Generalizations, Cultural Essentialism, and Metaphorical Gulfs

Abstract

An ongoing debate in comparative research is about whether we should see cultural diversities as manifestations of essential differences or as superficial variations on a universal blueprint. Edward Slingerland has pointed to cognitive science and the use of embodied metaphors to emphasize the universality of concept formation and cognition across cultures. He suggests that this should quiet the "cultural essentialists" who take fundamental differences in Eastern and Western thinking as their starting points. Michael Puett has also leveled a critique of cultural essentialism in support of a presuppositionless approach, and Slingerland's conclusions seem to offer him support. However, I will argue that even if all modern humans are broadly similar in metaphor use and cognitive processes, research in the humanities must continue to account for the differences implied by the particular metaphors employed and emphasized in diverse traditions. I contend that responsible hermeneutic practice does this through provisional, yet indispensable, generalizations.

Gu, Yanwu, Record of Daily Knowledge and Collected Poems and Essays: Selections

Chen, Yun 陳贇, The Essence of Zhuangzi’s Philosophy 莊子哲學的精神

Berger, Douglas L., Encounters of Mind: Luminosity and Personhood in Indian and Chinese Thought

Results of a nationwide epidemiologic survey of autosomal recessive congenital ichthyosis and ichthyosis syndromes in Japan

Autosomal recessive congenital ichthyosis (ARCI) and ichthyosis syndrome (IS) are rare genetic skin disorders.

Follicular Involvement is Frequent in Lentigo Maligna: Implications for Treatment

Follicular involvement is a characteristic of lentigo maligna (LM) with unknown frequency. 95.8% of LM specimens demonstrated intrafollicular lesional melanocytes, with a mean depth of 0.45mm. When managing LM, follicular involvement should be assumed.

Laser-assisted photodynamic therapy for actinic keratosis: A systematic review and meta-analysis

This meta-analysis suggests that photodynamic therapy combined with ablative laser treatment for actinic keratosis is more efficient but not more painful than either therapy alone. Laser-assisted photodynamic therapy is an attractive option for patients with multiple actinic keratoses or field cancerization

Optimizing clinical images with a smartphone and light-emitting diode

Treatment of oral mucosal neuromas with carbon dioxide laser

Camp Sun Safe: A community level sun safety intervention

The Infraorbital Artery: Clinical Relevance in Esthetic Medicine and Identification of Danger Zones of the midface

Over the past decade, cosmetic injections of dermal fillers or fat have become a popular procedure in facial rejuvenation in an overconsuming society. However, complications such as arterial embolism and occlusion can occur even with experienced injectors, especially in high-risks zones namely the glabella, the nasal dorsum or the nasolabial fold. The aim of this study was to define the vascular danger zones of the infraorbital area in order to provide guidelines helping avoid them.

Guideline on the use of onabotulinumtoxinA in chronic migraine: a consensus statement from the European Headache Federation

OnabotulinumtoxinA is being increasingly used in the management of chronic migraine (CM). Treatment with onabotulinumtoxinA poses challenges compared with traditional therapy with orally administered preventat...

A Content Analysis of Local Media Framing of Intimate Partner Violence

Violence and Gender, Ahead of Print.

Juvenile Spring Eruption Associated With Parvovirus B19 Infection

This case report describes the occurrence of juvenile spring eruption associated with parvovirus B19 infection.

Multispectral Optoacoustic Tomography for Vascular Malformations

This pilot study evaluates the use of multispectral optoacoustic tomography for assessment of biomarkers among patients with arteriovenous and venous malformation.

Identifying Disparities in Dermatology

Differences in Use of Outpatient Dermatology Services in the United States

This study examines nationwide differences in demographic and socioeconomic characteristics and use of outpatient dermatologic care among Medical Expenditure Panel Survey respondents.

Vasculitis

This Patient Page describes vasculitis, focusing especially on skin vasculitis, how to recognize it, and how it might be treated.

Increased Synthesis of Chondroitin Sulfate Proteoglycan Promotes Adult Hippocampal Neurogenesis in Response to Enriched Environment

Chondroitin sulfate proteoglycan (CSPG) is a candidate regulator of embryonic neurogenesis. The aim of this study was to specify the functional significance of CSPG in adult hippocampal neurogenesis using male mice. Here, we showed that neural stem cells and neuronal progenitors in the dentate gyrus were covered in part by CSPG. Pharmacological depletion of CSPG in the dentate gyrus reduced the densities of neuronal progenitors and newborn granule cells. 3D reconstruction of newborn granule cells showed that their maturation was inhibited by CSPG digestion. The novel object recognition test revealed that CSPG digestion caused cognitive memory impairment. Western blot analysis showed that expression of β-catenin in the dentate gyrus was decreased by CSPG digestion. The amount of CSPG in the dentate gyrus was increased by enriched environment (EE) and was decreased by forced swim stress. In addition, EE accelerated the recovery of CSPG expression in the dentate gyrus from the pharmacological depletion and promoted the restoration of granule cell production. Conversely, the densities of newborn granule cells were also decreased in mice that lacked chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGalNAcT1), a key enzyme for CSPG synthesis (T1KO mice). The capacity of EE to promote granule cell production and improve cognitive memory was impaired in T1KO mice. These findings indicate that CSPG is involved in the regulation of adult hippocampal neurogenesis and suggest that increased synthesis of CSPG by CSGalNacT1 may mediate promotion of granule cell production and improvement of cognitive memory in response to EE.

SIGNIFICANCE STATEMENT Chondroitin sulfate proteoglycan (CSPG) is a candidate regulator of embryonic neurogenesis. Here, we specified the role of CSPG in adult neurogenesis in the mouse hippocampus. Digestion of CSPG in the dentate gyrus impaired granule cell production and cognitive memory. Enriched environment (EE) promoted the recovery of CSPG expression and granule cell production from the CSPG digestion. Additionally, adult neurogenesis was impaired in mice that lacked a key enzyme for CSPG synthesis (T1KO mice). The capacity of EE to promote granule cell production and cognitive memory was impaired in T1KO mice. Altogether, these findings indicate that CSPG underlies adult hippocampal neurogenesis and suggest that increased synthesis of CSPG may mediate promotion of granule cell production in response to EE.

Coherent Activity between the Prelimbic and Auditory Cortex in the Slow-Gamma Band Underlies Fear Discrimination

The medial prefrontal cortex and the basolateral amygdala (BLA) are essential for discriminating between harmful and safe stimuli. The primary auditory cortex (Te1) sends projections to both sites, but whether and how it interacts with these areas during fear discrimination are poorly understood. Here we show that in male rats that can differentiate between a new tone and a threatening one, the selective optogenetic inhibition of Te1 axon terminals into the prelimbic (PL) cortex shifted discrimination to fear generalization. Meanwhile, no effects were detected when Te1 terminals were inhibited in the BLA. Using a combination of local field potential and multiunit recordings, we show that in animals that discriminate successfully between a new tone and a harmful one, the activity of the Te1 and the PL cortex becomes immediately and tightly synchronized in the slow-gamma range (40–70 Hz) at the onset of the new tone. This enhanced synchronization was not present in other frequency ranges, such as the theta range. Critically, the level of gamma synchrony predicted the behavioral choice (i.e., no freezing or freezing) of the animals. Moreover, in the same rats, gamma synchrony was absent before the fear-learning trial and when animals should discriminate between an olfactory stimulus and the auditory harmful one. Thus, our findings reveal that the Te1 and the PL cortex dynamically establish a functional connection during auditory fear-discrimination processes, and that this corticocortical oscillatory mechanism drives the behavioral choice of the animals.

SIGNIFICANCE STATEMENT Identifying neural networks that infer safety versus danger is of great interest in the scientific field. Fear generalization reduces the chances of an animal's survival and leads to psychiatric diseases, such as post-traumatic stress disorders and phobias in humans. Here we demonstrate that animals able to differentiate a new tone from a previous threating tone showed synchronization between the prefrontal and primary auditory cortices. Critically, this connectivity precedes and predicts the behavioral outcome of the animal. Optogenetic inhibition of this functional connectivity leads to fear generalization. To the best of our knowledge, this study is the first to demonstrate that a corticocortical dialogue occurring between sensory and prefrontal areas is a key node for fear-discrimination processes.

Feedback-Based Learning in Aging: Contributions and Trajectories of Change in Striatal and Hippocampal Systems

The striatum supports learning from immediate feedback by coding prediction errors (PEs), whereas the hippocampus (HC) plays a parallel role in learning from delayed feedback. Both regions show evidence of decline in human aging, but behavioral research suggests greater decline in HC versus striatal functions. The present study included male and female humans and used fMRI to examine younger and older adults' brain activation patterns during a learning task with choice feedback presented immediately or after a brief delay. Participants then completed a surprise memory task that tested their recognition of trial-unique feedback stimuli, followed by assessments of postlearning cue preference, outcome probability awareness, and willingness to pay. The study yielded three main findings. First, behavioral measures indicated similar rates of learning in younger and older adults across conditions, but postlearning measures indicated impairment in older adults' ability to subsequently apply learning to discriminate between cues. Second, PE signals in the striatum were greater for immediate versus delayed feedback in both age groups, but PE signals in the HC were greater for delayed versus immediate feedback only in younger adults. Third, unlike younger adults, older adults failed to exhibit enhanced episodic memory for outcome stimuli in the delayed-feedback condition. Together, these findings indicate that HC circuits supporting learning and memory decline more than striatal circuits in healthy aging, which suggests that declines in HC learning signals may be an important predictor of deficits in learning-dependent economic decisions among older adults.

SIGNIFICANCE STATEMENT The hippocampus (HC) and striatum play distinct and critical roles in learning. Substantial research suggests that age-related decline in learning supported by the HC outpaces decline in learning supported by the striatum; however, such inferences have been drawn by comparing performance in tasks with fundamentally different structures. The present study overcomes this obstacle by implementing a single fMRI-learning paradigm with a subtle variation in feedback timing to examine differential age effects on memory supported by the HC and striatum. Our results provide converging behavioral and brain-imaging evidence showing that HC circuits supporting learning and memory decline more than striatal circuits in healthy aging and that declines in HC learning signals may predict early deficits in learning-dependent decisions among older adults.

Transneuronal Downregulation of the Premotor Cholinergic System After Corticospinal Tract Loss

Injury to the supraspinal motor systems, especially the corticospinal tract, leads to movement impairments. In addition to direct disruption of descending motor pathways, spinal motor circuits that are distant to and not directly damaged by the lesion undergo remodeling that contributes significantly to the impairments. Knowing which spinal circuits are remodeled and the underlying mechanisms are critical for understanding the functional changes in the motor pathway and for developing repair strategies. Here, we target spinal premotor cholinergic interneurons (IN) that directly modulate motoneuron excitability via their cholinergic C-bouton terminals. Using a model of unilateral medullary corticospinal tract lesion in male rats, we found transneuronal downregulation of the premotor cholinergic pathway. Phagocytic microglial cells were upregulated in parallel with cholinergic pathway downregulation and both were blocked by minocycline, a microglia activation inhibitor. Additionally, we found a transient increase in interneuronal complement protein C1q expression that preceded cell loss. 3D reconstructions showed ongoing phagocytosis of C1q-expressing cholinergic INs by microglia 3 d after injury, which was complete by 10 d after injury. Unilateral motor cortex inactivation using the GABA_A receptor agonist muscimol replicated the changes detected at 3 d after lesion, indicating activity dependence. The neuronal loss after the lesion was rescued by increasing spinal activity using cathodal trans-spinal direct current stimulation. Our finding of activity-dependent modulation of cholinergic premotor INs after CST injury provides the mechanistic insight that maintaining activity, possibly during a critical period, helps to protect distant motor circuits from further damage and, as a result, may improve motor functional recovery and rehabilitation.

SIGNIFICANCE STATEMENT Supraspinal injury to the motor system disrupts descending motor pathways, leading to movement impairments. Whether and how intrinsic spinal circuits are remodeled after a brain injury is unclear. Using a rat model of unilateral corticospinal tract lesion in the medulla, we show activity-dependent, transneuronal downregulation of the spinal premotor cholinergic system, which is mediated by microglial phagocytosis, possibly involving a rapid and transient increase in neuronal C1q before neuronal loss. Spinal cord neuromodulation after injury to augment spinal activity rescued the premotor cholinergic system. Our findings provide the mechanistic insight that maintaining activity, possibly during an early critical period, could protect distant motor circuits from further damage mediated by microglia and interneuronal complement protein and improve motor functional outcomes.

Contextual-Dependent Attention Effect on Crowded Orientation Signals in Human Visual Cortex

A target becomes hard to identify with nearby visual stimuli. This phenomenon, known as crowding, places a fundamental limit on conscious perception and object recognition. To understand the neural representation of crowded stimuli, we used fMRI and a forward encoding model to reconstruct the target-specific feature from multivoxel activation patterns evoked by orientation patches. Orientation-selective response profiles were constructed in V1–V4 for a target embedded in different contexts. Subjects of both sexes either directed their attention over all the orientation patches or selectively to the target. In the context with a weak crowding effect, attending to the target enhanced the orientation selectivity of the response profile; such effect increased along the visual pathway. In the context with a strong crowding effect, attending to the target enhanced the orientation selectivity of the response profile in the earlier visual area, but not in V4. The increase and decrease of orientation selectivity along the visual hierarchy demonstrate a contextual-dependent attention effect on crowded orientation signals: in the context with a weak crowding effect, selective attention gradually resolves the target from nearby distractors along the hierarchy; in the context with a strong crowding effect, while selective attention maintains the target feature in the earlier visual area, its effect decreases in the downstream area. Our findings reveal how the human visual system represents the target-specific feature at multiple stages under the limit of attention selection in a cluttered scene.

SIGNIFICANCE STATEMENT Using fMRI and a forward encoding model, we reconstructed orientation-selective response profiles for a target embedded in crowded contexts. In the context with a weak crowding effect, attention gradually resolves the target from nearby distractors along the visual hierarchy. In the context with a strong crowding effect, while the feature of the target is preserved in the early visual cortex, it degrades in the later visual processing stage. The increase and decrease of orientation selectivity along the visual hierarchy reveal how the human visual system strikes to present the target-specific feature under the limit of attention selection in a cluttered scene.

Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice

Eph receptors play pivotal roles in the axon guidance of retinal ganglion cells (RGCs) at the optic chiasm and the establishment of the topographic retinocollicular map. We previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) is specifically involved in the control of retinotectal projections in chicks through the dephosphorylation of EphA and EphB receptors. We subsequently revealed that all the mouse R3 subfamily members (PTPRB, PTPRH, PTPRJ, and PTPRO) of the receptor protein tyrosine phosphatase (RPTP) family inhibited Eph receptors as their substrates in cultured mammalian cells. We herein investigated the functional roles of R3 RPTPs in the projection of mouse retinal axon of both sexes. Ptpro and Ptprj were expressed in mouse RGCs; however, Ptprj expression levels were markedly higher than those of Ptpro. Consistent with their expression levels, Eph receptor activity was significantly enhanced in Ptprj-knock-out (Ptprj-KO) retinas. In Ptprj-KO and Ptprj/Ptpro-double-KO (DKO) mice, the number of retinal axons that projected ipsilaterally or to the contralateral eye was significantly increased. Furthermore, retinal axons in Ptprj-KO and DKO mice formed anteriorly shifted ectopic terminal zones in the superior colliculus (SC). We found that c-Abl (Abelson tyrosine kinase) was downstream of ephrin–Eph signaling for the repulsion of retinal axons at the optic chiasm and in the SC. c-Abl was identified as a novel substrate for PTPRJ and PTPRO, and the phosphorylation of c-Abl was upregulated in Ptprj-KO and DKO retinas. Thus, PTPRJ regulates retinocollicular projections in mice by controlling the activity of Eph and c-Abl kinases.

SIGNIFICANCE STATEMENT Correct retinocollicular projection is a prerequisite for proper vision. Eph receptors have been implicated in retinal axon guidance at the optic chiasm and the establishment of the topographic retinocollicular map. We herein demonstrated that protein tyrosine phosphatase receptor type J (PTPRJ) regulated retinal axonal projections by controlling Eph activities. The retinas of Ptprj-knock-out (KO) and Ptpro/Ptprj double-KO mice exhibited significantly enhanced Eph activities over those in wild-type mice, and their axons showed defects in pathfinding at the chiasm and retinocollicular topographic map formation. We also revealed that c-Abl (Abelson tyrosine kinase) downstream of Eph receptors was regulated by PTPRJ. These results indicate that the regulation of the ephrin–Eph–c-Abl axis by PTPRJ plays pivotal roles in the proper central projection of retinal axons during development.

A Brain-Heart Biomarker for Epileptogenesis

Postinjury epilepsy is an potentially preventable sequela in as many as 20% of patients with brain insults. For these cases biomarkers of epileptogenesis are critical to facilitate identification of patients at high-risk of developing epilepsy and to introduce effective anti-epileptogenic interventions. Here, we demonstrate that delayed brain–heart coincidences serve as a reliable biomarker. In a murine model of post-infection acquired epilepsy, we used long-term simultaneous measurements of the brain activity via electroencephalography and autonomic cardiac activity via electrocardiography, in male mice, to quantitatively track brain–heart interactions during epileptogenesis. We find that abnormal cortical discharges precede abnormal fluctuations in the cardiac rhythm at the resolution of single beat-to-beat intervals. The delayed brain–heart coincidence is detectable as early as the onset of chronic measurements, 2–14 weeks before the first seizure, only in animals that become epileptic, and increases during epileptogenesis. Therefore, delayed brain–heart coincidence serves as a biomarker of epileptogenesis and could be used for phenotyping, diagnostic, and therapeutic purposes.

SIGNIFICANCE STATEMENT No biomarker that readily predicts and tracks epileptogenesis currently exists for the wide range of human acquired epilepsies. Here, we used long-term measurements of brain and heart activity in a mouse model of post-infection acquired epilepsy to investigate the potential of brain–heart interaction as a biomarker of epileptogenesis. We found that delayed coincidences from brain to heart can clearly separate the mice that became epileptic from those that did not weeks before development of epilepsy. Our findings allow for phenotyping and tracking of epileptogenesis in this and likely other models of acquired epilepsy. Such capability is critical for efficient adjunctive treatment development and for tracking the efficacy of such treatments.

S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit

Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe²⁺ uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn²⁺ or Fe²⁺ uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry, and DMT1 C23A or C540A substitutions abolished nitric oxide (NO)-mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe²⁺ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitor l-NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.

SIGNIFICANCE STATEMENT Neuroinflammation and high cytoplasmic Fe²⁺ levels have been implicated in the initiation and progression of neurodegenerative diseases. Here, we report the unexpected enhancement of the functional activity of transmembrane divalent metal transporter 1 (DMT1) by S-nitrosylation. We demonstrated that S-nitrosylation increased DMT1-mediated Fe²⁺ uptake, and two cysteines were identified by mass spectrometry to be the sites for S-nitrosylation and for enhanced iron uptake. One conceptual advance is that while DMT1 activity could be increased by external acidification because the gating of the DMT1 transporter is proton motive, we discovered that DMT1 activity could also be enhanced by S-nitrosylation. Significantly, lipopolysaccharide-induced nitric oxide (NO)-mediated neuronal death in the substantia nigra could be ameliorated by using l-NAME, a NO synthase inhibitor, or by ebselen, a DMT1-selective blocker.

This Week in The Journal

Posterior Parietal Cortex Dysfunction Is Central to Working Memory Storage and Broad Cognitive Deficits in Schizophrenia

PFC dysfunction is widely believed to underlie working memory (WM) deficits in people with schizophrenia (PSZ), but few studies have focused on measures of WM storage devoid of manipulation. Research in neurotypical individuals has shown that storage capacity is more closely related to posterior parietal cortex (PPC) than PFC, suggesting that reductions in WM storage capacity in schizophrenia that are associated with broad cognitive deficits may be related to neural activity in PPC. In the present human neuroimaging study, 37 PSZ and 37 matched healthy control subjects of either sex completed a change detection task with varying set sizes while undergoing fMRI. The task was designed to emphasize WM storage with minimal top-down control demands. Whole-brain analysis identified areas in which BOLD activity covaried with the number of items maintained in WM (K), as derived from task performance at a given set size. Across groups, K values independent of set size predicted BOLD activity in PPC, including superior and inferior parietal lobules and intraparietal sulcus, and middle occipital gyrus. Whole-brain interaction analysis found significantly less K-dependent signal modulation in PSZ than healthy control subjects in left PPC, a phenomenon that could not be explained by a narrower K value range. The slope between K and PPC activation statistically accounted for 43.4% of the between-group differences in broad cognitive function. These results indicate that PPC dysfunction is central to WM storage deficits in PSZ and may play a key role in the broad cognitive deficits associated with schizophrenia.

SIGNIFICANCE STATEMENT People with schizophrenia exhibit cognitive deficits across a wide range of tasks. Explaining these impairments in terms of a small number of core deficits with clearly defined neural correlates would advance the understanding of the disorder and promote treatment development. We show that a substantial portion of broad cognitive deficits in schizophrenia can be explained by a failure to flexibly modulate posterior parietal cortex activity as a function of the amount of information currently stored in working memory. Working memory deficits have long been considered central to schizophrenia-related cognitive deficits, but the focus has been on paradigms involving some form of top-down control rather than pure storage of information, which may have unduly narrowed the focus on prefrontal dysfunction.

Auditory Predictive Coding across Awareness States under Anesthesia: An Intracranial Electrophysiology Study

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70–150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC.

SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling

Excitatory synapses are specialized cell–cell contacts located on actin-rich dendritic spines that mediate information flow and storage in the brain. The postsynaptic adhesion-G protein-coupled receptor (A-GPCR) BAI1 is a critical regulator of excitatory synaptogenesis, which functions in part by recruiting the Par3-Tiam1 polarity complex to spines, inducing local Rac1 GTPase activation and actin cytoskeletal remodeling. However, a detailed mechanistic understanding of how BAI1 controls synapse and spine development remains elusive. Here, we confirm that BAI1 is required in vivo for hippocampal spine development, and we identify three distinct signaling mechanisms mediating BAI1's prosynaptogenic functions. Using in utero electroporation to sparsely knock down BAI1 expression in hippocampal pyramidal neurons, we show that BAI1 cell-autonomously promotes spinogenesis in the developing mouse brain. BAI1 appears to function as a receptor at synapses, as its extracellular N-terminal segment is required for both its prospinogenic and prosynaptogenic functions. Moreover, BAI1 activation with a Stachel-derived peptide, which mimics a tethered agonist motif found in A-GPCRs, drives synaptic Rac1 activation and subsequent spine and synapse development. We also reveal, for the first time, a trans-synaptic function for BAI1, demonstrating in a mixed-culture assay that BAI1 induces the clustering of presynaptic vesicular glutamate transporter 1 (vGluT1) in contacting axons, indicative of presynaptic differentiation. Finally, we show that BAI1 forms a receptor complex with the synaptogenic cell-adhesion molecule Neuroligin-1 (NRLN1) and mediates NRLN1-dependent spine growth and synapse development. Together, these findings establish BAI1 as an essential postsynaptic A-GPCR that regulates excitatory synaptogenesis by coordinating bidirectional trans-synaptic signaling in cooperation with NRLN1.

SIGNIFICANCE STATEMENT Adhesion-G protein-coupled receptors are cell-adhesion receptors with important roles in nervous system development, function, and neuropsychiatric disorders. The postsynaptic adhesion-G protein-coupled receptor BAI1 is a critical regulator of dendritic spine and excitatory synapse development. However, the mechanism by which BAI1 controls these functions remains unclear. Our study identifies three distinct signaling paradigms for BAI1, demonstrating that it mediates forward, reverse, and lateral signaling in spines. Activation of BAI1 by a Stachel-dependent mechanism induces local Rac1 activation and subsequent spinogenesis/synaptogenesis. BAI1 also signals trans-synaptically to promote presynaptic differentiation. Furthermore, BAI1 interacts with the postsynaptic cell-adhesion molecule Neuroligin-1 (NRLN1) and facilitates NRLN1-dependent spine growth and excitatory synaptogenesis. Thus, our findings establish BAI1 as a functional synaptogenic receptor that promotes presynaptic and postsynaptic development in cooperation with synaptic organizer NRLN1.

A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking

In substance use disorders, negative affect associated with drug withdrawal can elicit strong drug craving and promote relapse. One brain region implicated in those processes is the rostral agranular insular cortex (RAIC), although precisely how this region encodes negative affect associated with drug seeking is unknown. Here, a preclinical model was used where RAIC activity was examined in male Sprague Dawley rats during intraoral infusions of a sweet (saccharin) paired with impending but delayed access to cocaine self-administration, and for comparative purposes, during the sweet predicting saline self-administration or injection of lithium chloride (LiCl), or during intraoral infusions of a bitter taste (quinine). Consistent with previous work, cocaine-paired saccharin, LiCl-paired saccharin, and quinine all elicited aversive taste reactivity. However, the aversive taste reactivity elicited by the cocaine-paired tastant was qualitatively different from that evoked by the other two agents. Furthermore, differences in taste reactivity were reflected in RAIC cell firing, where distinct shifts in neural signaling were observed specifically after cocaine but not LiCl conditioning. Notably, low motivation for cocaine (indicated by low loading and slower latencies to lever press) was correlated with this shift in RAIC signaling, but aversive (gaping) responses were not. Collectively, these findings indicate that cocaine-paired tastants elicit unique aspects of aversive behaviors that differ from traditional conditioned taste aversion (LiCl) or quinine and that the RAIC plays a role in modulating drug-seeking behaviors driven by drug-induced dysphoria (craving), but not negative affect per se.

SIGNIFICANCE STATEMENT In substance use disorders, negative affect associated with drug cues can elicit craving and promote relapse; however, the underlying neurocircuitry of this phenomenon is unknown. Here, we investigated the role of the rostral agranular insula cortex (RAIC) in these processes using a preclinical model wherein intraoral delivery of a sweet is paired with delayed access to cocaine self-administration. The taste comes to elicit negative affect that predicts heightened drug seeking. Here, we found that a population of RAIC neurons became inhibited during presentation of the cocaine-paired tastant (when negative affect is high) and that this inhibitory neural profile predicted lower drug seeking. These findings suggest that the RAIC may function to oppose cue-induced cocaine craving and help reduce motivation for the drug.

A Functional riboSNitch in the 3' Untranslated Region of FKBP5 Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Post-Traumatic Pain

Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene–miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies.

SIGNIFICANCE STATEMENT FKBP5 is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of FKBP5 that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the FKBP5 rs3800373 minor allele alters the secondary structure of FKBP5 mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater FKBP5 translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.

TRPM2 Exacerbates Central Nervous System Inflammation in Experimental Autoimmune Encephalomyelitis by Increasing Production of CXCL2 Chemokines

Multiple sclerosis (MS) is a chronic inflammatory disorder of the CNS characterized by demyelination and axonal injury. Current therapies that mainly target lymphocytes do not fully meet clinical need due to the risk of severe side effects and lack of efficacy against progressive MS. Evidence suggests that MS is associated with CNS inflammation, although the underlying molecular mechanism is poorly understood. Transient receptor potential melastatin 2 (TRPM2), a Ca²⁺-permeable nonselective cation channel, is expressed at high levels in the brain and by immune cells, including monocyte lineage cells. Here, we show that TRPM2 plays a pathological role in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Knockout (KO) or pharmacological inhibition of TRPM2 inhibited progression of EAE and TRPM2-KO mice showed lower activation of Iba1-immunopositive monocyte lineage cells and neutrophil infiltration of the CNS than WT mice. Moreover, CXCL2 production in TRPM2-KO mice was significantly reduced at day 14, although the severity of EAE was the same as that in WT mice at that time point. In addition, we used BM chimeric mice to show that TRPM2 expressed by CNS-infiltrating macrophages contributes to progression of EAE. Because CXCL2 induces migration of neutrophils, these results indicate that reduced expression of CXCL2 in the CNS suppresses neutrophil infiltration and slows progression of EAE in TRPM2-KO mice. Together, the results suggest that TRPM2 plays an important role in progression of EAE pathology and shed light on its putative role as a therapeutic target for MS.

SIGNIFICANCE STATEMENT Current therapies for multiple sclerosis (MS), which mainly target lymphocytes, carry the risk of severe side effects and lack efficacy against the progressive form of the disease. Here, we found that the transient receptor potential melastatin 2 (TRPM2) channel, which is abundantly expressed in CNS-infiltrating macrophages, plays a crucial role in development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE progression was suppressed by Knockout (KO) or pharmacological inhibition of TRPM2; this was attributed to a reduction in CXCL2 chemokine production by CNS-infiltrating macrophages in TRPM2-KO mice, resulting in suppression of neutrophil infiltration into the CNS. These results reveal an important role of TRPM2 in the pathogenesis of EAE and shed light on its potential as a therapeutic target.

Interneuron Simplification and Loss of Structural Plasticity As Markers of Aging-Related Functional Decline

Changes in excitatory neuron and synapse structure have been recognized as a potential physical source of age-related cognitive decline. Despite the importance of inhibition to brain plasticity, little is known regarding aging-associated changes to inhibitory neurons. Here we test for age-related cellular and circuit changes to inhibitory neurons of mouse visual cortex. We find no substantial difference in inhibitory neuron number, inhibitory neuronal subtypes, or synapse numbers within the cerebral cortex of aged mice compared with younger adults. However, when comparing cortical interneuron morphological parameters, we find differences in complexity, suggesting that arbors are simplified in aged mice. In vivo two-photon microscopy has previously shown that in contrast to pyramidal neurons, inhibitory interneurons retain a capacity for dendritic remodeling in the adult. We find that this capacity diminishes with age and is accompanied by a shift in dynamics from balanced branch additions and retractions to progressive prevalence of retractions, culminating in a dendritic arbor that is both simpler and more stable. Recording of visually evoked potentials shows that aging-related interneuron dendritic arbor simplification and reduced dynamics go hand in hand with loss of induced stimulus-selective response potentiation (SRP), a paradigm for adult visual cortical plasticity. Chronic treatment with the antidepressant fluoxetine reversed deficits in interneuron structural dynamics and restored SRP in aged animals. Our results support a structural basis for age-related impairments in sensory perception, and suggest that declines in inhibitory neuron structural plasticity during aging contribute to reduced functional plasticity.

SIGNIFICANCE STATEMENT Structural alterations in neuronal morphology and synaptic connections have been proposed as a potential physical basis for age–related decline in cognitive function. Little is known regarding aging-associated changes to inhibitory neurons, despite the importance of inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps. Here we show that brain aging goes hand in hand with progressive structural simplification and reduced plasticity of inhibitory neurons, and a parallel decline in sensory map plasticity. Fluoxetine treatment can attenuate the concurrent age–related declines in interneuron structural and functional plasticity, suggesting it could provide an important therapeutic approach for mitigating sensory and cognitive deficits associated with aging.

Correction: Scheff and Gold, "Trafficking of Na+/Ca2+ exchanger to the site of persistent inflammation in nociceptive afferents"

Identification of cell-associated and secreted serine-type peptidases in multidrug-resistant emergent pathogens belonging to the Candida haemulonii complex

Abstract

The Candida haemulonii complex (Candida haemulonii, Candida haemulonii var. vulnera, and Candida duobushaemulonii) comprises emerging opportunistic human fungal pathogens with recognized multidrug-resistance profiles. Little is known about the virulence markers produced by this fungal complex. However, it is recognized that Candida spp. express a large array of peptidases, which play multiple roles in different aspects of fungal-host interactions. In the present study, we have identified proteolytic enzymes in clinical isolates of the C. haemulonii complex using zymographic assays. Peptidases able to hydrolyze gelatin, casein, albumin, hemoglobin, and immunoglobulin G were detected in cell-free supernatants and cellular extracts taken from the three species forming the C. haemulonii complex. Overall, peptidases were preferentially evidenced at physiological pH and temperatures of 37–42 °C, with molar masses between 35 and 85 kDa. Peptidase profiles of C. haemulonii and C. haemulonii var. vulnera isolates were quite similar, contrasting to the peptidases produced by C. duobushaemulonii. Almost all peptidases were inhibited by phenylmethanesulfonyl fluoride (PMSF), thus classifying them as serine-type peptidases. Additionally, proteolytic cleavage of soluble azoalbumin was blocked by PMSF (65–95% inhibition depending on the fungal isolate). These unprecedented results have demonstrated the capability of the C. haemulonii complex to produce serine-type peptidases with an ability to cleave a broad spectrum of proteins, including key host components.

Current Climate for Digital Game-Based Learning of Science in Further and Higher Education

Abstract

Digital game-based learning (DGBL) is being used increasingly as an alternative learning tool to teach science in further and higher education. A variety of digital game formats currently exists for science learning, alongside diverse methods for their implementation and evaluation. This paper aims to provide a broad summary of the field by discussing the current platforms for DGBL and examples of games played on them. These include gamified simulations and traditional digital games delivered through personal computer (PC) and online software; mobile games delivered through downloaded applications for devices such as tablets and mobile phones; and educational modifications of commercial games, known amongst gamers as 'mods'. To conclude the summary, the paper discusses the current challenges and barriers associated with DGBL in further and higher science education, and potential strategies researchers may consider to overcome them.

Molecular imaging reporting and data systems (MI-RADS): a generalizable framework for targeted radiotracers with theranostic implications

Abstract

Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET)-based imaging agents for prostate carcinoma and neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e., if the reader is familiar with one system, the other system can readily be applied, as well. In the present review, we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a potential future role of the umbrella framework MI-RADS compared to other classification systems.

Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial

Abstract

Background

Skeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs.

Methods

NRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity.

Results

261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p = 0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p = 0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (> 2) had a negative impact on OS (p < 0.0001, p = 0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p = 0.02). No other group differences were noted for QOL or toxicity.

Conclusion

The addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month.

Clinical Trial Registry

This protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1.

Diagnosing polymyalgia rheumatica on 18 F-FDG PET/CT: typical uptake patterns

Abstract

Objective

The diagnosis of polymyalgia rheumatica (PMR) is often challenging, since similar clinical features and laboratory findings can be observed in several inflammatory conditions. PMR involves affected sites in a specific manner, and ¹⁸F-FDG PET/CT has the advantage for assessing the disease activity of each site. The purpose of this study was to identify the patterns of ¹⁸F-FDG uptake that suggest the diagnosis of PMR.

Methods

We studied 60 patients who had undergone ¹⁸F-FDG PET/CT scans for workup of suspected PMR, arthritis, enthesitis, or myopathy. Final diagnoses were made by board-certified rheumatologists. The incidence of significant ¹⁸F-FDG uptake, higher than mediastinal blood pool, of the following sites were compared among PMR patients and patients with other diseases: wrists, elbows, shoulders, sternoclavicular joints, acromioclavicular joints, spinous processes, ischial tuberosities, and greater trochanters. For the spinous processes, the incidence of "Y"-shaped uptake along the interspinous bursae was also evaluated.

Results

A definitive diagnosis of PMR was given to 16 of 60 patients. The incidence of significant ¹⁸F-FDG uptake in the definitive PMR group was 6% for wrists and for elbows, 88% for glenohumeral and sternoclavicular joints, 25% for acromioclavicular joints, 81% for spinous processes, 69% for ischial tuberosities, and 81% for greater trochanters. Patients with PMR showed a significantly higher incidence of "Y"-shaped uptake along the interspinous bursae than the other patients (38 vs. 9%) (P = 0.016).

Conclusion

¹⁸F-FDG uptake distribution patterns and morphology can contribute to the diagnosis of PMR. Significant ¹⁸F-FDG uptake in the sternoclavicular joints is one of the characteristic findings in patients with PMR as well as the uptake in the shoulders, ischial tuberosities, and greater trochanters. "Y"-shaped spinous process uptake may be one of the specific findings for PMR.

CXCR4-directed theranostics in oncology and inflammation

Abstract

Given its prominent role in inflammation and cancer biology, the C-X-C motif chemokine receptor 4 (CXCR4) has gained a lot of attention in the recent years. This review gives a short overview of the physiology and pathology of chemokines and chemokine receptors and then focuses on the current experience of targeting CXCR4, using radiolabeled receptor ligands suitable for positron emission tomography (PET) imaging, in both hematologic and solid malignancy as well as in inflammatory conditions. Additionally, CXCR4-directed endoradiotherapy (ERT) as a new treatment option is discussed.

Volume-outcome relationship and minimum volume regulations in the German hospital sector – evidence from nationwide administrative hospital data for the years 2005–2007

This paper analyses the volume-outcome relationship and the effects of minimum volume regulations in the German hospital sector.

Development of intraoperative plantar pressure measuring system considering weight bearing axis

Abstract

Purpose

Surgical reconstructions in three dimensions are needed for treatment of foot and ankle deformities. However, surgical results might be influenced by the skill and experience of doctors which complement the limited information for reconstructions in three dimensions. To solve these, studies were carried out to measure plantar pressure distribution during surgery. Though, it was impossible to accurately measure plantar pressure distribution accurately during operation. Therefore, we proposed an intraoperative plantar pressure measurement (IPPM) device that enables proper navigation in the push direction.

Methods

For this purpose, first, we investigated how the physiological load axis passes through the human body to identify the pushing direction of the pressure sensor of the device toward the patient's foot. In particular, we hypothesized that the physiological load axis passes through the femoral head center and we evaluated this in a measurement experiment with nine healthy subjects. Second, based on these results, we developed the IPPM device that has two force sensors to identify the pushing direction toward the femoral head center and a conductive ink sensor to measure plantar pressure distribution. Finally, we conducted the experiments with nine healthy subjects and two users.

Results

From the first experimental results, the physiological load axis was found to pass through the femoral head center in normal standing posture. From the evaluation experiment, there are no significant differences statistically in plantar pressure distributions between the conditions of using IPPM device and without using it for both a medical student and a surgeon. However, in some cases the plantar pressure distribution can be reproduced similarly to that of the standing posture, and also from the evaluation experiment concerning the relation between CoP position and NCC, the NCC tends to increase when the position of the CoP is closer to that at the standing posture.

Conclusion

The IPPM device has possibility to reproduce the plantar pressure distribution during surgery and prevent the recurrence of surgical complications.

Low-dose blue light irradiation enhances the antimicrobial activities of curcumin against Propionibacterium acnes

Publication date: Available online 26 September 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Ming-Yeh Yang, Kai-Chih Chang, Liang-Yü Chen, Anren Hu

Abstract

Propionibacterium acnes (P. acnes) is an opportunistic infection in human skin that causes acne vulgaris. Antibiotic agents provide the effective eradication of microbes until the development of drug-resistant microbes. Photodynamic inactivation (PDI) is a non-antibiotic therapy for microbial eradication. In this study, the visible blue light (BL, λ_max = 462 nm) was used to enhance the antimicrobial activities of curcumin, a natural phenolic compound. Individual exposure to curcumin or BL irradiation does not generate cytotoxicity on P. acnes. The viability of P. acnes was decreased significantly in 0.09 J/cm² BL with 1.52 μM of curcumin. Furthermore, the low-dose blue light irradiation triggers a series of cytotoxic actions of curcumin on P. acnes. The lethal factors of photolytic curcumin were investigated based on the morphology of P. acnes by SEM and fluorescent images. The membrane disruption of microbes was observed on the PDI against P. acnes. Chromatography and mass spectrometry techniques were also used to identify the photolytic metabolites. Curcumin could be photolysed into vanillin through BL irradiation, which presents a strong linear relationship in quantitation. Because the safety of blue light in mammalian cell has been proven, the photolytic curcumin treatment could support non-antibiotic therapy to eradicate P. acnes on clinical dermatology.

Graphical abstract

Die operative Behandlung von Lippen-Kiefer-Gaumen-Spalten – Domaine des MKG-Chirurgen

Intérêt du dosage de la calprotectine fécale au cours des panniculites chroniques d’étiologie indéterminée

Publication date: Available online 25 September 2018

Source: Annales de Dermatologie et de Vénéréologie

Author(s): K. Kaddour, J. Lemasson, B. Haettich-Pialoux, N. Guedj, N. Belmatoug, X. Treton, H. Becheur, B. Fantin, V. Descamps, P. Le Bozec

Vehiculización de fármacos asistida por láser

Publication date: Available online 25 September 2018

Source: Actas Dermo-Sifiliográficas

Author(s): A. Alegre-Sánchez, N. Jiménez-Gómez, P. Boixeda

Resumen

La absorción de productos tópicos a través de la epidermis está limitada por la función de barrera cutánea. Existen distintas técnicas, tales como el microneedling, la dermoabrasión, la radiofrecuencia o los láseres, que se han empleado para aumentar la absorción de estas sustancias en una estrategia conocida como vehiculización transdérmica de fármacos. Entre estas técnicas destaca la vehiculización de fármacos asistida por láseres (VFAL), especialmente láseres fraccionales ablativos (CO₂/Er:YAG), por su capacidad de generar canales de microablación. En la VFAL se deben ajustar los parámetros en función del tipo de paciente, la dermatosis, la localización y el fármaco empleado. Se ha estudiado la VFAL en el uso de corticoides, fotosensibilizantes o inmunoterapia tópica (imiquimod o 5-fluorouracilo), entre otros, y en múltiples indicaciones: cicatrices, cáncer cutáneo no melanoma, fotodaño, etc. La VFAL es una técnica prometedora que permite aumentar la absorción de moléculas tópicas consiguiendo, además, el efecto sinérgico del láser.

Abstract

Absorption of topical products through the epidermis is limited by the skin's barrier function. Numerous techniques and agents such as microneedling, dermabrasion, radiofrequency, and lasers have been used to increase penetration within an approach known as transdermal drug delivery. One of these techniques is laser-assisted drug delivery (LADD), which often uses ablative fractional lasers (CO₂ or erbium:YAG lasers) because of their capacity to produce microscopic ablated channels. The parameters in LADD need to be adjusted to the patient, the skin condition and its location, and the drug. LADD has been used with various topical products, such as corticosteroids, photosensitizers, and immunotherapy agents (imiquimod or 5-fluorouracil) to treat numerous conditions, including scars, nonmelanoma skin cancer, and photodamage. LADD is a promising technique that enhances the absorption of topical molecules while adding the synergic effect of the laser.

Graphical abstract

Langzeitfolgen onkologischer Behandlungen

The Safety of Antibiotic Skin Testing in Severe T-cell-Mediated Hypersensitivity of immunocompetent and immunocompromised hosts

Publication date: Available online 26 September 2018

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

Author(s): Jason A. Trubiano, Abby P. Douglas, Michelle Goh, Monica A. Slavin, Elizabeth J. Phillips

A Case of Voriconazole-Induced Pseudoporphyria

Publication date: Available online 25 September 2018

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

Author(s): Guillermo Rodriguez-Nava, Archi Patel, Dima Youssef, George A. Youngberg, Alexei Gonzalez-Estrada

Toxicidad cutánea de los fármacos anti-PD-1/anti-PD-L1

Publication date: Available online 25 September 2018

Source: Piel

Author(s): Noelia Rivera, Aram Boada

Optimizing clinical images with a smartphone and light-emitting diode

Publication date: Available online 26 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Cheng Zhou, Man Li, Xi Chen, Bo Li, Xueyan Yao, Jianzhong Zhang

Follicular Involvement is Frequent in Lentigo Maligna: Implications for Treatment

Publication date: Available online 26 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Karen L. Connolly, Cerrene Giordano, Stephen Dusza, Klaus J. Busam, Kishwer Nehal

Abstract

Background

Follicular involvement of lentigo maligna (LM) is considered a histopathologic hallmark, but its prevalence and characteristics have not been well-defined. The depth of intrafollicular extension by neoplastic melanocytes may have clinical importance in the treatment of lentigo maligna.

Objective

To describe the prevalence and features of follicular involvement in LM, including depth of follicular growth by melanocytes.

Methods & Materials

Single-center retrospective study of 100 consecutive cases of surgically excised LM treated from 2013 to 2015. Slide review for cases with residual LM on debulk specimen was performed by a dermatologic surgeon and dermatopathologist to characterize follicular involvement.

Results

Seventy-two of 100 specimens met inclusion criteria for histopathologic evaluation. Follicular involvement was seen in 95.8% of specimens (95% CI: 88.3%-99.1%), with a mean 68% of follicles involved in a single specimen. The mean depth of intrafollicular growth by lesional melanocytes was 0.45 mm (SD=0.23, range 0.1 mm to 1.1 mm). Tumor cells were confined to the infundibular portion of the hair follicle in 60.9% of specimens.

Conclusion

Superficial follicular involvement is a ubiquitous finding in LM. When considering treatment options for LM with a depth-dependent modality aiming for tumor clearance, mean and maximum depths of involvement should be considered.

Camp Sun Safe: A community level sun safety intervention

Publication date: Available online 26 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Virginia A. Tracey, Katharine P. Saussy, Jacqueline G. Witt, Alexandra M. Haugh, Brittany J. Stumpf

Treatment of oral mucosal neuromas with carbon dioxide laser

Publication date: Available online 26 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Emily A. Weig, Gretchen M. Roth, Karolyn A. Wanat, Nkanyezi N. Ferguson

The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases

S100A8/A9 and S100A12 are released from activated monocytes and granulocytes and act as proinflammatory endogenous toll-like receptor (TLR)4-ligands. S100 serum concentrations correlate with disease activity, ...

How Intraoperative Tools and Techniques Have Changed the Approach to Brain Tumor Surgery

Abstract

Purpose of Review

Surgical treatment of brain tumors remains an integral part of a comprehensive treatment plan. Here, we review technological advances that have enhanced what surgeons are capable of doing within and outside the traditional operating room.

Recent Findings

Extent of surgical resection has improved with the use of MRI and fluorescent dyes intraoperatively. Neurological injury during brain tumor surgery has decreased with appropriate use of neurophysiological monitoring. New operative scopes have enhanced ability of surgeons to visualize tissues during dissection. Laser interstitial therapy and radiation treatment have made possible the treatment of previously considered non-operable brain tumors in addition to replacing or serving as adjunct to surgical treatment of brain tumors.

Summary

Surgery remains an important pillar in treatment of most brain tumors. Ongoing technological advances have augmented extent of what is possible in this realm.

Molecular Mechanisms of Cisplatin Chemoresistance and Its Circumventing in Testicular Germ Cell Tumors

Abstract

Purpose of Review

Testicular germ cell tumors (TGCTs) represent the most common solid tumors affecting young men. Majority of TGCTs respond well to cisplatin-based chemotherapy. However, patients with refractory disease have limited treatment modalities associated with poor prognosis. Here, we discuss the main molecular mechanisms associated with acquired cisplatin resistance in TGCTs and how their understanding might help in the development of new approaches to tackle this clinically relevant problem. We also discuss recent data on the strategies of circumventing the cisplatin resistance from different tumor types potentially efficient also in TGCTs.

Recent Findings

Recent data regarding deregulation of various signaling pathways as well as genetic and epigenetic mechanisms in cisplatin-resistant TGCTs have contributed to understanding of the mechanisms related to the resistance to cisplatin-based chemotherapy in these tumors. Understanding of these mechanisms enabled explaining why majority but not all TGCTs patients are curable with cisplatin-based chemotherapy. Moreover, it could lead to the development of more effective treatment of refractory TGCTs and potentially other solid tumors resistant to platinum-based chemotherapy.

Summary

This review provides additional insights into mechanisms associated with cisplatin resistance in TGCTs, which is a complex phenomenon, and there is a need for novel modalities to overcome it.

Patient‐reported outcomes: A 5‐year long study reveals previously unreported therapeutic, demographic, socio‐economic, and other correlations in vitiligo

Dermatologic Therapy, EarlyView.

Efficacy of oral tranexemic acid in refractory melasma: A clinico–immuno‐histopathological study

Dermatologic Therapy, EarlyView.

Occlusion therapy in inflammatory cutaneous diseases

Dermatologic Therapy, EarlyView.

Efficacy of topical calcineurin inhibitors in pyoderma gangrenosum

Dermatologic Therapy, EarlyView.

Sequential methyl‐aminolevulinate daylight photodynamic therapy and diclofenac plus hyaluronic acid gel treatment for multiple actinic keratosis evaluation

Dermatologic Therapy, EarlyView.

Remittive effect of Dupilumab in atopic dermatitis

Dermatologic Therapy, EarlyView.

Prevention and management of iatrogenic blindness associated with aesthetical filler injections

Dermatologic Therapy, EarlyView.

Efficacy, safety, and cost‐effectiveness of all‐trans retinoic acid/Clobetasol Propionate Compound Ointment in the treatment of mild to moderate psoriasis vulgaris: A randomized, single‐blind, multicenter clinical trial

Dermatologic Therapy, EarlyView.

Use of botulinum toxin in the treatment of aquagenic keratoderma: One case report

Dermatologic Therapy, EarlyView.

Controversies in the treatment of androgenetic alopecia: The history of finasteride

Dermatologic Therapy, EarlyView.

Solitary facial cutaneous chronic inflammatory lesions induced by anti‐tumour necrosis factor‐α antagonist

Clinical and Experimental Dermatology, EarlyView.

Topical sodium thiosulfate for calcinosis cutis associated with autoimmune connective tissue diseases: the Mayo Clinic experience, 2012–2017

Clinical and Experimental Dermatology, EarlyView.

Blaschkoid distribution of composite syringocystadenoma papilliferum and tubular apocrine adenoma without naevus sebaceous

Clinical and Experimental Dermatology, EarlyView.

Effectiveness and safety of 0·5% colchicine cream vs. photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratosis and skin field cancerization of the forearms: a randomized controlled trial

British Journal of Dermatology, EarlyView.

Expression and metabolic activity of flavin‐containing monooxygenase 1 in cynomolgus macaque kidney

Journal of Medical Primatology, EarlyView.

Hypotonic stress response of human keratinocytes involves LRRC8A as component of volume‐regulated anion channels

Experimental Dermatology, Volume 0, Issue ja, -Not available-.

Molecular identification and antifungal susceptibility of clinical fungal isolates from onychomycosis (uncommon and emerging species)

Mycoses, Volume 0, Issue ja, -Not available-.

Issue Information

Mycoses, Volume 61, Issue 10, Page 705-707, October 2018.

Acute generalized exanthematous pustulosis induced by terbinafine in a child confirmed by patch testing

International Journal of Dermatology, EarlyView.

Antineutrophil cytoplasmic antibodies negative levamisole‐induced leukocytoclastic vasculitis: a presumed case and literature review

International Journal of Dermatology, EarlyView.

Taking Stock of Engineering Epistemology: Multidisciplinary Perspectives

Abstract

How engineers know, and act on that knowledge, has a profound impact on society. Consequently, the analysis of engineering knowledge is one of the central challenges for the philosophy of engineering. In this article, we present a thematic multidisciplinary conceptual survey of engineering epistemology and identify key areas of research that are still to be comprehensively investigated. Themes are organized based on a survey of engineering epistemology including research from history, sociology, philosophy, design theory, and engineering itself. Five major interrelated themes are identified: the relationship between scientific and engineering knowledge, engineering knowledge as a distinct field of study, the social epistemology of engineering, the relationship between engineering knowledge and its products, and the cognitive aspects of engineering knowledge. We discuss areas of potential future research that are underdeveloped or "undone."

Telogen hair loss and androgenetic‐like alopecia in GAPO syndrome

Australasian Journal of Dermatology, EarlyView.

Reply: Measurement of warping angle in human rib graft; Experimental study

No abstract available

Processions, Seductions, Divine Battles: Aśvaghoṣa at the Foundations of Old Javanese Literature

Abstract

The influence of Aśvaghoṣa on the later tradition of kāvya was largely passed over in the South Asian tradition, even though the debt to his influence is clear in processional scenes developed by Kālidāsa and the attempted seduction of Arjuna developed by Bhāravi in his Kirātārjunīyam. We know from the testimony of the Chinese pilgrim Yijing that the Buddhacarita was a revered object of study in the Sumatran capital Śrībhoga near the close of the seventh century CE. It thus perhaps comes as no surprise that three tropes or themes developed by Aśvaghoṣa were developed by several important composers of kakawin, the Old Javanese literary genre comparable to the kāvya of South Asia. This paper looks at the development of the themes of processions, divine battles and attempted seductions in a long history beginning with Aśvaghoṣa and closing with the work of the Javanese author Mpu Tantular, who completed the Buddhist kakawin Sutasoma c. 1365–1389 CE. This paper is partly based on a revised perspective on the history of the Shailendra and Sañjaya dynasties of central Java developed by examining the role of the "Shailendra royal preceptors" in bringing Sanskrit learning to Central Java in the period 778–847 CE.

Evaluation of drug resistance mutations in patients with chronic hepatitis B

Abstract

Mutations occurring in viral polymerase gene of hepatitis B virus (HBV) due to the use of nucleos(t)id analogs reduce the activity of the drugs by causing antiviral resistance. In this study, it was aimed to evaluate mutations responsible for drug resistance and drug resistance mutation rates in patients followed up by the diagnosis of chronic hepatitis B (CHB). A total of 318 CHB patients were included in the study. HBV mutations were detected using the INNO-LiPA commercial kit based on the reverse hybridization principle. Drug resistance mutation was detected in 46.86% (149/318) of the patients. The rates of drug resistance were found 36.79% (117/318) for lamivudine resistance, 12.58% (40/318) for entecavir (ETV), and 7.86% (25/318) for adefovir. In 10 patients, the possible tenofovir (TDF) resistance (3.14%) was found. Single-drug and double-drug resistances were detected in 34.59% and in 11.01% of the patients, respectively. Triple drug resistance was detected in only 1.26% of the patients. Unlike various studies in Turkey and in other countries, remarkable resistance to ETV and TDF were found in this study. The high rate of the probable TDF resistance was striking, with 3.14%.

The surgical anatomy of the superficial and deep palmar arches: a Meta-analysis.

Related Articles

The surgical anatomy of the superficial and deep palmar arches: a Meta-analysis.

J Plast Reconstr Aesthet Surg. 2018 Aug 24;:

Authors: Zarzecki MP, Popieluszko P, Zayachkowski A, Pękala PA, Henry BM, Tomaszewski KA

Abstract
INTRODUCTION: The following study aimed to find the pooled prevalence estimate of anatomical variations in the palmar vasculature, namely the superficial palmar arch (SPA) and the deep palmar arch (DPA). The importance of understanding the vasculature of the hand has become critical with the increasing use of hand microsurgery.
METHODS: Major online medical databases (PubMed, EMBASE, ScienceDirect, and Web of Science) were extensively searched for terms pertaining to the SPA, the DPA, and their anatomy and variations. Articles reporting data on the SPA and/or the DPA were collected and their data extracted. Furthermore, a reference search was performed, allowing to pinpoint any articles that were not previously found. The collected data were analyzed using MetaXL 5.3.
RESULTS: The analysis included 36 studies (n = 4841 palmar arches). The SPA was found to be complete in 81.3% of cases, with the radioulnar anastomosis being the most common variant (72.0%). The incomplete SPA was present in 18.7% of cases, with the ulnar artery supplying the third finger from both radial and ulnar side as the most prevalent in 34.8%. The DPA was found to be complete in 95.2% of cases.
CONCLUSION: In this study, the SPA was predominantly complete, with the anastomosis between the radial and the ulnar artery being most prevalent. Furthermore, the DPA was also complete in the vast majority of cases. The palmar arches and their variations should be kept in mind when considering the use of palmar vasculature for cardiac catheterization and other medical procedures, due to the risk of iatrogenic ischemic hand complications.

PMID: 30245020 [PubMed - as supplied by publisher]

Zhu, Hanmin 朱漢民, Classics Hermeneutics and Reason(s) Embodiment–On the Historical Construction of Chinese Philosophy 經典詮釋與義理體認——中國哲學建構歷程片論

Association of extracellular heat shock protein 70 and insulin resistance in type 2 diabetes; independent of obesity and C-reactive protein

Abstract

Despite few studies on intracellular heat shock protein70, the clinical association between insulin resistance and extracellular heat shock protein70 (eHSP70) is not well studied. In the current study, we examined the association between homeostatic model assessment-insulin resistance (HOMA-IR) and eHSP70 in patients with type 2 diabetes (T2DM) and healthy controls. A total of 145 patients with T2DM and 41 matched healthy controls were selected. Patients and controls were divided based on waist circumference (WC) to two groups, and eHSP70 was compared between them. The association between HOMA-IR and eHSP70 was examined using regression models adjusted for age, high-sensitive C-reactive protein (hs-CRP), and central obesity as confounding factors. While eHSP70 and hs-CRP were significantly correlated with HOMA-IR in patients with T2DM (p = 0.032, 0.025, respectively), there was no correlation between eHSP70 and HOMA-IR in the control group. Extracellular HSP70 and hs-CRP were not correlated in healthy controls. But a significant association appeared between eHSP70 and hs-CRP in patients with T2DM (p = 0.05). Both BMI and WC were not correlated with eHSP70 in both groups. Extracellular HSP70 was positively associated with HOMA-IR in patients with T2DM, independent from hs-CRP and obesity. We also showed eHSP70 levels remained unchanged through increase in BMI or WC in patients with T2D and in healthy controls. Our findings suggest that eHSP70 may contribute to the pathogenesis of T2DM by increasing insulin resistance.

Beyond photoaging: additional factors involved in the process of skin aging

Identification and isolation of splenic tissue resident macrophage subpopulations by flow cytometry

Abstract

Tissue resident macrophages in the spleen, including red pulp and white pulp macrophages, marginal zone macrophages (MZMs), and marginal zone metallophilic macrophages (MMMs), are highly heterogeneous as a consequence of adaptation to tissue-specific environments. Each macrophage subpopulation in the spleen is usually identified based on the localization, morphology and membrane antigen expression by immunohistochemistry. However, their phenotypical and functional characteristics remain incompletely understood due to the difficulty of identification and isolation by flow cytometry. We used a cocktail of three enzymes (Collagenase D, Dispase I and DNase I), rather than traditional mechanical grinding, for isolation of each subpopulation, which resulted in significant improvement of isolation of these macrophage subpopulations, particularly MZMs and MMMs, as determined by CD11b^hiF4/80^medTim4^hi and CD11b^hiF4/80^medTim4^med, respectively. This method should be helpful for molecular and functional characterization of each splenic resident macrophage subpopulation.

Chemotherapy-induced metastasis: An unexpected foe?

By Yoskaly Lazo-Fernandez, PhD

Introduction

Evidence has accumulated recently indicating that common cancer therapies might stimulate metastasis in a significant number of cancer patients¹. In fact, neoadjuvant chemotherapy (NAC) drugs, which are administered preoperatively as a first line of treatment, have been associated with increased infiltration of endothelial progenitor cells and macrophages in primary tumors, resulting in higher angiogenesis and tumor regrowth². Mechanisms by which these cellular injury responses induce metastasis, both in preclinical in vivo models, and in human patients have been elucidated recently in two independent studies.

The tumor microenvironment of metastasis

In their excellent article, Karagiannis et al.³ relied heavily on the histological analysis and intravital-imaging functional assessment of a well-established marker for breast cancer metastasis, the tumor microenvironment of metastasis (TMEM)⁴. TMEMs are microanatomical assemblies of three different cell types inside tumors. These are: peritubular macrophages, tumor cells and endothelial cells. What is extraordinary about TMEMs is that their assembly seems to be indispensable for cancer cell intravasation and distant metastasis to occur⁵. Not surprisingly, the histopathological determination of TMEM scores in breast cancer patient biopsies has become a reliable prognosis marker associated with distant metastasis⁶.

VEGF165 was detected in immersion fixed frozen sections of human breast cancer tissue using 5 µg/mL Human VEGF165 Polyclonal Antibody (Catalog# AB-293-NA) overnight at 4℃. Tissue was stained (red) and counterstained with hematoxylin (blue). View our protocol for Chromogenic IHC Staining of Frozen Tissue Sections.

Mechanisms by which NAC induces breast cancer metastasis

Administration of NAC drugs such as paclitaxel or the doxorubicin/cyclophosphamide combination induced significant increases in TMEM scores in all of the 4 in vivo preclinical models of breast cancer that were tested in the project³. Moreover, these effects where functionally very relevant, as the same treatments stimulated all the molecular and functional markers associated with TMEM activity including:

1. The abundance of intra-tumoral perivascular macrophages, particularly those overexpressing the angiopoietin receptor TIE-2 and Vascular Endothelial Growth Factor (VEGF).
2. The intra-tumoral vascular permeability, with observable intervals of vessel leaking or bursting followed by tumor cell intravasation.
3. The plasmatic concentration of circulating tumor cells (CTC).
4. The incidence of lung metastasis and the number of metastasis per animal.
5. The expression of the mammalian enabled protein MENA, particularly of its tumor promoting isoform MENA^INV. Moreover, some of these results were replicated in samples from human breast cancer patients right after they received extensive NAC treatments.

The second paper by Chang et al.⁷ reported similar increases of TMEM activity in a breast cancer model after paclitaxel in vivo administration. In addition, this study showed that the pro-metastatic effects of chemotherapy extend to the metastatic host, non-cancerous, tissue. For example, in the metastatic lung, paclitaxel reduced the cytotoxic responses of T and NK cells and increased the presence of inflammatory monocytes, all of which stimulated the distant seeding and proliferation of cancer cells.

Significance

Overall these results regarding the pro-metastatic effects of paclitaxel and other chemotherapeutic drugs, are concerning and highly controversial. On the one hand, the curative and/or life-extending effects of these drugs in a number of cancer types, including a high percentage of breast cancer patients, needs to be defended. On the other, it wouldn't be ethical to allow the subset of cancer patients that could be severely harmed by chemotherapy to go through the high costs and harsh side effects of these treatments. An open discussion on these issues has undoubtedly started, fueled by the very recent publication of several reviews in high impact journals^1,8–10.

Further research on this area is urgent, particularly on the identification of the molecular determinants of the curative vs. the pro-metastatic and potentially harmful response to chemotherapy in cancer patients. Such advances could allow the implementation of more personalized chemotherapeutic approaches. In the meantime, novel combination pharmacotherapies are being tested that could significantly alleviate this problem. For example, Karagiannis³ eliminated the pro-metastatic effects of paclitaxel by pretreating the mice with the TIE-2 inhibitor, currently undergoing clinical trials, rebastinib. Chang⁷ also attained encouraging results in the identification of the novel potential target, the transcription factor ATF3, whose potential pharmacological inhibition could also counteract the harmful pro-metastatic effects of chemo. It seems reasonable to predict that a much more personalized and effective set of treatment protocols for breast- and other types of cancer, is around the corner, we can hardly wait.

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Yoskaly Lazo Fernandez, PhD
Research Assistant Professor, The University of Kansas Medical Center
Dr. Lazo-Fernandez is interested in the application of novel immunotherapies for the treatment of cancer, particularly ovarian cancer.

References

1. Martin OA, Anderson RL, Narayan K, MacManus MP. Does the mobilization of circulating tumour cells during cancer therapy cause metastasis? Nature Reviews Clinical Oncology. 2017;14(1):32-44. doi:10.1038/nrclinonc.2016.128 .
2. Daenen L, Houthuijzen J, Cirkel G, Roodhart J, Shaked Y, Voest E. Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies. Oncogene. 2014;33(11):1341. doi:10.1038/onc.2013.94 .
   
3. Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, Alfonso T, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Science Translational Medicine. 2017;9(397):eaan0026. doi:10.1126/scitranslmed.aan0026 .
   
4. Oktay MH, Jones JG. TMEM: a novel breast cancer dissemination marker for the assessment of metastatic risk. Biomarkers in Medicine. 2015;9(2):81-84. doi:10.2217/bmm.14.104 .
   
5. Roussos ET, Wang Y, Wyckoff JB, Sellers RS, Wang W, Li J, Pollard JW, Gertler FB, Condeelis JS. Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors. Breast Cancer Research. 2010;12(6):1-16. doi:10.1186/bcr2784 .
   
6. Robinson BD, Sica GL, Liu Y-F, Rohan TE, Gertler FB, Condeelis JS, Jones JG. Tumor Microenvironment of Metastasis in Human Breast Carcinoma: A Potential Prognostic Marker Linked to Hematogenous Dissemination. Clinical Cancer Research. 2009;15(7):2433-2441. doi:10.1158/1078-0432.CCR-08-2179 .
   
7. Chang Y, Jalgaonkar SP, Middleton JD, Hai T. Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proceedings of the National Academy of Sciences. 2017;114(34):E7159-E7168. doi:10.1073/pnas.1700455114 .
   
8. Martin OA, Anderson RL. Editorial: Therapy-induced metastasis. Clinical & Experimental Metastasis. 2018;35(4):219-221. doi:10.1007/s10585-018-9914-x .
   
9. Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis in breast cancer. Oncotarget. 2017;8(67):110733-110734. doi:10.18632/oncotarget.22717 .
   
10. Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clinical & experimental metastasis. 2018;35(4):269-284. doi:10.1007/s10585-017-9870-x .

 

 

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Onkologie und Versorgung in Fach- und Publikumsmedien

Deep learning with convolutional neural network for objective skill evaluation in robot-assisted surgery

Abstract

Purpose

With the advent of robot-assisted surgery, the role of data-driven approaches to integrate statistics and machine learning is growing rapidly with prominent interests in objective surgical skill assessment. However, most existing work requires translating robot motion kinematics into intermediate features or gesture segments that are expensive to extract, lack efficiency, and require significant domain-specific knowledge.

Methods

We propose an analytical deep learning framework for skill assessment in surgical training. A deep convolutional neural network is implemented to map multivariate time series data of the motion kinematics to individual skill levels.

Results

We perform experiments on the public minimally invasive surgical robotic dataset, JHU-ISI Gesture and Skill Assessment Working Set (JIGSAWS). Our proposed learning model achieved competitive accuracies of 92.5%, 95.4%, and 91.3%, in the standard training tasks: Suturing, Needle-passing, and Knot-tying, respectively. Without the need of engineered features or carefully tuned gesture segmentation, our model can successfully decode skill information from raw motion profiles via end-to-end learning. Meanwhile, the proposed model is able to reliably interpret skills within a 1–3 second window, without needing an observation of entire training trial.

Conclusion

This study highlights the potential of deep architectures for efficient online skill assessment in modern surgical training.

A retrospective analysis of esophageal eosinophilia in patients with aspirin-exacerbated respiratory disease.

Publication date: Available online 25 September 2018

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

Author(s): Ryan C. Eid, Marina Palumbo, Tanya M. Laidlaw, Kathleen M. Buchheit, Katherine N. Cahill

Basics of genome-scale metabolic modeling and applications on C1-utilization

Abstract

It is fundamental to understand the relationship between genotype and phenotype in biology. This requires comprehensive knowledge of metabolic pathways, genetic information and well-defined mathematic modeling. Integration of knowledge on metabolism with mathematical modeling results in genome-scale metabolic models which have proven useful to investigate bacterial metabolism and to engineer bacterial strains capable of producing value-added biochemical. Single carbon substrates such as methane and carbon monoxide have drawn interests and they assumed one of next-generation feedstocks because of their high abundance and low price. The methylotroph and acetogen-based biorefineries hold promises for bioconversion of C1 substrates into biofuels and high value compounds. As an effort on expanding our knowledge on C1 utilization approaches, in silico computational framework of C1-metabolism in methylotrophic and acetogenic bacteria have been developed. In this review, genome-scale metabolic models for C1-utilizing bacteria and well-established analysis tools are presented for potential uses for study of C1 metabolism at the genome-scale and its application in metabolic engineering.

The Colors of Biotechnology: general overview and developments of White, Green and Blue areas

Abstract

Biotechnology is responsible for the manipulation of living organisms or their components for the production of products that are of benefit to human kind. Due to the wide range of applications, colors have been used to differentiate the main areas of research, such as white (industrial), green (agricultural), and blue (marine and fresh-water), among others. Thus, this review outlines the impacts of these areas of biotechnology, emphasizing their impact and potential to replace carbon-based technologies with more sustainable technologies.

In This Issue

Two decades of the impact of Tasmanian Devil Facial Tumour Disease (DFTD)

Abstract

The Tasmanian Devil, a marsupial carnivore, has been restricted to the island state of Tasmania since its extinction on the Australian mainland about three thousand years ago. In the past two decades, this species has experienced severe population decline due to the emergence of devil facial tumour disease (DFTD), a transmissible cancer. During these twenty years, scientists have puzzled over the immunological and evolutionary responses by the Tasmanian devil to this transmissible cancer. Targeted strategies in population management and disease control have been developed as well as comparative processes to identify variation in tumor and host genetics. A multi-disciplinary approach with multi-institutional teams has produced considerable advances over the last decade. This has led to a greater understanding of the molecular pathogenesis and genomic classification of this cancer. New and promising developments in the Tasmanian devil's story include evidence that most immunized, and some wild devils, can produce an immune response to DFTD. Furthermore, epidemiology combined with genomic studies suggest a rapid evolution to the disease and that DFTD will become an endemic disease. Since 1998 there have been more than 350 publications, distributed over 37 Web of Science categories. A unique endemic island species has become an international curiosity that is in the spotlight of integrative and comparative biology research.

A Systematic Review of Evidence-Based Treatments for Prurigo Nodularis

Publication date: Available online 25 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Azam A. Qureshi, Laura E. Abate, Gil Yosipovitch, Adam J. Friedman

Abstract

Prurigo nodularis is a chronic dermatologic condition involving the development of multiple cutaneous nodules in the setting of intractable pruritus. Given emerging treatment options for this difficult-to-treat condition, a current review of therapeutics is needed. A systematic review was performed for clinical studies investigating prurigo nodularis treatment published from 1990 to present including at least 5 subjects. A total of 35 articles were assigned a level of evidence according to the Oxford Center for Evidence-based Medicine. All five studies investigating topical agents, including corticosteroids, calcineurin inhibitors, calcipotriol, and capsaicin, conveyed some beneficial effect with level of evidence 2b or higher. Six of eight reports investigating photo- and photochemotherapy achieved levels of evidence 2b or greater and showed good partial response rates. Thalidomide was studied by six reports providing evidence of good symptom response, but only two of which were rated level 2b or greater. Cyclosporine and methotrexate have demonstrated benefit in four combined studies, albeit with level four evidence. Pregabalin, amitriptyline, paroxetine, fluvoxamine, and neurokinin-1 receptor antagonists have demonstrated promising evidence in five level 2b studies. Higher-powered studies and additional randomized controlled trials are needed for evaluation of safe and efficacious systemic treatment options for prurigo nodularis.

Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers

Abstract

Background

Complex clusters of rearrangements in cancer genomes are a challenge to interpret. Some are clear amplifications of driver oncogenes but others are less well understood. Detailed analysis of rearrangements within these complex clusters could reveal new insights into selection, and underlying mutational mechanisms.

Results

Here, we systematically investigate rearrangements that are densely clustered in individual tumours in a cohort of 560 breast cancers. Applying an agnostic approach, we identify 21 hotspots where clustered rearrangements recur across cancers. Some hotspots coincide with known oncogene loci including CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC. Others contain cancer genes not typically associated with breast cancer: MCL1, PTP4A1 and MYB. Intriguingly, we identify clustered rearrangements that physically connect distant hotspots. In particular, we observe simultaneous amplification of chr8:ZNF703/FGFR1 and chr11:CCND1 where deep analysis reveals that a chr8-chr11 translocation is likely to be an early, critical, initiating event.

Conclusions

We present an overview of complex rearrangements in breast cancer, highlighting a potential new way for detecting drivers and revealing novel mechanistic insights into the formation of two common amplicons.

GTCreator: a flexible annotation tool for image-based datasets

Abstract

Purpose:

Methodology evaluation for decision support systems for health is a time-consuming task. To assess performance of polyp detection methods in colonoscopy videos, clinicians have to deal with the annotation of thousands of images. Current existing tools could be improved in terms of flexibility and ease of use.

Methods:

We introduce GTCreator, a flexible annotation tool for providing image and text annotations to image-based datasets. It keeps the main basic functionalities of other similar tools while extending other capabilities such as allowing multiple annotators to work simultaneously on the same task or enhanced dataset browsing and easy annotation transfer aiming to speed up annotation processes in large datasets.

Results:

The comparison with other similar tools shows that GTCreator allows to obtain fast and precise annotation of image datasets, being the only one which offers full annotation editing and browsing capabilites.

Conclusion:

Our proposed annotation tool has been proven to be efficient for large image dataset annotation, as well as showing potential of use in other stages of method evaluation such as experimental setup or results analysis.

The little story of the Journal de Mycologie Médicale/Journal of Medical Mycology

Publication date: Available online 24 September 2018

Source: Journal de Mycologie Médicale

Author(s): J.-M. Bastide