Association of level of anastomosis and anastomotic leak after esophagectomy in anterior mediastinal reconstruction

Abstract

Aim

The purpose of this study was to investigate modifiable predisposing factors associated with anastomotic leak in the anterior mediastinal (AM) reconstruction route.

Methods

We reviewed the data on 154 patients who underwent esophagectomy and gastric tube reconstruction using the AM route between 2008 and 2016. The data included computed tomography (CT) scans with sagittal reconstruction of the thoracic section. The level of the esophagogastric anastomosis (LEA) and pretracheal distance (PTD) was measured from sagittal reconstructed CT images. Vascularization of the gastric tube was evaluated by postoperative endoscopy. Variables associated with anastomotic leak were determined using univariate and multivariate analyses.

Results

Anastomotic leak developed in 13 patients (8%). The cut-off level at which the anastomosis was less likely to develop a leak, as determined by Chi-square tests, was 1.5 cm for LEA and 1.3 cm for PTD. On univariate analysis, the factors that were significantly associated with the risk of anastomotic leak included diabetes, hand-sewn anastomosis, the LEA ≥ 1.5 cm, and severe mucosal degeneration. On multivariate analysis, diabetes (OR 4.7, 95% CI 1.29–17.2), LEA ≥ 1.5 cm (OR 20.1, 95% CI 3.15–128), and severe mucosal degeneration (OR 7.2, 95% CI 1.42–36.8) were found to be statistically significant independent risk factors.

Conclusion

Use of the AM route to place the cervical anastomosis within 1.5 cm above the suprasternal notch might avoid excessive pressure on the gastric tube from the surrounding structures, resulting in a reduction in the risk of an anastomotic leak.

An exploratory study of energy reserves and biometry as potential tools for assessing the effects of pest management strategies on the earwig, Forficula auricularia L

Abstract

Apple orchards are heavily treated crops and some sprayed insecticides are recognized to have toxic effects on non-target arthropods. Earwigs are important natural enemies in pip-fruit orchards and contribute to the biological control of aphids. In addition, due to their ease of capture and identification, they are an interesting potential bioindicator of the possible detrimental effects of different orchard management strategies. In this study, we measured the energy reserves and some morphological traits of Forficula auricularia L. sampled in apple orchards under management strategies (organic versus integrated pest management (IPM)). We observed a significant decrease in mass (22 to 27%), inter-eye width (3%), and prothorax width (2 to 5%) in earwigs from IPM compared to organic orchards. Energy body reserves also confirmed these results with a significant decrease of 48% in glycogen and 25 to 42% in lipid content in earwigs from IPM compared to organic orchards. However, the protein content was approximately 70% higher in earwigs from IPM than in organic orchards. Earwigs sampled in IPM orchards may adapt to minimize the adverse toxic effects of pesticide treatments using a large number of strategies, which are reflected in changes to their energy reserves. These strategies could, in turn, influence the population dynamics of natural enemies and impair their role in the biological control of pests in apple orchards.

Molecular assessment of glyphosate-degradation pathway via sarcosine intermediate in Lysinibacillus sphaericus

Abstract

The widespread use of glyphosate has permeated not only small- and large-scale agriculture, but also the fight against drug trafficking and illicit crops. Health, alimentary security, and the rights of peasant and indigenous communities have been compromised in countries with intensive use of glyphosate-based herbicides. In 2015, the International Agency for Research on Cancer classified this substance as probably carcinogenic to humans, leading to the suspension of aerial glyphosate spraying the same year in countries like Colombia, where glyphosate has been extensively used in illicit crop eradication. Notwithstanding, according to a study of the U.S. Geological Survey, traces of glyphosate and its main degradation product, AMPA, remain in soil year after year. This underscores the urgency and importance of assessing new technologies to degrade glyphosate present in soils and waterbodies without leaving persistent byproducts. The aim of this study was to evaluate Lysinibacillus sphaericus' glyphosate uptake as a carbon and phosphorous source by a sarcosine-mediated metabolic pathway that releases glycine as final degradation product. To accomplish this, molecular and analytic evidence were collected in vitro from sarcosine oxidase activity, a key enzyme of a degradation pathway which releases byproducts that are easy to incorporate into natural biosynthesis routes.

Characterising boiler ash from a circulating fluidised bed municipal solid waste incinerator and distribution of PCDD/F and PCB

Abstract

In this study, ash samples were collected from five locations situated in the boiler of a circulating fluidised bed municipal solid waste incinerator (high- and low-temperature superheater, evaporator tubes and upper and lower economiser). These samples represent a huge range of flue gas temperatures and were characterised for their particle size distribution, surface characteristics, elemental composition, chemical forms of carbon and chlorine and distribution of polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and biphenyls (PCB). Enrichment of chlorine, one of the main elements of organochlorinated pollutants, and copper, zinc and lead, major catalytic metals for dioxin-like compounds, was observed in lower-temperature ash deposits. The speciation of carbon and chlorine on ash surfaces was established, showing a positive correlation between organic chlorine and oxygen-containing carbon functional groups. The load of PCDD/F and PCB (especially dioxin-like PCB) tends to rise rapidly with falling temperature of flue gas, reaching their highest value in economiser ashes. The formation of PCDD/F congeners through the chlorophenol precursor route apparently was enhanced downstream the boiler. Principal component analysis (PCA) was applied to study the links between the ash characteristics and distribution of chloro-aromatics. The primary purpose of this study is improving the understanding of any links between the characteristics of ash from waste heat systems and its potential to form PCDD/F and PCB. The question is raised whether further characterisation of fly ash may assist to establish a diagnosis of poor plant operation, inclusive the generation, destruction and eventual emission of persistent organic pollutants (POPs).

Co-N-doped MoO 2 modified carbon felt cathode for removal of EDTA-Ni in electro-Fenton process

Abstract

Metal ions removal is inhibited in aqueous solution containing ethylenediaminetetraacetic acid (EDTA). In this study, the non-noble metals-based Co-N-doped MoO₂ nanowires (Co-N-MoO₂) were successfully synthesized using cyanamide and Co(Ac)₂ as precursors by pyrolysis, then immobilized on carbon felt (CF), and firstly used as cathode to remove EDTA-Ni complex through oxygen reduction reaction (ORR) in electro-Fenton (EF) process. The X-ray diffraction (XRD) and scanning electron microscopy (SEM) results indicated that a synergetic coupling effect of doping of N and Co induced structural modifications of MoO₂ lattice, and produced more lattice defects. The electrochemical analysis results showed that the superior ORR electrochemical catalysis activities were obtained at pH = 3 with the lowest cathodic peak potentials (− 0.157 V vs. Ag/AgCl), the highest electrochemical active surface area (EASA: 3.971 mC cm⁻²), the extraordinarily high of the ring current (35.5 μA) and high H₂O₂ yield (> 20%). Under the optimum conditions, about 68% of EDTA-Ni was removed with the Co-N-MoO₂/CF as cathode after 120 min with lower specific energy consumption (0.0226 kW h mg⁻¹ (DOC)) in EF system. Mechanism analysis indicated that the production of strong oxidizing property of hydroxyl radical (•OH) on the cathode played an important role in the removal of EDTA-Ni in the EF process, synergetic effect of cobalt and nitrogen co-doped could facilitate the high generation of H₂O₂, which greatly promote the formation of •OH. The EF system with Co-N-MoO₂/CF cathode has a potential for breaking metal-complex with good stability, showing that this cathode is a candidate for application for applications in EAPOs.

Esophageal Squamous Cell Carcinoma Metastatic to the Orbit

A 74-year-old man presenting with proptosis and orbital inflammation was found on magnetic resonance imaging to have a unilateral intraconal mass. Biopsy revealed a high-grade malignant tumor that was interpreted as squamous cell carcinoma. Positron emission tomography-computed tomography imaging subsequently identified a primary lesion in the esophagus. Esophageal squamous cell carcinoma is a rare cause of orbital metastasis, with only 4 previously reported cases. The authors discuss an approach to orbital malignancies of obscure origin. Accepted for publication April 4, 2018. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Address correspondence and reprint requests to Norman C. Charles, M.D., NYU Langone Medical Center, 550 First Avenue, New York, NY 10016. E-mail: norman.charles@nyumc.org © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Histopathologic Findings of Linear Scleroderma Displaying Focal Trichiasis Secondary to Tarsal Thinning

Linear scleroderma en coup de sabre with ophthalmic findings has been previously described in the literature on numerous occasions. A 57-year-old woman presented with focal trichiasis secondary to tarsal thinning, adjacent to a linear brow and forehead deformity consistent with linear scleroderma en coup de sabre. Cases of linear scleroderma en coup de sabre involving the eyelids have been reported, most often with madarosis, ptosis, or skin atrophy; however, to the authors' knowledge, this is the first reported case of linear scleroderma associated with trichiasis and involvement of the deeper eyelid tissues, particularly the tarsus. Accepted for publication April 4, 2018. N.W. is funded by a Heed Ophthalmic Fellowship. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Frederick A. Jakobiec, M.D., D.Sc, David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, MA 02114. E-mail: Fred_Jakobiec@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Greater Proptosis Is Not Associated With Improved Compressive Optic Neuropathy in Thyroid Eye Disease

Purpose: Despite the paucity of supporting data, it has generally been held that proptosis in thyroid eye disease (TED) may provide relative protection from compressive optic neuropathy (CON) by producing spontaneous decompression. The objective of this study was to investigate this phenomenon in patients with bilateral TED-CON. Methods: We retrospectively reviewed the charts of 67 patients (134 orbits) with bilateral TED-CON at Columbia-Presbyterian Medical Center. Significant asymmetric proptosis (Hertel) was defined as ≥ 2 mm.1 Significant asymmetric CON was defined first, as the presence of an relative afferent pupillary defect. Those without an relative afferent pupillary defect were evaluated according to the TED-CON formula y = –0.69 – 0.31 × (motility) – 0.2 × (mean deviation) – 0.02 × (color vision) as previously established for the diagnosis of TED-CON.2 A difference in the formula result ≥ 1.0 between eyes was considered significant. Patients were then divided into 4 groups. Results: Forty-one of 67 patients demonstrated asymmetric CON (29 by relative afferent pupillary defect, 12 by formula). Twenty-one of 67 patients demonstrated asymmetric proptosis. Only 5 of 12 (41.6%) of the patients who had both asymmetric proptosis and asymmetric CON (group 1) showed greater proptosis in the eye with less CON. Twenty-nine patients (group 2) showed that asymmetric CON occurred despite symmetrical proptosis. Seventeen patients (group 3), showed the inverse, that asymmetric differences in proptosis occurred with symmetrical CON. Conclusion: Despite commonly held assumptions, our results suggest that greater proptosis is not associated with improved TED-CON. Combining groups 1 to 3—all of which demonstrated asymmetry of either proptosis, CON, or both—91.4% of patients did not show a relationship between greater proptosis and improved CON. Accepted for publication March 27, 2018. This article was presented at the ASOPRS 48th Annual Fall Scientific Symposium, New Orleans, Louisiana on November 10th, 2017. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Michael Kazim, M.D., Harkness Eye Institute, Columbia University Medical Center, 635 West 165th Street, New York, NY 10032. E-mail: mk48@columbia.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Diversity in the American Society of Ophthalmic Plastic and Reconstructive Surgery

Purpose: To assess the epidemiology of women and underrepresented minorities (URMs; Hispanic, African American, and Native American) in the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS). Methods: An observational retrospective study of living ASOPRS members was identified through the ASOPRS member directory, search engine-driven informatics, and direct communication. Members were profiled for gender, race, geographic location, and academic rank (or not). The percentage of women and URMs in the society over time was also assessed. Results: The authors identified 617 living ASOPRS members as of June 2017. Of these, 109 (17.7%) were female and 58 (9.4%) were URMs. Surgeons completed fellowships from 1961 (male) or 1973 (female) until 2015. Women members significantly increased from 7 (4.9% of the total) before 1986 to 24 (30.4%) between 2011 and 2015 (last 5 years). URMs significantly increased over time, with 0 female and 5 (3.4%) male minorities before 1985 to 5 (6.3%) females and 13 (16.5%) males within the last 5 years (p

Integrated rice-duck farming decreases global warming potential and increases net ecosystem economic budget in central China

Abstract

Over the past decades, many attempts have been made to assess the effects of integrated rice-duck farming on greenhouse gas emissions, use efficient of energy, soil fertility, and economic significance. However, very few studies have been focused on the effects of the farming on net ecosystem economic budget (NEEB). Here, a 2-year field experiment was conducted to comprehensively investigate the effects of ducks raised in paddy fields on CH₄ and N₂O emissions, global warming potential (GWP), rice grain yield, and NEEB in central China. The experiment included two treatments: integrated rice-duck farming (RD) and conventional rice farming (R). The introduction of ducks into the paddy fields markedly increased the rice grain yield due to enhanced tiller number and root bleeding rate. RD treatment significantly elevated the N₂O emissions (p < 0.05) but decreased CH₄ emissions (p < 0.05) during rice growing seasons compared with R treatment. Analysis of GWP based on CH₄ and N₂O emissions showed that compared with R treatment, RD treatment significantly decreased the GWP by 28.1 and 28.0% and reduced the greenhouse gas intensity by 30.6 and 29.8% in 2009 and 2010, respectively. In addition, RD treatment increased NEEB by 40.8 and 39.7% respectively in 2009 and 2010 relative to R treatment. Taken together, our results suggest that the integrated rice-duck farming system is an effective strategy to optimize the economic and environmental benefits of paddy fields in central China.

Estimation of soil-specific microbial degradation of alpha-cypermethrin by compound-specific stable isotope analysis

Abstract

In this study, the microbial degradation of alpha-cypermethrin was investigated in 14 different soil samples by compound-specific stable isotope analysis. After 40 and 80 days of microbial degradation, the stable carbon isotope ratios of alpha-cypermethrin shifted from − 32.18 to − 31.87‰ ~ − 31.12 and − 31.45‰ ~ − 29.75‰ in the soils, respectively. The microbial degradation percentages of alpha-cypermethrin were calculated as 15.6~44.3% after 40 days of incubation and 33.3~73.9% after 80 days of incubation. The effects of physicochemical properties of soil samples were then explored on the microbial degradation of alpha-cypermethrin. The results revealed that the microbial degradation percentages were positively correlated with the contents of organic carbon in soils with Pearson correlation coefficients of 0.794 and 0.843 for 40 and 80 days of microbial degradation, respectively, indicating that the microbial degradation of alpha-cypermethrin was faster in the soil with higher content of organic carbon. Accordingly, soil-specific use should be considered in practical agricultural application of alpha-cypermethrin to reduce the residue of the pesticide.

How does intensification influence the operational and environmental performance of photo-Fenton processes at acidic and circumneutral pH

Abstract

This study evaluates the technical, economical, and environmental impact of sodium persulfate (Na₂S₂O₈) as an enhancing agent in a photo-Fenton process within a solar-pond type reactor (SPR). Photo-Fenton (PF) and photo-Fenton intensified with the addition of persulfate (PFPS) processes decolorize 97% the azo dye direct blue 71 (DB71) and allow producing a highly biodegradable effluent. Intensification with persulfate allowed reducing treatment time in 33% (from 120 to 80 min) and the consumption of chemical auxiliaries needed for pH adjustment. Energy, reagents, and chemical auxiliaries are still and environmental hotspot for PF and PFPS; however, it is worth mentioning that their environmental footprint is lower than that observed for compound parabolic concentrator (CPC)-type reactors. A life-cycle assessment (LCA) confirms that H₂O₂, NaOH, and energy consumption are the variables with the highest impact from an environmental standpoint. The use of persulfate reduced the relative impact in 1.2 to 12% in 12 of the 18 environmental categories studied using the ReCiPe method. The PFPS process emits 1.23 kg CO₂ (CO₂-Eqv/m³ treated water). On the other hand, the PF process emits 1.28 kg CO₂ (CO₂-Eqv/m³ treated water). Process intensification, chemometric techniques, and the use of SPRs minimize the impact of some barriers (reagent and energy consumption, technical complexity of reactors, pressure drops, dirt on the reflecting surfaces, fragility of reactor materials), limiting the application of advanced oxidation systems at an industrial level, and decrease treatment cost as well as potential environmental impacts associated with energy and reagents consumption. Treatment costs for PF processes (US$0.78/m³) and PFPS processes (US$0.63/m³) were 20 times lower than those reported for photo-Fenton processes in CPC-type reactors.

Climate change and economic growth: a heterogeneous panel data approach

Abstract

Climate change is a global phenomenon. Its impact on economic growth must therefore be analyzed in accordance with its (time-varying) common effects. We present an econometric analysis that evaluates this effect taking into account its global nature. Contrary to previous evidence that ignores the global effects, we obtain that the rising temperature has not decreased growth in real GDP per capita in the second half of the twentieth century for the world countries. However, we obtain a negative effect of rising temperatures and a positive effect of rising precipitation in poor countries. This positive effect of rising precipitation is also confirmed for hot and temperate countries.

Hydrothermal synthesis of a magnetic adsorbent from wasted iron mud for effective removal of heavy metals from smelting wastewater

Abstract

A magnetic adsorbent (MA) was synthesized from wasted iron mud of a groundwater treatment plant using a novel one-step hydrothermal method. The results showed that Fe content of MA was 41.8 wt%, 2.5 times higher than that of iron mud, which was caused by hydrothermal dissolution of non-ferrous impurities under alkaline condition, such as quartz and albite, regardless of addition of ascorbic acid or not. Ferrihydrite was 92.7% in dry iron mud before adding ascorbic acid and gradually decreased to 58.1% by increasing the molar ratio of ascorbic acid to Fe following hydrothermal treatment. The strongest saturation magnetization of 16.29 emu/g was observed in the prepared MA-4 when the ascorbic acid to Fe molar ratio was 1. The highest surface site concentration of 1.31 mmol/g was observed in MA-2 when the ratio was 0.02. The mechanism of hydrothermal conversion of wasted iron mud to MA was reductive dissolution of ferrihydrite to form siderite, which was then reoxidized to maghemite. When 12.5 g/L of MA-2 was applied to treat smelting wastewater, over 99% removal of Cu²⁺, Zn²⁺, Pb²⁺, and Cd²⁺ was achieved. The major mechanisms of Cu²⁺ and Zn²⁺ adsorption by the adsorbent were cationic exchange.

Study of zinc oxide nanoparticles and zinc chloride toxicity to annelid Enchytraeus crypticus in modified agar-based media

Abstract

Acute toxicity of zinc oxide nanoparticle (ZnO-NP, mean particle size diameter of 10 nm) powder and water-soluble salt of zinc (ZnCl₂) to annelid Enchytraeus crypticus was tested using an agar-based nutrient-enriched medium with the addition of kaolin and humic acids (HA). Adults of the E. crypticus were cultivated in pure agar and in three types of modified exposure media containing different proportions of model soil constituents. Potworms were exposed to zinc in both forms (1–1000 mg kg⁻¹ of agar) for 96 h. In experiments with ZnCl₂, toxicity of zinc was the highest in pure agar followed by agar with HA and agar with kaolin and HA and the lowest toxicity was observed in agar with kaolin. The corresponding LC₅₀ values were 13.2, 28.8, 39.4, and 75.4 mg kg⁻¹ respectively. In contrast, zinc in the form of ZnO-NPs was most toxic in the presence of HA followed by pure agar, agar with kaolin, and kaolin with HA. In this case, LC₅₀ values were 15.8, 43.5, 111, and 122 mg kg⁻¹ respectively. Scanning electron microscopy revealed that the smallest agglomerates occurred in the presence of kaolin, where ZnO-NPs were sealed in a kaolin shell. This effect reduced the bioavailability and toxicity of the NPs. In contrast, larger agglomerates were observed in the presence of HA but a larger amount of zinc was dispersed in the volume of agar.

Ecological quality status evaluation of a monsoonal tropical estuary using benthic indices: comparison via a seasonal approach

Abstract

The use of biotic indices has garnered attention during the last decade due to its extensive application in evaluating ecological quality status (EcoQS) of marine waters and estuaries. Three seasonal surveys were conducted in the Kundalika estuary, India to evaluate the ecostatus using five benthic indices and comparing their effectiveness considering the estuarine salinity gradient and seasonality. All indices gave divergent results displaying a wide range of classes (good to bad) across salinity zones and seasons. Comparatively, M-AMBI discriminated the EcoQS suitably than other indices. Hence, a seasonally averaged approach for M-AMBI was proposed to obtain a final mean EcoQS which assigned moderate status to the euhaline and poly-mesohaline zones and poor status to the oligohaline zone. Considering the high degree of spatial heterogeneity and seasonality in the estuary, the monsoon data was found to lower the EcoQS due to natural stress in some cases; the exclusion of the monsoon season resulted in a more valid ecostatus. Therefore, this approach which combines information from the non-monsoon seasons stands out in providing a useful basis for ecological management by scrutinizing responses of macrobenthos. Also, we suggest salinity zone-wise evaluation for more effective classification chiefly in tropical monsoonal estuaries. An effort to establish a final EcoQS was performed; however, future in-depth studies are necessary to ascertain the reliability of the successful biotic index (M-AMBI) in estuaries with different stressors.

Seasonal variations of contamination and exoskeletal malformations in the white shrimps Palaemon longirostris in the Gironde estuary, France

Abstract

Since the end of the 1980s, white shrimps (Palaemon longirostris) from the Gironde estuary have exhibited exoskeletal malformations, mainly involving cephalothorax, rostrum, scaphocerites and uropods. An 8-month study was carried out in 2015. Each month, 200 individuals were sampled and examined for exoskeletal malformations. Temporal variations in malformation frequency were noted, particularly during the breeding period, along with decreases in the size of non-deformed shrimps related to the appearance of juveniles in breeding sites, and high mortality among deformed shrimps. A significant increase in proportions of deformed shrimp was observed, relating particularly to the size (and therefore the age) of individuals. No significant difference was found between shrimp proportions with different numbers of malformations (one to four) for a fixed size class, nor was there any variation in proportions within different size classes for a fixed number of malformations. This would appear to indicate that the number of malformations is acquired and new malformations do not seem to appear during the life cycle, except for the smallest (youngest) shrimps. The malformation spectrum showed no significant differences between the biggest and smallest individuals for the different malformation associations, except for those involving cephalothorax, rostrum and uropods. This would suggest that some malformation associations lead to a higher mortality rate in shrimps subjected to them, due to greater impairment of feeding and/or swimming behaviour. Multiple component analysis of the different types of malformation showed correlations between exoskeletal pieces (rostrum and cephalothorax) and appendixes (scaphocerites and uropods). Regarding metal contamination in shrimp, no significant difference was highlighted between deformed and non-deformed shrimps. Organic pollutants were not measured in tissues. Certain herbicides such as metolachlore and chlortoluron were detected at high concentrations in the Gironde estuary during the breeding period corresponding to the higher occurrence of exoskeletal malformations.

Guest Editor Introduction to the Book Symposium on Shannon Vallor, Technology and the Virtues: A Philosophical Guide to a Future Worth Wanting. Oxford: Oxford University Press, 2016

JSID's Fellowship Shiseido Research Grant

Conditional Bistability, a Generic Cellular Mnemonic Mechanism for Robust and Flexible Working Memory Computations

Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain the fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust and generic. and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability, and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the subthreshold input it requires, and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory.

SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property: conditional bistability. We show that, thanks to its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability (1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that (2) it accounts for essential neurodynamical features for the organization and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models.

Exploring Executive Functions Using a Distributed Circuit Model

Short-Term Plasticity Combines with Excitation-Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range

The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short-term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex.

SIGNIFICANCE STATEMENT Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high-frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate.

Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF)

The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not.

SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms.

Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb⁺, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.

SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.

Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset

The onset of the headache phase during attacks of migraine with aura, which occur in ~30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO₂) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO₂, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO₂ by preemptively increasing cortical blood flow using the ATP-sensitive potassium [K(ATP)] channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO₂ that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses, suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.

SIGNIFICANCE STATEMENT Cortical spreading depression (CSD)-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tissue partial pressure of oxygen by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization, but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for an effective migraine therapy.

The Affective and Neural Correlates of Heroin versus Cocaine Use in Addiction Are Influenced by Environmental Setting But in Opposite Directions

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values <0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes.

SIGNIFICANCE STATEMENT The rewarding effects of addictive drugs are often thought to depend on shared substrates. Yet, environmental influences can unmask striking differences between psychostimulants and opiates. Here we used emotional tasks and fMRI to explore the influence of setting on the response to heroin versus cocaine in individuals with addiction. Simply moving from one setting to another significantly decreased heroin pleasure but increased cocaine pleasure, and vice versa. Similar double dissociation was observed in the activity of the fronto-striatal-cerebellar network. These findings suggest that the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates and that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use.

GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC

Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (ACC) subregions were assessed as mediators of gene–personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with G carriers. The pgACC drove a significant interaction of genotype, region, and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated single nucleotide polymorphisms of the GABA synthesis related enzymes (GAD1, GAD2, and GLS) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated-mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women.

SIGNIFICANCE STATEMENT Anxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however, only in women.

This Week in The Journal

Distinguishing the Roles of Dorsolateral and Anterior PFC in Visual Metacognition

Visual metacognition depends on regions within the prefrontal cortex (PFC). Two areas in particular have been implicated repeatedly: the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we used online transcranial magnetic stimulation (TMS) to interfere causally with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision making and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability, but only for the second half of the experimental blocks. These results support a functional architecture in which DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgment by potentially incorporating additional, nonperceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation.

SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its subregions, the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC), have been specifically implicated in confidence generation. However, it is unclear whether these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation, we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, whereas targeting aPFC affected metacognitive scores specifically. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation.

Schaffer Collateral Inputs to CA1 Excitatory and Inhibitory Neurons Follow Different Connectivity Rules

Neural circuits, governed by a complex interplay between excitatory and inhibitory neurons, are the substrate for information processing, and the organization of synaptic connectivity in neural network is an important determinant of circuit function. Here, we analyzed the fine structure of connectivity in hippocampal CA1 excitatory and inhibitory neurons innervated by Schaffer collaterals (SCs) using mGRASP in male mice. Our previous study revealed spatially structured synaptic connectivity between CA3 and CA1 pyramidal cells (PCs). Surprisingly, parvalbumin-positive interneurons (PVs) showed a significantly more random pattern spatial structure. Notably, application of Peters' rule for synapse prediction by random overlap between axons and dendrites enhanced structured connectivity in PCs, but, by contrast, made the connectivity pattern in PVs more random. In addition, PCs in a deep sublayer of striatum pyramidale appeared more highly structured than PCs in superficial layers, and little or no sublayer specificity was found in PVs. Our results show that CA1 excitatory PCs and inhibitory PVs innervated by the same SC inputs follow different connectivity rules. The different organizations of fine scale structured connectivity in hippocampal excitatory and inhibitory neurons provide important insights into the development and functions of neural networks.

SIGNIFICANCE STATEMENT Understanding how neural circuits generate behavior is one of the central goals of neuroscience. An important component of this endeavor is the mapping of fine-scale connection patterns that underlie, and help us infer, signal processing in the brain. Here, using our recently developed synapse detection technology (mGRASP and neuTube), we provide detailed profiles of synaptic connectivity in excitatory (CA1 pyramidal) and inhibitory (CA1 parvalbumin-positive) neurons innervated by the same presynaptic inputs (CA3 Schaffer collaterals). Our results reveal that these two types of CA1 neurons follow different connectivity patterns. Our new evidence for differently structured connectivity at a fine scale in hippocampal excitatory and inhibitory neurons provides a better understanding of hippocampal networks and will guide theoretical and experimental studies.

Time-Restricted Feeding Prevents Ablation of Diurnal Rhythms in Gastric Vagal Afferent Mechanosensitivity Observed in High-Fat Diet-Induced Obese Mice

Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food-related stimuli, allowing time of day-specific satiety signaling. This diurnal rhythmicity is ablated in high-fat-diet (HFD)-induced obesity. Time-restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF. Eight-week-old male C57BL/6 mice (N = 256) were fed a standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks of diet acclimatization, the mice were fed either ad libitum or only during the light phase [Zeitgeber time (ZT) 0–12] or dark phase (ZT12–24) for 8 weeks. A subgroup of mice from all conditions (n = 8/condition) were placed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at ZT0. HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice, but decreased weight gain in the HFD mice regardless of the TRF period. In SLD mice, diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice, diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity were dampened. Loss of diurnal rhythmicity in HFD mice was abrogated by TRF. In conclusion, diurnal rhythmicity in GVA responses to food-related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.

SIGNIFICANCE STATEMENT Diurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time-restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high-fat-diet (HFD)-induced obese mice and, more importantly, prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.

Genetic Activation, Inactivation, and Deletion Reveal a Limited And Nuanced Role for Somatostatin-Containing Basal Forebrain Neurons in Behavioral State Control

Recent studies have identified an especially important role for basal forebrain GABAergic (BF^VGAT) neurons in the regulation of behavioral waking and fast cortical rhythms associated with cognition. However, BF^VGAT neurons comprise several neurochemically and anatomically distinct subpopulations, including parvalbumin-containing BF^VGAT neurons and somatostatin-containing BF^VGAT neurons (BF^SOM neurons), and it was recently reported that optogenetic activation of BF^SOM neurons increases the probability of a wakefulness to non-rapid-eye movement (NREM) sleep transition when stimulated during the rest period of the animal. This finding was unexpected given that most BF^SOM neurons are not NREM sleep active and that central administration of the synthetic somatostatin analog, octreotide, suppresses NREM sleep or increases REM sleep. Here we used a combination of genetically driven chemogenetic and optogenetic activation, chemogenetic inhibition, and ablation approaches to further explore the in vivo role of BF^SOM neurons in arousal control. Our findings indicate that acute activation or inhibition of BF^SOM neurons is neither wakefulness nor NREM sleep promoting and is without significant effect on the EEG, and that chronic loss of these neurons is without effect on total 24 h sleep amounts, although a small but significant increase in waking was observed in the lesioned mice during the early active period. Our in vitro cell recordings further reveal electrophysiological heterogeneity in BF^SOM neurons, specifically suggesting at least two distinct subpopulations. Together, our data support the more nuanced view that BF^SOM neurons are electrically heterogeneous and are not NREM sleep or wake promoting per se, but may exert, in particular during the early active period, a modest inhibitory influence on arousal circuitry.

SIGNIFICANCE STATEMENT The cellular basal forebrain (BF) is a highly complex area of the brain that is implicated in a wide range of higher-level neurobiological processes, including regulating and maintaining normal levels of electrocortical and behavioral arousal. The respective in vivo roles of BF cell populations and their neurotransmitter systems in the regulation of electrocortical and behavioral arousal remains incompletely understood. Here we seek to define the neurobiological contribution of GABAergic somatostatin-containing BF neurons to arousal control. Understanding the respective contribution of BF cell populations to arousal control may provide critical insight into the pathogenesis of a host of neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, and the cognitive impairments of normal aging.

R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System

Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1^–/– and R-Ras2^–/–-null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1^–/– and/or R-Ras2^–/– mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.

SIGNIFICANCE STATEMENT In this study, we show that R-Ras1 and R-Ras2 play essential roles in regulating myelination in vivo and control fundamental aspects of oligodendrocyte (OL) survival and differentiation through synergistic activation of PI3K/Akt and Erk1/2-MAPK signaling. Mice lacking R-Ras1 and/or R-Ras2 show a diminished OL population with a higher proportion of immature OLs, explaining the observed hypomyelination in main CNS tracts. In vivo electrophysiology recordings demonstrate a slower conduction velocity of nerve impulses in the absence of R-Ras1 and R-Ras2. Therefore, R-Ras1 and R-Ras2 are essential for proper axonal myelination and accurate neural transmission.

Neural Mechanisms Underlying Individual Differences in Control-Averse Behavior

When another person tries to control one's decisions, some people might comply, but many will feel the urge to act against that control. This control aversion can lead to suboptimal decisions and it affects social interactions in many societal domains. To date, however, it has been unclear what drives individual differences in control-averse behavior. Here, we address this issue by measuring brain activity with fMRI while healthy female and male human participants made choices that were either free or controlled by another person, with real consequences to both interaction partners. In addition, we assessed the participants' affects, social cognitions, and motivations via self-reports. Our results indicate that the social cognitions perceived distrust and lack of understanding for the other person play a key role in explaining control aversion at the behavioral level. At the neural level, we find that control-averse behavior can be explained by functional connectivity between the inferior parietal lobule and the dorsolateral prefrontal cortex, brain regions commonly associated with attention reorientation and cognitive control. Further analyses reveal that the individual strength of functional connectivity complements and partially mediates the self-reported social cognitions in explaining individual differences in control-averse behavior. These findings therefore provide valuable contributions to a more comprehensive model of control aversion.

SIGNIFICANCE STATEMENT Control aversion is a prevalent phenomenon in our society. When someone tries to control their decisions, many people tend to act against the control. This can lead to suboptimal decisions such as noncompliance to medical treatments or disobeying the law. The degree to which individuals engage in control-averse behavior, however, varies significantly. Understanding the proximal mechanisms that underlie individual differences in control-averse behavior has potential policy implications, for example, when designing policies aimed at increasing compliance with vaccination recommendations, and is therefore a highly relevant research goal. Here, we identify a neural mechanism between parietal and prefrontal brain regions that can explain individual differences in control-averse behavior. This mechanism provides novel insights into control aversion beyond what is accessible through self-reports.

Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20–30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.

SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20–30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

Pregnancy-Associated Plasma Protein-aa Regulates Photoreceptor Synaptic Development to Mediate Visually Guided Behavior

To guide behavior, sensory systems detect the onset and offset of stimuli and process these distinct inputs via parallel pathways. In the retina, this strategy is implemented by splitting neural signals for light onset and offset via synapses connecting photoreceptors to ON and OFF bipolar cells, respectively. It remains poorly understood which molecular cues establish the architecture of this synaptic configuration to split light-onset and light-offset signals. A mutant with reduced synapses between photoreceptors and one bipolar cell type, but not the other, could reveal a critical cue. From this approach, we report a novel synaptic role for pregnancy-associated plasma protein aa (pappaa) in promoting the structure and function of cone synapses that transmit light-offset information. Electrophysiological and behavioral analyses indicated pappaa mutant zebrafish have dysfunctional cone-to-OFF bipolar cell synapses and impaired responses to light offset, but intact cone-to-ON bipolar cell synapses and light-onset responses. Ultrastructural analyses of pappaa mutant cones showed a lack of presynaptic domains at synapses with OFF bipolar cells. pappaa is expressed postsynaptically to the cones during retinal synaptogenesis and encodes a secreted metalloprotease known to stimulate insulin-like growth factor 1 (IGF1) signaling. Induction of dominant-negative IGF1 receptor expression during synaptogenesis reduced light-offset responses. Conversely, stimulating IGF1 signaling at this time improved pappaa mutants' light-offset responses and cone presynaptic structures. Together, our results indicate Pappaa-regulated IGF1 signaling as a novel pathway that establishes how cone synapses convey light-offset signals to guide behavior.

SIGNIFICANCE STATEMENT Distinct sensory inputs, like stimulus onset and offset, are often split at distinct synapses into parallel circuits for processing. In the retina, photoreceptors and ON and OFF bipolar cells form discrete synapses to split neural signals coding light onset and offset, respectively. The molecular cues that establish this synaptic configuration to specifically convey light onset or offset remain unclear. Our work reveals a novel cue: pregnancy-associated plasma protein aa (pappaa), which regulates photoreceptor synaptic structure and function to specifically transmit light-offset information. Pappaa is a metalloprotease that stimulates local insulin-like growth factor 1 (IGF1) signaling. IGF1 promotes various aspects of synaptic development and function and is broadly expressed, thus requiring local regulators, like Pappaa, to govern its specificity.

Trichophyton erinacei Transmitted to a Pregnant Woman From Her Pet Hedgehogs

This case report describes a pregnant woman who developed tinea manus from Trichophyton erinacei infection transmitted to her from her pet hedgehogs.

Lentigo Maligna—Challenges, Observations, Imiquimod, Confocal Microscopy, and Personalized Treatment

The word melanoma imparts considerable fear and concern in patients. Fortunately, for patients with the lentigo maligna (LM) subtype of melanoma in situ, there is overall good prognosis. The challenge of LM, however, is that it has the highest rate of local recurrence (approximately 20%) of all melanoma subtypes when treated by standard surgical excision alone, owing to frequent, unpredictable, subclinical extension. To reduce this risk, the use of Mohs surgery or staged excision has consistently demonstrated lower recurrence rates of 0.3% to 2.2% yet requires larger surgical margins for histological clearance than other in situ melanoma subtypes. Moyer et al also demonstrated that with increasing lesion size, both the surgical margin required to clear the lesion and the risk of local recurrence increased, suggesting increased subclinical spread with increasing lesion size. In addition, LM is typically located in the head and neck area, a complex zone with potential cosmetic and functional impairment owing to extensive surgery. Finally, differentiating LM from background atypical melanocytic hyperplasia can be challenging. Thus, treatments directed toward reducing the extent of surgery, minimizing morbidity, and providing a cure would enhance patient outcomes.

Prevalence of Skin Cancer Examination Among Indoor Tanning Bed Users

This study uses weighted national survey data to examine the prevalence of skin cancer examinations among users of indoor tanning beds.

Lentigo Maligna Treated With Off-Label Neoadjuvant Imiquimod

This medical record review examines the rate of recurrence of lentigo maligna in patients treated with neoadjuvant topical imiquimod, 5%, cream prior to conservatively staged excisions.

Adolescents’ Perspectives on Atopic Dermatitis Treatment

This qualitative study examines the beliefs, experiences, and preferences of adolescents with atopic dermatitis toward their treatment via focus groups interviews.

Against epistemic partiality in friendship: value-reflecting reasons

Abstract

It has been alleged that the demands of friendship conflict with the norms of epistemology—in particular, that there are cases in which the moral demands of friendship would require one to give a friend the benefit of the doubt, and thereby come to believe something in violation of ordinary epistemic standards on justified or responsible belief (Baker in Pac Philos Q 68:1–13, 1987; Keller in Philos Pap 33(3):329–351, 2004; Stroud in Ethics 116(3):498–524, 2006; Hazlett in A luxury of the understanding: on the value of true belief, Oxford University Press, Oxford, 2013). The burden of this paper is to explain these appearances away. I contend that the impression of epistemic partiality in friendship dissipates once we acknowledge the sorts of practical and epistemic reasons that are generated by our values: value-reflecting reasons. The present proposal has several virtues: it requires fewer substantial commitments than other proposals seeking to resist the case for epistemic partiality (in particular, it eschews both Pragmatic Encroachment and Epistemic Permissivism); it is independently motivated, as it cites a phenomenon—value-reflecting reasons—we have independent reasons to accept; it provides a single, unified account of how various features of friendship bear on belief-formation; and makes clear how it is the very value we place on friendship itself that ensures against epistemic partiality.

Real World Experience With Peanut Oral Immunotherapy: Lessons Learned From 270 Patients

Publication date: Available online 30 May 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Richard L. Wasserman, Angela R. Hague, Deanna M. Pence, Robert W. Sugerman, Stacy K. Silvers, Joanna G. Rolen, Morley Herbert
BackgroundPeanut allergy (PA) is a significant and increasing problem, interfering with psychological development and family life. The standard recommendation to avoid peanut products and have access to injectable epinephrine is often inadequate. Oral immunotherapy for PA has been formally studied. Clinical observations of allergen immunotherapy have repeatedly enhanced patient care.ObjectiveThe purpose of this study is to report observations on the treatment of 270 PA patients over 8.5 years.MethodsThis is a retrospective record review of patients beginning peanut oral immunotherapy between January 1, 2009 and June 1, 2017 approved by the North Texas Institutional Review Board.Results270 patients aged 4 to 18 years comprising 107 girls and 163 boys were treated. 214/270 patients (79%) completed immunotherapy escalation. Age (p<0.001) and peanut IgE (p<0.001) correlate inversely with completing dose escalation. Epinephrine treated reactions in 63 and isolated gastrointestinal symptoms in 101 patients respectively were the most common adverse reactions to treatment but did not preclude success. Peanut IgE decreased by 65% after 3 years of maintenance treatment and 14/214 patients (6.5%) were able to achieve sustained unresponsiveness.ConclusionsIn an allergy office practice setting, 79% of patients are able to complete a peanut desensitization protocol and maintain the desensitized state indefinitely with daily dosing. With appropriate planning and precautions, peanut oral immunotherapy may be performed in an allergy office. Careful observations of clinical treatment can contribute to the development of effective treatment strategies.

Determining the clinical relevance of positive patch testing to gold in evaluation of contact dermatitis

Publication date: Available online 29 May 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Barbara Yang, Britta K. Sundquist, M. Asghar Pasha

A Retrospective Cohort Study of the Management and Outcomes of Children Hospitalized With Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis

Publication date: Available online 30 May 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): James W. Antoon, Jennifer L. Goldman, Samir S. Shah, Brian Lee
BackgroundSevere cutaneous adverse reactions are rare yet life threatening conditions. The current management and outcomes of these conditions in U.S. children is unclear.ObjectivesTo characterize the current management and outcomes of Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) across U.S. children's hospitals.MethodsWe performed a retrospective cohort study of children less than 18 years of age hospitalized with a primary diagnosis of SJS or TEN at 47 U.S. freestanding children's hospitals. We compared treatment (IVIG, steroids, antibiotics, other) and outcomes (length of stay, hospital mortality, readmission, recurrence, related complications, and adjusted hospital costs) across hospitals and by SJS versus TEN diagnoses.ResultsWe identified 898 pediatric patients hospitalized with a primary diagnosis of SJS or TEN. Of these patients, 167 (18.6%) were prescribed steroids only, 229 (25.5%) IVIG only, 153 (17.04%) both IVIG and steroids. Median length of stay was 8 days (IQR5, 13) with median hospital adjusted costs of $16,265. Readmissions were common, with 88 (9.9%) of patients readmitted within 30 days of discharge and a recurrence rate of 2.7%. Overall hospital mortality in children was low at 0.56%. TEN was associated with higher mortality (3.23%) compared to SJS (0.13%). There was no association between the use of IVIG, systemic steroids, or IVIG + steroids use during the first two days of hospitalization and decreased LOS or mechanical ventilation. Complex chronic conditions and TEN diagnoses were associated with increased LOS and increased odds of mechanical ventilation.ConclusionsSurvival in children with SJS and TEN is significantly better than observed in adults. However, there is variability in the management and outcomes in children diagnosed with these severe cutaneous reactions. Further studies are needed to determine the most effective treatment strategies given the extent of health care utilization and high rate of readmissions observed in this population.

Basic Fibroblast Growth Factor Influences Epidermal Homeostasis of Living Skin Equivalents through Affecting Fibroblast Phenotypes and Functions

Aims: To elucidate the possible mechanisms of how basic fibroblast growth factor (bFGF) influences epidermal homeostasis in a living skin equivalent (LSE) model. Methods: Several wound healing-related growth factors were analyzed at protein and mRNA levels for dermal fibroblasts of induced alpha-smooth muscle actin (α-SMA)-positive or α-SMA-negative phenotypes. During culturing an LSE model by seeding normal human keratinocytes on a fibroblast-populated type I collagen gel, bFGF or neutralizing antibody for keratinocyte growth factor (KGF) was added to investigate its effects on fibroblast phenotypes and, subsequently, epidermal homeostasis by histology and immunohistochemistry. Results: The α-SMA-positive phenotype of fibroblasts induced by transforming growth factor beta-1 (TGF-β₁) markedly suppressed the expression of KGF and hepatocyte growth factor (HGF), and slightly upregulated vascular endothelial growth factor (VEGF) and TGF-β₁ at mRNA and protein levels, compared with α-SMA-negative fibroblasts treated with bFGF. α-SMA expression of fibroblasts at the epidermal-mesenchymal junction of the LSEs was suppressed by the addition of bFGF, and a better-differentiated epidermis was presented. The abrogation of KGF from fibroblasts by the addition of the KGF neutralizing antibody disenabled the LSE culturing system to develop an epidermis. Conclusions: bFGF, through affecting the phenotypes and functions of fibroblasts, especially KGF expression, influenced epidermal homeostasis in an LSE model.
Skin Pharmacol Physiol 2018;31:229–237

Cyanotoxin level prediction in a reservoir using gradient boosted regression trees: a case study

Abstract

Cyanotoxins are a type of cyanobacteria that is poisonous and poses a health threat in waters that could be used for drinking or recreational purposes. Thus, it is necessary to predict their presence to avoid risks. This paper presents a nonparametric machine learning approach using a gradient boosted regression tree model (GBRT) for prediction of cyanotoxin contents from cyanobacterial concentrations determined experimentally in a reservoir located in the north of Spain. GBRT models seek and obtain good predictions in highly nonlinear problems, like the one treated here, where the studied variable presents low concentrations of cyanotoxins mixed with high concentration peaks. Two types of results have been obtained: firstly, the model allows the ranking or the dependent variables according to its importance in the model. Finally, the high performance and the simplicity of the model make the gradient boosted tree method attractive compared to conventional forecasting techniques.

The impact of biomass energy consumption on pollution: evidence from 80 developed and developing countries

Abstract

The aim of this research is to explore the effect of biomass energy consumption on CO₂ emissions in 80 developed and developing countries. To achieve robustness, the system generalised method of moment was used and several control variables were incorporated into the model including real GDP, fossil fuel consumption, hydroelectricity production, urbanisation, population, foreign direct investment, financial development, institutional quality and the Kyoto protocol. Relying on the classification of the World Bank, the countries were categorised to developed and developing countries. We also used a dynamic common correlated effects estimator. The results consistently show that biomass energy as well as fossil fuel consumption generate more CO₂ emissions. A closer look at the results show that a 100% increase in biomass consumption (tonnes per capita) will increase CO₂ emissions (metric tons per capita) within the range of 2 to 47%. An increase of biomass energy intensity (biomass consumption in tonnes divided by real gross domestic product) of 100% will increase CO₂ emissions (metric tons per capita) within the range of 4 to 47%. An increase of fossil fuel consumption (tonnes of oil equivalent per capita) by 100% will increase CO₂ emissions (metric tons per capita) within the range of 35 to 55%. The results further show that real GDP urbanisation and population increase CO₂ emissions. However, hydroelectricity and institutional quality decrease CO₂ emissions. It is further observed that financial development, foreign direct investment and openness decrease CO₂ emissions in the developed countries, but the opposite results are found for the developing nations. The results also show that the Kyoto Protocol reduces emission and that Environmental Kuznets Curve exists. Among the policy implications of the foregoing results is the necessity of substituting fossil fuels with other types of renewable energy (such as hydropower) rather than biomass energy for reduction of emission to be achieved.

Concentration characteristics, source apportionment, and oxidative damage of PM 2.5 -bound PAHs in petrochemical region in Xinjiang, NW China

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are of considerable concern due to their potential as human carcinogens. Thus, determining the characteristics, potential source, and examining the oxidative capacity of PAHs to protect human health is essential. This study investigated the PM_2.5-bound PAHs at Dushanzi, a large petrochemical region in Xinjiang as well as northwest China. A total of 33 PM_2.5 samples with 13 PAHs, together with molecular tracers (levoglucosan, and element carbon), were analyzed during the non-heating and heating periods. The results showed that the PM_2.5 concentrations were 70.22 ± 22.30 and 95.47 ± 61.73 μg/m³, while that of total PAHs were 4.07 ± 2.03 and 60.33 ± 30.80 ng/m³ in sampling period, respectively. The fluoranthene, pyrene, chrysene, benzo[b]fluoranthene, and benzo[k]fluoranthene were the most abundant (top five) PAHs, accounting for 71.74 and 72.80% of total PAH mass during non-heating and heating periods. The BaP equivalent (BaPeq) concentration exceeded 1 ng/m³ as recommended by National Ambient Air Quality Standards during heating period. The diagnostic ratios and positive matrix factorization indicated that oil industry, biomass burning, coal combustion, and vehicle emissions are the primary sources. The coal combustion remarkably increased during heating period. The plasmid scission assay (PSA) results showed that higher DNA damage rate was observed during heating period. PAHs in PM_2.5 such as Chr, BaP, and IcdP were found to have significantly positive correlations with the plasmid DNA damage rates. Additionally, the relationship among BaPeq and DNA damage rate suggested that synergistic reaction may modify the toxicity of PAHs.

Involved-field chemoradiotherapy for postoperative solitary lymph node recurrence of esophageal cancer

Abstract

Background

For patients with postoperative lymph node (LN) recurrent esophageal cancer, the appropriate irradiation field in chemoradiotherapy (CRT) remains controversial. We assessed the clinical outcomes and prognostic factors related to involved-field CRT for postoperative solitary LN recurrence of esophageal squamous cell carcinoma (ESCC).

Methods

We retrospectively evaluated 21 patients who had received curative resection, with LN recurrence of ESCC. Patients received CRT using 5-fluorouracil plus cisplatin or docetaxel, prescribed at 60 Gy in 30 fractions. We evaluated the pattern of failure, toxicities, survivals, and prognostic factors. We defined elective nodal failure (ENF) as recurrence in a regional LN without involved-field failure.

Results

The median follow-up duration was 32 months (range, 4–106 months). Nine patients experienced failure—4 (19%) within involved-field and 5 (24%) with distant metastasis. No patients had ENF. We observed no severe toxicities. The 2-year overall survival (OS) rate was 78%. In the univariate analysis of OS, two factors, the maximal diameter of the metastatic LN < 25 mm and the absence of serum p53 antibodies (s-p53-Abs), were associated with a significantly better prognosis (p = 0.025 and p = 0.01, respectively).

Conclusions

Involved-field CRT for postoperative solitary LN recurrence of ESCC did not cause ENF and was without severe toxicities. Two factors, a length of the metastatic LN < 25 mm and the absence of s-p53-Abs may improve the treatment outcome. Involved-field CRT is a treatment option worthy of consideration for postoperative solitary LN recurrence of ESCC.

Editorial Board

Neurosurgeons still wanted

It is tempting to speculate that advances in molecularly targeted therapy might diminish the important role that surgeons have always played in the care of patients with glioblastoma (GBM). Maximum safe resection of at least the contrast-enhancing portion of the tumor mass is the desired starting point for treatment regimens in modern neuro-oncology. Surgical excision of >70% of the enhancing tumor volume significantly prolongs the overall survival of patients with GBM who are treated with the proven combination of external-beam radiation and temozolomide chemotherapy after initial diagnosis.^1–3 We do not know, however, whether the survival advantage associated with surgery observed in the radiation–temozolomide era of neuro-oncology will carry over into the future as highly selective anticancer drugs and immunotherapy agents emerge from the development pipeline and enter the clinic. The results of the study published by Ellingson and colleagues indicate that neurosurgeons will likely remain an effective strike force in the war on GBM even as medical treatment methods improve.⁴

Nomograms based on Pre-operative Multi-parametric Magnetic Resonance Imaging for Prediction of Molecular Subgrouping in Medulloblastoma: Results from a Radiogenomics Study of 111 Patients

Abstract

Background

Novel biological insights have led to consensus classification of medulloblastoma into four distinct molecular subgroups – wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. We aimed to predict molecular subgrouping in medulloblastoma based on pre-operative multi-parametric magnetic resonance imaging (MRI) characteristics.

Methods

A set of 19 MRI features were evaluated in 111 patients with histologic diagnosis of medulloblastoma for prediction of molecular subgrouping. MRI characteristics were correlated with molecular subgroups derived from tissue samples in 111 patients (WNT=17, SHH=44, Group 3=27, and Group 4=23). Multinomial logistic regression of imaging parameters was performed on a training cohort (TC) of 76 patients, representing two-thirds of randomly-selected patients from each of four molecular subgroups, to generate binary nomograms. Validation of these nomograms was performed on the remaining 35 patients as the validation cohort (VC).

Results

Medulloblastoma subgroups could be accurately predicted by pre-operative MRI features in 74% of cases. Predictive accuracy was excellent for SHH (95%), acceptably high for Group 4 (78%), modest for Group 3 (56%) and worst for WNT (41%) subgroup medulloblastoma. SHH-specific nomogram was associated with excellent correlation between TC and VC, with area under the curve (AUC) of 0.939 and 0.991 respectively. AUC for Group 4 was acceptable at 0.851 and 0.788 in TC and VC respectively; however, these values were consistently suboptimal in WNT and Group 3 medulloblastoma.

Conclusion

The predictive accuracy of MRI-based nomograms was excellent for SHH and encouraging for Group 4 medulloblastoma. Further work is needed for Group 3 and WNT-pathway medulloblastoma.

Survivorship in Adults with Malignant Brain and other Central Nervous System Tumor from 2000-2014

Abstract

Background

The goal of this study was to provide up to date and comprehensive statistics on incidence, survival, and prevalence rates for selected malignant brain and other CNS tumors in adults.

Methods

The current study used CBTRUS data, provided by CDC, to examine incidence and SEER data to examine survival and prevalence in sixteen distinct malignant brain and other CNS histologies in adults (aged 20 years and older at diagnosis) from 2000-2014 overall and by sex, age group, race, and ethnicity.

Results

Glioblastoma had the highest incidence (4.40 per 100,000) and prevalence (9.23 per 100,000). Ependymal tumors had the highest 5- and 10-year relative survival (87.8% and 84.5%, respectively), while glioblastoma had the lowest 5- and 10-year relative survival (5.4% and 2.7%, respectively). Females generally had better survival and lower prevalence than males. Younger adults tended to have better survival than older adults, and prevalence varied greatly by age and histology. While survival did not vary significantly by race, White adults had higher prevalence than the other race groups. Hispanics generally had better survival rates and lower prevalence than non-Hispanics.

Conclusions

Survival varied greatly by age and ethnicity. Prevalence differed by sex, age, race, and ethnicity.

Occurrence and distribution of antibiotics in surface water impacted by crab culturing: a case study of Lake Guchenghu, China

Abstract

The objective of this study was to evaluate the occurrence, distribution, potential sources, and ecological risk of antibiotics in aqueous phase of Lake Guchenghu, China. Target antibiotics in surface water of Lake Guchenghu, adjacent streams, and crab ponds were detected seasonally. The results showed that erythromycin-H₂O (1.60–2450 ng/L), sulfadiazine (ND–654 ng/L), and florfenicol (ND–919 ng/L) were the predominant antibiotics in Lake Guchenghu. The concentrations of antibiotics in Lake Guchenghu Basin showed obvious seasonal variation, with the highest concentration in summer. In general, the concentrations of antibiotics in crab ponds and streams were higher than those in the lake and spatial distributions of antibiotics were affected by pollution sources. The types and origins of antibiotics indicated that wastewater from ponds was the main source of antibiotics in the lake. Risk assessment suggested that as individual compound, erythromycin-H₂O and clarithromycin posed a high risk to algae while other compounds might pose low or no risk. The mixture of antibiotics may pose a high risk to aquatic organisms in Lake Guchenghu. Overall, our study revealed the occurrence and spatiotemporal variation of antibiotics in Lake Guchenghu, which was related with crab culturing.

Effectiveness of transcutaneous electrical nerve stimulation for the treatment of migraine: a meta-analysis of randomized controlled trials

Migraine is now ranked as the second most disabling disorder worldwide reported by the Global Burden of Disease Study 2016. As a noninvasive neurostimulation technique, transcutaneous electrical nerve stimulat...

Treatment with TNF-α inhibitor rectifies M1 macrophage polarization from blood CD14+ monocytes in patients with psoriasis independent of STAT1 and IRF-1 activation

Psoriasis is a systemic inflammatory disease with dramatic responses to TNF-α inhibitors. TNF-α is mainly produced by macrophages. However, how macrophage polarization contributes to psoriasis remains unknown.

Ablative fractional laser-assisted photodynamic therapy provides superior long-term efficacy compared to standard methyl aminolevulinate photodynamic therapy for lower extremity Bowen’s disease

Ablative fractional laser-assisted methyl aminolevulinate photodynamic therapy (AFL-MAL-PDT) has shown significantly higher efficacy and lower recurrence rates at 12 months than conventional methyl aminolevulinate photodynamic therapy (MAL-PDT) for the treatment of Bowen's disease (BD). However, long-term follow-up data are not available.

Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study

Cutaneous adverse events are common with Programmed Death (PD)-1/ PD-Ligand (L)1 inhibitors. However, the nature of the specific cutaneous adverse event of dermatitis has not been investigated across various PD-1/PD-L1 inhibitors. Oncologic outcomes potentially associated with dermatitis are not well characterized.

A Step Toward Demystifying Melanomas of Unknown Primary Sites

Management of primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma: A retrospective study

Hierarchical protein export mechanism of the bacterial flagellar type III protein export apparatus

Abstract

The bacterial flagellum is supramolecular motility machinery consisting of the basal body, the hook and the filament. Flagellar proteins are translocated across the cytoplasmic membrane via a type III protein export apparatus, diffuse down the central channel of the growing structure and assemble at the distal end. Flagellar assembly begins with the basal body, followed by the hook and finally the filament. The completion of hook assembly is the most important morphological checkpoint of the sequential flagellar assembly process. When the hook reaches its mature length of about 55 nm in Salmonella enterica, the type III protein export apparatus switches export specificity from proteins required for the structure and assembly of the hook to those responsible for filament assembly, thereby terminating hook assembly and initiating filament assembly. Three flagellar proteins, namely FliK, FlhB and FlhA, are responsible for this substrate specificity switching. Upon completion of the switching event, interactions among FlhA, the cytoplasmic ATPase complex and flagellar type III export chaperones establish the assembly order of the filament at the hook tip. Here, we describe our current understanding of a hierarchical protein export mechanism used in flagellar type III protein export.

Fatty acids and their amide derivatives from endophytes: new therapeutic possibilities from a hidden source

Abstract

Fatty acid and their amide derivatives are natural self-defense agents in plants. They have been observed to be broadly bioactive against a variety of disease agents. The mechanism of action understood so far being their targeting the protein synthesis and causing leakage of the intracellular components. Owing to their broad bioactivity, the fatty acids and their amides as therapeutics can cover a wide range of indications such as cancer, bacterial infections, parasitic infection, inflammations, diabetes and obesity to name a few. The microorganisms residing inside the healthy plant tissues are a unique niche for exploration of novel bioactive compounds. The recent identification of fatty acid amide derivatives as well as prior reports from endophytes have drawn fresh attention to this unique source for their isolation. Hence, they represent an exciting opportunity for the development of new therapeutic agents against existing disease causative agents. In this paper, we will discuss the production of fatty acids and amide derivatives by plants and their associated endophytes. Their reported bioactivities establishing their potential benefit as possible therapeutic agents will also be examined.

Contamination levels and health risk assessments of heavy metals in an oasis-desert zone: a case study in northwest China

Abstract

Rapid and extensive social and economic development has caused severe soil contamination by heavy metals in China. The spatial distribution, pollution levels, and health risks of metals were identified in an oasis-desert zone of northwest China. The mean concentrations of six heavy metals exceeded their corresponding background contents, and each metal concentration in farmland samples was higher than that in Gobi samples. Moreover, these heavy metals followed a similar spatial pattern and showed significant positive correlations with each other, indicating that they have the same sources. The contamination features of heavy metals and ecological risks were calculated using several quality indicators, and their health risks for population groups were quantified. The results showed that the Gobi and farmland soils were uncontaminated to moderately contaminated by heavy metals, and that farmland pollution was more serious than that of Gobi. The Gobi and farmland soils posed low ecological risks. As a whole, the non-carcinogenic risk which was caused by heavy metals was low for local residents, and the carcinogenic risk was within an acceptable level. Comparatively speaking, children were the more vulnerable population to health risks. The Zn and Cu pollution was relatively serious, and Cr and V were major contributors to health risks.

Graphical abstract

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Combined toxicity of chlorantraniliprole, lambda-cyhalothrin, and imidacloprid to the silkworm Bombyx mori (Lepidoptera: Bombycidae)

Abstract

Insecticides with different modes of action may act in combination, in ways such as drifting, spray equipment residual, or utilizing concurrently in mulberry orchards or nearby agricultural fields. Silkworms may suffer from a diverse impact on the survival. In this study, the toxicity of chlorantraniliprole, lambda-cyhalothrin, and imidacloprid and their combinations to the second instar of silkworms (Bombyx mori (L.)(Lepidoptera: Bombycidae)) were evaluated after 48 and 72 h treatment by the leaf-dipping method and the combination index (CI)-isobologram equation. After 48 h treatment, results indicated that (1) the increasing order of toxicity was imidacloprid < chlorantraniliprole < lambda-cyhalothrin, and that (2) synergism was predominated in most combinations excepted for the lambda-cyhalothrin + imidacloprid combination which displayed an additive effect at f_a value 0.5. Then, after 72 h treatment, results exhibited that (1) the increasing order of toxicity was imidacloprid < lambda-cyhalothrin < chlorantraniliprole, and that (2) only the chlorantraniliprole + imidacloprid mixture yielded antagonism at f_a value 0.5; the other combinations performed an additive effect at least. Consequently, combined toxicity of mixtures may pose a worse effect on silkworm than single toxicity of insecticides. Therefore, we suggest that insecticide mixtures should be added into ecotoxicological risk assessment.

Monitoring and spatiotemporal variations of pyrethroid insecticides in surface water, sediment, and fish of the river Chenab Pakistan

Abstract

There is a serious concern regarding freshwater resources of Pakistan which have been mismanaged and now are depleting extensively due to other reasons like intensive application of agricultural pesticides and insecticides. The present study was conducted to determine the concentrations of cypermethrin, deltamethrin, permethrin, and bifenthrin in the samples of water, sediments, and fish collected from various locations of River Chenab, Pakistan, during summer and winter seasons. These locations include namely Marala, Khanki, Qadirabad, and Trimu Headworks. High-performance liquid chromatography (HPLC) was deployed for analysis and determination of pyrethroid concentrations in these samples. The analytics show the order of pyrethroid concentrations in river as fish> sediment>water. Whereas maximum concentrations of 0.472 μg g⁻¹ found in fish and minimum concentrations were determined in water, i.e., 0.087 μg L⁻¹ at the sampling locations of Trimu and Marala headworks, respectively. Moreover, highest mean concentrations of pyrethroid, i.e., 1.248 μg g⁻¹ in fish were detected in winter season as compared to summers, i.e., 0.087 μg L⁻¹. However, all the values of pyrethroid were found to be lower than the maximum permissible levels specified by EU and WHO-FAO. Whereas the levels of deltamethrin and permethrin in water were found much higher than the specific limits set by EU.

Mortality in women treated with assisted reproductive technology treatment – addressing the healthy patient effect

Abstract

Previous studies have reported reduced mortality among women undergoing assisted reproductive technology (ART) treatment, possibly related to selection of healthy women into ART treatment. The aim of this study was to explore the impact of relevant selection factors on the association between ART treatment and mortality and explore effect modification by parity. Women treated with ART in fertility clinics in Denmark during 1994–2009 (n = 42,897) were age-matched with untreated women from the background population (n = 204,514) and followed until ultimo 2010. With adjustment for relevant confounders, the risk of death was lower among ART-treated women immediately after ART treatment (HR = 0.68, 95% CI: 0.63, 0.74), but there was no apparent difference after 10 years (HR = 0.92, 95% CI: 0.79, 1.07). Having children prior to ART treatment was associated with a markedly reduced mortality (HR = 0.45, 95% CI: 0.38, 0.53), possibly due to better health among fertile women. While the frequency of previous medical and psychiatric diagnoses among ART-treated and untreated women was similar, differences in disease severity could explain the reduced mortality among ART-treated women, as poor prognosis would make ART treatment initiation unlikely. The survival advantage among ART-treated women is likely a selection rather than a biological phenomenon.

What makes an animal? The molecular quest for the origin of the Animal Kingdom

Synopsis

What makes an animal? To find the answer we need to integrate data from disciplines such as phylogenetics, palaeontology, ecology, development, anatomy and physiology, as well as molecular biology and genomics. Knowledge of which groups branched before and after the origin of animals is essential. Recent advances in molecular phylogenetics, together with the discovery of new eukaryotic lineages, have drawn a new picture of the ancestry of animals. The nature of the early diverging animal lineages and the timing of the transition are in a state of flux. Various factors have been linked to this striking transition to multicellularity, including changes in environmental conditions and the ecological interactions between unicellular eukaryotes. The current wealth of genomic data has also shed new light on this question. The analysis of the genome of various close relatives of animals has revealed the importance that recycling of ancient genes into metazoan biological functions played into animal origins. A recent study reconstructing the genome of the last common ancestor of extant animals has unveiled an unprecedented emergence of new genes, highlighting the role of genomic novelty in the origin of metazoans.

Insights into electroreceptor development and evolution from molecular comparisons with hair cells

Synopsis

The vertebrate lateral line system comprises a mechanosensory division, with neuromasts containing hair cells that detect local water movement ("distant touch"); and an electrosensory division, with electrosensory organs that detect the weak, low-frequency electric fields surrounding other animals in water (primarily used for hunting). The entire lateral line system was lost in the amniote lineage with the transition to fully terrestrial life; the electrosensory division was lost independently in several lineages, including the ancestors of frogs and of teleost fishes. (Electroreception with different characteristics subsequently evolved independently within two teleost lineages.) Recent gene expression studies in a non-teleost actinopterygian fish suggest that electroreceptor ribbon synapses employ the same transmission mechanisms as hair cell ribbon synapses, and show that developing electrosensory organs express transcription factors essential for hair cell development, including Atoh1 and Pou4f3. Previous hypotheses for electroreceptor evolution suggest either that electroreceptors and hair cells evolved independently in the vertebrate ancestor from a common ciliated secondary cell, or that electroreceptors evolved from hair cells. The close developmental and putative physiological similarities implied by the gene expression data support the latter hypothesis, i.e., that electroreceptors evolved in the vertebrate ancestor as a "sister cell-type" to lateral line hair cells.

IDH-mutation Status is Associated with Distinct Vascular Gene Expression Signatures in Lower Grade Gliomas

Abstract

Background

Vascular gene expression patterns in lower grade gliomas (LGG, diffuse WHO grade II-III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH)-mutation status affects vascular phenotype.

Methods

Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the TCGA database. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grade II-IV gliomas and non-malignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

Results

Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of LAMA4 and ANGPT2 in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including up-regulation of ANGPT2 and SERPINH, connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased TGFβ and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was up-regulated by stimulation of endothelial cells with TGFβ2, VEGF or CoCl₂in vitro.

Conclusion

IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGF and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

Bullous complex regional pain syndrome: A description of the clinical and histopathologic features

Journal of Cutaneous Pathology, EarlyView.

Impact of a static magnetic field on biodegradation of wastewater compounds and bacteria recombination

Abstract

The current study presents results concerning the effect of a static magnetic field (SMF) on synthetic wastewater biodegradation by activated sludge and on dehydrogenase activity of microorganisms of activated sludge. The highest process efficiency was obtained for a SMF of 0.0075 T among the tested magnetic flux density values of 0.005–0.14 T. Decrease in COD was 25% higher for the bioreactor exposed to SMF compared with control experiments. The positive effect of SMF 0.0075–0.0080 T was confirmed in experiments on the dehydrogenase activity of activated sludge. It was also shown that a SMF of 0.007 T increased p-nitroaniline removal from wastewater and influenced the recombination frequency in a streptomycin-resistant bacteria strain of Eschercihia coli.

Costunolide promotes the proliferation of human hair follicle dermal papilla cells and induces hair growth in C57BL/6 mice

Journal of Cosmetic Dermatology, EarlyView.

Pigmented transverse nasal band: A distinct presentation

Journal of Cosmetic Dermatology, EarlyView.