Medicine by Alexandros G. Sfakianakis: 08/29/18

Background: Tildrakizumab (TIL) is a high-affinity anti–IL-23p19 monoclonal antibody for the treatment of chronic plaque psoriasis. We assessed a subgroup of chronic plaque psoriasis patients who reported previous treatment with apremilast (APT), a phosphodiesterase 4 inhibitor, to evaluate its potential influence on efficacy in two large, phase 3 clinical studies of tildrakizumab.

Modified purse string closure for excisional biopsy of pigmented lesions on extremities

Proper selection of biopsy technique is imperative, especially when approaching a suspicious pigmented lesion on the extremity. When possible, a complete excisional biopsy with narrow margins is preferred to prevent partial sampling and inadequate evaluation of a lesion. A vertically oriented fusiform excisional biopsy is often selected for biopsy as it preserves lymphatics and prevents circumferential scarring. In this communication, we highlight possible pitfalls of selecting a fusiform ellipse for potential melanomas and provide a patient centered step-by-step guide to the use of narrow excisional biopsy with modified purse string closure.

Impact of palmoplantar psoriasis on clinical and patient-reported outcomes: Results from the Corrona Psoriasis Registry

Objective: Palmoplantar psoriasis (PPP) is associated with a profound negative impact on patients' quality of life and is difficult to treat. The objective of this study was to assess the impact of PPP on clinical and patient reported outcomes (PROs) among patients enrolled in the Corrona Psoriasis (Pso) Registry.

Cutaneous complications associated with intraosseous access placement: A retrospective cohort study

Purpose: Intraosseous (IO) access can provide a lifesaving means of vascular access in emergency settings. Insertion sites include the tibia, humerus, and sternum. IO access allows the administration of large volumes of fluids, vasopressors, blood products and other medications at flow rates of up to 125 mL/min using a 15 or 18 gauge needle. An additional benefit of IO access is the rare incidence of complications, with many recent studies revealing rates of <1%. The most common cited complications include compartment syndrome, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.

Laterality of skin cancer in the Utah population

Background: Previous retrospective studies have reported increased frequency of both malignant melanoma (MM, using population-based SEER data) and nonmelanoma skin cancer (NMSC) on the left side of the body. Population-based studies for basal and squamous cell carcinoma (BCC and SCC) have been very difficult as a database similar to SEER does not exist for NMSC, resulting in inferences from smaller retrospective cohorts to assess laterality. As Utah has one of the highest incidences of both MM and NMSC, we explored this question for both skin cancer types using a large database of all biopsies read by the University of Utah Dermatopathology Lab over the past decade.

Fibroadenoma of ectopic breast tissue masquerading as an axillary lipoma

Fibroadenoma of the breast is the most common benign breast condition found in up to 33% of women aged 35-50. Clinically, these are firm, mobile growths within the breast measuring 1-2 cm. The differential diagnosis include cysts, tubular adenoma and phyllodes tumors. The American College of Obstetricians and Gynecologists (ACOG) notes that fibroadenoma of the breast is associated with an elevated risk factor of 1.76 for future breast cancer. The clinician can differentiate between these growths using mammography and ultrasound.

Differential facial esthetic treatment considerations for African-American, Asian, and Hispanic skin color populations

Background: By 2050, more than half the U.S. population will be African American, Asian, or Hispanic. The unique anatomic needs, esthetic goals, and cultural considerations for these growing patient populations should be evaluated to optimize treatment expectations and outcomes. A study was performed to gain insights into areas of esthetic concern, prioritization of treatment areas, and barriers to receiving injectables among these populations.

Man with a perianal ulcer, what to think?

Perianal ulcers imply a vast differential diagnosis, including in the first place squamous cell carcinoma, follow by others such as Bowen's disease, Paget disease, acuminated condyloma, metastatic gastrointestinal carcinoma, Crohn's disease, and others. We present the case of a 51-year-old man that came to the emergency room with a 5-year-evolution perianal ulcer. He referred that it started as a perianal abscess that did not improve over the time and came progressively bigger. It was always asymptomatic and did not give him any problem until 2 weeks before the consultation when it started to hurt and had some episodes of diarrhea, what motivated the consultation.

Influence of mycosis fungoides immunophenotype on prognosis, a retrospective cohort study of 160 patients

Background: Mycosis fungoides (MF) typically has a CD4+CD8− T-cell phenotype. Rare cases of CD4-CD8+, CD4-CD8− or CD4+CD8+ immunophenotypes have been described. Little is known about the impact of MF immunophenotypes on disease behavior.

Health care delivery model effects on access to dermatologic care

Introduction: In contrast to direct access (DA) health care models, gatekeeper (GK) models require a referral for specialist evaluation. Upon dermatologist evaluation, a skin biopsy may be necessary. Under the gatekeeper model, preauthorization is required to perform this procedure. This entails that the patient visit his primary care provider (PCP) to obtain authorization and a following appointment for dermatologic biopsy. This introduces a waiting time to diagnosis and treatment. This is of concern in patients with melanoma, where staging correlates with survival.

Erythema nodosum–like eruption in the setting of sorafenib therapy

Background: Sorafenib, a small molecule inhibitor of RAF kinase and VEGFR-2/PDGFR-beta, is approved for use in several cancers. Numerous cutaneous adverse events from sorafenib therapy have been reported. To the best of our knowledge, we report the first case of erythema nodosum (EN)–like eruption concurrent with sorafenib therapy.

Effectiveness of a nature-based sensitive skin regimen (NBSSR) compared with a synthetic dermatologist-recommended control regimen (CR) in subjects with clinically diagnosed sensitive skin

Background: Sensitive skin is associated with complaints of discomfort and may result from epidermal barrier impairment. An NBSSR is formulated to be safe and effective for sensitive skin.

Definition and classification of chronic prurigo: First expert consensus

Pruriginous conditions may have numerous different causes and manifest with a wide range of clinical presentations, ranging from papules to large plaques. Owing to these characteristics, a plethora of terms have been associated with prurigo without clear criteria, leading to confusion among clinicians, researchers and patients. To address this issue, specialists of the Task Force Pruritus of the European Academy of Dermatology and Venereology gathered with the aim of reaching a clear definition and classification for chronic prurigo.

Comparison of the real-world costs associated with different treatment patterns in adults initiating apremilast or biologics for the treatment of psoriasis

Background: Apremilast, an oral, nonbiologic medication, was approved by the U.S. FDA in 2014 for the treatment of adult patients with active psoriatic arthritis and patients with moderate to severe plaque psoriasis. Treatment patterns in patients with psoriasis initiating apremilast or biologics are well described in the literature. However, cost differences associated with different treatment patterns have not been described in biologic-naive patients initiating apremilast compared with biologics for treatment of psoriasis.

Combined treatment of striae using calcium hydroxylapatite, ascorbic acid delivered by microneedling, and microfocused ultrasound

Background and objective: Striae (i.e., stretch marks) are associated with the loss of collagen and reduced fibrillin and elastin in the skin. Currently available treatments are less than optimal. The objective of this retrospective study was to evaluate improvements in straie appearance after combined treatment with microneedling, topical ascorbic acid, calcium hydroxylapatite (CaHA; Merz North America), and microfocused ultrasound with visualization (MFU-V; Ulthera).

Melanoma follow-up and mortality: A large-scale study of Medicare patients

Background: Cutaneous melanoma is one of the fastest growing skin cancers in the United States, yet is highly curable when detected early. Despite the growing impact of melanoma in the United States, current research on assessing how well patients follow-up and how follow-up and socioeconomic factors affect mortality in patients with melanoma has been limited.

Long-term incidence and geographic trends of follicular lymphoma in Canada: A population-based study

Rationale: Follicular lymphoma is the most common indolent lymphoma and the second most common non-Hodgkin lymphoma. Follicular lymphoma accounts for 10%-20% of all lymphomas in the Western world. Primary cutaneous follicular B-cell lymphoma arises in the skin, while the systemic extranodal follicular lymphoma often involves the skin. Epidemiology and geographic trends of follicular lymphoma have not been investigated in Canada. Our study's objective is to analyze incidence and geographic characteristics of follicular lymphoma in Canada.

Itching for answers: Prevalence and severity of pruritus in psoriasis

Introduction: Psoriasis is a very common skin pathology worldwide. Pruritus is the most frequently reported bothersome complaint or symptom for psoriasis patients. Despite the morbidity associated with pruritus in psoriasis there are few studies evaluating the prevalence of itch in psoriasis in the current context of biologic agents. The aims of this study were to ascertain the severity, characteristics and aggravators of itch in psoriasis.

Improving stratum corneum cell cohesion and skin appearance through an advanced ultramild lamellar cleanser comprising dual lipids with triglycerides and glyceryl monooleate

Background: The introduction of moisturizing liquid cleanser is one of the most significant changes to affect the personal cleansing market in recent years. A key factor contributing to the popularity of these products is that the advanced lipid-containing cleaner can be designed to deliver significant skin care benefits over the ordinary personal cleansing products.

Hypertrophic lichen planus–like eruption secondary to pembrolizumab for metastatic melanoma

A 52-year-old man presented with a new skin eruption primarily affecting the chest, upper extremities, palms, and soles. He previously received pembrolizumab for 3 months for metastatic melanoma, the last infusion of which coincided with the onset of rash. Physical examination revealed scaly, annular erythematous to violaceous plaques predominantly located on the forearms, hands, and feet, with lesser involvement on the chest. Small white papules were present on the buccal mucosa. A punch biopsy was obtained from the left arm.

Patch testing with meropenem following a severe cutaneous adverse drug reaction

Contact Dermatitis, EarlyView.

Contact urticaria caused by tocopherol

Contact Dermatitis, EarlyView.

Brainstem Steering of Locomotor Activity in the Newborn Rat

Control of locomotion relies on motor loops conveying modulatory signals between brainstem and spinal motor circuits. We investigated the steering control of the brainstem reticular formation over the spinal locomotor networks using isolated brainstem–spinal cord preparations of male and female neonatal rats. First, we performed patch-clamp recordings of identified reticulospinal cells during episodes of fictive locomotion. This revealed that a spinal ascending phasic modulation of reticulospinal cell activity is already present at birth. Half of the cells exhibited tonic firing during locomotion, while the other half emitted phasic discharges of action potentials phase locked to ongoing activity. We next showed that mimicking the phasic activity of reticulospinal neurons by applying patterned electrical stimulation bilaterally at the ventral caudal medulla level triggered fictive locomotion efficiently. Moreover, the brainstem stimuli-induced locomotor rhythm was entrained in a one-to-one coupling over a range of cycle periods (2–6 s). Additionally, we induced turning like motor outputs by either increasing or decreasing the relative duration of the stimulation trains on one side of the brainstem compared to the other. The ability of the patterned descending command to control the locomotor output depended on the functional integrity of ventral reticulospinal pathways and the involvement of local spinal central pattern generator circuitry. Altogether, this study provides a mechanism by which brainstem reticulospinal neurons relay steering and speed commands to the spinal locomotor networks.

SIGNIFICANCE STATEMENT Locomotor function allows the survival of most animal species while sustaining the expression of fundamental behaviors. Locomotor activities adapt from moment to moment to behavioral and environmental changes. We show that the brainstem can control the spinal locomotor network outputs through phasic descending commands that alternate bilaterally. Manipulating the periodicity and/or the relative durations of the left and right descending commands at the brainstem level is efficient to set the locomotor speed and sustain directional changes.

Persistent Sodium Current Drives Excitability of Immature Renshaw Cells in Early Embryonic Spinal Networks

Spontaneous network activity (SNA) emerges in the spinal cord (SC) before the formation of peripheral sensory inputs and central descending inputs. SNA is characterized by recurrent giant depolarizing potentials (GDPs). Because GDPs in motoneurons (MNs) are mainly evoked by prolonged release of GABA, they likely necessitate sustained firing of interneurons. To address this issue we analyzed, as a model, embryonic Renshaw cell (V1^R) activity at the onset of SNA (E12.5) in the embryonic mouse SC (both sexes). V1^R are one of the interneurons known to contact MNs, which are generated early in the embryonic SC. Here, we show that V1^R already produce GABA in E12.5 embryo, and that V1^R make synaptic-like contacts with MNs and have putative extrasynaptic release sites, while paracrine release of GABA occurs at this developmental stage. In addition, we discovered that V1^R are spontaneously active during SNA and can already generate several intrinsic activity patterns including repetitive-spiking and sodium-dependent plateau potential that rely on the presence of persistent sodium currents (I_Nap). This is the first demonstration that I_Nap is present in the embryonic SC and that this current can control intrinsic activation properties of newborn interneurons in the SC of mammalian embryos. Finally, we found that 5 μm riluzole, which is known to block I_NaP, altered SNA by reducing episode duration and increasing inter-episode interval. Because SNA is essential for neuronal maturation, axon pathfinding, and synaptogenesis, the presence of I_NaP in embryonic SC neurons may play a role in the early development of mammalian locomotor networks.

SIGNIFICANCE STATEMENT The developing spinal cord (SC) exhibits spontaneous network activity (SNA) involved in the building of nascent locomotor circuits in the embryo. Many studies suggest that SNA depends on the rhythmic release of GABA, yet intracellular recordings of GABAergic neurons have never been performed at the onset of SNA in the SC. We first discovered that embryonic Renshaw cells (V1^R) are GABAergic at E12.5 and spontaneously active during SNA. We uncover a new role for persistent sodium currents (I_NaP) in driving plateau potential in V1^R and in SNA patterning in the embryonic SC. Our study thus sheds light on a role for INaP in the excitability of V1^R and the developing SC.

Beyond Trial-Based Paradigms: Continuous Behavior, Ongoing Neural Activity, and Natural Stimuli

The vast majority of experiments examining perception and behavior are conducted using experimental paradigms that adhere to a rigid trial structure: each trial consists of a brief and discrete series of events and is regarded as independent from all other trials. The assumptions underlying this structure ignore the reality that natural behavior is rarely discrete, brain activity follows multiple time courses that do not necessarily conform to the trial structure, and the natural environment has statistical structure and dynamics that exhibit long-range temporal correlation. Modern advances in statistical modeling and analysis offer tools that make it feasible for experiments to move beyond rigid independent and identically distributed trial structures. Here we review literature that serves as evidence for the feasibility and advantages of moving beyond trial-based paradigms to understand the neural basis of perception and cognition. Furthermore, we propose a synthesis of these efforts, integrating the characterization of natural stimulus properties with measurements of continuous neural activity and behavioral outputs within the framework of sensory-cognitive-motor loops. Such a framework provides a basis for the study of natural statistics, naturalistic tasks, and/or slow fluctuations in brain activity, which should provide starting points for important generalizations of analytical tools in neuroscience and subsequent progress in understanding the neural basis of perception and cognition.

This Week in The Journal

An Eye for an Eye: Neural Correlates of the Preference for Punishment-Based Justice

The Drosophila Receptor Tyrosine Kinase Alk Constrains Long-Term Memory Formation

In addition to mechanisms promoting protein-synthesis-dependent long-term memory (PSD-LTM), the process appears to also be specifically constrained. We present evidence that the highly conserved receptor tyrosine kinase dAlk is a novel PSD-LTM attenuator in Drosophila. Reduction of dAlk levels in adult α/β mushroom body (MB) neurons during conditioning elevates LTM, whereas its overexpression impairs it. Unlike other memory suppressor proteins and miRNAs, dAlk within the MBs constrains PSD-LTM specifically but constrains learning outside the MBs as previously shown. Dendritic dAlk levels rise rapidly in MB neurons upon conditioning, a process apparently controlled by the 3'UTR of its mRNA, and interruption of the 3'UTR leads to enhanced LTM. Because its activating ligand Jeb is dispensable for LTM attenuation, we propose that postconditioning elevation of dAlk within α/β dendrites results in its autoactivation and constrains formation of the energy costly PSD-LTM, acting as a novel memory filter.

SIGNIFICANCE STATEMENT In addition to the widely studied molecular mechanisms promoting protein-synthesis-dependent long-term memory (PSD-LTM), recent discoveries indicate that the process is also specifically constrained. We describe a role in PSD-LTM constraint for the first receptor tyrosine kinase (RTK) involved in olfactory memory in Drosophila. Unlike other memory suppressor proteins and miRNAs, dAlk limits specifically PSD-LTM formation as it does not affect 3 h, or anesthesia-resistant memory. Significantly, we show conditioning-dependent dAlk elevation within the mushroom body dendrites and propose that its local abundance may activate its kinase activity, to mediate imposition of PSD-LTM constraints through yet unknown mechanisms.

Identification of VAPA and VAPB as Kv2 Channel-Interacting Proteins Defining Endoplasmic Reticulum-Plasma Membrane Junctions in Mammalian Brain Neurons

Membrane contacts between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are ubiquitous in eukaryotic cells and are platforms for lipid and calcium signaling and homeostasis. Recent studies have revealed proteins crucial to the formation and function of ER-PM junctions in non-neuronal cells, but little is known of the ER-PM junctions prominent in aspiny regions of mammalian brain neurons. The Kv2.1 voltage-gated potassium channel is abundantly clustered at ER-PM junctions in brain neurons and is the first PM protein that functions to organize ER-PM junctions. However, the molecular mechanism whereby Kv2.1 localizes to and remodels these junctions is unknown. We used affinity immunopurification and mass spectrometry-based proteomics on brain samples from male and female WT and Kv2.1 KO mice and identified the resident ER vesicle-associated membrane protein-associated proteins isoforms A and B (VAPA and VAPB) as prominent Kv2.1-associated proteins. Coexpression with Kv2.1 or its paralog Kv2.2 was sufficient to recruit VAPs to ER-PM junctions. Multiplex immunolabeling revealed colocalization of Kv2.1 and Kv2.2 with endogenous VAPs at ER-PM junctions in brain neurons from male and female mice in situ and in cultured rat hippocampal neurons, and KO of VAPA in mammalian cells reduces Kv2.1 clustering. The association of VAPA with Kv2.1 relies on a "two phenylalanines in an acidic tract" (FFAT) binding domain on VAPA and a noncanonical phosphorylation-dependent FFAT motif comprising the Kv2-specific clustering or PRC motif. These results suggest that Kv2.1 localizes to and organizes neuronal ER-PM junctions through an interaction with VAPs.

SIGNIFICANCE STATEMENT Our study identified the endoplasmic reticulum (ER) proteins vesicle-associated membrane protein-associated proteins isoforms A and B (VAPA and VAPB) as proteins copurifying with the plasma membrane (PM) Kv2.1 ion channel. We found that expression of Kv2.1 recruits VAPs to ER-PM junctions, specialized membrane contact sites crucial to distinct aspects of cell function. We found endogenous VAPs at Kv2.1-mediated ER-PM junctions in brain neurons and other mammalian cells and that knocking out VAPA expression disrupts Kv2.1 clustering. We identified domains of VAPs and Kv2.1 necessary and sufficient for their association at ER-PM junctions. Our study suggests that Kv2.1 expression in the PM can affect ER-PM junctions via its phosphorylation-dependent association to ER-localized VAPA and VAPB.

Notice of Concern: Chen et al., An Agonist of the Protective Factor SIRT1 Improves Functional Recovery and Promotes Neuronal Survival by Attenuating Inflammation after Spinal Cord Injury

In Spoken Word Recognition, the Future Predicts the Past

Speech is an inherently noisy and ambiguous signal. To fluently derive meaning, a listener must integrate contextual information to guide interpretations of the sensory input. Although many studies have demonstrated the influence of prior context on speech perception, the neural mechanisms supporting the integration of subsequent context remain unknown. Using MEG to record from human auditory cortex, we analyzed responses to spoken words with a varyingly ambiguous onset phoneme, the identity of which is later disambiguated at the lexical uniqueness point. Fifty participants (both male and female) were recruited across two MEG experiments. Our findings suggest that primary auditory cortex is sensitive to phonological ambiguity very early during processing at just 50 ms after onset. Subphonemic detail is preserved in auditory cortex over long timescales and re-evoked at subsequent phoneme positions. Commitments to phonological categories occur in parallel, resolving on the shorter timescale of ~450 ms. These findings provide evidence that future input determines the perception of earlier speech sounds by maintaining sensory features until they can be integrated with top-down lexical information.

SIGNIFICANCE STATEMENT The perception of a speech sound is determined by its surrounding context in the form of words, sentences, and other speech sounds. Often, such contextual information becomes available later than the sensory input. The present study is the first to unveil how the brain uses this subsequent information to aid speech comprehension. Concretely, we found that the auditory system actively maintains the acoustic signal in auditory cortex while concurrently making guesses about the identity of the words being said. Such a processing strategy allows the content of the message to be accessed quickly while also permitting reanalysis of the acoustic signal to minimize parsing mistakes.

Reward Learning over Weeks Versus Minutes Increases the Neural Representation of Value in the Human Brain

Over the past few decades, neuroscience research has illuminated the neural mechanisms supporting learning from reward feedback. Learning paradigms are increasingly being extended to study mood and psychiatric disorders as well as addiction. However, one potentially critical characteristic that this research ignores is the effect of time on learning: human feedback learning paradigms are usually conducted in a single rapidly paced session, whereas learning experiences in ecologically relevant circumstances and in animal research are almost always separated by longer periods of time. In our experiments, we examined reward learning in short condensed sessions distributed across weeks versus learning completed in a single "massed" session in male and female participants. As expected, we found that after equal amounts of training, accuracy was matched between the spaced and massed conditions. However, in a 3-week follow-up, we found that participants exhibited significantly greater memory for the value of spaced-trained stimuli. Supporting a role for short-term memory in massed learning, we found a significant positive correlation between initial learning and working memory capacity. Neurally, we found that patterns of activity in the medial temporal lobe and prefrontal cortex showed stronger discrimination of spaced- versus massed-trained reward values. Further, patterns in the striatum discriminated between spaced- and massed-trained stimuli overall. Our results indicate that single-session learning tasks engage partially distinct learning mechanisms from distributed training. Our studies begin to address a large gap in our knowledge of human learning from reinforcement, with potential implications for our understanding of mood disorders and addiction.

SIGNIFICANCE STATEMENT Humans and animals learn to associate predictive value with stimuli and actions, and these values then guide future behavior. Such reinforcement-based learning often happens over long time periods, in contrast to most studies of reward-based learning in humans. In experiments that tested the effect of spacing on learning, we found that associations learned in a single massed session were correlated with short-term memory and significantly decayed over time, whereas associations learned in short massed sessions over weeks were well maintained. Additionally, patterns of activity in the medial temporal lobe and prefrontal cortex discriminated the values of stimuli learned over weeks but not minutes. These results highlight the importance of studying learning over time, with potential applications to drug addiction and psychiatry.

Surprise About Sensory Event Timing Drives Cortical Transients in the Beta Frequency Band

Learning the statistical structure of the environment is crucial for adaptive behavior. Humans and nonhuman decision-makers seem to track such structure through a process of probabilistic inference, which enables predictions about behaviorally relevant events. Deviations from such predictions cause surprise, which in turn helps improve inference. Surprise about the timing of behaviorally relevant sensory events drives phasic responses of neuromodulatory brainstem systems, which project to the cerebral cortex. Here, we developed a computational model-based magnetoencephalography (MEG) approach for mapping the resulting cortical transients across space, time, and frequency, in the human brain (N = 28, 17 female). We used a Bayesian ideal observer model to learn the statistics of the timing of changes in a simple visual detection task. This model yielded quantitative trial-by-trial estimates of temporal surprise. The model-based surprise variable predicted trial-by-trial variations in reaction time more strongly than the externally observable interval timings alone. Trial-by-trial variations in surprise were negatively correlated with the power of cortical population activity measured with MEG. This surprise-related power suppression occurred transiently around the behavioral response, specifically in the beta frequency band. It peaked in parietal and prefrontal cortices, remote from the motor cortical suppression of beta power related to overt report (button press) of change detection. Our results indicate that surprise about sensory event timing transiently suppresses ongoing beta-band oscillations in association cortex. This transient suppression of frontal beta-band oscillations might reflect an active reset triggered by surprise, and is in line with the idea that beta-oscillations help maintain cognitive sets.

SIGNIFICANCE STATEMENT The brain continuously tracks the statistical structure of the environment to anticipate behaviorally relevant events. Deviations from such predictions cause surprise, which in turn drives neural activity in subcortical brain regions that project to the cerebral cortex. We used magnetoencephalography in humans to map out surprise-related modulations of cortical population activity across space, time, and frequency. Surprise was elicited by variable timing of visual stimulus changes requiring a behavioral response. Surprise was quantified by means of an ideal observer model. Surprise predicted behavior as well as a transient suppression of beta frequency-band oscillations in frontal cortical regions. Our results are in line with conceptual accounts that have linked neural oscillations in the beta-band to the maintenance of cognitive sets.

Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons

Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in postmitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMAs) and the presence of this posttranslational modification provides protection against environmental stress. We identify protein arginine methyltransferase 8 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in postmitotic neurons. Male PRMT8 knock-out mice display decreased muscle strength with aging due to premature destabilization of neuromuscular junctions. Mechanistically, inhibition of methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double-stranded breaks and decrease in the cAMP response-element-binding protein 1 (CREB1) level. As a consequence, the expression of CREB1-mediated prosurvival and regeneration-associated immediate early genes is dysregulated in aging PRMT8 knock-out mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived postmitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration.

SIGNIFICANCE STATEMENT Although most of the cells in our body have a very short lifespan, postmitotic neurons must survive for many decades. Longevity of a cell within the organism depends on its ability to properly regulate signaling pathways that counteract perturbations, such as DNA damage, oxidative stress, or protein misfolding. Here, we provide evidence that tissue-specific regulators of stress tolerance exist in postmitotic neurons. Specifically, we identify protein arginine methyltransferase 8 (PRMT8) as a cell-type-restricted arginine methyltransferase in spinal cord motoneurons (MNs). PRMT8-dependent arginine methylation is required for neuroprotection against age-related increased of cellular stress. Tissue-restricted expression and the enzymatic activity of PRMT8 make it an attractive target for drug development to delay the onset of neurodegenerative disorders.

Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce–BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce–BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce–BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce–BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components.

SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.

Cerebrospinal Fluid-Contacting Neurons Sense pH Changes and Motion in the Hypothalamus

CSF-contacting (CSF-c) cells are present in the walls of the brain ventricles and the central canal of the spinal cord and found throughout the vertebrate phylum. We recently identified ciliated somatostatin-/GABA-expressing CSF-c neurons in the lamprey spinal cord that act as pH sensors as well as mechanoreceptors. In the same neuron, acidic and alkaline responses are mediated through ASIC3-like and PKD2L1 channels, respectively. Here, we investigate the functional properties of the ciliated somatostatin-/GABA-positive CSF-c neurons in the hypothalamus by performing whole-cell recordings in hypothalamic slices. Depolarizing current pulses readily evoked action potentials, but hypothalamic CSF-c neurons had no or a very low level of spontaneous activity at pH 7.4. They responded, however, with membrane potential depolarization and trains of action potentials to small deviations in pH in both the acidic and alkaline direction. Like in spinal CSF-c neurons, the acidic response in hypothalamic cells is mediated via ASIC3-like channels. In contrast, the alkaline response appears to depend on connexin hemichannels, not on PKD2L1 channels. We also show that hypothalamic CSF-c neurons respond to mechanical stimulation induced by fluid movements along the wall of the third ventricle, a response mediated via ASIC3-like channels. The hypothalamic CSF-c neurons extend their processes dorsally, ventrally, and laterally, but as yet, the effects exerted on hypothalamic circuits are unknown. With similar neurons being present in rodents, the pH- and mechanosensing ability of hypothalamic CSF-c neurons is most likely conserved throughout vertebrate phylogeny.

SIGNIFICANCE STATEMENT CSF-contacting neurons are present in all vertebrates and are located mainly in the hypothalamic area and the spinal cord. Here, we report that the somatostatin-/GABA-expressing CSF-c neurons in the lamprey hypothalamus sense bidirectional deviations in the extracellular pH and do so via different molecular mechanisms. They also serve as mechanoreceptors. The hypothalamic CSF-c neurons have extensive axonal ramifications and may decrease the level of motor activity via release of somatostatin. In conclusion, hypothalamic somatostatin-/GABA-expressing CSF-c neurons, as well as their spinal counterpart, represent a novel homeostatic mechanism designed to sense any deviation from physiological pH and thus constitute a feedback regulatory system intrinsic to the CNS, possibly serving a protective role from damage caused by changes in pH.

A Closely Associated Phospholipase C Regulates Cation Channel Function through Phosphoinositide Hydrolysis

In the hemaphroditic sea snail, Aplysia californica, reproduction is initiated when the bag cell neurons secrete egg-laying hormone during a protracted afterdischarge. A source of depolarization for the afterdischarge is a voltage-gated, nonselective cation channel, similar to transient receptor potential (TRP) channels. Once the afterdischarge is triggered, phospholipase C (PLC) is activated to hydrolyze phosphatidylinositol-4,5-bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol trisphosphate (IP₃). We previously reported that a DAG analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), activates a prominent, inward whole-cell cationic current that is enhanced by IP₃. To examine the underlying mechanism, we investigated the effect of exogenous OAG and IP₃, as well as PLC activation, on cation channel activity and voltage dependence in excised, inside-out patches from cultured bag cell neurons. OAG transiently elevated channel open probability (P_O) when applied to excised patches; however, coapplication of IP₃ prolonged the OAG-induced response. In patches exposed to OAG and IP₃, channel voltage dependence was left-shifted; this was also observed with OAG, but not to the same extent. Introducing the PLC activator, m-3M3FBS, to patches increased channel P_O, suggesting PLC may be physically linked to the channels. Accordingly, blocking PLC with U-73122 ablated the m-3M3FBS-induced elevation in P_O. Treatment with m-3M3FBS left-shifted cation channel voltage dependence to a greater extent than exogenous OAG and IP₃. Finally, OAG and IP₃ potentiated the stimulatory effect of PKC, which is also associated with the channel. Thus, the PLC-PKC signaling system is physically localized such that PIP₂ breakdown products liberated during the afterdischarge modulate the cation channel and temporally influence neuronal activity.

SIGNIFICANCE STATEMENT Using excised patches from Aplysia bag cell neurons, we present the first evidence of a nonselective cation channel physically associating with phospholipase C (PLC) at the single-channel level. PLC-mediated breakdown of phospholipids generates diacylglycerol and inositol trisphosphate, which activate the cation channel. This is mimicked by exogenous lipids; furthermore, these second messengers left-shift channel voltage dependence and enhance the response of the channel to protein kinase C. PLC-mediated lipid signaling controls single-channel currents to ensure depolarization is maintained for an extended period of firing, termed the afterdischarge, when the bag cell neurons secrete egg-laying hormone to trigger reproduction.

C9orf72 Dipeptide Repeats Cause Selective Neurodegeneration and Cell-Autonomous Excitotoxicity in Drosophila Glutamatergic Neurons

The arginine-rich dipeptide repeats (DPRs) are highly toxic products from the C9orf72 repeat expansion mutations, which are the most common causes of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the effects of DPRs in the synaptic regulation and excitotoxicity remain elusive, and how they contribute to the development of FTD is primarily unknown. By expressing DPRs with different toxicity strength in various neuronal populations in a Drosophila model, we unexpectedly found that Glycine-Arginine/Proline-Arginine (GR/PR) with 36 repeats could lead to neurodegenerative phenotypes only when they were expressed in glutamatergic neurons, including motor neurons. We detected increased extracellular glutamate and intracellular calcium levels in GR/PR-expressing larval ventral nerve cord and/or adult brain, accompanied by significant increase of synaptic boutons and active zones in larval neuromuscular junctions. Inhibiting the vesicular glutamate transporter expression or blocking the NMDA receptor in presynaptic glutamatergic motor neurons could effectively rescue the motor deficits and shortened life span caused by poly GR/PR, thus indicating a cell-autonomous excitotoxicity mechanism. Therefore, our results have revealed a novel mode of synaptic regulation by arginine-rich C9 DPRs expressed at more physiologically relevant toxicity levels and provided a mechanism that could contribute to the development of C9-related ALS and FTD.

SIGNIFICANCE STATEMENT C9orf72 dipeptide repeats (DPRs) are key toxic species causing ALS/FTD, but their roles in synaptic regulation and excitotoxicity are unclear. Using C9orf72 DPRs with various toxicity strength, we have found that the arginine-rich DPRs cause selective degeneration in Drosophila glutamatergic neurons and revealed an NMDA receptor-dependent cell-autonomous excitotoxicity mechanism. Therefore, this study has advanced our understanding of C9orf72 DPR functions in synaptic regulation and excitotoxicity and provided a new mechanism that could contribute to the development of C9-related ALS and FTD.

EZH2 Methyltransferase Activity Controls Pten Expression and mTOR Signaling during Fear Memory Reconsolidation

Memory retrieval induces a transient period of increased transcriptional and translational regulation in neurons called reconsolidation, which is regulated by the protein kinase B (AKT)–mammalian target of rapamycin (mTOR) pathway. However, it is currently unknown how activation of the AKT–mTOR pathway is regulated during the reconsolidation process. Here, we found that in male rats retrieval of a contextual fear memory transiently increased Enhancer of Zeste Homolog 2 (EZH2) levels along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, which correlated with decreased levels of phosphatase and tensin homolog (PTEN), a potent inhibitor of AKT–mTOR-dependent signaling in the hippocampus. Further experiments found increased H3K27me3 levels and DNA methylation across the Pten promoter and coding regions, indicating transcriptional silencing of the Pten gene. Pten H3K27me3 levels did not change following training or after the retrieval of a remote (old) fear memory, suggesting that this mechanism of Pten repression was specific to the reconsolidation of a new memory. In vivo siRNA-mediated knockdown of Ezh2 in the hippocampus abolished retrieval-induced increases in H3K27me3 and prevented decreases in PTEN levels. Ezh2 knockdown attenuated increases in the phosphorylation of AKT and mTOR following retrieval, which could be restored by simultaneously reducing Pten, suggesting that H3K27me3 regulates AKT–mTOR phosphorylation via repression of Pten. Consistent with these results, knockdown of Ezh2 in area CA1 before retrieval impaired memory on later tests. Collectively, these results suggest that EZH2-mediated H3K27me3 plays a critical role in the repression of Pten transcription necessary for AKT–mTOR activation and memory reconsolidation following retrieval.

SIGNIFICANCE STATEMENT Understanding how critical translation pathways, like mTOR-mediated protein synthesis, are regulated during the memory storage process is necessary for improving memory impairments. This study tests whether mTOR activation is coupled to epigenetic mechanisms in the hippocampus following the retrieval of a contextual fear memory. Specifically, this study evaluates the role of epigenetic modifications in the form of histone methylation in downstream mTOR translational control during learning-dependent synaptic plasticity in neurons. Considering the broad implications of transcriptional and translational mechanisms in synaptic plasticity, psychiatric, and neurological and neurodegenerative disorders, these data are of interest to the neuroscience community due to the robust and specific regulation of mTOR signaling we found to be dependent on repressive histone methylation.

Correction: Even-Chen et al., "Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption"

Topical inhibition of PUMA signaling mitigates radiation injury

Wound Repair and Regeneration, Volume 0, Issue ja, -Not available-.

Issue Information

Experimental Dermatology, Volume 27, Issue 9, Page 939-940, September 2018.

Altered expression of matrix remodelling associated 7 (MXRA7) in psoriatic epidermis: Evidence for a protective role in the psoriasis imiquimod mouse model

Experimental Dermatology, Volume 27, Issue 9, Page 1038-1042, September 2018.

Clinical Snippets

Experimental Dermatology, Volume 27, Issue 9, Page i-i, September 2018.

Defining and validating a Body Skin Discomfort Index (BSDI)

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

Drug reaction with eosinophilia and systemic symptoms (DRESS) and multiple organ dysfunction syndrome (MODS): one more reason for a new effective treatment against leishmaniasis

International Journal of Dermatology, EarlyView.

Acacia seyal and Terminalia brownii associated airborne contact dermatitis (Dukhan dermatitis)

International Journal of Dermatology, EarlyView.

A novel approach to the classification of epidermodysplasia verruciformis

International Journal of Dermatology, EarlyView.

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.

A Child With Multiple Hypopigmented Macules on the Abdomen

A child presented with multiple, asymptomatic, scattered white macules on the lower abdomen and pubic area, which were present at birth and had gradually increased in size and number; there was no history of any systemic disorder and no family history of similar lesions. What is your diagnosis?

Analysis of the Effect of Gentian Violet on Apoptosis and Proliferation in Cutaneous T-Cell Lymphoma in an In Vitro Study

This preclinical in vitro study identifies novel small molecules that induce extrinsic apoptosis and serve as an alternative treatment for cutaneous T-cell lymphoma.

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.

Mepolizumab for the Treatment of Aspirin Exacerbated Respiratory Disease Associated with Coronary Spasm

Publication date: Available online 29 August 2018

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

Author(s): David Hagin, Yacov Shacham, Shmuel Kivity, Shira Benor

Which opioids in case of mast cell activation disorders?

Publication date: Available online 29 August 2018

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

Author(s): Marion Lepelley, Charles Khouri, Pauline Pralong, Julien Rossignol, Céline Greco, Laurence Bouillet, Isabelle Boccon Gibod

Pathways to Improved Antibiotic Allergy and Antimicrobial Stewardship Practice - The Validation of a Beta-Lactam Antibiotic Allergy Assessment Tool

Publication date: Available online 29 August 2018

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

Author(s): Misha Devchand, Karen Urbancic, Sharmila Khumra, Abby Douglas, Olivia Smibert, Emma Cohen, Michael Sutherland, Elizabeth J. Phillips, Jason A. Trubiano

Summary

The validation of a beta-lactam antibiotic allergy assessment allows non-allergists to effectively phenotype patient-reported antibiotic allergies and direct them to appropriate 'de-labeling' stratergies.

Racial disparities in asthma-related health outcomes in children with severe/difficult-to-treat asthma

Publication date: Available online 29 August 2018

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

Author(s): Theresa Guilbert, Robert S. Zeiger, Tmirah Haselkorn, Ahmar Iqbal, Cynthia Alvarez, David R. Mink, Bradley E. Chipps, Stanley J. Szefler

Abstract

Background

There are limited data which examine differences in asthma etiology between Black and White children with severe or difficult-to-treat asthma.

Objective

To describe demographic, clinical, and asthma-related outcomes in Black and White children and examine whether differences in outcomes are explained by confounding factors in sequential multivariable models.

Methods

Black (n=86) and White (n=262) children ages 6–11 years from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) 3-year observational study were analyzed. Baseline demographics and clinical characteristics were described for both cohorts and outcomes at Month 12 were analyzed using statistical models, sequentially adjusting for potential confounders.

Results

Black children were more likely to be male (79.1% vs. 66.4%, P<0.05), obese (12.8% vs. 1.5%, P<0.001), and from a lower income stratum (43,400 vs. 55,770 USD; P<0.001) than White children. Black children had higher geometric mean immunoglobulin E levels (434.8 vs. 136.8 IU/mL; P<0.001), were more likely to have very poorly controlled asthma (72.1% vs. 53.4%), use long-term systemic corticosteroids (30.2% vs 9.2%; P<0.001), have poorer quality of life (5.5 vs. 6.1; P<0.001), and have an emergency department visit (27.4% vs. 7.7%, p<0.001) in the three months prior to Month 12. Differences in asthma control and the severity of exacerbations persisted even after accounting for all confounding factors.

Conclusion

Among children with severe or difficult-to-treat asthma, asthma burden is greater in Black than White children particularly related to several clinical and patient-reported outcome measures which are not explained by differences in background or clinical characteristics.

Cross-reactive aeroallergens: which need to cross our mind in food allergy diagnosis?

Publication date: Available online 29 August 2018

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

Author(s): Margaretha A. Faber, Athina L. Van Gasse, Ine I. Decuyper, Vito Sabato, Margo M. Hagendorens, Christel Mertens, Chris H. Bridts, Luc S. De Clerck, Didier G. Ebo

Abstract

Secondary food allergies due to cross-reactivity between inhalant- and food allergens are a significant and increasing global health issue. Cross-reactive food allergies predominantly involve plant-derived foods resulting from a prior sensitization to cross-reactive components present in pollen (grass, tree, weeds) and natural rubber latex (NRL). But also primary sensitisation to allergens present in fungi, insects and both non-mammalian and mammalian meat might induce cross-reactive food allergic syndromes. Correct diagnosis of these associated food allergies is not always straight forward and can pose a difficult challenge. As a matter of fact, cross-reactive allergens might hamper food allergy diagnosis, as they can cause clinically irrelevant positive tests to cross-reacting foods that are safely consumed.

This review summarizes the most relevant cross-reactivity syndromes between inhalant and food allergens. Particular focus is paid to the potential and limitations of confirmatory testing such as skin testing, sIgE assays, molecular diagnosis (CRD) and basophil activation test (BAT).

Reconstruction mammaire par lambeau de grand dorsal autologue

Publication date: Available online 28 August 2018

Source: Annales de Chirurgie Plastique Esthétique

Author(s): E. Delay, A.S. Florzac, P. Frobert

Résumé

Le lambeau de grand dorsal autologue ou lambeau de grand dorsal sans prothèse est la technique la plus récente et la technique qui a le plus profité des progrès au cours de ces dernières années. La technique chirurgicale est bien codifiée et permet de prélever les différentes zones graisseuses adjacentes au muscle grand dorsal, pour permettre une reconstruction autologue. La vascularisation du lambeau est fiable, grâce au pédicule thoracodorsal, ce qui permet l'utilisation de ce lambeau dans de nombreuses indications, y compris dans les cas de contre-indications au TRAM et au DIEP. Le lipomodelage du décolleté, dès le temps initial, permet de restaurer le décolleté. Puis deux mois plus tard, le lipomodelage de l'ensemble du sein reconstruit permet d'obtenir le volume souhaité pour le sein reconstruit. Suivant les cas, une ou deux séances de lipomodelage sont nécessaires pour obtenir le résultat escompté. Les avantages de ce lambeau sont sa fiabilité, sa sécurité, sa trophicité et le très faible taux de complications. Les inconvénients sont actuellement très faibles, une fois que la courbe d'apprentissage a été faite, puisque le principal inconvénient de cette technique était la survenue d'un sérome dorsal, et que cet inconvénient a été réduit de façon majeure depuis l'utilisation de la technique du capitonnage dorsal au fil cranté. Finalement, la reconstruction par lambeau de grand dorsal autologue s'est imposée dans notre équipe comme la meilleure technique de reconstruction mammaire autologue, et a actuellement supplanté les techniques utilisant le lambeau abdominal, que ce soit le TRAM flap et le DIEP.

Summary

Amongst various techniques of breast reconstruction, Autologous Latissimus Dorsi (ALD) flap without breast implant is the newest technique that took advantage of recent improvement during the last decade. Surgical procedure is well standardized, and allows to harvest various fat areas attached to the muscle, to obtain an autologous reconstruction. Thoracodorsal pedicle is steady and makes ALD the most reliable flap that can be used in several indications, especially when DIEP or TRAM flap are inappropriate. Lipomodeling of the cleavage is performed during the first surgery. Additionnal lipomodeling is performed in the whole reconstructed breast area at 2 months to get the expected volume. In some cases, two lipomodelings may be required. Advantages of ALD flap are numerous such as its reliability, its trophicity, and a very low complications rate. After a learning curve, drawbacks are well controlled, since quilting suture of the donor site helped to reduce drastically seroma rate. Finally, ALD flap became the best technique, and the most used in our team for autologous breast reconstruction, and surpassed abdominal flaps such as TRAM flap or DIEP flap.

The Use of Pulse Oximetry to Diagnose Limb Ischaemia

Publication date: Available online 28 August 2018

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery

Author(s): Richard Mark Kwasnicki, Asmat H Din, Shehan Hettiaratchy