Are epistemic reasons perspective-dependent?

Abstract

This paper focuses on the relation between epistemic reasons and the subject's epistemic perspective. It tackles the questions of whether epistemic reasons are dependent on the perspective of the subject they are reasons for, and if so, whether they are dependent on the actual or the potential perspective. It is argued that epistemic reasons are either independent or minimally dependent on the subject's epistemic perspective. In particular, I provide three arguments supporting the conclusion that epistemic reasons are not dependent on the subject's actual perspective. Furthermore, I show that variants of these arguments apply against popular views holding that epistemic reasons depend on the subject's potential perspective, such as the view that epistemic reasons are facts that one is in a position to know.

The natural history of cutaneous sarcoidosis. Clinical spectrum and histological analysis of 40 cases

International Journal of Dermatology, EarlyView.

Allergic contact dermatitis caused by Dermabond in a paediatric patient undergoing skin surgery

Contact Dermatitis, EarlyView.

Allergic contact dermatitis caused by vinylpyrrolidone/eicosene copolymer in a sunscreen

Contact Dermatitis, EarlyView.

Deficiency of sun protection advertising exists in consumer magazines across demographic groups and varies by target demographic

Galeatomy: A Useful Technique Aiding High-Tension Scalp Closures

Re-evaluating the Need for Routine Laboratory Monitoring in Isotretinoin Patients: A Retrospective Analysis

Enhancer connectome nominates target genes of inherited risk variants from inflammatory skin disorders

The vast majority of polymorphisms for human dermatologic diseases fall in non-coding DNA regions, leading to difficulty interpreting their functional significance. Recent work utilizing chromosome conformation capture (3C) technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking non-coding variants within active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4+ Naïve, TH17, and Treg), to 21 dermatologic conditions associated with single nucleotide polymorphisms (SNPs) from 106 genome-wide association studies (GWAS).

BP180 Autoantibodies Target Different Epitopes in Multiple Sclerosis or Alzheimer’s Disease than in Bullous Pemphigoid

Neurological patients have an increased risk for bullous pemphigoid (BP) in which autoantibodies target BP180, a cutaneous basement membrane protein also expressed in the brain. Here we show that 53.6% sera of patients with multiple sclerosis (MS) (n=56) had IgG reactivity against full-length BP180 in immunoblotting, while in BP180-NC16A ELISA (n=143), only 7.7% MS samples studied were positive. Epitope mapping with 13 fusion proteins covering the entire BP180 polypeptide revealed that, in MS and Alzheimer's disease (AD) patients, IgG autoantibodies target regions located in the intracellular and mid-extracellular parts of BP180, but not the well-known BP epitopes located in the NC16A domain and the distal part of extracellular domain.

Influenza Vaccination Rates in Adults with Psoriasis Compared to Adults with Other Chronic Diseases

Oxygen treatment for cluster headache attacks at different flow rates: a double-blind, randomized, crossover study

Cluster headache attacks can, in many patients, be successfully treated with oxygen via a non-rebreather mask. In previous studies oxygen at flow rates of both 7 L/min and 12 L/min was shown to be effective. T...

Eczema Drug Dupilumab Spurs Hair Regrowth in Alopecia Totalis

Shared immune characteristics of alopecia totalis and atopic dermatitis might explain the hair regrowth in a patient with alopecia totalis being treated with dupilumab for persistent eczema.
Medscape Medical News

Successful treatment of a traumatic tattoo in a pediatric patient using a 755‐nm picosecond laser

Pediatric Dermatology, EarlyView.

A comparison of international management guidelines for atopic dermatitis

Pediatric Dermatology, EarlyView.

Langzeitergebnisse nach Schweißdrüsenresektion bei axillärer Hyperhidrose

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1286-1288, October 2018.

ÖGDV Preisträger stellen sich vor: Der MEDA Non Melanoma Skin Cancer Forschungspreis 2017 ging an Mag. rer. nat. Bettina Huber, PhD, aus Wien

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1298-1299, October 2018.

Journal‐Club

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1297-1297, October 2018.

An Early History of Medical Translation

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1300-1301, October 2018.

Muscle hypertrophy and onychodystrophy

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1278-1281, October 2018.

Die histologische intraläsionale Heterogenität aktinischer Keratosen als Zeichen von Feldkanzerisierung

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1211-1218, October 2018.

Delayed bullous pressure urticaria: the puzzling role of eosinophils

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1253-1255, October 2018.

Bienen‐ und Wespengiftallergie: Sensibilisierung und spezifische Immuntherapie

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1228-1248, October 2018.

Perifolliculitis capitis abscedens et suffodiens: eine Fallserie mit 66 Patienten und ein Vorschlag zur Klassifikation

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1219-1227, October 2018.

Wirksamkeit einer ablationsbasierten Kombinationstherapie bei Vitiligo: Eine systematische Übersichtsarbeit und Metaanalyse

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1197-1210, October 2018.

Dermatological aspects of the S2k guidelines on Down syndrome in childhood and adolescence

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1289-1295, October 2018.

Kongresskalender 2018

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, October 2018.

Honeybee and wasp venom allergy: Sensitization and immunotherapy

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1228-1247, October 2018.

Akne bei erwachsenen Frauen: Physiologische und psychologische Erwägungen und Management

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1185-1196, October 2018.

Dermatologische Aspekte aus der S2k‐Leitlinie zum Down‐Syndrom im Kindes‐ und Jugendalter

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1289-1296, October 2018.

Adulte Akne (Acne tarda) der Frau: Eine Herausforderung für den Dermatologen

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1177-1179, October 2018.

Mehrere livid‐erythematöse Maculae und Plaques mit leichter Abschuppung bei einem jungen Mann

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1282-1285, October 2018.

Muskelhypertrophie und Onychodystrophie

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 10, Page 1278-1281, October 2018.

Influence of the emollient on emulsions containing lamellar liquid crystals: from molecular organization towards applicative properties

International Journal of Cosmetic Science, Volume 0, Issue ja, -Not available-.

Onychomycosis caused by Scopulariopsis brevicaulis: The third documented case in Japan

The Journal of Dermatology, EarlyView.

Comprehensive mapping of human body skin hydration: A pilot study

Skin Research and Technology, EarlyView.

Assessment of serious infections in pemphigus and pemphigoid by a national registry

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1623-1624, October 2018.

Announcement

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1828-1828, October 2018.

Pioneers in dermatology and venereology: an interview with Prof. Helmut Kerl

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1629-1630, October 2018.

Issue Information

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1617-1622, October 2018.

Commentary to “Mogamulizumab‐induced photosensitivity in patients with mycosis fungoides and other T‐cell neoplasms” by Y. Masuda et al.

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1626-1626, October 2018.

Hidradenitis suppurativa in Korea

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1625-1625, October 2018.

Forthcoming Events

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1827-1827, October 2018.

Psoriasis: identifying trends through search engines

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1628-1628, October 2018.

New attempts to improve in vitro diagnosis of contact allergy are still far from regular clinical practice

Journal of the European Academy of Dermatology and Venereology, Volume 32, Issue 10, Page 1627-1627, October 2018.

Risk Factors for Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis

This case series evaluates 12 patients with atopic dermatitis who experienced conjunctivitis secondary to injectable dupilumab treatment to investigate severity and common risk factors for secondary conjunctivitis.

Laser Treatment Performed Decades After Napalm Burns

This case report describes the use of laser treatment beginning in 2015 to treat napalm burns sustained by the famous Vietnamese "Napalm Girl" in 1972.

Myths, Truths, and Clinical Relevance of Comedogenicity Product Labeling

This Viewpoint evaluates the meaning of the noncomedogenic label and the need for an objective assay for assessment of facial products.

Aprepitant for the Treatment of Pruritus in Sézary Syndrome

This randomized clinical trial assesses whether treatment with the neurokinin 1 receptor antagonist aprepitant decreases pruritus vs placebo in patients with Sézary syndrome.

Increasing Minority Representation in the Dermatology Department

This Viewpoint reviews Johns Hopkins' successful experience in increasing the number of faculty physicians in dermatology from groups underrepresented in medicine and suggests steps that other institutions can take to replicate this success.

October 2018 Issue Highlights

Core Outcome Sets for Psoriasis Clinical Trials

Standardized and relevant psoriasis-specific outcome measures would contribute to a better understanding of the benefits of a growing list of highly effective therapies. To this end, in this issue of JAMA Dermatology, Callis Duffin et al present the results of an effort to define core outcome sets (COSs) for clinical trials of psoriasis. Under the auspices of the International Dermatology Outcome Measures group, the authors conducted a Delphi survey and determined that the following 6 domains should be addressed in all psoriasis trials: (1) psoriatic skin manifestations (including location), (2) an investigator global assessment, (3) an evaluation of signs and symptoms of both psoriasis and psoriatic arthritis, (4) a patient global assessment of his or her condition, (5) an assessment of treatment satisfaction, and (6) a measure of health-related quality of life.

Persistent Malar Erythema With Atrophy in a Young Woman

A young woman had asymptomatic, facial redness that flared in sunlight, previously treated with doxycycline and topical sulfacetamide with no effect; on her cheeks and nasal bridge there were multiple erythematous, annular plaques with focal areas of atrophy. What is your diagnosis?

Identifying a Core Domain Set to Assess Psoriasis in Clinical Trials

This Delphi survey of patients, health care professionals, and other stakeholders identifies a core set of 6 domains that should be measured in all clinical trials for psoriasis therapies.

Dupilumab for the Treatment of Recalcitrant Bullous Pemphigoid

This case report describes the use of dupilumab to treat recalcitrant bullous pemphigoid.

Hair Regrowth Outcomes of Contact Immunotherapy for Patients With Alopecia Areata

This systematic review and meta-analysis uses standardized criteria and prognostic factors to examine the clinical hair regrowth outcomes of contact immunotherapy with diphenylcyclopropenone or squaric acid dibutyl ester for patients with alopecia areata.

Performance of Dermatology Physician Assistants—Reply

In Reply We thank Marghoob et al for the opportunity to address their concerns regarding our study. Number needed to biopsy (NNB) (or excise) is a well-established measure consistent with prior publications, including studies by Marghoob and colleagues. While NNB can vary with disease prevalence, patients in both cohorts in our study had similar rates of keratinocyte carcinomas and invasive melanomas. Patients were also similarly distributed by age and sex, and our NNB findings remained consistent when patients with a melanoma history were excluded.

Association of Bullous Pemphigoid With Dipeptidyl-Peptidase 4 Inhibitors in Patients With Diabetes

This case-control study evaluates the association between use of dipeptidyl-peptidase 4 (DPP-4) inhibitors and development of bullous pemphigoid (BP) in patients with diabetes and characterizes those patients who develop DPP-4 inhibitor–associated BP.

Safety Risk of Dermatoscope Magnets in Patients With Cardiovascular Implanted Electronic Devices

This observational cross-sectional study assesses the magnets in 3 different dermatoscopes to determine their ability to disrupt the functionality of pacemakers, defibrillators, and other implanted devices in patients.

Interpretation of Melanocytic Lesions in the Digital Era vs Traditional Microscopy

This study of 87 pathologists compares the use of digital whole-slide imaging vs traditional microscopy in pathologists' ability to accurately interpret melanocytic lesions and reproduce correct diagnoses.

An Annular Eruption in a Young Child

A young child had a 6-month history of an asymptomatic expanding erythematous eruption on the lower legs, abdomen, and buttocks; clinical examination was significant for faint, nonscaling annular serpiginous, erythematous plaques. What is your diagnosis?

Self-reported Patient Motivations for Seeking Cosmetic Procedures

This multicenter observational study assesses the importance of self-reported factors that motivate patients to undergo minimally invasive cosmetic surgical procedures.

An Elderly Woman With Painful Buttock and Vulvar Ulcers

A woman in her 80s presented with somnolence, fatigue, lower urinary tract symptoms, and progressively worsening vulvar and buttock pain. What is your diagnosis?

Combined Reflectance Confocal Microscopy–Optical Coherence Tomography for Basal Cell Carcinoma

This pilot study of 85 lesions from 55 patients assesses the accuracy of a handheld imaging device that combines reflective confocal microscopy (RCM) and optical coherence tomography (OCT) to detect, diagnose, and estimate the depth of basal cell carcinoma in adults.

Program Director and Resident Perspectives on New Parent Leave in Dermatology Residency

This study investigates how new parent leave policies are perceived by dermatology program directors and residents.

Risk of Melanoma in Moderately Dysplastic Nevi Excisionally Biopsied but With Positive Margins

This multicenter cohort study examines the outcomes and risk for the development of subsequent cutaneous melanoma in moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins, observed for 3 years or more.

Association Between Psoriasis and Sexual and Erectile Dysfunction in Epidemiologic Studies

This systematic review evaluates the main characteristics of the studies of psoriasis and sexual dysfunction (SD) or erectile dysfunction (ED), including level of evidence, tools used to assess SD or ED, and prevalence and incidence of SD or ED.

Hair Regrowth After Long-standing Alopecia Totalis and Atopic Dermatitis Treated With Dupilumab

This case report describes hair regrowth in a patient with long-standing alopecia totalis and atopic dermatitis treated with dupilumab.

Observation of Moderately Dysplastic Nevi With Positive Margins

The management of dysplastic nevi is a quotidian part of the clinical practice of dermatology, yet even directors of pigmented lesion clinics in the United States demonstrate significant practice variation with observation or therapeutic excision of dysplastic nevi. This scenario is particularly true for biopsies of dysplastic nevi that have histologically positive margins. A 2015 consensus statement summarizing this practice gap included a call for further study of this common clinical question. There are several important challenges in establishing evidence-based guidelines for the management of dysplastic nevi, and thus establishing practice consensus for the management of dysplastic nevi, including the lack of definitive evidence that dysplastic nevi are precursor lesions to melanoma, interobserver histopathologic variation in gradation of dysplasia, longitudinal risk of monitoring for clinical recurrence, and variation in diagnostic biopsy procedures (ie, risk of incisional or partial biopsies).

Treatment of Severe Hailey-Hailey Disease With Apremilast

This case series describes 4 adult patients who received apremilast (a phosphodiesterase-4 inhibitor) for treatment-resistant Hailey-Hailey disease.

Blistering Distal Dactylitis

This case report describes a case of blistering distal dactylitis.

Freedom, self-prediction, and the possibility of time travel

Abstract

Do time travellers retain their normal freedom and abilities when they travel back in time? Lewis, Horwich and Sider argue that they do. Time-travelling Tim can kill his young grandfather, his younger self, or whomever else he pleases—and so, it seems can reasonably deliberate about whether to do these things. He might not succeed. But he is still just as free as a non-time traveller. I'll disagree. The freedom of time travellers is limited by a rational constraint. Tim can't reasonably deliberate on killing his grandfather, certain that he'll fail. If Tim follows his evidence, and appropriately self-predicts, he will be certain he won't kill his grandfather. So if Tim is both evidentially and deliberatively rational, he can't deliberate on killing his grandfather. This result has consequences. Firstly, it shows how evidential limits in the actual world contribute to our conception of the future as open. Secondly, it undercuts arguments against the possibility of time travel. Thirdly, it affects how we evaluate counterfactuals in time travel worlds, as well as our own. I'll use the constraint to motivate an evidential and temporally neutral method of evaluating counterfactuals that holds fixed what a relevant deliberating agent has evidence of, independently of her decision. Using this method, an agent's local abilities may be affected by what happens globally at other times, including the future.

BOS is associated with decreased HDAC2 from steroid resistant lymphocytes in the small airways

Clinical &Experimental Immunology, Volume 0, Issue ja, -Not available-.

Microglia Play an Active Role in Obesity-Associated Cognitive Decline

Obesity affects >600 million people worldwide, a staggering number that appears to be on the rise. One of the lesser known consequences of obesity is its deleterious effects on cognition, which have been well documented across many cognitive domains and age groups. To investigate the cellular mechanisms that underlie obesity-associated cognitive decline, we used diet-induced obesity in male mice and found memory impairments along with reductions in dendritic spines, sites of excitatory synapses, increases in the activation of microglia, the brain's resident immune cells, and increases in synaptic profiles within microglia, in the hippocampus, a brain region linked to cognition. We found that partial knockdown of the receptor for fractalkine, a chemokine that can serve as a "find me" cue for microglia, prevented microglial activation and cognitive decline induced by obesity. Furthermore, we found that pharmacological inhibition of microglial activation in obese mice was associated with prevention of both dendritic spine loss and cognitive degradation. Finally, we observed that pharmacological blockade of microglial phagocytosis lessened obesity-associated cognitive decline. These findings suggest that microglia play an active role in obesity-associated cognitive decline by phagocytosis of synapses that are important for optimal function.

SIGNIFICANCE STATEMENT Obesity in humans correlates with reduced cognitive function. To investigate the cellular mechanisms underlying this, we used diet-induced obesity in mice and found impaired performance on cognitive tests of hippocampal function. These deficits were accompanied by reduced numbers of dendritic spines, increased microglial activation, and increased synaptic profiles within microglia. Inhibition of microglial activation by transgenic and pharmacological methods prevented cognitive decline and dendritic spine loss in obese mice. Moreover, pharmacological inhibition of the phagocytic activity of microglia was also sufficient to prevent cognitive degradation. This work suggests that microglia may be responsible for obesity-associated cognitive decline and dendritic spine loss.

Medial Auditory Thalamus Is Necessary for Expression of Auditory Trace Eyelid Conditioning

Transforming a brief sensory event into a persistent neural response represents a mechanism for linking temporally disparate stimuli together to support learning. The cerebellum requires this type of persistent input during trace conditioning to engage associative plasticity and acquire adaptively timed conditioned responses (CRs). An initial step toward identifying the sites and mechanisms generating and transmitting persistent signals to the cerebellum is to identify the input pathway. The medial auditory thalamic nuclei (MATN) are the necessary and sufficient source of auditory input to the cerebellum for delay conditioning in rodents and a possible input to forebrain sites generating persistent signals. Using pharmacological and computational approaches, we test (1) whether the necessity of MATN during auditory eyelid conditioning is conserved across species, (2) whether the MATN are necessary for the expression of trace eyelid CRs, and if so, (3)whether this relates to the generation of persistent signals. We find that contralateral inactivation of MATN with muscimol largely abolished trace and delay CRs in male rabbits. Residual CRs were decreased in amplitude, but CR timing was unaffected. Results from large-scale cerebellar simulations are consistent with previous experimental demonstrations that silencing only CS-duration inputs does not abolish trace CRs, and instead affects their timing. Together, these results suggest that the MATN are a necessary component of both the direct auditory stimulus pathway to the cerebellum and the pathway generating task-essential persistent signals.

SIGNIFICANCE STATEMENT Persistent activity is required for working memory-dependent tasks, such as trace conditioning, and represents a mechanism by which sensory information can be used over time for learning and cognition. This neuronal response entails the transformation of a discrete sensory-evoked response into a signal that extends beyond the stimulus event. Understanding the generation and transmission of this stimulus transformation requires identifying the input sources necessary for task-essential persistent signals. We report that the medial auditory thalamic nuclei are required for the expression of auditory trace conditioning and suggest that these nuclei are a component of the pathway-generating persistent signals. Our study provides a foundation for testing circuit-level mechanisms underlying persistent activity in a cerebellar learning model with identified inputs and well defined behavioral outputs.

Experimental Traumatic Brain Injury Identifies Distinct Early and Late Phase Axonal Conduction Deficits of White Matter Pathophysiology, and Reveals Intervening Recovery

Traumatic brain injury (TBI) patients often exhibit slowed information processing speed that can underlie diverse symptoms. Processing speed depends on neural circuit function at synapses, in the soma, and along axons. Long axons in white matter (WM) tracts are particularly vulnerable to TBI. We hypothesized that disrupted axon–myelin interactions that slow or block action potential conduction in WM tracts may contribute to slowed processing speed after TBI. Concussive TBI in male/female mice was used to produce traumatic axonal injury in the corpus callosum (CC), similar to WM pathology in human TBI cases. Compound action potential velocity was slowed along myelinated axons at 3 d after TBI with partial recovery by 2 weeks, suggesting early demyelination followed by remyelination. Ultrastructurally, dispersed demyelinated axons and disorganized myelin attachment to axons at paranodes were apparent within CC regions exhibiting traumatic axonal injury. Action potential conduction is exquisitely sensitive to paranode abnormalities. Molecular identification of paranodes and nodes of Ranvier detected asymmetrical paranode pairs and abnormal heminodes after TBI. Fluorescent labeling of oligodendrocyte progenitors in NG2CreER;mTmG mice showed increased synthesis of new membranes extended along axons to paranodes, indicating remyelination after TBI. At later times after TBI, an overall loss of conducting axons was observed at 6 weeks followed by CC atrophy at 8 weeks. These studies identify a progression of both myelinated axon conduction deficits and axon–myelin pathology in the CC, implicating WM injury in impaired information processing at early and late phases after TBI. Furthermore, the intervening recovery reveals a potential therapeutic window.

SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a major global health concern. Across the spectrum of TBI severities, impaired information processing can contribute to diverse functional deficits that underlie persistent symptoms. We used experimental TBI to exploit technical advantages in mice while modeling traumatic axonal injury in white matter tracts, which is a key pathological feature of human TBI. A combination of approaches revealed slowed and failed signal conduction along with damage to the structure and molecular composition of myelinated axons in the white matter after TBI. An early regenerative response was not sustained yet reveals a potential time window for intervention. These insights into white matter abnormalities underlying axon conduction deficits can inform strategies to improve treatment options for TBI patients.

Presynaptic Inhibition of Primary Nociceptive Signals to Dorsal Horn Lamina I Neurons by Dopamine

The dorsal horn of the spinal cord represents the first relay station in the pain pathway where primary nociceptive inputs are modulated by local circuits and by descending signals before being relayed to supraspinal nuclei. To determine whether dopamine can modulate primary nociceptive A- and C-fiber signals, the effects of dopamine were tested on the excitatory postsynaptic currents (EPSCs) recorded from large lamina I neurons and from retrograde-labeled spinoparabrachial lamina I neurons upon stimulation of the L4/L5 dorsal root in horizontal spinal cord slices in vitro. Dopamine inhibited the EPSCs in a dose-dependent manner, with substantial inhibition (33%) at 1 μm and maximum inhibition (~70%) at 10–20 μm. Dopamine reduced the frequency of miniature EPSCs recorded from large lamina I neurons, increased the paired pulse depression ratio of paired EPSCs, and induced similar inhibition of EPSCs after dialysis of large lamina I neurons with GDP-β-S, consistent with actions at presynaptic sites. Pharmacological experiments suggested that the inhibitory effects of dopamine were largely mediated by D4 receptors (53%). Similar inhibition (66%) by dopamine was observed on EPSCs recorded from ipsilateral large lamina I neurons 6 d after injection of complete Freund's adjuvant in the hindpaw, suggesting that dopamine downregulates primary nociceptive inputs to lamina I neurons during chronic inflammatory pain. We propose that presynaptic inhibition of primary nociceptive inputs to lamina I projection neurons is a mechanism whereby dopamine can inhibit incoming noxious stimuli to the dorsal horn of the spinal cord.

SIGNIFICANCE STATEMENT Lamina I projection neurons represent the main output for the pain signals from the dorsal horn of the spinal cord to brainstem and thalamic nuclei. We found that dopamine inhibits the nociceptive A- and C-fiber synaptic inputs to lamina I projection neurons via presynaptic actions. Similar inhibitory effects of dopamine on the EPSCs were observed in rats subjected to complete Freund's adjuvant to induce peripheral inflammation, suggesting that dopamine inhibits the synaptic inputs to lamina I neurons in the setting of injury. A better understanding of how primary nociceptive inputs to the dorsal horn of the spinal cord are modulated by descending monoaminergic signals may help in the development of new pharmacological strategies to selectively downregulate the output from lamina I projection neurons.

Regulators of G-Protein Signaling (RGS) Proteins Promote Receptor Coupling to G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels

Regulators of G-protein signaling (RGS) proteins negatively modulate presynaptic μ-opioid receptor inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG). Paradoxically, we find that G-protein-coupled receptor (GPCR) activation of G-protein-gated inwardly rectifying K⁺ channels (GIRKs) in the vlPAG is reduced in an agonist- and receptor-dependent manner in transgenic knock-in mice of either sex expressing mutant RGS-insensitive Gαo proteins. μ-Opioid receptor agonist activation of GIRK currents was reduced for DAMGO and fentanyl but not for [Met⁵]-enkephalin acetate salt hydrate (ME) in the RGS-insensitive heterozygous (Het) mice compared with wild-type mice. The GABA_B agonist baclofen-induced GIRK currents were also reduced in the Het mice. We confirmed the role of Gαo proteins in μ-opioid receptor and GABA_B receptor signaling pathways in wild-type mice using myristoylated peptide inhibitors of Gαo₁ and Gαi_1–3. The results using these inhibitors indicate that receptor activation of GIRK channels is dependent on the preference of the agonist-stimulated receptor for Gαo versus that for Gαi. DAMGO and fentanyl-mediated GIRK currents were reduced in the presence of the Gαo₁ inhibitor, but not the Gαi_1–3 inhibitors. In contrast, the Gαo₁ peptide inhibitor did not affect ME activation of GIRK currents, which is consistent with results in the Het mice, but the Gαi_1–3 inhibitors significantly reduced ME-mediated GIRK currents. Finally, the reduction in GIRK activation in the Het mice plays a role in opioid- and baclofen-mediated spinal antinociception, but not supraspinal antinociception. Thus, our studies indicate that RGS proteins have multiple mechanisms of modulating GPCR signaling that produce negative and positive regulation of signaling depending on the effector.

SIGNIFICANCE STATEMENT Regulators of G-protein signaling (RGS) proteins positively modulate GPCR coupling to GIRKs, and this coupling is critical for opioid- and baclofen-mediated spinal antinociception, whereas μ-opioid receptor-mediated supraspinal antinociception depends on presynaptic inhibition that is negatively regulated by RGS proteins. The identification of these opposite roles for RGS proteins has implications for signaling via other GPCRs.

Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin-LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing LRP4 for NMJ stability in aged mice.

SIGNIFICANCE STATEMENT This study provides evidence that LRP4, a receptor of agrin that is critical for NMJ formation and maintenance, is reduced at protein level in aged muscles. Transgenic expression of LRP4 in muscles ameliorates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, demonstrating a critical role of the agrin-LRP4-MuSK signaling. Our study also reveals a novel function of SGα to prevent LRP4 degradation in aged muscles. Finally, we show that NMJ decline in aged mice can be mitigated by AAV9-mediated expression of SGα in muscles. These observations provide insight into pathological mechanisms of age-related NMJ decline and suggest that improved agrin-LRP4-MuSK signaling may be a target for potential therapeutic intervention.

Retinal Detachment-Induced Müller Glial Cell Swelling Activates TRPV4 Ion Channels and Triggers Photoreceptor Death at Body Temperature

Using region-specific injection of hyaluronic acid, we developed a mouse model of acute retinal detachment (RD) to investigate molecular mechanisms of photoreceptor cell death triggered by RD. We focused on the transient receptor potential vanilloid 4 (TRPV4) ion channel, which functions as a thermosensor, osmosensor, and/or mechanosensor. After RD, the number of apoptotic photoreceptors was reduced by ~50% in TRPV4KO mice relative to wild-type mice, indicating the possible involvement of TRPV4 activation in RD-induced photoreceptor cell death. Furthermore, TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Together, our results suggest that RD adversely impacts photoreceptor viability via TRPV4-dependent cytokine release from Müller glial cells and that TRPV4 is part of a novel molecular pathway that could exacerbate the effects of hypoxia on photoreceptor survival after RD.

SIGNIFICANCE STATEMENT Identification of the mechanisms of photoreceptor death in retinal detachment is required for establishment of therapeutic targets for preventing loss of visual acuity. In this study, we found that TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Hence, TRPV4 inhibition could suppress cell death in RD pathological conditions and suggests that TRPV4 in Müller glial cells might be a novel therapeutic target for preventing photoreceptor cell death after RD.

This Week in The Journal

Muscle Synergies Obtained from Comprehensive Mapping of the Cortical Forelimb Representation Using Stimulus Triggered Averaging of EMG Activity

Neuromuscular control of voluntary movement may be simplified using muscle synergies similar to those found using non-negative matrix factorization. We recently identified synergies in electromyography (EMG) recordings associated with both voluntary movement and movement evoked by high-frequency long-duration intracortical microstimulation applied to the forelimb representation of the primary motor cortex (M1). The goal of this study was to use stimulus-triggered averaging (StTA) of EMG activity to investigate the synergy profiles and weighting coefficients associated with poststimulus facilitation, as synergies may be hard-wired into elemental cortical output modules and revealed by StTA. We applied StTA at low (LOW, ~15 μA) and high intensities (HIGH, ~110 μA) to 247 cortical locations of the M1 forelimb region in two male rhesus macaques while recording the EMG of 24 forelimb muscles. Our results show that 10–11 synergies accounted for 90% of the variation in poststimulus EMG facilitation peaks from the LOW-intensity StTA dataset while only 4–5 synergies were needed for the HIGH-intensity dataset. Synergies were similar across monkeys and current intensities. Most synergy profiles strongly activated only one or two muscles; all joints were represented and most, but not all, joint directions of motion were represented. Cortical maps of the synergy weighting coefficients suggest only a weak organization. StTA of M1 resulted in highly diverse muscle activations, suggestive of the limiting condition of requiring a synergy for each muscle to account for the patterns observed.

SIGNIFICANCE STATEMENT Coordination of muscle activity and the neural origin of potential muscle synergies remains a fundamental question of neuroscience. We previously demonstrated that high-frequency long-duration intracortical microstimulation-evoked synergies were unrelated to voluntary movement synergies and were not clearly organized in the cortex. Here we present stimulus-triggered averaging facilitation-related muscle synergies, suggesting that when fundamental cortical output modules are activated, synergies approach the limit of single-muscle control. Thus, we conclude that if the CNS controls movement via linear synergies, those synergies are unlikely to be called from M1. This information is critical for understanding neural control of movement and the development of brain–machine interfaces.

Brief, But Not Prolonged, Pauses in the Firing of Midbrain Dopamine Neurons Are Sufficient to Produce a Conditioned Inhibitor

Prediction errors are critical for associative learning. In the brain, these errors are thought to be signaled, in part, by midbrain dopamine neurons. However, although there is substantial direct evidence that brief increases in the firing of these neurons can mimic positive prediction errors, there is less evidence that brief pauses mimic negative errors. Whereas pauses in the firing of midbrain dopamine neurons can substitute for missing negative prediction errors to drive extinction, it has been suggested that this effect might be attributable to changes in salience rather than the operation of this signal as a negative prediction error. Here we address this concern by showing that the same pattern of inhibition will create a cue able to meet the classic definition of a conditioned inhibitor by showing suppression of responding in a summation test and slower learning in a retardation test. Importantly, these classic criteria were designed to rule out explanations founded on attention or salience; thus the results cannot be explained in this manner. We also show that this pattern of behavior is not produced by a single, prolonged, ramped period of inhibition, suggesting that it is precisely timed, sudden change and not duration that conveys the teaching signal.

SIGNIFICANCE STATEMENT Here we show that brief pauses in the firing of midbrain dopamine neurons are sufficient to produce a cue that meets the classic criteria defining a conditioned inhibitor, or a cue that predicts the omission of a reward. These criteria were developed to distinguish actual learning from salience or attentional effects; thus these results formally show that brief pauses in the firing of dopamine neurons can serve as key teaching signals in the brain. Interestingly, this was not true for gradual prolonged pauses, suggesting it is the dynamic change in firing that serves as the teaching signal.

Thalamus Controls Development and Expression of Arousal States in Visual Cortex

Two major checkpoints of development in cerebral cortex are the acquisition of continuous spontaneous activity and the modulation of this activity by behavioral state. Despite the critical importance of these functions, the circuit mechanisms of their development remain unknown. Here we use the rodent visual system as a model to test the hypothesis that the locus of circuit change responsible for the developmental acquisition of continuity and state dependence measured in sensory cortex is relay thalamus, rather than the local cortical circuitry or the interconnectivity of the two structures. We conducted simultaneous recordings in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (VC) of awake, head-fixed male and female rats using linear multielectrode arrays throughout early development. We find that activity in dLGN becomes continuous and positively correlated with movement (a measure of state dependence) on P13, the same day as VC, and that these properties are not dependent on VC activity. By contrast, silencing dLGN after P13 causes activity in VC to become discontinuous and movement to suppress, rather than augment, cortical firing, effectively reversing development. Thalamic bursting, a core characteristic of non-aroused states, emerged later, on P16, suggesting these processes are developmentally independent. Together our results indicate that cellular or circuit changes in relay thalamus are critical drivers for the maturation of background activity, which occurs around term in humans.

SIGNIFICANCE STATEMENT The developing brain acquires two crucial features, continuous spontaneous activity and its modulation by arousal state, around term in humans and before the onset of sensory experience in rodents. This developmental transition in cortical activity, as measured by electroencephalogram (EEG), is an important milestone for normal brain development and indicates a good prognosis for babies born preterm and/or suffering brain damage such as hypoxic-ischemic encephalopathy. By using the awake rodent visual system as a model, we identify changes occurring at the level of relay thalamus, the major input to cortex, as the critical driver of EEG maturation. These results could help understand the circuit basis of human EEG development to improve diagnosis and treatment of infants in vulnerable situations.

Granulocyte Colony Stimulating Factor Enhances Reward Learning through Potentiation of Mesolimbic Dopamine System Function

Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocyte-colony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor α. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli.

SIGNIFICANCE STATEMENT Emerging evidence has highlighted the importance of the immune system in psychiatric diseases states. However, the effects of peripheral cytokines on motivation and cognitive function are largely unknown. Here, we report that granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine with known trophic and neuroprotective properties in the brain, acts directly on dopaminergic circuits to enhance their function. These changes in dopaminergic dynamics enhance reward learning and motivation for natural stimuli. Together, these results suggest that targeting immune factors may provide a new avenue for therapeutic intervention in the multiple psychiatric disorders that are characterized by motivational and cognitive deficits.

Anterolateral Motor Cortex Connects with a Medial Subdivision of Ventromedial Thalamus through Cell Type-Specific Circuits, Forming an Excitatory Thalamo-Cortico-Thalamic Loop via Layer 1 Apical Tuft Dendrites of Layer 5B Pyramidal Tract Type Neurons

The anterolateral motor cortex (ALM) and ventral medial (VM) thalamus are functionally linked to support persistent activity during motor planning. We analyzed the underlying synaptic interconnections using optogenetics and electrophysiology in mice (female/male). In cortex, thalamocortical (TC) axons from VM thalamus excited VM-projecting pyramidal tract (PT) neurons in layer 5B of ALM. These axons also strongly excited layer 2/3 neurons (which strongly excite PT neurons, as previously shown) but not VM-projecting corticothalamic (CT) neurons in layer 6. The strongest connections in the VM -> PT circuit were localized to apical tuft dendrites of PT neurons, in layer 1. These tuft inputs were selectively augmented after blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In thalamus, axons from ALM PT neurons excited ALM-projecting VM neurons, located medially in VM. These axons provided weak input to neurons in mediodorsal nucleus, and little or no input either to neurons in the GABAergic reticular thalamic nucleus or to neurons in VM projecting to primary motor cortex (M1). Conversely, M1 PT axons excited M1- but not ALM-projecting VM neurons. Our findings indicate, first, a set of cell type-specific connections forming an excitatory thalamo-cortico-thalamic loop for ALM VM communication and a circuit-level substrate for supporting reverberant activity in this system. Second, a key feature of this loop is the prominent involvement of layer 1 synapses onto apical dendrites, a subcellular compartment with distinct signaling properties, including HCN-mediated gain control. Third, the segregation of the ALM VM loop from M1-related circuits of VM adds cellular-level support for the concept of parallel pathway organization in the motor system.

SIGNIFICANCE STATEMENT Anterolateral motor cortex (ALM), a higher-order motor area in the mouse, and ventromedial (VM) thalamus are anatomically and functionally linked, but their synaptic interconnections at the cellular level are unknown. Our results show that ALM pyramidal tract neurons monosynaptically excite ALM-projecting thalamocortical neurons in a medial subdivision of VM thalamus, and vice versa. The thalamo-cortico-thalamic loop formed by these recurrent connections constitutes a circuit-level substrate for supporting reverberant activity in this system.

Differentiating between Models of Perceptual Decision Making Using Pupil Size Inferred Confidence

During perceptual decisions, subjects often rely more strongly on early, rather than late, sensory evidence, even in tasks when both are equally informative about the correct decision. This early psychophysical weighting has been explained by an integration-to-bound decision process, in which the stimulus is ignored after the accumulated evidence reaches a certain bound, or confidence level. Here, we derive predictions about how the average temporal weighting of the evidence depends on a subject's decision confidence in this model. To test these predictions empirically, we devised a method to infer decision confidence from pupil size in 2 male monkeys performing a disparity discrimination task. Our animals' data confirmed the integration-to-bound predictions, with different internal decision bounds and different levels of correlation between pupil size and decision confidence accounting for differences between animals. However, the data were less compatible with two alternative accounts for early psychophysical weighting: attractor dynamics either within the decision area or due to feedback to sensory areas, or a feedforward account due to neuronal response adaptation. This approach also opens the door to using confidence more broadly when studying the neural basis of decision making.

SIGNIFICANCE STATEMENT An animal's ability to adjust decisions based on its level of confidence, sometimes referred to as "metacognition," has generated substantial interest in neuroscience. Here, we show how measurements of pupil diameter in macaques can be used to infer their confidence. This technique opens the door to more neurophysiological studies of confidence because it eliminates the need for training on behavioral paradigms to evaluate confidence. We then use this technique to test predictions from competing explanations of why subjects in perceptual decision making often rely more strongly on early evidence: the way in which the strength of this effect should depend on a subject's decision confidence. We find that a bounded decision formation process best explains our empirical data.

The Role of Cholinergic Midbrain Neurons in Startle and Prepulse Inhibition

One of the two major cholinergic centers of the mammalian brain is located in the midbrain, i.e., the pedunculopontine tegmentum (PPTg) and the adjacent laterodorsal tegmentum. These cholinergic neurons have been shown to be important for e.g., arousal, reward associations, and sleep. They also have been suggested to mediate sensorimotor gating, measured as prepulse inhibition of startle (PPI). PPI disruptions are a hallmark of schizophrenia and are observed in various other psychiatric disorders, where they are associated with, and often predictive of, other cognitive symptoms. PPI has been proposed to be mediated by a short midbrain circuitry including inhibitory cholinergic projections from PPTg to the startle pathway. Although the data indicating the involvement of the PPTg is very robust, some more recent evidence challenges that there is a cholinergic contribution to PPI. We here use transient optogenetic activation of specifically the cholinergic PPTg neurons in male and female rats to address their role in startle modulation in general, and in PPI specifically. Although we could confirm the crucial role of PPTg cholinergic neurons in associative reward learning, validating our experimental approach, we found that activation of cholinergic PPTg neurons did not inhibit startle responses. In contrast, activation of cholinergic PPTg neurons enhanced startle, which is in accordance with their general role in arousal and indicate a potential involvement in sensitization of startle. We conclude that noncholinergic PPTg neurons mediate PPI in contrast to the longstanding hypothetical view that PPI is mediated by cholinergic PPTg neurons.

SIGNIFICANCE STATEMENT Activation of cholinergic neurons in the midbrain has been assumed to mediate prepulse inhibition of startle (PPI), a common measure of sensorimotor gating that is disrupted in schizophrenia and other psychiatric disorders. We here revisit this long-standing hypothesis using optogenetic activation of these specific neurons combined with startle testing in rats. In contrast to the hypothetical role of these neurons in startle modulation, we show that their activation leads to an increase of baseline startle and to prepulse facilitation. This supports recent data by others that have started to cast some doubt on the cholinergic hypothesis of PPI, and calls for a revision of the theoretical construct of PPI mechanisms.

Modulation of Beta Bursts in the Subthalamic Nucleus Predicts Motor Performance

Considerable evidence suggests a role of beta-band oscillations in voluntary movements. However, most of the studies linking beta power to motor performance are based on data averaged across trials that ignore the fast dynamics of oscillatory activity and trial-to-trial variations in motor responses. Recently, emphasis has shifted from the functional implications of the mean beta power to the presence and nature of episodic bursts of beta activity. Here we test the hypothesis that beta bursts, though short in duration in more physiological state, may help explain spontaneous variations in motor behavior of human adults at the single-trial level. To this end, we recorded local field potential activity from the subthalamic nucleus of parkinsonian patients of both genders whose motor behavior had been normalized as far as possible through treatment with the dopamine prodrug, levodopa. We found that beta bursts present in a time-limited window well before movement onset in the contralateral subthalamic nucleus reduce the peak velocity of that movement and that this effect is further amplified by the amplitude of the burst. Additionally, prolonged reaction times are observed when bursts occur immediately after the GO cue. Together, these results suggest that the modulation of the timing and amplitude of beta bursts might serve to dynamically adapt motor performance. These results offer new insight in the pathology of Parkinson's disease, and suggest that beta bursts whose presence and nature are modulated by context may have a physiological role in modulating behavior.

SIGNIFICANCE STATEMENT Beta oscillations (~13–30 Hz) have been increasingly interpreted as transient bursts rather than as rhythmically sustained oscillations (Feingold et al., 2015). Prolonged and increased probability of beta bursts in the subthalamic nucleus correlates with the severity of motor impairment in Parkinson's disease (Tinkhauser et al., 2017a, b). However, it remains unclear whether beta bursts act to modify motor performance on a trial-by-trial basis under more physiological condition. Here, we found that, according to the time window in which they fall, beta bursts reduced the velocity of the forthcoming movement or prolonged the reaction time. These results offer new insight in the pathology of Parkinson's disease and also suggest that the modulation of beta bursts might serve to dynamically adapt motor performance.

Quantitative analysis of the coupling coefficients between energy flow, value flow, and material flow in a Chinese lead-acid battery system

Abstract

To reveal the historic characteristics of the material flow, energy flow and value flow in a lead-acid battery (LAB) system, a framework for the coupling relationship among the three flows was established based on material flow analysis and the characteristics of the energy and value flows. The coupling coefficients between energy and material (CCEM) and value and material (CCVM) were also defined. The investigation used by China as a case to study changes in stages and the historic evolution. The results show that the CCEM for lead in LABs was highest in the usage stage, approximately 5–16 times greater than in the other stages. The CCEM for production was almost twice as high for primary lead as for secondary lead, and the CCEM was lowest for the fabrication and product manufacture stage. The CCVM for lead in LABs was 2.5–6 times higher than for other types of lead. The CCVM was lower for scrap lead than for lead ore, and the CCVM was approximately 1.7 times higher for refined lead than for scrap and refined lead. For lead trade, CCVM was correlated with domestic and overseas markets. From 1990 to 2014, the CCEM for each stage was in decline, whereas the opposite was the case for CCVM. The influencing factors were analyzed in terms of resources, the environment, and markets. Increasing the circulation rate of scrap lead is an effective way to rapidly save resources, reduce lead pollution, and promote a circular economy. The limitations and potential value of the study are also highlighted, and future research is outlined.

Modulation of quorum sensing-controlled virulence.factors in Chromobacterium violaceum by selective amino acids

Abstract

Bacterial pathogenesis regulation requires N-acyl homoserine lactone (AHL)—based quorum sensing (QS). The main objective of this study was to assess the anti-quorum sensing and anti-biofilm potential of five different amino acids namely serine, aspartic acid, lysine, leucine, and tryptophan. The selected amino acids were assessed for their ability in inhibiting QS activity such as exopolysaccharide (EPS) production, biofilm formation, pigment production in Chromobacterium violaceum, and swarming motility. At 0.684 mM concentration, lysine inhibited the biofilm formation by 16% at 24 h, chitinolytic activity by 88.3% at 24 h and EPS production by 12.5% at 24 h. It also exhibited inhibition of swarming motility in C. violaceum. Confocal Laser Scanning Microscopy (CLSM) revealed a decrease in the average thickness of the biofilms when treated with lysine. Modulation in the expression of cvi I and cvi A was observed when treated with all the amino acids, with lysine observed to be decreased the most among the other amino acids. Our results conclude that the amino acid lysine showed anti-QS and significant anti-biofilm activities; it could be further exploited as a main constituent in the synthesis of peptide/protein, and thereby testing the same for treatment of bacterial infections, eventually reducing the utilization of conventional antibiotics.

Non-steroidal anti-inflammatory drugs, Acetaminophen and Ibuprofen, induce phenotypic antibiotic resistance in Escherichia coli: roles of marA and acrB

Abstract

The factors contributing to antibiotic resistance in bacteria are an important area of study. Sodium salicylate (NaSal), a non-steroidal anti-inflammatory drug (NSAID), increases antibiotic resistance by inducing the expression of MarA, a transcription factor, which increases the AcrAB-TolC efflux pump. MarA is a substrate of Lon protease and the Δlon strain displays a high degree of antibiotic resistance. This study was initiated to identify commonly used NSAIDs that may induce antibiotic resistance and to compare their efficacies with NaSal and acetyl salicylic acid (ASA). Quantitative real time expression analysis revealed induction of marA and acrB by NaSal, ASA, Acetaminophen and Ibuprofen. Further, dose studies demonstrated that NaSal and ASA induce resistance at ∼2 mM while APAP and Ibuprofen induce resistance ∼5-10 mM. To dissect the roles of key molecules, atomic force microscopy and functional studies were performed using WT, Δlon, ΔmarA, ΔacrB, ΔlonΔmarA and ΔlonΔacrB strains. The induction of antibiotic resistance by NaSal, ASA, and Acetaminophen is relatively higher and is partly dependent on marA whereas Ibuprofen which induces lower antibiotic resistance shows complete marA-dependence. Notably, NaSal, ASA, Acetaminophen and Ibuprofen induce antibiotic resistance in an acrB-dependent manner. The possible significance of some NSAIDs in inducing antibiotic resistance is discussed.

CDK4/6 inhibitors as neoadjuvant treatment in breast cancer – what can we learn?

Deficiencies in health-related quality of life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016

Abstract

Background

Quality of life (QoL) is a relevant endpoint and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an endpoint in cancer phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of underreporting and delay of publication.

Methods

All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about endpoints was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed.

Results

446 publications were eligible. In 210 (47.1%), QoL was not included among endpoints. QoL was not an endpoint in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory endpoint, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as endpoint or with missing QoL results was relevant in all tumour types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials.

Conclusions

QoL is not included among endpoints in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant underreporting and delay in publication.

Effect of Collagenase ointment versus Mebo ointment on healing of full‐thickness burns in mice by removing of necrotic tissue

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.

Aproximación a un uso racional y reglado de omalizumab en la urticaria crónica

Publication date: Available online 9 October 2018

Source: Actas Dermo-Sifiliográficas

Author(s): R. Ruiz-Villaverde

Inducción de fototolerancia con ultravioleta B de banda estrecha en urticaria solar

Publication date: Available online 9 October 2018

Source: Actas Dermo-Sifiliográficas

Author(s): P. Aguilera

Is Skin Testing Required Prior to Drug Challenges?

Publication date: Available online 10 October 2018

Source: The Journal of Allergy and Clinical Immunology: In Practice

Author(s): Eric Macy, Luis Felipe Ensina

Asthma-related impact of extending US parents' health insurance coverage to young adults

Publication date: Available online 10 October 2018

Source: The Journal of Allergy and Clinical Immunology: In Practice

Author(s): Joy Hsu, Xiaoting Qin, Maria C. Mirabelli

Corrigendum to “ROS mediated crosstalk between endoplasmic reticulum and mitochondria by Phloxine B under environmental UV irradiation” Journal of Photochemistry & Photobiology, B: Biology 161 (2016) 284–294

Publication date: Available online 9 October 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Shruti Goyal, Saroj Kumar Amar, Ajeet Kumar Srivastav, Deepti Chopra, Manish Kumar Pal, Nidhi Arjaria, Ratan Singh Ray

An inexpensive method of negative pressure wound therapy for extremities

International Wound Journal, EarlyView.

Experience with gluteal V‐Y fasciocutaneous advancement flaps in vulvar reconstruction after oncological resection and a modification to the marking: Playing with tension lines

International Wound Journal, EarlyView.

Comparison of bleach, acetic acid, and other topical anti‐infective treatments in pediatric atopic dermatitis: A retrospective cohort study on antibiotic exposure

Pediatric Dermatology, EarlyView.

Métastases cutanées des extrémités

Publication date: Available online 10 October 2018

Source: Annales de Dermatologie et de Vénéréologie

Author(s): H. Martin, M. Mariano-Bourin, L. Antunes, A. Bonhomme, J.-F. Cuny, L. Dubouis, F. Truchetet, A. Schoeffler

Résumé

Introduction

Les métastases cutanées (MC) localisées aux extrémités sont des complications exceptionnelles des cancers solides, au pronostic sévère. Dans la majorité des cas, elles simulent une infection. Nous en rapportons deux nouvelles observations de présentation originale.

Observations

Cas n^o 1 : un homme de 71 ans consultait pour suspicion de botryomycomes de la main gauche évoluant depuis 3 mois. Il avait pour antécédent deux carcinomes épidermoïdes (lingual et pulmonaire) en rémission. L'examen clinique objectivait trois lésions bourgeonnantes de la main gauche. La biopsie d'une des lésions concluait à une métastase de carcinome épidermoïde. Au bilan d'extension, on notait l'apparition de micronodules pulmonaires disséminés suspects de localisations secondaires. Cas n^o 2 : un homme de 68 ans consultait pour un œdème du membre inférieur droit infiltré, dur, mal limité, qui évoluait depuis plusieurs mois. Six mois auparavant, il avait eu un adénocarcinome bronchique traité par lobectomie supérieure gauche et dont le bilan d'extension ne révélait pas de lésion secondaire. Cliniquement, on notait un œdème induré prédominant au pied. La biopsie cutanée objectivait une métastase d'adénocarcinome. Le bilan d'extension montrait des lésions ostéolytiques du tarse droit ainsi que des adénomégalies.

Discussion

Nous rapportons deux cas originaux de MC des extrémités ayant permis de diagnostiquer une évolution tumorale. Il s'agit d'une complication rare, de présentation clinique variable, ayant un impact sur la prise en charge du cancer et sur le pronostic vital du patient. Ces observations illustrent l'importance d'évoquer le diagnostic en cas de lésions cutanées distales persistantes, a fortiori en cas d'antécédents néoplasiques.

Summary

Background

Cutaneous metastases (CM) on the extremities are rare complication of cancer with poor prognosis. In general, lesions simulate an infection. Herein, we report two new cases with atypical presentation.

Patients and methods

Case no 1: a 71-year-old man consulted for suspicion of left hand pyogenic granuloma present for 3 months. His history revealed two treated squamous-cell carcinomas (tongue and lung). On physical examination, he presented three budding and foul-smelling lesions on his left hand. Histopathology showed metastasis of squamous-cell carcinoma. Radiographic examination revealed spread of pulmonary nodules with suspicion of metastasis. Case no 2: a 68-year-old man was hospitalized for indurated edema of the right leg present for several months. Six months earlier, he had undergone surgery for left pulmonary adenocarcinoma without metastasis. Physical examination revealed an indurated edema on the right foot. Histopathology showed metastasis from adenocarcinoma. A scan revealed several osteolytic lesions in the right foot as well as lymphadenopathy.

Discussion

Herein, we report two original cases of CM of the extremities diagnosed as tumor progression. This is a rare complication of variable clinical presentation and impacts both cancer management and prognosis. It is important to consider the diagnosis when distal cutaneous lesions persist, particularly where there is a history of cancer.

Androgens in Women: Hormone modulating therapies for skin disease (Part II)

Publication date: Available online 10 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Sarah Azarchi, Amanda Bienenfeld, Kristen Lo Sicco, Shari Marchbein, Jerry Shapiro, Arielle R. Nagler

Abstract

Androgen-mediated cutaneous disorders (AMCDs) in women including acne, hirsutism, and female pattern hair loss (FPHL) can be treated with hormone-modulating therapies. In the second part of this Continuing Medical Education series, we discuss the hormone-modulating therapies available to dermatologists for the treatment of AMCDs including combined oral contraceptives, spironolactone, finasteride, dutasteride, and flutamide. Available hormone-modulating treatments utilized for each AMCDs are reviewed, along with mechanisms of androgen modulation, safety profile, contraindications, monitoring parameters, and evidence of efficacy. Medications discussed include ones that are FDA-approved for certain AMCDs as well as some that are used off-label. Despite the ubiquity of hormone-modulating therapies used for AMCDs, this review highlights the need for more rigorous studies to evaluate these therapies for acne, hirsutism, and FPHL.

Androgens in Women: Androgen mediated skin disease and patient evaluation (Part I)

Publication date: Available online 10 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Amanda Bienenfeld, Sarah Azarchi, Kristen Lo Sicco, Shari Marchbein, Jerry Shapiro, Arielle R. Nagler

Abstract

Androgens are produced throughout the body in steroid-producing organs, such as the adrenal glands and ovaries, as well as in other tissues, like the skin. Several androgens are found normally in women, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), testosterone, dihydrotestosterone (DHT), and androstenedione. These androgens are essential in the development of several common cutaneous conditions in women, including acne, hirsutism, and female pattern hair loss (FPHL) – androgen mediated cutaneous disorders (AMCDs). However, the role of androgens in the pathophysiology of these diseases is complicated and incompletely understood. In the first article in this Continuing Medical Education series, we discuss the role of the skin in androgen production as well as the impact of androgens on the skin in women. Specifically, we review the necessary, but insufficient role that androgens play in the development of acne, hirsutism, and FPHL in women. Dermatologists face the challenge of differentiating physiologic from pathologic presentations of AMCDs in women. There are currently no dermatology guidelines outlining the indications for endocrinologic evaluation in women presenting with acne, hirsutism, and/or FPHL. We review available evidence regarding when to consider an endocrinologic work-up in women presenting with AMCDs, including the appropriate type and timing of testing.

Actions Speak Louder than Words: Examining the Relationship Between Violent Behaviors and Bullying Victimization Among Adolescents

Violence and Gender, Ahead of Print.

Editorial Board

Publication date: November 2018

Source: Annales de Chirurgie Plastique Esthétique, Volume 63, Issues 5–6

Author(s):

Self-assembled three-dimensional double network graphene oxide/polyacrylic acid hybrid aerogel for removal of Cu 2+ from aqueous solution

Abstract

Three-dimensional (3D) double network graphene oxide/polyacrylic acid (GO/PAA) hybrid aerogels were fabricated under mild conditions from the mixture of GO and acrylic acid (AA) monomers using a one-pot in situ solution polymerization process which included the polymerization of AA and the self-assembly of functional GO sheets. The PAA chains served as not only binder to assemble GO sheets into 3D framework but also modifier to provide more active functional groups. The adsorbents based on such material exhibited superior adsorption performance towards Cu²⁺ ions in aqueous media due to rich mesopores, high specific surface area, and abundant active sites. This work brings a new vision for assembling 3D porous graphene-based nanomaterials as adsorbents in environmental protection.

The Comorbidity Burden of Hidradenitis Suppurativa in the United States: A Claims Data Analysis

Abstract

Introduction

Prior studies have reported that hidradenitis suppurativa (HS) is accompanied by a myriad of physical and mental conditions. However, given the small sample sizes and the limited number of pre-selected comorbidities, these studies do not provide a complete picture of the comorbidity burden of HS in the USA. Moreover, the relationship between HS severity and comorbidity burden has yet to be characterized. Using a large US claims database, we estimated the comorbidity burden associated with HS, stratified by disease severity.

Methods

A retrospective matched cohort design was used. Patients with HS were classified into two severity cohorts (milder and more severe) using an empirical algorithm based on treatments received. The comorbidity burden was compared between each HS cohort and their matched HS-free cohort, and between patients with milder vs. those with more severe forms of HS.

Results

Several physical and mental comorbidities were found to be more prevalent in both cohorts of patients with milder and more severe forms of HS than in their matched HS-free cohorts. The comorbidity burden also increased greatly as the disease progressed to more severe forms.

Conclusions

The results of this study highlight the complexity of the comorbidity burden of HS patients and the need for a multidisciplinary approach to optimize the management of HS and its numerous associated comorbidities.

Funding

AbbVie, Inc.

Adalimumab treatment in Japanese patients with generalized pustular psoriasis: Results of an open‐label phase 3 study

The Journal of Dermatology, EarlyView.

Unique dermoscopic feature of a long‐standing pencil core granuloma on the head

The Journal of Dermatology, EarlyView.

Compound heterozygous missense mutations p.Leu207Pro and p.Tyr544Cys in TGM1 cause a severe form of lamellar ichthyosis

The Journal of Dermatology, EarlyView.

Macrophages express βKlotho in skin lesions of psoriatic patients and the skin of imiquimod‐treated mice

The Journal of Dermatology, EarlyView.

Polymorphous light eruption with complication of solar urticaria revealed by phototesting

The Journal of Dermatology, EarlyView.

Linearly distributed multiple lipomas: An unusual case report

The Journal of Dermatology, EarlyView.

Bed and suspended sediment-associated rare earth element concentrations and fluxes in a polluted Brazilian river system

Abstract

Rare earth elements (REEs) have been recently recognized as emergent pollutants in rivers. However, data regarding REE fluxes in association with either bed or suspended are scarce. To address this knowledge gap, we determined the concentrations and fluxes of La, Ce, Pr, Nd, Sm, Eu, Gd, Yb, Lu, Dy, Er, Ho, Tb, and Tm in bed and suspended sediment samples of a representative polluted Brazilian River. Sediment-associated data on REEs were placed in the context of corresponding background concentrations in soils under natural conditions along the Ipojuca watershed. Light rare earth elements (LREEs) comprised more than 94% of the total REEs associated with bed and suspended sediments. Suspended sediments accounted for more than 95% of the total REE flux. The Ce and Nd fluxes of about 7 t year⁻¹ underscore the importance of including REEs in future estimations of global suspended sediment-associated element fluxes. In contrast, bedload often transported less than 0.0007 t year⁻¹ of each REE. The main sources of pollution in the Ipojuca River are anthropogenic, likely due to domestic effluent and waste water from industrial and agricultural operations—major causes of sediment-associated Gd transport in polluted streams.

Biocontrol, new questions for Ecotoxicology?