LRRK2 G2019S Induces Anxiety/Depression-like Behavior before the Onset of Motor Dysfunction with 5-HT1A Receptor Upregulation in Mice

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology of LRRK2 mutation-related PD, including increased dopaminergic neurodegeneration and Lewy bodies, is indistinguishable from that of idiopathic PD. The subtle nonmotor phenotypes of LRRK2 mutation-related PD have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S. Through multiple behavioral tests, including light–dark test, elevated plus maze, sucrose preference test, forced swimming test, and tail-suspension test, we found that anxiety/depression-like behavior appeared in middle-aged (43–52 weeks) Tg mice before the onset of PD-like motor dysfunction. These behavioral tests were performed using both male and female mice, and there were no sex-related differences in behavioral changes in the middle-aged Tg mice. Along with behavioral changes, serotonin levels also significantly declined in the hippocampus of Tg mice. Additionally, increases in the expression of the 5-HT_1A receptor (5-HT_1AR) grew more significant with aging and were detected in the hippocampus, amygdala, and dorsal raphe nucleus. In vitro study using the serotonergic RN46A and hippocampal HT22 cells showed that 5-HT_1AR upregulation was related to enhanced expression of LRRK2 G2019S and was attenuated by the LRRK2 inhibitor LRRK2-IN-1. Wild-type LRRK2 had no significant effect on 5-HT_1AR transcription. The present study provides the first in vivo and in vitro evidence demonstrating abnormal regulation of 5-HT_1AR along with the manifestation of anxiety/depression-like, nonmotor symptom in PD related to LRRK2.

SIGNIFICANCE STATEMENT Parkinson's disease (PD), the second most common neurodegenerative disorder, is clinically characterized by motor dysfunctions. In most cases, various nonmotor symptoms present several years before the onset of the classical motor features of PD and severely affect the quality of life of patients. Here, we demonstrate the causative role of leucine-rich repeat kinase 2 (LRRK2), a common PD-linked mutation, in the development of anxiety/depression-like behaviors. We found that age-dependent 5-HT_1A receptor upregulation in the hippocampus, amygdala, and dorsal raphe nucleus is accompanied by the expression of the LRRK2 mutant phenotype. Our findings demonstrating a potential mechanism for nonmotor psychiatric symptoms produced by LRRK2 mutation suggest that directly targeting the 5-HT_1A receptor can improve the therapeutic efficacy of drugs for PD-associated depression.

Signal Complexity of Human Intracranial EEG Tracks Successful Associative-Memory Formation across Individuals

Memory performance is highly variable among individuals. Most studies examining human memory, however, have largely focused on the neural correlates of successful memory formation within individuals, rather than the differences among them. As such, what gives rise to this variability is poorly understood. Here, we examined intracranial EEG (iEEG) recordings captured from 43 participants (23 male) implanted with subdural electrodes for seizure monitoring as they performed a paired-associates verbal memory task. We identified three separate but related signatures of neural activity that tracked differences in successful memory formation across individuals. High-performing individuals consistently exhibited less broadband power, flatter power spectral density slopes, and greater complexity in their iEEG signals. Furthermore, within individuals across three separate time scales ranging from seconds to days, successful recall was positively associated with these same metrics. Our data therefore suggest that memory ability across individuals can be indexed by increased neural signal complexity.

SIGNIFICANCE STATEMENT We show that participants whose intracranial EEG exhibits less low-frequency power, flatter power spectrums, and greater sample entropy overall are better able to memorize associations, and that the same metrics track fluctuations in memory performance across time within individuals. These metrics together signify greater neural signal complexity, which may index the brain's ability to flexibly engage with information and generate separable memory representations. Critically, the current set of results provides a unique window into the neural markers of individual differences in memory performance, which have hitherto been underexplored.

Diversity and Connectivity of Layer 5 Somatostatin-Expressing Interneurons in the Mouse Barrel Cortex

Inhibitory interneurons represent 10–15% of the neurons in the somatosensory cortex, and their activity powerfully shapes sensory processing. Three major groups of GABAergic interneurons have been defined according to developmental, molecular, morphological, electrophysiological, and synaptic features. Dendritic-targeting somatostatin-expressing interneurons (SST-INs) have been shown to display diverse morphological, electrophysiological, and molecular properties and activity patterns in vivo. However, the correlation between these properties and SST-IN subtype is unclear. In this study, we aimed to correlate the morphological diversity of layer 5 (L5) SST-INs with their electrophysiological and molecular diversity in mice of either sex. Our morphological analysis demonstrated the existence of three subtypes of L5 SST-INs with distinct electrophysiological properties: T-shaped Martinotti cells innervate L1, and are low-threshold spiking; fanning-out Martinotti cells innervate L2/3 and the lower half of L1, and show adapting firing patterns; non-Martinotti cells innervate L4, and show a quasi-fast spiking firing pattern. We estimated the proportion of each subtype in L5 and found that T-shaped Martinotti, fanning-out Martinotti, and Non-Martinotti cells represent ~10, ~50, and ~40% of L5 SST-INs, respectively. Last, we examined the connectivity between the three SST-IN subtypes and L5 pyramidal cells (PCs). We found that L5 T-shaped Martinotti cells inhibit the L1 apical tuft of nearby PCs; L5 fanning-out Martinotti cells also inhibit nearby PCs but they target the dendrite mainly in L2/3. On the other hand, non-Martinotti cells inhibit the dendrites of L4 neurons while avoiding L5 PCs. Our data suggest that morphologically distinct SST-INs gate different excitatory inputs in the barrel cortex.

SIGNIFICANCE STATEMENT Morphologically diverse layer 5 SST-INs show different patterns of activity in behaving animals. However, little is known about the abundance and connectivity of each morphological type and the correlation between morphological subtype and spiking properties. We demonstrate a correlation between the morphological and electrophysiological diversity of layer 5 SST-INs. Based on these findings we built a classifier to infer the abundance of each morphological subtype. Last, using paired recordings combined with morphological analysis, we investigated the connectivity of each morphological subtype. Our data suggest that, by targeting different cell types and cellular compartments, morphologically diverse SST-INs might gate different excitatory inputs in the mouse barrel cortex.

Sox2 Is Essential for Oligodendroglial Proliferation and Differentiation during Postnatal Brain Myelination and CNS Remyelination

In the CNS, myelination and remyelination depend on the successful progression and maturation of oligodendroglial lineage cells, including proliferation and differentiation of oligodendroglial progenitor cells (OPCs). Previous studies have reported that Sox2 transiently regulates oligodendrocyte (OL) differentiation in the embryonic and perinatal spinal cord and appears dispensable for myelination in the postnatal spinal cord. However, the role of Sox2 in OL development in the brain has yet to be defined. We now report that Sox2 is an essential positive regulator of developmental myelination in the postnatal murine brain of both sexes. Stage-specific paradigms of genetic disruption demonstrated that Sox2 regulated brain myelination by coordinating upstream OPC population supply and downstream OL differentiation. Transcriptomic analyses further supported a crucial role of Sox2 in brain developmental myelination. Consistently, oligodendroglial Sox2-deficient mice developed severe tremors and ataxia, typical phenotypes indicative of hypomyelination, and displayed severe impairment of motor function and prominent deficits of brain OL differentiation and myelination persisting into the later CNS developmental stages. We also found that Sox2 was required for efficient OPC proliferation and expansion and OL regeneration during remyelination in the adult brain and spinal cord. Together, our genetic evidence reveals an essential role of Sox2 in brain myelination and CNS remyelination, and suggests that manipulation of Sox2 and/or Sox2-mediated downstream pathways may be therapeutic in promoting CNS myelin repair.

SIGNIFICANCE STATEMENT Promoting myelin formation and repair has translational significance in treating myelin-related neurological disorders, such as periventricular leukomalacia and multiple sclerosis in which brain developmental myelin formation and myelin repair are severely affected, respectively. In this report, analyses of a series of genetic conditional knock-out systems targeting different oligodendrocyte stages reveal a previously unappreciated role of Sox2 in coordinating upstream proliferation and downstream differentiation of oligodendroglial lineage cells in the mouse brain during developmental myelination and CNS remyelination. Our study points to the potential of manipulating Sox2 and its downstream pathways to promote oligodendrocyte regeneration and CNS myelin repair.

Abdominal Vagal Afferents Modulate the Brain Transcriptome and Behaviors Relevant to Schizophrenia

Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions.

SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions.

This Week in The Journal

Sensorimotor Functional and Structural Networks after Intracerebral Stem Cell Grafts in the Ischemic Mouse Brain

Past investigations on stem cell-mediated recovery after stroke have limited their focus on the extent and morphological development of the ischemic lesion itself over time or on the integration capacity of the stem cell graft ex vivo. However, an assessment of the long-term functional and structural improvement in vivo is essential to reliably quantify the regenerative capacity of cell implantation after stroke. We induced ischemic stroke in nude mice and implanted human neural stem cells (H9 derived) into the ipsilateral cortex in the acute phase. Functional and structural connectivity changes of the sensorimotor network were noninvasively monitored using magnetic resonance imaging for 3 months after stem cell implantation. A sharp decrease of the functional sensorimotor network extended even to the contralateral hemisphere, persisting for the whole 12 weeks of observation. In mice with stem cell implantation, functional networks were stabilized early on, pointing to a paracrine effect as an early supportive mechanism of the graft. This stabilization required the persistent vitality of the stem cells, monitored by bioluminescence imaging. Thus, we also observed deterioration of the early network stabilization upon vitality loss of the graft after a few weeks. Structural connectivity analysis showed fiber-density increases between the cortex and white matter regions occurring predominantly on the ischemic hemisphere. These fiber-density changes were nearly the same for both study groups. This motivated us to hypothesize that the stem cells can influence, via early paracrine effect, the functional networks, while observed structural changes are mainly stimulated by the ischemic event.

SIGNIFICANCE STATEMENT In recent years, research on strokes has made a shift away from a focus on immediate ischemic effects and towards an emphasis on the long-range effects of the lesion on the whole brain. Outcome improvements in stem cell therapies also require the understanding of their influence on the whole-brain networks. Here, we have longitudinally and noninvasively monitored the structural and functional network alterations in the mouse model of focal cerebral ischemia. Structural changes of fiber-density increases are stimulated in the endogenous tissue without further modulation by the stem cells, while functional networks are stabilized by the stem cells via a paracrine effect. These results will help decipher the underlying networks of brain plasticity in response to cerebral lesions and offer clues to unravelling the mystery of how stem cells mediate regeneration.

The Primary Role of Flow Processing in the Identification of Scene-Relative Object Movement

Retinal image motion could be due to the movement of the observer through space or an object relative to the scene. Optic flow, form, and change of position cues all provide information that could be used to separate out retinal motion due to object movement from retinal motion due to observer movement. In Experiment 1, we used a minimal display to examine the contribution of optic flow and form cues. Human participants indicated the direction of movement of a probe object presented against a background of radially moving pairs of dots. By independently controlling the orientation of each dot pair, we were able to put flow cues to self-movement direction (the point from which all the motion radiated) and form cues to self-movement direction (the point toward which all the dot pairs were oriented) in conflict. We found that only flow cues influenced perceived probe movement. In Experiment 2, we switched to a rich stereo display composed of 3D objects to examine the contribution of flow and position cues. We moved the scene objects to simulate a lateral translation and counter-rotation of gaze. By changing the polarity of the scene objects (from light to dark and vice versa) between frames, we placed flow cues to self-movement direction in opposition to change of position cues. We found that again flow cues dominated the perceived probe movement relative to the scene. Together, these experiments indicate the neural network that processes optic flow has a primary role in the identification of scene-relative object movement.

SIGNIFICANCE STATEMENT Motion of an object in the retinal image indicates relative movement between the observer and the object, but it does not indicate its cause: movement of an object in the scene; movement of the observer; or both. To isolate retinal motion due to movement of a scene object, the brain must parse out the retinal motion due to movement of the eye ("flow parsing"). Optic flow, form, and position cues all have potential roles in this process. We pitted the cues against each other and assessed their influence. We found that flow parsing relies on optic flow alone. These results indicate the primary role of the neural network that processes optic flow in the identification of scene-relative object movement.

BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic Neurons In Vivo and in Human Induced Pluripotent and Neural Stem Cells

The embryonic formation of midbrain dopaminergic (mDA) neurons in vivo provides critical guidelines for the in vitro differentiation of mDA neurons from stem cells, which are currently being developed for Parkinson's disease cell replacement therapy. Bone morphogenetic protein (BMP)/SMAD inhibition is routinely used during early steps of stem cell differentiation protocols, including for the generation of mDA neurons. However, the function of the BMP/SMAD pathway for in vivo specification of mammalian mDA neurons is virtually unknown. Here, we report that BMP5/7-deficient mice (Bmp5^–/–; Bmp7^–/–) lack mDA neurons due to reduced neurogenesis in the mDA progenitor domain. As molecular mechanisms accounting for these alterations in Bmp5^–/–; Bmp7^–/– mutants, we have identified expression changes of the BMP/SMAD target genes MSX1/2 (msh homeobox 1/2) and SHH (sonic hedgehog). Conditionally inactivating SMAD1 in neural stem cells of mice in vivo (Smad1^Nes) hampered the differentiation of progenitor cells into mDA neurons by preventing cell cycle exit, especially of TH⁺SOX6⁺ (tyrosine hydroxylase, SRY-box 6) and TH⁺GIRK2⁺ (potassium voltage-gated channel subfamily-J member-6) substantia nigra neurons. BMP5/7 robustly increased the in vitro differentiation of human induced pluripotent stem cells and induced neural stem cells to mDA neurons by up to threefold. In conclusion, we have identified BMP/SMAD signaling as a novel critical pathway orchestrating essential steps of mammalian mDA neurogenesis in vivo that balances progenitor proliferation and differentiation. Moreover, we demonstrate the potential of BMPs to improve the generation of stem-cell-derived mDA neurons in vitro, highlighting the importance of sequential BMP/SMAD inhibition and activation in this process.

SIGNIFICANCE STATEMENT We identify bone morphogenetic protein (BMP)/SMAD signaling as a novel essential pathway regulating the development of mammalian midbrain dopaminergic (mDA) neurons in vivo and provide insights into the molecular mechanisms of this process. BMP5/7 regulate MSX1/2 (msh homeobox 1/2) and SHH (sonic hedgehog) expression to direct mDA neurogenesis. Moreover, the BMP signaling component SMAD1 controls the differentiation of mDA progenitors, particularly to substantia nigra neurons, by directing their cell cycle exit. Importantly, BMP5/7 increase robustly the differentiation of human induced pluripotent and induced neural stem cells to mDA neurons. BMP/SMAD are routinely inhibited in initial stages of stem cell differentiation protocols currently being developed for Parkinson's disease cell replacement therapies. Therefore, our findings on opposing roles of the BMP/SMAD pathway during in vitro mDA neurogenesis might improve these procedures significantly.

KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats

Potassium voltage-gated channel interacting protein 3 (KChIP3), also termed downstream regulatory element antagonist modulator (DREAM) and calsenilin, is a multifunctional protein belonging to the neuronal calcium sensor (NCS) family. Recent studies revealed the expression of KChIP3 in dorsal root ganglion (DRG) neurons, suggesting the potential role of KChIP3 in peripheral sensory processing. Herein, we show that KChIP3 colocalizes with transient receptor potential ion channel V1 (TRPV1), a critical molecule involved in peripheral sensitization during inflammatory pain. Furthermore, the N-terminal 31-50 fragment of KChIP3 is capable of binding both the intracellular N and C termini of TRPV1, which substantially decreases the surface localization of TRPV1 and the subsequent Ca²⁺ influx through the channel. Importantly, intrathecal administration of the transmembrane peptide transactivator of transcription (TAT)-31-50 remarkably reduces Ca²⁺ influx via TRPV1 in DRG neurons and alleviates thermal hyperalgesia and gait alterations in a complete Freund's adjuvant-induced inflammatory pain model in male rats. Moreover, intraplantar injection of TAT-31-50 attenuated the capsaicin-evoked spontaneous pain behavior and thermal hyperalgesia, which further strengthened the regulatory role of TAT-31-50 on TRPV1 channel. In addition, TAT-31-50 could also alleviate inflammatory thermal hyperalgesia in kcnip3^–/– rats generated in our study, suggesting that the analgesic effect mediated by TAT-31-50 is independent of endogenous KChIP3. Our study reveals a novel peripheral mechanism for the analgesic function of KChIP3 and provides a potential analgesic agent, TAT-31-50, for the treatment of inflammatory pain.

SIGNIFICANCE STATEMENT Inflammatory pain arising from inflamed or injured tissues significantly compromises the quality of life in patients. This study aims to elucidate the role of peripheral potassium channel interacting protein 3 (KChIP3) in inflammatory pain. Direct interaction of the KChIP3 N-terminal 31-50 fragment with transient receptor potential ion channel V1 (TRPV1) was demonstrated. The KChIP3–TRPV1 interaction reduces the surface localization of TRPV1 and thus alleviates heat hyperalgesia and gait alterations induced by peripheral inflammation. Furthermore, the transmembrane transactivator of transcription (TAT)-31-50 peptide showed analgesic effects on inflammatory hyperalgesia independently of endogenous KChIP3. This work reveals a novel mechanism of peripheral KChIP3 in inflammatory hyperalgesia that is distinct from its classical role as a transcriptional repressor in pain modulation.

Diagnosis uPGrade—Advances in Pyoderma Gangrenosum

In this issue of JAMA Dermatology, 2 large, well-constructed studies remind dermatologists that even though pyoderma gangrenosum (PG) is a quintessential disease in medical dermatology, we still need data to better define the disease and reduce the risk of cognitive biases. We know the results of these biases well; even at referral centers and in clinical trials, alternative diagnoses can prevail 7% to 20% of the time. In these articles, one of the largest retrospective PG databases and a new tool for PG diagnosis validation are presented.

Age and Pyoderma Gangrenosum Presentation and Comorbidities

This cohort study evaluates the association of age with the clinical presentation and disease associations of pyoderma gangrenosum.

Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum

This consensus statement proposes and validates diagnostic criteria for ulcerative pyoderma gangrenosum.

Lenalidomide Treatment for Recurrent Erythema Multiforme

This case report describes 3 patients treated with lenalidomide as an alternative to thalidomide for recurrent erythema multiforme.

Dermatologists Should Speak Out Against a Word Ban at CDC

This Viewpoint details why dermatologists must speak out against the current US political administration's word ban at the Centers for Disease Control and Prevention.

Gray-Brown Patches on the Face of a 62-Year-Old Woman

A 62-year-old woman with a history of rosacea and melasma presented with worsening gray-brown patches on the face; no oral or other cutaneous lesions were reported. What is your diagnosis?

Voice quality outcomes of idiopathic Parkinson disease medical treatment: a systematic review

Abstract

Introduction

To investigate voice quality (VQ) impairments in idiopathic Parkinson's disease (IPD) and to explore the impact of medical treatments and L-Dopa challenge testing on voice.

Methods

Relevant studies published between January 1980 and June 2017 describing VQ evaluations in IPD were retrieved using PubMed, Scopus, Biological Abstracts, BioMed Central, and Cochrane databases. Issues of clinical relevance, including IPD treatment efficiency and voice quality outcomes, were evaluated for each study. The grade of recommendation for each publication was determined according to the Oxford Centre for Evidence-Based Medicine evidence levels.

Results

The database research yielded 106 relevant publications, of which 33 studies met the inclusion criteria, for a total of 964 IPD patients. Data were extracted by 3 independent physicians who identified 21, 11, and 1 trials with IIIb, IIb, and IIa evidence levels, respectively. The main VQ assessment tools used were acoustic testing (N=27), aerodynamic testing (N=10), subjective measurements (N=8), and videolaryngostroboscopy (N=3). The majority of trials (N=32/33) identified subjective or objective VQ improvements after medical treatment (N=10) or better VQ evaluations in healthy subjects compared to patients with IPD (N=22). Especially, our analysis supports that VQ overall improves during the L-Dopa challenge testing, making the VQ evaluation an additional tool for the IPD diagnosis. The methodology used to assess subjective and objective VQ substantially varied from one study to another. All of the included studies took into consideration the patient's clinical profile in the VQ analysis.

Conclusion

The majority of studies supported that VQ assessments remain useful as outcome measures of the effectiveness of medical treatment and could be helpful for the IPD diagnosis based on L-Dopa challenge testing. Further controlled studies using standardized and transparent methodology for measuring acoustic parameters are necessary to confirm the place of each tool in both IPD diagnosis and treatment evaluation.

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Moral realism and reliance on moral testimony

Abstract

Moral realism and some of its constitutive theses, e.g., cognitivism, face the following challenge. If they are true, then it seems that we should predict that deference to moral testimony is appropriate under the same conditions as deference to non-moral testimony. Yet, many philosophers intuit that deference to moral testimony is not appropriate, even in otherwise ordinary conditions. In this paper I show that the challenge is cogent only if the appropriateness in question is disambiguated in a particular way. To count against realism and its constitutive theses, moral deference must fail to be appropriate in specifically the way that the theses predict it is appropriate. I argue that this is not the case. In brief, I argue that realism and allied theses predict only that deference to moral testimony is epistemically appropriate, but that the intuitive data plausibly show only that it is not morally appropriate. If I am right, then there is reason to doubt the metaethical relevance of much of the skepticism regarding moral deference in recent literature.

Review of the methods for determination of reactive oxygen species and suggestion for their application in advanced oxidation induced by dielectric barrier discharges

Abstract

Advanced oxidation processes (AOPs) particularly non-thermal plasmas based on electrical discharges have been widely investigated for water and wastewater treatment. Dielectric barrier discharges (DBDs) generate large amounts of selective and non-selective reactive oxygen species (ROS) such as ozone, hydrogen peroxide, atomic oxygen, superoxide molecular anions and hydroxyl radicals, having been proved to be efficient for water decontamination among various forms of electrical discharge systems. The detection and quantification methods of these oxygen species in non-thermal plasmas have been reviewed. However, their application in dielectric barrier discharge has not been well studied. It is therefore imperative to summarise the various detection and quantification methods for oxygen-based species determination in AOPs, aqueous systems and non-thermal plasma processes. Thereafter, reviewed methods are suggested for the determination of ROS in DBD configurations to understand the consumption trend of these oxidants during treatment of water effluents and to evaluate the performance of the treatment reactor configuration towards the degradation of targeted pollutants.

Pheochromocytoma as a frequent false-positive in adrenal washout CT: A systematic review and meta-analysis

Abstract

Objective

To evaluate the proportion of pheochromocytomas meeting the criteria for adenoma on adrenal washout CT and the diagnostic performance of adrenal washout CT for differentiating adenoma from pheochromocytoma.

Methods

MEDLINE and EMBASE were searched to 28 March 2017. We included studies that used adrenal washout CT for characterisation of pheochromocytomas. Two independent reviewers assessed the methodological quality using Quality Assessment of Diagnostic Accuracy Studies-2. Proportions were pooled using an inverse variance method for calculating weights (random-effects). Sensitivity and specificity were pooled using hierarchical logistic regression modelling and plotted in a hierarchical summary receiver-operating-characteristics (HSROC) plot.

Results

Ten studies (114 pheochromocytomas) were included. The pooled proportion of pheochromocytomas meeting the criteria for adenomas was 35 % (95 % CI 20–51). For eight studies providing information on diagnostic performance, the pooled sensitivity and specificity for differentiating adenoma from pheochromocytoma were 0.97 (95 % CI 0.93–0.99) and 0.67 (95 % CI 0.44–0.84), respectively. The area under the HSROC curve was 0.97 (95 % CI 0.95–0.98).

Conclusions

There was a non-negligible proportion of pheochromocytomas meeting the criteria for adenoma on adrenal washout CT. Although overall diagnostic performance was excellent for differentiating adenoma from pheochromocytoma, specificity was relatively low.

Key Points

• Non-negligible proportion of pheochromocytomas can be mistaken for adenoma.

• Adrenal washout CT showed good sensitivity (97%) but relatively low specificity (67%).

• Findings other than washout percentage should be used when diagnosing pheochromocytomas

The Left Atrio-Vertebral Ratio: a new simple means for assessing left atrial enlargement on Computed Tomography

Abstract

Objective

The purpose of this study is to describe a new method to quickly estimate left atrial enlargement (LAE) on Computed Tomography.

Methods

Left atrial (LA) volume was assessed with a 3D-threshold Hounsfield unit detection technique, including left atrial appendage and excluding pulmonary venous confluence, in 201 patients with ECG-gated 128-slice dual-source CT and indexed to body surface area. LA and vertebral axial diameter and area were measured at the bottom level of the right inferior pulmonary vein ostium. Ratio of LA diameter and surface on vertebra (LAVD and LAVA) were compared to LA volume. In accordance with the literature, a cutoff value of 78 ml/m² was chosen for maximal normal LA volume.

Results

18% of LA was enlarged. The best cutoff values for LAE assessment were 2.5 for LAVD (AUC: 0.65; 95% CI: 0.58-0.73; sensitivity: 57%; specificity: 71%), and 3 for LAVA (AUC: 0.78; 95% CI: 0.72-0.84; sensitivity: 67%; specificity: 79%), with higher accuracy for LAVA (P=0.015). Inter-observer and intra-observer variability were either good or excellent for LAVD and LAVA (respective intraclass coefficients: 0.792 and 0.910; 0.912 and 0.937).

Conclusion

A left atrium area superior to three times the vertebral area indicates LAE with high specificity.

Key points

• Left atrial enlargement is a frequent condition associated with poor cardiac outcome.

• Left atrial enlargement is highly time-consuming to diagnose on CT.

• The left atrio-vertebral ratio quickly assesses left atrial enlargement.

• A left atrial area > three times vertebral area is highly specific.

The effects of mild germinal matrix-intraventricular haemorrhage on the developmental white matter microstructure of preterm neonates: a DTI study

Abstract

Objectives

To evaluate white matter (WM) microstructural changes in preterm neonates (PN) with mild germinal matrix-intraventricular haemorrhage (mGMH-IVH) (grades I and II) and no other associated MRI abnormalities, and correlate them with gestational age (GA) and neurodevelopmental outcome.

Methods

Tract-based spatial-statistics (TBSS) was performed on DTI of 103 patients studied at term-equivalent age, to compare diffusional parameters (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)) between mGMH-IVH neonates (24/103) and controls matched by GA at birth and sex. The relationship between DTI abnormalities, GA and neurodevelopmental outcome assessed with Griffiths' Developmental Scale-Revised:0-2 was explored using TBSS and Spearman-correlation analysis (p < .05).

Results

Affected neonates had lower FA, higher RD and MD of the corpus callosum, limbic pathways and cerebellar tracts. Extremely preterm neonates (GA < 29 weeks) presented more severe microstructural impairment (higher RD and MD) in periventricular regions. Neonates of GA ≥ 29 weeks had milder WM alterations (lower FA), also in subcortical WM. DTI abnormalities were associated with poorer locomotor, eye-hand coordination and performance outcomes at 24 months.

Conclusions

WM microstructural changes occur in PN with mGMH-IVH with a GA-dependent selective vulnerability of WM regions, and correlate with adverse neurodevelopmental outcome at 24 months.

Key Points

• DTI-TBSS analysis identifies WM microstructural changes in preterm neonates with mGMH-IVH.

• Extremely preterm neonates with mGMH-IVH presented more severe impairment of WM microstructure.

• Extremely preterm neonates with mGMH-IVH presented microstructural impairment of periventricular WM.

• mGMH-IVH affects subcortical WM in preterm neonates with gestational age ≥ 29 weeks.

• WM microstructural alterations are related to neurodevelopmental impairments at 24 months.

Microflow imaging: New Doppler technology to detect low-grade inflammation in patients with arthritis

Abstract

Aim

To assess the efficacy of microvascular imaging in detecting low-grade inflammation in arthritis compared with Power Doppler ultrasound (PDUS).

Method and materials

Patients presenting for ultrasound with arthralgia were assessed with grey-scale, PDUS and Superb Microvascular Imaging (SMI). Videoclips were stored for analysis at a later date. Three musculoskeletal radiologists scored grey-scale changes, signal on PDUS and/or SMI within these joints. If a signal was detected on both PDUS and SMI, the readers graded the conspicuity of vascular signal from the two Doppler techniques using a visual analogue scale.

Results

Eighty-three patients were recruited with 134 small joints assessed. Eighty-nine of these demonstrated vascular flow with both PD and SMI, whilst in five no flow was detected. In 40 joints, vascularity was detected with SMI but not with PDUS (p = 0.007). Out of the 89 joints with vascularity on both SMI and PDUS, 23 were rated as being equal; while SMI scored moderately or markedly better in 45 cases (p <0.001).

Conclusion

SMI is a new Doppler technique that increases conspicuity of Doppler vascularity in symptomatic joints when compared to PDUS. This allows detection of low grade inflammation not visualised with Power Doppler in patients with arthritis.

Key Points

• SMI detects vascularity with improved resolution and sensitivity compared to Power Doppler.

• SMI can detect low-grade inflammation not seen with Power Doppler.

• Earlier detection of active inflammation could have significant impact on treatment paradigms.

Carpal tunnel syndrome assessment with diffusion tensor imaging: Value of fractional anisotropy and apparent diffusion coefficient

Abstract

Objectives

To quantitatively assess carpal tunnel syndrome (CTS) with DTI by evaluating two approaches to determine cut-off values.

Methods

In forty patients with CTS diagnosis confirmed by nerve conduction studies (NCs) and 14 healthy subjects (mean age 58.54 and 57.8 years), cross-sectional area (CSA), apparent diffusion coefficient (ADC) and fractional anisotropy (FA) at single and multiple levels with intraobserver agreement were evaluated.

Results

Maximum and mean CSA and FA showed significant differences between healthy subjects and patients (12.85 mm² vs. 28.18 mm², p < 0.001, and 0.613 vs. 0.524, p=0.007, respectively) (10.12 mm² vs. 19.9 mm², p<0.001 and 0.617 vs. 0.54, p=0.003, respectively), but not maximum and mean ADC (p > 0.05). For cut-off values, mean and maximum CSA showed the same sensitivity and specificity (93.3 %). However, mean FA showed better sensitivity than maximum FA (82.6 % vs. 73.9 %), but lower specificity (66.7 % vs. 80 %), and significant correlation for maximum CSA, 97 % (p < 0.01), with good correlation for maximum ADC and FA, 84.5 % (p < 0.01) and 62 % (p=0.056), respectively.

Conclusions

CSA and FA showed significant differences between healthy subjects and patients. Single measurement at maximum CSA is suitable for FA determination.

Key Points

• DTI showed that FA is stronger than ADC for CTS diagnosis.

• Single- and multiple-level approaches were compared to determine FA and ADC.

• Single-level evaluation at the thickest MN cross-sectional area is sufficient.

Thermal ablation of thyroid nodules: are radiofrequency ablation, microwave ablation and high intensity focused ultrasound equally safe and effective methods?

Abstract

Objectives

This study compares volume reduction of benign thyroid nodules three months after Radiofrequency Ablation (RFA), Microwave Ablation (MWA) or High Intensity Focused Ultrasound (HIFU) to evaluate which of these methods is the most effective and safe alternative to thyroidectomy or radioiodine therapy.

Material and Methods

Ninety-four patients (39 male, 55 female) with a total of 118 benign, symptomatic thyroid nodules were divided into three subgroups. HIFU was applied to 14 patients with small nodules. The other 80 patients were divided up into two groups of 40 patients each for RFA and MWA in the assumption that both methods are comparable effective. The pre-ablative and post-ablative volume was measured by ultrasound.

Results

RFA showed a significant volume reduction of nodules of 50 % (p<0.05), MWA of 44 % (p<0.05) and HIFU of 48 % (p<0.05) three months after ablation. None of the examined ablation techniques caused serious or permanent complications.

Conclusion

RFA, MWA and HIFU showed comparable results considering volume reduction. All methods are safe and effective treatments of benign thyroid nodules.

Key Points

• Thermal Ablation can be used to treat benign thyroid nodules

• Thermal Ablation can be an alternative to thyroidectomy or radioiodine therapy

• Radiofrequency Ablation, Microwave Ablation, High Intensity Focused Ultrasound are safe and effective

Safety analysis of holmium-166 microsphere scout dose imaging during radioembolisation work-up: A cohort study

Abstract

Objective

Radioembolisation is generally preceded by a scout dose of technetium-99m-macroaggregated albumin to estimate extrahepatic shunting of activity. Holmium-166 microspheres can be used as a scout dose (±250 MBq) and as a therapeutic dose. The general toxicity of a holmium-166 scout dose (¹⁶⁶Ho-SD) and safety concerns of an accidental extrahepatic deposition of ¹⁶⁶Ho-SD were investigated.

Methods

All patients who received a ¹⁶⁶Ho-SD in our institute were reviewed for general toxicity and extrahepatic depositions. The absorbed dose in extrahepatic tissue was calculated on SPECT/CT and correlated to clinical toxicities.

Results

In total, 82 patients were included. No relevant clinical toxicity occurred. Six patients had an extrahepatic deposition of ¹⁶⁶Ho-SD (median administered activity 270 MBq). The extrahepatic depositions (median activity 3.7 MBq) were located in the duodenum (3x), gastric fundus, falciform ligament and the lesser curvature of the stomach, and were deposited in a median volume of 15.3 ml, which resulted in an estimated median absorbed dose of 3.6 Gy (range 0.3–13.8 Gy). No adverse events related to the extrahepatic deposition of the ¹⁶⁶Ho-SD occurred after a median follow-up of 4 months (range 1–12 months).

Conclusion

These results support the safety of 250 MBq ¹⁶⁶Ho-SD in a clinical setting.

Key Points

• A holmium-166 scout dose is safe in a clinical setting.

• Holmium-166 scout dose is a safe alternative for ^99m Tc-MAA for radioembolisation work-up.

• Holmium-166 scout dose potentially has several benefits over ^99m Tc-MAA for radioembolisation work-up.

Rapid volumetric photoacoustic tomographic imaging with a Fabry-Perot ultrasound sensor depicts peripheral arteries and microvascular vasomotor responses to thermal stimuli

Abstract

Purpose

To determine if a new photoacoustic imaging (PAI) system successfully depicts (1) peripheral arteries and (2) microvascular circulatory changes in response to thermal stimuli.

Methods

Following ethical permission, 8 consenting subjects underwent PAI of the dorsalis pedis (DP) artery, and 13 completed PAI of the index fingertip. Finger images were obtained after immersion in warm (30-35 °C) or cold (10-15 °C) water to promote vasodilation or vasoconstriction. The PAI instrument used a Fabry-Perot interferometeric ultrasound sensor and a 30-Hz 750-nm pulsed excitation laser. Volumetric images were acquired through a 14 × 14 × 14-mm volume over 90 s. Images were evaluated subjectively and quantitatively to determine if PAI could depict cold-induced vasoconstriction. The full width at half maximum (FWHM) of resolvable vessels was measured.

Results

Fingertip vessels were visible in all participants, with mean FWHM of 125 μm. Two radiologists used PAI to correctly identify vasoconstricted fingertip capillary beds with 100% accuracy (95% CI 77.2-100.0%, p < 0.001). The number of voxels exhibiting vascular signal was significantly smaller after cold water immersion (cold: 5263 voxels; warm: 363,470 voxels, p < 0.001). The DP artery was visible in 7/8 participants (87.5%).

Conclusion

PAI achieves rapid, volumetric, high-resolution imaging of peripheral limb vessels and the microvasculature and is responsive to vasomotor changes induced by thermal stimuli.

Key points

• Fabry-Perot interferometer-based photoacoustic imaging (PAI) generates volumetric, high-resolution images of the peripheral vasculature.

• The system reliably detects thermally induced peripheral vasoconstriction (100% correct identification rate, p < 0.001).

• Vessels measuring less than 100 μm in diameter can be depicted in vivo.

Differences in myocardial strain between pectus excavatum patients and healthy subjects assessed by cardiac MRI: a pilot study

Abstract

Objectives

To evaluate differences in myocardial strain between pectus excavatum (PE) patients and healthy subjects (HS) assessed by cardiac MRI using the feature-tracking algorithm.

Methods

Cardiac MRI was performed in 14 PE patients and 14 HS (9:5 male to female in each group; age 11–30 years) using a 3T scanner. Post-examination analysis included manual biventricular contouring with volumetry and ejection fraction measurement by two independent radiologists. Dedicated software was used for automated strain assessment.

Results

In five of the PE patients, the right ventricular ejection fraction was slightly impaired (40–44 %). PE patients had a significantly higher left ventricular longitudinal strain (P=0.004), mid (P=0.035) and apical (P=0.001) circumferential strain as well as apical circumferential strain rate (P=0.001), mid right ventricular circumferential strain (P=0.008) and strain rate (P=0.035), and apical right ventricular circumferential strain (P=0.012) and strain rate (P=0.044) than HS. The right ventricular longitudinal strain and strain rate did not differ significantly between PE patients and HS.

Conclusions

Myocardial strain differs significantly between PE patients and HS. Higher myocardial strain in the mid and apical ventricles of PE patients indicates a compensation mechanism to enhance ventricular output against basal sternal compression.

Key Points

• The right ventricle is frequently affected by the pectus excavatum deformity.

• Cardiac MRI revealed differences in myocardial strain in pectus excavatum patients.

• Pectus excavatum patients exhibited higher strain in the mid/apical ventricles.

• A compensation mechanism to enhance ventricular output against sternal compression is possible.

Diffusion-weighted imaging in relation to morphology on dynamic contrast enhancement MRI: the diagnostic value of characterizing non-puerperal mastitis

Abstract

Objectives

To demonstrate the value of diffusion-weighted imaging (DWI) in the characterisation of mastitis lesions.

Methods

Sixty-one non-puerperal patients with pathologically confirmed single benign mastitis lesions underwent preoperative examinations with conventional MRI and axial DWI. Patients were categorised into three groups: (1) periductal mastitis (PDM), (2) granulomatous lobular mastitis (GLM), and (3) infectious abscess (IAB). Apparent diffusion coefficient (ADC) values of each lesion were recorded. A one-way ANOVA with logistic analysis was performed to compare ADC values and other parameters. Discriminative abilities of DWI modalities were compared using the area under the receiver operating characteristic curve (AUC). P < 0.05 was considered statistically significant.

Results

ADC values differed significantly among the three groups (P = 0.003) as well as between PDM and IAB and between PDM and GLM. The distribution of non-mass enhancement on dynamic contrast-enhanced (DCE) MRI differed significantly among the three groups (P = 0.03) but not between any two groups specifically. There were no differences in lesion location, patient age, T₂WI or DWI signal intensity, enhancement type, non-mass internal enhancement, or mass enhancement characteristics among the three groups.

Conclusions

ADC values and the distribution of non-mass enhancement are valuable in classifying mastitis subtypes.

Key points

• Mastitis subtypes exhibit different characteristics on DWI and DCE MRI.

• ADC values are helpful in isolating PDM from other mastitis lesions.

• Distribution of non-mass enhancement also has value in comparing mastitis subtypes.

Late iodine enhancement computed tomography with image subtraction for assessment of myocardial infarction

Abstract

Objective

To evaluate the feasibility of image subtraction in late iodine enhancement CT (LIE-CT) for assessment of myocardial infarction (MI).

Methods

A comprehensive cardiac CT protocol and late gadolinium enhancement MRI (LGE-MRI) was used to assess coronary artery disease in 27 patients. LIE-CT was performed after stress CT perfusion (CTP) and CT angiography. Subtraction LIE-CT was created by subtracting the mask volume of the left ventricle (LV) cavity from the original LIE-CT using CTP dataset. The %MI volume was quantified as the ratio of LIE to entire LV volume, and transmural extent (TME) of LIE was classified as 0%, 1–24%, 25–49%, 50–74% or 75–100%. These results were compared with LGE-MRI using the Spearman rank test, Bland-Altman method and chi-square test.

Results

One hundred twenty-five (29%) of 432 segments were positive on LGE-MRI. Correlation coefficients for original and subtraction LIE-CT to LGE-MRI were 0.79 and 0.85 for %MI volume. Concordances of the 5-point grading scale between original and subtraction LIE-CT with LGE-MRI were 75% and 84% for TME; concordance was significantly improved using the subtraction technique (p <0.05).

Conclusion

Subtraction LIE-CT allowed more accurate assessment of MI extent than the original LIE-CT.

Key Points

• Subtraction LIE-CT allows for accurate assessment of the extent of myocardial infarction.

• Subtraction LIE-CT shows a close correlation with LGE-MRI in %MI volume.

• Subtraction LIE-CT has significantly higher concordance with TME assessment than original LIE-CT.

CT myocardial perfusion imaging: ready for prime time?

Abstract

The detection of functional coronary artery stenosis with coronary CT angiography (CCTA) is suboptimal. Additional CT myocardial perfusion imaging (CT-MPI) may be helpful to identify patients with myocardial ischaemia in whom coronary revascularization therapy would be beneficial. CT-MPI adds incremental diagnostic and prognostic value over obstructive disease on CCTA. It allows for the quantitation of myocardial blood flow and calculation of coronary flow reserve and shows good correlation with ¹⁵O-H₂O positron emission tomography and invasive fractional flow reserve. In addition, patients prefer CCTA/CT-MPI over SPECT, MRI and invasive coronary angiography. CT-MPI is ready for clinical use for detecting myocardial ischaemia caused by obstructive disease. Nevertheless, the clinical utility of CT-MPI to identify ischaemia in patients with non-obstructive/microvascular disease still has to be established.

Key Points

• CT-MPI can improve the positive predictive value of CCTA for lesion-specific ischaemia.

• CT-MPI adds incremental prognostic value over CCTA for major adverse cardiac events.

• CT-MPI correlates with ¹⁵ O-H ₂ O PET.

• CT-MPI/CCTA shows high overall patient satisfaction.

Prediction of survival by texture-based automated quantitative assessment of regional disease patterns on CT in idiopathic pulmonary fibrosis

Abstract

Objectives

To retrospectively investigate whether the baseline extent and 1-year change in regional disease patterns on CT can predict survival of patients with idiopathic pulmonary fibrosis (IPF).

Methods

A total of 144 IPF patients with CT scans at the time of diagnosis and 1 year later were included. The extents of five regional disease patterns were quantified using an in-house texture-based automated system. The fibrosis score was defined as the sum of the extent of honeycombing and reticular opacity. The Cox proportional hazard model was used to determine the independent predictors of survival.

Results

A total of 106 patients (73.6%) died during the follow-up period. Univariate analysis revealed that age, baseline forced vital capacity, total lung capacity, diffusing capacity of the lung for carbon monoxide, six-minute walk distance, desaturation_, honeycombing, reticular opacity, fibrosis score, and interval changes in honeycombing and fibrosis score were significantly associated with survival. Multivariate analysis revealed that age, desaturation, fibrosis score and interval change in fibrosis score were significant independent predictors of survival (p = 0.003, <0.001, 0.001 and <0.001). The C-index for the developed model was 0.768.

Conclusion

Texture-based, automated CT quantification of fibrosis can be used as an independent predictor of survival in IPF patients.

Key Points

• Automated quantified fibrosis on CT was a significant predictor of survival.

• Automated quantified interval change in fibrosis on CT was an independent predictor.

• The predictive model showed comparable discriminative power with a C-index of 0.768.

• Automated CT quantification can be considered to evaluate prognosis in routine practice.

Visible Light Degradation of Naproxen by Enhanced Photocatalytic Activity of NiO and NiS, Scavenger Study and Focus on Catalyst Support and Magnetization

Abstract

This research was aimed to prepare a magnetically photocatalyst enabling to degrade pharmaceutical wastewater and detoxification of pollutant such as naproxen, by visible light irradiation. The nano-sized NiS and NiO photocatalysts exhibit higher reactivity than their micro-sized counterparts but separation of the used photocatalyst from the degradation solution is hard and imperfect. To remove this difficulty, magnetic polypyrrole core-shell (Fe₃O₄@PPY) was synthesized and employed as catalyst support. The magnetization property of the synthesized photocatalysts measured by VSM technique indicated that the photocatalysts were sufficiently magnetized to be readily separated from degradation solution by use of external magnetic field. The DRS study showed that the band gap of the photocatalysts shifted to lower energy after immobilization on the support materials leading to higher degradation efficiency. The optimal efficiency was obtained with the catalysts loaded with 50% of NiO and 50% of NiS. The augmenting effect of H₂O₂ and the inhibition influence of some organic and inorganic compounds on the degradation process were studied. Regeneration of the used photocatalyst was performed by heat treatment and the catalyst treated at 400°C retained most of its initial capacity. The degradation capacity was kinetically fast and the equilibrium was attained within 30 min.

This article is protected by copyright. All rights reserved.

Intravenous Immunoglobulins for Rituximab-resistant Mucous Membrane Pemphigoid

Abstract

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease that is notoriously difficult to treat. Rituximab (anti-CD20) and high-dose intravenous immunoglobulins (IVIG) have both been reported to be effective in refractory MMP.^1,2 Furthermore, treatment regimens based on the concomitant use of rituximab and IVIG in ocular MMP have been published.^3,4In the current report, we present 5 patients with treatment-resistant MMP who failed to respond to rituximab but rapidly achieved remission on IVIG.

This article is protected by copyright. All rights reserved.

Potentially useful elements (Al, Fe, Ga, Ge, U) in coal gangue: a case study in Weibei coal mining area, Shaanxi Province, northwestern China

Abstract

Coal gangue has become one of the largest industrial solid waste in China, but it is also a kind of reserve resources. Representative coal gangue samples from different coal mines (mainly in Permo-Carboniferous and Jurassic) in Weibei area in Shaanxi Province are collected, and potentially useful elements (Al, Fe, Ga, Ge, U) in coal gangue are analyzed. The results show that the reserves of Al and Fe in Chinese coal gangue are 262 million tons and 196 million tons, respectively, based on the geometric mean values of Al₂O₃ (15.18%, weight percent) and Fe₂O₃ (6.24%, weight percent). Meanwhile, the crude reserves estimation of Ga, Ge, and U are 55,282, 6867, and 32,981 tons, respectively, based on the weighted mean contents of Ga, Ge, and U in coal gangue at 17.55, 2.18, and 10.47 mg/kg, respectively. Furthermore, Ga and Al contents in quite a large number of coal gangue mines exceed the cutoff value, which has a prospect of development and utilization from coal gangue. The policy implications from this study may include that (1) recycling of useful elements in Chinese coal gangue should be treated as an integral part of sustainable development with professional legislations and (2) establishing a basic database of coal gangue and authoritative system with relevant departments for solid waste management may effectively improve comprehensive utilization of coal gangue in the future.

Use of an Autologous Bony Crossbar Graft for the Management of Caudal Septal Deviation: Our Experience in Twenty-Two Patients

Abstract

Septoplasty for a deviated caudal septum is a technique challenging surgery. The two goals of surgery are adequate correction of the deviated septum and maintenance of the nasal tip structural support.

Use of an autologous bony crossbar graft to correct a deviate caudal septum offers the following advantages. No difficult drilling or suturing procedure is needed because the graft was kept in place by the elastic properties of the buttonhole cartilage incisions. Second, a simple endonasal approach is sufficient to expose the entire surgical field. Third, the small strip-shaped bone graft can help preserve the natural mobility of nose.

Bone resorption and subsequent recurrence is one concern of this technique, however, previous reports have shown the reliability and persistence of bone graft in caudal septoplasty.

Correction of a deviated caudal septum with an autologous bony crossbar graft has the potential to be a useful option for the management of caudal septal deviation.

This article is protected by copyright. All rights reserved.

Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization

Abstract

Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency. Endogenous capillary regression was characterized by a progressive thinning and remodeling of angiogenic capillaries and inflammatory cell retreat in vivo in the rat cornea. By whole-genome longitudinal microarray analysis, early suppression of VEGF ligand-receptor signaling and inflammatory pathways preceded an unexpected later-phase preferential activation of LXR/RXR, PPARα/RXRα and STAT3 canonical pathways, with a concurrent attenuation of LPS/IL-1 inhibition of RXR function and Wnt/β-catenin signaling pathways. Potent downstream inflammatory cytokines such as Cxcl5, IL-1β, IL-6 and Ccl2 were concomitantly downregulated during the remodeling phase. Upstream regulators of the inflammatory pathways included Socs3, Sparc and ApoE. A complex and coordinated time-dependent interplay between pro- and anti-inflammatory signaling pathways highlights a potential anti-inflammatory role of LXR/RXR, PPARα/RXRα and STAT3 signaling pathways in resolving inflammatory corneal angiogenesis.

Pharmaceuticals and detergents in hospital and urban wastewater: comparative monitoring, treatment, and assessment of impacts

Healing potential of Adiantum capillus-veneris L. plant extract on bisphenol A-induced hepatic toxicity in male albino rats

Abstract

Bisphenol A (BPA) is a widely used environmental pollutant in the production of plastics but causes hepatotoxicity in mammals. In the present study, we studied the BPA-induced oxidative stress in rats and ameliorative potential of Adiantum capillus-veneris L. plant. It was concluded that the BPA can reduce the body and liver weight, increase in biochemical levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total bilirubin, and disturb the normal hepatic physiology, histology, and metabolism. Additionally, liver histology shows hepatic necrosis, congestion, and vacuolization in exposed individuals. In contrast, simultaneous exposure of A. capillus-veneris and BPA showed declining trend in serum biomarker levels and normal histopathological structures. We conclude that the A. capillus-veneris plant is antioxidant in nature and can reduce the BPA-induced toxicity. These findings are very helpful to understand the BPA-induced hepatic toxicity and ameliorative potential of A. capillus-veneris plant and are of great importance in risk assessment of xenobiotics.

Removal of MCs by Bi 2 O 2 CO 3 : adsorption and the potential of photocatalytic degradation

Abstract

Microcystins (MCs) is a kind of hepatotoxin, which is the secondary metabolite of cyanobacteria. Bi₂O₂CO₃ (BOC) is a kind of cheap and nontoxic semiconductor material. BOC was synthetized by solvothermal method and then microcystin-LR (MC-LR) and microcystin-RR (MC-RR) were removed by BOC, through adsorption and photocatalytic degradation. When the dosage of BOC is 6 g/L, the MC-LR and MC-RR in the natural water sample can be completely adsorbed in 30 min and then after 12 h irradiation, MC-LR and MC-RR were photocatalytically degraded by BOC.

Comparing the adsorption mechanism of Cd by rice straw pristine and KOH-modified biochar

Abstract

Biochar was considered as an effective and novel sorbent for cadmium (Cd) adsorption from aqueous solution. In this study, the adsorption isotherm investigations were conducted to examine the effect of biochar produced via pyrolysis from rice straw on removing aqueous Cd before and after modification by 2 M KOH solution. Langmuir and Freundlich adsorption isotherms can preferably describe the adsorption process. Results showed that the highest adsorption capacity of pristine rice straw biochar was 12.17 mg g⁻¹. The chemically modified rice straw biochar showed greater Cd adsorption capacity of 41.9 mg g⁻¹, which was more than three times that of pristine biochar. Increase of surface area and changes of porous structure, especially the functional groups on the surface of modified biochar, were the major contributors to its more efficient adsorption of Cd. The possible mechanisms for Cd adsorption by biochar mainly involve (1) surface precipitation by forming insoluble Cd compounds in alkaline condition and (2) ion exchange for Cd with exchangeable cations in the biochar, such as calcium ions, which were confirmed by FTIR, XRD, SEM, and zeta potential determination.

Achieving an extraordinary high organic and hydraulic loadings with good performance via an alternative operation strategy in a multi-stage constructed wetland system

Abstract

In this study, a high organic loading rate of 58–146 g BOD₅/m² day with a hydraulic loading rate (HLR) of 1.63 m³/m² day and retention time (RT) of 16 h was achieved to maximize the treatment capacity of a four-stage alum sludge-based constructed wetland (CW) system. An alternative operation strategy, i.e., the first stage anaerobic up-flow and the remaining stage tidal flow with effluent recirculation, was investigated to achieve the goal with good treatment performance of 82% COD, 91% BOD₅, 92% SS, 94% NH₄-N, and 82% TN removal. Two kinetic models, i.e., first-order model and Monod plus continuous stirred-tank reactor (CSTR) flow model, were employed for predicting the removal dynamics. The results showed that the tidal flow strategy enhances oxygen transport and diffusion, thus improving reduction of organics and NH₄-N. Effluent recirculation could further increase elimination of organics by extending the interaction time and also benefit the denitrification process. In addition, denitrification could be further enhanced by anaerobic up-flow in the first stage.

Characteristics and mechanisms of cadmium adsorption from aqueous solution using lotus seedpod-derived biochar at two pyrolytic temperatures

Abstract

Herein, biochar derived from lotus seedpods, as an effective adsorbent, was prepared by pyrolysis method at 300 and 600 °C. The physicochemical characteristics and cadmium adsorption properties were studied systematically by batch adsorption experiments, FTIR, SEM–EDX, XRD, and XPS. Cd adsorption onto lotus seedpod-derived biochar was better fitted using Freundlich isotherm and pseudo-second-order model. Adsorption capacity of biochar produced at 300 and 600 °C was 31.69 and 51.18 mg g⁻¹, respectively. The Cd adsorption capacity of biochar was related to its characteristics determined by pyrolysis temperature, including carbonization, surface area, surface morphology, and surface functional groups. Cd adsorption on lotus seedpod-derived biochar revealed that adsorption was controlled by multiple mechanisms including surface complexation, ion exchange, surface precipitation, and Cd–π interaction. This study showed that lotus seedpod-derived biochar is an effective and environmentally friendly adsorbent for water treatment.

Evaluation of vulnerable PM 2.5 -exposure individuals: a repeated-measure study in an elderly population

Abstract

Numerous studies have shown that elderly people are susceptible to high-level particles with aerodynamic diameter ≤ 2.5 μm (PM_2.5) exposure. However, not all elderly people exposed to PM_2.5 suffer from diseases. In this study, we aim to establish a method to predict the vulnerable PM_2.5-exposure individuals among elderly population. Fourteen elderly people were recruited from May 8 to July 4, 2016, in Nanjing, China. Ten physiological indicators were repeatedly measured for 15 times. Liner mixed-effects model, principal component analysis (PCA), and PM_2.5 lag score were used to estimate the effects of PM_2.5 on blood pressure, pulse, and lung function. As a result, each quartile increase of ambient PM_2.5 was significantly associated with increased pulse (P < 0.05 for lag0, 1, 4, 0–1, 0–2, 0–3, and 0–5 days), decreased blood pressure (P < 0.05 for lag4 and 0–3 days), and decreased lung function (P < 0.05 for lag0, 1, 0–1, and 0–2 days) among the 14 elderly people. In terms of pulse or lung function, three elderly people were considered as vulnerable PM_2.5-exposure individuals. No vulnerable individual was found for blood pressure. Blood pressure, pulse, and lung function could be affected by high-level PM_2.5 exposure in elderly people. This method for screening three elderly people may provide a new insight on identifying the vulnerable PM_2.5-exposure individuals.

Wet work and healthcare workers: use of hand disinfectants not associated with self-reported eczema

Linked Article: Hamnerius et al. Br J Dermatol 2018; 178:452–461.

Image Gallery: Pigmented mammary Paget disease: a rare clinicopathological variant mimicking melanoma

Image Gallery: Periumbilical purpura: a dermatological clue for disseminated strongyloidiasis

The time healthcare workers wear disposable gloves daily is associated with hand eczema in a dose-dependent fashion

Linked Article: Hamnerius et al. Br J Dermatol 2018; 178:452–461.

IV阶段一对一随机对照试验就治疗面部或头皮光化性角化病比较了巨大戟醇甲基丁烯酸酯0.015%凝胶与双氯芬酸钠3%凝胶

Summary

这项在德国、西班牙和英国开展的研究比较了两种凝胶疗法对治疗面部或头皮光化性角化病(AK)的有效性。AK是指皮肤表面出现小型、穗状、有鳞片或类似砂纸状的晒伤区域。有很小的比例会发展成皮肤鳞状细胞癌。当整个头皮等大面积区域受到多处AK影响时,建议在皮肤表面擦拭膏药或凝胶。研究人员在502名患者中比较了巨大戟醇甲基丁烯酸酯0.015%凝胶(IngMeb)和双氯芬酸钠3%凝胶(DS),这些患者大部分是男性且几乎都是白皮肤。IngMeb每天擦一次,连续擦三天,而DS则每天擦两次,连续擦90天(一般建议用量)。使用IngMeb的患者在第八周时如果有新增或剩余的AK,则可进行第二个三天周期,这意味着,此群体中有一半以上的患者使用了两次IngMeb。在第17周(DS疗程完成约4周后,IngMeb第二疗程(如使用)完成9周后,以及IngMeb第一(或唯一)疗程完成17周后)观察治疗区域时发现,IngMeb群体中完全清除AK的患者人数几乎是DS群体的两倍。在IngMeb群体中,即便AK并未完全消失,但更多的AK已部分清除,并且AK总数也显著下降。副作用也相当温和或适中,最常见的是擦拭凝胶的区域出现红斑。

Beyond country-specific incidence and mortality: the global burden of melanoma

Laser treatment of congenital melanocytic naevi: a systematic review

Summary

Most people have a few brown spots on their skin known as melanocytic naevi or moles. Moles are harmless but can occasionally transform into a potentially lethal tumour called malignant melanoma. Congenital melanocytic nevi (CMN) are ones that are present at birth or develop in the first few weeks of life. Congenital nevi, in particular those that are large in size and on visible areas of skin, can be a great burden when people are unhappy with how they look. Moreover, there is an increased risk of developing malignant melanoma in patients with CMN, especially in the larger CMN. The lifetime risk of malignant melanoma in patients with CMN is thought to be about 0.7% to 2.9%. Surgically removing (excision of) the CMN to decrease the risk of melanoma has been a common treatment, however, this has not been proven to reduce the risk of melanoma. CMN can be too large to completely remove with excision, and excision can cause scarring. Therefore, in more recent years, other treatments have been explored, including the use of lasers to remove the CMN. This option is controversial, mainly because of the lack of evidence on efficacy, and safety concerns. Some state that lasers may reduce the risk of malignancy by decreasing the melanocytic mass while others are concerned about the potential cancer-causing risk of laser damage. The objective of this study from the Netherlands was to review the efficacy and safety of different laser types used for CMN. The researchers found that a great variety of laser devices and combinations of lasers have been used for treatment of congenital nevi. There is very low quality evidence that laser therapy in CMN is effective and safe in the short term, however there were high incidences of scarring, repigmentation (colour coming back) and complications. More high quality studies are required in order to really answer the question regarding efficacy and safety of laser treatment in CMN.

Impact of dupilumab on health-related quality of life in patients with atopic dermatitis

Linked Article: Tsianakas et al. Br J Dermatol 2018; 178:406–414.

Phase IV head-to-head randomized controlled trial comparing ingenol mebutate 0·015% gel with diclofenac sodium 3% gel for the treatment of actinic keratosis on the face or scalp

Summary

This study from Germany, Spain and the U.K. compared the effectiveness of two gel treatments for actinic keratosis (AK) on the face or scalp. An AK is a small, spiky, scaly or sandpaper-like area of sun damage on the skin surface. A very small proportion progress to squamous cell skin cancer. Creams or gels rubbed into the skin are recommended when a large area such as the entire scalp is affected by multiple AKs. Ingenol mebutate 0·015% gel (IngMeb) and diclofenac sodium 3% gel (DS) were compared in 502 patients, mostly male and almost all white-skinned. IngMeb was applied once daily for three consecutive days and DS twice daily for 90 days (the normal recommendations for use). Patients using IngMeb were allowed to apply it for a second three-day period if they had new or residual AKs at week 8, which meant that more than half this group used IngMeb twice. Looking at the treated area at week 17 - approximately four weeks after finishing the course of DS, nine weeks after the second course of IngMeb (if used), and 17 weeks after the first (or only) course of IngMeb - almost twice as many patients in the IngMeb group were completely clear of AKs than in the DS group. Even if they had not disappeared completely, more AKs had partially cleared up, and the total number had decreased significantly more, in the IngMeb group. Side effects were mild or moderate, most commonly redness where either gel was applied.

Safety, efficacy, and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis

Summary

Psoriasis, a common disease affecting 2-3% of the world's population, may in moderate-to-severe cases require systemic treatment with biological drugs (biologics). Treatment is usually permanent, but these drugs may loose their effect over time. When the patent for the original (originator) drug expires, other companies can produce a biosimilar, i.e. a drug that is very similar (but not completely identical, since biologics are derived from living human genes) to the originator. This Danish study compared safety, efficacy, and drug survival (i.e. how long patients stay on therapy) for five biologics: adalimumab, etanercept, infliximab, secukinumab, and ustekinumab. The study also compared the originator versions of etanercept and infliximab to their biosimilar versions. Data was examined from 3495 treatment series in 2161 patients. Drug survival was significantly higher for ustekinumab than for the other drugs. Secukinumab had the shortest survival and thereby also the highest risk of discontinuation of therapy. Adverse events also occurred the most frequently with secukinumab. Switching from an originator to a biosimilar version did not significantly affect drug survival. Among patients that obtained complete skin clearance, this occurred more rapidly for those treated with secukinumab as their first-ever biologic. Over a 10-year period, discontinuation of therapy occurred in 45·7% (adalimumab), 64·9% (etanercept), and 54·4% (infliximab) of patients. Ustekinumab and secukinumab have only been available for 8 and 2 years, respectively, during which time 30·3% and 28·8% of patients discontinued these therapies, respectively. Over time, response to therapy was generally highest for ustekinumab, followed by adalimumab.

Do perioperative antibiotics reduce the risk of surgical-site infections following excision of ulcerated skin cancers? A Critically Appraised Topic

Summary

Skin cancer is the commonest type of cancer in the United Kingdom and the numbers are increasing worldwide. Most skin cancers are treated with surgery to remove the cancer from the skin. The risk of having a wound infection after skin surgery is less than 5%. Current evidence suggests that this risk is increased if there is a break on the surface of the skin cancer – called ulceration. At present, there is no guidance in the U.K. for using antibiotics after skin surgery to potentially reduce the risk of infection. This report aimed to review all the research evidence available to help doctors decide if prescribing antibiotics to patients having skin cancers removed by surgery, reduces the chances of wound infection after their skin surgery. A total of 1018 scientific articles were identified in the English Language. The team identified 13 trials as high quality (called randomised controlled trials) where different types of antibiotics were used to see if they reduced infection rates after skin surgery. These included antibiotics applied on the wound surface, antibiotics ingested by mouth, antibiotics given by injection into the muscle or directly into the bloodstream. The research team concluded that based on this review there is not enough evidence to show that taking any form of antibiotic reduces the chances of wound infections following skin cancer surgery. The authors recommend that in the future, researchers should perform a well-designed clinical trial to answer this question, as this may help prevent some people receiving antibiotics after skin surgery when it may not be needed.

Time, Psoriasis Area and Severity Index and Dermatology Life Quality Index of patients with psoriasis who drop out of clinical trials on etanercept because of lack of efficacy: a pooled analysis from 10 clinical trials

Summary

Psoriasis is a common skin disease, and clinical trials are a way of measuring how effective different treatments for psoriasis are. During such trials, researchers generally use specific methods for measuring improvements in patients' symptoms and quality of life. These include the Psoriasis Area Severity Index (PASI, for which the lower the score, the worse the severity of the disease), the Physician Global Assessment (PGA) and the Dermatology Life Quality Index (DLQI). If a treatment has not become effective by a certain time point, it may increase the likelihood of patients being dissatisfied and leaving a clinical study. In this study, the researchers looked at clinical trials involving a drug for psoriasis called etanercept, to learn more about the number of patients who drop out due to 'lack of efficacy', when they most commonly do so, and how this relates to their PASI and DLQI. Of 6119 patients taking part in the studies looked at, 128 dropped out due to 'lack of efficacy'. The highest increase of patients dropping out happened between Day 75 and 85. The lowest PASI score of patients dropping out was 6.3 within 120 days. Dropouts who achieved ≥ PASI 75 were rare. The authors conclude that around Day 80 is the critical time when many patients might have lost their willingness to wait for their treatment with etanercept to show a better effect. Most of the patients dropping out had experienced little or no improvement, or worsening of their psoriasis.

Establishing and prioritizing research questions for the prevention, diagnosis and treatment of hair loss (excluding alopecia areata): the Hair Loss Priority Setting Partnership

Summary

Hair and scalp problems are common. Various conditions can result in hair loss and may present as increased hair shedding, hair thinning or patchy to complete hair loss. In some conditions the hair may regrow, in others the alopecia (hair loss) is permanent. Frequently overlooked is the psychological impact of hair loss on an individual. The visible nature of hair loss and fear of progression may lead to low self-esteem, anxiety and depression. Unfortunately, there is a lot of uncertainty around the most effective treatments for these disorders. This study, funded by the charity Alopecia UK, aimed to identify uncertainties in hair loss management, prevention, diagnosis and treatment that are important both to people with hair loss and to healthcare professionals. This was done by creating a hair loss 'priority setting partnership' (PSP) between patients, their carers and relatives, and healthcare professionals, to identify the most important uncertainties in hair loss. This study presents the top 10 research priorities for hair loss (excluding alopecia areata) to guide researchers and funding bodies to support studies important both to patients and clinicians.

Prognostic features for acral lentiginous melanoma

Linked Article: Teramoto et al. Br J Dermatol 2018; 178:443–451.

Development of an international core outcome set for peripheral vascular malformations: the OVAMA project

Summary

Peripheral vascular malformations (VMs) are birthmarks or swellings caused by the faulty development of blood vessels in the embryo. Different types are classified according to whether the components are mainly lymph vessels (LMs), veins (VMs) or combined arteries and veins (AVMs). It is hard to assess the various medical and surgical treatments available because there are no agreed methods for measuring the outcome. This international group carried out an on-line survey of health professionals and patients to decide which factors would be important to record in future clinical trials. First they listed aspects of the condition and its treatment in 36 domains covering 97 specific items. Then they asked 167 doctors and 134 patients and parents of patients to score the domains from 0 (not important) to 4 (crucial). The options were progressively narrowed down over 3 rounds of the survey and a consensus conference. The finally agreed "core outcome set" covered: scan results, doctors' assessment of problems caused by pressure from the VM, patient or parent's assessments of symptoms, pain and quality of life, and their satisfaction with the treatment, outcome and any adverse effects. Additional specific factors for LMs were infections and lymphatic fluid leakage, for VMs thrombosis and for AVMs heart function and bleeding. Recurrence after treatment and appearance were also recommended for inclusion. This international consensus establishes what factors should be assessed in future trials of treatments for vascular malformations, but further work is required to decide exactly how they should be measured and reported.

British Society for Paediatric Dermatology 32nd Annual Meeting, Aston Conference Centre, Birmingham, 10–11 November 2017

抗生素是否有助于降低治疗皮肤癌的皮肤外科手术后的创面感染风险?

Summary

皮肤癌是英国最常见的癌症之一,并且全球范围内的发病人数还在不断增加。大部分皮肤癌都会通过外科手术去除皮肤中的癌细胞。而皮肤外科手术后发生创面感染的风险低于5%。目前的证据显示,如果皮肤癌病灶表面出现裂口(称为溃疡),则发生创面感染的风险就会增加。目前,英国尚未制定在皮肤外科手术后使用抗生素以潜在降低感染风险的指导。此报告旨在审查所有可用的研究证据,以帮助医生决定是否要为接受皮肤癌外科手术的患者开具抗生素处方,以减少术后发生创面感染的几率。该团队共找出1018份英文科学文章,并发现了13项高质量试验(称为随机对照试验),这些试验使用了多种不同类型的抗生素,以确定它们是否能降低皮肤外科手术后的感染率。其中包括创面抗生素、口服抗生素、肌肉注射抗生素或血液注射抗生素。该研究团队总结道,基于上述审查,尚未有充足的证据能够证明采用任何形式的抗生素能够降低皮肤癌外科手术后发生创面感染的几率。作者建议,研究人员将来可以通过一项精心设计的临床试验来回答此问题,因为这样可能有助于防止一些患者在不必要的情况下,在皮肤外科手术后接受抗生素治疗。

Beyond Second-Line Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review

Abstract

Background

The optimal chemotherapeutic regimen for use beyond the second-line for patients with metastatic colorectal cancer (mCRC) remains unclear.

Materials and methods

We systematically searched the Cochrane Database of Systematic Reviews, EMBASE and Medline for records published between January 2002 and May 2017, and cancer congress databases for records published between January 2014 and June 2017. Eligible studies evaluated the efficacy, safety and patient-reported outcomes of monotherapies or combination therapies at any dose and number of treatment cycles for use beyond the second line in patients with mCRC. Studies were assessed for design and quality, and a qualitative data synthesis was conducted to understand the impact of treatment on overall survival (OS) and other relevant cancer-related outcomes.

Results

The search yielded 938 references of which 68 were included for qualitative synthesis. There was limited evidence to support rechallenge with chemotherapy, targeted therapy or both. Compared with placebo, an OS benefit for trifluridine/tipiracil (also known as TAS-102) or regorafenib has been shown for patients previously treated with conventional chemotherapy and targeted therapy. There was no evidence to suggest a difference in efficacy between these treatments. Patient choice and quality of life at this stage of treatment should also be considered when choosing an appropriate therapy.

Conclusions

These findings support the introduction of an approved agent such as trifluridine/tipiracil or regorafenib beyond the second-line before any rechallenge in patients with mCRC who have failed second-line treatment.

Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers

Abstract

Background

Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed.

Patients and methods

We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment.

Results

We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity.

Conclusions

A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer.

Short description

Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage.

Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane

Abstract

Background

Capecitabine is an approved standard therapy for anthracycline- and taxane-pretreated locally advanced or metastatic breast cancer (BC). Vinflunine has demonstrated single-agent activity in phase II studies in this setting, and activity and tolerability when combined with capecitabine. We compared the combination of vinflunine plus capecitabine (VC) with single-agent capecitabine.

Patients and methods

Patients with locally recurrent/metastatic BC previously treated or resistant to an anthracycline and resistant to taxane therapy were randomly assigned to either vinflunine (280 mg/m², day 1) plus oral capecitabine (825 mg/m² twice daily [bid], days 1–14) every 3 weeks (q3w) or single-agent oral capecitabine (1250 mg/m² bid, days 1–14) q3w. The primary end point was progression-free survival (PFS) assessed by an independent review committee. The study had 90% power to detect a 30% improvement in PFS.

Results

Overall, 770 patients were randomised. PFS was significantly longer with VC than with capecitabine alone (hazard ratio 0.84, 95% confidence interval [CI] 0.71–0.99; log-rank P = 0.043; median 5.6 versus 4.3 months, respectively). Median overall survival was 13.9 versus 11.7 months with VC versus capecitabine alone, respectively (hazard ratio 0.98, 95% CI 0.83–1.15; log-rank P = 0.77). No difference in quality of life was observed between the two treatment arms. The most common adverse events in the combination arm were haematological and gastrointestinal. Grade 4 neutropenia was more frequent with VC (12% versus 1% with capecitabine alone); febrile neutropenia occurred in 2% versus 0.5%, respectively. Hand-foot syndrome was less frequent with VC (grade 3: 4% versus 19% for capecitabine alone). Peripheral neuropathy was uncommon in both arms (grade 3: 1% versus 0.3%).

Conclusions

Vinflunine combined with capecitabine demonstrated a modest improvement in PFS and an acceptable safety profile compared with capecitabine alone in patients with anthracycline- and taxane-pretreated locally recurrent/metastatic breast cancer.

ClinicalTrials.gov

NCT01095003

Congenital Abnormalities of the Male Reproductive System and Risk of Autism Spectrum Disorders

Abstract

Androgens have an extensive influence on brain development in regions of the brain that are relevant for autism spectrum disorder (ASD), yet their etiological involvement remains unclear. Hypospadias (abnormal positioning of the urethral opening) and cryptorchidism (undescended testes) are 2 relatively common male birth defects that are strongly associated with prenatal androgen deficiencies. Having either disorder is a proxy indicator of atypical gestational androgen exposure, yet the association between these disorders and autism has not been extensively studied. We analyzed male singleton live births (n = 224,598) occurring from January 1, 1999, through December 31, 2013, in a large Israeli health-care organization. Boys with autism, cryptorchidism, and hypospadias were identified via International Classification of Diseases, Ninth Revision, codes, with further verification of autism case status by review of medical records. In multivariable-adjusted analyses, the odds ratio for ASD among boys with either condition was 1.62 (95% confidence interval (CI): 1.44, 1.82). The odds ratio for boys with cryptorchidism only was 1.55 (95% CI: 1.34, 1.78), and that for boys with hypospadias only was 1.65 (95% CI: 1.38, 1.98). ASD risk was not elevated among unaffected brothers of hypospadias or cryptorchidism cases, despite familial aggregation of all 3 conditions, providing some indication for the possibility of pregnancy-specific risk factors driving the observed associations. Results suggest that in-utero hypoandrogenicity could play a role in ASD etiology.

Invited Commentary: Male Reproductive System Congenital Malformations and the Risk of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a prevalent developmental disorder. Studies indicate that while ASD etiology has a genetic component, the risk is polygenic, with gene-environment interactions being likely. The prenatal period is a critical exposure window for nongenetic risk factors. Previous studies have found positive associations between congenital malformations (all types) and ASD; a few also found specific associations between genitourinary system malformations and ASD; and one study found an association between hypospadias and ASD. In the accompanying article, Rotem et al. (Am J Epidemiol. 2018;000(00):000–000) describe how they conducted a comprehensive analysis focusing on the shared risk of ASD with hypospadias or cryptorchidism, using existing data from a large Israeli health services system, which afforded several advantages because of the large sample size and low attrition of the patient population. The authors conducted a careful analysis, including sensitivity analyses, to account for risk factor and case misclassifications that might have occurred had they relied solely on preexisting diagnostic codes to define exposures and outcome. They observed positive associations between both hypospadias and cryptorchidism and ASD that were independent of numerous sociodemographic and pregnancy health factors. This study advances our understanding of ASD etiology and illustrates how existing data might be used to assess some ASD risk factors.

Transformation of heavy metal fractionation under changing environments: a case study of a drainage system in an e-waste dismantling community

Abstract

The change in environmental conditions during the transportation of contaminated soil and sediment was expected to affect the transformation of heavy metal fractionation. This study disclosed the serious contamination of copper (Cu), lead (Pb), and zinc (Zn) in the sewer sediment of an e-waste dismantling community in Thailand which may be caused by flushed contaminated soil and e-waste fragments. Two environmental conditions were simulated to observe the transformation of heavy metal fractionation. The anoxic sewer condition was induced using high substrate and sulfate in a closed container. The aeration of anoxic contaminated sediment was applied to simulate the transformation to an oxidative environment. The BCR sequential extraction was applied for heavy metal fractionation in this study. The study results exhibited that when heavy metal contaminated soil was transferred into this induced anoxic condition, fractionation was redistributed based on the chemical change of system that tends to be associated into F3 (oxidizable fraction) > F2 (reducible fraction) > F1 (acid soluble/exchangeable fraction). Cu exhibited the outstanding capability association to F3. The iron sulfide was not observed as usual due to its lower capability than Cu, Pb, and Zn. When contaminated sediment was transported to a more oxidative environment, the heavy metals fractionation would be redistributed again among those new environment media. It is noteworthy that F3 of Cu was stable even in oxic conditions. F2 of Fe was not developed by this oxic condition, possibly because its dehydration process was limited. The redistribution under an oxic environment became F1 > F2 > F3 indicating their more available form. This transformation was imperative and should be taken into account in heavy metal contaminated site management and control.

Green synthesis of silver nanoparticles using Piper nigrum : tissue-specific bioaccumulation, histopathology, and oxidative stress responses in Indian major carp Labeo rohita

Abstract

The aim of the present investigation is to assess the sublethal toxicity of biologically synthesized silver nanoparticles (Ag NPs) in Indian major carp Labeo rohita. Ag NPs used in the study were synthesized by using AgNO₃ with aqueous leaf extract of Piper nigrum. Median lethal concentration (LC₅₀) of synthesized Ag NPs was determined for 96 h (25 μg/L); 2.5 μg/L (1/10th LC₅₀) and 5 μg/L (1/5th LC₅₀) were taken as sublethal concentrations to evaluate the toxicity for 35 days. The results of the TEM, SEM, and EDX analyses revealed that Ag NPs were considerably accumulated in the gill, liver, and kidney of fish at both concentrations (2.5 and 5 μg/L). Consequently, the activity of the antioxidant enzymes, SOD and CAT, was significantly (P < 0.05) decreased in the gill, liver, and kidney when compared to the control group during the study period. However, lipid peroxidase (LPO) activity in the gill, liver, and kidney was significantly (P < 0.05) increased, and the result concluded a possible sign of free radical-induced oxidative stress in Ag NP-exposed fish than the sham-exposed individuals. The histopathological study also confirmed the alterations such as degeneration of lamella, lifting of lamellar epithelium, hepatic necrosis, pyknotic nuclei, increased intracellular space, and shrinkage of glomerulus elicited by Ag NPs in the gill, liver, and kidney of Labeo rohita with two different concentrations. The findings of the present study revealed that green synthesis of Ag NPs from Piper nigrum at sublethal concentrations leads to accumulation of Ag, oxidative stress, and histopathological alterations in the target organs of the fish, Labeo rohita.

The wave-function as a multi-field

Abstract

It is generally argued that if the wave-function in the de Broglie–Bohm theory is a physical field, it must be a field in configuration space. Nevertheless, it is possible to interpret the wave-function as a multi-field in three-dimensional space. This approach hasn't received the attention yet it really deserves. The aim of this paper is threefold: first, we show that the wave-function is naturally and straightforwardly construed as a multi-field; second, we show why this interpretation is superior to other interpretations discussed in the literature; third, we clarify common misconceptions.

Editorial: Thematic series on scholarly communications in the digital age

Characterization of a novel MIIA domain-containing protein (MdcE) in Bradyrhizobium spp.

Abstract

Several genes coding for proteins with metal ion-inducible autocleavage (MIIA) domains were identified in type III secretion system tts gene clusters from draft genomes of recently isolated Bradyrhizobium spp. MIIA domains have been first described in the effectors NopE1 and NopE2 of Bradyrhizobium diazoefficiens USDA 110. All identified genes are preceded by tts box promoter motifs. The identified proteins contain one or two MIIA domains. A phylogenetic analysis of 35 MIIA domain sequences from 16 Bradyrhizobium strains revealed four groups. The protein from Bradyrhizobium sp. LmjC strain contains a single MIIA domain and was designated MdcE (MdcE_LmjC). It was expressed as a fusion to maltose-binding protein (MalE) in Escherichia coli and subsequently purified by affinity chromatography. Recombinant MalE-MdcE_LmjC-Strep protein exhibited autocleavage in the presence of Ca²⁺, Cu²⁺, Cd²⁺ and Mn²⁺, but not in the presence of Mg²⁺, Ni²⁺ or Co²⁺. Site-directed mutagenesis at the predicted cleavage site abolished autocleavage activity of MdcE_LmjC. An LmjC mdcE⁻ mutant was impaired in the ability to nodulate Lupinus angustifolius and Macroptilium atropurpureum.

Transcriptional and environmental control of bacterial denitrification and N2O emissions

Abstract

In oxygen-limited environments, denitrifying bacteria can switch from oxygen-dependent respiration to nitrate (NO₃⁻) respiration in which the NO₃⁻ is sequentially reduced via nitrite (NO₂⁻), nitric oxide (NO) and nitrous oxide (N₂O) to dinitrogen (N₂). However, atmospheric N₂O continues to rise, a significant proportion of which is microbial in origin. This implies that the enzyme responsible for N₂O reduction, nitrous oxide reductase (NosZ), does not always carry out the final step of denitrification either efficiently or in synchrony with the rest of the pathway. Despite a solid understanding of the biochemistry underpinning denitrification, there is a relatively poor understanding of how environmental signals and respective transcriptional regulators control expression of the denitrification apparatus. This minireview describes the current picture for transcriptional regulation of denitrification in the model bacterium, Paracoccus denitrificans, highlighting differences in other denitrifying bacteria where appropriate, as well as gaps in our understanding. Alongside this, the emerging role of small regulatory RNAs in regulation of denitrification is discussed. We conclude by speculating how this information, aside from providing a better understanding of the denitrification process, can be translated into development of novel greenhouse gas mitigation strategies.

National survey of patch testing in the United Kingdom and Republic of Ireland: what proportion of the population is and should be tested?

Summary

Background

An initial study of patch testing practices across Wales, United Kingdom, showed wide variation in practice against a standardized set of guidelines and best practice recommendations.

Objectives

To evaluate (i) current patch testing practice on a national level in the United Kingdom and Republic of Ireland (ROI), (ii) compliance with the current published guidelines, and (iii) the proportion of the catchment population tested by patch testing centres.

Methods

In consultation with the British Association of Dermatologists and British Society for Cutaneous Allergy, proformas addressing clinical guidelines and best practice recommendations were sent to all dermatology units in the United Kingdom and ROI.

Results

Ninety one of 325 centres (28%) performed patch testing. The optimum proportion of annual tests was not being achieved in the United Kingdom and ROI. The range tested varied between 1:1200 and 1:1600.

Conclusions

Most centres achieved a high level of best practice outcomes. Shortcomings were found in the recording of minimum data, benchmarking, and attendance at meetings. We suggest that the findings of this study should be used as evidence to help improve services locally.

Removal of organochlorine pesticides from lindane production wastes by electrochemical oxidation

Abstract

This study is focused on the effective removal of recalcitrant pollutants hexaclorocyclohexanes (HCHs, isomers α, β, γ, and δ) and chlorobenzenes (CBs) present in a real groundwater coming from a landfill of an old lindane factory. Groundwater is characterized by a total organic carbon (TOC) content of 9 mg L⁻¹, pH₀ = 7, conductivity = 3.7 mS cm⁻¹, high salt concentration (SO₄²⁻, HCO₃⁻, Cl⁻), and ferrous iron in solution. The experiments were performed using a BDD anode and a carbon felt (CF) cathode at the natural groundwater pH and without addition of supporting electrolyte. The complete depletion of the four HCH isomers and a mineralization degree of 90% were reached at 4-h electrolysis with a current intensity of 400 mA, the residual TOC (0.8 mg L⁻¹) corresponding mainly to formic acid. A parallel series reaction pathway was proposed: HCHs and CBs are transformed into chlorinated and hydroxylated intermediates that are rapidly oxidized to non-toxic carboxylic acids and/or mineralized, leading to a rapid decrease in solution pH.

A hyperpigmented rash on face and chest

Chronic inducible urticarias in children

Publication date: Available online 14 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Maddalena Napolitano, Matteo Megna, Claudia Costa, Nicola Balato, Cataldo Patruno

Food-dependent exercise-induced anaphylaxis due to almond in a PR-10–sensitized patient

Publication date: Available online 13 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): A.S. Senders, A. Ruiz Oropeza, B. Kristensen, E. Eller, H.F. Kjaer, C. Bindslev-Jensen, C.G. Mortz

Patients Taking β-Blockers Do Not Require Increased Doses of Epinephrine for Anaphylaxis

Publication date: Available online 13 February 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Jennifer L. White, Katie C. Greger, Sangil Lee, Robert J. Kahoud, James T. Li, Christine M. Lohse, Ronna L. Campbell
Backgroundβ-Blocker use has been associated with increased anaphylaxis severity.ObjectiveWe aimed to assess for an association between β-blocker use and requirement for more than 1 dose of epinephrine for anaphylaxis management.MethodsWe conducted a retrospective observational study of patients seen in our emergency department for anaphylaxis between April 2008 and January 2015. The primary outcome measure was the number of doses of epinephrine. Associations with repeat epinephrine administration (>1 vs ≤1 dose of epinephrine) and associations with any epinephrine administration (>0 vs 0 dose) were evaluated using logistic regression models and summarized as odds ratio (OR) and 95% CIs. The study was powered to detect a 10% or greater difference in need for repeat epinephrine administration between patients who were and were not taking β-blocker medications.ResultsOf 789 patient visits with a documented medication history included in the study, 63 (8%) required more than 1 epinephrine dose and 83 (11%) were on β-blocker therapy. Among patients who required more than 1 epinephrine dose, 8 (13%) were taking a β-blocker, compared with 75 patients (10%) who received 0 or 1 dose of epinephrine (OR, 1.26; 95% CI, 0.58-2.75). Among patients who required at least 1 epinephrine dose, 41 (9%) were taking a β-blocker, compared with 42 patients (12%) who received no epinephrine (OR, 0.73; 95% CI, 0.46-1.14).Conclusionsβ-Blocker use may not be clinically significant with regard to the need for epinephrine dosing among emergency department patients with anaphylaxis.