Etiology and Treatment of Congenital Festoons

Abstract

Background

Festoons and malar bags present a particular challenge to the plastic surgeon and commonly persist after the traditional lower blepharoplasty. They are more common than we think and a trained eye will be able to recognize them. Lower blepharoplasty in these patients requires addressing the lid-cheek junction and midcheek using additional techniques such as orbicularis retaining ligament (ORL) and zygomaticocutaneous ligament (ZCL) release, midface lift, microsuction, or even direct excision (Kpodzo e al. in Aesthet Surg J 34(2):235–248, 2014; Goldberg et al. in Plast Reconstr Surg 115(5):1395–1402, 2005; Mendelson et al. in Plast Reconstr Surg 110(3):885–896, 2002). The goal in these patients is to restore a smooth contour from the lower eyelid to the cheek. The review of literature shows the need for more than one surgery for treatment of the festoons (Furnas in Plast Reconstr Surg 61(4):540–546, 1978). One of the reasons WHY these cases are so challenging is that the festoons tend to persist even after surgical treatment. As Furnas said, "Malar mounds have acquired some notoriety for their persistence in the face of surgical efforts to remove them" (Furnas in Clin Plast Surg 20(2):367–385, 1993). This could be due to different etiology between acquired and congenital festoons. There are currently no cases of congenital festoons described in the literature. In the last 10 years, we have treated a total of 59 patients with festoons or malar mounds. We used the terminology of festoon for acquired cases and malar mound for congenital ones (Kpodzo et al. 2014). We were successful with treating 56 patients who developed acquired festoons later on in life; however, three cases required an additional treatment to improve residual puffiness that they had after the first operation. From the above findings, we hypothesized that there should be something common in patients with congenital festoons or malar mounds which are different from acquired festoons. All of these three patients had one thing in common, and that was a history of puffiness of the prezygomatic space since childhood. Each of these patients expressed that these conditions have been present since a young age but became worse with aging over time. To date, there are no descriptions of the cause or treatment for congenital festoons. Here, we present the first case series of three patients with congenital festoons. We discuss the possible etiology of congenital festoons, the physical exam, and the surgical approaches.

Methods

We performed a retrospective review of 59 patients who had surgical correction of festoons in the past 10 years, three of which were presented since childhood. In this paper, we will discuss the pathophysiology and the surgical treatments for congenital festoons. Only patients with festoons present since birth were included. The first two cases were treated with a subciliary blepharoplasty with release of the orbicularis retaining and zygomaticocutaneous ligaments and midface lift with canthopexy and orbicularis muscle suspension. The third case had a subciliary lower blepharoplasty approach, skin, and muscle flap and direct excision of the fat through the orbicularis from the subcutaneous space. In addition, each patient required further treatments to address supra-orbicularis fat by various methods.

Results

All patients with acquired festoons had successful results with one operation by subciliary skin muscle flap, release of the ORL and ZCL, midface lift, and muscle suspension. All three patients with congenital festoons had residual puffiness that required surgical and non-surgical treatments. There were no complications. Our first case required three surgical treatments for complete correction. The second and third cases required Kybella injections after their initial surgical treatments. The specimen of the first patient, Fig. 10, who had direct excision, showed localized fat collection immediately under the skin and above the orbicularis oculi muscle.

Conclusions

Correction of congenital festoons or malar mounds requires a combination of subciliary lower blepharoplasty with skin muscle flap, midface lift, and orbicularis muscle suspension, as well as addressing the supra-orbicularis fat via direct excision, off-label Kybella injection or liposuction.

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 www.springer.com/00266.

Studies on the effects of storage stability of bio-oil obtained from pyrolysis of Calophyllum inophyllum deoiled seed cake on the performance and emission characteristics of a direct-injection diesel engine

Abstract

The highly unbalanced nature of bio-oil composition poses a serious threat in terms of storage and utilization of bio-oil as a viable fuel in engines. So it becomes inevitable to study the variations in physicochemical properties of the bio-oil during storage to value its chemical instability, for designing stabilization methodologies. The present study aims to investigate the effects of storage stability of bio-oil extracted from pyrolyzing Calophyllum inophyllum (CI) deoiled seed cake on the engine operating characteristics. The bio-oil is produced in a fixed bed reactor at 500 °C under the constant heating rate of 30 °C/min. All the stability analysis methods involve an accelerated aging procedure based on standards established by ASTM (D5304 and E2009) and European standard (EN 14112). Gas chromatography-mass spectrometry was employed to analytically characterize the unaged and aged bio-oil samples. The results clearly depict that stabilizing Calophyllum inophyllum bio-oil with 10% (w/w) methanol improved its stability than that of the unstabilized sample thereby reducing the aging rate of bio-oil to 0.04 and 0.13 cst/h for thermal and oxidative aging respectively. Engine testing of the bio-oil sample revealed that aged bio-oil samples deteriorated engine performance and increased emission levels at the exhaust. The oxidatively aged sample showed the lowest BTE (24.41%), the highest BSEC (20.14 MJ/kWh), CO (1.51%), HC (132 ppm), NOx (1098 ppm) and smoke opacity (34.8%).

Stabilization of Microtubules Restores Barrier Function after Cytokine-induced Defects in Reconstructed Human Epidermis

A variety of human skin disorders is characterized by defects in the epidermal barrier, leading to dehydration, itchiness, and rashes. Previously published literature suggests that microtubule stabilization at the cortex of differentiating keratinocytes is necessary for the formation of the epidermal barrier.

Feedstock composition influences vermicomposting performance of Dichogaster annae relative to Eudrilus eugeniae and Perionyx excavatus

Abstract

Carbon to nitrogen (C/N) ratio influences substrate combinations and earthworm performance in vermicomposting systems. To elucidate these factor effects, a comparative evaluation of species, C/N ratio combined with feed rate, was conducted on three local earthworm species: Perionyx excavatus, Eudrilus eugeniae, and Dichogaster annae. Earthworms were stocked at similar densities and fed shredded paper (SP), cattle manure (CM), and lawn clippings (LC) combined to form C/N ratios of 28, 36, and 53. Earthworms were fed at rates of 1, 1.25, and 2 g feed (dry wt.)/g worm/day for a period of 8 weeks. Percent vermiconversion, earthworm adult and juvenile biomass, and vermicast quality were measured. Vermicast production was significantly affected by the combination of C/N ratio and feed rate and varied among species. All treatment combinations resulted in > 70% conversion, except E. eugenaie fed at the medium rate. Vermiconversion increased for P. excavatus and D. annae with increasing C/N ratio but decreased with increasing the feed rate. Vermicast EC, pH, and C/N ratio was strongly affected by species, relative to other experimental factors. D. annae showed the greatest change in biomass, which peaked at the highest feed rate and lowest C/N ratio. Average adult biomass decreased for P. excavatus with increasing feed rate, while differences were nonsignificant for E. eugenaie and D. annae. Significant increases in average juvenile biomass were only evident for D. annae in response to increasing feed rates. Feed rate had a greater influence on earthworm population dynamics and vermicast quality compared to initial feedstock C/N ratio.

Chronic obstructive pulmonary diseases related to outdoor PM 10 , O 3 , SO 2 , and NO 2 in a heavily polluted megacity of Iran

Abstract

This study was conducted to quantify, by an approach proposed by the World Health Organization (WHO), the daily hospital admissions for chronic obstructive pulmonary disease (COPD) related to exposure to particulate matter (PM₁₀) and oxidants such as ozone (O₃), sulfur dioxide (SO₂), and nitrogen dioxide (NO₂) in a heavily polluted city in Iran. For the health impact assessment, in terms of COPD, the current published relative risk (RR) and baseline incidence (BI) values, suggested by the WHO, and the 1-h O₃ concentrations and daily PM₁₀, NO₂, and SO₂ concentrations were compiled. The results showed that 5.9, 4.1, 1.2, and 1.9% of the COPD daily hospitalizations in 2011 and 6.6, 1.9, 2.3, and 2.1% in 2012 were attributed to PM₁₀, O₃, SO₂, and NO₂ concentrations exceeding 10 μg/m³, respectively. This study indicates that air quality and the high air pollutant levels have an effect on COPD morbidity. Air pollution is associated with visits to emergency services and hospital admissions. A lower relative risk can be achieved if some stringent control strategies for reducing air pollutants or emission precursors are implemented.

Interactions between tetrahydroisoindoline-1,3-dione derivatives and human serum albumin via multiple spectroscopy techniques

Abstract

Some tetrahydroisoindoline-1,3-dione derivatives (TDDs) possess potent herbicidal activity. To assess possible impacts of TDDs on humans, the interactions between TDDs and human serum albumin (HSA) were evaluated with steady-state and time-resolved fluorescence spectroscopy, synchronous fluorescence spectroscopy, Fourier transform-infrared spectroscopy, and circular dichroism spectroscopy. The thermodynamic data obtained at temperatures of 298, 307, and 316 K indicate that TDDs spontaneously bind to HSA and thus form a TDD-HSA complex. The conformation and secondary structure of HSA are changed, and the intrinsic fluorescence of HSA is statically quenched by TDDs. Moreover, the TDD-HSA complex is formed primarily through electrostatic interactions and has only one binding site on HSA. A competitive ligand-binding assay revealed that site II (subdomain IIIA) displays the greatest affinity for TDDs. In addition, an acute toxicity bioassay showed no zebrafish mortality upon exposure to 4000 μg L⁻¹ of TDDs. This work is helpful for understanding interactions between TDDs and HSA.

Answer to the comment on Castien et al. (2018) pressure pain thresholds over the cranio-cervical region in headache - a systematic review and meta-analysis

The NRP1 migraine risk variant shows evidence of association with menstrual migraine

In 2016, a large meta-analysis brought the number of susceptibility loci for migraine to 38. While sub-type analysis for migraine without aura (MO) and migraine with aura (MA) found some loci showed specificit...

Polar pesticide contamination of an urban and peri-urban tropical watershed affected by agricultural activities (Yaoundé, Center Region, Cameroon)

Abstract

Urban agriculture is crucial to local populations, but the risk of it contaminating water has rarely been documented. The aim of this study was to assess pesticide contamination of surface waters from the Méfou watershed (Yaoundé, Cameroon) by 32 selected herbicides, fungicides, and insecticides (mainly polar) according to their local application, using both grab sampling and polar organic compounds integrative samplers (POCIS). Three sampling campaigns were conducted in the March/April and October/November 2015 and June/July 2016 rainy seasons in urban and peri-urban areas. The majority of the targeted compounds were detected. The quantification frequencies of eight pesticides were more than 20% with both POCIS and grab sampling, and that of diuron and atrazine reached 100%. Spatial differences in contamination were evidenced with higher contamination in urban than peri-urban rivers. In particular, diuron was identified as an urban contaminant of concern because its concentrations frequently exceeded the European water quality guideline of 0.200 μg/L in freshwater and may thus represent an ecological risk due to a risk quotient > 1 for algae observed in 94% of grab samples. This study raises concerns about the impacts of urban agriculture on the quality of water resources and to a larger extent on the health of the inhabitants of cities in developing countries.

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Osteopenia and Multiple Fractures in an Infant With Harlequin Ichthyosis

This case report describes the occurrence of osteopenia and multiple fractures in an infant with harlequin ichthyosis.

Error in Data

In the recent article by Ashchyan et al, there were errors in the Abstract, Results, and Discussion. The correct number (percentage) of patients with comorbidities is 238 (66.9%). The article has been corrected online.

Association of Marital Status With T Stage and Management of Early-Stage Melanoma

This population-based study evaluates the association between marital status and T stage at the time of presentation and the decision for sentinel lymph node biopsy in patients with early-stage melanoma included in the Surveillance, Epidemiology, and End Results database.

Warty Fingers and Toes in a Child With Congenital Lymphedema

This case report describes the occurrence of warty fingers and toes in a child with congenital lymphedema.

Accuracy of Skin Cancer Diagnosis by Physician Assistants Compared With Dermatologists

This medical record review evaluates biopsy reports from skin cancer screening examinations to compare dermatologist vs physician assistant accuracy in diagnosing skin cancer in a large health care system.

Skin Examination Patterns and Thinner Nodular vs Superficial Spreading Melanoma at Diagnosis

This cross-sectional pooled analysis analyzes the association between skin examination practices and diagnosis with thin nodular or superficial spreading melanoma.

Erythematous Plaque on the Inferior Eyelid

A 40-year-old woman presented with an 8-year history of a growing erythematous plaque on the left lower eyelid; physical examination revealed a single plaque involving the left lower eyelid, including its border, and eyelashes were absent. What is your diagnosis?

Primary Traumatic Axonopathy in Mice Subjected to Impact Acceleration: A Reappraisal of Pathology and Mechanisms with High-Resolution Anatomical Methods

Traumatic axonal injury (TAI) is a common neuropathology in traumatic brain injury and is featured by primary injury to axons. Here, we generated TAI with impact acceleration of the head in male Thy1-eYFP-H transgenic mice in which specific populations of neurons and their axons are labeled with yellow fluorescent protein. This model results in axonal lesions in multiple axonal tracts along with blood–brain barrier disruption and neuroinflammation. The corticospinal tract, a prototypical long tract, is severely affected and is the focus of this study. Using optimized CLARITY at single-axon resolution, we visualized the entire corticospinal tract volume from the pons to the cervical spinal cord in 3D and counted the total number of axonal lesions and their progression over time. Our results divulged the presence of progressive traumatic axonopathy that was maximal at the pyramidal decussation. The perikarya of injured corticospinal neurons atrophied, but there was no evidence of neuronal cell death. We also used CLARITY at single-axon resolution to explore the role of the NMNAT2-SARM1 axonal self-destruction pathway in traumatic axonopathy. When we interfered with this pathway by genetically ablating SARM1 or by pharmacological strategies designed to increase levels of Nicotinamide (Nam), a feedback inhibitor of SARM1, we found a significant reduction in the number of axonal lesions early after injury. Our findings show that high-resolution neuroanatomical strategies reveal important features of TAI with biological implications, especially the progressive axonopathic nature of TAI and the role of the NMNAT2-SARM1 pathway in the early stages of axonopathy.

SIGNIFICANCE STATEMENT In the first systematic application of novel high-resolution neuroanatomical tools in neuropathology, we combined CLARITY with 2-photon microscopy, optimized for detection of single axonal lesions, to reconstruct the injured mouse brainstem in a model of traumatic axonal injury (TAI) that is a common pathology associated with traumatic brain injury. The 3D reconstruction of the corticospinal tract at single-axon resolution allowed for a more advanced level of qualitative and quantitative understanding of TAI. Using this model, we showed that TAI is an axonopathy with a prominent role of the NMNAT2-SARM1 molecular pathway, that is also implicated in peripheral neuropathy. Our results indicate that high-resolution anatomical models of TAI afford a level of detail and sensitivity that is ideal for testing novel molecular and biomechanical hypotheses.

Variations in Ca2+ Influx Can Alter Chelator-Based Estimates of Ca2+ Channel-Synaptic Vesicle Coupling Distance

The timing and probability of synaptic vesicle fusion from presynaptic terminals is governed by the distance between voltage-gated Ca²⁺ channels (VGCCs) and Ca²⁺ sensors for exocytosis. This VGCC-sensor coupling distance can be determined from the fractional block of vesicular release by exogenous Ca²⁺ chelators, which depends on biophysical factors that have not been thoroughly explored. Using numerical simulations of Ca²⁺ reaction and diffusion, as well as vesicular release, we examined the contributions of conductance, density, and open duration of VGCCs, and the influence of endogenous Ca²⁺ buffers on the inhibition of exocytosis by EGTA. We found that estimates of coupling distance are critically influenced by the duration and amplitude of Ca²⁺ influx at active zones, but relatively insensitive to variations of mobile endogenous buffer. High concentrations of EGTA strongly inhibit vesicular release in close proximity (20-30 nm) to VGCCs if the flux duration is brief, but have little influence for longer flux durations that saturate the Ca²⁺ sensor. Therefore, the diversity in presynaptic action potential duration is sufficient to alter EGTA inhibition, resulting in errors potentially as large as 300% if Ca²⁺ entry durations are not considered when estimating VGCC–sensor coupling distances.

SIGNIFICANT STATEMENT The coupling distance between voltage-gated Ca²⁺ channels and Ca²⁺ sensors for exocytosis critically determines the timing and probability of neurotransmitter release. Perfusion of presynaptic terminals with the exogenous Ca²⁺ chelator EGTA has been widely used for both qualitative and quantitative estimates of this distance. However, other presynaptic terminal parameters such as the amplitude and duration of Ca²⁺ entry can also influence EGTA inhibition of exocytosis, thus confounding conclusions based on EGTA alone. Here, we performed reaction–diffusion simulations of Ca²⁺-driven synaptic vesicle fusion, which delineate the critical parameters influencing an accurate prediction of coupling distance. Our study provides guidelines for characterizing and understanding how variability in coupling distance across chemical synapses could be estimated accurately.

How Does the Brain Tell Self-Motion from Object Motion?

A Gain-of-Function Mutation in the {alpha}9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity

Gain control of the auditory system operates at multiple levels. Cholinergic medial olivocochlear (MOC) fibers originate in the brainstem and make synaptic contacts at the base of the outer hair cells (OHCs), the final targets of several feedback loops from the periphery and higher-processing centers. Efferent activation inhibits OHC active amplification within the mammalian cochlea, through the activation of a calcium-permeable α9α10 ionotropic cholinergic nicotinic receptor (nAChR), functionally coupled to calcium activated SK2 potassium channels. Correct operation of this feedback requires careful matching of acoustic input with the strength of cochlear inhibition (Galambos, 1956; Wiederhold and Kiang, 1970; Gifford and Guinan, 1987), which is driven by the rate of MOC activity and short-term facilitation at the MOC–OHC synapse (Ballestero et al., 2011; Katz and Elgoyhen, 2014). The present work shows (in mice of either sex) that a mutation in the α9α10 nAChR with increased duration of channel gating (Taranda et al., 2009) greatly elongates hair cell-evoked IPSCs and Ca²⁺ signals. Interestingly, MOC–OHC synapses of L9'T mice presented reduced quantum content and increased presynaptic facilitation. These phenotypic changes lead to enhanced and sustained synaptic responses and OHC hyperpolarization upon high-frequency stimulation of MOC terminals. At the cochlear physiology level these changes were matched by a longer time course of efferent MOC suppression. This indicates that the properties of the MOC–OHC synapse directly determine the efficacy of the MOC feedback to the cochlea being a main player in the "gain control" of the auditory periphery.

SIGNIFICANCE STATEMENT Plasticity can involve reciprocal signaling across chemical synapses. An opportunity to study this phenomenon occurs in the mammalian cochlea whose sensitivity is regulated by efferent olivocochlear neurons. These release acetylcholine to inhibit sensory hair cells. A point mutation in the hair cell's acetylcholine receptor that leads to increased gating of the receptor greatly elongates IPSCs. Interestingly, efferent terminals from mutant mice present a reduced resting release probability. However, upon high-frequency stimulation transmitter release facilitates strongly to produce stronger and far longer-lasting inhibition of cochlear function. Thus, central neuronal feedback on cochlear hair cells provides an opportunity to define plasticity mechanisms in cholinergic synapses other than the highly studied neuromuscular junction.

Lateral Habenula Instructs Behaviors Using Cues for the Lack of Reward

HIPK2-Mediated Transcriptional Control of NMDA Receptor Subunit Expression Regulates Neuronal Survival and Cell Death

NMDA receptors are critical for neuronal communication. Dysfunction in NMDA receptors has been implicated in neuropsychiatric diseases. While it is well recognized that the composition of NMDA receptors undergoes a GluN2B-to-GluN2A switch in early postnatal life, the mechanism regulating this switch remains unclear. Using transcriptomic and functional analyses in brain tissues from male and female Hipk2^+/+ and Hipk2^–/– mice, we showed that the HIPK2-JNK–c-Jun pathway is important in suppressing the transcription of Grin2a and Grin2c, which encodes the GluN2A and GluN2C subunits of the NMDA receptors, respectively. Loss of HIPK2 leads to a significant decrease in JNK–c-Jun signaling, which in turn derepresses the transcription of Grin2a and Grin2c mRNA and upregulates GluN2A and GluN2C protein levels. These changes result in a significant increase of GluN2A/GluN2B ratio in synapse and mitochondria, a persistent activation of the ERK-CREB pathway and the upregulation of synaptic activity-regulated genes, which collectively contribute to the resistance of Hipk2^–/– neurons to cell death induced by mitochondrial toxins.

SIGNIFICANCE STATEMENT We identify HIPK2-JNK–c-Jun signaling as a key mechanism that regulates the transcription of NMDA receptor subunits GluN2A and GluN2C in vivo. Our results provide insights into a previously unrecognized molecular mechanism that control the switch of NMDA receptor subunits in early postnatal brain development. Furthermore, we provide evidence that changes in the ratio of NMDA subunits GluN2A/GluN2B can also be detected in the synapse and mitochondria, which contributes to a persistent activation of the prosurvival ERK-CREB pathway and its downstream target genes. Collectively, these changes protect HIPK2 deficient neurons from mitochondrial toxins.

Fractone Bulbs Derive from Ependymal Cells and Their Laminin Composition Influence the Stem Cell Niche in the Subventricular Zone

Fractones are extracellular matrix structures in the neural stem cell niche of the subventricular zone (SVZ), where they appear as round deposits named bulbs or thin branching lines called stems. Their cellular origin and what determines their localization at this site is poorly studied, and it remains unclear whether they influence neural stem and progenitor cell formation, proliferation, and/or maintenance. To address these questions, we analyzed whole-mount preparations of the lateral ventricle of male and female mice by confocal microscopy using different extracellular matrix and cell markers. We found that bulbs are rarely connected to stems and that they contain laminin α5 and α2 chains, respectively. Fractone bulbs were profusely distributed throughout the SVZ and appeared associated with the center of pinwheels, a critical site for adult neurogenesis. We demonstrate that bulbs appear at the apical membrane of ependymal cells at the end of the first week after birth. The use of transgenic mice lacking laminin α5 gene expression (Lama5) in endothelium and in FoxJ1-expressing ependymal cells revealed ependymal cells as the source of laminin α5-containing fractone bulbs. Deletion of laminin α5 from ependymal cells correlated with a 60% increase in cell proliferation, as determined by phospho-histone H3 staining, and with a selective reduction in the number of slow-dividing cells. These results indicate that fractones are a key component of the SVZ and suggest that laminin α5 modulates the physiology of the neural stem cell niche.

SIGNIFICANCE STATEMENT Our work unveils key aspects of fractones, extracellular matrix structures that are present in the SVZ that still lack a comprehensive characterization. We show that fractones extensively interact with neural stem cells, whereas some of them are located precisely at pinwheel centers, which are hotspots for adult neurogenesis. Our results also demonstrate that fractones increase in size during aging and that their interactions with neural stem and progenitor cells become more complex in old mice. Last, we show that fractone bulbs are produced by ependymal cells and that their laminin content regulates neural stem cells.

This Week in The Journal

Major Vault Protein, a Candidate Gene in 16p11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity

Microdeletion of a region in chromosome 16p11.2 increases susceptibility to autism. Although this region contains exons of 29 genes, disrupting only a small segment of the region, which spans five genes, is sufficient to cause autistic traits. One candidate gene in this critical segment is MVP, which encodes for the major vault protein (MVP) that has been implicated in regulation of cellular transport mechanisms. MVP expression levels in MVP^+/– mice closely phenocopy those of 16p11.2 mutant mice, suggesting that MVP^+/– mice may serve as a model of MVP function in 16p11.2 microdeletion. Here we show that MVP regulates the homeostatic component of ocular dominance (OD) plasticity in primary visual cortex. MVP^+/– mice of both sexes show impairment in strengthening of open-eye responses after several days of monocular deprivation (MD), whereas closed-eye responses are weakened as normal, resulting in reduced overall OD plasticity. The frequency of miniature EPSCs (mEPSCs) in pyramidal neurons is decreased in MVP^+/– mice after extended MD, suggesting a reduction of functional synapses. Correspondingly, upregulation of surface GluA1 AMPA receptors is reduced in MVP^+/– mice after extended MD, and is accompanied by altered expression of STAT1 and phosphorylated ERK, which have been previously implicated in OD plasticity. Normalization of STAT1 levels by introducing STAT1 shRNA rescues surface GluA1 and open-eye responses, implicating STAT1 as a downstream effector of MVP. These findings demonstrate a specific role for MVP as a key molecule influencing the homeostatic component of activity-dependent synaptic plasticity, and potentially the corresponding phenotypes of 16p11.2 microdeletion syndrome.

SIGNIFICANCE STATEMENT Major vault protein (MVP), a candidate gene in 16p11.2 microdeletion syndrome, has been implicated in the regulation of several cellular processes including transport mechanisms and scaffold signaling. However, its role in brain function and plasticity remains unknown. In this study, we identified MVP as an important regulator of the homeostatic component of experience-dependent plasticity, via regulation of STAT1 and ERK signaling. This study helps reveal a new mechanism for an autism-related gene in brain function, and suggests a broader role for neuro-immune interactions in circuit level plasticity. Importantly, our findings might explain specific components of the pathophysiology of 16p11.2 microdeletion syndrome.

Robust Visual Responses and Normal Retinotopy in Primate Lateral Geniculate Nucleus following Long-term Lesions of Striate Cortex

Lesions of striate cortex (V1) trigger massive retrograde degeneration of neurons in the LGN. In primates, these lesions also lead to scotomas, within which conscious vision is abolished. Mediation of residual visual capacity within these regions (blindsight) has been traditionally attributed to an indirect visual pathway to the extrastriate cortex, which involves the superior colliculus and pulvinar complex. However, recent studies have suggested that preservation of the LGN is critical for behavioral evidence of blindsight, raising the question of what type of visual information is channeled by remaining neurons in this structure. A possible contribution of LGN neurons to blindsight is predicated on two conditions: that the neurons that survive degeneration remain visually responsive, and that their receptive fields continue to represent the region of the visual field inside the scotoma. We tested these conditions in male and female marmoset monkeys (Callithrix jacchus) with partial V1 lesions at three developmental stages (early postnatal life, young adulthood, old age), followed by long recovery periods. In all cases, recordings from the degenerated LGN revealed neurons with well-formed receptive fields throughout the scotoma. The responses were consistent and robust, and followed the expected eye dominance and retinotopy observed in the normal LGN. The responses had short latencies and preceded those of neurons recorded in the extrastriate middle temporal area. These findings suggest that the pathway that links LGN neurons to the extrastriate cortex is physiologically viable and can support residual vision in animals with V1 lesions incurred at various ages.

SIGNIFICANCE STATEMENT Patients with a lesion of the primary visual cortex (V1) can retain certain visually mediated behaviors, particularly if the lesion occurs early in life. This phenomenon ("blindsight") not only sheds light on the nature of consciousness, but also has implications for studies of brain circuitry, development, and plasticity. However, the pathways that mediate blindsight have been the subject of debate. Recent studies suggest that projections from the LGN might be critical, but this finding is puzzling given that the lesions causes severe cell death in the LGN. Here we demonstrate in monkeys that the surviving LGN neurons retain a remarkable level of visual function and could therefore be the source of the visual information that supports blindsight.

Kainate Receptors Inhibit Glutamate Release Via Mobilization of Endocannabinoids in Striatal Direct Pathway Spiny Projection Neurons

Kainate receptors are members of the glutamate receptor family that function by both generating ionotropic currents through an integral ion channel pore and coupling to downstream metabotropic signaling pathways. They are highly expressed in the striatum, yet their roles in regulating striatal synapses are not known. Using mice of both sexes, we demonstrate that GluK2-containing kainate receptors expressed in direct pathway spiny projection neurons (dSPNs) inhibit glutamate release at corticostriatal synapses in the dorsolateral striatum. This inhibition requires postsynaptic kainate-receptor-mediated mobilization of a retrograde endocannabinoid (eCB) signal and activation of presynaptic CB1 receptors. This pathway can be activated during repetitive 25 Hz trains of synaptic stimulation, causing short-term depression of corticostriatal synapses. This is the first study to demonstrate a role for kainate receptors in regulating eCB-mediated plasticity at the corticostriatal synapse and demonstrates an important role for these receptors in regulating basal ganglia circuits.

SIGNIFICANCE STATEMENT The GRIK2 gene, encoding the GluK2 subunit of the kainate receptor, has been linked to several neuropsychiatric and neurodevelopmental disorders including obsessive compulsive disorder (OCD). Perseverative behaviors associated with OCD are known to result from pathophysiological changes in the striatum and kainate receptor knock-out mice have striatal-dependent phenotypes. However, the role of kainate receptors in striatal synapses is not known. We demonstrate that GluK2-containing kainate receptors regulate corticostriatal synapses by mobilizing endocannabinoids from direct pathway spiny projection neurons. Synaptic activation of GluK2 receptors during trains of synaptic input causes short-term synaptic depression, demonstrating a novel role for these receptors in regulating striatal circuits.

Cholinergic Modulation of Frontoparietal Cortical Network Dynamics Supporting Supramodal Attention

A critical function of attention is to support a state of readiness to enhance stimulus detection, independent of stimulus modality. The nucleus basalis magnocellularis (NBM) is the major source of the neurochemical acetylcholine (ACh) for frontoparietal cortical networks thought to support attention. We examined a potential supramodal role of ACh in a frontoparietal cortical attentional network supporting target detection. We recorded local field potentials (LFPs) in the prelimbic frontal cortex (PFC) and the posterior parietal cortex (PPC) to assess whether ACh contributed to a state of readiness to alert rats to an impending presentation of visual or olfactory targets in one of five locations. Twenty male Long–Evans rats underwent training and then lesions of the NBM using the selective cholinergic immunotoxin 192 IgG-saporin (0.3 μg/μl; ACh-NBM-lesion) to reduce cholinergic afferentation of the cortical mantle. Postsurgery, ACh-NBM-lesioned rats had less correct responses and more omissions than sham-lesioned rats, which changed parametrically as we increased the attentional demands of the task with decreased target duration. This parametric deficit was found equally for both sensory targets. Accurate detection of visual and olfactory targets was associated specifically with increased LFP coherence, in the beta range, between the PFC and PPC, and with increased beta power in the PPC before the target's appearance in sham-lesioned rats. Readiness-associated changes in brain activity and visual and olfactory target detection were attenuated in the ACh-NBM-lesioned group. Accordingly, ACh may support supramodal attention via modulating activity in a frontoparietal cortical network, orchestrating a state of readiness to enhance target detection.

SIGNIFICANCE STATEMENT We examined whether the neurochemical acetylcholine (ACh) contributes to a state of readiness for target detection, by engaging frontoparietal cortical attentional networks independent of modality. We show that ACh supported alerting attention to an impending presentation of either visual or olfactory targets. Using local field potentials, enhanced stimulus detection was associated with an anticipatory increase in power in the beta oscillation range before the target's appearance within the posterior parietal cortex (PPC) as well as increased synchrony, also in beta, between the prefrontal cortex and PPC. These readiness-associated changes in brain activity and behavior were attenuated in rats with reduced cortical ACh. Thus, ACh may act, in a supramodal manner, to prepare frontoparietal cortical attentional networks for target detection.

Effects of Aging on Cortical Neural Dynamics and Local Sleep Homeostasis in Mice

Healthy aging is associated with marked effects on sleep, including its daily amount and architecture, as well as the specific EEG oscillations. Neither the neurophysiological underpinnings nor the biological significance of these changes are understood, and crucially the question remains whether aging is associated with reduced sleep need or a diminished capacity to generate sufficient sleep. Here we tested the hypothesis that aging may affect local cortical networks, disrupting the capacity to generate and sustain sleep oscillations, and with it the local homeostatic response to sleep loss. We performed chronic recordings of cortical neural activity and local field potentials from the motor cortex in young and older male C57BL/6J mice, during spontaneous waking and sleep, as well as during sleep after sleep deprivation. In older animals, we observed an increase in the incidence of non-rapid eye movement sleep local field potential slow waves and their associated neuronal silent (OFF) periods, whereas the overall pattern of state-dependent cortical neuronal firing was generally similar between ages. Furthermore, we observed that the response to sleep deprivation at the level of local cortical network activity was not affected by aging. Our data thus suggest that the local cortical neural dynamics and local sleep homeostatic mechanisms, at least in the motor cortex, are not impaired during healthy senescence in mice. This indicates that powerful protective or compensatory mechanisms may exist to maintain neuronal function stable across the life span, counteracting global changes in sleep amount and architecture.

SIGNIFICANCE STATEMENT The biological significance of age-dependent changes in sleep is unknown but may reflect either a diminished sleep need or a reduced capacity to generate deep sleep stages. As aging has been linked to profound disruptions in cortical sleep oscillations and because sleep need is reflected in specific patterns of cortical activity, we performed chronic electrophysiological recordings of cortical neural activity during waking, sleep, and after sleep deprivation from young and older mice. We found that all main hallmarks of cortical activity during spontaneous sleep and recovery sleep after sleep deprivation were largely intact in older mice, suggesting that the well-described age-related changes in global sleep are unlikely to arise from a disruption of local network dynamics within the neocortex.

Visual Mismatch and Predictive Coding: A Computational Single-Trial ERP Study

Predictive coding (PC) posits that the brain uses a generative model to infer the environmental causes of its sensory data and uses precision-weighted prediction errors (pwPEs) to continuously update this model. While supported by much circumstantial evidence, experimental tests grounded in formal trial-by-trial predictions are rare. One partial exception is event-related potential (ERP) studies of the auditory mismatch negativity (MMN), where computational models have found signatures of pwPEs and related model-updating processes. Here, we tested this hypothesis in the visual domain, examining possible links between visual mismatch responses and pwPEs. We used a novel visual "roving standard" paradigm to elicit mismatch responses in humans (of both sexes) by unexpected changes in either color or emotional expression of faces. Using a hierarchical Bayesian model, we simulated pwPE trajectories of a Bayes-optimal observer and used these to conduct a comprehensive trial-by-trial analysis across the time x sensor space. We found significant modulation of brain activity by both color and emotion pwPEs. The scalp distribution and timing of these single-trial pwPE responses were in agreement with visual mismatch responses obtained by traditional averaging and subtraction (deviant-minus-standard) approaches. Finally, we compared the Bayesian model to a more classical change model of MMN. Model comparison revealed that trial-wise pwPEs explained the observed mismatch responses better than categorical change detection. Our results suggest that visual mismatch responses reflect trial-wise pwPEs, as postulated by PC. These findings go beyond classical ERP analyses of visual mismatch and illustrate the utility of computational analyses for studying automatic perceptual processes.

SIGNIFICANCE STATEMENT Human perception is thought to rely on a predictive model of the environment that is updated via precision-weighted prediction errors (pwPEs) when events violate expectations. This "predictive coding" view is supported by studies of the auditory mismatch negativity brain potential. However, it is less well known whether visual perception of mismatch relies on similar processes. Here we combined computational modeling and electroencephalography to test whether visual mismatch responses reflected trial-by-trial pwPEs. Applying a Bayesian model to series of face stimuli that violated expectations about color or emotional expression, we found significant modulation of brain activity by both color and emotion pwPEs. A categorical change detection model performed less convincingly. Our findings support the predictive coding interpretation of visual mismatch responses.

Convergent Spinal Circuits Facilitating Human Wrist Flexors

Noninvasive assessment of spinal circuitry in humans is limited, especially for Ib pathways in the upper limb. We developed a protocol in which we evoke the H-reflex in flexor carpi radialis (FCR) by median nerve stimulation and condition it with electrical stimulation above motor threshold over the extensor carpi radialis (ECR) muscle belly. Eighteen healthy adults (8 male, 10 female) took part in the study. There was a clear reflex facilitation at a 30 ms interstimulus interval (ISI) and suppression at a 70 ms ISI, which was highly consistent across subjects. We investigated the following two hypotheses of the possible source of the facilitation: (1) ECR Ib afferents from Golgi tendon organs, activated by the twitch following ECR stimulation; and (2) FCR afferents, from spindles and/or Golgi tendon organs, activated by the wrist extension movement that follows ECR stimulation. Several human and monkey experiments indicated a role for both of these sets of afferents. Our results provide evidence for a spinal circuit in which flexor motoneurons receive convergent excitatory input from flexor afferents as well as from extensor Ib afferents; this circuit can be straightforwardly assessed noninvasively in humans.

SIGNIFICANCE STATEMENT Here we described a novel spinal circuit, which is easy to assess noninvasively in humans. Understanding this circuit in more detail could be beneficial for the design of clinical tests in neurological conditions.

Modified Origins of Cortical Projections to the Superior Colliculus in the Deaf: Dispersion of Auditory Efferents

Following the loss of a sensory modality, such as deafness or blindness, crossmodal plasticity is commonly identified in regions of the cerebrum that normally process the deprived modality. It has been hypothesized that significant changes in the patterns of cortical afferent and efferent projections may underlie these functional crossmodal changes. However, studies of thalamocortical and corticocortical connections have refuted this hypothesis, instead revealing a profound resilience of cortical afferent projections following deafness and blindness. This report is the first study of cortical outputs following sensory deprivation, characterizing cortical projections to the superior colliculus in mature cats (N = 5, 3 female) with perinatal-onset deafness. The superior colliculus was exposed to a retrograde pathway tracer, and subsequently labeled cells throughout the cerebrum were identified and quantified. Overall, the percentage of cortical projections arising from auditory cortex was substantially increased, not decreased, in early-deaf cats compared with intact animals. Furthermore, the distribution of labeled cortical neurons was no longer localized to a particular cortical subregion of auditory cortex but dispersed across auditory cortical regions. Collectively, these results demonstrate that, although patterns of cortical afferents are stable following perinatal deafness, the patterns of cortical efferents to the superior colliculus are highly mutable.

SIGNIFICANCE STATEMENT When a sense is lost, the remaining senses are functionally enhanced through compensatory crossmodal plasticity. In deafness, brain regions that normally process sound contribute to enhanced visual and somatosensory perception. We demonstrate that hearing loss alters connectivity between sensory cortex and the superior colliculus, a midbrain region that integrates sensory representations to guide orientation behavior. Contrasting expectation, the proportion of projections from auditory cortex increased in deaf animals compared with normal hearing, with a broad distribution across auditory fields. This is the first description of changes in cortical efferents following sensory loss and provides support for models predicting an inability to form a coherent, multisensory percept of the environment following periods of abnormal development.

Comprehensive Registry of Esophageal Cancer in Japan, 2011

Molekulargenetische Diagnostik – zielgerichtete Therapie des malignen Melanoms

Zusammenfassung

Hintergrund

Mit der Identifizierung der Schlüsselrolle des MAPK-Signalwegs (MAPK „mitogen-activated protein kinase") für die Entstehung und Progression des malignen Melanoms gelang ein Durchbruch in dessen Behandlung. Die Entwicklung zielgerichteter Therapien und Immuntherapien führte zu einem breiten therapeutischen Spektrum in der Behandlung fortgeschrittener oder metastasierter Melanome.

Ziel

Dieser Artikel befasst sich mit der Wirksamkeit der aktuellen selektiven Kinaseinhibitoren bei der Behandlung des malignen Melanoms mit nachgewiesener BRAF-Mutation und auch den seltener vorkommenden Mutationen im NRAS- und cKIT-Gen. Die Ergebnisse neuester klinischer Studien einschließlich des Toxizitätsprofils sowie neue Therapieansätze werden beschrieben.

Material und Methoden

Diese Arbeit basiert auf einer selektiven Literaturrecherche in der Datenbank PubMed und ClinicalTrials zum Thema Behandlung des fortgeschrittenen Melanoms.

Ergebnisse

Eine Kombination von BRAF- und MEK-Inhibitoren führt zu einer Steigerung des Therapieansprechens und des Gesamtüberlebens im Vergleich zur Chemotherapie oder Monotherapie. Weitere spezifische Inhibitoren zeigen vielversprechende Resultate.

Diskussion

Durch die zielgerichtete Therapie und Checkpointblockade hat sich die Prognose des fortgeschrittenen und metastasierten Melanoms deutlich verbessert. Eine Kombination dieser therapeutischen Ansätze, könnte zukünftig in der Behandlung des Melanoms eine wichtige Rolle spielen. Sowohl eine detaillierte genetische Analyse des Tumors als auch ein besseres Verständnis der biologischen Prozesse sind notwendig, um insbesondere hinsichtlich der Resistenzmechanismen die Wirksamkeit moderner Melanomtherapien zu verbessern.

Purification, characterization and biological activity of melanin from Streptomyces sp.

Abstract

Melanins are enigmatic biological macromolecules that can be produced by plants, animals and microorganisms and are especially suited for production in fermentation broth, which is prone to industrialization and few inputs. This research was conducted to purify, characterize and determine the biological activity of extracellular melanin extracted from Streptomyces sp. The extracellular melanin (M) was extracted from Streptomyces sp. with a yield of 1.46 g/L. Ma, Mb, Mc and Md were fractionated from M using a Sephadex G-50 column. Ma was detected as the homogeneous component. After studying its ultraviolet-visible absorbance, infrared, and electron paramagnetic resonance spectra as well as the scanning electron microscopy images, Ma was confirmed to be typical melanin. Based on its elemental analysis, Ma consisted of C, H, N, O, and S, the percentages of which suggesting that phaeomelanin was the main component. In addition, Ma showed significant anti-radiation and free radical scavenging activity. Thus, these results indicated that Streptomyces sp. could be a new source to obtain melanin. Ma might be a potential antioxidant and ultraviolet protector and could be used in cosmetics, pesticides, food and other industries.

Corrigendum: Gender, Work, and Health

Annals of Work Exposures and Health, 2018; 62(4): 389–392.

Gender, Work, and Health

Women and men occupy different positions in the labor market and, in turn, have different work-related exposures and subsequent health effects. There is growing recognition that occupational studies need new methods to account for these differences in order to improve the workplace (Kilbom et al., 1998; Messing, 1998; Doyal, 2003; Messing et al., 2003; Johnson et al., 2009; Eng et al., 2011; Springer et al., 2012; Lewis and Mathiassen, 2013; Locke et al., 2014). Women and men can have different experiences of work exposures and health due to their sex, referring to biological differences, or to their gender, referring to socially constructed differences. Many occupational studies continue to ignore sex and gender considerations or use single sex samples and assume that findings can be generalized to both men and women (Hohenadel et al., 2015). While some researchers present results separately for men and women, which is a starting point, newer more comprehensive methods for modeling and data analyses are needed to advance the field.

Gender and Ageing at Work in Chile: Employment, Working Conditions, Work–Life Balance and Health of Men and Women in an Ageing Workforce

Abstract

Objectives

In Chile, working after retirement age has grown substantially over the last years. This, in addition to the country's current discussion about extending retirement age, motivates the need of generating evidence on the occupational health and safety of the working old, with a special focus on women, who are critically disadvantaged in Chile's labour market. The objective of this paper is to describe and compare the ageing workforce of women and men in Chile in terms of labour market participation, employment and working conditions, work–life balance, and health. The social determinants of health and employment sustainability frameworks guide this study.

Data Sources

Cross-sectional data from three publicly available sources: the Chilean Labour Force Survey, NENE (2010); the first Chilean Employment and working conditions survey, ENETS (2009–2010) and the second National Health Survey, ENS (2009).

Methods

Participation rates and employment conditions (NENE and ENETS), working conditions, occupational health and work–life balance (ENETS) and chronic health conditions (ENS) were described by 5-year age groups separately for women and men. Descriptions cover all age groups in order to identify trends and patterns characteristic of older workers.

Results

Rates of occupation decrease sharply after age 54 in women and 59 in men. Ageing women and men who continue to work are more likely to be in own-account (self-employed) work than younger workers; in the case of women, in households as domestic workers, and men, in agriculture. Social protection and workplace rights are markedly reduced in older workers. Part-time work increases from the age of 50 onwards, especially among women, but average working hours do not decrease under 30 h a week for either women or men. Interestingly, between ages 60 and 64, there is a peak increase of day and night shift-work among women, which co-occurs with a peak in domestic work, possibly corresponding to women working as caretakers of elderly people. Several workplace risks continue to be high into old age: intensive work and demanding physical work, especially in men, and the combination of paid and unpaid care work in women, which continues to be high up to the age of 70 years. The health of older workers is better than that of non-working people of the same age, a gap which is markedly larger for women than men and tends to increase among women as they age.

Conclusion

Results indicate that Chileans working into old age face precarious jobs with limited protection and several adverse working conditions. Noteworthy, women carry the double burden of paid and unpaid work into their late years. In addition, results suggest they are affected more profoundly by the healthy worker effect whereby the health condition determines the probability of finding and keeping a job—also known as a health selection mechanism—which increases as they age. These employment and working conditions indicate that working into old age is not yet sustainable in Chile and counts as evidence that needs to be taken into account in discussions about delaying the retirement age in the country, as well as incorporating support systems to alleviate the double work burden of ageing working women.

Observed Differences between Males and Females in Surgically Treated Carpal Tunnel Syndrome Among Non-manual Workers: A Sensitivity Analysis of Findings from a Large Population Study

Abstract

Objectives

We aimed at assessing whether differences among males and females in carpal tunnel syndrome (CTS) epidemiology might be attributable to segregation with respect to occupational biomechanical exposures or differential access to care by sex.

Methods

We analysed surgically treated cases of CTS occurring among non-manual workers in Tuscany between 1997 and 2000. We conducted a Monte Carlo simulation to estimate the difference in occupational biomechanical exposures between males and females necessary to explain the observed incidence rate ratios. We also accounted for the sex-specific probability of receiving surgery after the diagnosis of CTS, as women were reported to be more likely to undergo surgery in a subset of our study population. We quantified the hypothetical biomechanical overload through the hand activity level (HAL) metric proposed by the American Conference of Governmental Industrial Hygienists. To quantify the effect of HAL on CTS risk, we assumed a prior distribution based on findings from two large cohort studies of industrial workers.

Results

After adjustment for the probability of receiving surgery, women showed a 4-fold incidence of CTS as compared with men. To explain this association among non-manual workers, women should have an average value of HAL at least 5 points higher.

Conclusions

Our analysis does not support the hypothesis that the difference in CTS incidence between males and females is entirely attributable to occupational risk factors or to differential access to surgery. The causal pathway between sex and CTS might include more determinants such as hormonal factors, anthropometric characteristics, and non-occupational exposure to biomechanical overload (e.g. household tasks).

Randomized phase 3 and extension studies: Efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer

Abstract

Background

The efficacy and safety of naldemedine (a peripherally-acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase 3, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary endpoint, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary endpoints including quality of life (QOL) assessments from these studies.

Patients and methods

In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n=97) or placebo (n=96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n=131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 hours post-initial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at Week 1 and Week 2. Time to the first SBM or CSBM post-initial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires.

Results

Naldemedine improved bowel function for all secondary efficacy assessments vs placebo (all P≤0.0002). The timely onset of naldemedine activity vs placebo was evidenced by median time to the first SBM (4.7 vs 26.6 hours) and CSBM (24.0 vs 218.5 hours) post-initial dose (all P<0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P=0.045) and PAC-QOL dissatisfaction domain (P=0.015). In COMPOSE-5, naldemedine significantly improved overall and individual domain scores of PAC-SYM and PAC-QOL from baseline (all P≤0.03).

Conclusions

Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer.

Trial registration ID

www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials

Abstract

BACKGROUND

Driven by reduced intakes and metabolic alterations, malnutrition in cancer patients adversely affects quality of life, treatment tolerance and survival. We examined evidence for oral nutritional interventions during chemo(radio)therapy.

DESIGN

We performed a systematic review of randomized controlled trials (RCT) with either dietary counseling (DC), high-energy oral nutritional supplements (ONS) aiming at improving intakes, or ONS enriched with protein and n-3 polyunsaturated fatty acids (PUFA) additionally aiming for modulation of cancer-related metabolic alterations. Meta-analyses were performed on body weight (BW) response to nutritional interventions, with subgroup analyses for DC and/or high-energy ONS or high-protein n-3 PUFA-enriched ONS.

RESULTS

Eleven studies were identified. Meta-analysis showed overall benefit of interventions on BW during chemo(radio)therapy (+1.31kg, 95% CI 0.24-2.38, P=0.02, heterogeneity Q = 21.1, P=0.007). Subgroup analysis showed no effect of DC and/or high-energy ONS (+0.80kg, 95%CI -1.14-2.74, P=0.32; Q = 10.5, P=0.03), possibly due to limited compliance and intakes falling short of intake goals. A significant effect was observed for high-protein n-3 PUFA-enriched intervention compared to isocaloric controls (+1.89kg, 95%CI 0.51-3.27, P=0.022; Q = 3.1 P=0.37). High-protein, n-3 PUFA-enriched ONS studies showed attenuation of lean body mass loss (N=2 studies) and improvement of some quality of life domains (N=3 studies). Overall, studies were limited in number, heterogeneous, and inadequately powered to show effects on treatment toxicity or survival.

CONCLUSION

This systematic review suggests an overall positive effect of nutritional interventions during chemo(radio)therapy on BW. Subgroup analyses showed effects were driven by high-protein n-3 PUFA-enriched ONS, suggesting the benefit of targeting metabolic alterations. DC and/or high-energy ONS were less effective, likely due to cumulative caloric deficits despite interventions. We highlight the need and provide recommendations for well-designed RCT to determine the effect of nutritional interventions on clinical outcomes, with specific focus on reaching nutritional goals and providing the right nutrients, as part of an integral supportive care approach.

Selective RET Kinase Inhibition for Patients with RET-Altered Cancers

Abstract

Purpose

Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed inhibit diverse RET fusions, activating mutations and acquired resistance mutations.

Patients and Methods

Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, multikinase inhibitor-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.

Results

LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six multikinase inhibitor regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and calcitonin-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.

Conclusions

These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

HPV status, like politics, is local- Evaluating p16 staining and a new staging system in a Dutch cohort of oropharynx cancer

Reply to: Preventive role of ramelteon and suvorexant for postoperative delirium after pharyngolaryngectomy with esophagectomy

Automatic planning of needle placement for robot-assisted percutaneous procedures

Abstract

Purpose

Percutaneous procedures allow interventional radiologists to perform diagnoses or treatments guided by an imaging device, typically a computed tomography (CT) scanner with a high spatial resolution. To reduce exposure to radiations and improve accuracy, robotic assistance to needle insertion is considered in the case of X-ray guided procedures. We introduce a planning algorithm that computes a needle placement compatible with both the patient's anatomy and the accessibility of the robot within the scanner gantry.

Methods

Our preoperative planning approach is based on inverse kinematics, fast collision detection, and bidirectional rapidly exploring random trees coupled with an efficient strategy of node addition. The algorithm computes the allowed needle entry zones over the patient's skin (accessibility map) from 3D models of the patient's anatomy, the environment (CT, bed), and the robot. The result includes the admissible robot joint path to target the prescribed internal point, through the entry point. A retrospective study was performed on 16 patients datasets in different conditions: without robot (WR) and with the robot on the left or the right side of the bed (RL/RR).

Results

We provide an accessibility map ensuring a collision-free path of the robot and allowing for a needle placement compatible with the patient's anatomy. The result is obtained in an average time of about 1 min, even in difficult cases. The accessibility maps of RL and RR covered about a half of the surface of WR map in average, which offers a variety of options to insert the needle with the robot. We also measured the average distance between the needle and major obstacles such as the vessels and found that RL and RR produced needle placements almost as safe as WR.

Conclusion

The introduced planning method helped us prove that it is possible to use such a "general purpose" redundant manipulator equipped with a dedicated tool to perform percutaneous interventions in cluttered spaces like a CT gantry.

Robotic ultrasound-guided facet joint insertion

Abstract

Purpose

Facet joint insertion is a common treatment of chronic pain in the back and spine. This procedure is often performed under fluoroscopic guidance, where the staff's repetitive radiation exposure remains an unsolved problem. Robotic ultrasound (rUS) has the potential to reduce or even eliminate the use of radiation by using ultrasound with a robotic-guided needle insertion. This work presents first clinical data of rUS-based needle insertions extending previous work of our group.

Methods

Our system implements an automatic US acquisition protocol combined with a calibrated needle targeting system. This approach assists the physician by positioning the needle holder on a trajectory selected in a 3D US volume of the spine.

Results

By the time of submission, nine facets were treated with our approach as first data from an ongoing clinical study. The insertion success rate was shown to be comparable to current clinical practice. Furthermore, US imaging offers additional anatomical context for needle trajectory planning.

Conclusion

This work shows first clinical data for robotic ultrasound-assisted facet joint insertion as a promising solution that can easily be incorporated into the clinical workflow. Presented results show the clinical value of such a system.

Efficacy of combination therapies of topical 5% imiquimod and liquid nitrogen for penile molluscum contagiosum

The Journal of Dermatology, EarlyView.

Type 1 diabetes in a melanoma patient treated with ipilimumab after nivolumab

The Journal of Dermatology, EarlyView.

Comparative study of remediation of Cr(VI)-contaminated soil using electrokinetics combined with bioremediation

Abstract

The purpose of this research is to design a new bioremediation-electrokinetic (Bio-EK) remediation process to increase treatment efficiency of chromium contamination in soil. Upon residual chromium analysis, it is shown that traditional electrokinetic-PRB system (control) does not have high efficiency (80.26%) to remove Cr(VI). Bio-electrokinetics of exogenous add with reduction bacteria Microbacterium sp. Y2 and electrokinetics can enhance treatment efficiency Cr(VI) to 90.67% after 8 days' remediation. To optimize the overall performance, integrated bio-electrokinetics were designed by synergy with 200 g humic substances (HS) into the systems. According to our results, Cr(VI) (98.33%) was effectively removed via electrokinetics. Moreover, bacteria and humic substances are natural, sustainable, and economical enhancement agents. The research results indicated that the use of integrated bio-electrokinetics is an effective method to remediate chromium-contaminated soils.