In vivo evaluation of some biophysical parameters of the facial skin of Indian subjects living in Mumbai. Part II: Variability with age and gender

Abstract

Background

A previously published work explored the diversity of some biophysical parameters (colour, elasticity, sebum production, skin micro relief….) of the skin of 1204 Indian women, differently aged, living in 4 Indian cities (Chennai, Delhi, Kolkata, Mumbai). The present work aimed at completing such research by focusing on possible gender-related differences in the same skin parameters, between Indian men and women living in the same Indian city (Mumbai).

Methods

297 Indian men, differently aged (18-70y) were recruited in Mumbai, completing the panel of 303 women who were previously recruited in this same city. The same instrumental measurements of facial skin colour and its homogeneity, its mechanical properties, the sebum production, skin pores size, skin relief etc.. as in the previous work, were conducted.

Results

Overall, the facial skin colour shows a darker complexion in men as compared to women, on forehead, ocular region, lips, chin and cheek. The skin colour unevenness, which increases with age, was found higher in men, as compared to women. At comparable age, women and men present a same density of skin pores, whereas those of men appear larger, up to 55y. The deepness of Crow's feet wrinkles does not significantly differ between genders. A lesser extensibility was found on then cheeks of men. In men, the sebum production was found significantly higher than that of women at ages above 40y.

Conclusions

This work indicates some commonly shared age-related skin features between women and men from Mumbai, despite slight different characteristics such as skin pigmentation, forehead/cheek colour contrast, mechanical properties and sebum production.

This article is protected by copyright. All rights reserved.

Associations of Abdominal Subcutaneous and Visceral Fat with Insulin Resistance and Secretion Differ Between Men and Women: The Netherlands Epidemiology of Obesity Study

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

A patient with chronic labial oedema and nodular palatal lesions

Suspected hypersensitivity to cervicovaginal fluid – what can we learn from the seminal plasma allergy story?

Forthcoming Events

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Issue Information

Beyond the headlines – JEADV editor's pick of the year 2017

Fragrance contact allergy

Editors’ letter

Cryolipolysis for the treatment of submental fat: Review of the literature

Summary

Background

Submental fat accumulation is a common cosmetic concern. Cryolipolysis utilizes noninvasive cooling to lyse adipocytes. A cryolipolysis device was recently approved for treatment of submental fat.

Objective

This manuscript provides a review of the preclinical work and clinical trials related to cryolipolysis for the treatment of submental fat. Settings, efficacy, and side effects are also discussed.

Materials and Methods

A literature search was performed through Pubmed, EMBASE, Web of Science, and CINAHL, using the search terms "cryolipolysis," "submental," and "paradoxical adipose hyperplasia". Additional sources from the original source bibliographies were used to further supplement this review.

Results

There are 4 clinical trials and one case series (total 101 patients) that evaluated the use of cryolipolysis for treatment of submental fat. In these studies, there was a statistically significant reduction in submental fat and patients expressed high satisfaction with the treatment. Adverse effects were mild and transient.

Conclusions

Cryolipolysis is a noninvasive cooling technique that is safe and effective for treatment of submental fat. To date, there are no reports of marginal mandibular nerve injury or paradoxical adipose hyperplasia following treatment with this device.

The acute effects of erythromycin and oxytetracycline on enhanced biological phosphorus removal system: shift in bacterial community structure

Abstract

Since extensive application, an increasing amount of antibiotics has been released into wastewater treatment plants. In this study, the enhanced biological phosphorus removal (EBPR) system was fed with synthetic wastewater containing erythromycin (ERY) and oxytetracycline (OTC) for 7 days to evaluate the variations of solution ortho-P (SOP), volatile fatty acid (VFA), poly-bhydroxyalkanoates (PHAs), specific oxygen uptake rater (SOUR), and microbial community in the EBPR system. The obtained results showed that the P-removal efficiency decreased to 0.0%, and at the end of the experiment, only less than 20% of the VFA could be consumed. Besides, the variable processes of P and PHAs were destroyed. Moreover, to better grasp the inhibitory mechanism of antibiotics, microbial community compositions of activated sludge sampled in all reactors were investigated by high-throughput sequencing techniques. Results of comparative and evolutionary analysis revealed that high concentrations (5 and 10 mg/L) of ERY and OTC could seriously shift microbial communities, while combined antibiotics could induce more. Additionally, Accumulibacter and Competibacter were two primary microorganisms at the genus level in the EBPR system. Accumulibacter decreased seriously for exposure to antibiotics, while Competibacter increased in all experimental reactors especially in combined antibiotics reactor.

Epidermal permeability barrier function and sphingolipid content in the skin of sphingomyelin synthase 2 deficient mice

Abstract

Background

Sphingomyelin synthase (SMS) is an enzyme that generates sphingomyelin (SM) from ceramide (CER) and phosphatidylcholine. SM in the epidermis is a precursor of CER, an important lipid for epidermal permeability barrier function. However, the physiological role of SMS in skin is unclear.

Objectives

To uncover the function of SMS in skin, we investigated sphingolipid metabolism enzyme activity in skin, SM content in the epidermis, CER content in the stratum corneum (SC) and transepidermal water loss (TEWL) as an indicator of barrier function in SMS2-knockout (KO) mice.

Methods

The activities of sphingolipid metabolism enzymes in skin homogenates were measured using a fluorescently labeled substrate. Enzymatic reaction products were detected by high performance liquid chromatography (HPLC). Lipids in the epidermis or SC were extracted and quantified by high performance thin layer chromatography (HPTLC). TEWL was measured using a Tewameter TM300.

Results

In SMS2-KO mice, SMS activity in skin homogenates, epidermal SM content and SC CER content were significantly decreased relative to wild type (WT) mice. The TEWL of SMS2-KO mice was significantly increased compared to WT mice.

Conclusion

Our data indicate that SMS2 generate SM in the epidermis and contribute to epidermal permeability barrier function and will support understanding of SM related metabolic disorders.

This article is protected by copyright. All rights reserved.

Laterality and Left-sidedness in the Nose, Face, and Body: A New Finding

Background: Asymmetry is a common occurrence in bilaterian animals, particularly human beings. Through examination of patients and their photographs during rhinoplasty, we noted wider left-sided nasal and facial features in most patients. This observation led us to hypothesize that this might be consistent to the whole body. Methods: We conducted a study in 3 parts to test the question above. First, we analyzed operating notes of 50 rhinoplasty patients to determine the wider side of the upper, middle, and lower thirds of the nose. Second, we analyzed the width of the face and chest wall in 31 patients to discern any correlation between facial and bodily asymmetry. Third, computerized tomographic scans of the thorax and body of 48 patients were studied to measure the width of the hemithorax and hemipelvic bone. Results: (1) Upper vault width was wider on left side (78%). Left middle vault width was wider (88%). The lower lateral cartilage, lateral crura convexity was more prominent on left side (48%), and a wider scroll area was found and trimmed in 21 (left) and 0 (right) cases. The alar base was wider on left side (56%). (2) In the body and face analysis, 64.5% had a wider left-sided face and body. (3) In the computed tomographic scan analysis, same-sided thorax and pelvis asymmetry was seen (85.35%), 33 and 7 of which were left- and right-sided, respectively. Conclusion: We observed generalized asymmetry of the face and body with left-sided predominance.

Late-Onset Inflammatory Response to Hyaluronic Acid Dermal Fillers

Objective: Even though injectable hyaluronic acid (HA)–based fillers are considered safe, rare complications, such as late-onset inflammatory reactions have been reported. Possible causes and effective treatments have not been formally described, so this work aims to discuss these and offer a formal protocol for treatment. Methods: This article presents 5 clinical cases of late-onset inflammatory response occurring at least 3 months after uneventful injection of HA dermal filler. Results: Inflammation appeared spontaneously, usually 4–5 months after the last injection, but in 1 patient, almost 14 months later. One patient was injected at the same time with fillers manufactured by 2 different technologies. In this case, all areas treated with the same filler showed diffuse swelling of inflammatory nature, whereas the lips, treated with the second filler brand, remained unaffected. Four patients reported a flu-like illness or gastrointestinal upset a few days before the onset of dermal filler inflammation. Conclusion: Late-onset inflammatory reactions to HA fillers may be self-limiting but are easily and rapidly treatable with oral steroids, and with hyaluronidase in the case of lumps. It is likely these reactions are due to a Type IV delayed hypersensitivity response. Delayed inflammation associated with HA fillers is nonbrand specific. However, the case where 2 different brands were injected during the same session, but only 1 brand triggered a hypersensitivity reaction, suggests that the technology used in the manufacturing process, and the subsequent differing products of degradation, may have an influence on potential allergic reactions to HA fillers.

Intentional Lower Pole Rotation of Anatomic Breast Implants in Chest Wall Deformities

Summary: Several methods have been described for the correction of congenital thoracic wall deformities. Our aim was to investigate the feasibility and clinical results of using standard anatomic breast implants with modified anatomic positioning according to the defect in congenital thoracic wall deformities. Between 2014 and 2015, 5 patients diagnosed with pectus excavatum (PE, n = 4) or pectus carinatum (PC, n = 1) and breast asymmetry or hypoplasia were evaluated. In all patients, a submammary incision and dual-plane subpectoral placement of texturized, anatomic implants were performed. In patients with PE, the lower pole of the implant was positioned medially to compensate for the caved chest. In patients with PC, the lower pole of the anatomic implant was positioned laterally to compensate for the prominent sternum. Outcome measures were satisfaction, minor and major complications, and morbidity. The mean surgery time was 95 ± 14 minutes, and the mean implant volume was 287 ± 56 cm3 (273 ± 60 cm3 on the right side and 305 ± 60 cm3 on the left side). After a median follow-up of 25 months (range: 2–35), all patients healed uneventfully, and a satisfactory correction of the thoracic wall deformity was achieved. Thus, by adjusting the lower pole of anatomic breast implants in a horizontal plane according to the thoracic defect, we showed satisfactory results. Our technique has a low complication rate and can be recommended for the correction of mild to moderate PE or PC.

Venous Anastomosis for Prevention of Venous Congestion in Distally Based Flaps

Background: Distally based flaps are useful for the treatment of skin defects of the extremities. However, congestion in the peripheral part of the flap due to reverse flow can cause partial flap necrosis. Previously, we reported on the effectiveness of venous anastomoses to rescue peripheral congestion of distally based flaps and applied this idea in a clinical setting. In this report, we present clinical cases of distally based flaps with venous supercharge anastomoses for changing the reverse venous flow into physiological flow, thereby reducing venous congestion. Methods: Four patients with skin defects of the extremities (2 cases with defects of the knee and the upper third of the lower leg, 1 case of the lower third of the lower leg, and 1 case of the distal third of the forearm) were treated with local flaps (2 cases with distally based greater saphenous venoadipofascial sartorius muscle combined flaps, 1 case with a distally based lesser saphenous venoadipofascial flap, and 1 case with a distally based ulnar artery perforator flap). In each reconstruction, 1 or 2 veins in the flaps were anastomosed with superficial veins in the recipient area to change the reverse venous flow into a normal, physiologic flow. Result: All flaps healed completely without any obvious venous congestion or flap necrosis. The coverage quality provided by these defects was satisfactory. Conclusions: Adding venous anastomoses may reduce the risk of venous congestion and improve the outcomes of the distally based flaps.

An Ethenoadenine FAD Analog Accelerates UV Dimer Repair by DNA Photolyase

Editorial (2018, Issue 1)

Issue Information

New Insights on the Role of Residue 673 of APP in Alzheimer's Disease

Correction: Schlüter et al., The Impact of Dopamine on Aggression: An [18F]-FDOPA PET Study in Healthy Males

Alpha Oscillations Reduce Temporal Long-Range Dependence in Spontaneous Human Brain Activity

Ongoing neural dynamics comprise both frequency-specific oscillations and broadband-features, such as long-range dependence (LRD). Despite both being behaviorally relevant, little is known about their potential interactions. In humans, 8–12 Hz α oscillations constitute the strongest deviation from 1/f power-law scaling, the signature of LRD. We postulated that α oscillations, believed to exert active inhibitory gating, downmodulate the temporal width of LRD in slower ongoing brain activity. In two independent "resting-state" datasets (electroencephalography surface recordings and magnetoencephalography source reconstructions), both across space and dynamically over time, power of α activity covaried with the power slope <5 Hz (i.e., greater α activity shortened LRD). Causality of α activity dynamics was implied by its temporal precedence over changes of slope. A model where power-law fluctuations of the α envelope inhibit baseline activity closely replicated our results. Thus, α oscillations may provide an active control mechanism to adaptively regulate LRD of brain activity at slow temporal scales, thereby shaping internal states and cognitive processes.

SIGNIFICANCE STATEMENT The two prominent features of ongoing brain activity are oscillations and temporal long-range dependence. Both shape behavioral performance, but little is known about their interaction. Here, we demonstrate such an interaction in EEG and MEG recordings of task-free human brain activity. Specifically, we show that spontaneous dynamics in alpha activity explain ensuing variations of dependence in the low and ultra-low-frequency range. In modeling, two features of alpha oscillations are critical to account for the observed effects on long-range dependence, scale-free properties of alpha oscillations themselves, and a modulation of baseline levels, presumably inhibitory. Both these properties have been observed empirically, and our study hence establishes alpha oscillations as a regulatory mechanism governing long-range dependence or "memory" in slow ongoing brain activity.

Retrieval Demands Adaptively Change Striatal Old/New Signals and Boost Subsequent Long-Term Memory

The striatum is a central part of the dopaminergic mesolimbic system and contributes both to the encoding and retrieval of long-term memories. In this regard, the co-occurrence of striatal novelty and retrieval success effects in independent studies underlines the structure's double duty and suggests dynamic contextual adaptation. To test this hypothesis and further investigate the underlying mechanisms of encoding and retrieval dynamics, human subjects viewed pre-familiarized scene images intermixed with new scenes and classified them as indoor versus outdoor (encoding task) or old versus new (retrieval task), while fMRI and eye tracking data were recorded. Subsequently, subjects performed a final recognition task. As hypothesized, striatal activity and pupil size reflected task-conditional salience of old and new stimuli, but, unexpectedly, this effect was not reflected in the substantia nigra and ventral tegmental area (SN/VTA), medial temporal lobe, or subsequent memory performance. Instead, subsequent memory generally benefitted from retrieval, an effect possibly driven by task difficulty and activity in a network including different parts of the striatum and SN/VTA. Our findings extend memory models of encoding and retrieval dynamics by pinpointing a specific contextual factor that differentially modulates the functional properties of the mesolimbic system.

SIGNIFICANCE STATEMENT The mesolimbic system is involved in the encoding and retrieval of information but it is unclear how these two processes are achieved within the same network of brain regions. In particular, memory retrieval and novelty encoding were considered in independent studies, implying that novelty (new > old) and retrieval success (old > new) effects may co-occur in the striatum. Here, we used a common framework implicating the striatum, but not other parts of the mesolimbic system, in tracking context-dependent salience of old and new information. The current study, therefore, paves the way for a more comprehensive understanding of the functional properties of the mesolimbic system during memory encoding and retrieval.

Role of the Axon Initial Segment in the Control of Spontaneous Frequency of Nigral Dopaminergic Neurons In Vivo

The spontaneous tonic discharge activity of nigral dopamine neurons plays a fundamental role in dopaminergic signaling. To investigate the role of neuronal morphology and architecture with respect to spontaneous activity in this population, we visualized the 3D structure of the axon initial segment (AIS) along with the entire somatodendritic domain of adult male mouse dopaminergic neurons, previously recorded in vivo. We observed a positive correlation of the firing rate with both proximity and size of the AIS. Computational modeling showed that the size of the AIS, but not its position within the somatodendritic domain, is the major causal determinant of the tonic firing rate in the intact model, by virtue of the higher intrinsic frequency of the isolated AIS. Further mechanistic analysis of the relationship between neuronal morphology and firing rate showed that dopaminergic neurons function as a coupled oscillator whose frequency of discharge results from a compromise between AIS and somatodendritic oscillators. Thus, morphology plays a critical role in setting the basal tonic firing rate, which in turn could control striatal dopaminergic signaling that mediates motivation and movement.

SIGNIFICANCE STATEMENT The frequency at which nigral dopamine neurons discharge action potentials sets baseline dopamine levels in the brain, which enables activity in motor, cognitive, and motivational systems. Here, we demonstrate that the size of the axon initial segment, a subcellular compartment responsible for initiating action potentials, is a key determinant of the firing rate in these neurons. The axon initial segment and all the molecular components that underlie its critical function may provide a novel target for the regulation of dopamine levels in the brain.

Dopamine-Dependent Sensitization of Rod Bipolar Cells by GABA Is Conveyed through Wide-Field Amacrine Cells

The vertebrate retina has the remarkable ability to support visual function under conditions of limited illumination, including the processing of signals evoked by single photons. Dim-light vision is regulated by several adaptive mechanisms. The mechanism explored in this study is responsible for increasing the light sensitivity and operational range of rod bipolar cells, the retinal neurons operating immediately downstream of rod photoreceptors. This sensitization is achieved through the sustained dopamine-dependent GABA release from other retinal neurons. Our goals were to identify the cell type responsible for the GABA release and the site of its modulation by dopamine. Previous studies have suggested the involvement of amacrine and/or horizontal cells. We now demonstrate, using mice of both sexes, that horizontal cells do not participate in this mechanism. Instead, sustained GABA input is provided by a subpopulation of wide-field amacrine cells, which stimulate the GABA_C receptors at rod bipolar cell axons. We also found that dopamine does not act directly on either of these cells. Rather, it suppresses inhibition imposed on these wide-field cells by another subpopulation of upstream GABAergic amacrine cells, thereby sustaining the GABA_C receptor activation required for rod bipolar cell sensitization.

SIGNIFICANCE STATEMENT The vertebrate retina has an exquisite ability to adjust information processing to ever-changing conditions of ambient illumination, from bright sunlight to single-photon counting under dim starlight. Operation under each of these functional regimes requires an engagement of specific adaptation mechanisms. Here, we describe a mechanism optimizing the performance of the dim-light channel of vision, which consists of sensitizing rod bipolar cells by a sustained GABAergic input originating from a population of wide-field amacrine cells. Wide-field amacrine cells span large segments of the retina, making them uniquely equipped to normalize and optimize response sensitivity across distant receptive fields and preclude any bias toward local light-intensity fluctuations.

Scale-Free Amplitude Modulation of Neuronal Oscillations Tracks Comprehension of Accelerated Speech

Speech comprehension is preserved up to a threefold acceleration, but deteriorates rapidly at higher speeds. Current models posit that perceptual resilience to accelerated speech is limited by the brain's ability to parse speech into syllabic units using / oscillations. Here, we investigated whether the involvement of neuronal oscillations in processing accelerated speech also relates to their scale-free amplitude modulation as indexed by the strength of long-range temporal correlations (LRTC). We recorded MEG while 24 human subjects (12 females) listened to radio news uttered at different comprehensible rates, at a mostly unintelligible rate and at this same speed interleaved with silence gaps. , , and low- oscillations followed the nonlinear variation of comprehension, with LRTC rising only at the highest speed. In contrast, increasing the rate was associated with a monotonic increase in LRTC in high- activity. When intelligibility was restored with the insertion of silence gaps, LRTC in the , , and low- oscillations resumed the low levels observed for intelligible speech. Remarkably, the lower the individual subject scaling exponents of / oscillations, the greater the comprehension of the fastest speech rate. Moreover, the strength of LRTC of the speech envelope decreased at the maximal rate, suggesting an inverse relationship with the LRTC of brain dynamics when comprehension halts. Our findings show that scale-free amplitude modulation of cortical oscillations and speech signals are tightly coupled to speech uptake capacity.

SIGNIFICANCE STATEMENT One may read this statement in 20–30 s, but reading it in less than five leaves us clueless. Our minds limit how much information we grasp in an instant. Understanding the neural constraints on our capacity for sensory uptake is a fundamental question in neuroscience. Here, MEG was used to investigate neuronal activity while subjects listened to radio news played faster and faster until becoming unintelligible. We found that speech comprehension is related to the scale-free dynamics of and bands, whereas this property in high- fluctuations mirrors speech rate. We propose that successful speech processing imposes constraints on the self-organization of synchronous cell assemblies and their scale-free dynamics adjusts to the temporal properties of spoken language.

Compressive Temporal Summation in Human Visual Cortex

Combining sensory inputs over space and time is fundamental to vision. Population receptive field models have been successful in characterizing spatial encoding throughout the human visual pathways. A parallel question, how visual areas in the human brain process information distributed over time, has received less attention. One challenge is that the most widely used neuroimaging method, fMRI, has coarse temporal resolution compared with the time-scale of neural dynamics. Here, via carefully controlled temporally modulated stimuli, we show that information about temporal processing can be readily derived from fMRI signal amplitudes in male and female subjects. We find that all visual areas exhibit subadditive summation, whereby responses to longer stimuli are less than the linear prediction from briefer stimuli. We also find fMRI evidence that the neural response to two stimuli is reduced for brief interstimulus intervals (indicating adaptation). These effects are more pronounced in visual areas anterior to V1-V3. Finally, we develop a general model that shows how these effects can be captured with two simple operations: temporal summation followed by a compressive nonlinearity. This model operates for arbitrary temporal stimulation patterns and provides a simple and interpretable set of computations that can be used to characterize neural response properties across the visual hierarchy. Importantly, compressive temporal summation directly parallels earlier findings of compressive spatial summation in visual cortex describing responses to stimuli distributed across space. This indicates that, for space and time, cortex uses a similar processing strategy to achieve higher-level and increasingly invariant representations of the visual world.

SIGNIFICANCE STATEMENT Combining sensory inputs over time is fundamental to seeing. Two important temporal phenomena are summation, the accumulation of sensory inputs over time, and adaptation, a response reduction for repeated or sustained stimuli. We investigated these phenomena in the human visual system using fMRI. We built predictive models that operate on arbitrary temporal patterns of stimulation using two simple computations: temporal summation followed by a compressive nonlinearity. Our new temporal compressive summation model captures (1) subadditive temporal summation, and (2) adaptation. We show that the model accounts for systematic differences in these phenomena across visual areas. Finally, we show that for space and time, the visual system uses a similar strategy to achieve increasingly invariant representations of the visual world.

Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair

The MAPK/ERK pathway has a critical role in PNS development. It is required for Schwann cell (SC) differentiation and myelination; sustained embryonic MAPK/ERK activation in SCs enhances myelin growth overcoming signals that normally end myelination. Excess activation of this pathway can be maladaptive as in adulthood acute strong activation of MAPK/ERK has been shown to cause SC dedifferentiation and demyelination. We used a mouse model (including male and female animals) in which the gain-of-function MEK1DD allele produces sustained MAPK/ERK activation in adult SCs, and we determined the impact of such activation on nerve repair. In the uninjured nerve, MAPK/ERK activation neither impaired myelin nor reactivated myelination. However, in the injured nerve it was detrimental and resulted in delayed repair and functional recovery. In the early phase of injury, the rate of myelin clearance was faster. Four weeks following injury, when nerve repair is normally advanced, myelinated axons of MEK1DD mutants demonstrated higher rates of myelin decompaction, a reduced number of Cajal bands. and decreased internodal length. We noted the presence of abnormal Remak bundles with long SCs processes and reduced numbers of C-fibers/Remak bundle. Both the total number of regenerating axons and the intraepidermal nerve fiber density in the skin were reduced. Sustained activation of MAPK/ERK in adult SCs is therefore deleterious to successful nerve repair, emphasizing the differences in the signaling processes coordinating nerve development and repair. Our results also underline the key role of SCs in axon regeneration and successful target reinnervation.

SIGNIFICANCE STATEMENT The MAPK/ERK pathway promotes developmental myelination and its sustained activation in SCs induced continuous myelin growth, compensating for the absence of essential myelination signals. However, the strength of activation is fundamental because acute strong induction of MAPK/ERK in adulthood induces demyelination. What has been unknown is the effect of a mild but sustained MAPK/ERK activation in SCs on nerve repair in adulthood. This promoted myelin clearance but led to abnormalities in nonmyelinating and myelinating SCs in the later phases of nerve repair, resulting in slowed axon regeneration, cutaneous reinnervation, and functional recovery. Our results emphasize the distinct role of the MAPK/ERK pathway in developmental myelination versus remyelination and the importance of signaling between SCs and axons for successful axon regeneration.

Object Representations in Human Visual Cortex Formed Through Temporal Integration of Dynamic Partial Shape Views

We typically recognize visual objects using the spatial layout of their parts, which are present simultaneously on the retina. Therefore, shape extraction is based on integration of the relevant retinal information over space. The lateral occipital complex (LOC) can represent shape faithfully in such conditions. However, integration over time is sometimes required to determine object shape. To study shape extraction through temporal integration of successive partial shape views, we presented human participants (both men and women) with artificial shapes that moved behind a narrow vertical or horizontal slit. Only a tiny fraction of the shape was visible at any instant at the same retinal location. However, observers perceived a coherent whole shape instead of a jumbled pattern. Using fMRI and multivoxel pattern analysis, we searched for brain regions that encode temporally integrated shape identity. We further required that the representation of shape should be invariant to changes in the slit orientation. We show that slit-invariant shape information is most accurate in the LOC. Importantly, the slit-invariant shape representations matched the conventional whole-shape representations assessed during full-image runs. Moreover, when the same slit-dependent shape slivers were shuffled, thereby preventing their spatiotemporal integration, slit-invariant shape information was reduced dramatically. The slit-invariant representation of the various shapes also mirrored the structure of shape perceptual space as assessed by perceptual similarity judgment tests. Therefore, the LOC is likely to mediate temporal integration of slit-dependent shape views, generating a slit-invariant whole-shape percept. These findings provide strong evidence for a global encoding of shape in the LOC regardless of integration processes required to generate the shape percept.

SIGNIFICANCE STATEMENT Visual objects are recognized through spatial integration of features available simultaneously on the retina. The lateral occipital complex (LOC) represents shape faithfully in such conditions even if the object is partially occluded. However, shape must sometimes be reconstructed over both space and time. Such is the case in anorthoscopic perception, when an object is moving behind a narrow slit. In this scenario, spatial information is limited at any moment so the whole-shape percept can only be inferred by integration of successive shape views over time. We find that LOC carries shape-specific information recovered using such temporal integration processes. The shape representation is invariant to slit orientation and is similar to that evoked by a fully viewed image. Existing models of object recognition lack such capabilities.

Repositioning of Somatic Golgi Apparatus Is Essential for the Dendritic Establishment of Adult-Born Hippocampal Neurons

New dentate granule cells (DGCs) are continuously generated, and integrate into the preexisting hippocampal network in the adult brain. How an adult-born neuron with initially simple spindle-like morphology develops into a DGC, consisting of a single apical dendrite with further branches, remains largely unknown. Here, using retroviruses to birth date and manipulate newborn neurons, we examined initial dendritic formation and possible underlying mechanisms. We found that GFP-expressing newborn cells began to establish a DGC-like morphology at ~7 d after birth, with a primary dendrite pointing to the molecular layer, but at this stage, with several neurites in the neurogenic zone. Interestingly, the Golgi apparatus, an essential organelle for neurite growth and maintenance, was dynamically repositioning in the soma of newborn cells during this initial integration stage. Two weeks after birth, by which time most neurites in the neurogenic zone were eliminated, a compact Golgi apparatus was positioned exclusively at the base of the primary dendrite. We analyzed the presence of Golgi-associated genes using single-cell transcriptomes of newborn DGCs, and among Golgi-related genes, found the presence of STK25 and STRAD, regulators of embryonic neuronal development. When we knocked down either of these two proteins, we found Golgi mislocalization and extensive aberrant dendrite formation. Furthermore, overexpression of a mutated form of STRAD, underlying the disorder polyhydramnios, megalencephaly, and symptomatic epilepsy, characterized by abnormal brain development and intractable epilepsy, caused similar defects in Golgi localization and dendrite formation in adult-born neurons. Together, our findings reveal a role for Golgi repositioning in regulating the initial integration of adult-born DGCs.

SIGNIFICANCE STATEMENT Since the discovery of the continuous generation of new neurons in the adult hippocampus, extensive effort was directed toward understanding the functional contribution of these newborn neurons to the existing hippocampal circuit and associated behaviors, while the molecular mechanisms controlling their early morphological integration are less well understood. Dentate granule cells (DGCs) have a single, complex, apical dendrite. The events leading adult-born DGCs' to transition from simple spindle-like morphology to mature dendrite morphology are largely unknown. We studied establishment of newborn DGCs dendritic pattern and found it was mediated by a signaling pathway regulating precise localization of the Golgi apparatus. Furthermore, this Golgi-associated mechanism for dendrite establishment might be impaired in a human genetic epilepsy syndrome, polyhydramnios, megalencephaly, and symptomatic epilepsy.

A New, High-Efficacy, Noninvasive Transcranial Electric Stimulation Tuned to Local Neurodynamics

In this paper, we pose the following working hypothesis: in humans, transcranial electric stimulation (tES) with a time course that mimics the endogenous activity of its target is capable of altering the target's excitability. In our case, the target was the primary motor cortex (M1). We identified the endogenous neurodynamics of hand M1's subgroups of pyramidal neuronal pools in each of our subjects by applying Functional Source Separation (FSS) to their EEG recordings. We then tested whether the corticospinal excitability of the hand representation under the above described stimulation, which we named transcranial individual neurodynamics stimulation (tIDS), was higher than in the absence of stimulation (baseline). As a check, we compared tIDS with the most efficient noninvasive facilitatory corticospinal tES known so far, which is 20 Hz transcranial alternating current stimulation (tACS). The control conditions were as follows: (1) sham, (2) transcranial random noise stimulation (tRNS) in the same frequency range as tIDS (1–250 Hz), and (3) a low current tIDS (tIDS_low). Corticospinal excitability was measured with motor-evoked potentials under transcranial magnetic stimulation. The mean motor-evoked potential amplitude increase was 31% of the baseline during tIDS (p < 0.001), and it was 15% during tACS (p = 0.096). tRNS, tIDS_low, and sham induced no effects. Whereas tACS did not produce an enhancement in any subject at the individual level, tIDS was successful in producing an enhancement in 8 of the 16 subjects. The results of the present proof-of-principle study showed that proper exploitation of local neurodynamics can enhance the efficacy of personalized tES.

SIGNIFICANCE STATEMENT This study demonstrated that, in humans, transcranial individual neurodynamics stimulation (tIDS), which mimics the endogenous dynamics of the target neuronal pools, effectively changes the excitability of these pools. tIDS holds promise for high-efficacy personalized neuromodulations based on individual local neurodynamics.

Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior

Cocaine self-administration increases expression of GluA1 subunits in ventral tegmental area (VTA) dopamine neurons, which subsequently enhance the motivation for cocaine. This increase in GluA1 may be dependent on concomitant NMDA receptor (NMDAR) activation during self-administration, similar to cocaine-induced long-term potentiation in the VTA. In this study, we used viral-mediated expression of a dominant-negative GluN1 subunit (HSV-dnGluN1) in VTA neurons to study the effect of transient NMDAR inactivation on the GluA1 increases induced by chronic cocaine self-administration in male rats. We found that dnGluN1 expression in the VTA limited to the 3 weeks of cocaine self-administration prevents the subsequent increase in tissue GluA1 levels when compared with control infusions of HSV-LacZ. Surprisingly, dnGluN1 expression led to an enhancement in the motivation to self-administer cocaine as measured using a progressive ratio reinforcement schedule and to enhanced cocaine seeking measured in extinction/reinstatement tests following an extended 3 week withdrawal period. Despite blocking tissue GluA1 increases in cocaine self-administering animals, the HSV-dnGluN1 treatment resulted in increased membrane levels of GluA1 and GluN2B, along with markedly higher locomotor responses to intra-VTA infusions of AMPA, suggesting a paradoxical increase in VTA AMPA receptor responsiveness. Together, these data suggest that NMDARs mediate cocaine-induced increases in VTA GluA1 expression, but such transient NMDAR inactivation also leads to compensatory scaling of synaptic AMPA receptors that enhance the motivational for cocaine.

SIGNIFICANCE STATEMENT Dopamine neurons in the ventral tegmental area (VTA) are critical substrates of drug rewards. Animal models indicate that chronic cocaine use enhances excitatory glutamatergic input to these neurons, making them more susceptible to environmental stimuli that trigger drug craving and relapse. We previously found that self-administration of cocaine increases AMPA glutamate receptors in the VTA, and this effect enhances motivation for cocaine. Here we report that the mechanism for this upregulation involves NMDA receptor activity during cocaine use. While interference with NMDA receptor function blocks AMPA receptor upregulation, it also produces a paradoxical enhancement in membrane AMPA receptor subunits, AMPA responsiveness, and the motivation for cocaine. Thus, pharmacotherapy targeting NMDA receptors may inadvertently produce substantial adverse consequences for cocaine addiction.

Phosphorylated CCAAT/Enhancer Binding Protein {beta} Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies

Chronic pain is increasingly recognized as an important comorbidity of HIV-infected patients, however, the exact molecular mechanisms of HIV-related pain are still elusive. CCAAT/enhancer binding proteins (C/EBPs) are expressed in various tissues, including the CNS. C/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO₂^·–), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNFα bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO₂^·–, pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targeted O₂^·–scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBPβ. Knockdown of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBPβ. These results suggested that the pathway of TNFα/TNFRI–mtO₂^·––pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα in vitro and repeated intrathecal injection of recombinant TNFα in naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment.

SIGNIFICANCE STATEMENT Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPβ (pC/EBPβ) influences AIDS progression, but it is still not clear about the exact role of pC/EBPβ and the detailed upstream factors of pC/EBPβ in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPβ was triggered by TNFα/TNFRI–mtO₂^·––pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα in vitro, and by repeated intrathecal injection of recombinant TNFα in naive rats. The present results revealed the functional significance of TNFα/TNFRI–mtO₂^·––pCREB–pC/EBPβ signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.

Local Inhibition of PERK Enhances Memory and Reverses Age-Related Deterioration of Cognitive and Neuronal Properties

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of four known kinases that respond to cellular stress by deactivating the eukaryotic initiation factor 2 α (eIF2α) or other signal transduction cascades. Recently, both eIF2α and its kinases were found to play a role in normal and pathological brain function. Here, we show that reduction of either the amount or the activity of PERK, specifically in the CA1 region of the hippocampus in young adult male mice, enhances neuronal excitability and improves cognitive function. In addition, this manipulation rescues the age-dependent cellular phenotype of reduced excitability and memory decline. Specifically, the reduction of PERK expression in the CA1 region of the hippocampus of middle-aged male mice using a viral vector rejuvenates hippocampal function and improves hippocampal-dependent learning. These results delineate a mechanism for behavior and neuronal aging and position PERK as a promising therapeutic target for age-dependent brain malfunction.

SIGNIFICANCE STATEMENT We found that local reduced protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) expression or activity in the hippocampus enhances neuronal excitability and cognitive function in young normal mice, that old CA1 pyramidal cells have reduced excitability and increased PERK expression that can be rescued by reducing PERK expression in the hippocampus, and that reducing PERK expression in the hippocampus of middle-aged mice enhances hippocampal-dependent learning and memory and restores it to normal performance levels of young mice. These findings uncover an entirely new biological link among PERK, neuronal intrinsic properties, aging, and cognitive function. Moreover, our findings propose a new way to fight mild cognitive impairment and aging-related cognitive deterioration.

Endocannabinoid-Specific Impairment in Synaptic Plasticity in Striatum of Huntington's Disease Mouse Model

Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Before a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High-frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128 SPNs. Indirect pathway SPNs, which are more vulnerable in HD, were most affected. Our experiments show metabotropic glutamate receptor and endocannabinoid 2-arachidonoylglycerol-dependent plasticity, as well as direct CB1 activation by agonists, was similar in YAC128 and FVB/N wild-type SPNs suggesting that presynaptic CB1 is functioning normally. These results are consistent with a specific impairment in postsynaptic anandamide synthesis in YAC128 SPN. Strikingly, although suppression of degradation of anandamide was not effective, elevating 2-arachidonoylglycerol levels restored long-term depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in HD.

SIGNIFICANCE STATEMENT Huntington's disease (HD) is an inherited neurodegenerative disease with no cure. Recent studies find impairment of the endocannabinoid system in animal models but the functional implication for synaptic plasticity in HD remains unclear. Sepers et al. show a selective deficit in synaptic plasticity mediated by the endocannabinoid anandamide, but not 2-arachidonoylglycerol in a mouse model of HD. The deficit is rescued by selectively elevating levels of 2-arachidonoylglycerol produced on-demand. This mechanism could be targeted in the development of future therapeutics for HD.

Entorhinal Tau Pathology, Episodic Memory Decline, and Neurodegeneration in Aging

The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with β-amyloid (Aβ). We used [¹⁸F]AV-1451 and [¹¹C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how in vivo tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults (n = 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aβ status. There was no interactive effect of MTL tau with Aβ on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aβ. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (n = 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aβ.

SIGNIFICANCE STATEMENT Tau tangles and β-amyloid (Aβ) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aβ affects this relationship. Using tau-specific and Aβ-specific positron emission tomography tracers, we show that in vivo MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aβ. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.

MT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding

Cell-surface molecules are dynamically regulated at the synapse to assemble and disassemble adhesive contacts that are important for synaptogenesis and for tuning synaptic transmission. Metalloproteinases dynamically regulate cellular behaviors through the processing of cell surface molecules. In the present study, we evaluated the role of membrane-type metalloproteinases (MT-MMPs) in excitatory synaptogenesis. We find that MT3-MMP and MT5-MMP are broadly expressed in the mouse cerebral cortex and that MT3-MMP loss-of-function interferes with excitatory synapse development in dissociated cortical neurons and in vivo. We identify Nogo-66 receptor (NgR1) as an MT3-MMP substrate that is required for MT3-MMP-dependent synapse formation. Introduction of the shed ectodomain of NgR1 is sufficient to accelerate excitatory synapse formation in dissociated cortical neurons and in vivo. Together, our findings support a role for MT3-MMP-dependent shedding of NgR1 in regulating excitatory synapse development.

SIGNIFICANCE STATEMENT In this study, we identify MT3-MMP, a membrane-bound zinc protease, to be necessary for the development of excitatory synapses in cortical neurons. We identify Nogo-66 receptors (NgR1) as a downstream target of MT3-MMP proteolytic activity. Furthermore, processing of surface NgR1 by MT3-MMP generates a soluble ectodomain fragment that accelerates the formation of excitatory synapses. We propose that MT3-MMP activity and NgR1 shedding could stimulate circuitry remodeling in the adult brain and enhance functional connectivity after brain injury.

Sleep-Stage-Dependent Hippocampal Coordination with Cingulate and Retrosplenial Association Cortices

New Reviewer Mentoring Program

Long-Term Safety and Efficacy of Botulinum Toxin A Treatment in Adolescent Patients with Axillary Bromhidrosis

Abstract

Background

For adolescent bromhidrosis, the long-term safety and efficacy of botulinum toxin type A (BTX-A) treatment are not clear to date.

Patients and Methods

From June 2011 to July 2016, 62 adolescent patients with primary axillary bromhidrosis were recruited and 50 U of BTX-A was administered in each axilla. Repetitive injections were performed when the malodor returned.

Results

The average follow-up was 2.64 years. There were no reported local or systemic adverse effects. After the first BTX-A injection, 61.3% of patients (38/62) maintained the duration of more than 4 weeks. Of these patients, 21 patients underwent two sessions, 8 patients underwent three sessions, and 4 patients underwent four sessions. Twenty-four of sixty-two (38.7%) of patients had the duration of < 4 weeks. The second injection with the same dose was immediately administered, and the resulting duration increased to 9 weeks. Nineteen patients received the third injection with 100 U per underarm, and the resulting duration was extended up to 16 weeks. Overall, 82% of patients (51/62) ranked the BTX-A treatment to be very good or good.

Conclusion

For adolescent axillary bromhidrosis, BTX-A injection is safe and effective over a long-term follow-up. The duration of efficacy is variable, and the dosage should be fine-tuned based on the individual response.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

Bosentan for Cutaneous Ulcers in Anti-MDA5 Dermatomyositis

This case report describes the use of bosentan for treatment of cutaneous ulcers in a patient with anti-MDA5 dermatomyositis.

Nonhealing Crusted Scalp Lesions in a 4-Year-Old Boy

A 4-year-old boy presented with a 3-year history of nonhealing scalp lesions; physical examination revealed multiple disseminated erythematous papules, petechial hemorrhages, and yellowish crusts. What is your diagnosis?

Variable Response to Naltrexone in Patients With Hailey-Hailey Disease

This case series presents 3 cases of patients with Hailey-Hailey disease demonstrating varying responses to naltrexone.

Generalized Lichen Nitidus Following Anti–PD-1 Antibody Treatment

This case report describes the occurrence of generalized lichen nitidus following anti–PD-1 antibody treatment.

Skin Microbiome and Gene Mutations in Adult Atopic Dermatitis

This case-control study examines skin and nasal microbiome diversity and composition in patients with atopic dermatitis.

Mechanistic investigation of visible light driven photocatalytic inactivation of E. coli by Ag-AgCl/ZnFe 2 O 4

Abstract

In this study, photocatalytic inactivation of Escherichia coli was investigated over magnetic nanocomposite Ag-AgCl/ZnFe₂O₄. The nanocomposite demonstrated efficient photocatalytic activity by complete inactivation of the bacteria within 60 min of visible light irradiation. The anions HPO₄²⁻ and SO₄²⁻ were found to play the most important role in the inhibition of photocatalytic inactivation of E. coli. A systematic investigation of mechanism of photocatalytic bacterial inactivation was carried out based on cell membrane injury test, scanning electron microscopy (SEM) of bacterial morphology changes, Fourier transform infrared (FTIR) spectroscopy of E. coli cells before and after treatment, superoxide dismutase (SOD) and catalase (CAT) activity assay, and role of various reactive oxygen species (ROS). The activities of SOD and CAT enzymes were found to decrease due to the ROSs attacks during photocatalytic inactivation. The ROS produced in the photocatalytic disinfection severely altered the bacterial permeability and led to protein fragmentation, release of ions, and generation of protein carbonyl derivatives. The leaked cytoplasmic substances and cell debris were further degraded and, ultimately, mineralized with prolonged photocatalytic treatment.

Novel Injection Technique for Malar Cheek Volume Restoration

Carboxytherapy for treatment of localized chronic plaque psoriasis: Clinical and histopathologic evaluation

Summary

Background

Multiple treatment options are introduced in treatment of chronic localized plaque psoriasis but with poor adherence and poor patients' satisfaction resulting in poor treatment outcome.

Objective

In this pilot study, we investigated the safety and efficacy of carboxytherapy in treatment of chronic localized plaque psoriasis.

Methods

Thirty adult patients with chronic localized plaque psoriasis were enrolled in this study. The patients received carboxytherapy injection once/week for 8 weeks. Patients were clinically and histpathologically evaluated 2 weeks after the last treatment. Clinical response was evaluated by investigator's global assessment, total sign score, and 5-point scale for perilesional erythema. We performed 10-point visual analog scale for patient's satisfaction, and side effects. Three months after the last session we evaluate recurrence using 10-point scale.

Results

Carboxytherapy achieved treatment success in 26.6% according to investigator's global assessment and total sign score and 70% of the patients demonstrated absence of perilesional erythema. Patients were satisfied with no reported side effects. Recurrence area was within 1% -10% of the baseline area in 83.3% of the improved patients.

Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer.

Nivolumab associated bone marrow necrosis

Nivolumabimmunotherapybone marrow necrosis

Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis on Bronchiolitis Hospitalizations among High-risk Infants

Abstract

We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born 1996-2008 and enrolled in Kaiser Permanente Northern California. During the RSV season (November-March), RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days as unprotected period(s). Bronchiolitis hospitalizations were determined using the International Classification of Diseases Ninth Revision codes during RSV season. We used proportional hazard model to estimate bronchiolitis hospitalization risk comparing infants' protected period(s) with unprotected period(s). Infants who ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when comparing protected periods to unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk in bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94). Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible based on in-place AAP guidelines at birth would no longer be eligible, but nearly all with CLD remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt under the new AAP guidelines.

Response to Braun

Differential Susceptibility in Ambient Particle-Related First-Ever Stroke Onset Risk: Findings From a National Case-Crossover Study

Abstract

Different populations may respond differently to ambient fine particulate (PM_2.5) exposure; however, less is known about the distribution of susceptible individuals among the entire population. We conducted a time-stratified case-crossover design to assess associations between stroke risk and PM_2.5. During 2013–2015, 1,356 first-ever stroke onset events were derived from a large representative sample, the China National Stroke Screening Survey (CNSSS) database; daily PM_2.5 averages with a spatial resolution of 0.1° were estimated using a data assimilation approach combining satellite measurements, air model simulations and monitoring values. The distribution of susceptibility was derived according to individual-specific effects of PM_2.5 modified by different combinations of individual-level characteristics and their joint frequencies among all the CNSSS participants (n = 1,292,010). We found that the first-ever stroke onset was statistically significant associated with PM_2.5 (odds ratio = 1.049 (95% confidence interval: 1.038, 1.061) per 10-μg/m³). This association was modified by demographic (e.g., sex), lifestyle (e.g., overweight/obesity) and medical history variables (e.g., diabetes). The combined effects of PM_2.5 varied from 0.966 (0.920, 1.013) to 1.145 (1.080, 1.215) per 10-μg/m³ increment in different subpopulations. We found that most of the CNSSS participants were at increased risk of PM_2.5-related stroke, while only a small proportion were highly susceptible.

Neighborhood disadvantage and body mass index: a study of residential relocation

Abstract

Natural experiments, such as longitudinal observational studies which follow-up residents as they relocate, provide a strong basis to infer causation between the neighborhood environment and health. This study examined whether changes in the level of neighborhood disadvantage were associated with changes in body mass index (BMI) following residential relocation. This analysis included data from 928 residents who relocated between 2007 and 2013, across four waves of the HABITAT study in Brisbane, Australia. Neighborhood disadvantage was measured using a census-derived composite index. For individual-level data participants self-reported their height, weight, education, occupation and household income. Data were analyzed using multilevel (hybrid) linear models. Women residing in less disadvantaged neighborhoods had a lower BMI, but there was no association among men. Neighborhood disadvantage was not associated with within-individual changes in BMI among men or women when moving to a new neighborhood. Despite a growing body of literature suggesting an association between neighborhood disadvantage and BMI, the current study suggests that this association may not be causal among mid-older aged adults. Observing associations between neighborhood socioeconomic disadvantage and BMI over the life course, including the impact of residential relocation in the younger years remains a priority for future research.

When do Exposure Biomarkers Reflect More than Just Exposure?

Histological features and outcome of inverted type-A melanocytic nevi

Abstract

The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a preexisting nevus, causing over-interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark's) level of IV-V, there was no ulceration, significant regression or inflammation. Up to two mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that "inverted type A nevus" might be considered a variant of the two.

Reliability and Validity of iscorEB (Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa)

Summary

Background

Epidermolysis bullosa (EB) is a group of rare and currently incurable genetic blistering disorders. As more pathogenic driven therapies are being developed, the need for EB-specific validated outcomes measures designed for use in clinical trials is becoming important.

Objectives

We previously reported on development of an instrument for scoring clinical outcomes of research for Epidermolysis Bullosa (iscorEB), a new combined clinician and patient reported outcomes tool. We proceeded to test the reliability and construct validity of iscorEB in this study.

Methods

Observational study consisting of independent one-day assessments (6 assessors) at 2 academic hospitals. The assessments consisted of iscorEB clinician (iscorEB-c), Birmingham Epidermolysis Bullosa Severity (BEBS), and global severity assessment for physicians; and iscorEB patient (iscorEB-p), Quality of Life in Epidermolysis Bullosa (QOLEB) and Children's Dermatology Life Quality Index (CDLQI) for patients. Construct validity and intra-class correlation coefficients (ICC) for inter-observer, intra-observer, and test-retest reliability were calculated.

Results

Thirty one patients with a mean age of 19.5 years (1.8-45.2) were included. Disease severity was mild in 42%, moderate in 29% and severe in 29% of cases. The inter-observer ICC was 0.96 for both the clinician-reported section of iscorEB-c and BEBS. The ICC for intra-observer reliability was 0.91 and 0.70 for the skin and mucosal domains of iscorEB-c, respectively. Cronbach's alpha for iscorEB-c was 0.89. iscorEB-p's test-retest reliability was 0.97, and Cronbach's alpha was 0.84. The clinical score differentiated between subjects with mild, moderate and severe disease, and both clinical and patient subscores discriminated between recessive dystrophic EB and other EB subtypes.

Conclusion

iscorEB has robust reliability and construct validity, including strong ability to distinguish EB types and severities. Further studies are planned to test its responsiveness to change.

This article is protected by copyright. All rights reserved.

Localised inflammatory reactions at sites of subcutaneous methotrexate injections during treatment with ultraviolet B

Abstract

Ultraviolet B (UVB) phototherapy may be used in combination with methotrexate to treat psoriasis. When given in high doses as chemotherapy, methotrexate can induce a "radiation recall" reaction where a rash develops at sites of previous exposure to sunlight or radiotherapy, and where keratinocyte necrosis is a prominent histopathological finding¹. However, this reaction does not seem to occur when methotrexate, given orally in conventional dermatological doses, is combined with UVB^{2, 3}.

This article is protected by copyright. All rights reserved.

The use of methotrexate in adolescents: contraception, confidentiality and consent

The British Association of Dermatologist's recently published guidelines for safe and effective prescribing of methotrexate address on- and off-licence use in adults and children,¹ but should more attention be paid to the group in between, adolescents?

This article is protected by copyright. All rights reserved.

Treatment of disabling headache with greater occipital nerve injections in a large population of childhood and adolescent patients: a service evaluation

Pediatric headache disorders can be extremely disabling, with marked reduction in the quality of life of children and their carers. Evidenced-based options for the treatment of primary headache disorders with ...

High lithium tolerance of Apocynum venetum seeds during germination

Abstract

Identification and use of lithium (Li) accumulator plants is a promising strategy to remediate Li-contaminated soil. Apocynum venetum is reported as a Li accumulator. However, its tolerance to Li salt during germination is still unknown. The primary aim of this study was to investigate the effects of two Li salts on seed germination of A. venetum. At the same concentrations, germination percentages in LiCl solution were higher than that in Li₂CO₃ solution. At 25 °C, seeds germinated to 4–90% at 0–400 mmol L⁻¹ LiCl and 3–91% at 0–150 mmol L⁻¹ Li₂CO₃. Low concentration (0–50 mmol L⁻¹) of LiCl did not significantly affect germination percentage. The simulated critical value (when germination percentage is 50%) in LiCl solution is 196 mmol L⁻¹, and 36 mmol L⁻¹ for Li₂CO₃. Activity of α-amylase, contents of MDA, soluble sugar, and proline were dramatically affected by Li salts, especially at medium and late germination stages. When compared with control, α-amylase activity of seeds under 25 mmol L⁻¹ LiCl and 10 mmol L⁻¹ Li₂CO₃ did not show significant difference. Germination percentage and index, radicle length, and physiological parameters indicate A. venetum seeds are highly tolerant to Li salts during germination, especially LiCl.

Anticancer activity of crocin against cervical carcinoma (HeLa cells): Bioassessment and toxicity evaluation of crocin in male albino rats

Publication date: Available online 17 January 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Zuiming Jiang, Min Gu, Jiaqiang Liu, Huiyuan Li, Jun Peng, Yuejun Zhang
The present study was aimed to investigate anticancer activity of crocin against cervical carcinoma and bio-assessment and toxicological evaluation in male albino rats. Effect of crocin on cell viability (anticancer activity) was determined against cervical carcinoma cells. Chronic effect of crocin on body weight changes, serum enzymes, serum biochemical markers, lipid peroxidation, hematological markers and DNA damage in male albino rats were determined. Cell survival rate was reduced 98.4, 95.7, 87.2, 81.1 and 73.1% at 25, 50, 75, 100 and 125 mg/l of crocin respectively. Cell viability was reduced 97.1, 96.4, 85.5, 78.4 and 70.2% at 25, 50, 75, 100 and 125 mg/l of crocin respectively. Crocin reduced body weight significantly at 30 and 60th day. Alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, bilirubin, albumin and total protein were decreased, while glucose, cholesterol, TG, and GSH were increased. Hemoglobin (Hb), white blood cells (WBC), lymphocytes, neutrophil and packed cell volume (PCV) were altered following crocin treatment. Necrosis, fibrosis, mononuclear infiltration, angiogenesis and DNA fragmentation were also noted. Taking all these data together, it is suggested that the crocin could be a potential antitumor agent against cervical carcinoma. However, the altered histological, biochemical and hematological markers may lead to an adverse effect on the cellular metabolism and physiological activity.

Developmental variation during seed germination and biochemical responses of Brassica rapa exposed to various colored lights

Publication date: Available online 16 January 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Tausif Nawaz, Nisar Ahmad, Shahid Ali, Maaz Khan, Hina Fazal, Shahid Akbar Khalil
Light acting as elicitor or stress inducer, it plays a pivotal role in all developmental processes of plant providing necessary building blocks for growth and primary and secondary metabolites production. The main objective of the current study was to investigate the individual effect of colored lights on developmental processes and production of polyphenolics contents in Brassica rapa. In this study, the red and white lights (control) were found to be the most effective sources for seed germination (91%) in Brassica rapa. Similarly, red light enhanced radicle growth (102 mm), while green light suppressed radicle growth (60 mm) as compared to control (67 mm). The red light also promoted the plumule growth (50 mm) as compared to control (37 mm). The maximum biomass gain (67 mg) was observed under red light as compared to control (55 mg). Currently, the maximum total phenolics content (9.49 mg/g-DW) and phenolics production (379.616 mg/L) was observed under the influence of blue lights as compared to control (0.23 mg/g-DW and 8.91 mg/L). Similarly, the blue lights also enhanced the biosynthesis of total flavonoids content (2.2611 mg/g-DW) and flavonoids production (90.44 mg/L) as compared to control (0.0318 md/g-DW and 0.8268 mg/L). The current results represents that red and blue lights are the most effective sources for plantlets development and production of polyphenolics content in Brassica rapa.

Surface active gold nanoparticles biosynthesis by new approach for bionanocatalytic activity

Publication date: Available online 16 January 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): S. Vasantharaj, N. Sripriya, M. Shanmugavel, E. Manikandan, A. Gnanamani, P. Senthilkumar
In the present day, nanotechnology is one of the most promising leading scientific and potentials areas in modern key technology development toward to the humankind. The synthesis of noble metal nanoparticles (NPs) is an expanding research area due to the possible applications for the development of bio-medical applications. Eco-friendly approach for the biosynthesis of gold nanoparticles (AuNPs) using the aqueous extract from Ruellia tuberosa and Phyllanthus acidus (leaf and twig) for the first time. Surface active AuNPs were characterized by UV–Vis spectroscopy, FTIR (Fourier transform infrared) spectroscopy, DSC (differential scanning colorimetry), DLS (dynamic light scattering) and environmental SEM (scanning electron microscope) analysis at room temperature (RT). Enhanced surface plasmon resonance (SPR) absorbance UV visible optical spectra were detected in the range of 552, 548, 558 and 536 nm. SEM and DLS (transmission mode) analysis confirmed the morphology of the nanoparticles to be spherical with the average size in the range of 88.37, 94.31, 82.23 and 81.36 nm. Further they have enhanced the enzyme activity on α-amylase, cellulase, and xylanase. The results suggest that the phyto-fabricated AuNPs from R. tuberosa and P. acidus is simple, less expensive, eco-friendly, green synthesis and also can be exploited for the potential future industrial and bio-medical applications.

Graphical abstract

Near-infrared heat lamp therapeutic effect on paraoxonase 1 and myeloperoxidase as potential biomarkers of redox state changes induced by γ-irradiation in albino rats

Publication date: Available online 16 January 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): N. Abdel-Magied, A.G. Ahmed, S.M. Shedid
Infrared radiation has a potential therapeutic effect in some diseases. The aim of this study was to estimate the therapeutic role of near infrared heat lamp (NIRHL) on the variations of the activity of paraoxonase 1 (PON1) and myeloperoxidase (MPO), in relation to lipid disorders, associated with oxidative stress in rats gamma-irradiated. In addition, study the effect of the duration of NIRHL treatment. Animals were divided into six groups. The results revealed that irradiated rats treated with NIRHL 20 min/once/day showed positive modulation of PON1 and MPO linked to significant improvement of lipid disorders evidenced by lower triglycerides, low density lipoprotein cholesterol (LDL-C), oxidized low density lipoprotein cholesterol (oxLDL-C) and higher density lipoprotein cholesterol (HDL-C) as well as significant amelioration of redox state, manifested by markedly increase of glutathione (GSH) content, total antioxidant capacity (TAC) associated with a noticeable decrease of pro-inflammatory cytokines.(TNF-α, IL-1 beta and IL-6), nitric oxide (NO), nitric oxide synthase (NOs), malondialdehyde (MDA), compared to irradiated rats. The results showed also that the NIRHL treatment for 20 min/twice/day had negative effects on the previous parameters and on the behavior of rats such as itching, irritability, dyspnea and death in normal as well as, irradiated rats. In conclusion, the results in this study show that NIRHL therapy for a short time can effectively prevent the lipid disorders induced by radiation through the positive modulation mechanism of PON1 and MPO enzymes and improvement of oxidative stress.

Development of bupivacaine decorated reduced graphene oxide and its local anesthetic effect—In vivo study

Publication date: Available online 16 January 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Zhi Zhang, Xin Zhang, Aixiang Li, Chuangen Ma
The present works aims to develop bupivacaine modified reduced graphene oxide (BPV/RGO), and comparative evaluation of their anesthetic effect with free bupivacaine (BPV). The prepared BPV/RGO was studied by using various spectroscopic and microscopic characterization studies. In vitro drug release from BPV/RGO was studied using HPLC analysis. The cytotoxicity of BPV/RGO was studied against fibroblast (3T3) cells. In vivo evaluation of anesthetic effects was performed on animal models. BPV/RGO showed a prolonged in vitro release and lower cytotoxicity when compared to free BPV. Also, BPV/RGO showed a significantly prolonged analgesic effect when compared to free BPV. Further, the prepared BPV/RGO drug delivery system demonstrated to function as gifted to overcome the drawbacks of free BPV and other available drug delivery systems by prolonging the anesthetic effect with poor cytotoxicity.

Graphical abstract

Analysis of metal tolerance in Rhizobium leguminosarum strains isolated from an ultramafic soil

Abstract

Natural habitats containing high amounts of heavy metals provide a valuable source of bacteria adapted to deal with metal toxicity. A functional analysis of the population of legume endosymbiotic bacteria in an ultramafic soil was undertaken by studying a collection of Rhizobium leguminosarum bv viciae (Rlv) isolates obtained using pea as trap plant. One of the isolates, Rlv UPM1137, was selected on the basis of its higher tolerance to nickel and cobalt and presence of inducible mechanisms for such tolerance. A random transposon mutagenesis of Rlv UPM1137 allowed the generation of fourteen transposant derivatives with increased nickel sensitivity; five of these transposants were also more sensitive to cobalt. Sequencing of the insertion sites revealed that one of the transposants (D2250) was affected in a gene homologous to the Cation Diffusion Facilitator (CDF) gene dmeF first identified in the metal-resistant bacterium Cupriavidus metallidurans CH34. The symbiotic performance of D2250 and two other transposants bearing single transposon insertions was unaffected under high metal conditions, suggesting that, in contrast to previous observations in other Rlv strain, metal tolerance in UPM1137 under symbiotic conditions might be supported by functional redundancy between several mechanisms.

The unexpected function of a Flavin-dependent oxidoreductase (Fox) from Variovorax paradoxus TBEA6.

Abstract

3,3'-Thiodipropionic acid (TDP) is used as an additive in food and cosmetic industry and as precursor substrate for biotechnical polythioester production. Its catabolism was investigated in Variovorax paradoxus TBEA6 previous to this study. It was reported that the insertion of the transposon Tn5::mob into a gene showing high homology to flavin-dependent oxidoreductases (fox) resulted in impaired growth with TDP. Therefore, it was assumed that the initial cleavage of TDP is catalyzed by an FAD-dependent oxidoreductase (Fox, VPARA_05580). Accordingly, fox was heterologously expressed as a thioredoxin fusion protein. Analytical size exclusion chromatography revealed a homodimeric structure and the presence of the cofactor FAD. In vitro experiments showed that Fox_TBEA6 is a D-2-hydroxy acid specific dehydrogenase and that its activity is enhanced in presence of either Ni²⁺, Co²⁺ or Zn²⁺. Cleavage of TDP by Fox_TBEA6 was not observed. The findings are contrary to restricted growth with TDP of the transposon mutants and the previously published deletion mutant V. paradoxus TBEA6 Δfox. In this study, this contradiction was investigated by generation of additional deletion mutants, in which partial or complete deletion of fox did not affect utilization of TDP, and the mapping of single nucleotide polymorphisms (SNPs) in V. paradoxus TBEA6 Δfox.

Is consciousness intrinsically valuable?

Abstract

There are some things that we think are intrinsically valuable, or valuable for their own sake. Is consciousness—subjective, qualitative experience—one of those things? Some theorists favor the positive view, according to which consciousness is intrinsically valuable. According to a positive theorist, consciousness itself accrues intrinsic value, independent of the particular kind of experience instantiated. In contrast, I favor the neutral view, according to which consciousness is neither intrinsically valuable nor disvaluable. The primary purpose of this paper is to clarify what is at stake when we ask whether consciousness is intrinsically valuable, to carve out the theoretical space, and to evaluate the question rigorously. The secondary purpose is to show why the neutral view is attractive and why certain arguments for the positive view do not work.

Introspecting knowledge

Abstract

If we use "introspection" just as a label for that essentially first-person way we have of knowing about our own mental states, then it's pretty obvious that if there is such a thing as introspection, we know on that basis what we believe, and want, and intend, at least in many ordinary cases. I assume there is such a thing as introspection. So I think the hard question is how it works. But can you know that you know on the basis of introspection? Well, that all depends on how introspection works. I present one account of how introspection works and argue that on that account, you can know that you know ordinary empirical things on the basis of introspection. As far as how we know about them is concerned, there's no principled difference between the factive and non-factive mental states.

Calcium hydroxylapatite treatment of human skin: evidence of collagen turnover through picrosirius red staining and circularly polarized microscopy

Aicardi-Goutières syndrome: cold-induced acral blemish is not always cryoglobulinaemic vasculitis or chilblain lupus

Subcutaneous basal cell carcinoma

Dermoscopy of basal cell carcinoma

Summary

Dermoscopy is widely used in dermatological practice. The method increases the accuracy of basal cell carcinoma (BCC) detection. Pigmented and nonpigmented variants of basal cell carcinoma present different dermoscopic features. Specific dermoscopy criteria have been recognized in different subtypes of BCC. Differentiation of superficial BCC from other subtypes is the most important issue, as it may determine further management decisions.

Acute generalized exanthematous pustulosis induced by a digestive enzyme drug, Festal®

The relationship between target joints and direct resource use in severe haemophilia

Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related dir...

Hair Cortisol is Elevated in Erythropoietic Protoporphyria Patients and Correlates with Body Mass Index and Quality of Life

Entartungsrisiko von gutartigen Knochenläsionen

Zusammenfassung

Ziel

Benigne Knochenläsionen wie einige Tumoren oder nichtneoplastische Läsionen besitzen in bestimmten Fällen ein nicht unerhebliches Risiko einer malignen Entartung. Das Wissen um dieses ist wesentlich, da die Patientenberatung und -führung entsprechend angepasst werden muss. Ziel dieser Arbeit ist es, die typischen Läsionen aufzuzeigen sowie das relative Risiko und den potenziellen Verlauf darzustellen.

Material und Methoden

Aus der vorhandenen Literatur und der klinischen Erfahrung wurden jene Knochenläsionen benannt, bei denen ein Potenzial zur sekundären Malignisierung besteht oder vermutet wird. Dieses wurde dann in einer dezidierten Literaturrecherche evaluiert.

Ergebnisse

Belege für die Dedifferenzierung oder sekundäre Malignität fanden sich für kartilaginäre Exostosen, Enchondromatose, Morbus Paget, fibröse Dysplasie, osteofibröse Dysplasie, Knocheninfarkt, Osteomyelitis und die synoviale Chondromatose. Für den notochordalen Tumor, das Osteoblastom und die aneurysmale Knochenzyste ist die Datenlage zu gering, um eine solche zu postulieren.

Schlussfolgerung

Es gibt benigne Läsionen, die in einer Inzidienz von bis zu 40 % in ein sekundäres Malignom übergehen können. Dieses muss in der Patientenberatung vermittelt werden. Geeignete Vorsorgeuntersuchungen, wie z. B. das Ganzkörper-MRT bei den multiplen chondroiden Läsionen, sind aufwendig, in diesen Fällen jedoch auch zu rechtfertigen.

Multicenter French harmonization study for PD-L1 IHC testing in non-small cell lung cancer

Abstract

Background

Various PD-L1 immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 testing in non-small cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDT).

Methods

IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers), platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For non-matching platforms and other antibodies, LDT were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively.

Results

28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the 5 Dako or Ventana platforms. Among 27 LDT developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance as compared to reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms.Lower concordance was observed for immune cells staining when using a 4-categories scale.

Conclusion

28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across 7 centers. Some LDT on Dako, Ventana and Leica platform achieved similar concordance, but caution is warranted for their validation. These LDT will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.

A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC.

Patients and Methods

Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and "20/20+" ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters.

Results

We identified 26 SMGs, including eight novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C>T at CpG, APOBEC overactive C>T at TpCp[A/T], and a signature featured by T>C substitution. The T>C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade.

Conclusions

We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

In reply to “Concurrent Cisplatin and radiotherapy versus Cetuximab and radiotherapy, an unsolved problem” by Guler et al.

Joint Adolescent - Adult Early Phase Clinical Trials to Improve Access to New Drugs for Adolescents with Cancer Proposals from the Multi-stakeholder Platform - ACCELERATE

Abstract

The impressive progress recently observed in adult cancers through the introduction of new drugs has not yet been translated to adolescents between 12 and 17 years of age. Currently adolescents are grouped with children, so their access to new, effective drugs already available for adults is delayed because paediatric drug development starts late relative to adult programmes. Moreover, specific early phase trials designed exclusively for adolescents in rare diseases recruit poorly, even if conducted internationally. Evidence has shown that adolescents demonstrate similar toxicity profiles, maximum tolerated doses and pharmacokinetic parameters to adults. Although they may have specific vulnerabilities and their interests should be protected, they are, in many countries in Europe, entitled to provide informed consent themselves. There are no insurmountable scientific, medical, or regulatory barriers to their participation in Phase-I to III adult trials. Based on a review of the literature, the multi-stakeholder platform ACCELERATE, with representatives from academia, patient/parent advocacy groups, regulatory agencies and pharmaceutical companies, proposes the inclusion of adolescents in adult Phase-I to III trials of cancer drugs targeting a relevant disease or mechanism of action, without requiring preceding specific paediatric trials. The trials, however, should be delivered in age-appropriate clinical care settings by clinicians with adolescent trial expertise. Joint adolescent-adult trials will not exclude adolescents from participating in paediatric trials, as these approaches are complementary. This strategy is considered to be safe, rational, efficient and would provide more clinical trial options and accelerate drug development for adolescents with cancer.

Critical appraisal of the oxidative stress pathway in vitiligo: a systematic review and meta-analysis

Abstract

Background

The pathogenesis of vitiligo remains a topic of extensive debate. This is partly due to the moderate efficacy of current treatments. The role of oxidative stress pathway in vitiligo is a popular although controversial research topic.

Objective

To clarify the role of the oxidative stress pathway in vitiligo compared to other inflammatory skin disorders and to assess the therapeutic role of antioxidants.

Methods

We conducted a systematic search of the existing literature on the aberrancies of the oxidative stress pathway in vitiligo. Subsequently, the efficacy of both topical and oral antioxidants in clinical trials was investigated.

Results

A deregulated oxidative pathway is clearly evident with elevated superoxide dismutase (SOD), decreased catalase (CAT) and increased lipid peroxidation. However, similar results have been obtained in other inflammatory skin diseases such as psoriasis, atopic dermatitis, lichen planus and urticaria. This questions the unique role of oxidative stress in the development of vitiligo. Some isolated successes have been reported with oral ginkgo biloba, polypodium leucotomos and vitamin C and E preparations, while other clinical trials have failed to show reproducible results. The use of topical antioxidants delivers in general no beneficial results.

Conclusion

The oxidative pathway is affected in vitiligo but its unique initiating or contributory role in the pathogenesis is less evident. Interesting data support the added value of oral antioxidants in vitiligo although confirmatory studies are missing.

This article is protected by copyright. All rights reserved.

Atypical presentation of eosinophilic annular erythema in a 5-year old girl

Abstract

A 5-year-old female presented with a 1-year history of slightly pruritic erythematous annular plaques covering her trunk and limbs (Figure 1). The remaining integument as wells as the mucous membranes were not affected. The lesions persisted for about one week slowly developing a more violaceous hue before disappearing.

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Dermoscopy versus reflectance confocal microscopy for the diagnosis of lentigo maligna

Abstract

Background

Several dermoscopic and in vivo reflectance confocal microscopy (RCM) diagnostic criteria of lentigo maligna (LM)/lentigo maligna melanoma (LMM) have been identified. However, no study compared the diagnostic accuracy of these techniques.

Objective

We evaluated the diagnostic accuracy of dermoscopy and RCM for LM/LMM using a holistic assessment of the images.

Methods

223 facial lesions were evaluated by 21 experts. Diagnostic accuracy of the clinical, dermoscopic and RCM examination were compared. Inter-investigator variability and confidence level in the diagnosis were also evaluated.

Results

Overall diagnostic accuracy of the two imaging techniques was good (area under the curve of the sROC function: 0.89). RCM was more sensitive (80%, versus 61%) and less specific (81% versus 92%) than dermoscopy for LM/LMM. In particular RCM showed a higher sensitivity for hypomelanotic and recurrent LM/LMM. RCM had a higher inter-investigator agreement and a higher confidence level in the diagnosis than dermoscopy.

Conclusion

RCM and dermoscopy are both useful techniques for the diagnosis of facial lesions and in particular LM/LMM. RCM is particularly suitable for the identification of hypomelanotic and recurrent LM/LMM.

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Socioeconomic Deprivation and the Burden of Head and Neck Cancer- Regional variations of Incidence and Mortality in Merseyside and Cheshire, North West, England

Abstract

Objectives

The aim of this longitudinal study is to examine the distribution of head and neck cancer (HANC) disease burden across the region comparing it to national trends.

Design

We undertook a retrospective study of routine data combining it with indicators of deprivation and lifestyle at small geographical areas within the nine Local Authorities (LAs) of Merseyside and Cheshire Network (MCCN)for head and neck cancers.

Data from the North West of England and England were used as comparator regions.

Setting

This research was undertaken by the Cheshire and Merseyside Public Health Collaborative, UK.

Participants

The Merseyside and Cheshire Region serves a population of 2.2 million. Routine data allowed us to identify HANC patients diagnosed with cancers coded ICD C00-C14 and C30-C32 within three cohorts 1998-2000, 2008-2010 and 2009-2011 for our analysis.

Main Outcome Measures

Directly age standardised incidence rates and directly age standardised mortality rates in the LAs and comparator regions were measured. Lifestyle and deprivation indicators were plotted against themand measured by Pearson's correlation coefficients.

Results

The incidence of head and neck cancer has increased across the region from 1998-2000 to 2008-2010 with a peak incidence for Liverpool males at 35/100,000 population.

Certain Middle Super Output Areas contribute disproportionately to the significant effect of incidence and mortality within LAs. Income deprivation had the strongest correlation with incidence (r =0.59) and mortality (r =0.53) of head and neck cancer.

Conclusion

Our study emphasizes notable geographical variations within the region which need to be addressed through public health measures

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