Phosphoinositol-4,5-Bisphosphate Regulates Auditory Hair-Cell Mechanotransduction-Channel Pore Properties and Fast Adaptation

Membrane proteins, such as ion channels, interact dynamically with their lipid environment. Phosphoinositol-4,5-bisphosphate (PIP₂) can directly or indirectly modify ion-channel properties. In auditory sensory hair cells of rats (Sprague Dawley) of either sex, PIP₂ localizes within stereocilia, near stereocilia tips. Modulating the amount of free PIP₂ in inner hair-cell stereocilia resulted in the following: (1) the loss of a fast component of mechanoelectric-transduction current adaptation, (2) an increase in the number of channels open at the hair bundle's resting position, (3) a reduction of single-channel conductance, (4) a change in ion selectivity, and (5) a reduction in calcium pore blocking effects. These changes occur without altering hair-bundle compliance or the number of functional stereocilia within a given hair bundle. Although the specific molecular mechanism for PIP₂ action remains to be uncovered, data support a hypothesis for PIP₂ directly regulating channel conformation to alter calcium permeation and single-channel conductance.

SIGNIFICANCE STATEMENT How forces are relayed to the auditory mechanoelectrical transduction (MET) channel remains unknown. However, researchers have surmised that lipids might be involved. Previous work on bullfrog hair cells showed an effect of phosphoinositol-4,5-bisphosphate (PIP₂) depletion on MET current amplitude and adaptation, leading to the postulation of the existence of an underlying myosin-based adaptation mechanism. We find similar results in rat cochlea hair cells but extend these data to include single-channel analysis, hair-bundle mechanics, and channel-permeation properties. These additional data attribute PIP₂ effects to actions on MET-channel properties and not motor interactions. Further findings support PIP₂'s role in modulating a fast, myosin-independent, and Ca²⁺-independent adaptation process, validating fast adaptation's biological origin. Together this shows PIP₂'s pivotal role in auditory MET, likely as a direct channel modulator.

Exploring the Role of CaMKIV in Homeostatic Plasticity

Neuromedin B Expression Defines the Mouse Retrotrapezoid Nucleus

The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial region of the medulla oblongata. An unknown proportion of RTN neurons are central respiratory chemoreceptors and there is mounting evidence for biochemical diversity among these cells. Here, we used multiplexed in situ hybridization and single-cell RNA-Seq in male and female mice to provide a more comprehensive view of the phenotypic diversity of RTN neurons. We now demonstrate that the RTN of mice can be identified with a single and specific marker, Neuromedin B mRNA (Nmb). Most (~75%) RTN neurons express low-to-moderate levels of Nmb and display chemoreceptor properties. Namely they are activated by hypercapnia, but not by hypoxia, and express proton sensors, TASK-2 and Gpr4. These Nmb-low RTN neurons also express varying levels of transcripts for Gal, Penk, and Adcyap1, and receptors for substance P, orexin, serotonin, and ATP. A subset of RTN neurons (~20–25%), typically larger than average, express very high levels of Nmb mRNA. These Nmb-high RTN neurons do not express Fos after hypercapnia and have low-to-undetectable levels of Kcnk5 or Gpr4 transcripts; they also express Adcyap1, but are essentially devoid of Penk and Gal transcripts. In male rats, Nmb is also a marker of the RTN but, unlike in mice, this gene is expressed by other types of nearby neurons located within the ventromedial medulla. In sum, Nmb is a selective marker of the RTN in rodents; Nmb-low neurons, the vast majority, are central respiratory chemoreceptors, whereas Nmb-high neurons likely have other functions.

SIGNIFICANCE STATEMENT Central respiratory chemoreceptors regulate arterial PCO₂ by adjusting lung ventilation. Such cells have recently been identified within the retrotrapezoid nucleus (RTN), a brainstem nucleus defined by genetic lineage and a cumbersome combination of markers. Using single-cell RNA-Seq and multiplexed in situ hybridization, we show here that a single marker, Neuromedin B mRNA (Nmb), identifies RTN neurons in rodents. We also suggest that >75% of these Nmb neurons are chemoreceptors because they are strongly activated by hypercapnia and express high levels of proton sensors (Kcnk5 and Gpr4). The other RTN neurons express very high levels of Nmb, but low levels of Kcnk5/Gpr4/pre-pro-galanin/pre-pro-enkephalin, and do not respond to hypercapnia. Their function is unknown.

Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway

Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.

SIGNIFICANCE STATEMENT Our study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.

Optogenetic Activation of the fruitless-Labeled Circuitry in Drosophila subobscura Males Induces Mating Motor Acts

It remains an enigma how the nervous system of different animal species produces different behaviors. We studied the neural circuitry for mating behavior in Drosophila subobscura, a species that displays unique courtship actions not shared by other members of the genera including the genetic model D. melanogaster, in which the core courtship circuitry has been identified. We disrupted the D. subobscura fruitless (fru) gene, a master regulator for the courtship circuitry formation in D. melanogaster, resulting in complete loss of mating behavior. We also generated fru^soChrimV, which expresses the optogenetic activator Chrimson fused with a fluorescent marker under the native fru promoter. The fru-labeled circuitry in D. subobscura visualized by fru^soChrimV revealed differences between females and males, optogenetic activation of which in males induced mating behavior including attempted copulation. These findings provide a substrate for neurogenetic dissection and manipulation of behavior in non-model animals, and will help to elucidate the neural basis for behavioral diversification.

SIGNIFICANCE STATEMENT How did behavioral specificity arise during evolution? Here we attempted to address this question by comparing the parallel genetically definable neural circuits controlling the courtship behavior of Drosophila melanogaster, a genetic model, and its relative, D. subobscura, which exhibits a courtship behavioral pattern unique to it, including nuptial gift transfer. We found that the subobscura fruitless circuit, which is required for male courtship behavior, was slightly but clearly different from its melanogaster counterpart, and that optogenetic activation of this circuit induced subobscura-specific behavior, i.e., regurgitating crop contents, a key element of transfer of nuptial gift. Our study will pave the way for determining how and which distinctive cellular elements within the fruitless circuit determine the species-specific differences in courtship behavior.

Optogenetic Inhibition Reveals Distinct Roles for Basolateral Amygdala Activity at Discrete Time Points during Risky Decision Making

Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (risky decision-making task) in which rats choose between a small, "safe" reward and a large reward accompanied by varying probabilities of footshock punishment. Male Long–Evans rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the risky decision-making task. Laser delivery during the task occurred during intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did laser delivery affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active.

SIGNIFICANCE STATEMENT To date, most behavioral neuroscience research on neural mechanisms of decision making has used techniques that preclude assessment of distinct phases of the decision process. Here we show that optogenetic inhibition of the BLA has opposite effects on choice behavior in a rat model of risky decision making, depending on the phase in which inhibition occurs. BLA inhibition during a period of deliberation between small, safe and large, risky outcomes decreased risky choice. In contrast, BLA inhibition during receipt of the large, punished outcome increased risky choice. These findings highlight the importance of temporally targeted approaches to understand neural substrates underlying complex cognitive processes. More importantly, they reveal novel information about dynamic BLA modulation of risky choice.

Frontal Eye Field Inactivation Diminishes Superior Colliculus Activity, But Delayed Saccadic Accumulation Governs Reaction Time Increases

Stochastic accumulator models provide a comprehensive framework for how neural activity could produce behavior. Neural activity within the frontal eye fields (FEFs) and intermediate layers of the superior colliculus (iSC) support such models for saccade initiation by relating variations in saccade reaction time (SRT) to variations in such parameters as baseline, rate of accumulation of activity, and threshold. Here, by recording iSC activity during reversible cryogenic inactivation of the FEF in four male nonhuman primates, we causally tested which parameter(s) best explains concomitant increases in SRT. While FEF inactivation decreased all aspects of ipsilesional iSC activity, decreases in accumulation rate and threshold poorly predicted accompanying increases in SRT. Instead, SRT increases best correlated with delays in the onset of saccade-related accumulation. We conclude that FEF signals govern the onset of saccade-related accumulation within the iSC, and that the onset of accumulation is a relevant parameter for stochastic accumulation models of saccade initiation.

SIGNIFICANCE STATEMENT The superior colliculus (SC) and frontal eye fields (FEFs) are two of the best-studied areas in the primate brain. Surprisingly, little is known about what happens in the SC when the FEF is temporarily inactivated. Here, we show that temporary FEF inactivation decreases all aspects of functionally related activity in the SC. This combination of techniques also enabled us to relate changes in SC activity to concomitant increases in saccadic reaction time (SRT). Although stochastic accumulator models relate SRT increases to reduced rates of accumulation or increases in threshold, such changes were not observed in the SC. Instead, FEF inactivation delayed the onset of saccade-related accumulation, emphasizing the importance of this parameter in biologically plausible models of saccade initiation.

Orientation Tuning of Correlated Activity in the Developing Lateral Geniculate Nucleus

Neural circuits and the cells that comprise them undergo developmental changes in the spatial organization of their connections and in their temporal response properties. Within the lateral geniculate nucleus (LGN) of the dorsal thalamus, these changes have pronounced effects on the spatiotemporal receptive fields (STRFs) of neurons. An open and unresolved question is how STRF maturation affects stimulus-evoked correlated activity between pairs of LGN neurons during development. This is an important question to answer because stimulus-evoked correlated activity likely plays a role in establishing the specificity of thalamocortical connectivity and the receptive fields (RFs) of postsynaptic cortical neurons. Using multielectrode recording methods and white noise stimuli, we recorded neural activity from ensembles of LGN neurons in cats across early development. As expected, there was a progressive maturation of the spatial and temporal properties of visual responses. Using drifting bar stimuli and cross-correlation analysis, we also determined the orientation-tuning bandwidth of correlated activity between pairs of LGN neurons at different stages of development (Sillito and Jones, 2002; Andolina et al., 2007; Stanley et al., 2012; Kelly et al., 2014). Despite the larger RFs and slower responses of immature LGN neurons compared with mature neurons, our results show that correlated activity in the LGN was as tightly tuned for orientation early in development as it was in the adult. Closer examination revealed this age-invariant orientation tuning of correlated activity likely involves cellular mechanisms related to spike fatigue in young animals and a progressive decrease in response latency with development.

SIGNIFICANCE STATEMENT Orientation tuning is a fundamental property of neurons in primary visual cortex. An important and unresolved question is how orientation tuning emerges during brain development. This study explores a potential mechanism for the establishment of orientation tuning based on correlated activity patterns among ensembles of maturing neurons in the lateral geniculate nucleus (LGN) of the thalamus. Results show that correlated activity between pairs of LGN neurons is more tightly tuned than predictions based simply on receptive field size, indicating that correlated activity has the properties needed to play an important role in the development of geniculocortical circuits and the emergence of cortical orientation tuning.

This Week in The Journal

HuD and the Survival Motor Neuron Protein Interact in Motoneurons and Are Essential for Motoneuron Development, Function, and mRNA Regulation

Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation. Here we show using zebrafish as a model system that SMN interacts with the RNA binding protein (RBP) HuD in motoneurons in vivo during formation of axonal branches and dendrites. To determine the function of HuD in motoneurons, we generated zebrafish HuD mutants and found that they exhibited decreased motor axon branches, dramatically fewer dendrites, and movement defects. These same phenotypes are present in animals expressing low levels of SMN, indicating that both proteins function in motoneuron development. HuD binds and transports mRNAs and one of its target mRNAs, Gap43, is involved in axonal outgrowth. We found that Gap43 was decreased in both HuD and SMN mutants. Importantly, transgenic expression of HuD in motoneurons of SMN mutants rescued the motoneuron defects, the movement defects, and Gap43 mRNA levels. These data support that the interaction between SMN and HuD is critical for motoneuron development and point to a role for RBPs in SMA.

SIGNIFICANCE STATEMENT In zebrafish models of the motoneuron disease spinal muscular atrophy (SMA), motor axons fail to form the normal extent of axonal branches and dendrites leading to decreased motor function. SMA is caused by low levels of the survival motor neuron (SMN) protein. We show in motoneurons in vivo that SMN interacts with the RNA binding protein, HuD. Novel mutants reveal that HuD is also necessary for motor axonal branch and dendrite formation. Data also revealed that both SMN and HuD affect levels of an mRNA involved in axonal growth. Moreover, expressing HuD in SMN-deficient motoneurons can rescue the motoneuron development and motor defects caused by low levels of SMN. These data support that SMN:HuD complexes are essential for normal motoneuron development and indicate that mRNA handling is a critical component of SMA.

Why Do Irrelevant Alternatives Matter? An fMRI-TMS Study of Context-Dependent Preferences

Both humans and animals are known to exhibit a violation of rationality known as "decoy effect": introducing an irrelevant option (a decoy) can influence choices among other (relevant) options. Exactly how and why decoys trigger this effect is not known. It may be an example of fast heuristic decision-making, which is adaptive in natural environments, but may lead to biased choices in certain markets or experiments. We used fMRI and transcranial magnetic stimulation to investigate the neural underpinning of the decoy effect of both sexes. The left ventral striatum was more active when the chosen option dominated the decoy. This is consistent with the hypothesis that the presence of a decoy option influences the valuation of other options, making valuation context-dependent even when choices appear fully rational. Consistent with the idea that control is recruited to prevent heuristics from producing biased choices, the right inferior frontal gyrus, often implicated in inhibiting prepotent responses, connected more strongly with the striatum when subjects successfully overrode the decoy effect and made unbiased choices. This is further supported by our transcranial magnetic stimulation experiment: subjects whose right inferior frontal gyrus was temporarily disrupted made biased choices more often than a control group. Our results suggest that the neural basis of the decoy effect could be the context-dependent activation of the valuation area. But the differential connectivity from the frontal area may indicate how deliberate control monitors and corrects errors and biases in decision-making.

SIGNIFICANCE STATEMENT Standard theories of rational decision-making assume context-independent valuations of available options. Motivated by the importance of this basic assumption, we used fMRI to study how the human brain assigns values to available options. We found activity in the valuation area to be consistent with the hypothesis that values depend on irrelevant aspects of the environment, even for subjects whose choices appear fully rational. Such context-dependent valuations may lead to biased decision-making. We further found differential connectivity from the frontal area to the valuation area depending on whether biases were successfully overcome. This suggests a mechanism for making rational choices despite the potential bias. Further support was obtained by a transcranial magnetic stimulation experiment, where subjects whose frontal control was temporarily disrupted made biased choices more often than a control group.

Recruitment of Foveal Retinotopic Cortex During Haptic Exploration of Shapes and Actions in the Dark

The role of the early visual cortex and higher-order occipitotemporal cortex has been studied extensively for visual recognition and to a lesser degree for haptic recognition and visually guided actions. Using a slow event-related fMRI experiment, we investigated whether tactile and visual exploration of objects recruit the same "visual" areas (and in the case of visual cortex, the same retinotopic zones) and if these areas show reactivation during delayed actions in the dark toward haptically explored objects (and if so, whether this reactivation might be due to imagery). We examined activation during visual or haptic exploration of objects and action execution (grasping or reaching) separated by an 18 s delay. Twenty-nine human volunteers (13 females) participated in this study. Participants had their eyes open and fixated on a point in the dark. The objects were placed below the fixation point and accordingly visual exploration activated the cuneus, which processes retinotopic locations in the lower visual field. Strikingly, the occipital pole (OP), representing foveal locations, showed higher activation for tactile than visual exploration, although the stimulus was unseen and location in the visual field was peripheral. Moreover, the lateral occipital tactile–visual area (LOtv) showed comparable activation for tactile and visual exploration. Psychophysiological interaction analysis indicated that the OP showed stronger functional connectivity with anterior intraparietal sulcus and LOtv during the haptic than visual exploration of shapes in the dark. After the delay, the cuneus, OP, and LOtv showed reactivation that was independent of the sensory modality used to explore the object. These results show that haptic actions not only activate "visual" areas during object touch, but also that this information appears to be used in guiding grasping actions toward targets after a delay.

SIGNIFICANCE STATEMENT Visual presentation of an object activates shape-processing areas and retinotopic locations in early visual areas. Moreover, if the object is grasped in the dark after a delay, these areas show "reactivation." Here, we show that these areas are also activated and reactivated for haptic object exploration and haptically guided grasping. Touch-related activity occurs not only in the retinotopic location of the visual stimulus, but also at the occipital pole (OP), corresponding to the foveal representation, even though the stimulus was unseen and located peripherally. That is, the same "visual" regions are implicated in both visual and haptic exploration; however, touch also recruits high-acuity central representation within early visual areas during both haptic exploration of objects and subsequent actions toward them. Functional connectivity analysis shows that the OP is more strongly connected with ventral and dorsal stream areas when participants explore an object in the dark than when they view it.

White Matter Structure in Older Adults Moderates the Benefit of Sleep Spindles on Motor Memory Consolidation

Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical–cortical propagation of sleep spindles and their related memory benefits.

SIGNIFICANCE STATEMENT Numerous studies have shown that sleep spindle expression is reduced and sleep-dependent motor memory is impaired in older adults. However, the mechanisms underlying these alterations have remained unknown. The present study reveals that age-related degeneration of white matter within select fiber tracts is associated with reduced sleep spindles in older adults. We further demonstrate that, within these same fiber tracts, the degree of degeneration determines whether sleep spindles can promote motor memory consolidation. Therefore, white matter integrity in the human brain, more than age per se, determines the magnitude of decline in sleep spindles in later life and, with it, the success (or lack thereof) of sleep-dependent motor memory consolidation in older adults.

A Presynaptic Function of Shank Protein in Drosophila

Human genetic studies support that loss-of-function mutations in the SH3 domain and ankyrin repeat containing family proteins (SHANK1-3), the large synaptic scaffolding proteins enriched at the postsynaptic density of excitatory synapses, are causative for autism spectrum disorder and other neuropsychiatric disorders in humans. To better understand the in vivo functions of Shank and facilitate dissection of neuropathology associated with SHANK mutations in human, we generated multiple mutations in the Shank gene, the only member of the SHANK family in Drosophila melanogaster. Both male and female Shank null mutants were fully viable and fertile with no apparent morphological or developmental defects. Expression analysis revealed apparent enrichment of Shank in the neuropils of the CNS. Specifically, Shank coexpressed with another PSD scaffold protein, Homer, in the calyx of mushroom bodies in the brain. Consistent with high expression in mushroom body calyces, Shank mutants show an abnormal calyx structure and reduced olfactory acuity. These morphological and functional phenotypes were fully rescued by pan-neuronal reexpression of Shank, and only partially rescued by presynaptic but no rescue by postsynaptic reexpression of Shank. Our findings thus establish a previously unappreciated presynaptic function of Shank.

SIGNIFICANCE STATEMENT Mutations in SHANK family genes are causative for idiopathic autism spectrum disorder. To understand the neural function of Shank, a large scaffolding protein enriched at the postsynaptic densities, we examined the role of Drosophila Shank in synapse development at the peripheral neuromuscular junctions and the central mushroom body calyx. Our results demonstrate that, in addition to its conventional postsynaptic function, Shank also acts presynaptically in synapse development in the brain. This study offers novel insights into the synaptic role of Shank.

Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial {beta}-Endorphin Expression

The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial β-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced β-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-α, IL-1β, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-α, IL-1β, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and β-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated β-endorphin expression in cultured primary microglia, whereas treatment with β-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of β-endorphin in vitro and in vivo and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38β, but not siRNA/p38α, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-α mRNA using siRNA fully inhibited exenatide-induced spinal microglial β-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and β-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated β-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38β/CREB and subsequent IL-10 receptor/STAT3 signal pathways.

SIGNIFICANCE STATEMENT Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor β-endorphin from microglia. GLP-1 receptor agonism induces β-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and β-endorphin expression subsequently through the Gs-cAMP/PKA/p38β/CREB and IL-10/IL-10 receptor-α/STAT3 signal transduction pathways.

Stimulation of the Locus Ceruleus Modulates Signal-to-Noise Ratio in the Olfactory Bulb

Norepinephrine (NE) has been shown to influence sensory, and specifically olfactory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio (S/N). The present study is the first to look at NE modulation of olfactory bulb (OB) in regards to S/N in vivo. We show, in male rats, that locus ceruleus stimulation and pharmacological infusions of NE into the OB modulate both spontaneous and odor-evoked neural responses. NE in the OB generated a non-monotonic dose–response relationship, suppressing mitral cell activity at high and low, but not intermediate, NE levels. We propose that NE enhances odor responses not through direct potentiation of the afferent signal per se, but rather by reducing the intrinsic noise of the system. This has important implications for the ways in which an animal interacts with its olfactory environment, particularly as the animal shifts from a relaxed to an alert behavioral state.

SIGNIFICANCE STATEMENT Sensory perception can be modulated by behavioral states such as hunger, fear, stress, or a change in environmental context. Behavioral state often affects neural processing via the release of circulating neurochemicals such as hormones or neuromodulators. We here show that the neuromodulator norepinephrine modulates olfactory bulb spontaneous activity and odor responses so as to generate an increased signal-to-noise ratio at the output of the olfactory bulb. Our results help interpret and improve existing ideas for neural network mechanisms underlying behaviorally observed improvements in near-threshold odor detection and discrimination.

Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury

Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.

SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI.

Deficiency of the Thyroid Hormone Transporter Monocarboxylate Transporter 8 in Neural Progenitors Impairs Cellular Processes Crucial for Early Corticogenesis

Thyroid hormones (THs) are essential for establishing layered brain structures, a process called corticogenesis, by acting on transcriptional activity of numerous genes. In humans, deficiency of the monocarboxylate transporter 8 (MCT8), involved in cellular uptake of THs before their action, results in severe neurological abnormalities, known as the Allan–Herndon–Dudley syndrome. While the brain lesions predominantly originate prenatally, it remains unclear how and when exactly MCT8 dysfunction affects cellular processes crucial for corticogenesis. We investigated this by inducing in vivo RNAi vector-based knockdown of MCT8 in neural progenitors of the chicken optic tectum, a layered structure that shares many developmental features with the mammalian cerebral cortex. MCT8 knockdown resulted in cellular hypoplasia and a thinner optic tectum. This could be traced back to disrupted cell-cycle kinetics and a premature shift to asymmetric cell divisions impairing progenitor cell pool expansion. Birth-dating experiments confirmed diminished neurogenesis in the MCT8-deficient cell population as well as aberrant migration of both early-born and late-born neuroblasts, which could be linked to reduced reelin signaling and disorganized radial glial cell fibers. Impaired neurogenesis resulted in a reduced number of glutamatergic and GABAergic neurons, but the latter additionally showed decreased differentiation. Moreover, an accompanying reduction in untransfected GABAergic neurons suggests hampered intercellular communication. These results indicate that MCT8-dependent TH uptake in the neural progenitors is essential for early events in corticogenesis, and help to understand the origin of the problems in cortical development and function in Allan–Herndon–Dudley syndrome patients.

SIGNIFICANCE STATEMENT Thyroid hormones (THs) are essential to establish the stereotypical layered structure of the human forebrain during embryonic development. Before their action on gene expression, THs require cellular uptake, a process facilitated by the TH transporter monocarboxylate transporter 8 (MCT8). We investigated how and when dysfunctional MCT8 can induce brain lesions associated with the Allan–Herndon–Dudley syndrome, characterized by psychomotor retardation. We used the layered chicken optic tectum to model cortical development, and induced MCT8 deficiency in neural progenitors. Impaired cell proliferation, migration, and differentiation resulted in an underdeveloped optic tectum and a severe reduction in nerve cells. Our data underline the need for MCT8-dependent TH uptake in neural progenitors and stress the importance of local TH action in early development.

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Highlights from the Literature

Transition: Message from the Editor-in-Chief

With this issue I will step down as Editor-In-Chief of Neuro-Oncology. My recent election as President of the Society for Neuro-Oncology precludes me from holding both positions at the same time. I will always be grateful for the tremendous privilege of serving as Editor-In-Chief for the past four years. With the support of the neuro-oncology community, the Society for Neuro-Oncology (SNO), the European Association of Neuro-Oncology (EANO), and the Japanese Society for Neuro-Oncology (JSNO) the journal has flourished. Neuro-Oncology has increasingly become a forum for important research in the field, with the impact factor rising to 7.786 and submissions on track to exceed 900 this year. This success would not be possible without the dedication and hard work of our Managing Editor, Elizabeth Martinson, the team at Oxford University Press led by Phil Bishop, and the support and invaluable guidance of our Executive Editors (Kenneth Aldape, Ryo Nishikawa, and Riccardo Soffietti), our Associate Editors (Terri Armstrong, Karla Ballman, E. Antonio Chiocca, Frank Furnari, Monika Hegi, Koichi Ichimura, Mark Kieran, Minesh Mehta, Whitney Pope, David Schiff, and Wolfgang Wick), and our Editorial Board. I will always be indebted to them.

IDH mutation testing in gliomas—where do we draw the line?

See the article by DeWitt et al on pages 1640–1650.

Corrigenda

Corrigendum to Zhang et al. HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro Oncol (doi: 10.1093/neuonc/not131) first published online November 7, 2013.

The endothelial prostate-specific membrane antigen is highly expressed in gliosarcoma and visualized by [ 68 Ga]-PSMA-11 PET: a theranostic outlook for brain tumor patients?

gliomagliosarcomaPSMAtheranostics

Putting “multiforme” back into glioblastoma: intratumoral transcriptome heterogeneity is a consequence of its complex morphology

genomicsglioblastomaheterogeneityhistologytranscriptome

Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study

Abstract

Background

Patients treated for medulloblastoma who experience posterior fossa syndrome (PFS) demonstrate increased risk for neurocognitive impairment at one year post diagnosis. The aim of the study was to examine longitudinal trajectories of neuropsychological outcomes in patients who experienced PFS compared with patients who did not.

Methods

Participants were 36 patients (22 males) who experienced PFS and 36 comparison patients (21 males) who were matched on age at diagnosis and treatment exposure but did not experience PFS. All patients underwent serial evaluation of neurocognitive functioning spanning 1 to 5 years post diagnosis.

Results

The PFS group demonstrated lower estimated mean scores at 1, 3, and 5 years post diagnosis on measures of general intellectual ability, processing speed, broad attention, working memory, and spatial relations compared with the non-PFS group. The PFS group exhibited estimated mean scores that were at least one standard deviation below the mean for intellectual ability, processing speed, and broad attention across all time points and for working memory by 5 years post diagnosis. Processing speed was stable over time. Attention and working memory declined over time. Despite some change over time, caregiver ratings of executive function and behavior problem symptoms remained within the average range.

Conclusion

Compared with patients who do not experience PFS, patients who experience PFS exhibit greater neurocognitive impairment, show little recovery over time, and decline further in some domains. Findings highlight the particularly high risk for long-term neurocognitive problems in patients who experience PFS and the need for close follow-up and intervention.

Corrigenda

Corrigendum to Raleigh et al. Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome. Neuro Oncol (2017) 19 (1): 78–88 first published online June 9, 2016.

A description of familial clustering of meningiomas in the Utah population

Abstract

Background

Meningiomas are common intracranial tumors in adults, yet the genetics and cause of sporadic meningiomas are not well understood. Few familial clusters have been reported. The aim of this study was to investigate the familiality of meningiomas within the Utah Population Database.

Methods

Meningioma cases reported in the Utah Cancer Registry were identified. Relative risk of their relatives was calculated. All possible cases were assessed with the Genealogical Index of Familiality (GIF), which measures average pairwise relatedness of all possible pairs using the Malecot coefficient of kinship. Clusters of cases descending from a common ancestor were identified.

Results

Eight hundred fifty-eight meningioma cases were reported. The relative risk of a first- or second-degree relative was 3.13 (95% CI: 1.67, 5.36) or 2.28 (1.30, 3.70), respectively. The GIF statistic demonstrated a clear excess of relationships for genetic distance <4 (closer than first cousins). We identified 920 pedigrees, including 2–21 meningioma cases. One hundred eighty-nine of these pedigrees, including 2–15 cases, had a significant excess (P < 0.05) of meningioma cases over what was expected.

Conclusions

This Utah population–based analysis of meningiomas shows clear evidence of familial clustering and supports both a familial and a germline variant basis for meningioma. These clusters may allow identification of genes likely to contribute to tumorigenesis in high-risk pedigrees. These relative risk data provide the basis for further investigations of genetic contributions to meningioma. These data may contribute to developing a basis for determining screening criteria of higher-risk pedigrees for the presence of meningiomas.

Outcome of patients with intracranial non-germinomatous germ cell tumors—lessons from the SIOP-CNS-GCT-96 trial

Abstract

Background

Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy.

Methods

All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites.

Results

Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort.

Conclusion

In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.

Cost-effectiveness of radiation and chemotherapy for high-risk low-grade glioma

Abstract

Background

The addition of procarbazine, lomustine, vincristine (PCV) chemotherapy to radiotherapy (RT) for patients with high-risk (≥40 y old or subtotally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy.

Methods

A decision tree with an integrated 3-state Markov model was created to follow patients with high-risk LGG after surgery treated with RT versus RT+PCV. Patients existed in one of 3 health states: stable, progressive, or dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the health care perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters.

Results

Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs 5.17 for RT alone) at an incremental cost of $48635 ($188234 for RT+PCV vs $139598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100000 per QALY.

Conclusion

The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.

Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations

Abstract

Background

Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines.

Methods

From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods.

Results

In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine.

Conclusion

The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.

Corrigenda

Corrigendum to Zhou et al. MRI features predict survival and molecular markers in diffuse lower-grade gliomas. Neuro Oncol (2017) 19 (6): 862–870 first published online January 24, 2017.

Corrigenda

Corrigendum to Arif et al. VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties. Neuro Oncol (doi:10.1093/neuonc/now297) first published online February 28, 2017.

Corrigenda

Corrigendum to Cicone et al. Comment to Hatzoglou et al: dynamic contrast-enhanced MRI perfusion versus 18FDG PET/CT in differentiating brain tumor progression from radiation injury. Neuro Oncol (doi:10.1093/neuonc/now283) first published online 10 February 2017.

PET imaging in patients with meningioma—report of the RANO/PET Group

Abstract

Meningiomas are the most frequent nonglial primary brain tumors and represent about 30% of brain tumors. Usually, diagnosis and treatment planning are based on neuroimaging using mainly MRI or, rarely, CT. Most common treatment options are neurosurgical resection and radiotherapy (eg, radiosurgery, external fractionated radiotherapy). For follow-up after treatment, a structural imaging technique such as MRI or CT is used. However, these structural imaging modalities have limitations, particularly in terms of tumor delineation as well as diagnosis of posttherapeutic reactive changes. Molecular imaging techniques such as PET can characterize specific metabolic and cellular features which may provide clinically relevant information beyond that obtained from structural MR or CT imaging alone. Currently, the use of PET in meningioma patients is steadily increasing. In the present article, we provide recommendations for the use of PET imaging in the clinical management of meningiomas based on evidence generated from studies being validated by histology or clinical course.

Golgi phosphoprotein 3 promotes glioma progression via inhibiting Rab5-mediated endocytosis and degradation of epidermal growth factor receptor

Abstract

Background

Golgi phosphoprotein 3 (GOLPH3) is associated with worse prognosis of gliomas, but its role and mechanism in glioma progression remain largely unknown. This study aimed to explore the role and mechanism of GOLPH3 in glioma progression.

Methods

The expression of GOLPH3 in glioma tissues was detected by quantitative PCR, immunoblotting, and immunohistochemistry. GOLPH3's effect on glioma progression was examined using cell growth assays and an intracranial glioma model. The effect of GOLPH3 on epidermal growth factor receptor (EGFR) stability, endocytosis, and degradation was examined by immunoblotting and immunofluorescence. The activity of Rab5 was checked by glutathione S-transferase pulldown assay.

Results

GOLPH3 was upregulated in gliomas, and its downregulation inhibited glioma cell proliferation both in vitro and in vivo. Furthermore, GOLPH3 depletion dampened EGFR signaling by enhancing EGFR endocytosis, driving EGFR into late endosome and promoting lysosome-mediated degradation. Interestingly, GOLPH3 bound to Rab5 and GOLPH3 downregulation promoted the activation of Rab5. In addition, Rab5 depletion abolished the effect of GOLPH3 on EGFR endocytosis and degradation.

Conclusion

Our results imply that GOLPH3 promotes glioma cell proliferation via inhibiting Rab5-mediated endocytosis and degradation of EGFR, thereby activating the phosphatidylinositol-3 kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling pathway. We find a new mechanism by which GOLPH3 promotes tumor progression through regulating cell surface receptor trafficking. Extensive and intensive understanding of the role of GOLPH3 in glioma progression may provide an opportunity to develop a novel molecular therapeutic target for gliomas.

Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis

Abstract

Background

Glioblastoma represents an archetypal example of a heterogeneous malignancy. To understand the diverse molecular consequences of this complex tumor ecology, we analyzed RNA-seq data generated from commonly identified intratumoral structures in glioblastoma enriched using laser capture microdissection.

Methods

Raw gene-level values of fragments per kilobase of transcript per million reads mapped and the associated clinical data were acquired from the publicly available Ivy Glioblastoma Atlas Project database and analyzed using MetaboAnalyst (v3.0). The database includes gene expression data generated from multiple structural features commonly identified in glioblastoma enriched by laser capture microdissection.

Results

We uncovered a relationship between subtype heterogeneity in glioblastoma and its unique tumor microenvironment, with infiltrating cells harboring a proneural signature while the mesenchymal subtype was enriched in perinecrotic regions. When evaluating the tumors' transcriptional profiles in the context of their derived structural regions, there was a relatively small amount of intertumoral heterogeneity in glioblastoma, with individual regions from different tumors clustering tightly together. Analyzing the transcriptional profiles in the context of evolutionary progression identified unique cellular programs associated with specific phases of gliomagenesis. Mediators of cell signaling and cell cycle progression appear to be critical events driving proliferation in the tumor core, while in addition to a multiplex strategy for promoting angiogenesis and/or an immune-tolerant environment, transformation to perinecrotic zones involved global metabolic alterations.

Conclusion

These findings suggest that intratumoral heterogeneity in glioblastoma is a conserved, predictable consequence to its complex microenvironment, and combinatorial approaches designed to target these unequivocally present tumor biomes may lead to therapeutic gains.

Diagnostic challenges in meningioma

Abstract

Advances in molecular profiling and the application of advanced imaging techniques are currently refreshing diagnostic considerations in meningioma patients. Not only technical refinements but also sophisticated histopathological and molecular studies have the potential to overcome some of the challenges during meningioma management. Exact tumor delineation, assessment of tumor growth, and pathophysiological parameters were recently addressed by "advanced" MRI and PET. In the field of neuropathology, high-throughput sequencing and DNA methylation analysis of meningioma tissue has greatly advanced the knowledge of molecular aberrations in meningioma patients. These techniques allow for more reliable prediction of the biological behavior and clinical course of meningiomas and subsequently have the potential to guide individualized meningioma therapy. However, higher costs and longer duration of full molecular work-up compared with histological assessment may delay the implementation into clinical routine.This review highlights the diagnostic challenges of meningiomas from both the neuroimaging as well as the neuropathological side and presents the latest scientific achievements and studies potentially helping in overcoming these challenges. It complements the recently proposed European Association of Neuro-Oncology guidelines on treatment and diagnosis of meningiomas by integrating data on nonstandard imaging and molecular assessments most likely impacting the future.

Not your garden-variety bacteremia: Gardnerella in an immunocompromised man

Abstract

Gardnerella is a common colonizer of the genitourinary tract, but systemic Gardnerella infections are rare and are usually associated with surgical instrumentation of the genitourinary tract. Presented is a case of symptomatic and transient Gardnerella bacteremia in an adult male patient with AIDS following a traumatic urinary catheter insertion.

Augmented marker tracking for peri-acetabular osteotomy surgery

Abstract

Objective

To develop a hybrid augmented marker-based navigation system for acetabular reorientation during peri-acetabular osteotomy (PAO).

Methods

The system consists of a tracking unit attached to the patient's pelvis, augmented marker attached to the acetabular fragment and a host computer to do all the computations and visualization. The augmented marker is comprised of an external planar Aruco marker facing toward the tracking unit and an internal inertial measurement unit (IMU) to measure its orientation. The orientation output from the IMU is sent to the host computer. The tracking unit streams a live video of the augmented marker to the host computer, where the planar marker is detected and its pose is estimated. A Kalman filter-based sensor fusion combines the output from marker tracking and the IMU. We validated the proposed system using a plastic bone study and a cadaver study. Every time, we compared the inclination and anteversion values measured by the proposed system to those from a previously developed optical tracking-based navigation system.

Results

Mean absolute differences for inclination and anteversion were 1.34 ( \(\pm \,1.50\) ) and 1.21 ( \(\pm \, 1.07\) ) \(^\circ \) , respectively, for the cadaver study. Mean absolute differences were 1.63 ( \(\pm \,1.48\) ) and 1.55 ( \(\pm \,1.49\) ) \(^\circ \) for inclination and anteversion for the plastic bone study. In both validation studies, very strong correlations were observed.

Conclusion

We successfully demonstrated the feasibility of our system to measure the acetabular orientation during PAO.

Case study: Scoliosis in a Bonobo (Pan paniscus)

Abstract

Differential diagnosis of observed morphological features on an adult male bonobo skeleton was consistent with idiopathic scoliosis. Directional asymmetry was an order of magnitude higher compared with asymptomatic skeletons. This possible case of idiopathic scoliosis contributes to data that suggest a weaker tie between bipedalism and scoliosis than previously hypothesized.

What the Jeweller’s Hand Tells the Jeweller’s Brain: Tool Use, Creativity and Embodied Cognition

Abstract

The notion that human activity can be characterised in terms of dynamic systems is a well-established alternative to motor schema approaches. Key to a dynamic systems approach is the idea that a system seeks to achieve stable states in the face of perturbation. While such an approach can apply to physical activity, it can be challenging to accept that dynamic systems also describe cognitive activity. In this paper, we argue that creativity, which could be construed as a 'cognitive' activity par excellence, arises from the dynamic systems involved in jewellery making. Knowing whether an action has been completed to a 'good' standard is a significant issue in considering acts in creative disciplines. When making a piece of jewellery, there a several criteria which can define 'good'. These are not only the aesthetics of the finished piece but also the impact of earlier actions on subsequent ones. This suggests that the manner in which an action is coordinated is influenced by the criteria by which the product is judged. We see these criteria as indicating states for the system, e.g. in terms of a space of 'good' outcomes and a complementary space of 'bad' outcomes. The skill of the craftworker is to navigate this space of available states in such a way as to minimise risk, effort and other costs and maximise benefit and quality of the outcome. In terms of postphenomonology, this paper explores Ihde's human-technology relations and relates these to the concepts developed here.

Long-term effect of the insoluble thread-lifting technique.

Related Articles

Long-term effect of the insoluble thread-lifting technique.

Clin Cosmet Investig Dermatol. 2017;10:483-491

Authors: Fukaya M

Abstract
Background: Although the thread-lifting technique for sagging faces has become more common and popular, medical literature evaluating its effects is scarce. Studies on its long-term prognosis are particularly uncommon.
Patients and methods: One hundred individuals who had previously undergone insoluble thread-lifting were retrospectively investigated. Photos in frontal and oblique views from the first and last visits were evaluated by six female individuals by guessing the patients' ages. The mean guessed age was defined as the apparent age, and the difference between the real and apparent ages was defined as the youth value. The difference between the youth values before and after the thread-lift was defined as the rejuvenation effect and analyzed in relation to the time since the operation, the number of threads used and the number of thread-lift operations performed.
Results: The rejuvenation effect decreased over the first year after the operation, but showed an increasing trend thereafter. The rejuvenation effect increased with the number of threads used and the number of thread-lift operations performed.
Conclusion: The insoluble thread-lifting technique appears to be associated with both early and late effects. The rejuvenation effect appeared to decrease during the first year, but increased thereafter. A multicenter trial is necessary to confirm these findings.

PMID: 29180885 [PubMed]

Redefining face contour with a novel anti-aging cosmetic product: an open-label, prospective clinical study.

Related Articles

Redefining face contour with a novel anti-aging cosmetic product: an open-label, prospective clinical study.

Clin Cosmet Investig Dermatol. 2017;10:473-482

Authors: Garre A, Martinez-Masana G, Piquero-Casals J, Granger C

Abstract
Background: Skin aging is accelerated by multiple extrinsic factors: ultraviolet radiation, smoking and pollution increase oxidative activity, damaging cellular and extracellular components such as DNA, proteins, and lipids. With age, collagen and hyaluronic acid levels decline, resulting in loss of elasticity and moisture of the skin. Over time this damage leads to characteristic signs that make the skin look older: altered facial contour, sagging skin, wrinkles, and an uneven complexion. This study evaluated the anti-aging effects of a new facial cream formulated with carnosine, Alteromonas ferment extract, crosspolymer hyaluronic acid, and a tripeptide.
Methods: An open-label intra-individual study to assess the anti-aging efficacy of the investigational product in 33 women aged 45 to 65 years. The product was applied twice daily for 56 days. Facial contour and skin deformation, elasticity, hydration, and complexion were measured with specialized equipment at baseline and days 28 and 56. Additionally, subjects completed questionnaires at days 28 and 56 on the perceived efficacy and cosmetic characteristics of the product.
Results: After 56 days of use of the investigational product, a redefining effect was observed, with a significant decrease in sagging jawline (7%). Skin was significantly more hydrated (12%), firmer (29%), and more elastic (20%) (P<0.001 for all). On complexion assessment, skin texture (a measure of skin smoothness) and spots (brown and red skin lesions) also improved significantly (12% and 6% decrease, respectively). In the subjective self-evaluation, the majority of subjects reported that the skin was visibly tightened and more elastic, flexible, and moisturized (91%, 88%, 91%, and 90%, respectively). The product was well tolerated with no adverse events reported during the study.
Conclusion: This new cosmetic product demonstrated anti-aging effects after 56 days of use, most notably a redefined facial contour and improved complexion. It is a safe and effective anti-aging product.

PMID: 29180884 [PubMed]

Revision Surgery for Zygoma Reduction: Causes, Indications, Solutions, and Results from a 5-Year Review of 341 Cases.

Related Articles

Revision Surgery for Zygoma Reduction: Causes, Indications, Solutions, and Results from a 5-Year Review of 341 Cases.

Aesthetic Plast Surg. 2017 Feb;41(1):161-170

Authors: Lee SW, Jeong YW, Myung Y

Abstract
BACKGROUND: Many patients undergo a revision surgery after malar reduction, which is one of the most popular aesthetic surgeries in Asia. We reviewed the leading causes of revision for malar reduction surgery to establish proper indications for revision, seek adequate surgical strategies, and share the results from revision surgical cases.
METHODS: A retrospective review was conducted involving 341 patients who underwent malar reduction reoperation between March 2010 and June 2015. Surgical strategies were decided based upon specific problems and complaints from the previous surgery. Facial photographs, cephalography, and computed tomography images were analyzed, and a patient satisfaction survey was conducted before and after the surgery.
RESULTS: A total of 341 patients (321 women, 20 men; average age, 26.6 years, range 18-40 years) were included. The main causes of reoperations were subjective dissatisfaction and nonunion-related symptoms. Undercorrection of the zygomatic body and arch (n = 175, 51.3%) was the most frequent reason for dissatisfaction. The patients underwent revision surgeries via different techniques and strategies based on previous problems from primary surgery, and postoperative patient satisfaction was high. Complications occurred in 35 patients (10.3%) after revision.
CONCLUSIONS: Based on the results of this study, patient dissatisfaction with the procedure can be minimized beforehand through accurate goal identification and careful planning. Bone nonunion is usually due to excessive bone resection during zygoma reduction surgery. Careful selection of the reposition site and appropriate fixation based on a thorough understanding of masseter action are essential in ensuring satisfactory outcomes without adverse side effects.
LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj .

PMID: 28032152 [PubMed - indexed for MEDLINE]

EANO guidelines for the diagnosis and treatment of ependymal tumors

Abstract

Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level of evidence of diagnostic and therapeutic interventions is higher in the pediatric compared with the adult patient population.The diagnosis and disease staging is performed by craniospinal MRI. Tumor classification is achieved by histological and molecular diagnostic assessment of tissue specimens according to the World Health Organization (WHO) classification 2016. Surgery is the crucial initial treatment in both children and adults. In pediatric patients with intracranial ependymomas of WHO grades II or III, surgery is followed by local radiotherapy regardless of residual tumor volume. In adults, radiotherapy is employed in patients with anaplastic ependymoma WHO grade III, and in case of incomplete resection of WHO grade II ependymoma. Chemotherapy alone is reserved for young children <12 months and for adults with recurrent disease when further surgery and irradiation are no longer feasible. A gross total resection is the mainstay of treatment in spinal ependymomas, and radiotherapy is reserved for incompletely resected tumors. Nine subgroups of ependymal tumors across different anatomical compartments (supratentorial, posterior fossa, spinal) and patient ages have been identified with distinct genetic and epigenetic alterations, and with distinct outcomes. These findings may lead to more precise diagnostic and prognostic assessments, molecular subgroup-adapted therapies, and eventually new recommendations pending validation in prospective studies.

ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma

Abstract

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

2017 Reviewer Acknowledgment List

The editors of Clinical Infectious Diseases thank the following reviewers for their time and efforts. The quality of the journal depends in large part on their expertise.

Crystal Clear Haematuria

(See pages 2154–5 for the Answer to the Photo Quiz.)

Cover

Crystal Clear Haematuria

(See page 2153 for the Photo Quiz.)

In the Literature

2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea

Abstract

These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.

Erratum

An error appeared in the 1 September 2016 issue of the journal [Kalil AC, Metersky ML, Klompas M, et al. Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016; 63(5):e61–e111]. The online supplementary data file was not uploaded with the published articles. The supplementary data files are now available at http://ift.tt/2h95bN3.

A Population-Based Study of Recurrent Symptomatic Bordetella pertussis Infections in Children in California, 2010–2015

Abstract

Background

Natural infection with Bordetella pertussis is thought to result in 4–20 years of immunity against subsequent symptomatic pertussis infection. However, these estimates are based on studies in unvaccinated or whole-cell pertussis–vaccinated children. We conducted a population-based study of pertussis infection and reinfection during a 5-year period in California in an cohort vaccinated exclusively with acellular pertussis (aP) vaccine.

Methods

California surveillance data were reviewed to identify all children with 2 reported incidents of pertussis with symptom onset between 1 January 2010 and 31 December 2015. Case investigation reports were reviewed, and children with ≥2 episodes of symptomatic pertussis infection that met the case definition were included.

Results

Of 26259 pertussis cases reported in children (aged <18 years), 27 children met the inclusion criteria. Recurrent cases occurred among children of all ages; 5 (19%) were <6 months of age at the time of their first illness. The time from initial infection to reinfection was <1 year in 11 (41%) cases. Twenty-one children (78%) had received ≥3 doses of diphtheria and tetanus toxoids and aP vaccine at the time of their first pertussis infection, 1 (4%) had received 1 dose, and 5 (19%) were unvaccinated.

Conclusions

Recurrent cases of pertussis infection are extremely rare. Based on this surveillance data, approximately 0.1% of children who were infected with pertussis experienced a clinically significant second episode of pertussis within 4 years. More research is needed to understand the immune response to B. pertussis infection in children vaccinated with aP vaccines.

Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study

Abstract

Background

Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort.

Methods

This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus.

Results

Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35–4.45]), body mass index ≥25 kg/m² (OR, 2.64 [95% CI, 1.48–4.72]), and hyperglycemia at admission (6–11 mM: OR, 2.93 [95% CI, 1.54–5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58–113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001).

Conclusions

Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.

Investigation of a Cluster of Sequence Type 22 Methicillin-Resistant Staphylococcus aureus Transmission in a Community Setting

Abstract

Background

Whole-genome sequencing (WGS) has typically been used to confirm or refute hospital/ward outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) identified through routine practice. However, appropriately targeted WGS strategies that identify routinely "undetectable" transmission remain the ultimate aim.

Methods

WGS of MRSA isolates sent to a regional microbiological laboratory was performed as part of a 12-month prospective observational study. Phylogenetic analyses identified a genetically related cluster of E-MRSA15 isolated from patients registered to the same general practice (GP) surgery. This led to an investigation to identify epidemiological links, find additional cases, and determine potential for ongoing transmission.

Results

We identified 15 MRSA-positive individuals with 27 highly related MRSA isolates who were linked to the GP surgery, 2 of whom died with MRSA bacteremia. Of the 13 cases that were further investigated, 11 had attended a leg ulcer/podiatry clinic. Cases lacked epidemiological links to hospitals, suggesting that transmission occurred elsewhere. Environmental and staff screening at the GP surgery did not identify an ongoing source of infection.

Conclusions

Surveillance in the United Kingdom shows that the proportion of MRSA bacteremias apportioned to hospitals is decreasing, suggesting the need for greater focus on the detection of MRSA outbreaks and transmission in the community. This case study confirms that the typically nosocomial lineage (E-MRSA15) can transmit within community settings. Our study exemplifies the continued importance of WGS in detecting outbreaks, including those which may be missed by routine practice, and suggests that universal WGS of bacteremia isolates may help detect outbreaks in low-surveillance settings.

Glycemic Control and the Prevalence of Tuberculosis Infection: A Population-based Observational Study

Abstract

Background

Several cohort studies demonstrate that diabetics are at increased risk for active tuberculosis, and poor glycemic control may exacerbate this risk. A higher prevalence of tuberculosis infection at baseline among diabetics may partially explain these results; however, no population-based studies have investigated this association. Furthermore, whether glycemic control modifies the relationship between diabetes and tuberculosis infection, as it does with active tuberculosis, is unknown.

Methods

Diabetics were diagnosed through physician evaluation and using 3 laboratory tests including hemoglobin A_1C (HbA_1C), fasting plasma glucose (FPG), or 2-hour plasma glucose (PG). Tuberculosis infection was diagnosed through tuberculin skin tests, and glycemic control was assessed linearly and categorically using recommended targets.

Results

Among 4215 participants, the prevalence of tuberculosis infection was 4.1%, 5.5%, and 7.6% in nondiabetic, prediabetic, and diabetic participants (P_trend = .012). In multivariate analysis, diabetes was associated with tuberculosis infection (adjusted odds ratio [AOR], 1.5; 95% confidence interval [CI], 1.0–2.2). Compared to nondiabetics, diabetics who were undiagnosed (AOR, 2.2 and 1.2 in diagnosed diabetics), FPG >130 mg/dL (AOR, 2.6 and 1.3 in diabetics with FPG ≤130 mg/dL), or not on insulin (AOR, 1.7 and 0.8 in diabetics on insulin) had elevated tuberculosis infection rates. In a linear dose–response analysis, increasing values of FPG (AOR, 1.02 per 1-mg/dL; 95% CI, 1.01–1.03), PG (AOR, 1.02 per 1-mg/dL; 95% CI, 1.01–1.04), and HbA_1C (AOR, 1.13 per 1%; 95% CI, 1.04–1.22) all predicted tuberculosis infection.

Conclusions

Our results suggest glycemic control may modify the relationship between tuberculosis infection and diabetes.

2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea

Abstract

These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.

2017 Infectious Diseases Society of America Infectious Diarrhea Guidelines: A View From the Clinical Laboratory

gastroenteritisculture-independent diagnostic testsmultiplex panelsIDSA guidelinesdiagnosis

News

Bacterial Infections After Burn Injuries: Impact of Multidrug Resistance

Abstract

Patients who are admitted to the hospital after sustaining a large burn injury are at high risk for developing hospital-associated infections. If patients survive the initial 72 hours after a burn injury, infections are the most common cause of death. Ventilator-associated pneumonia is the most important infection in this patient population. The risk of infections caused by multidrug-resistant bacterial pathogens increases with hospital length of stay in burn patients. In the first days of the postburn hospitalization, more susceptible, Gram-positive organisms predominate, whereas later more resistant Gram-negative organisms are found. These findings impact the choice of empiric antibiotics in critically ill burn patients. A proactive infection control approach is essential in burn units. Furthermore, a multidisciplinary approach to burn patients with a team that includes an infectious disease specialist and a pharmacist in addition to the burn surgeon is highly recommended.

Impact of the US Maternal Tetanus, Diphtheria, and Acellular Pertussis Vaccination Program on Preventing Pertussis in Infants <2 Months of Age: A Case-Control Evaluation

Abstract

Background

Infants aged <1 year are at highest risk for pertussis-related morbidity and mortality. In 2012, Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccine was recommended for women during each pregnancy to protect infants in the first months of life; data on effectiveness of this strategy are currently limited.

Methods

We conducted a case-control evaluation among pertussis cases <2 months old with cough onset between 1 January 2011 and 31 December 2014 from 6 US Emerging Infection Program Network states. Controls were hospital-matched and selected by birth certificate. Mothers were interviewed to collect information on demographics, household characteristics, and healthcare providers. Provider-verified immunization history was obtained on mothers and infants. Mothers were considered vaccinated during pregnancy if Tdap was received ≥14 days before delivery; trimester was calculated using Tdap date, infant's date of birth, and gestational age. Odds ratios were calculated using multivariable conditional logistic regression; vaccine effectiveness (VE) was estimated as (1 – odds ratio) × 100%.

Results

A total of 240 cases and 535 controls were included; 17 (7.1%) case mothers and 90 (16.8%) control mothers received Tdap during the third trimester of pregnancy. The multivariable VE estimate for Tdap administered during the third trimester of pregnancy was 77.7% (95% confidence interval [CI], 48.3%–90.4%); VE increased to 90.5% (95% CI, 65.2%–97.4%) against hospitalized cases.

Conclusions

Vaccination during pregnancy is an effective way to protect infants during the early months of life. With a continuing resurgence in pertussis, efforts should focus on maximizing Tdap uptake among pregnant women.

Trial Evaluating Ambulatory Therapy of Travelers’ Diarrhea (TrEAT TD) Study: A Randomized Controlled Trial Comparing 3 Single-Dose Antibiotic Regimens With Loperamide

Abstract

Background

Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations.

Methods

A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool.

Results

Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events.

Conclusions

Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea.

Clinical Trial Registration

NCT01618591

Linezolid-Resistant Enterococcus faecalis Infection Following Prolonged Low-Dosage Linezolid Treatment for Multidrug-Resistant Tuberculosis

To the Editor—Linezolid is a last-resort option for infections caused by multidrug-resistant (MDR) gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. Linezolid resistance can be mediated by chromosomal mutations in ribosomal RNA (rRNA) or protein genes (23S rRNA, rplC, rplD) altering the ribosomal target [1], and by plasmid-encoded ribosomal methylases (eg, Cfr and Cfr[B]) or ribosomal protection proteins (eg, OptrA) [1–3].

Please, No More Gastric Aspirate to Diagnose Pulmonary Tuberculosis in Children

To the Editor—Moore and collaborators recently presented a prospective study questioning the diagnostic value of repeated induced sputum vs gastric aspirate for the accurate diagnosis of pulmonary tuberculosis in children [1]. In fact, the question had been already answered in Clinical Infectious Diseases, exactly 10 years ago [2].

Influence of Phoslock® on legacy phosphorus, nutrient ratios, and algal assemblage composition in hypereutrophic water resources

Abstract

Acceleration of eutrophication in freshwater resources can result in prolific growth of nuisance algae, notably cyanobacteria. In this research, we evaluated the ability of an in situ P binding technology (Phoslock®) to alter available water column and sediment P, and the subsequent impact on nutrient ratios and algal assemblage composition. Two golf course irrigation ponds with legacy nutrient loads and chronic cyanobacterial blooms were treated with Phoslock and monitored for 2 years post-treatment. Phoslock significantly (P < 0.05) decreased water column total P levels and shifted mobile sediment P fractions (i.e., labile, reductant-soluble, organic) to the residual fraction. Total N/P ratios (by mass) significantly increased and were sustained at over 30:1 in the Hickory Meadows irrigation pond and 100:1 in the Chockyotte irrigation pond throughout the study. Consequent changes in the algal assemblage included decreases in dominance and overall density of cyanobacteria as well as a shift away from scum-forming genera (e.g., Microcystis spp. and Anabaena [Dolichospermum] sp.) to planktonic forms (e.g., Pseudanabaena sp. and Planktolyngbya sp.). This research provides information regarding mitigation of in situ water and sediment P toward shifting nutrient ratios and altering algal assemblage composition.

Evaluation of a new fluorescent reagent, fluorescent brightener 85, for the diagnosis of suspected onychomycosis compared with potassium hydroxide

Abstract

Background

Onychomycosis is a common fungal infection in dermatology clinics. The commonly used diagnostic method, potassium hydroxide (KOH) direct microscopy, does not have a high positive detection rate. Therefore, a new diagnostic method is needed to confirm onychomycosis.

Objectives

The objective of this research was to use fluorescent brightener 85 (FB 85), a new fluorescent reagent for fungi detection, and to evaluate this new method based on the diagnostic positive rate, accuracy and efficiency in suspected onychomycosis compared with the KOH method.

Methods

Subungual debris were collected from clinically suspected onychomycosis cases and divided into two parts. The parts were examined by FB 85 and 10% KOH solution, respectively.

Results

In total, 108 patients with suspected onychomycosis were recruited. The positive rates of FB 85 and KOH were 88.9% and 55.6%, respectively. The patients showed significant statistical differences (P<0.001).

Conclusions

Compared with the KOH method, the FB 85 fluorescent method was an accurate and efficient method with a higher positive rate. This method could increase the diagnostic accuracy and efficiency of onychomycosis detection.

This article is protected by copyright. All rights reserved.

Facial Contouring Surgery—Mandibuloplasty: Genioplasty and Mandible Angle Correction

No abstract available

Solving Hand/Finger Pain Problems with the Pencil Test and Relative Motion Splinting

No abstract available

A Breast Reconstruction Using a Breast Prosthesis and Capsular Flap for a Lymphocele Patient

Summary: We encountered a very rare condition where the patient had a lymphocele under the skin envelope of the breast following mastectomy during the course of breast reconstruction with a tissue expander. The incidence rate of axillary lymphoceles is reported as 2.2–50% in breast cancer patients, but there have been no reports mentioning lymphoceles under the breast skin during the course of breast reconstruction with a prosthesis. The patient had a lymphocele in the lower lateral part of the breast following mastectomy and had multiple cellulitis-like inflammations. These inflammations were treated with conservative therapy such as administration of antibiotics, resting, and cooling. After 6 months of the initial surgery, the patient underwent complete resection of the lymphocele, preventative elimination of a possible lymphatic leakage, and breast reconstruction using a prosthesis combined with a capsular flap. The capsular flap is a transposition flap that uses capsular tissue around the expander to cover adjacent thinned skin. There were no postoperative complications such as breast skin necrosis, exposure of the prosthesis, or recurrence of the lymphocele and cellulitis. The patient had a successful breast reconstruction even though a lymphocele of the breast was observed. Even though a patient may have a lymphocele in the breast following mastectomy, with careful resection of the lymphocele, complete elimination of possible lymphatic leakage, and by performing the capsular flap technique, complete breast reconstruction with a breast prosthesis may be successful.

Rolle der Vegetation im Hochwasserabfluss – Interaktion mit Hydrodynamik und Sedimenttransport

Zusammenfassung

Vegetation ist ein integraler Bestandteil der Fließgewässer und ihrer Überflutungsflächen. Neben ihren Funktionen für ein intaktes Ökosystem ist die Vegetation auch maßgeblich am Abflussgeschehen beteiligt. Der Einfluss flexibler Vegetation auf Strömung und Sedimenthaushalt ist komplex, da die Strömung die Form der Pflanze und diese wiederum die Strömung beeinflusst. Es ist wichtig den Einfluss zu kennen, um zum Beispiel Hochwasseranschlagslinien und morphodynamische Auswirkungen richtig ermitteln und abschätzen zu können.

Zur Interaktion zwischen Vegetation und Sedimenttransport wurden bereits zahlreiche Laboruntersuchungen durchgeführt, wobei größere Vegetationsverbände aufgrund der nicht möglichen Skalierung noch nicht untersucht werden konnten. An realen Flussabschnitten wiederum fehlt es an kontrollierten Versuchsbedingungen, wodurch sich Felduntersuchungen auf Beobachtungen oder grobskalige Messungen beschränken.

Wir stellen das von der Österreichischen Forschungsförderungsgesellschaft geförderte Projekt „VEGSED" vor, in welchem in einem 5 m breiten Forschungsgerinne Versuche im Maßstab 1:1 mit Durchflüssen von bis zu 10 m³ s⁻¹ und bis zu 3 m Wassertiefe unter Laborbedingungen durchgeführt werden können, wodurch die Vorteile von Laboruntersuchungen mit jenen der Felduntersuchungen vereint werden. Dieser Artikel behandelt die Wirkung eines Vegetationsverbands auf die Hydrodynamik und den Sedimenttransport sowohl innerhalb als auch außerhalb des Verbands, sowie die Verwendung der gewonnenen Daten für die Überprüfung eines verbesserten Pflanzenverformungsmodells und dessen Kopplung mit einem zweidimensionalen Hydrodynamik- und Sedimenttransportmodell.

Erzielte Verbesserungen und verbleibender Handlungsbedarf im Integrierten Hochwasserrisikomanagement in Österreich – FloodRisk_E(valuierung)

Zusammenfassung

FloodRisk_E(valuierung) analysiert die erzielten Verbesserungen und den verbleibenden Handlungsbedarf im Integrierten Hochwasserrisikomanagement in Österreich und beurteilt die Umsetzung der Empfehlungen aus FloodRisk I sowie FloodRisk II unter Berücksichtigung der EU-Hochwasserrichtlinie. Einerseits erfolgt eine Darstellung der Verbesserung der Ist-Situation gegenüber dem Referenzjahr 2002 mit dem damaligen Katastrophenhochwasser und andererseits wird der weitere Untersuchungs- und Handlungsbedarf aufgezeigt. Der Bearbeitung wurden Leitfragen zugrunde gelegt. Zur Beurteilung diente eine fünfstufige Bewertungsskala. Es zeigte sich, dass in allen acht Themenfeldern Meteorologie und Hydrologie, Geomorphologie, Hochwasserrisikomanagement, Ökologie, Katastrophenmanagement, Ökonomische Aspekte, Öffentlichkeitsbeteiligung und Bewusstseinsbildung sowie Recht und Raumordnung bedeutende Fortschritte erzielt wurden und sich die institutionelle Zusammenarbeit in gemeinsamen integralen Projekten verbessert hat. Gleichzeitig besteht noch ein Untersuchungs- und Handlungsbedarf, zu dem ein Umsetzungsvorschlag gemacht wurde. Dieser umfasst einerseits eine Auflistung von konkreten Maßnahmen, die zentral im Hochwasserrisikomanagementplan realisiert werden können. Andererseits sind nähere, wissenschaftlich basierte Abklärungen notwendig.

‘Nothing but Nonsense’: A Kantian account of ugliness 1

Lipid Droplet Fusion in Mammary Epithelial Cells is Regulated by Phosphatidylethanolamine Metabolism

Abstract

Mammary epithelial cells (MEC) secrete fat in the form of milk fat globules (MFG) which are found in milk in diverse sizes. MFG originate from intracellular lipid droplets, and the mechanism underlying their size regulation is still elusive. Two main mechanisms have been suggested to control lipid droplet size. The first is a well-documented pathway, which involves regulation of cellular triglyceride content. The second is the fusion pathway, which is less-documented, especially in mammalian cells, and its importance in the regulation of droplet size is still unclear. Using biochemical and molecular inhibitors, we provide evidence that in MEC, lipid droplet size is determined by fusion, independent of cellular triglyceride content. The extent of fusion is determined by the cell membrane's phospholipid composition. In particular, increasing phosphatidylethanolamine (PE) content enhances fusion between lipid droplets and hence increases lipid droplet size. We further identified the underlying biochemical mechanism that controls this content as the mitochondrial enzyme phosphatidylserine decarboxylase; siRNA knockdown of this enzyme reduced the number of large lipid droplets threefold. Further, inhibition of phosphatidylserine transfer to the mitochondria, where its conversion to PE occurs, diminished the large lipid droplet phenotype in these cells. These results reveal, for the first time to our knowledge in mammalian cells and specifically in mammary epithelium, the missing biochemical link between the metabolism of cellular complex lipids and lipid-droplet fusion, which ultimately defines lipid droplet size.

Basispflege lindert Nebenwirkungen der Medikation

Hautschutz im Herbst

Hautkrebs: Basalzellkarzinom folgt Plattenepithelkarzinom

Wie häufig entwickelt sich nach einem ersten Melanom, Plattenepithel- oder Basalzellkarzinom ein anderer maligner Hauttumor? Die höchsten kumulativen Risiken fanden niederländische Dermatologen für die Entstehung keratinozytischer Zweittumoren.

Alopecia areata: Welche Rolle spielen Mikronährstoffe?

Nur langsam zeichnen sich erste Hinweise darauf ab, welche Rolle Spurenelemente und Vitamine bei der Alopecia areata spielen könnten. Für Expertenempfehlungen erscheint die Datenlage noch zu dünn, so das Autorenresümee einer US-Studie.

Ausgezeichnete Innovationen

Im Rahmen einer Gala in Berlin ist der von Springer Medizin gestiftete Galenus-von-Pergamon-Preis für pharmazeutische Innovationen verliehen worden. Mit dem CharityAward wurde auch ehrenamtliches Engagement gewürdigt.

Verbesserte Wundheilung nach Lasertherapie

Faites moi belle, madame d’Ora!

Wer sich von Madame d'Ora porträtieren ließ, verlieh seiner Person einen Hauch französische Eleganz. Nun widmet das Museum für Kunst und Gewerbe Hamburg dem Schaffen der Künstlerin eine eigene Ausstellung.

Behandlung mithilfe Vakuum-assistierter Subzision

Im Kampf gegen Cellulite hat sich ein ertragreicher Absatzmarkt entwickelt. Weltweit werden von Frauen jährlich Milliarden ausgegeben, um die ästhetisch wenig ansprechenden Dellen an der Hautoberfläche zu beseitigen. Während bestimmte Übungen, Massagen und topische Anwendungen bisher zu den klassischen Anwendungen bei Cellulite gehörten, fehlte es bis vor wenigen Jahren an medizinischen Ansätzen, den als Cellulite bezeichneten Makel tatsächlich zu beheben oder deutlich und längerfristig zu verbessern.

Narben wirksam behandeln

Inhaltsverzeichnis

ADK-Grundkurs ein voller Erfolg!

Mikronährstoffe als Begleittherapie des kreisrunden Haarausfalls

Microneedling zur Verbesserung des Hautbildes

Weißer Hautkrebs — jedes Jahr mehr Neuerkrankungen

Weltweit steigt die Zahl der nicht melanozytären Hautkrebserkrankungen von Jahr zu Jahr. Das ist in Deutschland nicht anders, wie Dermatologen aus Tübingen hochgerechnet haben. Und eine Trendwende ist nicht in Sicht.

Melanom: Je später die Operation, desto höher die Mortalität

Wird bei Patienten mit einem Melanom der Haut im Frühstadium nach der Biopsie die Zeit bis zur Operation hinausgezögert, erhöht das möglicherweise die Sterberate. Eine entsprechende Assoziation hat jetzt die Auswertung von US-Registerdaten ergeben.

Annual User Meeting Symposia L

Ein Siegel aus KV-Hand

Die KV Telematik GmbH will ab 2018 zur Anlaufstelle im App-Dschungel werden — für Gründer aber auch für Ärzte.

Umgang mit privaten Kostenträgern

Das Analogverzeichnis erleichtert die Abrechnung analoger Leistungen. Neu entstandene Leistungen fehlen darin jedoch häufig. Weitere Hürden, wie vertraglich ausgeschlossene Analogabrechnungen der Krankenversicherer, müssen im Vorfeld der Behandlung ebenfalls bedacht werden.

Stressfaktor Nummer eins: die Bürokratie

Die Bürokratie begleitet Ärzte im Alltag auf Schritt und Tritt. Fast die Hälfte sowohl der leitenden Klinikärzte wie auch der Praxischefs identifiziert die Dokumentationsanforderungen als Hauptursache für Stress im Versorgungsalltag.

En memoria del doctor Demetrio Luis Alvarado Moncayo

Publication date: December 2017
Source:Actas Dermo-Sifiliográficas, Volume 108, Issue 10
Author(s): E. Serra Baldrich

El libro blanco del cáncer de piel de la AEDV

Publication date: December 2017
Source:Actas Dermo-Sifiliográficas, Volume 108, Issue 10
Author(s): L. Ríos Buceta

Lipoblastoma en la extremidad inferior de un lactante. Un caso representativo

Publication date: Available online 28 November 2017
Source:Actas Dermo-Sifiliográficas
Author(s): L. Giraldo Mordecay, M.P. Novoa Candia, C.E. Torres Fuentes, A.M. Sastre Zuluaga

Tatuaje de fresa en 3D

Publication date: December 2017
Source:Actas Dermo-Sifiliográficas, Volume 108, Issue 10
Author(s): A. Imbernón-Moya, E. Fernández-Cogolludo, M.Á. Gallego-Valdés