SQ House Dust Mite Sublingual Immunotherapy Tablet

Publication date: Available online 10 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Hendrik Nolte, David I. Bernstein, Gordon L. Sussman, Bodil Svanholm Fogh, Susan Lu, Bernt Husøy, Harold S. Nelson
BackgroundIt has been recommended that sublingual immunotherapy (SLIT) safety be assessed using solicited adverse event (AE) collection methods.ObjectivesTo describe the impact on the safety profile of SQ house dust mite (HDM) SLIT-tablet (12 SQ-HDM dose) when pre-specified local application site reactions were solicited vs unsolicited, and discuss ramifications of AE solicitation.MethodsSubjects were randomized to daily 12 SQ-HDM or placebo for up to 52 weeks in 4 double-blinded, multicenter trials. In one trial (NCT01700192; N=1,272), subjects documented daily the presence or absence of 15 World Allergy Organization-defined local application site reactions using a structured questionnaire of closed-ended questions (solicited AEs). Subjects in the other trials were not asked about specific AEs (unsolicited AEs) and AE data were pooled (N=1,287). Analysis was limited to adults aged 18-65 years.ResultsWhether AEs were solicited or unsolicited, the most common AEs leading to study discontinuation with 12 SQ-HDM were throat irritation and oral pruritus. Approximately 95% of treatment-related AEs were mild-to-moderate. Placebo-subtracted frequencies of local application site reactions associated with 12 SQ-HDM were higher when solicited vs unsolicited (i.e., throat irritation, 46% vs 13%, respectively; oral pruritus, 47% vs 17%; ear pruritus, 40% vs 4%; mouth swelling, 8% vs 2%; tongue ulceration, 10% vs 0%; mouth ulceration, 7% vs <1%).ConclusionsQualitatively, the safety profile of 12 SQ-HDM was similar when AEs were solicited vs unsolicited; hence, solicitation did not alter the safety profile. Higher observed frequencies of local application site reactions with AE solicitation may be partly due to suggestive reporting bias, as observed in placebo-treated subjects.

Implementation of Guidelines for Early Peanut Introduction at a Pediatric Academic Center

Publication date: Available online 9 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): David R. Stukus, Ben T. Prince, Irene Mikhail

Conjunctivitis Occurring in Atopic Dermatitis Patients Treated with Dupilumab - Clinical Characteristics and Treatment

Publication date: Available online 9 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Andreas Wollenberg, Lieneke Ariens, Stephan Thurau, Chantal van Luijk, Marlene Seegräber, Marjolein de Bruin-Weller

Use of ICS/LABA Combinations or LAMA is Associated with a Lower Risk of Acute Exacerbation in Patients with Coexistent COPD and Asthma

Publication date: Available online 10 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Vincent Yi-Fong Su, Kuang-Yao Yang, Yao-Hsu Yang, Ying-Huang Tsai, Diahn-Warng Perng, Wei-Juin Su, Kun-Ta Chou, Kang-Cheng Su, Yung-Feng Yen, Pau-Chung Chen
BackgroundBased on current guidelines, more research is urgently needed to guide appropriate treatment for patients with asthma−chronic obstructive pulmonary disease overlap.ObjectiveThe objective of this study was to investigate medication effects on acute exacerbation in patients with coexistent COPD and asthma.MethodsUsing Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study to evaluate medication effects in patients with COPD and asthma. Patients diagnosed with both asthma and COPD between 1997 and 2012 were enrolled as the COPD + asthma cohort. The primary endpoint was acute exacerbation. The definitions of COPD and asthma were validated. The validation study confirmed the accuracy of definitions of COPD (86.2% sensitivity) and asthma (92.0% sensitivity).ResultsThe study included 251,398 patients with COPD + asthma and 514,522 patients with COPD alone, with a mean follow-up period of 9.85 years. After adjustment, hazard ratios (HRs) for long-acting muscarinic antagonist (LAMA) and inhaled corticosteroid/long-acting beta 2 agonist (ICS/LABA) combinations were lower [time-dependent model, 1 year: LAMA, HR 0.51, 95% confidence interval (CI) 0.49–0.54; ICS/LABA combinations, HR 0.61, 95% CI 0.60–0.62; all p < 0.0001] than were those for LABAs or ICSs in patients with COPD and asthma.ConclusionsLAMA or ICS/LABA combinations use was associated with a lower risk of acute exacerbation in patients with COPD and asthma in this study.

Noninvasive quantitative analysis of ceramide in skin of healthy Chinese population

Abstract

Objective

The objective of this study was to make noninvasive quantitative analysis of ceramide (CER) in skin of healthy Chinese population by high performance liquid chromatography tandem mass spectrometry.

Methods

Seven healthy subjects were selected and the stratified skin samples were available using cyanoacrylate adhesion method. High performance liquid chromatography tandem mass spectrometry, use ceramide Subclass Standard C42H85NO3 Quantification of the 12 corresponding ceramide subclass in the epidermis on the 7 skin samples, which cannot get all the standard of ceramides subclass since the stratum corneum ceramide is complex and diverse. Data were collected and analyzed using full-flow lipid analysis software (LipidSearch).

Results

All the seven skin samples contained 12 subclasses of ceramide and the samples were quantitated with ceramide C42H85NO3 standard. The average contents were 33.63, 27.59, 108.57, 220.75, 149.20, 43.06, and 22.78 μg/mL, respectively.

Conclusion

Ceramide is an important lipid in the epidermis and is closely related to the skin barrier function. There are 12 subtypes of ceramide detected in the skin of Chinese healthy people, and there is a difference in the concentration between individuals. The difference may be associated with the skin barrier condition, and may also be related to the unavoidable error in the process of sampling, treatment, and detection.

Systemic juvenile xanthogranuloma: a case report and brief review

First report of COL7A1 mutations in two patients with recessive dystrophic epidermolysis bullosa from Peru

Multiplatform next-generation sequencing identifies novel RNA molecules and transcript isoforms of the endogenous retrovirus isolated from cultured cells

Abstract

In this study, we applied short- and long-read RNA sequencing techniques, as well as PCR analysis to investigate the transcriptome of the porcine endogenous retrovirus (PERV) expressed from cultured porcine kidney cell line PK-15. This analysis has revealed six novel transcripts and eight transcript isoforms, including five length and three splice variants. We were able to establish whether a deletion in a transcript is the result of the splicing of mRNAs or of genomic deletion in one of the PERV clones. Additionally, we re-annotated the formerly identified RNA molecules. Our analysis revealed a higher complexity of PERV transcriptome than it was earlier believed.

Identification of intermediates, acute toxicity removal, and kinetics investigation to the Ametryn treatment by direct photolysis (UV 254 ), UV 254 /H 2 O 2 , Fenton, and photo-Fenton processes

Abstract

This paper reports the degradation of 10 mg L⁻¹ Ametryn solution with different advanced oxidation processes and by ultraviolet (UV₂₅₄) irradiation alone with the main objective of reducing acute toxicity and increase biodegradability. The investigated factors included Fe²⁺ and H₂O₂ concentrations. The effectiveness of the UV₂₅₄ and UV₂₅₄/H₂O₂ processes were investigated using a low-pressure mercury UV lamp (254 nm). Photo-Fenton process was explored using a blacklight blue lamp (BLB, λ = 365 nm). The UV₂₅₄ irradiation process achieved complete degradation of Ametryn solution after 60 min. The degradation time of Ametryn was greatly improved by the addition of H₂O₂. It is worth pointing out that a high rate of Ametryn removal was attained even at low concentrations of H₂O₂. The kinetic constant of the reaction between Ametryn and HO^● for UV₂₅₄/H₂O₂ was 3.53 × 10⁸ L mol⁻¹ s⁻¹. The complete Ametryn degradation by the Fenton and photo-Fenton processes was observed following 10 min of reaction for various combinations of Fe²⁺ and H₂O₂ under investigation. Working with the highest concentration (150 mg L⁻¹ H₂O₂ and 10 mg L⁻¹ Fe²⁺), around 30 and 70% of TOC removal were reached within 120 min of treatment by Fenton and photo-Fenton processes, respectively. Although it did not obtain complete mineralization, the intermediates formed in the degradation processes were hydroxylated and did not promote acute toxicity of Vibrio fischeri. Furthermore, a substantial improvement of biodegradability was obtained for all studied processes.

Complexation of sulfamethazine with Cd(II) and Pb(II): implication for co-adsorption of SMT and Cd(II) on goethite

Abstract

This study quantified the complex stability constants of sulfamethazine (SMT) with cadmium (Cd²⁺) and lead (Pb²⁺) under different pH conditions. The UV-Vis spectrophotometer was used for acquiring the complexation data. Results showed that the complex stability constants of SMT with cadmium (Cd²⁺) and lead (Pb²⁺) increased as a function of the solution pH. In the investigated pH range, Cd²⁺ showed stronger complex affinity with SMT than Pb²⁺. It appeared that cation-π interactions might dominate the complex between SMT with Pb²⁺ and Cd²⁺ at acid environment, and the covalent bonding might play a major role at neutral environment. Batch adsorption equilibrium experiment showed that the sorption capacity of Cd²⁺ on goethite increased from 3.83 to 7.64 mg/g along with the addition of 1 mg/L SMT, indicating SMT can impede the transportation of Cd. In general, this study worked out the complexation constants and clarified the complexation mechanism between SMT with lead and cadmium, while sorption experiment indicated that sorption of Cd onto goethite was enhanced with SMT.

“Looking Up” and “Looking Down”: On the Dual Character of Mechanistic Explanations

Abstract

Mechanistic explanation is at present the received view of scientific explanation. One of its central features is the idea that mechanistic explanations are both "downward looking" and "upward looking": they explain by offering information about the internal constitution of the mechanism as well as the larger environment in which the mechanism is situated. That is, they offer both constitutive and contextual explanatory information. Adequate mechanistic explanations, on this view, accommodate the full range of explanatory factors both "above" and "below" the target phenomenon. The aim of this paper is to demonstrate that mechanistic explanation cannot furnish both constitutive and contextual information simultaneously, because these are different types of explanation with distinctly different aims. Claims that they can, I argue, depend on several intertwined confusions concerning the nature of explanation. Particularly, such claims tend to conflate mechanistic and functional explanation, which I argue ought to be understood as distinct. Conflating them threatens to oversell the explanatory power of mechanisms and obscures the means by which they explain. I offer two broad reasons in favor of distinguishing mechanistic and functional explanation: the first concerns the direction of explanation of each, and the second concerns the type of questions to which these explanations offer answers. I suggest an alternative picture on which mechanistic explanation is understood as fundamentally constitutive, and according to which an adequate understanding of a phenomenon typically requires supplementing the mechanistic explanation with a functional explanation.

Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Leptomeningeal contrast enhancement is found in patients with multiple sclerosis, though reported rates have varied. The use of 3D-fluid-attenuated inversion recovery pre- and postcontrast subtraction imaging may more accurately determine the frequency of leptomeningeal contrast enhancement. The purpose of this study was to investigate the frequency of leptomeningeal contrast enhancement using the pre- and postcontrast subtraction approach and to evaluate 3 different methods of assessing the presence of leptomeningeal contrast enhancement.

MATERIALS AND METHODS:

We enrolled 258 consecutive patients with MS (212 with relapsing-remitting MS, 32 with secondary-progressive MS, and 14 with clinically isolated syndrome) who underwent both pre- and 10-minute postcontrast 3D-FLAIR sequences after a single dose of gadolinium injection on 3T MR imaging. The analysis included leptomeningeal contrast-enhancement evaluation on 3D-FLAIR postcontrast images in native space (method A), on pre- and postcontrast 3D-FLAIR images in native space (method B), and on pre-/postcontrast 3D-FLAIR coregistered and subtracted images (method C, used as the criterion standard).

RESULTS:

In total, 51 (19.7%) patients with MS showed the presence of leptomeningeal contrast enhancement using method A; 39 (15.1%), using method B; and 39 (15.1%), using method C (P = .002). Compared with method C as the criterion standard, method A showed 89.8% sensitivity and 92.7% specificity, while method B showed 84.6% sensitivity and 97.3% specificity (P < .001) at the patient level. Reproducibility was the highest using method C ( agreement, r = 088, P < .001). The mean time to analyze the 3D-FLAIR images was significantly lower with method C compared with methods A and B (P < .001).

CONCLUSIONS:

3D-FLAIR postcontrast imaging offers a sensitive method for detecting leptomeningeal contrast enhancement in patients with MS. However, the use of subtraction imaging helped avoid false-positive cases, decreased reading time, and increased the accuracy of leptomeningeal contrast-enhancement foci detection in a clinical routine.

Dual-Energy CT in Hemorrhagic Progression of Cerebral Contusion: Overestimation of Hematoma Volumes on Standard 120-kV Images and Rectification with Virtual High-Energy Monochromatic Images after Contrast-Enhanced Whole-Body Imaging [ADULT BRAIN]

BACKGROUND AND PURPOSE:

In patients with hemorrhagic contusions, hematoma volumes are overestimated on follow-up standard 120-kV images obtained after contrast-enhanced whole-body CT. We aimed to retrospectively determine hemorrhagic progression of contusion rates on 120-kV and 190-keV images derived from dual-energy CT and the magnitude of hematoma volume overestimation.

MATERIALS AND METHODS:

We retrospectively analyzed admission and follow-up CT studies in 40 patients with hemorrhagic contusions. After annotating the contusions, we measured volumes from admission and follow-up 120-kV and 190-keV images using semiautomated 3D segmentation. Bland-Altman analysis was used for hematoma volume comparison.

RESULTS:

On 120-kV images, hemorrhagic progression of contusions was detected in 24 of the 40 patients, while only 17 patients had hemorrhagic progression of contusions on 190-keV images (P = .008). Hematoma volumes were systematically overestimated on follow-up 120-kV images (9.68 versus 8 mm³; mean difference, 1.68 mm³; standard error, 0.37; P < .001) compared with 190-keV images. There was no significant difference in volumes between admission 120-kV and 190-keV images. Mean and median percentages of overestimation were 29% (95% CI, 18–39) and 22% (quartile 3 – quartile 1 = 36.8), respectively.

CONCLUSIONS:

The 120-kV images, which are comparable with single-energy CT images, significantly overestimated the hematoma volumes, hence the rate of hemorrhagic progression of contusions, after contrast-enhanced whole-body CT. Hence, follow-up of hemorrhagic contusions should be performed on dual-energy CT, and 190-keV images should be used for the assessment of hematoma volumes.

Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging.

MATERIALS AND METHODS:

Brain MR imaging using T1-weighted MP2RAGE at 500-μm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry.

RESULTS:

MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage.

CONCLUSIONS:

A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

Brain Imaging in Cases with Positive Serology for Dengue with Neurologic Symptoms: A Clinicoradiologic Correlation [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Dengue is a common arboviral disease, which uncommonly involves the brain. There has been a recent surge in dengue cases and dengue-related deaths in tropical countries. The aim of this study was to describe brain imaging findings in patients with dengue infection having neurologic symptoms.

MATERIALS AND METHODS:

Thirty-five patients with positive serology for dengue with CNS symptoms undergoing imaging of the brain were included in the study. Clinical, laboratory, and imaging parameters were assessed and correlated to poor outcome.

RESULTS:

A Glasgow Coma Scale score of ≤12 at presentation, clinical classification of severe-type dengue, and the presence of acute renal failure were associated with poor outcome. Imaging parameters associated with poor outcome were involvement of the thalami and cerebellar peduncles and the presence of diffusion restriction and hemorrhagic foci in the brain parenchyma.

CONCLUSIONS:

Although not specific, dengue infection has imaging findings that can be used to narrow down the differential list and help in prognostication.

Iron-Insensitive Quantitative Assessment of Subcortical Gray Matter Demyelination in Multiple Sclerosis Using the Macromolecular Proton Fraction [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Fast macromolecular proton fraction mapping is a recent quantitative MR imaging method for myelin assessment. The objectives of this study were to evaluate the macromolecular proton fraction as a measure of demyelination in subcortical GM structures in multiple sclerosis and assess a potential relationship between demyelination and excess iron deposition using the macromolecular proton fraction and T2* mapping.

MATERIALS AND METHODS:

Macromolecular proton fraction and T2* maps were obtained from 12 healthy controls, 18 patients with relapsing-remitting MS, and 12 patients with secondary-progressive MS using 3T MR imaging. Parameter values in the caudate nucleus, globus pallidus, putamen, substantia nigra, and thalamus were compared between groups and correlated to clinical data.

RESULTS:

The macromolecular proton fraction in all subcortical structures and T2* in the globus pallidus, putamen, and caudate nucleus demonstrated a significant monotonic decrease from controls to patients with relapsing-remitting MS and from those with relapsing-remitting MS to patients with secondary-progressive MS. The macromolecular proton fraction in all subcortical structures significantly correlated with the Expanded Disability Status Scale and MS Functional Composite scores with absolute Pearson correlation coefficient (r) values in a range of 0.4–0.6. Significant correlations (r = –0.4 to –0.6) were also identified between the macromolecular proton fraction and the 9-Hole Peg Test, indicating a potential relationship with nigrostriatal pathway damage. Among T2* values, weak significant correlations with clinical variables were found only in the putamen. The macromolecular proton fraction did not correlate with T2* in any of the studied anatomic structures.

CONCLUSIONS:

The macromolecular proton fraction provides an iron-insensitive measure of demyelination. Myelin loss in subcortical GM structures in MS is unrelated to excess iron deposition. Subcortical GM demyelination is more closely associated with the disease phenotype and disability than iron overload.

Endovascular Thrombectomy in Wake-Up Stroke and Stroke with Unknown Symptom Onset [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Mechanical thrombectomy in acute ischemic stroke within 6 hours of symptom onset is effective and safe. However, in many patients, information on the beginning of symptoms is not available. Patients can be divided into those with wake-up stroke and daytime-unwitnessed stroke. Evidence on outcome and complications after mechanical thrombectomy in wake-up stroke and daytime-unwitnessed stroke is rare. A potential beneficial effect of mechanical thrombectomy in selected patients with wake-up stroke or daytime-unwitnessed stroke is suspected.

MATERIALS AND METHODS:

We analyzed 1073 patients with anterior circulation stroke undergoing mechanical thrombectomy between 2010 and 2016. Patients with wake-up stroke and daytime-unwitnessed stroke were compared with controls receiving mechanical thrombectomy as the standard of care. We assessed good functional outcome (mRS ≤ 2 at 3 months), mortality rates, and frequencies of symptomatic intracranial hemorrhage. Subgroup analyses tried to detect influences of patient selection via further imaging modalities (MR imaging, CTP; wake-up stroke [advanced], daytime-unwitnessed stroke [advanced]) on outcome and safety.

RESULTS:

There was no significant difference in good functional outcome between patients with wake-up stroke and controls (35.9% versus 38.3%, P = .625). Outcome in patients with daytime-unwitnessed stroke was inferior compared with controls (27.3%, P = .007). Groups did not differ in all-cause mortality at day 90 (P = .224) and the rate of symptomatic intracranial hemorrhage (P = .292). Advanced imaging improved the frequency of good functional outcome (non-wake-up stroke [advanced] versus wake-up stroke [advanced]: OR, 2.92; 95% CI, 1.32–6.45; non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 2.09; 95% CI, 1.03–4.25) with an additional reduction in all-cause mortality (non-daytime-unwitnessed stroke [advanced] versus daytime-unwitnessed stroke [advanced]: OR, 0.42; 95% CI, 0.20–0.88).

CONCLUSIONS:

Mechanical thrombectomy in selected patients with wake-up stroke allows a good functional outcome comparable with that of controls. Outcome after mechanical thrombectomy in daytime-unwitnessed stroke seems to be inferior compared with that in controls. Advanced imaging modalities may increase the frequency of good functional outcome in both patients with wake-up stroke and daytime-unwitnessed stroke.

Antibiotic residues in liquid manure from swine feedlot and their effects on nearby groundwater in regions of North China

Abstract

A survey was conducted in regions of North China to better understand the effect of antibiotic residue pollution from swine feedlots to nearby groundwater environment. A total of nine experimental sites located in the regions of Beijing, Hebei, and Tianjin were selected to analyze the presence of residues of 11 most commonly used antibiotics, including tetracyclines (TCs), fluoroquinolones (FQNs), sulfonamides (SAs), macrolides, and fenicols, by using liquid chromatography spectrometry. The three most common antibiotics were TCs, FQNs, and SAs, with mean concentrations of 416.4, 228.8, and 442.4 μg L⁻¹ in wastewater samples; 19.9, 11.8, and 0.3 μg L⁻¹ in groundwater samples from swine feedlots; and 29.7, 14.0, and 0 μg L⁻¹ in groundwater samples from villages. Ordination analysis revealed that the composition and distribution of antibiotics and antibiotic resistance genes (AGRs) were similar in groundwater samples from swine feedlots and villages. FQNs and TCs occurred along the path from wastewater to groundwater at high concentrations and showed correlations with ARGs, with a strong correlation between FQN resistance gene (qnrA) copy number. FQN concentration was also found (P < 0.01) in wastewater and groundwater in villages (P < 0.01). Therefore, antibiotics discharged from swine feedlots through wastewater could disseminate into surrounding groundwater environments together with ARG occurrence (i.e., qnrA, sulI, sulII, tetG, tetM, and tetO). Overall, this study suggests that the spread of veterinary antibiotics from swine feedlots to groundwater environments should be highly attended and controlled by restricting excess antibiotic usage or improving the technology of manure management.

In vitro and in vivo investigation of a novel amniotic-based chitosan dressing for wound healing

Abstract

It is more than a decade that amniotic membrane has been used as a wound dressing because of its anti-inflammatory, anti-microbial, anti-fibrotic, anti-scaring properties, as well as its pain relieving and epithelialization promoting features. However, amniotic membrane had limited applications because it needs to suture in surgery, is highly fragile, firmly adhere to the wound and may cause bleeding and pain when changing the bandage. This study investigated the possibility of development of a novel amniotic-based chitosan gel dressing as a potential wound repair substrate with marked efficacy. In this experiment, amniotic gel prepared based on chitosan/PVP gel containing human amniotic membrane extract (AME-Gel) was investigated in terms of wound-healing efficacy and scar preventive effects in a rat burn model. The levels of re-epithelialization and dermal regeneration were examined by histological assessment using H&E and Masson's trichrome staining. Also, we clarified the mechanism of healing and cytokine-releasing activities of AME as well as its effect on epithelization, angiogenesis and fibroblast growth and migration. Our results revealed that AME-Gel induces epidermal and dermal regeneration at a shorter time through formation of granulation tissue, enhancement of fibroblast proliferation and improvement of blood capillary formation concomitant with developing collagen bundles. Therefore, AME-Gel could be considered a simple and easy to be used as a biological dressing for any type of superficial burn wounds, without any adverse effects. This article is protected by copyright. All rights reserved.

Transcriptional Regulator ZEB2 Is Essential for Bergmann Glia Development

Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat–Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat–Wilson syndrome.

SIGNIFICANCE STATEMENT Bergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat–Wilson syndrome.

Locus Coeruleus Activity Strengthens Prioritized Memories Under Arousal

Recent models posit that bursts of locus ceruleus (LC) activity amplify neural gain such that limited attention and encoding resources focus even more on prioritized mental representations under arousal. Here, we tested this hypothesis in human males and females using fMRI, neuromelanin MRI, and pupil dilation, a biomarker of arousal and LC activity. During scanning, participants performed a monetary incentive encoding task in which threat of punishment motivated them to prioritize encoding of scene images over superimposed objects. Threat of punishment elicited arousal and selectively enhanced memory for goal-relevant scenes. Furthermore, trial-level pupil dilations predicted better scene memory under threat, but were not related to object memory outcomes. fMRI analyses revealed that greater threat-evoked pupil dilations were positively associated with greater scene encoding activity in LC and parahippocampal cortex, a region specialized to process scene information. Across participants, this pattern of LC engagement for goal-relevant encoding was correlated with neuromelanin signal intensity, providing the first evidence that LC structure relates to its activation pattern during cognitive processing. Threat also reduced dynamic functional connectivity between high-priority (parahippocampal place area) and lower-priority (lateral occipital cortex) category-selective visual cortex in ways that predicted increased memory selectivity. Together, these findings support the idea that, under arousal, LC activity selectively strengthens prioritized memory representations by modulating local and functional network-level patterns of information processing.

SIGNIFICANCE STATEMENT Adaptive behavior relies on the ability to select and store important information amid distraction. Prioritizing encoding of task-relevant inputs is especially critical in threatening or arousing situations, when forming these memories is essential for avoiding danger in the future. However, little is known about the arousal mechanisms that support such memory selectivity. Using fMRI, neuromelanin MRI, and pupil measures, we demonstrate that locus ceruleus (LC) activity amplifies neural gain such that limited encoding resources focus even more on prioritized mental representations under arousal. For the first time, we also show that LC structure relates to its involvement in threat-related encoding processes. These results shed new light on the brain mechanisms by which we process important information when it is most needed.

Regulation of Lateral Hypothalamic Orexin Activity by Local GABAergic Neurons

Orexin (also known as hypocretin) neurons are considered a key component of the ascending arousal system. They are active during wakefulness, at which time they drive and maintain arousal, and are silent during sleep. Their activity is controlled by long-range inputs from many sources, as well as by more short-range inputs, including from presumptive GABAergic neurons in the lateral hypothalamus/perifornical region (LH/PF). To characterize local GABAergic input to orexin neurons, we used channelrhodopsin-2-assisted circuit mapping in brain slices. We expressed channelrhodopsin-2 in GABAergic neurons (Vgat⁺) in the LH/PF and recorded from genetically identified surrounding orexin neurons (LH/PF^Vgat -> Orx). We performed all experiments in mice of either sex. Photostimulation of LH/PF GABAergic neurons inhibited the firing of orexin neurons through the release of GABA, evoking GABA_A-mediated IPSCs in orexin neurons. These photo-evoked IPSCs were maintained in the presence of TTX, indicating direct connectivity. Carbachol inhibited LH/PF^Vgat -> Orx input through muscarinic receptors. By contrast, application of orexin was without effect on LH/PF^Vgat -> Orx input, whereas dynorphin, another peptide produced by orexin neurons, inhibited LH/PF^Vgat -> Orx input through -opioid receptors. Our results demonstrate that orexin neurons are under inhibitory control by local GABAergic neurons and that this input is depressed by cholinergic signaling, unaffected by orexin and inhibited by dynorphin. We propose that local release of dynorphin may, via collaterals, provides a positive feedback to orexin neurons and that, during wakefulness, orexin neurons may be disinhibited by acetylcholine and by their own release of dynorphin.

SIGNIFICANCE STATEMENT The lateral hypothalamus contains important wake-promoting cell populations, including orexin-producing neurons. Intermingled with the orexin neurons, there are other cell populations that selectively discharge during nonrapid eye movement or rapid eye movement sleep. Some of these sleep-active neurons release GABA and are thought to inhibit wake-active neurons during rapid eye movement and nonrapid eye movement sleep. However, this hypothesis had not been tested. Here we show that orexin neurons are inhibited by a local GABAergic input. We propose that this local GABAergic input inhibits orexin neurons during sleep but that, during wakefulness, this input is depressed, possibly through cholinergically mediated disinhibition and/or by release of dynorphin from orexin neurons themselves.

Nonselective Wiring Accounts for Red-Green Opponency in Midget Ganglion Cells of the Primate Retina

In primate retina, "red-green" color coding is initiated when signals originating in long (L) and middle (M) wavelength-sensitive cone photoreceptors interact antagonistically. The center-surround receptive field of "midget" ganglion cells provides the neural substrate for L versus M cone-opponent interaction, but the underlying circuitry remains unsettled, centering around the longstanding question of whether specialized cone wiring is present. To address this question, we measured the strength, sign, and spatial tuning of L- and M-cone input to midget receptive fields in the peripheral retina of macaque primates of either sex. Consistent with previous work, cone opponency arose when one of the cone types showed a stronger connection to the receptive field center than to the surround. We implemented a difference-of-Gaussians spatial receptive field model, incorporating known biology of the midget circuit, to test whether physiological responses we observed in real cells could be captured entirely by anatomical nonselectivity. When this model sampled nonselectively from a realistic cone mosaic, it accurately reproduced key features of a cone-opponent receptive field structure, and predicted both the variability and strength of cone opponency across the retina. The model introduced here is consistent with abundant anatomical evidence for nonselective wiring, explains both local and global properties of the midget population, and supports a role in their multiplexing of spatial and color information. It provides a neural basis for human chromatic sensitivity across the visual field, as well as the maintenance of normal color vision despite significant variability in the relative number of L and M cones across individuals.

SIGNIFICANCE STATEMENT Red-green color vision is a hallmark of the human and nonhuman primate that starts in the retina with the presence of long (L)- and middle (M)-wavelength sensitive cone photoreceptor types. Understanding the underlying retinal mechanism for color opponency has focused on the broad question of whether this characteristic can emerge from nonselective wiring, or whether complex cone-type-specific wiring must be invoked. We provide experimental and modeling support for the hypothesis that nonselective connectivity is sufficient to produce the range of red-green color opponency observed in midget ganglion cells across the retina. Our nonselective model reproduces the diversity of physiological responses of midget cells while also accounting for systematic changes in color sensitivity across the visual field.

Neural Integration of Stimulus History Underlies Prediction for Naturalistically Evolving Sequences

Forming valid predictions about the environment is crucial to survival. However, whether humans are able to form valid predictions about natural stimuli based on their temporal statistical regularities remains unknown. Here, we presented subjects with tone sequences with pitch fluctuations that, over time, capture long-range temporal dependence structures prevalent in natural stimuli. We found that subjects were able to exploit such naturalistic statistical regularities to make valid predictions about upcoming items in a sequence. Magnetoencephalography (MEG) recordings revealed that slow, arrhythmic cortical dynamics tracked the evolving pitch sequence over time such that neural activity at a given moment was influenced by the pitch of up to seven previous tones. Importantly, such history integration contained in neural activity predicted the expected pitch of the upcoming tone, providing a concrete computational mechanism for prediction. These results establish humans' ability to make valid predictions based on temporal regularities inherent in naturalistic stimuli and further reveal the neural mechanisms underlying such predictive computation.

SIGNIFICANCE STATEMENT A fundamental question in neuroscience is how the brain predicts upcoming events in the environment. To date, this question has primarily been addressed in experiments using relatively simple stimulus sequences. Here, we studied predictive processing in the human brain using auditory tone sequences that exhibit temporal statistical regularities similar to those found in natural stimuli. We observed that humans are able to form valid predictions based on such complex temporal statistical regularities. We further show that neural response to a given tone in the sequence reflects integration over the preceding tone sequence and that this history dependence forms the foundation for prediction. These findings deepen our understanding of how humans form predictions in an ecologically valid environment.

Retrosplenial Cortex Indexes Stability beyond the Spatial Domain

Retrosplenial cortex (RSC) is highly responsive to landmarks in the environment that remain fixed in a permanent location, and this has been linked with its known involvement in scene and spatial processing. However, it is unclear whether RSC representations of permanence are a purely spatial phenomenon or whether they extend into behavioral and conceptual domains. To test this, during functional MRI scanning, we had people (males and females) read three different types of sentences that described either something permanent or transient. The first two sentence types were imageable, with a focus either on a spatial landmark or on an action. The third type of sentence involved non-imageable abstract concepts. We found that, in addition to being more active for sentences describing landmarks with a permanent location in space, RSC was also significantly engaged by sentences describing stable and consistent behaviors or actions, as long as they were rooted within a concrete imageable setting. RSC was not responsive to abstract concepts, even those that embodied the notion of stability. Similarly, it was not engaged by imageable sentences with transient contents. In contrast, parahippocampal cortex was more engaged by imageable sentences describing landmarks, whereas the hippocampus was active for all imageable sentences. In addition, for imageable sentences describing permanence, there was bidirectional functional coupling between RSC and these medial temporal lobe structures. It appears, therefore, that RSC-mediated permanence representations could be helpful for more than spatially mapping environments and may also provide information about the reliability of events occurring within them.

SIGNIFICANCE STATEMENT The retrosplenial cortex (RSC) is known to process information about landmarks in the environment that have a fixed, permanent location. Here we tested whether this permanence response was apparent beyond the spatial domain, which could have implications for understanding the role of the RSC more widely across cognition. We found that the RSC was engaged not only by permanent landmarks but also by stable and consistent actions. It was not responsive to transient landmarks or actions or to abstract concepts, even those that embodied the notion of stability. We conclude that the RSC might do more than help to map spatial environments, by possibly also providing information about the reliability of events occurring within them.

Intraneural Injection of ATP Stimulates Regeneration of Primary Sensory Axons in the Spinal Cord

Injury to the peripheral axons of sensory neurons strongly enhances the regeneration of their central axons in the spinal cord. It remains unclear on what molecules that initiate such conditioning effect. Because ATP is released extracellularly by nerve and other tissue injury, we hypothesize that injection of ATP into a peripheral nerve might mimic the stimulatory effect of nerve injury on the regenerative state of the primary sensory neurons. We found that a single injection of 6 μl of 150 μm ATP into female rat sciatic nerve quadrupled the number of axons growing into a lesion epicenter in spinal cord after a concomitant dorsal column transection. A second boost ATP injection 1 week after the first one markedly reinforced the stimulatory effect of a single injection. Single ATP injection increased expression of phospho-STAT3 and GAP43, two markers of regenerative activity, in sensory neurons. Double ATP injections sustained the activation of phospho-STAT3 and GAP43, which may account for the marked axonal growth across the lesion epicenter. Similar studies performed on P2X7 or P2Y2 receptor knock-out mice indicate P2Y2 receptors are involved in the activation of STAT3 after ATP injection or conditioning lesion, whereas P2X7 receptors are not. Injection of ATP at 150 μm caused little Wallerian degeneration and behavioral tests showed no significant long-term adverse effects on sciatic nerve functions. The results in this study reveal possible mechanisms underlying the stimulation of regenerative programs and suggest a practical strategy for stimulating axonal regeneration following spinal cord injury.

SIGNIFICANCE STATEMENT Injury of peripheral axons of sensory neurons has been known to strongly enhance the regeneration of their central axons in the spinal cord. In this study, we found that injection of ATP into a peripheral nerve can mimic the effect of peripheral nerve injury and significantly increase the number of sensory axons growing across lesion epicenter in the spinal cord. ATP injection increased expression of several markers for regenerative activity in sensory neurons, including phospho-STAT3 and GAP43. ATP injection did not cause significant long-term adverse effects on the functions of the injected nerve. These results may lead to clinically applicable strategies for enhancing neuronal responses that support regeneration of injured axons.

Proliferating NG2-Cell-Dependent Angiogenesis and Scar Formation Alter Axon Growth and Functional Recovery After Spinal Cord Injury in Mice

Spinal cord injury (SCI) induces a centralized fibrotic scar surrounded by a reactive glial scar at the lesion site. The origin of these scars is thought to be perivascular cells entering lesions on ingrowing blood vessels and reactive astrocytes, respectively. However, two NG2-expressing cell populations, pericytes and glia, may also influence scar formation. In the periphery, new blood vessel growth requires proliferating NG2⁺ pericytes; if this were also true in the CNS, then the fibrotic scar would depend on dividing NG2⁺ pericytes. NG2⁺ glial cells (also called oligodendrocyte progenitors or polydendrocytes) also proliferate after SCI and accumulate in large numbers among astrocytes in the glial scar. Their effect there, if any, is unknown. We show that proliferating NG2⁺ pericytes and glia largely segregate into the fibrotic and glial scars, respectively; therefore, we used a thymidine kinase/ganciclovir paradigm to ablate both dividing NG2⁺ cell populations to determine whether either scar was altered. Results reveal that loss of proliferating NG2⁺ pericytes in the lesion prevented intralesion angiogenesis and completely abolished the fibrotic scar. The glial scar was also altered in the absence of acutely dividing NG2⁺ cells, displaying discontinuous borders and significantly reduced GFAP density. Collectively, these changes enhanced edema, prolonged hemorrhage, and impaired forelimb functional recovery. Interestingly, after halting GCV at 14 d postinjury, scar elements and vessels entered the lesions over the next 7 d, as did large numbers of axons that were not present in controls. Collectively, these data reveal that acutely dividing NG2⁺ pericytes and glia play fundamental roles in post-SCI tissue remodeling.

SIGNIFICANCE STATEMENT Spinal cord injury (SCI) is characterized by formation of astrocytic and fibrotic scars, both of which are necessary for lesion repair. NG2⁺ cells may influence both scar-forming processes. This study used a novel transgenic mouse paradigm to ablate proliferating NG2⁺ cells after SCI to better understand their role in repair. For the first time, our data show that dividing NG2⁺ pericytes are required for post-SCI angiogenesis, which in turn is needed for fibrotic scar formation. Moreover, loss of cycling NG2⁺ glia and pericytes caused significant multicellular tissue changes, including altered astrocyte responses and impaired functional recovery. This work reveals previously unknown ways in which proliferating NG2⁺ cells contribute to endogenous repair after SCI.

Differentiation and Characterization of Excitatory and Inhibitory Synapses by Cryo-electron Tomography and Correlative Microscopy

As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure ~12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25–60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABA_A receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions.

SIGNIFICANCE STATEMENT To understand functional properties of neuronal synapses, it is desirable to analyze their structure at molecular resolution. We have developed an integrative approach combining cryo-electron tomography and correlative fluorescence microscopy to visualize 3D ultrastructural features of intact excitatory and inhibitory synapses in their native state. Our approach shows that inhibitory synapses contain uniform thin sheet-like postsynaptic densities (PSDs), while excitatory synapses contain previously known mesh-like PSDs. We discovered "discus-shaped" ellipsoidal synaptic vesicles, and their distributions along with regular spherical vesicles in synaptic types are characterized. High-resolution tomograms further allowed identification of putative neurotransmitter receptors and their heterogeneous interaction with synaptic scaffolding proteins. The specificity and resolution of our approach enables precise in situ analysis of ultrastructural organization underlying distinct synaptic functions.

POU6f1 Mediates Neuropeptide-Dependent Plasticity in the Adult Brain

The mouse olfactory bulb (OB) features continued, activity-dependent integration of adult-born neurons, providing a robust model with which to examine mechanisms of plasticity in the adult brain. We previously reported that local OB interneurons secrete the neuropeptide corticotropin-releasing hormone (CRH) in an activity-dependent manner onto adult-born granule neurons and that local CRH signaling promotes expression of synaptic machinery in the bulb. This effect is mediated via activation of the CRH receptor 1 (CRHR1), which is developmentally regulated during adult-born neuron maturation. CRHR1 is a G_S-protein-coupled receptor that activates CREB-dependent transcription in the presence of CRH. Therefore, we hypothesized that locally secreted CRH activates CRHR1 to initiate circuit plasticity programs. To identify such programs, we profiled gene expression changes associated with CRHR1 activity in adult-born neurons of the OB. Here, we show that CRHR1 activity influences expression of the brain-specific Homeobox-containing transcription factor POU Class 6 Homeobox 1 (POU6f1). To elucidate the contributions of POU6f1 toward activity-dependent circuit remodeling, we targeted CRHR1⁺ neurons in male and female mice for cell-type-specific manipulation of POU6f1 expression. Whereas loss of POU6f1 in CRHR1⁺ neurons resulted in reduced dendritic complexity and decreased synaptic connectivity, overexpression of POU6f1 in CRHR1⁺ neurons promoted dendritic outgrowth and branching and influenced synaptic function. Together, these findings suggest that the transcriptional program directed by POU6f1 downstream of local CRH signaling in adult-born neurons influences circuit dynamics in response to activity-dependent peptide signaling in the adult brain.

SIGNIFICANCE STATEMENT Elucidating mechanisms of plasticity in the adult brain is helpful for devising strategies to understand and treat neurodegeneration. Circuit plasticity in the adult mouse olfactory bulb is exemplified by both continued cell integration and synaptogenesis. We previously reported that these processes are influenced by local neuropeptide signaling in an activity-dependent manner. Here, we show that local corticotropin-releasing hormone (CRH) signaling induces dynamic gene expression changes in CRH receptor expressing adult-born neurons, including altered expression of the transcription factor POU6f1. We further show that POU6f1 is necessary for proper dendrite specification and patterning, as well as synapse development and function in adult-born neurons. Together, these findings reveal a novel mechanism by which peptide signaling modulates adult brain circuit plasticity.

Role of Purinergic Receptor P2Y1 in Spatiotemporal Ca2+ Dynamics in Astrocytes

Fine processes of astrocytes enwrap synapses and are well positioned to sense neuronal information via synaptic transmission. In rodents, astrocyte processes sense synaptic transmission via Gq-protein coupled receptors (GqPCR), including the P2Y1 receptor (P2Y1R), to generate Ca²⁺ signals. Astrocytes display numerous spontaneous microdomain Ca²⁺ signals; however, it is not clear whether such signals are due to local synaptic transmission and/or in what timeframe astrocytes sense local synaptic transmission. To ask whether GqPCRs mediate microdomain Ca²⁺ signals, we engineered mice (both sexes) to specifically overexpress P2Y1Rs in astrocytes, and we visualized Ca²⁺ signals via a genetically encoded Ca²⁺ indicator, GCaMP6f, in astrocytes from adult mice. Astrocytes overexpressing P2Y1Rs showed significantly larger Ca²⁺ signals in response to exogenously applied ligand and to repetitive electrical stimulation of axons compared with controls. However, we found no evidence of increased microdomain Ca²⁺ signals. Instead, Ca²⁺ waves appeared and propagated to occupy areas that were up to 80-fold larger than microdomain Ca²⁺ signals. These Ca²⁺ waves accounted for only 2% of total Ca²⁺ events, but they were 1.9-fold larger and 2.9-fold longer in duration than microdomain Ca²⁺ signals at processes. Ca²⁺ waves did not require action potentials for their generation and occurred in a probenecid-sensitive manner, indicating that the endogenous ligand for P2Y1R is elevated independently of synaptic transmission. Our data suggest that spontaneous microdomain Ca²⁺ signals occur independently of P2Y1R activation and that astrocytes may not encode neuronal information in response to synaptic transmission at a point source of neurotransmitter release.

SIGNIFICANCE STATEMENT Astrocytes are thought to enwrap synapses with their processes to receive neuronal information via Gq-protein coupled receptors (GqPCRs). Astrocyte processes display numerous microdomain Ca²⁺ signals that occur spontaneously. To determine whether GqPCRs play a role in microdomain Ca²⁺ signals and the timeframe in which astrocytes sense neuronal information, we engineered mice whose astrocytes specifically overexpress the P2Y1 receptor, a major GqPCR in astrocytes. We found that overexpression of P2Y1 receptors in astrocytes did not increase microdomain Ca²⁺ signals in astrocyte processes but caused Ca²⁺ wavelike signals. Our data indicate that spontaneous microdomain Ca²⁺ signals do not require activation of P2Y1 receptors.

Recruitment of Additional Corticospinal Pathways in the Human Brain with State-Dependent Paired Associative Stimulation

Standard brain stimulation protocols modify human motor cortex excitability by modulating the gain of the activated corticospinal pathways. However, the restoration of motor function following lesions of the corticospinal tract requires also the recruitment of additional neurons to increase the net corticospinal output. For this purpose, we investigated a novel protocol based on brain state-dependent paired associative stimulation.

Motor imagery (MI)-related electroencephalography was recorded in healthy males and females for brain state-dependent control of both cortical and peripheral stimulation in a brain–machine interface environment. State-dependency was investigated with concurrent, delayed, and independent stimulation relative to the MI task. Specifically, sensorimotor event-related desynchronization (ERD) in the β-band (16–22 Hz) triggered peripheral stimulation through passive hand opening by a robotic orthosis and transcranial magnetic stimulation to the respective cortical motor representation, either synchronously or subsequently. These MI-related paradigms were compared with paired cortical and peripheral input applied independent of the brain state. Cortical stimulation resulted in a significant increase in corticospinal excitability only when applied brain state-dependently and synchronously to peripheral input. These gains were resistant to a depotentiation task, revealed a nonlinear evolution of plasticity, and were mediated via the recruitment of additional corticospinal neurons rather than via synchronization of neuronal firing. Recruitment of additional corticospinal pathways may be achieved when cortical and peripheral inputs are applied concurrently, and during β-ERD. These findings resemble a gating mechanism and are potentially important for developing closed-loop brain stimulation for the treatment of hand paralysis following lesions of the corticospinal tract.

SIGNIFICANCE STATEMENT The activity state of the motor system influences the excitability of corticospinal pathways to external input. State-dependent interventions harness this property to increase the connectivity between motor cortex and muscles. These stimulation protocols modulate the gain of the activated pathways, but not the overall corticospinal recruitment. In this study, a brain–machine interface paired peripheral stimulation through passive hand opening with transcranial magnetic stimulation to the respective cortical motor representation during volitional β-band desynchronization. Cortical stimulation resulted in the recruitment of additional corticospinal pathways, but only when applied brain state-dependently and synchronously to peripheral input. These effects resemble a gating mechanism and may be important for the restoration of motor function following lesions of the corticospinal tract.

Chemogenetic Excitation of Accumbens-Projecting Infralimbic Cortical Neurons Blocks Toluene-Induced Conditioned Place Preference

Abuse rates for inhalants among adolescents continue to be high, yet preclinical models for studying mechanisms underlying inhalant abuse remain limited. Our laboratory has previously shown that, in male rats, an acute binge-like exposure to toluene vapor that mimics human solvent abuse modifies the intrinsic excitability of mPFC pyramidal neurons projecting to the NAc. These changes showed region (infralimbic; IL vs prelimbic; PRL), layer (shallow; 2/3 vs deep; 5/6), target (core vs shell), and age (adolescent vs adult) dependent differences (Wayman and Woodward, 2017). To expand these findings using reward-based models that may better mimic human drug abuse, we used whole-cell electrophysiology and drug receptors exclusively activated by designer drugs to examine changes in neuronal function and behavior in rats showing a conditioned place preference (CPP) to toluene. Repeated pairings of adolescent rats to binge concentrations of toluene vapor previously shown to enhance dopamine release in reward-sensitive areas of the brain produced CPP that persisted for 7 but not 30 d. Toluene-induced CPP was associated with increased excitability of IL5/6 mPFC neurons projecting to the core of the NAc and reduced excitability of those projecting to the NAc shell. No changes in PRL-NAc-projecting neurons were found in toluene-CPP rats. Chemogenetic reversal of the toluene-induced decrease in IL5/6-NAc shell neurons blocked the expression of toluene-induced CPP while manipulating IL5/6-NAc core neuron activity had no effect. These data reveal that alterations in selective mPFC-NAc pathways are required for expression of toluene-induced CPP.

SIGNIFICANCE STATEMENT Disturbed physiology of pyramidal neurons projecting from the mPFC to the NAc has been shown to have different roles in drug-seeking behaviors for a number of drugs (e.g., methamphetamine, cocaine, ecstasy, alcohol, heroin). Here, we report that rats repeatedly exposed to the volatile organic solvent toluene, a member of the class of abused inhalants often used for intoxicating purposes by adolescents, induces a preference for the drug-paired environment that is accompanied by altered physiology of a specific population of NAc-projecting mPFC neurons. Chemogenetic correction of this deficit before testing prevented expression of drug preference. Overall, these findings highlight the importance of corticolimbic circuitry in mediating the rewarding properties of abused inhalants.

Activity in the Ventral Medial Prefrontal Cortex Is Necessary for the Therapeutic Effects of Extinction in Rats

Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed in vmPFC before administering chronic unpredictable stress (CUS). vmPFC projection neurons were then inhibited during extinction treatment by administering clozapine-N-oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq 24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reduced mPFC responsivity, assessed by measuring afferent-evoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects.

SIGNIFICANCE STATEMENT Stress-related psychiatric disorders remain poorly treated. Psychotherapies can be effective, but their mechanisms remain unknown, hindering progress toward improved treatment. We used a rat model of behavioral therapy to identify potential targets for enhancing treatment. Fear extinction as a therapeutic behavioral intervention reversed stress-induced cognitive dysfunction and passive coping in rats, modeling components of stress-related psychiatric disease. Extinction also reversed stress-induced attenuation of mPFC responsivity. The therapeutic effects were prevented by blocking activity of glutamatergic neurons in the mPFC during extinction, and were mimicked by inducing activity in lieu of extinction. Thus, activity and plasticity in the mPFC underlie the beneficial effects of extinction on cognitive flexibility and coping behavior compromised by stress, and could be targets to enhance behavioral therapy.

Perceptual Surprise Improves Action Stopping by Nonselectively Suppressing Motor Activity via a Neural Mechanism for Motor Inhibition

Motor inhibition is a cognitive control ability that allows humans to stop actions rapidly even after initiation. Understanding and improving motor inhibition could benefit adaptive behavior in both health and disease. We recently found that presenting surprising, task-unrelated sounds when stopping is necessary improves the likelihood of successful stopping. In the current study, we investigated the neural underpinnings of this effect. Specifically, we tested whether surprise-related stopping improvements are due to a genuine increase in motor inhibition. In Experiment 1, we measured motor inhibition in primary motor cortex of male and female humans by quantifying corticospinal excitability (CSE) via transcranial magnetic stimulation and electromyography during a hybrid surprise–Go/NoGo task. Consistent with prior studies of motor inhibition, successful stopping was accompanied by nonselective suppression of CSE; that is, CSE was suppressed even in task-unrelated motor effectors. Importantly, unexpected sounds significantly increased this motor-system inhibition to a degree that was directly related to behavioral improvements in stopping. In Experiment 2, we then used scalp encephalography to investigate whether unexpected sounds increase motor-inhibition-related activity in the CNS. We used an independent stop-signal localizer task to identify a well characterized frontocentral low-frequency EEG component that indexes motor inhibition. We then investigated the activity of this component in the surprise–Go/NoGo task. Consistent with Experiment 1, this signature of motor inhibition was indeed increased when NoGo signals were followed by unexpected sounds. Together, these experiments provide converging evidence suggesting that unexpected events improve motor inhibition by automatically triggering inhibitory control.

SIGNIFICANCE STATEMENT The ability to stop ongoing actions rapidly allows humans to adapt their behavior flexibly and rapidly. Action stopping is important in daily life (e.g., stopping to cross the street when a car approaches) and is severely impaired in many neuropsychiatric disorders. Therefore, finding ways to improve action stopping could aid adaptive behaviors in health and disease. Our current study shows that presenting unexpected sounds in stopping situations facilitates successful stopping. This improvement is specifically due to a surprise-related increase in a neural mechanism for motor inhibition, which rapidly suppresses the excitability of the motor system after unexpected events. These findings suggest a tight interaction between the neural systems for surprise processing and motor inhibition and yield a promising avenue for future research.

A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons

Visual Short-Term Memory Activity in Parietal Lobe Reflects Cognitive Processes beyond Attentional Selection

Visual short-term memory (VSTM) and attention are distinct yet interrelated processes. While both require selection of information across the visual field, memory additionally requires the maintenance of information across time and distraction. VSTM recruits areas within human (male and female) dorsal and ventral parietal cortex that are also implicated in spatial selection; therefore, it is important to determine whether overlapping activation might reflect shared attentional demands. Here, identical stimuli and controlled sustained attention across both tasks were used to ask whether fMRI signal amplitude, functional connectivity, and contralateral visual field bias reflect memory-specific task demands. While attention and VSTM activated similar cortical areas, BOLD amplitude and functional connectivity in parietal cortex differentiated the two tasks. Relative to attention, VSTM increased BOLD amplitude in dorsal parietal cortex and decreased BOLD amplitude in the angular gyrus. Additionally, the tasks differentially modulated parietal functional connectivity. Contrasting VSTM and attention, intraparietal sulcus (IPS) 1–2 were more strongly connected with anterior frontoparietal areas and more weakly connected with posterior regions. This divergence between tasks demonstrates that parietal activation reflects memory-specific functions and consequently modulates functional connectivity across the cortex. In contrast, both tasks demonstrated hemispheric asymmetries for spatial processing, exhibiting a stronger contralateral visual field bias in the left versus the right hemisphere across tasks, suggesting that asymmetries are characteristic of a shared selection process in IPS. These results demonstrate that parietal activity and patterns of functional connectivity distinguish VSTM from more general attention processes, establishing a central role of the parietal cortex in maintaining visual information.

SIGNIFICANCE STATEMENT Visual short-term memory (VSTM) and attention are distinct yet interrelated processes. Cognitive mechanisms and neural activity underlying these tasks show a large degree of overlap. To examine whether activity within the posterior parietal cortex (PPC) reflects object maintenance across distraction or sustained attention per se, it is necessary to control for attentional demands inherent in VSTM tasks. We demonstrate that activity in PPC reflects VSTM demands even after controlling for attention; remembering items across distraction modulates relationships between parietal and other areas differently than during periods of sustained attention. Our study fills a gap in the literature by directly comparing and controlling for overlap between visual attention and VSTM tasks.

The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.

SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates daily rhythms including sleep–wake, hormone release, and gene expression. The cells of the SCN must synchronize to each other to drive these circadian rhythms in the rest of the body. The ontogeny of circadian cycling and intercellular coupling in the SCN remains poorly understood. Recent in vitro studies have recorded circadian rhythms from the whole embryonic SCN. Here, we tracked the onset and precision of rhythms in PERIOD2 (PER2), a clock protein, within the SCN isolated from embryonic and postnatal mice of undetermined sex. We found that a few SCN cells developed circadian periodicity in PER2 by 14.5 d after mating (E14.5) with no evidence for daily cycling on E13.5. On E15.5, the fraction of competent oscillators increased dramatically corresponding with stabilization of their circadian periods. The cells of the SCN harvested at E15.5 expressed sustained, synchronous daily rhythms. By postnatal day 2 (P2), SCN oscillators displayed the daily, dorsal-ventral phase wave in clock gene expression typical of the adult SCN. Strikingly, vasoactive intestinal polypeptide (VIP), a neuropeptide critical for synchrony in the adult SCN, and its receptor, VPAC2R, reached detectable levels after birth and after the onset of circadian synchrony. Antagonists of GABA or VIP signaling or action potentials did not disrupt circadian synchrony in the E15.5 SCN. We conclude that endogenous daily rhythms in the fetal SCN begin with few noisy oscillators on E14.5, followed by widespread oscillations that rapidly synchronize on E15.5 by an unknown mechanism.

SIGNIFICANCE STATEMENT We recorded the onset of PER2 circadian oscillations during embryonic development in the mouse SCN. When isolated at E13.5, the anlagen of the SCN expresses high, arrhythmic PER2. In contrast, a few cells show noisy circadian rhythms in the isolated E14.5 SCN and most show reliable, self-sustained, synchronized rhythms in the E15.5 SCN. Strikingly, this synchrony at E15.5 appears before expression of VIP or its receptor and persists in the presence of blockers of VIP, GABA or neuronal firing. Finally, the dorsal-ventral phase wave of PER2 typical of the adult SCN appears ~P2, indicating that multiple signals may mediate circadian synchrony during the ontogeny of the SCN.

An Insula-Central Amygdala Circuit for Guiding Tastant-Reinforced Choice Behavior

For animals to survive, they must reliably predict during foraging which substances are suitable for consumption. Despite extensive study, the neural circuit mechanisms underlying such adaptive behavior remain poorly understood. Here, using a tastant (sucrose/quinine)-reinforced "go/no-go" task in male and female mice, we examined the anatomical and functional connectivity of the circuit linking the insular cortex (IC) to the central amygdala (CeA) and the role of this circuit in the establishment of appropriate behavioral responses. Using anatomic tracing approaches combined with optogenetics-assisted circuit mapping, we found that the gustatory region of the IC sends direct excitatory projections to the lateral division of the CeA (CeL), making monosynaptic excitatory connections with distinct populations of CeL neurons. Specific inhibition of neurotransmitter release from the CeL-projecting IC neurons prevented mice from acquiring the "no-go" response, and impaired the "go" responses in the go/no-go task. Furthermore, selective activation of the IC–CeL pathway with optogenetics drove unconditioned lick suppression in thirsty animals, induced aversive responses, and was sufficient to instruct conditioned action suppression in response to a cue predicting the optogenetic activation. These results indicate that activities in the IC–CeL circuit are critical for establishing taste-reinforced behavioral responses, including avoidance responses to an aversive tastant, and are sufficient to drive learning of anticipatory avoidance. Our findings suggest that the IC–CeL circuit plays an important role in guiding appropriate choices during foraging.

SIGNIFICANCE STATEMENT An animal's ability to predict which substances are suitable for consumption and then produce an appropriate action to those substances is critical for survival. Here we found that activity in the circuit that links the insular cortex (IC) to the central amygdala (CeA) is necessary for establishing appropriate behavioral responses to taste-predicting cues. This neural circuit seems to be particularly tuned to avoid an unpleasant tastant, and is also sufficient to drive learning of such avoidance responses. These results suggest that the IC–CeA circuit is critical for generating appropriate behavioral responses during foraging when facing different choices.

RFA versus robotic partial nephrectomy for T1a renal cell carcinoma: a propensity score-matched comparison of mid-term outcome

Abstract

Objective

To compare oncological and functional mid-term outcomes following robotic partial nephrectomy (RPN) and radiofrequency ablation (RFA) for treating T1a renal cell carcinoma (RCC) using propensity score-matching.

Methods

Between December 2008–April 2016, 63 patients from each treatment group were propensity score-matched for age, sex, American Society of Anesthesiologists score, tumour size, tumour laterality, tumour histology, R.E.N.A.L. nephrometry score and preoperative estimated glomerular filtration rate (eGFR). Post-treatment follow-up periods for RPN and RFA ranged from 1–90 months (median, 24.6) and 1–65 months (21), respectively. Tumour location, percentage of eGFR preservation and 2-year recurrence-free survival rate were compared between groups.

Results

Exophytic and endophytic RCC occurred in 73.0 % (46/63) and 27.0 % (17/63) of the RPN group, and 52.4 % (33/63) and 47.6 % (30/63) of the RFA group, respectively (p=0.017). There was 91.7 % preservation of eGFR in the RPN group and 86.8 % in the RFA group (p=0.088). Two-year recurrence-free survival rate was 100 % in the RPN and 95.2 % in the RFA group (p=0.029).

Conclusions

RPN provides a higher recurrence-free survival rate than RFA. However, RFA is a better treatment option for an endophytic or recurrent RCC that is difficult to treat with RPN.

Key Points

• RPN provides a higher recurrence-free survival rate than RFA.

• Unlike RPN, repeat RFA is easy to perform for recurrent RCC.

• Endophytic RCC could be better treated with RFA.

Coronary CT angiography in patients with atrial fibrillation: Standard-dose and low-dose imaging with a high-resolution whole-heart CT scanner

Abstract

Objective

To compare image quality, observer confidence, radiation exposure in the standard-dose (SD-CCTA) and low-dose (LD-CCTA) protocols of coronary CT angiography (CCTA) in patients with atrial fibrillation (AF).

Material and methods

CCTA was performed in 303 patients using a CT scanner with 16-cm coverage (111 scans during sinus rhythm (SR); 192 during AF). LD-CCTA was used in 218 patients; SD-CCTA in 85 patients suspected of having coronary artery disease (CAD). Image quality and observer confidence were evaluated on 5-point scales. Radiation doses were recorded.

Results

Image quality was superior in the SD-CCTA compared to the LD-CCTA (SR 1.45±0.40; AF 1.72±0.46; vs. SR 1.83±0.48; AF 1.92±0.50; p < 0.001). Observers were more confident with SD-CCTA than with LD-CCTA (SR 1.38±0.33; AF 1.61±0.43; vs. SR 1.70±0.45; AF 1.82±0.50; p < 0.001). Radiation doses in AF were significantly higher than in the SR (LD-CCTA, 1.68±0.71 mSv; SD-CCTA, 3.72±1.95 mSv; vs. LD-CCTA, 1.3 ±0.52 mSv; SD-CCTA, 2.67±1.47 mSv; p < 0.001).

Conclusion

Using a low-dose protocol in AF, radiation exposure can be decreased by 50 % at the expense of 20 % impaired image quality. A low-dose CCTA protocol can be considered in young patients, whereas the standard-dose protocol is recommended for older patients and those suspected of having CAD.

Key Points

• Whole-heart CT allows visualization of the coronary arteries in atrial fibrillation.

• Low-dose CT decreases radiation exposure by 50%, image quality by 20%.

• Standard-dose CT seems advantageous when concomitant coronary artery disease is suspected.

Magnetic resonance post-contrast vascular hyperintensities at 3 T: a new highly sensitive sign of vascular occlusion in acute ischaemic stroke

Abstract

Background

Magnetic resonance imaging (MRI) is the diagnostic cornerstone for precisely identifying acute ischaemic strokes and locating vascular occlusions, especially since mechanical thrombectomy has become a reference treatment. We observed that a post-contrast three-dimensional turbo-spin-echo T1-weighted sequence showed striking post-contrast vascular hyperintensities (PCVH) in ischaemic territories. We aimed to evaluate the prevalence and the meaning of this finding.

Methods

This retrospective single centre study included 130 consecutive patients admitted for acute ischaemic stroke with a 3-T MRI performed in the first 12 h of symptom onset from September 2014 through September 2016. Two neuroradiologists blinded to clinical data analysed the first MRI assessments. The association between PCVH and clinical, radiological and follow-up findings was assessed, as well as inter- and intra-observer agreements.

Results

Of 130 patients, 105 (81%) had PCVH in the ischaemic territory. PCVH were associated with the presence of thrombus on susceptibility weighted imaging (p < 0.0001) and vascular occlusions on MR angiography (p < 0.0001). All patients with a visible thrombus had PCVH closely surrounding the clot. PCVH were associated with higher initial (p < 0.01) and follow-up (p < 0.01) National Institutes of Health Stroke Scale score, and higher mRS score (p < 0.05). Thrombectomy was the reference treatment for all patients with arterial occlusions. Inter- and intra-observer agreements for the detection of PCVH were excellent (κ = 0.95 and κ = 0.91, respectively).

Conclusions

PCVH during acute strokes are a striking sensitive and reproducible tool for diagnosing and locating vascular occlusions. It may help triage patients who can benefit from thrombectomy.

Key points

• Post-contrast vascular hyperintensities (PCVH) are a sensitive MR finding in acute stroke

• PCVH are strongly associated with the presence and location of arterial occlusions

• Inter- and intra-observer agreements for the detection of PCVH are excellent

• PCVH are visible even in the case of significant motion artefacts

• PCVH may help triage patients who can benefit from mechanical thrombectomy

What are the predictors of clinical success after percutaneous vertebroplasty for osteoporotic vertebral fractures?

Abstract

Objectives

Osteoporotic vertebral fractures are responsible for acute pain and disability that may persist for more than 2 months. We wanted to identify predicting factors for mid-term outcome after vertebroplasty.

Methods

We included consecutive patients who underwent vertebroplasty for fragility fractures with persistent and intense pain between January 2014–June 2016. Outcome was assessed by an independent clinician after 1 month using a standardized questionnaire. Patients were classified as having either a favorable or a poor outcome. Presence of an intravertebral cleft and bone oedema mean signal intensity was assessed by an independent radiologist blinded to the clinical data. Pre-intervention clinical or radiological factors were analysed as predictors for outcome.

Results

In the 78 included patients (females 71%, age 75 ± 8.3 years), 61.5% had a favourable outcome. When vertebroplasty was performed within 2 months after fracture, the outcome was favourable in 19 patients (39.6%) and poor in five (16.7%; estimate for favourable outcome: OR = 4.1, 95% CI 1.2–13.8, p = 0.021). Absence of intravertebral cleft on pre-intervention imaging was also a predictor of favourable outcome (OR = 3.7, 95% CI 1.2–11.8, p = 0.024). On pre-intervention MRI, vertebral body oedema intensity signal did not influence the outcome.

Conclusions

In patients with persistent and intense pain after an osteoporotic vertebral fracture, early intervention and absence of intravertebral cleft were predictors of favourable outcome at 1 month after vertebroplasty.

Key Points

• Performing vertebroplasty within 2 months following a fragility fracture increases success rate.

• Presence of an intravertebral cleft at baseline is a predictor of poor mid-term outcome.

• A pre-intervention MRI should be performed to ascertain the indication of vertebroplasty.

New concepts in anammox processes for wastewater nitrogen removal: Recent advances and future prospects.

Abstract

The discovering of Anaerobic Ammonium Oxidation (anammox) process led to the development of autotrophic nitrogen removal systems for the treatment of effluents with low C:N rate. The anammox processes provide an efficient way to remove high concentrations of ammonium compounds from industrial and urban wastewater and covert them to dinitrogen. Nevertheless, recently obtained results suggest new ways for research on autotrophic nitrogen removal system including possibility for low temperature operation, adaptation to high organic matter loads and antibiotics inhibition effect. For these reasons, the prevalence and spatial distribution of anammox communities in autotrophic nitrogen removal wastewater treatment technologies, as well as their role in formation of fixed biofilms, are reviewed here in order to illustrate the present and future significance of these microorganisms in environmental biotechnology.

Harnessing the power of communities: Career networking strategies for bioscience PhD students and postdoctoral researchers

Abstract

With an ever more competitive global labour market, coupled with an ever-increasing population of PhD-qualified graduates, the ability to communicate effectively and build strategic connections with others can be advantageous in the job-search process. Whether in pursuit of a tenure-track or non-academic position, many postdoctoral researchers and PhD students will benefit from networking as early as possible to enhance their career propsects. Sometimes viewed cynically as 'using people' or dismissed as 'the old boy network', the ability to make meaningful connections and build relationships can be more valuable than other job-related skills in order to gain entry to, and progress within, many professions.This mini-review highlights the positive influence of networking and how bioscience PhD students and postdoctoral researchers can harness the power of communities to achieve career success. It is argued that those who make connections and promote personal patronage through networking can gain an advantage over their contemporaries. A summary of key theories and research studies that underpin the practice of networking provide credence to these assertions, which are further substantiated with examples pertinent to the academic community. Although primarily focussed on the biosciences, much of the content is applicable to other scientists at a similar career stage.

Assimilation of cyanide and cyano–derivatives by Pseudomonas pseudoalcaligenes CECT5344: from omic approaches to biotechnological applications

Abstract

Mining, jewellery and metal–processing industries use cyanide for extracting gold and other valuable metals, generating large amounts of highly toxic wastewater. Biological treatments may be a clean alternative under the environmental point of view to the conventional physical or chemical processes used to remove cyanide and related compounds from these industrial effluents. Pseudomonas pseudoalcaligenes CECT5344 can grow under alkaline conditions using cyanide, cyanate or different nitriles as the sole nitrogen source, and is able to remove up to 12 mM total cyanide from a jewellery industry wastewater that contains cyanide free and complexed to metals. Complete genome sequencing of this bacterium has allowed the application of transcriptomic and proteomic techniques, providing a holistic view of the cyanide biodegradation process. The complex response to cyanide by the cyanotrophic bacterium Pseudomonas pseudoalcaligenes CECT5344 and the potential biotechnological applications of this model organism in the bioremediation of cyanide–containing industrial residues are reviewed.

Issue Information

Sesquiterpene-Enriched Extract of Curcuma aeruginosa Roxb. Retards Axillary Hair Growth: A Randomised, Placebo-Controlled, Double-Blind Study

Background: Sesquiterpenes in Curcuma aeruginosa Roxb. inhibit steroid 5α-reductase and dihydrotestosterone production, and reverse androgenic alopecia. This study sought to show that a high sesquiterpene C. aeruginosa extract (CA-ext) retards axillary hair growth in women. Methods: Thirty women (age 20–52 years) were recruited into a 12-week, double-blind, placebo-controlled intervention for CA-ext treatment, where they were randomly allocated to a left or right armpit group. At weekly intervals, axillary hair length was measured videometrically, the hair was shaved, and lotion was applied (to the contralateral axilla) twice daily via roll-on applicators containing either CA-ext or placebo. The primary endpoint of the study was hair growth. Results: Participants showed 22% (range 8–56%, p #x3c; 0.0001) reduced axillary hair growth with CA-ext compared to placebo, albeit delayed by 6 weeks. Participants were satisfied with the treatment and no apparent adverse effects were reported. The quantities of lotion used for each axilla were identical between test and placebo throughout the trial for each participant. Participants reported having shorter and finer armpit hair with the test lotion but disliked its smell, even though it was perfumed. The "free of irritation" description gained the highest questionnaire ratings. Conclusion: CA-ext in lotion is an efficacious inhibitor of axillary hair growth, the preparation was well accepted and matched the effectiveness of finasteride. Thus, with some refinement, it should provide an alternative pharmacological treatment for unwanted androgenic hair.
Skin Pharmacol Physiol 2018;31:99–106

Holocaust Laughter and Edgar Hilsenrath’s The Nazi and the Barber : Towards a Critical Pedagogy of Laughter and Humor in Holocaust Education

Abstract

This article tries to defend the position that Holocaust Education can be enriched by appreciating laughter and humor as critical and transformative forces that not only challenge dominant discourses about the Holocaust and its representational limits, but also reclaim humanity, ethics, and difference from new angles and juxtapositions. Edgar Hilsenrath's novel The Nazi and the Barber is discussed here as an example of literature that departs from representations of Holocaust as celebration of resilience and survival, portraying a world in which lies, hatred and violence are still perpetuated. Because of its transgressive qualities, Hilsenrath's narrative of the Holocaust as a satire with elements of black comedy can offer pedagogical openings for using laughter to interrupt normative constructions of the Holocaust as an unspeakable and sacred event that lies outside history, and thus beyond the capacities of human understanding. It is argued that laughter is an important modality for inviting deep thinking about the Holocaust, to move it from a transcendent phenomenon to an immanent event, situated clearly in the realm of human action and worthy of understanding so as to prevent it from happening again.

Energy crops on landfills: functional, environmental, and costs analysis of different landfill configurations

Abstract

The cultivation of energy crops on landfills represents an important challenge for the near future, as the possibility to use devalued sites for energy production is very attractive. In this study, four scenarios have been assessed and compared with respect to a reference case defined for northern Italy. The scenarios were defined taking into consideration current energy crops issues. In particular, the first three scenarios were based on energy maximisation, phytotreatment ability, and environmental impact, respectively. The fourth scenario was a combination of these characteristics emphasised by the previous scenarios. A multi-criteria analysis, based on economic, energetic, and environmental aspects, was performed. From the analysis, the best scenario resulted to be the fourth, with its ability to pursue several objectives simultaneously and obtain the best score relatively to both environmental and energetic criteria. On the contrary, the economic criterion emerges as weak, as all the considered scenarios showed some limits from this point of view. Important indications for future designs can be derived. The decrease of leachate production due to the presence of energy crops on the top cover, which enhances evapotranspiration, represents a favourable but critical aspect in the definition of the results.

Screening cyhalothrin degradation strains from locust epiphytic bacteria and studying Paracoccus acridae SCU-M53 cyhalothrin degradation process

Abstract

All locust epiphytic bacteria were screened and a total of 62 epiphytic bacteria were obtained from samples of Acrida cinerea. Via phylogenetic analysis, the 62 epiphytic bacteria were allocated to 27 genera, 18 families, 13 orders, six classes, and four phylums. Then, cyhalothrin degradation experiments were conducted, and the 10 strains that degraded more than 30% cyhalothrin and Paracoccus acridae SCU-M53 showed the highest cyhalothrin degradation rate of 70.5%. Furthermore, Paracoccus acridae SCU-M53 was selected for optimal cyhalothrin biodegradation conditions via the response surface method (Design-Expert). Under the optimum conditions (28 °C, 75 mg/L, and 180 rpm), the cyhalothrin degradation rate reached 79.84% after 2 days. This suggests the possibility that isolating biodegradation cyhalothrin strains from Acrida cinerea is feasible.

Climate and environmental factors affecting the incidence of cutaneous leishmaniasis in Isfahan, Iran

Abstract

Cutaneous leishmaniasis (CL) is a vector-borne human disease caused by Leishmania, a parasite transmitted by sand flies. CL is endemic in the Isfahan Province, Iran. This study was designed to identify the climate and environmental factors associated with CL incidence in Isfahan Province. Data included incident cases of CL, climate, and environmental factors, which were collected across 23 districts of province from 2007 to 2015. Analyses were performed with generalized linear models (GLMs) to fit a function to the relationships between the response and predictors. We used negative binomial regression due to over-dispersed distribution of CL cases. The effects of all seven climate and environmental factors were found to be significant (all p < 0.01), and the model explained 40% of the deviance of CL incidence. There was a positive relation between mean temperature, relative humidity, and slope of area with disease incidence; however, negative association was demonstrated between maximum wind speed, rainfall, altitude, and vegetation cover with CL incidence. Cutaneous leishmaniasis continues to be a widespread challenge, especially in northwestern parts of Iran. Climate and environmental factors should be considered when selecting the most appropriate strategies for preventing and controlling CL.

Genotoxicity of spent pot liner as determined with the zebrafish ( Danio rerio ) experimental model

Abstract

Spent pot liner (SPL) is a solid waste generated during the primary smelting of aluminum, and its toxicity is attributed to the presence of fluoride, cyanide, and aluminum salts, which can be leached into aquatic ecosystems. Since the effects of this waste on aquatic life forms have not yet been investigated, the objective of our study was to evaluate the toxicity of simulated leachates of SPL on zebrafish (Danio rerio). Animals were exposed to 0 (control), 0.32, 0.64, or 0.95 g L⁻¹ of SPL for 24, 72, and 96 h, and genotoxicity was accessed through micronucleus and comet assays. All of the tested treatments induced DNA fragmentation, and the observed frequency of micronuclei and damaged nucleoids generally increased with increasing SPL concentration. The highest frequency of micronuclei (3.3 per 3000 erythrocytes) was detected after 96 h of exposure with 0.95 g L⁻¹ SPL. In the comet assay, nucleoids classified with highest level of damage in relation to the control were observed principally after 24 and 96 h of exposure. The data obtained in this study confirm the genotoxicaction and mutagenic potential of SPL and indicate that open-air deposits of the waste material could represent a health risk to humans and ecosystems alike.

Linear and non-linear impact of Internet usage and financial deepening on electricity consumption for Turkey: empirical evidence from asymmetric causality

Abstract

This study investigates the relationship between Internet usage, financial development, economic growth, capital and electricity consumption using quarterly data from 1993Q1 to 2014Q4. The integration order of the series is analysed using the structural break unit root test. The ARDL bounds test for cointegration in addition to the Bayer–Hanck (2013) combined cointegration test is applied to analyse the existence of cointegration among the variables. The study found strong evidence of a long-run relationship between the variables. The long-run results under the ARDL framework confirm the existence of an inverted U-shaped relationship between financial development and electricity consumption, not only in the long-run, but also in the short-run. The study also confirms the existence of a U-shaped relationship between Internet usage and electricity consumption; however, the effect is insignificant. Additionally, the influence of trade, capital and economic growth is examined in both the long run and short run (ARDL-ECM). Finally, the results of asymmetric causality suggest a positive shock in electricity consumption that has a positive causal impact on Internet usage. The authors recommend that the Turkish Government should direct financial institutions to moderate the investment in the ICT sector by advancing credits at lower cost for purchasing energy-efficient technologies. In doing so, the Turkish Government can increase productivity in order to achieve sustainable growth, while simultaneously reducing emissions to improve environmental quality.

Effect of biochar on growth and ion contents of bean plant under saline condition

Abstract

A pot experiment was conducted with three biochar ratios (non-biochar, 5, and 10% total pot mass) and three salinities (control, 6, and 12 dSm⁻¹ sodium chloride) treatments. At the flowering stage, we harvested common bean (Phaseolus vulgaris L. cv. Derakhshan) plants and measured growth characteristics and nutrient contents. As an average, salt stress decreased shoot and root dry weight, leaf area, relative water content, chlorophyll fluorescence (Fv/Fm) and leaf chlorophyll content, however, increased root length, sodium (Na) content of root and shoot, Na uptake, and translocation of bean plants, compared to control. On the other hand, the growth and ion contents of bean were affected positively by use of biochar, but Na translocation was not changed. Addition of biochar improved content of chlorophylls a, b, and total, and potassium (K), calcium (Ca), and magnesium (Mg) contents, while, diminished Na content and uptakes. Moreover, in case of measured parameters, 10% biochar was more effective compared to 5%. Overall, biochar enhanced growth of a bean under saline condition, which may have contributed to the reduction of Na uptake and enhance of K, Ca, and Mg contents.

Issue Information

Kinetic and isothermal adsorption-desorption of PAEs on biochars: effect of biomass feedstock, pyrolysis temperature, and mechanism implication of desorption hysteresis

Abstract

Biochar has the potential to sequester biomass carbon efficiently into land, simultaneously while improving soil fertility and crop production. Biochar has also attracted attention as a potential sorbent for good performance on adsorption and immobilization of many organic pollutants such as phthalic acid esters (PAEs), a typical plasticizer in plastic and presenting a current environmental issue. Due to lack of investigation on the kinetic and thermodynamic adsorption-desorption of PAEs on biochar, we systematically assessed adsorption-desorption for two typical PAEs, dimethyl phthalate (DMP) and diethyl phthalate (DEP), using biochar derived from peanut hull and wheat straw at different pyrolysis temperatures (450, 550, and 650 °C). The aromaticity and specific surface area of biochars increased with the pyrolysis temperature, whereas the total amount of surface functional groups decreased. The quasi-second-order kinetic model could better describe the adsorption of DMP/DEP, and the adsorption capacity of wheat straw biochars was higher than that of peanut hull biochars, owing to the O-bearing functional groups of organic matter on exposed minerals within the biochars. The thermodynamic analysis showed that DMP/DEP adsorption on biochar is physically spontaneous and endothermic. The isothermal desorption and thermodynamic index of irreversibility indicated that DMP/DEP is stably adsorbed. Sorption of PAEs on biochar and the mechanism of desorption hysteresis provide insights relevant not only to the mitigation of plasticizer mobility but also to inform on the effect of biochar amendment on geochemical behavior of organic pollutants in the water and soil.