The Bow and Arrow and Early Human Sociality: an Enactive Perspective on Communities and Technical Practice in the Middle Stone Age

Abstract

In this paper, I draw on postphenomenology and material engagement theory to consider the material and emergent character of sociality in Homo faber. I approach this through the context of the bow and arrow, which is a technology that has received recent attention in cognitive archeology as a proxy for assessing criteria that made early human cognition distinct from that of other hominins. Through an ethnographic case study, I scrutinize the forms of knowledge that are required to use the technology in the dynamic field of environmental practices that constitute the hunt. I demonstrate that the learning of the skill is a transformational process where beginners develop self and intentionality by attuning subjective capacities for sensory awareness and creative responsiveness. Through mutual participation, the bow and arrow aligns disposition and rapport among those whose life processes are shaped by the skill. As a mechanism of shared experience, the bow and arrow generates a community can together perceive and act creatively in an impermanent world. Through these observations, I argue that early human sociality was built not on a pre-evolved capacity for symbolic representation but on technical experience, and I consider important questions this raises about the nature of evolutionary processes at work in the development of communities through time.

Commiserating with Devastated Things: Milan Kundera and the Entitlement of Thinking

Commiserating with Devastated Things: Milan Kundera and the Entitlement of ThinkingWIRTHJASON M.fordham university press. 2016. pp. 227227. £54.00. (hbk).

Management of Morgellons Disease With Low-Dose Trifluoperazine

This medical record review examines the novel use of low-dose trifluoperazine, a high-potency typical antipsychotic, in a cohort of patients with Morgellons disease.

Diagnosis of Neurofibromatosis Type 2 From Congenital Skin Plaques

This genetic testing study reports a case of an early diagnosis of neurofibromatosis type 2 (NF2) in a child after genetic analysis of congenital skin plaques, with confirmation of these findings by analysis of skin plaques from 6 unrelated patients with NF2.

Intertriginous Condyloma-like Plaques and Ulcers

A woman in her 50s with a medical history of hypertension and depression was evaluated by the inpatient dermatology consult service for a 1.5-year history of painful intertriginous wounds; she was previously diagnosed with hidradenitis suppurativa. What is your diagnosis?

Human Herpesvirus 8–Associated Inflammatory Cytokine Syndrome

This case report describes a patient with human herpesvirus 8–associated inflammatory cytokine syndrome.

Comorbidity Development in Children With Psoriasis

This cohort study examines the risk ocomorbidities in children with and without psoriasis, after accounting for obesity.

Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep–wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep–wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep–wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3–36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep–wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep.

SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY_3–36 can reverse this neurochemical imbalance and acutely restore sleep composition. These findings add insight into how innate behaviors such as feeding and sleep are integrated and suggest a novel mechanism through which diet-induced obesity during puberty imposes its long-lasting effects on sleep–wake behavior.

Cognitive Control, the Anterior Cingulate, and Nicotinic Receptors: A Case of Heterozygote Advantage

A Critical Role for Dopamine D5 Receptors in Pain Chronicity in Male Mice

Dopaminergic modulation of spinal cord plasticity has long been recognized, but circuits affected by this system and the precise receptor subtypes involved in this modulation have not been defined. Dopaminergic modulation from the A11 nucleus of the hypothalamus contributes to plasticity in a model of chronic pain called hyperalgesic priming. Here we tested the hypothesis that the key receptor subtype mediating this effect is the D5 receptor (D5R). We find that a spinally directed lesion of dopaminergic neurons reverses hyperalgesic priming in both sexes and that a D1/D5 antagonist transiently inhibits neuropathic pain. We used mice lacking D5Rs (DRD5KO mice) to show that carrageenan, interleukin 6, as well as BDNF-induced hyperalgesia and priming are reduced specifically in male mice. These male DRD5KO mice also show reduced formalin pain responses and decreased heat pain. To characterize the subtypes of dorsal horn neurons engaged by dopamine signaling in the hyperalgesic priming model, we used c-fos labeling. We find that a mixed D1/D5 agonist given spinally to primed mice activates a subset of neurons in lamina III and IV of the dorsal horn that coexpress PAX2, a transcription factor for GABAergic interneurons. In line with this, we show that gabazine, a GABA-A receptor antagonist, is antihyperalgesic in primed mice exposed to spinal administration of a D1/D5 agonist. Therefore, the D5R, in males, and the D1R, in females, exert a powerful influence over spinal cord circuitry in pathological pain likely via modulation of deep dorsal horn GABAergic neurons.

SIGNIFICANCE STATEMENT Pain is the most prominent reason why people seek medical attention, and chronic pain incidence worldwide has been estimated to be as high as 33%. This study provides new insight into how descending dopamine controls pathological pain states. Our work demonstrates that dopaminergic spinal projections are necessary for the maintenance of a chronic pain state in both sexes; however, D5 receptors seem to play a critical role in males whereas females rely more heavily on D1 receptors, an effect that could be explained by sexual dimorphisms in receptor expression levels. Collectively, our work provides new insights into how the dopaminergic system interacts with spinal circuits to promote pain plasticity.

Does Auditory Cortex Code Temporal Information from Acoustic and Cochlear Implant Stimulation in a Similar Way?

Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation

Cocaine abuse disrupts dopamine system function, and reduces cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criterion for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were twofold; we sought to (1) identify the molecular mechanisms by which cocaine exposure produces tolerance and (2) determine whether amphetamine-induced reductions in cocaine intake are connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats, we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed cocaine tolerance. Amphetamine treatment also reversed escalated cocaine intake and decreased motivation to obtain cocaine as measured in a behavioral economics task, thereby linking tolerance to multiple facets of cocaine use. Finally, using fluorescence resonance energy transfer imaging, we found that cocaine tolerance is associated with the formation of DAT-DAT complexes, and that amphetamine disperses these complexes. In addition to extending our basic understanding of DATs and their role in cocaine reinforcement, we serendipitously identified a novel therapeutic target: DAT oligomer complexes. We show that dispersion of oligomers is concomitant with reduced cocaine intake, and propose that pharmacotherapeutics aimed at these complexes may have potential for cocaine addiction treatment.

SIGNIFICANCE STATEMENT Tolerance to cocaine's subjective effects is a cardinal symptom of cocaine addiction and a DSM-V criterion for substance abuse disorders. However, elucidating the molecular adaptions that produce tolerance and determining its behavioral impact have proven difficult. Using cocaine self-administration in rats, we link tolerance to cocaine effects at the dopamine transporter (DAT) with aberrant cocaine-taking behaviors. Further, tolerance was associated with multi-DAT complexes, which formed after cocaine exposure. Treatment with amphetamine deconstructed DAT complexes, reversed tolerance, and decreased cocaine seeking. These data describe the behavioral consequence of cocaine tolerance, provide a putative mechanism for its development, and suggest that compounds that disperse DAT complexes may be efficacious treatments for cocaine addiction.

Behavioral, Modeling, and Electrophysiological Evidence for Supramodality in Human Metacognition

Human metacognition, or the capacity to introspect on one's own mental states, has been mostly characterized through confidence reports in visual tasks. A pressing question is to what extent results from visual studies generalize to other domains. Answering this question allows determining whether metacognition operates through shared, supramodal mechanisms or through idiosyncratic, modality-specific mechanisms. Here, we report three new lines of evidence for decisional and postdecisional mechanisms arguing for the supramodality of metacognition. First, metacognitive efficiency correlated among auditory, tactile, visual, and audiovisual tasks. Second, confidence in an audiovisual task was best modeled using supramodal formats based on integrated representations of auditory and visual signals. Third, confidence in correct responses involved similar electrophysiological markers for visual and audiovisual tasks that are associated with motor preparation preceding the perceptual judgment. We conclude that the supramodality of metacognition relies on supramodal confidence estimates and decisional signals that are shared across sensory modalities.

SIGNIFICANCE STATEMENT Metacognitive monitoring is the capacity to access, report, and regulate one's own mental states. In perception, this allows rating our confidence in what we have seen, heard, or touched. Although metacognitive monitoring can operate on different cognitive domains, we ignore whether it involves a single supramodal mechanism common to multiple cognitive domains or modality-specific mechanisms idiosyncratic to each domain. Here, we bring evidence in favor of the supramodality hypothesis by showing that participants with high metacognitive performance in one modality are likely to perform well in other modalities. Based on computational modeling and electrophysiology, we propose that supramodality can be explained by the existence of supramodal confidence estimates and by the influence of decisional cues on confidence estimates.

Dissociable Decoding of Spatial Attention and Working Memory from EEG Oscillations and Sustained Potentials

In human scalp EEG recordings, both sustained potentials and alpha-band oscillations are present during the delay period of working memory tasks and may therefore reflect the representation of information in working memory. However, these signals may instead reflect support mechanisms rather than the actual contents of memory. In particular, alpha-band oscillations have been tightly tied to spatial attention and may not reflect location-independent memory representations per se. To determine how sustained and oscillating EEG signals are related to attention and working memory, we attempted to decode which of 16 orientations was being held in working memory by human observers (both women and men). We found that sustained EEG activity could be used to decode the remembered orientation of a stimulus, even when the orientation of the stimulus varied independently of its location. Alpha-band oscillations also carried clear information about the location of the stimulus, but they provided little or no information about orientation independently of location. Thus, sustained potentials contain information about the object properties being maintained in working memory, consistent with previous evidence of a tight link between these potentials and working memory capacity. In contrast, alpha-band oscillations primarily carry location information, consistent with their link to spatial attention.

SIGNIFICANCE STATEMENT Working memory plays a key role in cognition, and working memory is impaired in several neurological and psychiatric disorders. Previous research has suggested that human scalp EEG recordings contain signals that reflect the neural representation of information in working memory. However, to conclude that a neural signal actually represents the object being remembered, it is necessary to show that the signal contains fine-grained information about that object. Here, we show that sustained voltages in human EEG recordings contain fine-grained information about the orientation of an object being held in memory, consistent with a memory storage signal.

The Role of Cysteine String Protein {alpha} Phosphorylation at Serine 10 and 34 by Protein Kinase C{gamma} for Presynaptic Maintenance

Protein kinase C (PKC) knock-out (KO) animals exhibit symptoms of Parkinson's disease (PD), including dopaminergic neuronal loss in the substantia nigra. However, the PKC substrates responsible for the survival of dopaminergic neurons in vivo have not yet been elucidated. Previously, we found 10 potent substrates in the striatum of PKC-KO mice. Here, we focused on cysteine string protein α (CSPα), a protein from the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles. We found that in cultured cells, PKC phosphorylates CSPα at serine (Ser) 10 and Ser34. Additionally, apoptosis was found to have been enhanced by the overexpression of a phosphorylation-null mutant of CSPα, CSPα(S10A/S34A). Compared with wild-type (WT) CSPα, the CSPα(S10A/S34A) mutant had a weaker interaction with HSP70. However, in sharp contrast, a phosphomimetic CSPα(S10D/S34D) mutant, compared with WT CSPα, had a stronger interaction with HSP70. In addition, total levels of synaptosomal-associated protein (SNAP) 25, a main downstream target of the HSC70/HSP70 chaperone complex, were found to have decreased by the CSPα(S10A/S34A) mutant through increased ubiquitination of SNAP25 in PC12 cells. In the striatum of 2-year-old male PKC-KO mice, decreased phosphorylation levels of CSPα and decreased SNAP25 protein levels were observed. These findings indicate the phosphorylation of CSPα by PKC may protect the presynaptic terminal from neurodegeneration. The PKC–CSPα–HSC70/HSP70–SNAP25 axis, because of its role in protecting the presynaptic terminal, may provide a new therapeutic target for the treatment of PD.

SIGNIFICANCE STATEMENT Cysteine string protein α (CSPα) is a protein belonging to the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles, which maintain the presynaptic terminal. However, the function of CSPα phosphorylation by protein kinase C (PKC) for neuronal cell survival remains unclear. The experiments presented here demonstrate that PKC phosphorylates CSPα at serine (Ser) 10 and Ser34. CSPα phosphorylation at Ser10 and Ser34 by PKC protects the presynaptic terminal by promoting HSP70 chaperone activity. This report suggests that CSPα phosphorylation, because of its role in modulating HSP70 chaperone activity, may be a target for the treatment of neurodegeneration.

Brainstem Pain-Control Circuitry Connectivity in Chronic Neuropathic Pain

Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top–down engagement of the circuitry alongside altered reward processing in pain conditions.

SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain-modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain-modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative for the development of more efficacious therapies.

The Microtubule-Associated Protein Tau Mediates the Organization of Microtubules and Their Dynamic Exploration of Actin-Rich Lamellipodia and Filopodia of Cortical Growth Cones

Proper organization and dynamics of the actin and microtubule (MT) cytoskeleton are essential for growth cone behaviors during axon growth and guidance. The MT-associated protein tau is known to mediate actin/MT interactions in cell-free systems but the role of tau in regulating cytoskeletal dynamics in living neurons is unknown. We used cultures of cortical neurons from postnatal day (P)0–P2 golden Syrian hamsters (Mesocricetus auratus) of either sex to study the role of tau in the organization and dynamics of the axonal growth cone cytoskeleton. Here, using super resolution microscopy of fixed growth cones, we found that tau colocalizes with MTs and actin filaments and is also located at the interface between actin filament bundles and dynamic MTs in filopodia, suggesting that tau links these two cytoskeletons. Live cell imaging in concert with shRNA tau knockdown revealed that reducing tau expression disrupts MT bundling in the growth cone central domain, misdirects trajectories of MTs in the transition region and prevents single dynamic MTs from extending into growth cone filopodia along actin filament bundles. Rescue experiments with human tau expression restored MT bundling, MT penetration into the growth cone periphery and close MT apposition to actin filaments in filopodia. Importantly, we found that tau knockdown reduced axon outgrowth and growth cone turning in Wnt5a gradients, likely due to disorganized MTs that failed to extend into the peripheral domain and enter filopodia. These results suggest an important role for tau in regulating cytoskeletal organization and dynamics during growth cone behaviors.

SIGNIFICANCE STATEMENT Growth cones are the motile tips of growing axons whose guidance behaviors require interaction of the dynamic actin and microtubule cytoskeleton. Tau is a microtubule-associated protein that stabilizes microtubules in neurons and in cell-free systems regulates actin–microtubule interaction. Here, using super resolution microscopy, live-cell imaging, and tau knockdown, we show for the first time in living axonal growth cones that tau is important for microtubule bundling and microtubule exploration of the actin-rich growth cone periphery. Importantly tau knockdown reduced axon outgrowth and growth cone turning, due to disorganized microtubules that fail to enter filopodia and co-align with actin filaments. Understanding normal tau functions will be important for identifying mechanisms of tau in neurodegenerative diseases such as Alzheimer's.

This Week in The Journal

CD44 Signaling Mediates High Molecular Weight Hyaluronan-Induced Antihyperalgesia

We studied, in male Sprague Dawley rats, the role of the cognate hyaluronan receptor, CD44 signaling in the antihyperalgesia induced by high molecular weight hyaluronan (HMWH). Low molecular weight hyaluronan (LMWH) acts at both peptidergic and nonpeptidergic nociceptors to induce mechanical hyperalgesia that is prevented by intrathecal oligodeoxynucleotide antisense to CD44 mRNA, which also prevents hyperalgesia induced by a CD44 receptor agonist, A6. Ongoing LMWH and A6 hyperalgesia are reversed by HMWH. HMWH also reverses the hyperalgesia induced by diverse pronociceptive mediators, prostaglandin E₂, epinephrine, TNFα, and interleukin-6, and the neuropathic pain induced by the cancer chemotherapy paclitaxel. Although CD44 antisense has no effect on the hyperalgesia induced by inflammatory mediators or paclitaxel, it eliminates the antihyperalgesic effect of HMWH. HMWH also reverses the hyperalgesia induced by activation of intracellular second messengers, PKA and PKC, indicating that HMWH-induced antihyperalgesia, although dependent on CD44, is mediated by an intracellular signaling pathway rather than as a competitive receptor antagonist. Sensitization of cultured small-diameter DRG neurons by prostaglandin E₂ is also prevented and reversed by HMWH. These results demonstrate the central role of CD44 signaling in HMWH-induced antihyperalgesia, and establish it as a therapeutic target against inflammatory and neuropathic pain.

SIGNIFICANCE STATEMENT We demonstrate that hyaluronan (HA) with different molecular weights produces opposing nociceptive effects. While low molecular weight HA increases sensitivity to mechanical stimulation, high molecular weight HA reduces sensitization, attenuating inflammatory and neuropathic hyperalgesia. Both pronociceptive and antinociceptive effects of HA are mediated by activation of signaling pathways downstream CD44, the cognate HA receptor, in nociceptors. These results contribute to our understanding of the role of the extracellular matrix in pain, and indicate CD44 as a potential therapeutic target to alleviate inflammatory and neuropathic pain.

Inverted Encoding Models of Human Population Response Conflate Noise and Neural Tuning Width

Channel-encoding models offer the ability to bridge different scales of neuronal measurement by interpreting population responses, typically measured with BOLD imaging in humans, as linear sums of groups of neurons (channels) tuned for visual stimulus properties. Inverting these models to form predicted channel responses from population measurements in humans seemingly offers the potential to infer neuronal tuning properties. Here, we test the ability to make inferences about neural tuning width from inverted encoding models. We examined contrast invariance of orientation selectivity in human V1 (both sexes) and found that inverting the encoding model resulted in channel response functions that became broader with lower contrast, thus apparently violating contrast invariance. Simulations showed that this broadening could be explained by contrast-invariant single-unit tuning with the measured decrease in response amplitude at lower contrast. The decrease in response lowers the signal-to-noise ratio of population responses that results in poorer population representation of orientation. Simulations further showed that increasing signal to noise makes channel response functions less sensitive to underlying neural tuning width, and in the limit of zero noise will reconstruct the channel function assumed by the model regardless of the bandwidth of single units. We conclude that our data are consistent with contrast-invariant orientation tuning in human V1. More generally, our results demonstrate that population selectivity measures obtained by encoding models can deviate substantially from the behavior of single units because they conflate neural tuning width and noise and are therefore better used to estimate the uncertainty of decoded stimulus properties.

SIGNIFICANCE STATEMENT It is widely recognized that perceptual experience arises from large populations of neurons, rather than a few single units. Yet, much theory and experiment have examined links between single units and perception. Encoding models offer a way to bridge this gap by explicitly interpreting population activity as the aggregate response of many single neurons with known tuning properties. Here we use this approach to examine contrast-invariant orientation tuning of human V1. We show with experiment and modeling that due to lower signal to noise, contrast-invariant orientation tuning of single units manifests in population response functions that broaden at lower contrast, rather than remain contrast-invariant. These results highlight the need for explicit quantitative modeling when making a reverse inference from population response profiles to single-unit responses.

Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla

Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action. Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB₁ receptors by the acetaminophen metabolite and endocannabinoid reuptake inhibitor AM 404. However, the contribution of the cannabinoid system to antihyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB₁ receptors have remained elusive. Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent antihyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their antihyperalgesic activity in CB₁^–/– mice, confirming the involvement of the cannabinoid system. Consistent with a mechanism downstream of proinflammatory prostaglandin formation, acetaminophen also reversed hyperalgesia induced by intrathecal prostaglandin E₂. To distinguish between a peripheral/spinal and a supraspinal action, we administered acetaminophen and AM 404 to hoxB8-CB₁^–/– mice, which lack CB₁ receptors from the peripheral nervous system and the spinal cord. These mice exhibited unchanged antihyperalgesia indicating a supraspinal site of action. Accordingly, local injection of the CB₁ receptor antagonist rimonabant into the rostral ventromedial medulla blocked acetaminophen-induced antihyperalgesia, while local rostral ventromedial medulla injection of AM 404 reduced hyperalgesia in wild-type mice but not in CB₁^–/– mice. Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB₁ receptors reside in the rostral ventromedial medulla.

SIGNIFICANCE STATEMENT Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action, including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue-specific CB₁ receptor-deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.

Modulation of Ether-a-Go-Go Related Gene (ERG) Current Governs Intrinsic Persistent Activity in Rodent Neocortical Pyramidal Cells

While cholinergic receptor activation has long been known to dramatically enhance the excitability of cortical neurons, the cellular mechanisms responsible for this effect are not well understood. We used intracellular recordings in rat (both sexes) neocortical brain slices to assess the ionic mechanisms supporting persistent firing modes triggered by depolarizing stimuli following cholinergic receptor activation. We found multiple lines of evidence suggesting that a component of the underlying hyperexcitability associated with persistent firing reflects a reduction in the standing (leak) K⁺ current mediated by Ether-a-go-go-Related Gene (ERG) channels. Three chemically diverse ERG channel blockers (terfenadine, ErgToxin-1, and E-4031) abolished persistent firing and the underlying increase in input resistance in deep pyramidal cells in temporal and prefrontal association neocortex. Calcium accumulation during triggering stimuli appears to attenuate ERG currents, leading to membrane potential depolarization and increased input resistance, two critical elements generating persistent firing. Our results also suggest that ERG current normally governs cortical neuron responses to depolarizing stimuli by opposing prolonged discharges and by enhancing the poststimulus repolarization. The broad expression of ERG channels and the ability of ERG blocks to abolish persistent firing evoked by both synaptic and intracellular step stimuli suggest that modulation of ERG channels may underlie many forms of persistent activity observed in vivo.

SIGNIFICANCE STATEMENT Persistent activity, where spiking continues beyond the triggering stimulus, is a common phenomenon observed in many types of neurons. Identifying the mechanism underlying this elementary process of memory is a step forward in understanding higher cognitive function including short-term memory. Our results suggest that a reduction in the currents normally mediated by Ether-a-go-go-Related Gene (ERG) K⁺ channels contributes to persistent firing in neocortical pyramidal cells. ERG currents have been previously studied primarily in the heart; relatively little is known about ERG function in the brain, although mutations in ERG channels have recently been linked to schizophrenia. The present study is among the first to describe its role in neocortex in relation to biophysical correlates of memory function.

Tonotopic Variation of the T-Type Ca2+ Current in Avian Auditory Coincidence Detector Neurons

Neurons in avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and are characterized by striking structural variations in dendrites and axon initial segment (AIS) according to their acoustic tuning [characteristic frequency (CF)]. T-type Ca²⁺ (CaT) channels regulate synaptic integration and firing behavior at these neuronal structures. However, whether or how CaT channels contribute to the signal processing in NL neurons is not known. In this study, we addressed this issue with whole-cell recording and two-photon Ca²⁺ imaging in brain slices of posthatch chicks of both sexes. We found that the CaT current was prominent in low-CF neurons, whereas it was almost absent in higher-CF neurons. In addition, a large Ca²⁺ transient occurred at the dendrites and the AIS of low-CF neurons, indicating a localization of CaT channels at these structures in the neurons. Because low-CF neurons have long dendrites, dendritic CaT channels may compensate for the attenuation of EPSPs at dendrites. Furthermore, the short distance of AIS from the soma may accelerate activation of axonal CaT current in the neurons and help EPSPs reach spike threshold. Indeed, the CaT current was activated by EPSPs and augmented the synaptic response and spike generation of the neurons. Notably, the CaT current was inactivated during repetitive inputs, and these augmenting effects predominated at the initial phase of synaptic activity. These results suggested that dendritic and axonal CaT channels increase the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation in low-CF NL neurons.

SIGNIFICANCE STATEMENT Neurons in nucleus laminaris are binaural coincidence detectors for sound localization. We report that T-type Ca²⁺ (CaT) current was prominent at dendrites and the axonal trigger zone in neurons tuned to low-frequency sound. Because these neurons have long dendrites and a closer trigger zone compared with those tuned to higher-frequency sound, the CaT current augmented EPSPs at dendrites and accelerated spike triggers in the neurons, implying a strategic arrangement of the current within the nucleus. This effect was limited to the onset of repetitive inputs due to progressive inactivation of CaT current. The results suggested that the CaT current increases the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation of low-frequency sound.

Disrupted Neuroglial Metabolic Coupling after Peripheral Surgery

Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction.

SIGNIFICANCE STATEMENT A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.

The Mouse Pulvinar Nucleus Links the Lateral Extrastriate Cortex, Striatum, and Amygdala

The pulvinar nucleus is a large thalamic structure involved in the integration of visual and motor signals. The pulvinar forms extensive connections with striate and extrastriate cortical areas, but the impact of these connections on cortical circuits has not previously been directly tested. Using a variety of anatomical, optogenetic, and in vitro physiological techniques in male and female mice, we show that pulvinocortical terminals are densely distributed in the extrastriate cortex where they form synaptic connections with spines and small-diameter dendrites. Optogenetic activation of these synapses in vitro evoked large excitatory postsynaptic responses in the majority of pyramidal cells, spiny stellate cells, and interneurons within the extrastriate cortex. However, specificity in pulvinar targeting was revealed when recordings were targeted to projection neuron subtypes. The neurons most responsive to pulvinar input were those that project to the striatum and amygdala (76% responsive) or V1 (55%), whereas neurons that project to the superior colliculus were rarely responsive (6%). Because the pulvinar also projects directly to the striatum and amygdala, these results establish the pulvinar nucleus as a hub linking the visual cortex with subcortical regions involved in the initiation and control of movement. We suggest that these circuits may be particularly important for coordinating body movements and visual perception.

SIGNIFICANCE STATEMENT We found that the pulvinar nucleus can strongly influence extrastriate cortical circuits and exerts a particularly strong impact on the activity of extrastriate neurons that project to the striatum and amygdala. Our results suggest that the conventional hierarchical view of visual cortical processing may not apply to the mouse visual cortex. Instead, our results establish the pulvinar nucleus as a hub linking the visual cortex with subcortical regions involved in the initiation and control of movement, and predict that the execution of visually guided movements relies on this network.

Zinc Inhibits TRPV1 to Alleviate Chemotherapy-Induced Neuropathic Pain

Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1.

SIGNIFICANCE STATEMENT The chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.

The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization

UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs). However, the underlying cellular and molecular neurobiology remains less clear. Here we report the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites. This remodeling effect is mediated by the ubiquitination and degradation of XIAP (X-linked inhibitors of aptosis protein) by E6AP, which leads to activation of caspase-3 and cleavage of microtubules. In vivo, male and female Ube3A 2X ASD mice show decreased XIAP levels, increased caspase-3 activation, and elevated levels of tubulin cleavage. Consistently, dendritic branching and spine density are reduced in cortical neurons of Ube3A 2X ASD mice. In revealing an important role for Ube3A/E6AP in ASD-related developmental alteration in dendritic arborization and synapse formation, our findings provide new insights into the pathogenesis of Ube3A/E6AP-dependent ASD.

SIGNIFICANCE STATEMENT Copy number variation of the UBE3A gene and aberrant overexpression of the gene product E6AP protein is a common cause of autism spectrum disorders (ASDs). During brain development, dendritic growth and remodeling play crucial roles in neuronal connectivity and information integration. We found that in primary neurons and in Ube3A transgenic autism mouse brain, overexpression of E6AP leads to significant loss of dendritic arborization. This effect is mediated by the ubiquitination of XIAP (X-linked inhibitor of aptosis protein) by E6AP, subsequent activation of caspases, and the eventual cleavage of microtubules, leading to local degeneration and retraction at the tips of dendritic branches. These findings demonstrate dysregulation in neuronal structural stability as a major cellular neuropathology in ASD.

Chronisch spontane Urtikaria

Operative Behandlungsoptionen bei Hidradenitis suppurativa/Acne inversa

Zusammenfassung

Hidradenitis suppurativa/Acne inversa (HS/AI) ist eine chronisch inflammatorische Hauterkrankung, für deren Behandlung konservative und operative Therapieoptionen zur Verfügung stehen. Im Hurley-Stadium II und III stellt die operative Sanierung von irreversibel destruiertem Gewebe die Methode der Wahl dar. Resektionstechniken unterschiedlicher Invasivität werden in der Literatur beschrieben. Bisher herrscht kein allgemein akzeptierter Konsens über den Einsatz verschiedener Resektions- und Rekonstruktionstechniken sowie die postoperative Nachbehandlung. Die Beurteilung von Rezidiven nach chirurgischer Intervention wird durch fehlende Rezidivdefinitionen sowie eine heterogene Studienlage erschwert.

Panorama Dermatologische Praxis

Allergen Concerns and Popular Skin Care Products

To the Editor We read with great interest the article by Xu et al published in a recent issue of JAMA Dermatology highlighting the high prevalence of contact allergens in common moisturizers. Their data mirror similar results in our recent study investigating contact allergens in pediatric personal care products marketed as hypoallergenic, dermatologist recommended and/or tested, fragrance free, or paraben free. Similar to the study by Xu et al, which found that 88% of common moisturizers contained at least 1 common contact allergen, we found that 167 of 187 of our selection of pediatric products (89%) contained at least 1 allergen.

Vegetating Darier Disease Treated With Botulinum Toxin

This case report describes a patient with vegetating Darier disease treated with botulinum toxin.

Dermatology Practice Consolidation Fueled by Private Equity Investment

This Viewpoint discusses the consolidation of dermatology practices facilitated by private equity investment and the potential consequences for the specialty and patients.

Dermatology’s Grandest Piano

This is a story about a piano that played a small but special role in dermatology's history. It belonged to Stephen Rothman, MD (1894-1963), one of the most influential dermatologists of the 20th century. He was also an accomplished pianist.

The Importance of Population-Based Estimates of Melanocytic Pathology

In this issue of JAMA Dermatology, Lott et al describe a novel and innovative approach to estimating the prevalence of different types of melanocytic lesions in all adults undergoing skin biopsies in a population. Using an automated natural language processing tool, they analyzed 80 368 written pathology reports of skin biopsies from 47 529 adult patients drawn from an underlying health system patient population, which was representative of the general adult population. For analysis of each pathology report, the diagnosis was first dichotomized as either a melanocytic or nonmelanocytic lesion. For melanocytic lesions, the cases were then assigned to 1 of 4 diagnostic categories based on the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx), with differing management implications: class I, benign lesion requiring no further treatment; class II, low-risk lesion requiring complete excision with narrow (<5-mm) margins; class III, higher-risk lesion such as melanoma in situ requiring reexcision with 5-mm to 1-cm margins; and class IV/V, invasive melanoma requiring wide reexcision with 1-cm margins or greater. Approximately one-quarter of all skin biopsies were of melanocytic lesions. Of these, over 90% were benign or low risk (class I or II); 4.5% were melanoma in situ or similar-risk lesion (class III); and 4.1% were invasive melanoma (class IV/V).

Hair Repigmentation With Anti–PD-1 and Anti–PD-L1 Immunotherapy

To the Editor We read with great interest the article by Rivera and colleagues reporting on hair repigmentation in patients receiving immunotherapy with anti–programmed cell death 1 (PD-1) and anti–programmed cell death 1 ligand 1 (PD-L1) immunotherapy.

Population-Based Frequencies and Distribution of Melanocytic Lesions

This large-scale analysis of pathology reports in electronic medical records, using the natural language processing technique, evaluates population-based distributions and pathologic characteristics of melanocytic proliferations.

Spanish Fly—Cantharidin’s Alter Ego

Cantharidin, derived from the Greek word for beetle, kantharis, is an odorless, colorless terpenoid produced by up to 2000 species of beetles collectively referred to as blister beetles. Male blister beetles synthesize and use cantharidin as a defensive chemical and nuptial gift. Females receive cantharidin during mating and use the compound to coat their eggs to ward off predators. It functions as a potent vesicant on skin contact, but it is also a systemic poison if ingested, with toxic effects comparable with those of strychnine and cyanide. If properly dosed and applied, however, its blistering properties can be used therapeutically.

Geographic Distribution of Nonphysicians Who Billed Medicare for Dermatologic Services

This study uses Medicare and US Census data to discover which dermatology-related services are independently billed by nonphysician clinicians treating Medicare beneficiaries, and where these clinicians are located.

Topical Timolol for Paronychia and Pseudopyogenic Granuloma

This study evaluated the efficacy and tolerability of topical timolol, 0.5%, gel as a treatment of paronychia and pseudopyogenic granuloma induced by antineoplastic agents.

Probiotic Strains for Children With Moderate Atopic Dermatitis

This randomized clinical trial investigates whether a mixture of oral probiotics is safe and effective in the treatment of atopic dermatitis symptoms and evaluates its influence on the use of topical steroids in children.

Treatment of Refractory Mycosis Fungoides With Brentuximab Vedotin

This case report describes the treatment of CD30-negative refractory mycosis fungoides with brentuximab vedotin.

Factors Associated With Remission of Skin Disease in Dermatomyositis

This cohort study examines factors associated with clinical remission of skin disease in dermatomyositis.

Hair Repigmentation With Anti–PD-1 and Anti–PD-L1 Immunotherapy—Reply

In Reply We read with interest the letter by Manson et al. They describe another case of hair repigmentation (HR) in a male patient with concomitant advanced colorectal cancer and Hodgkin lymphoma treated with nivolumab and showing a good response. Interestingly, this new case seems to support the association between a good response and HR.

Preference-Based QOL Measures for Economic Evaluations in Early Melanoma

This study uses randomized clinical trial data to compare utility scores from the AQoL-8D and the FACT-M and evaluate the sensitivity of both instruments in identifying the influence of fear of cancer recurrence on health-related quality of life in patients with early-stage melanoma.

Error in Figure Legend

In the article titled "Factors Associated With Clinical Remission of Skin Disease in Dermatomyositis" by Wolstencroft et al, published online November 7, 2017, there was an error in the key for Figure 1B. This article was corrected online.

Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients

This cohort study addresses whether current skin surveillance intervals and threshold for biopsy of suspicious lesions are adequate for the increased tendency of solid organ transplant recipients to develop potentially aggressive cutaneous squamous cell carcinomas.

Sporty Spots

During the 2016 summer Olympic Games in Rio de Janeiro, Brazil, many viewers questioned the origins of the purple spots seen on US swimmer Michael Phelps during a relay event. Similarly, in recent years public attention has been drawn to the tell-tale circular markings on various other celebrities' bodies, including Justin Bieber, Jennifer Aniston, and Gwyneth Paltrow. The origin of these markings is an ancient practice called "cupping," which uses suction to attach a cup to skin for purported therapeutic benefit. In recent times, the practice has been popularized in the United States as a form of complementary and alternative medicine (CAM) practice.

Tanning Salon Compliance in States With Legislation to Protect Youth Access

This cross-sectional telephone survey investigates compliance rates in the 42 states and the District of Columbia with legislation restricting tanning bed use in minors.

January 2018 Issue Highlights

A Comparative Evaluation of Changes in Soft Tissues After Single-Jaw Surgery and Bimaxillary Surgery in Skeletal Class III Patients

Abstract

Aims and Objectives

The aim of this study was to compare cephalograms for the hard and soft tissue changes observed in skeletal Class III patients of Indian origin who had undergone either single-jaw mandibular setback (BSSO) or bimaxillary surgery (Le Fort I advancement + BSSO setback) and also to derive a correlation between the changes brought about in the soft tissues by the surgical alteration in hard tissue.

Materials and Methods

The study included records comprising 18 treated skeletal Class III patients, who were divided into two groups based on the surgical procedures advocated: Group I: single-jaw procedure comprised of only mandibular set back, Group II: bimaxillary surgery. Presurgical and post-treatment cephalograms were calibrated and traced using Ilexis FACAD AB-2014 Version 3.8.0.0 software and analyzed with COGS hard tissue analysis and soft tissue analysis. All values for the hard tissue and soft tissue measurements were compared with the norms prescribed for the Indian population.

Results

Upper lip changes were evident in both groups but greater significance was observed in bi-jaw group. Single-jaw patients showed positive correlation for hard to soft tissue mandibular position. Bi-jaw surgical cases exhibited positive correlations between changes Wits variable to soft tissue convexity as well as mandibular position.

Conclusion

The soft tissues changes between Class III patients treated by single-jaw surgery and those treated by bimaxillary surgery when compared revealed that significant differences were observed only in relation to certain measurements such as facial convexity, maxillary prognathism, and upper lip protrusion.

To B- or not to B- a relation

Abstract

In his seminal work, McTaggart (Mind 17(68):457–484, 1908; The nature of existence, Cambridge University Press, Cambridge, 1927) dismissed the possibility of understanding the B-Relations (earlier than, simultaneity, and later than) as irreducibly temporal relations, and with it dismissing the B-Theory of time, which assumes the reality of irreducible B-relations. Instead, he thought they were mere constructions from irreducible A-determinations (pastness, presentness, and futurity) and timeless ordering relations (his C-Relations). However, since, philosophers have almost universally dismissed his dismissal of irreducible B-relations. This paper argues that McTaggart was correct to dismiss the possibility of B-relations, and that would be B-theorists should be C-theorists and its concomitant commitment to the unreality of time. I do this by first elaborating C-Theory, noting that B-relations appear indiscernible from C-relations on close examination. This establishes an onus on B-theorists to distinguish B-relations from C-relations by elaborating the distinctively temporal character of the former. I then present a problem for the possibility of accommodating temporal character in B-relations. Following this, I question from whence derives our sense of the temporal character that purportedly resides in the irreducible B-relations. Finally, I extend the challenge against irreducible B-relations to a series of irreducible abstract temporal relations—so called Ersatz-B-Relations—modelled on them.

Einfluss onkogener Viren beim oralen Plattenepithelkarzinom

Zusammenfassung

Hintergrund

Ausgelöst durch die nun mittlerweile routinemäßige Bestimmung des Humanen Papillomavirus (HPV) beim Oropharynxkarzinom rücken onkogene Viren als Ko- oder singuläres Karzinogen in den Fokus der personalisierten Medizin. Es scheint nun Konsens darüber zu bestehen, dass die viralen onkogenen Eigenschaften des HPV auch bei bestimmten Kopf-Hals-Karzinomen ätiologisch bedeutsam sind. Hierbei spielen Lokalisation des Primärtumors und Nachweismethoden (Immunhistochemie [ICH] vs. Polymerase-Kettenreaktion [PCR] und In-Situ-Hybridisierung [ISH]) eine essenzielle Rolle. Kontrollstudien und Metaanalysen deuten darauf hin, dass bei ca. 6–25 % der oralen Plattenepithelkarzinome (OSCC) eine zusätzliche HPV-Infektion vorliegt. Bezüglich der anderen potenziellen Onkogene Epstein-Barr-Virus (EBV) und Herpes-Simplex-Typ 1-(HSV-1) sind die ätiologischen Erkenntnisse beim oralen Karzinom wesentlich fraglicher.

Methoden

Im Rahmen eines Literaturüberblicks werden die aktuell gesicherten Erkenntnisse auf tierexperimenteller und humaner Studienbasis für HPV, HSV und EBV dargestellt. Diese werden unter dem Gesichtspunkt eines möglichen ätiologischen und prognostischen Einflusses auf das OSCC bewertet.

Schlussfolgerungen

Möglicherweise spielt eine gesicherte HPV-Infektion mit den High-Risk-Subtypen 16 und 18 eine zusätzliche Rolle, wesentlich ist aber, dass gleichzeitig bekannte Noxen wie Nikotin hinsichtlich der Ätiologie definitiv überwiegen. HPV-16 ist der wichtigste Subtyp im Zusammenhang mit dem OSCC. Bei oropharyngealen oder Tonsillenkarzinomen stellt eine Infektion mit den HPV-High-Risk-Subtypen 16 und 18 dagegen ein eigenes Subkollektiv dar, für das therapeutische Modifikationen denkbar sind. Beim HSV-1 und EBV sind ätiologische Erkenntnisse in Bezug auf das OSCC sehr fraglich. Bei der HSV-1-Infektion könnte eine kokarzinogene Komponente vor allem in Kombination mit HPV-16 vorliegen, während dies beim EBV höchstwahrscheinlich vernachlässigt werden kann. Dagegen ist eine Koinfektion mit mehreren onkogenen Viren gesichert als Risikofaktor anzusehen, wobei die Gewichtung des Einflusses einzelner onkogener Viren unklar ist. Während die PCR das derzeit sensitivste Verfahren zum HPV-Nachweis darstellt, kann die IHC zu falsch-positiven Resultaten führen.

The Association Between Serum Vaspin and Omentin-1 Levels in Obese Children with Metabolic Syndrome

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.

In Vivo and Ex Vivo Inflammatory Markers of Common Metabolic Phenotypes in Humans

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.

Interaction of Metabolic Health and Obesity on Subclinical Target Organ Damage

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.

Performance of ceramic ultrafiltration and reverse osmosis membranes in treating car wash wastewater for reuse

Abstract

Reusing treated effluents in industries is a great option to conserve freshwater resources. For example, car wash centres all over Australia are estimated to use 17.5 billion litres of water and discharge it as wastewater and spend $75 million a year for both purchasing fresh water and for treating and/or discharging the wastewater. Therefore, it is important to develop simple but reliable systems that can help to treat and reuse car wash wastewater. Significant savings could also be associated with the implementation of such systems. This study evaluates the performance of granular and membrane filtration systems with coagulation/flocculation and sedimentation in treating car wash wastewater for the purpose of reuse. Overall, 99.9% of turbidity, 100% of suspended solids and 96% of COD were removed from the car wash wastewater after treating by coagulation, flocculation, sedimentation, sand filtration, ceramic ultrafiltration and reverse osmosis and the treated water meets the standards required for class A recycled water in Australia and standards imposed in Belgium and China. The treated water can be reused. However, optimisation is required to reduce the sludge produced by this system.

Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: polychlorinated biphenyls as an example

Abstract

Toxicological studies use "specialty chemicals" and, thus, should assess and report both identity and degree of purity (homogeneity) of the chemicals (or toxicants) under investigation to ensure that other scientists can replicate experimental results. Although detailed reporting criteria for the synthesis and characterization of organic compounds have been established by organic chemistry journals, such criteria are inconsistently applied to the chemicals used in toxicological studies. Biologically active trace impurities may lead to incorrect conclusions about the chemical entity responsible for a biological response, which in turn may confound risk assessment. Based on our experience with the synthesis of PCBs and their metabolites, we herein propose guidelines for the "authentication" of synthetic PCBs and, by extension, other organic toxicants, and provide a checklist for documenting the authentication of toxicants reported in the peer-reviewed literature. The objective is to expand guidelines proposed for different types of biomedical and preclinical studies to include a thorough authentication of specialty chemicals, such as PCBs and their derivatives, with the goal of ensuring transparent and open reporting of scientific results in toxicology and the environmental health sciences.

Characterization of ectopic lymphoid structures in different types of acute renal allograft rejection

Summary

Background: We hypothesize that T cells such as IL-21+BCL6+ T follicular helper cells can regulate B cell mediated immunity within the allograft during acute T-cell mediated rejection, this process may feed chronic allograft rejection on long term. To investigate this mechanism we determined the presence and activation status of organized T and B cells in so-called ectopic lymphoid structures (ELSs) in different types of acute renal allograft rejection.

Methods: Biopsies showing the following primary diagnosis were included: acute/active antibody-mediated rejection, C4d+ (a/aABMR), acute T cell-mediated rejection grade I (aTCMRI), and acute T cell-mediated rejection grade II (aTCMRII). Paraffin sections were stained for T cells (CD3 and CD4), B cells (CD20), follicular dendritic cells (FDCs, CD23), activated B cells (CD79A), immunoglobulin D (IgD), cell proliferation (Ki67), and double immunofluorescent stainings for IL-21 and BCL6 were performed.

Results: Infiltrates of T cells were detected in all biopsies. In aTCMRI, B cells formed aggregates surrounded by T cells. In these aggregates, FDCs, IgD and Ki67 were detected, suggesting the presence of ELSs. In contrast, a/aABMR and aTCMRII showed diffuse infiltrates of T and B cells but no FDCs and IgD. IL-21 was present in all biopsies. However, co-localization with BCL6 was mainly observed in aTCMRI biopsies.

Conclusion: ELSs with an activated phenotype are predominantly found in aTCMRI where T cells co-localize with B cells. These findings suggest a direct pathway of B cell allo-activation at the graft site during T cell mediated rejection. This article is protected by copyright. All rights reserved.

Phototoxic drug reaction with the novel agent rovalpituzumab tesirine

Decision support system for management of reactive nitrogen flows in wastewater system

Abstract

The change in nitrogen balance causes many environmental and socioeconomic impacts. In relation to food production and nitrogen release in wastewater systems, wastewater and sludge discharge and mineral fertilizer use intensify nitrogen imbalance of a region. The replacement of mineral fertilizer by nitrogen from treated wastewater, biosolids, and treated urine is a promising alternative. This work presents a model to support decision taking for the management of reactive nitrogen flows in wastewater systems based on system dynamics. Six scenarios were simulated for nitrogen flows in wastewater systems and related components.

The Boomerang-shaped Pectoralis Major Musculocutaneous Flap for Reconstruction of Circular Defect of Cervical Skin

Summary: We report on a patient with a recurrence of oral cancer involving a cervical lymph node. The patient's postexcision cervical skin defect was nearly circular in shape, and the size was about 12 cm in diameter. The defect was successfully reconstructed with a boomerang-shaped pectoralis major musculocutaneous flap whose skin paddle included multiple intercostal perforators of the internal mammary vessels. This flap design is effective for reconstructing an extensive neck skin defect and enables primary closure of the donor site with minimal deformity.

Strategy for Nasal Reconstruction in Atypical Facial Clefts

Summary: It is difficult to put forward a strategy for the treatment of nasal clefts due to the rarity and diversity of anatomical aberrations of these cases contrary to the common nasal affection in cleft lip and palate patients, which differ in severity rather than differing in the morbid anatomy. This simple strategy for correction of these nasal clefts will hopefully help surgeons to achieve better results. In the mean time I intended to describe the morbid anatomy of these cases by choosing examples of each morbid anatomy.

The science behind skin care: Moisturizers

Summary

Moisturizers provide functional skin benefits, such as making the skin smooth and soft, increasing skin hydration, and improving skin optical characteristics; however, moisturizers also function as vehicles to deliver ingredients to the skin. These ingredients may be vitamins, botanical antioxidants, peptides, skin-lightening agents, botanical anti-inflammatories, or exfoliants. This discussion covers the science of moisturizers.

Does ALK-rearrangement predict favorable response to the therapy of bevacizumab plus pemetrexed in advanced non-small-cell lung cancer? Case report and literature review

Advanced ALK-rearranged non-small cell lung cancer (NSCLC) patients will develop acquired resistance after anaplastic lymphoma kinase (ALK) inhibitors therapies. Vascular endothelial growth factor-A (VEGF-A) p...

Daylight Photodynamic Therapy Versus 5-Fluorouracil for the Treatment of Actinic Keratosis: A Case Series

Abstract

Introduction

The incidence of actinic keratosis (AK) continues to increase worldwide. Currently available options for the treatment of AK include topical 5-fluorouracil (5-FU) and daylight-mediated photodynamic therapy (DL-PDT). This split-face pilot study compared DL-PDT using 16% methyl aminolevulinate (MAL) cream versus 5-FU cream in patients with AK on the face/scalp.

Methods

Five male subjects (mean age 70 years) with grade I–III AK on the face/scalp were enrolled. Subjects received a single session of DL-PDT with 16% MAL on one side and topical 5% 5-FU for 21 days on the other side. Evaluations of efficacy, safety, and subject satisfaction were conducted 48 h, 7 days, 14 days, 1 month, and 3 months after treatment.

Results

At 3 months, the lesion complete response rate was 80% and 93% for DL-PDT and 5-FU, respectively. Lesion partial response was 20% and 7%, respectively. Fewer treatment-related adverse events (AEs) were reported with DL-PDT than with 5-FU, and they resolved spontaneously in 5–7 and 27–30 days, respectively. Subjects preferred DL-PDT because of the lower incidence of AEs and rapid recovery compared with 5-FU.

Conclusion

DL-PDT is a convenient alternative to 5-FU with good efficacy and a favorable safety profile, allowing patients to effectively treat their AK without compromising their social life.

Funding

Galderma.

Malignancy-associated generalized perforating granuloma annulare

Oxidative burst and Dectin-1 triggered phagocytosis affected by Norepinephrine and Endocannabinoids - Implications for fungal clearance under stress

Abstract

A prolonged stress burden is known to hamper the efficiency of both the innate and adaptive immune systems and to attenuate the stress responses by the catecholaminergic and endocannabinoid (EC) systems. Key mechanisms of innate immunity are the eradication of pathogens through phagocytosis and the respiratory burst. We tested the concentration-dependent, spontaneous and stimulated (via TNFα and fMLP) release of reactive oxygen species (ROS) by human PMNs in vitro in response to norepinephrine (NE) and AM1241, a pharmacological ligand for the endocannabinoid receptor CB₂. We evaluated phagocytosis of Dectin-1 ligating zymosan particles and tested the cytokine response against Candida antigen in an in vitro cytokine release assay. Increasing concentrations of NE did not affect phagocytosis, yet stimulated ROS release was attenuated gradually reaching maximum suppression at 500nM. Adrenergic receptor (AR) mechanisms using non-AR-selective (labetalol) as well as specific α–(prazosin) and β–(propranolol) receptor antagonists were tested. Results show that only labetalol and propranolol were capable to recuperate cytotoxicity in the presence of NE, evidencing a β-receptor mediated effect. The CB₂ agonist, AM1241, inhibited phagocytosis at 10μM and spontaneous peroxide release by PMNs. Use of the inverse CB₂ receptor agonist SR144528 led to partial recuperation of ROS production, confirming the functional role of CB₂. Additionally, AM1241 delayed early activation of monocytes and induced suppression of IL-2 and IL-6 levels in response to Candida via lower activity of mTOR. These findings provide new insights into key mechanisms of innate immunity under stressful conditions where ligands to the sympatho-adrenergic and endocannabinoid system are released.

Erratum à « Le lifting cervical : évolutions récentes » [Annales de chirurgie plastique esthétique 2017;62:461–73. DOI: 10.1016/j.anplas.2017.08.002]

Publication date: Available online 9 January 2018
Source:Annales de Chirurgie Plastique Esthétique
Author(s): D. Labbé, P. Guerreschi

Effective debridement with micro water jet technology (MWT): A retrospective clinical application observation of 90 patients with acute and chronic wounds

Publication date: Available online 9 January 2018
Source:Wound Medicine
Author(s): M. Reber, P. Nussbaumer
ObjectiveThis retrospective clinical application observation study shall demonstrate the effect of a wound debridement using micro water jet technology (MWT) as an efficient method promoting wound healing. The final goal is to accomplish a decrease in wound size (reepithelization) due to debridement with MWT. Through the application of MWT, the wound shall receive a healing stimulus. Besides the use of MWT, there are other water-based cleaning/rinsing systems available.MethodFrom two wound care centers (Kantonsspital Obwalden, Spital Lachen), all data from patients treated with MWT and different types of wound, over a time period of 3 years, were retrospectively analyzed. All patients, except one, could be treated in an outpatient setting. Fewest of the patients did receive a local anesthetic. Included were all patients, independent from gender and age.ResultsThe retrospective data analysis was carried out on 90 patients (46 m/44 f) with an average age of 68.5 years (17/93 years) and a total of 95 different wounds. 58 wounds were completely closed at exit from the wound care center within a median treatment time of 59 days (8.4 weeks). The average treatment time for all 95 wounds was 39 days (5.6 weeks) per wound at the end of debridement, the average wound size 6.1 cm². The reduction of healing time compared to traditional methods was approximately 30%.ConclusionThe result of the retrospective data analysis on patients with predominantly chronic and persistent wounds shows that debriding with micro water jet technology is an efficient, tissue-preserving, precise and time-saving method for outpatient wound care – with excellent healing outcomes. Patient safety was high and we have seen no adverse effects. The MWT is comparable to other water jet-based cleaning/rinsing systems.

Ampliando el perfil genético del síndrome de Hay-Wells

Publication date: Available online 9 January 2018
Source:Actas Dermo-Sifiliográficas
Author(s): D. Romero-Pérez, B. Encabo-Durán, R. Ramón-Sapena

Facilitators and Barriers to Disclosure of Postpartum Mood Disorder Symptoms to a Healthcare Provider

Abstract

Objectives This study explored perceived barriers and facilitators to disclosure of postpartum mood disorder (PPMD) symptoms to healthcare professionals among a community-based sample. Methods A sample of predominantly white, middle class, partnered, adult women from an urban area in the southeast United States (n = 211) within 3 years postpartum participated in an online survey including the Perceived Barriers to Treatment Scale, the Maternity Social Support Scale, the Depression, Anxiety and Stress Scales-21, and items querying PPMD disclosure. Perceived barriers were operationalized as factors, from the patient's perspective, that impede or reduce the likelihood of discussing her postpartum mood symptoms with a healthcare provider. Analyses examined: (1) characteristics associated with perceived barriers; (2) characteristics associated with perceived social support; and (3) characteristics, perceived barriers, and perceived social support as predictors of disclosure. Results Over half of the sample reported PPMD symptoms, but one in five did not disclose to a healthcare provider. Approximately half of women reported at least one barrier that made help-seeking "extremely difficult" or "impossible." Over one-third indicated they had less than adequate social support. Social support and stress, but not barriers, were associated with disclosure in multivariable models. Conclusions for Practice Many women experiencing clinically-significant levels of distress did not disclose their symptoms of PPMD. Beyond universal screening, efforts to promote PPMD disclosure and help-seeking should target mothers' social support networks.

The Association Between Preconception Care Receipt and the Timeliness and Adequacy of Prenatal Care: An Examination of Multistate Data from Pregnancy Risk Assessment Monitoring System (PRAMS) 2009–2011

Abstract

Objectives Prenatal care (PNC) is a critical preventive health service for pregnant women and infants. While timely PNC has been associated with improved birth outcomes, improvements have slowed since the late 1990s. Therefore, focus has shifted to interventions prior to pregnancy. Preconception care is recommended for all women of reproductive age. This study aimed to examine preconception care and its association with timeliness and adequacy of PNC. Methods This retrospective cohort study used data from a large sample of United States first-time mothers (n = 13,509) who participated in the 2009–2011 Pregnancy Risk Assessment Monitoring System in ten states. Timeliness and adequacy of PNC data came from birth certificates, while preconception care receipt was self-reported. Logistic regression provided odds ratios (ORs) and 95% confidence intervals (CIs) to model the association between preconception care receipt and the two PNC outcomes. Results After adjustment, women who received preconception care had statistically significant increased odds of timely (OR 1.30, 95% CI 1.08, 1.57), but not adequate PNC (OR 1.08, 95% CI 0.94, 1.24) as compared to women who did not receive preconception care. Pregnancy intention modified these associations. Associations were strongest among women with intended pregnancies (timely PNC: OR 1.63 and adequate PNC: OR 1.22). Conclusions for Practice Given that untimely PNC is associated with adverse birth outcomes, the observed association warrants increased focus on implementing preconception care. Future studies should investigate how specific components of preconception care are associated with PNC timeliness/adequacy, health behaviors during pregnancy, and birth outcomes.

Adolescent Reproductive and Contraceptive Knowledge and Attitudes and Adult Contraceptive Behavior

Abstract

Objectives Ineffective and inconsistent contraceptive use is common among adults, perhaps due to limited knowledge about reproduction and unfavorable attitudes toward contraception. Knowledge and attitudes are first developed in adolescence. We test whether adolescent knowledge and attitudes have long-term implications for adult contraceptive behavior. Methods Using the National Longitudinal Survey of Adolescent to Adult Health, our analytical sample (n = 6662) consists of those asked sex and contraception questions at Wave I (1995; students aged 15 and older) and who were sexually active and not pregnant at the time of the Wave IV (2007–2008) survey. We examined whether adolescent attitudes toward contraception, knowledge of condoms and reproduction, and confidence in contraceptive knowledge were predictive of adult contraceptive efficacy and consistency using logistic regression. Results In models adjusted for a range of socioeconomic, demographic, and life course factors, favorable attitudes toward contraception in adolescence increased the odds (aOR 1.21, CI 1.08–1.36) of using more effective methods rather than a less effective or no method of contraception in adulthood, as did more accurate condom knowledge (aOR 1.07, CI 1.00-1.14) and more accurate reproductive knowledge (aOR 1.07, CI 1.00-1.13). Adolescents with more favorable attitudes toward contraception also used contraception more consistently as adults (aOR 1.27, CI 1.14–1.43), as did those with more accurate condom knowledge (aOR 1.10, CI 1.03–1.18). Conclusions Attitudes towards contraception and knowledge about condoms and reproduction acquired during adolescence are predictive of adult contraceptive behavior. Results suggest that comprehensive sex education during adolescence could improve effective contraceptive behavior throughout the life course.

Associations Between Peer Counseling and Breastfeeding Initiation and Duration: An Analysis of Minnesota Participants in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC)

Abstract

Background Peer counseling (PC) has been associated with increased breastfeeding initiation and duration, but few analyses have examined the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) model for peer counseling or the continuation of breastfeeding from birth through 12 months postpartum. Objectives Identify associations between Minnesota WIC Peer Breastfeeding Support Program services and breastfeeding initiation and continuation. Methods Retrospective analysis of observational data from the Minnesota WIC program's administrative database of women who gave birth in 2012 and accepted a PC program referral prenatally (n = 2219). Multivariate logistic regression and Cox regression models examined associations between peer services and breastfeeding initiation and continuation of any breastfeeding. Results Among women who accepted referral into a PC program, odds of initiation were significantly higher among those who received peer services (Odds Ratio (OR): 1.66; 95% CI 1.19–2.32), after adjusting for confounders. Women who received peer services had a significantly lower hazard of breastfeeding discontinuation from birth through 12 months postpartum than women who did not receive services. (Hazard Ratio (HR) month one: 0.45; 95% CI 0.33–0.61; months two through twelve: 0.33; 95% CI 0.18–0.60). The effect of peer counseling did not differ significantly by race and ethnicity, taking into account mother's country of origin. Conclusion for practice Receipt of peer services was positively associated with breastfeeding initiation and continued breastfeeding from birth through 12 months postpartum. Making peer services available to more women, especially in communities with low initiation and duration, could improve maternal and child health in Minnesota.

Assessing the Risk of Having Small for Gestational Age Newborns Among Lebanese Underweight and Normal Pre-pregnancy Weight Women

Abstract

Introduction It has been established that underweight women with low gestational weight gain (GWG) are at a higher risk of having Small for Gestational Age (SGA) newborns. However, the association remains poorly studied in Middle Eastern societies exhibiting different ethnic groups, genetic predisposing factors along with differences in nutritional food intake during pregnancy. The aim of this study is to assess the risk of having a SGA newborn among underweight and normal weight BMI women while studying the role of GWG in this association. Methods This is a retrospective cross-sectional study of 62,351 singleton pregnancies from the National Collaborative Perinatal Neonatal Network between 2001 and 2009 from 27 hospitals across Lebanon. Women who had underweight and normal pre-pregnancy BMI were included. Results A total of 8.6% newborns were SGA and 6.6% of women were underweight. Among women with normal and underweight pre-pregnancy BMI, 8.6 and 12.4% had SGA births respectively. Overall, the adjusted OR of having SGA newborns was significantly higher among underweight women (OR = 1.448; 95%CI = 1.287–1.630) compared to normal pre-pregnancy BMI. Below normal weight gain significantly increased the odds of SGA for both normal and underweight pre-pregnancy BMI women, with adjusted ORs of 1.535 (95% CI = 1.418–1.661) and 1.970 (95%CI = 1.515–2.560) respectively. Discussion Higher risks of SGA newborns in underweight and normal BMI women with low GWG were observed. In addition, normal weight gain couldn't protect underweight women of having risk for SGA newborns. Hence, all pregnant women should be encouraged to maintain healthy BMI before pregnancy and attain adequate GWG.

Travel Time to Hospital for Childbirth: Comparing Calculated Versus Reported Travel Times in France

Abstract

Objectives Timely access to health care is critical in obstetrics. Yet obtaining reliable estimates of travel times to hospital for childbirth poses methodological challenges. We compared two measures of travel time, self-reported and calculated, to assess concordance and to identify determinants of long travel time to hospital for childbirth. Methods Data came from the 2010 French National Perinatal Survey, a national representative sample of births (N = 14 681). We compared both travel time measures by maternal, maternity unit and geographic characteristics in rural, peri-urban and urban areas. Logistic regression models were used to study factors associated with reported and calculated times ≥30 min. Cohen's kappa coefficients were also calculated to estimate the agreement between reported and calculated times according to women's characteristics. Results In urban areas, the proportion of women with travel times ≥30 min was higher when reported rather than calculated times were used (11.0 vs. 3.6%). Longer reported times were associated with non-French nationality [adjusted odds ratio (aOR) 1.3 (95% CI 1.0–1.7)] and inadequate prenatal care [aOR 1.5 (95% CI 1.2–2.0)], but not for calculated times. Concordance between the two measures was higher in peri-urban and rural areas (52.4 vs. 52.3% for rural areas). Delivery in a specialised level 2 or 3 maternity unit was a principal determinant of long reported and measured times in peri-urban and rural areas. Conclusions for Practice The level of agreement between reported and calculated times varies according to geographic context. Poor measurement of travel time in urban areas may mask problems in accessibility.

Breastfeeding and Exposure to Past, Current, and Neighborhood Violence

Abstract

Objectives Breastfeeding has short- and long-term health benefits for children and mothers, but US breastfeeding rates are suboptimal. Exposure to violence may contribute to these low rates, which vary by race/ethnicity. We studied: (1) whether patterns of violence exposure differ by race/ethnicity and (2) whether these patterns are associated with breastfeeding outcomes. Methods We conducted a secondary analysis of data drawn from self-report surveys completed by a convenience sample of low-income postpartum women (n = 760) in upstate New York. Latent class analysis was used to identify groups of women with similar responses to seven violence measures, including childhood physical and/or sexual violence, experience of partner violence during or just after pregnancy (physical, emotional, verbal), and neighborhood violence (perceived or by ZIP code). Logistic regression and survival analysis were utilized to determine if classes were associated with breastfeeding initiation, duration, and exclusivity, controlling for demographics. Results Exposure to at least one form of violence was high in this sample (87%). We identified 4 classes defined by violence exposure (combining current and historical exposures). Violence exposure patterns differed between racial/ethnic groups, but patterns were inconsistently associated with breastfeeding plans or outcomes. For White women, history of violence exposure increased the likelihood of earlier breastfeeding cessation. By contrast, among Black women, history of violence exposure increased the likelihood of having a breastfeeding plan and initiating breastfeeding. Conclusions for Practice Some differences between violence exposure classes are likely due to the correlation between race/ethnicity and socioeconomic status in the community studied. Additional studies are warranted to better understand how exposure to violence is related to breastfeeding and how best to support women making decisions about intention, initiation, and duration of breastfeeding.

Potential Impacts of Modifiable Behavioral and Environmental Exposures on Reducing Burden of Under-five Mortality Associated with Household Air Pollution in Nepal

Abstract

Objectives Household air pollution (HAP) is one of the leading causes of respiratory illness and deaths among young children in low and lower-middle income countries. This study examines for the first time trends in the association between HAP from cooking fuel and under-five mortality and measures the potential impact of interventions to reduce HAP using Nepal Demographic and Health Survey datasets (2001–2011). Methods A total of 17,780 living children across four age-groups (neonatal 0–28 days, post-neonatal 1–11 months, child 12–59 months and under-five 0–59 months) were included and multi-level logistic regression models were used for analyses. Population attributable fractions of key risk factors and potential impact fractions assessing the impact of previous interventions to reduce exposure prevalence were also calculated. Results Use of cooking fuel was associated with total under-five mortality (OR 2.19, 95% CI 1.37–3.51, P = 0.001) in Nepal, with stronger associations evident for sub-group analyses of neonatal mortality (OR 2.67, 95% CI 1.47–4.82, P = 0.001). Higher association was found in rural areas and for households without a separate kitchen using polluting fuel for cooking, and in women who had never breastfed for all age-groups of children. PIF estimates, assuming a 63% of reduction of HAP based on previously published interventions in Nepal, suggested that a burden of 40% of neonatal and 33% of under-five mortality cases associated with an indoor kitchen using polluting fuel could be avoidable. Conclusion Improved infrastructure and behavioral interventions could help reduce the pollution from cooking fuel in the household resulting in further reduction in under-five mortality in Nepal.

What Do Pediatricians Tell Parents About Bed-Sharing?

Abstract

Background and objectives Despite the risks of bed-sharing, little is known about what pediatricians tell parents about bed-sharing with infants and whether pediatricians provide specific recommendations outlined by the American Academy of Pediatrics (AAP). This study aimed to understand pediatricians' opinions about bed-sharing and the advice pediatricians provide to parents about bed sharing. Methods The study employed a qualitative study design and the conceptual framework of the Theory of Planned Behavior. 24 primary care pediatricians from a variety of practice settings were interviewed about the anticipatory guidance they provide to families whose infants are in the at-risk age group for SIDS. Results Pediatricians' opinions about bed-sharing differed widely both with respect to identifying bed-sharing as a topic they routinely address in anticipatory guidance as well as in what they tell parents about bed sharing. Some strongly and routinely advise against bed-sharing and identify bed-sharing as a clear risk to infants. Others believe bed-sharing to be both safe and useful. A third group allow the content of anticipatory guidance to be driven by parental concerns. Most pediatricians are clearer in their recommendation to place infants supine to sleep than in their recommendation to avoid bed-sharing. Conclusions Overall, there is considerable variation among pediatricians in the advice they provide about bed-sharing, and most advice is not congruent with the AAP recommendations. Additional efforts to educate pediatricians may be necessary to change attitudes and behaviors with respect to anticipatory guidance about safe sleep.

Guidelines of care for the management of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of human cancer and has an increasing annual incidence. Although most cSCC is cured with office-based therapy, advanced cSCC poses a significant risk for morbidity, impact on quality of life, and death. This document provides evidence-based recommendations for the management of patients with cSCC. Topics addressed include biopsy techniques and histopathologic assessment, tumor staging, surgical and nonsurgical management, follow-up and prevention of recurrence, and management of advanced disease.

Guidelines of care for the management of basal cell carcinoma

Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC.

Superficial mycosis of the foot caused by Cladophialophora boppii

Erratum: Tinea Capitis in Children: A Report of Four Cases Trichoscopic with Trichoscopic features

Indian Journal of Paediatric Dermatology 2018 19(1):91-91

Modification of the Fitzpatrick system of skin phototype classification for the Indian population, and its correlation with narrowband diffuse reflectance spectrophotometry

Summary

Background

The Fitzpatrick classification for skin phototyping is widely used, but its usefulness in dark-skinned populations has been questioned by some researchers. Recently, skin colour measurement has been proposed for phototyping skin colour objectively.

Aims

To modify the Fitzpatrick system of skin phototyping for the Indian population and to study its correlation with skin colour using narrowband diffuse reflectance spectrophotometry

Methods

Answer choices for three items (eye colour, hair colour, colour of unexposed skin) out of 10 in the original Fitzpatrick questionnaire were modified, followed by self-administration of the original and the modified Fitzpatrick questionnaire by 70 healthy Indian volunteers. Skin colour (melanin and erythema indices) was measured from two photoexposed and two photoprotected sites using a narrowband reflectance spectrophotometer.

Results

The mean ± SD scores for the original and modified Fitzpatrick questionnaires were 25.40 ± 4.49 and 23.89 ± 4.82, respectively (r = 0.97, P < 0.001). The two items related to tanning habits were deemed irrelevant based on the subjects' response and were removed from the modified questionnaire. The Melanin Index (MI) of all sites correlated moderately well with both the modified (r = 0.61–0.64, P < 0.001) and original Fitzpatrick questionnaire scores (r = 0.64–0.67, P < 0.001), while the Erythema Index showed poor correlation with both. An MI value of ≧42 was found to be the cut-off between skin phototypes I–III and IV, and ≥ 47 between IV and V–VI.

Conclusions

Our modification of the Fitzpatrick questionnaire makes it more relevant to the Indian population. Spectrophotometry can be a useful objective tool for skin phototyping.

Dermoscopic characterization of cutaneous lymphomas: a pilot survey

Abstract

Background

While substantial dermoscopic analysis of melanocytic lesions has been performed, dermoscopic characterization of cutaneous lymphoid proliferations has been limited. Cutaneous lymphoma, particularly early mycosis fungoides (MF) and its variants, is often challenging to clinically and pathologically distinguish from inflammatory processes of the skin. This study aimed to survey the dermoscopic findings of cutaneous lymphomas and to discern whether any patterns might potentially serve as specific signatures.

Methods

Fifteen patients with an established diagnosis of cutaneous lymphoma were prospectively recruited and seen in the university multidisciplinary cutaneous lymphoma program with MF, an MF- variant, CD30-positive lymphoproliferative disorder, or cutaneous B-cell lymphomas and were included in our study. Dermoscopic findings, histologic features, clinical characteristics, and demographic data were analyzed.

Results

Patch stage MF was characterized by interconnected white structureless patches encircling small fine linear vessels, yielding an overall trabeculated to fenestrated pattern under dermoscopy. Corresponding histopathologic findings for these patterns included epidermotropism, atypical pleomorphic cells, and lichenoid infiltrates. Folliculotropic mycosis fungoides (FMF) was characterized by folliculocentric erosions surrounded by dotted and fine linear vessels, loss of terminal follicles, comedo-like openings, and interconnected regular-appearing structureless patches. Corresponding histopathologic findings in these FMF cases were typical of FMF. Notably, these changes were not appreciated in lymphomatoid papulosis. Primary cutaneous follicle center B cell lymphoma showed crystalline structures and vascular pseudopods.

Conclusions

Cutaneous lymphomas appear to demonstrate characteristic dermoscopic patterns, reflective of the specific lymphoma type and its corresponding histopathology, which have not been seen in inflammatory skin conditions, such as psoriasis and eczematous dermatitis.

The early repigmentation pattern of vitiligo is related to the source of melanocytes and by the choice of therapy: a retrospective cohort study

Abstract

Background

Patients with vitiligo present with different repigmentation patterns in the early recovery stage.

Objectives

To analyze the relationships between early repigmentation patterns in vitiliginous patches, their clinical characteristics, and therapeutic choices.

Methods

Patients with vitiligo seen in the Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University from 2010 to 2015, were included, and their clinical records, especially photographs and medical treatments, were reviewed.

Results

One hundred and sixteen patients were included in this study, and 326 lesions with different degrees of depigmentation, locations, stages, distributions, therapies, and repigmentation patterns were included and analyzed. Perifollicular repigmentation occurred more frequently in lesions with complete depigmentation (P = 0.005), in non-sun exposed areas (P < 0.001), a stable stage (P = 0.008), and lesions treated with narrow band ultraviolet B (NB-UVB) (P < 0.001, despite lesion distributions). Marginal repigmentation is more frequent in lesions with complete depigmentation (P = 0.016), lesions treated without NB-UVB (P = 0.002), and facial lesions treated with topical vitamin D analogs (TVDAs) monotherapy (P = 0.022). Diffuse repigmentation is the predominant pattern in lesions with incomplete depigmentation (P < 0.001), in sun-exposed areas (P < 0.001), progressive stage (P = 0.044), and truncal lesions treated with TVDAs (P < 0.001).

Conclusions

The different repigmentation patterns of vitiligo lesions depend on the different source and status of melanocytes and their abilities to produce melanin on the choice of therapy.

Interested in global health? Here is where to start: a checklist for United States dermatology residents

Isolation and molecular characterization of zoonotic Buffalopox virus from skin lesions of humans in India

Efficacy and safety of noncultured melanocyte-keratinocyte transplant procedure for vitiligo and other leukodermas: a critical analysis of the evidence

Abstract

Vitiligo is an acquired pigmentary skin of depigmentation occurring secondary to melanocyte destruction. Vitiligo and other leukodermas have a profound impact on quality of life. Current therapies include medical options, such as phototherapy, topical and systemic corticosteroids, topical calcineurin inhibitors, immunomodulators, and antioxidiants, and surgical options. Surgical options provide melanocytic cells to previously depigmented areas and use either tissue grafting or cellular grafting methods. Topical treatments are often insufficient, and many of the current surgical procedures have shown variable response rates. In this review, we discuss the process of the cellular grafting melanocyte-keratinocyte transplantation procedure (MKTP) and critically analyze its efficacy and safety in the treatment of vitiligo and other leukodermas. PubMed was searched for studies (2001–2017) describing the use of MKTP in patients with vitiligo or other leukodermas. Articles or trials discussing the use of MKTP for these patients were selected for in-depth review. Clinically relevant results regarding efficacy and safety of MKTP in vitiligo and leukoderma patients were analyzed. Numerous trials and case series/reports have demonstrated tolerability and efficacy of MKTP with repigmentation for patients with refractory, stable vitiligo. However, the response rates have been variable, likely influenced by vitiligo type and affected areas. Future research and clinical reporting will provide more insight on which phenotypes may benefit from MKTP.

Hypopigmented mycosis fungoides: a 20-case retrospective series

Abstract

Background

Hypopigmented mycosis fungoides (hMF) is a rare subtype of mycosis fungoides. The aim of this study was to identify the clinical–epidemiological profile of our patient group and also to provide additional information about treatment responses and prognosis.

Methods

This is a cross-sectional retrospective observational study, with exploratory analysis. The outcome variables were disease progression and related death.

Results

Twenty patients with hMF were selected from a group of 102 patients diagnosed with MF. There was no gender difference (10 females and 10 males). Mean age at diagnosis was 43.85 years, and most patients had mixed or black skin color. The mean time between the onset of the lesions and the diagnosis was 66.75 months. Patients were equally distributed in stages IA (50%) and IB (50%). Photochemotherapy (psoralen and ultraviolet A) was the predominant therapeutic modality. The mean follow-up time was 7.25 years. In 10%, disease progression was observed. Death related to the disease occurred in one patient.

Conclusions

The clinical and epidemiological profile of patients with hypopigmented MF found in our sample is in agreement with what is described in the literature, with the exception of the age at diagnosis, higher than expected. Diagnostic delay time, despite long, is also consistent with the medical literature; however, in this sample, we had two cases of disease progression, with death of one patient, despite the treatment, which is extremely important since hypopigmented MF is usually associated with good prognosis.

The usefulness of nail plate and intraoperative dermoscopy in subungual glomus tumor

Eruptive keratoacanthomas secondary to nivolumab immunotherapy

Idiopathic chilblains in myelomonocytic leukemia: not a simple association

Localized nodular pemphigoid

Evaluation of ICAM-1 expression and vascular changes in the skin of patients with plaque, pustular, and erythrodermic psoriasis

Abstract

Background

Psoriasis is a chronic inflammatory disease. Pustular, erythrodermic, and extensive plaque psoriasis are responsible for systemic complications. Systemic capillary leak syndrome is the complication with greater progression to death and occurs due to vascular changes.

Purpose

The aim of this study was to evaluate vascular changes through the expression of CD34 and ICAM-1 in plaque, pustular, and erythrodermic psoriasis.

Methods

The sample consisted of seven patients with erythrodermic psoriasis, 24 with moderate-severe plaque psoriasis, 14 with mild plaque psoriasis and 13 with pustular psoriasis. Patients were submitted to physical examination and skin biopsy for histopathological examination and immunohistochemical analysis with anti-CD34 and anti-ICAM-1 antibodies. Subsequently, tissue fragments were organized by groups using the Tissue Macroarray (TMA) technique to perform immunohistochemistry.

Results

In 58 patients, analysis of vessels using anti-CD34 demonstrated vascular immunostaining in superficial dermis and between dermal papillae. There were more blood vessels in erythrodermic psoriasis, followed by plaque psoriasis. In erythrodermic psoriasis, there were small and few tortuous blood vessels with great dilatation, while plaque psoriasis presented larger vessels that were less dilated and more tortuous. There was an intense and localized expression of ICAM-1 in endothelial and lymphocytic cells in all groups, with significant differences.

Conclusions

Vascular alterations are important in psoriasis, with an increase in the number of blood vessels and ICAM-1 overexpression, especially in erythrodermic form. Therefore, vascular changes and the expression of intercellular adhesion molecules could help to diagnose the erythrodermic form of psoriasis.

Dermoscopy of childhood flexural comedones: description of 4 cases