Effectiveness and safety of polidocanol for the treatment of hemangiomas and vascular malformations: A meta-analysis

Abstract

A meta-analysis was conducted to investigate the efficacy and safety of polidocanol versus other conventional therapies in treating hemangiomas (HMs) and vascular malformations (VMs). Literature search was conducted in the Cochrane, Embase, PubMed, Web of Science, CNKI, CBM, VIP, and WanFang databases until March 5, 2017. A meta-analysis was conducted using Revman 5.3 software. A total of 19 randomized controlled trials (RCTs) involving 1,514 participants met the inclusion criteria. Regarding the effectiveness, statistically significant differences were observed between polidocanol and all the independent treatments (p = .006), but not between polidocanol and pingyangmycin (p = .16). Combination therapy of polidocanol with any other conventional treatments (p = .0001), pingyangmycin (p = .005) or hemoclip (p = .008) elicited a better response compared to treatment with these treatments independently. A meta-analysis on the risk of adverse events (AEs) showed a lower risk for polidocanol versus other treatments, for example, all the conventional treatments used independently (p < .00001) and pingyangmycin (p < .00001). Combination therapy of polidocanol with pingyangmycin also yielded a significantly lower risk of AEs (p < .00001). Polidocanol is at least as effective as other conventional therapies on HMs and VMs (especially venous malformations). The former is much safer. Combining its use with other treatments may produce excellent results. Our study provides strong evidence supporting the use of polidocanol for HMs and VMs.

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Comparison of clinical efficacy and safety of thermotherapy versus cryotherapy in treatment of skin warts: A randomized controlled trial

Abstract

The effect of thermotherapy in the treatment of skin warts in comparison to cryotherapy, as the standard conventional method, has remained uncertain. This study aimed to assess the clinical efficacy and safety of thermotherapy and cryotherapy in removing skin warts. This randomized controlled trial was conducted on 52 patients aged 18 years and over with ≤ 10 skin warts. The participants were randomly assigned into two groups to receive cryotherapy (every 2 to 3 weeks up to six sessions if required) or thermotherapy (one session). The patients in both groups were followed every 2 to 3 weeks for the first three months, and then three months after the last treatment session. The clearance rate was 79.2% in the thermotherapy group and 58.3% in the cryotherapy group with no significant difference (p = 0.212). The rate of scarring in the thermotherapy group was 20% (p = .018). A higher clearance rate was achieved in the thermotherapy group. However, this result was not statistically significant. There were some minimal post-treatment complications. Patients needed only one session of thermotherapy. Due to the risk of scarring, we suggest thermotherapy only as a suitable treatment method for palmoplantar warts.

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Issue Information

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Bioavailability and toxicity of trace metals (Cd, Cr, Cu, Ni, and Zn) in sediment cores from the Shima River, South China

Publication date: February 2018
Source:Chemosphere, Volume 192
Author(s): Lei Gao, Zhuowei Wang, Shaoheng Li, Jianyao Chen
Five sediment cores (S1−S5) were collected from the Shima River to determine the bioavailability of trace metals (Cd, Cr, Cu, Ni, and Zn) using the modified European Community Bureau of Reference (BCR) procedure. The toxic effects of polluted sediment were assessed using the LUMISTox^® bioassay with Vibrio fischeri and chemical models such as the toxicity unit (TU) of each metal, sum of all TUs (∑TU), and toxic risk index (TRI). The results showed that Cd, Ni, and Zn were present mainly in the acid-soluble and residual fractions, and the residual fraction of Cr accounted for the majority of the metal content (44%), while Cu was present mainly in the reducible and residual fractions. Cd had a mean enrichment factor (EF) of 15.1 and was considered to be severely enriched, while there was a minor enrichment of Cr and moderately severe enrichment of Zn, Cu, and Ni. From the LUMISTox^® bioassay, an acute TU (TUa) value exceeding 0.4 was found at the upper and middle reach sites and was considered to represent slightly acute toxicity, whereas little acute toxicity was found at the lower reach site. The acid-soluble fraction of trace metals was the geochemical fraction mainly responsible for the acute toxicity of the sediment, and acid-soluble Zn and Ni were identified as important contributors to sediment toxicity.



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Unconventional use of fractional ablative CO2 laser in facial cutaneous sarcoïdosis

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2. Do repeated limbic seizures induce depression-like behavior in rats?

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): W. McIntyre Burnham, Brian W. Scott
It has been reported that rapid kindling of the hippocampus produces lasting depression-like behavior in rats, as evidenced by increased immobility in the forced swim test and a loss of preference for sweetened water (Mazarati et al., 2007). This might suggest that repeated limbic seizure activity could be the cause of the depression often seen in patients with temporal lobe epilepsy.Sixty-day old male Wistar rats were implanted with electrodes in the amygdala and ventral hippocampus and kindled (or sham kindled) daily to a criterion of 10 stage 5 seizures. Two weeks later subjects were tested in the forced swim and sweet taste preference tests. No differences were found between the kindled and sham kindled animals.Subsequently, twenty-one day old male Wistar rat pups were implanted and quick kindled (or sham kindled) in the ventral hippocampus. Kindling was accomplished in a single day by stimulating every 5min for 84 stimulations. Four days or two weeks later they were tested in the forced swim and sweet taste preference tests. No differences were found between the kindled and sham kindled animals.The present data do not support the idea that repeated limbic seizures induce depression-like behavior in rats.



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Machine-based classification of ADHD and nonADHD participants using time/frequency features of event-related neuroelectric activity

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Hüseyin Öztoprak, Mehmet Toycan, Yaşar Kemal Alp, Orhan Arıkan, Elvin Doğutepe, Sirel Karakaş
ObjectiveAttention-deficit/hyperactivity disorder (ADHD) is the most frequent diagnosis among children who are referred to psychiatry departments. Although ADHD was discovered at the beginning of the 20th century, its diagnosis is still confronted with many problems.MethodA novel classification approach that discriminates ADHD and nonADHD groups over the time-frequency domain features of event-related potential (ERP) recordings that are taken during Stroop task is presented. Time-Frequency Hermite-Atomizer (TFHA) technique is used for the extraction of high resolution time-frequency domain features that are highly localized in time-frequency domain. Based on an extensive investigation, Support Vector Machine-Recursive Feature Elimination (SVM-RFE) was used to obtain the best discriminating features.ResultsWhen the best three features were used, the classification accuracy for the training dataset reached 98%, and the use of five features further improved the accuracy to 99.5%. The accuracy was 100% for the testing dataset. Based on extensive experiments, the delta band emerged as the most contributing frequency band and statistical parameters emerged as the most contributing feature group.ConclusionThe classification performance of this study suggests that TFHA can be employed as an auxiliary component of the diagnostic and prognostic procedures for ADHD.SignificanceThe features obtained in this study can potentially contribute to the neuroelectrical understanding and clinical diagnosis of ADHD.



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Interindividual variability in response to continuous theta-burst stimulation in healthy adults

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Ali Jannati, Gabrielle Block, Lindsay M. Oberman, Alexander Rotenberg, Alvaro Pascual-Leone
ObjectiveWe used complete-linkage cluster analysis to identify healthy subpopulations with distinct responses to continuous theta-burst stimulation (cTBS).Methods21 healthy adults (age±SD, 36.9±15.2years) underwent cTBS of left motor cortex. Natural log-transformed motor evoked potentials (LnMEPs) at 5–50min post-cTBS (T5–T50) were calculated.ResultsTwo clusters were found; Group 1 (n=12) that showed significant MEP facilitation at T15, T20, and T50 (p's<0.006), and Group 2 (n=9) that showed significant suppression at T5–T15 (p's<0.022). LnMEPs at T10 and T40 were best predictors of, and together accounted for 80% of, cluster assignment.In an exploratory analysis, we examined the roles of brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) polymorphisms in the cTBS response. Val66Met participants showed greater facilitation at T10 than Val66Val participants (p=0.025). BDNF and cTBS intensity predicted 59% of interindividual variability in LnMEP at T10. APOE did not significantly affect LnMEPs at any time point (p's>0.32).ConclusionsData-driven cluster analysis can identify healthy subpopulations with distinct cTBS responses. T10 and T40 LnMEPs were best predictors of cluster assignment. T10 LnMEP was influenced by BDNF polymorphism and cTBS intensity.SignificanceHealthy adults can be sorted into subpopulations with distinct cTBS responses that are influenced by genetics.



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Effect of local cooling on excitation-contraction coupling in myasthenic muscle: Another mechanism of ice-pack test in myasthenia gravis

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Daisuke Yamamoto, Tomihiro Imai, Emiko Tsuda, Takayoshi Hozuki, Rika Yamauchi, Shin Hisahara, Jun Kawamata, Shun Shimohama
ObjectiveThe ice-pack test is a convenient diagnostic testing procedure for myasthenia gravis (MG). We investigated the underlying mechanism of the ice-pack test performed on bilateral masseters.MethodsWe performed trigeminal repetitive nerve stimulation (RNS), excitation-contraction (E-C) coupling assessment (Imai's method) and bite force measurement before and after cooling of the masseters in MG patients and normal controls. After placing the ice-pack on the masseters for 3min, serial recordings of the three tests were performed at various time intervals during 10min after cooling.ResultsThe bite force increased significantly after cooling in ice-pack-positive MG patients. The acceleration and acceleration ratio (acceleration at a given time to baseline acceleration) of jaw movement increased significantly after cooling of the masseters in ice-pack-positive MG patients compared to ice-pack-negative patients and normal controls. The prolonged effect of cooling continued until the end of recording even though decremental response to RNS had returned to baseline value.ConclusionsCooling of myasthenic muscle may induce two effects. One is relatively short effect on electrical synaptic transmission at the endplate, and another is prolonged effect on E-C coupling in the muscle.SignificanceThe ice-pack test induces a prolonged effect of ameliorating impaired E-C coupling in MG.



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Reduced motor cortical inhibition in migraine: A blinded transcranial magnetic stimulation study

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): J.P. Neverdahl, P.M. Omland, M. Uglem, M. Engstrøm, T. Sand
ObjectiveTo investigate motor cortical excitability, inhibition, and facilitation with navigated transcranial magnetic stimulation (TMS) in migraine in a blinded cross-sectional study.MethodsResting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were compared in 27 interictal migraineurs and 33 controls. 24 female interictal migraineurs and 27 female controls were compared in subgroup analyses. Seven preictal migraineurs were also compared to the interictal group in a hypothesis-generating analysis. Investigators were blinded for diagnosis during recording and analysis of data.ResultsSICI was decreased in interictal migraineurs when compared to healthy controls (p=0.013), CSP was shortened in female interictal migraineurs (p=0.041). ICF was decreased in preictal compared to interictal migraineurs (p=0.023). RMT and ICF were not different between interictal migraineurs and controls.ConclusionCortical inhibition was decreased in migraineurs between attacks, primarily in a female subgroup, indicating an importance of altered cortical inhibition in migraine.SignificancePrevious studies on motor cortical excitability in migraineurs have yielded varying results. This relatively large and blinded study provides support for altered cortical inhibition in migraine. Measuring intracortical facilitation in the period preceding migraine attacks may be of interest for future studies.



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Intermittent theta-burst stimulation induces correlated changes in cortical and corticospinal excitability in healthy older subjects

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Tamara Gedankien, Peter J. Fried, Alvaro Pascual-Leone, Mouhsin M. Shafi
ObjectiveWe studied the correlation between motor evoked potentials (MEPs) and early TMS-evoked EEG potentials (TEPs) from single-pulse TMS before and after intermittent Theta Burst Stimulation (iTBS) to the left primary motor cortex (M1) in 17 healthy older participants.MethodsTMS was targeted to the hand region of M1 using a MRI-guided navigated brain stimulation system and a figure-of-eight biphasic coil. MEPs were recorded from the right first dorsal interosseous muscle using surface EMG. TEPs were extracted from a 61-channel EEG recording. Participants received 90 single TMS pulses at 120% of resting motor threshold before and after iTBS.ResultsAcross all participants, the change in N15-P30 TEP and MEP amplitudes were significantly correlated (r=0.69; p<0.01). Average TEP responses did not change significantly after iTBS, whereas MEP amplitudes showed a significant increase.ConclusionsChanges in corticospinal reactivity and cortical reactivity induced by iTBS are related. However, the effect of iTBS on TEPs, unlike MEPs, is not straightforward.SignificanceOur findings help elucidate the relationship between changes in cortical and corticospinal excitability in healthy older individuals. Going forward, TEPs may be used to evaluate the effects of theta-burst stimulation in non-motor brain regions.



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Corticomuscular coherence in the acute and subacute phase after stroke

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Lisbeth Hoejkjaer Larsen, Ivan Chrilles Zibrandtsen, Troels Wienecke, Troels Wesenberg Kjaer, Mark Schram Christensen, Jens Bo Nielsen, Henning Langberg
ObjectiveStroke is one of the leading causes of physical disability due to damage of the motor cortex or the corticospinal tract. In the present study we set out to investigate the role of adaptations in the corticospinal pathway for motor recovery during the subacute phase after stroke.MethodsWe examined 19 patients with clinically diagnosed stroke and 18 controls. The patients had unilateral mild to moderate weakness of the hand. Each patient attended two sessions at approximately 3days (acute) and 38days post stroke (subacute). Task-related changes in the communication between motor cortex and muscles were evaluated from coupling in the frequency domain between EEG and EMG during movement of the paretic hand.ResultsCorticomuscular coherence (CMC) and intermuscular coherence (IMC) were reduced in patients as compared to controls. Paretic hand motor performance improved within 4–6weeks after stroke, but no change was observed in CMC or IMC.ConclusionsCMC and IMC were reduced in patients in the early phase after stroke. However, changes in coherence do not appear to be an efficient marker for early recovery of hand function following stroke.SignificanceThis is the first study to demonstrate sustained reduced coherence in acute and subacute stroke.



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Editorial Board

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11





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Contents

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11





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4. Prevention of trauma-induced epileptogenesis in mice via manipulation of the network excitability

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): S. Soltani, J. Seigneur, S. Chauvette, I. Timofeev
A large proportion of patients with severe brain damage become epileptic several months to years after the trauma. The mechanisms leading to the development of epilepsy (epileptogenesis) are unknown. We hypothesize that brain damage leads to partial deafferentation and a drop in excitability of the affected area. To compensate, the brain employs a variety of mechanisms to restore this drop of excitability and if not properly controlled, this leads to epilepsy. We performed undercut in the somatosensory area in adult C57/BL6 mice and implanted LFP and EMG electrodes for continuous electrographic recordings for at least two months. We proposed to manipulate (increase or decrease) network activities in order to prevent/enhance epileptogenesis applying DREADD technology. Target cortical regions were injected with AAV-hM3D(Gq) or AAV-hM4D(Gi). Activation of the designed receptor in infected neurons was achieved by clozapine-N-oxide continuously injected via an osmotic pump. Activation of hM3D(Gq) leads to depolarization and increased firing in infected neurons, while the activation of hM4D(Gi) induces a hyperpolarization of neurons. If our hypothesis is true, we expect to obtain epileptogenesis in adult mice without DREADD manipulations, either abolition or strong reduction of epileptogenesis in hM3D(Gq) mice, and increased epileptogenesis symptoms in hM4D(Gi) mice. In the following weeks all adult mice without DREADD manipulations revealed recurrent seizure activities. Mice in which hM4D(Gi) was activated revealed earlier and more severe seizures. Mice with hM3D(Gq) activation did not reveal paroxysmal activities. These results will lead to the development of new preventive treatments of epileptogenesis induced by brain damage.Supported by CIHR and NSERC.



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Electrical impedance myography changes after incomplete cervical spinal cord injury: An examination of hand muscles

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Le Li, Henry Shin, Argyrios Stampas, Xiaoyan Li, Ping Zhou
ObjectiveThis study was to apply the newly developed electrical impedance myography (EIM) technique to examine hand muscles in patients with an incomplete cervical spinal cord injury (SCI).MethodsEIM was performed on the thenar, hypothenar, and first dorsal interosseous (FDI) muscles of SCI (n=16) and age-matched healthy control (n=18) subjects. By sending low intensity and high frequency current through the skin and measuring the consequent voltage, EIM estimates the major impedance parameters, which include resistance (R), reactance (X) and phase angle (θ).ResultsThe SCI group had lower reactance and phase angle (p<0.0001) as compared to the control group in all three muscles, and lower resistance in the thenar muscle (p<0.05). The SCI group also demonstrated a smaller anisotropy in resistance (p<0.0001) and larger anisotropy in phase angle (p<0.05) compared to those from healthy controls.ConclusionThe reduced reactance and phase angle of paralyzed muscles could be due tochanges of membrane integrity and fat infiltration, whereas the change in the anisotropy may reflect the rearrangement of muscle fiber geometry.SignificanceThe EIM provides a quick and convenient tool for examination of muscle alterations after SCI.



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Plasticity induced by non-invasive transcranial brain stimulation: A position paper

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Ying-Zu Huang, Ming-Kue Lu, Andrea Antal, Joseph Classen, Michael Nitsche, Ulf Ziemann, Michael Ridding, Masashi Hamada, Yoshikazu Ugawa, Shapour Jaberzadeh, Antonio Suppa, Walter Paulus, John Rothwell
Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.



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After-effects of transcranial alternating current stimulation on evoked delta and theta power

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Miles Wischnewski, Dennis J.L.G. Schutter
ObjectivePhase synchronization is suggested to be among the mechanisms that can explain the effects of transcranial alternating current stimulation (tACS). However, little is known about the effects of tACS on event-related oscillatory activity. Therefore the objective was to investigate frequency-related effects of frontal tACS on event-related oscillatory power.MethodsIn a double blind randomized controlled cross-over design, twenty-four participants received 12min of delta (2.5Hz), theta tACS (5Hz) and sham tACS at an intensity of 1mA peak-to-peak. Event-related delta- and theta-related oscillatory activity was recorded to reward- and punishment-related feedback signals.ResultsDelta tACS decreased feedback-related oscillatory power in the 1.5 and 3.5Hz frequency range. This effect was driven by power changes below the tACS frequency stimulation.ConclusionExogenous field potentials can attenuate event-related oscillatory activity in a rhythm slightly below the stimulation frequency. Our findings suggest an interaction between tACS and event-related rhythmic activity that extends beyond phase synchronization.SignificanceThese findings add novel insights into the mechanisms of tACS after-effects.



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1. Across all the seven seas: Fifty years in neurology, EEG and epilepsies

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Paul Hwang
Since the 1960s, major neuroscience advances have facilitated the development of new antiepilepsy drugs (AEDs) targeting specific neurotransmitter-receptor systems, particularly the GABAergic, the NMDA-receptors and voltage-gated ion channels. In addition to the classical AEDs, carbamazepine and cogeners act at the voltage-gates sodium channels, while ethosuxumide acts at the calcium channel, improving the treatment of partial and generalized seizures. But approximately 30% of partial complex seizures remain refractory to AEDs, leading to novel AEDs: levetiracetam, tiagabine, lacosamide, perampanel and others. The pharmacoresistant epilepsies are typically dyscognitive partial-onset, arising from limbic structures of mesial temporal lobes, better visualised by improved neuroimaging methods eg. MRI and PET. Together with invasive intracranial monitoring in specialized units with long-term recording of multichannelled EEG and videorecording of behaviour, the localization of the seizure-onset zone has allowed targeted excision of the epileptogenic tissue for better outcome.Functional neurosurgical methods include vagal nerve stimulation and deep brain stimulation of selected targets in affected circuits, mapped by new EEG criteria including gamma rhythm, HFOs, ripples and clusters. Novel intervention in refractory epilepsies include the ketogenic diet and variants, neurosteroids, hormones eg. progestins and ACTH. A number of genetic mutations and copy number variants have been linked to epilepsies. It remains to be seen how expanded knowledge of the genetic bases of the epilepsies and epileptic encephalopathies leads to new intervention improving long-term prognosis and quality of life in persons afflicted with this ancient curse of the human condition, 'The Falling Sickness' also known as 'The Sacred Disease' (Hippocrates).In the words of Sir William Osler: 'He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all' ('Aequanimitas' by Osler), quoted in Herbert Ho Ping Kong, 'The Art of Medicine: Healing and the Limits of Technology' (ECW Press, 2014 Toronto).



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3. Asymmetric hypsarrythmia: An insight into the pathophysiology of infantile spasms. A retrospective cohort

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): B. Desnous, M. Arbour, H.S. Nguyen, A. Lortie, D. Chartrand, E. Rossignol, P. Diadori, P. Major, L. Carmant, A. Birca
Infantile spasms (IS) is a catastrophic epilepsy where treatment precocity improves outcome. Previous studies demonstrated an association between asymmetric hypsarrhythmia on EEG and ipsilateral hemispheric lesions on MRI, suggesting a possible role of cortical lesions in the initiation of IS. Epileptiform abnormalities appearing during early infancy have also been linked to IS emergence. We hypothesized that focal lateralized EEG abnormalities during the prehyspasrrhythmic period will be associated with asymmetric hypsarrhythmia at IS onset.We recruited a retrospective cohort of 80 infants, 7.4±3.6months old at the onset of hypsarrhythmia and IS, admitted to Sainte-Justine Hospital between 2007 and 2016. Seven infants showed an asymmetric hypsarrhythmia pattern and, as expected, all of them had lateralized lesions on MRI. Of the remaining 73, 42 had abnormal MRI, but only 3 infants had lateralized lesions (100% vs 7.1%, p<0.01). Thirty-four patients had pre-hypsarrhythmic EEG recordings at the age of 4.6±2.6months, 3±2months before IS onset, including four infants with asymmetric hypsarrhythmia. Five infants had no pre-hypsarrhythmic epileptiform abnormalities.Six had focal lateralized, while 23 multifocal abnormalities. The proportion of patients with focal abnormalities was higher in those who developed asymmetric compared to symmetric hypsarrhythmia (50% vs 13.3%, p<0.05).Our data confirm the link between asymmetric hypsarrhythmia and lateralized MRI lesions. Moreover, we show that focal lateralized EEG abnormalities precede asymmetric hypsarrythmia, which supports the involvement of cerebral cortex in the IS genesis. More sensitive EEG biomarkers of high IS risk may help developing preventative treatments that will improve outcomes in IS.



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Neural network topology in ADHD; evidence for maturational delay and default-mode network alterations

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): T.W.P. Janssen, A. Hillebrand, A. Gouw, K. Geladé, R. Van Mourik, A. Maras, J. Oosterlaan
ObjectiveAttention-deficit/hyperactivity disorder (ADHD) has been associated with widespread brain abnormalities in white and grey matter, affecting not only local, but global functional networks as well. In this study, we explored these functional networks using source-reconstructed electroencephalography in ADHD and typically developing (TD) children. We expected evidence for maturational delay, with underlying abnormalities in the default mode network.MethodsElectroencephalograms were recorded in ADHD (n=42) and TD (n=43) during rest, and functional connectivity (phase lag index) and graph (minimum spanning tree) parameters were derived. Dependent variables were global and local network metrics in theta, alpha and beta bands.ResultsWe found evidence for a more centralized functional network in ADHD compared to TD children, with decreased diameter in the alpha band (ηp²=0.06) and increased leaf fraction (ηp²=0.11 and 0.08) in the alpha and beta bands, with underlying abnormalities in hub regions of the brain, including default mode network.ConclusionsThe finding of a more centralized network is in line with maturational delay models of ADHD and should be replicated in longitudinal designs.SignificanceThis study contributes to the literature by combining high temporal and spatial resolution to construct EEG network topology, and associates maturational-delay and default-mode interference hypotheses of ADHD.



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5. Epilepsy and EEG activity in early-onset Alzheimer’s disease

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Ángela Milán-Tomás, Paul Hwang
ObjectiveThe aim of this review was to evaluate and summarize the current literature regarding the incidence and features of epileptic seizures in early onset Alzheimer's disease (AD) as well as its epileptiform characteristics as described by electroencephalography (EEG).BackgroundThe incidence of epilepsy in AD is higher than in the general population, although the true prevalence of seizures has remained unclear due to methodological problems detecting these events in a cognitively impaired population.Design/MethodsA literature search using Medline with PubMed and EMBASE was carried out identifying papers published focusing on EEG and epilepsy in early-onset Alzheimer's disease (EOAD). A total of 767 abstracts were obtained, 55 full publications were screened and references were checked for additional material where appropriate.ResultsOnly 20 studies included EEG data regarding epilepsy in Alzheimer's disease of which 11 were animal models. AD due to amyloid precursor protein (APP) mutations has been described as one of the most common early-onset AD forms presenting with epileptic seizures. Neurodegeneration of the hippocampal region causing aberrant excitatory neuronal activity is the most accepted hypothesis for the occurrence of epilepsy in AD.ConclusionsThere is a need for better methodological studies addressing the role of EEG in the diagnosis and characterization of seizures in AD. Subclinical epileptiform activity may lead to a faster decline in cognition and they occur more often during sleep stages, therefore a prolonged sleep EEG can be an effective diagnostic tool for detecting this activity.



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Contents Continued

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60





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Age-dependent association of thyroid function with brain morphology and microstructural organization: evidence from brain imaging

Publication date: January 2018
Source:Neurobiology of Aging, Volume 61
Author(s): Layal Chaker, Lotte G.M. Cremers, Tim I.M. Korevaar, Marius de Groot, Abbas Dehghan, Oscar H. Franco, Wiro J. Niessen, M. Arfan Ikram, Robin P. Peeters, Meike W. Vernooij
Thyroid hormone (TH) is crucial during neurodevelopment, but high levels of TH have been linked to neurodegenerative disorders. No data on the association of thyroid function with brain imaging in the general population are available. We therefore investigated the association of thyroid-stimulating hormone and free thyroxine (FT4) with magnetic resonance imaging (MRI)-derived total intracranial volume, brain tissue volumes, and diffusion tensor imaging measures of white matter microstructure in 4683 dementia- and stroke-free participants (mean age 60.2, range 45.6–89.9 years). Higher FT4 levels were associated with larger total intracranial volumes (β = 6.73 mL, 95% confidence interval = 2.94–9.80). Higher FT4 levels were also associated with larger total brain and white matter volumes in younger individuals, but with smaller total brain and white matter volume in older individuals (p-interaction 0.02). There was a similar interaction by age for the association of FT4 with mean diffusivity on diffusion tensor imaging (p-interaction 0.026). These results are in line with differential effects of TH during neurodevelopmental and neurodegenerative processes and can improve the understanding of the role of thyroid function in neurodegenerative disorders.



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Intercellular transfer of pathogenic α-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal

Publication date: January 2018
Source:Neurobiology of Aging, Volume 61
Author(s): Shi Zhang, Erez Eitan, Tsung-Yu Wu, Mark P. Mattson
Parkinson's disease (PD) is characterized by accumulations of toxic α-synuclein aggregates in vulnerable neuronal populations in the brainstem, midbrain, and cerebral cortex. Recent findings suggest that α-synuclein pathology can be propagated transneuronally, but the underlying molecular mechanisms are unknown. Advances in the genetics of rare early-onset familial PD indicate that increased production and/or reduced autophagic clearance of α-synuclein can cause PD. The cause of the most common late-onset PD is unclear, but may involve metabolic compromise and oxidative stress upstream of α-synuclein accumulation. As evidence, the lipid peroxidation product 4-hydroxynonenal (HNE) is elevated in the brain during normal aging and moreso in brain regions afflicted with α-synuclein pathology. Here, we report that HNE increases aggregation of endogenous α-synuclein in primary neurons and triggers the secretion of extracellular vesicles (EVs) containing cytotoxic oligomeric α-synuclein species. EVs released from HNE-treated neurons are internalized by healthy neurons which as a consequence degenerate. Levels of endogenously generated HNE are elevated in cultured cells overexpressing human α-synuclein, and EVs released from those cells are toxic to neurons. The EV-associated α-synuclein is located both inside the vesicles and on their surface, where it plays a role in EV internalization by neurons. On internalization, EVs harboring pathogenic α-synuclein are transported both anterogradely and retrogradely within axons. Focal injection of EVs containing α-synuclein into the striatum of wild-type mice results in spread of synuclein pathology to anatomically connected brain regions. Our findings suggest a scenario for late-onset PD in which lipid peroxidation promotes intracellular accumulation and then extrusion of EVs containing toxic α-synuclein species; the EVs are then internalized by adjacent neurons, so propagating the neurodegenerative process.



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Parkin absence accelerates microtubule aging in dopaminergic neurons

Publication date: January 2018
Source:Neurobiology of Aging, Volume 61
Author(s): Daniele Cartelli, Alida Amadeo, Alessandra Maria Calogero, Francesca Vittoria Marialuisa Casagrande, Carmelita De Gregorio, Mariarosa Gioria, Naoko Kuzumaki, Ilaria Costa, Jenny Sassone, Andrea Ciammola, Nobutaka Hattori, Hideyuki Okano, Stefano Goldwurm, Laurent Roybon, Gianni Pezzoli, Graziella Cappelletti
Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell–derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease.



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Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60
Author(s): Valerie Sackmann, Anna Ansell, Christopher Sackmann, Harald Lund, Robert A. Harris, Martin Hallbeck, Camilla Nilsberth
Neuroinflammation plays an influential role in Alzheimer's disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oAβ) between differentiated SH-SY5Y cells. We also investigated how the different inflammatory environments related to intercellular and intracellular changes. We demonstrate that M2 products decrease interneuronal transfer of oAβ, while recombinant interleukin (IL)-4, IL-10, and IL-13 increase transfer. There were no alterations to the mRNA of a number of AD-related genes in response to the combination of oAβ and M0, M1, or M2, but several intracellular proteins, some relating to protein trafficking and the endosomal/lysosomal system, were altered. Stimulating microglia to an M2 phenotype may thus slow down the progression of AD and could be a target for future therapies.



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Response to a letter to the editor: sleep disturbance as a stressor event in elderly's life

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60
Author(s): Sami Ouanes, José Haba-Rubio, Julius Popp




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Altered mGluR5 binding potential and glutamine concentration in the 6-OHDA rat model of acute Parkinson's disease and levodopa-induced dyskinesia

Publication date: January 2018
Source:Neurobiology of Aging, Volume 61
Author(s): Melissa Crabbé, Anke Van der Perren, Akila Weerasekera, Uwe Himmelreich, Veerle Baekelandt, Koen Van Laere, Cindy Casteels
Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [¹⁸F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology.



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Association of postoperative delirium with markers of neurodegeneration and brain amyloidosis: a pilot study

Publication date: January 2018
Source:Neurobiology of Aging, Volume 61
Author(s): Elena Rolandi, Enrica Cavedo, Michela Pievani, Samantha Galluzzi, Federica Ribaldi, Christopher Buckley, Colm Cunningham, Ugo Paolo Guerra, Monica Musarra, Sabrina Morzenti, Silvia Magnaldi, Mirko Patassini, Flavio Terragnoli, Luca Matascioli, Simone Franzoni, Giorgio Annoni, Lucio Carnevali, Giuseppe Bellelli, Giovanni B. Frisoni
The aim of the study was to investigate the association between postoperative delirium (POD) and in vivo markers of Alzheimer's disease pathology in nondemented hip fracture surgery patients. POD was assessed with the Confusion Assessment Method. Amyloid load was quantified on ¹⁸F-Flutemetamol positron emission tomography images as standardized uptake value ratio. Secondary outcome measures were gray matter volumes, white matter integrity, and functional connectivity at rest. All the patients with POD (POD+, N = 5) were amyloid negative (standardized uptake value ratio <0.59), whereas 6 out of 11 patients without POD (POD−) showed brain amyloid positivity. POD+ compared to POD− displayed: lower gray matter volumes in the amygdala (p = 0.003), in the middle temporal gyrus and in the anterior cingulate cortex (p < 0.001), increased diffusivity in the genu of the corpus callosum and in the anterior corona radiata (p < 0.05), and higher functional connectivity within the default mode network (p < 0.001). POD patients showed altered gray and white matter integrity in the fronto-limbic regions in absence of brain amyloidosis. Based on this preliminary investigation, delirium pathophysiology might be independent of Alzheimer's disease. Future studies on larger samples are needed to confirm this hypothesis.



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White-matter microstructure and hearing acuity in older adults: a population-based cross-sectional DTI study

Publication date: January 2018
Source:Neurobiology of Aging, Volume 61
Author(s): Stephanie C. Rigters, Lotte G.M. Cremers, M. Arfan Ikram, Marc P. van der Schroeff, Marius de Groot, Gennady V. Roshchupkin, Wiro J.N. Niessen, Robert J. Baatenburg de Jong, André Goedegebure, Meike W. Vernooij
To study the relation between the microstructure of white matter in the brain and hearing function in older adults we carried out a population-based, cross-sectional study. In 2562 participants of the Rotterdam Study, we conducted diffusion tensor imaging to determine the microstructure of the white-matter tracts. We performed pure-tone audiogram and digit-in-noise tests to quantify hearing acuity. Poorer white-matter microstructure, especially in the association tracts, was related to poorer hearing acuity. After differentiating the separate white-matter tracts in the left and right hemisphere, poorer white-matter microstructure in the right superior longitudinal fasciculus and the right uncinate fasciculus remained significantly associated with worse hearing. These associations did not significantly differ between middle-aged (51–69 years old) and older (70–100 years old) participants. Progressing age was thus not found to be an effect modifier. In a voxel-based analysis no voxels in the white matter were significantly associated with hearing impairment.



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Editorial Advisory Board

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60





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Sleep disturbance as a stressor event in elderly's life

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60
Author(s): Heloisa Galanjauskas, Paula Araujo, Sergio Tufik, Monica L. Andersen




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Note in reference to “Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase” [Neurobiol. Aging 33(12) (2012) 2855-2868]

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60
Author(s): Manal A. Farg, Kai Y. Soo, Adam K. Walker, Hong Pham, Jacqueline Orian, Malcolm K. Horne, Sadaf T. Warraich, Kelly L. Williams, Ian P. Blair, Julie D. Atkin




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Contents

Publication date: December 2017
Source:Neurobiology of Aging, Volume 60





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Editorial board

Publication date: January 2018
Source:Biomaterials, Volume 151





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Bio-artificial tongue with tongue extracellular matrix and primary taste cells

Publication date: January 2018
Source:Biomaterials, Volume 151
Author(s): Jung Seung Lee, Ann-Na Cho, Yoonhee Jin, Jin Kim, Suran Kim, Seung-Woo Cho
Artificial taste devices for tastant sensing and taste information standardization are attracting increasing attention with the exponential growth of the food and beverage industries. Despite recent developments in artificial taste sensors incorporating polymers, lipid membranes, and synthetic vesicles, current devices have limited functionality and sensitivity, and are complex to manufacture. Moreover, such synthetic systems cannot simulate the taste signal transmissions that are critical for complicated taste perception. The current document describes a primary taste cell-based artificial tongue that can mimic taste sensing. To maintain viable and functional taste cells required for in vitro tastant sensing, a tongue extracellular matrix (TEM) prepared by decellularization of tongue tissue was applied to two- and three-dimensional taste cell cultures. The TEM-based system recreates the tongue's microenvironment and significantly improves the functionality of taste cells for sensing tastant molecules by enhancing cellular adhesion and gustatory gene expression compared with conventional collagen-based systems. The TEM-based platform simulates signal transmission from tastant-treated taste cells to adjacent neuronal cells, which was impossible with previous artificial taste sensors. The artificial tongue device may provide highly efficient, functional sensors for tastant detection and in vitro organ models that mimic the tongue allowing elucidation of the mechanisms of taste.



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Reviewer Awards and Acknowledgments

Publication date: January–February 2018
Source:Current Problems in Diagnostic Radiology, Volume 47, Issue 1
Author(s): Puneet Bhargava




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Down-regulation of Notch signaling pathway reverses the Th1/Th2 imbalance in tuberculosis patients

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Qifeng Li, Hui Zhang, Liang Yu, Chao Wu, Xinhui Luo, He Sun, Jianbing Ding
Th1/Th2 imbalance to Th2 is of significance in the peripheral immune responses in Tuberculosis (TB) development. However, the mechanisms for Th1/Th2 imbalance are still not well determined. Notch signaling pathway is involved in the peripheral T cell activation and effector cell differentiation. However, whether it affects Th1/Th2 imbalance in TB patients is still not known. Here, we used γ-secretase inhibitor (DAPT) to treat the peripheral blood mononuclear cells (PBMCs) from healthy people or individuals with latent or active TB infection in vitro, respectively. Then, the Th1/Th2 ratios were determined by flow cytometry, and cytokines of IFN-γ, IL-4, IL-10 in the culture supernatant were measured by CBA method. The Notch signal pathway associated proteins Hes1, GATA3 and T-bet were quantitated by real-time PCR or immunoblotting. Our results showed that DAPT effectively inhibited the protein level of Hes1. In TB patients, the Th2 ratio increased in the PBMCs, alone with the high expression of GATA3 and IL-4, resulting in the high ratios of Th2/Th1 and GATA3/T-bet in TB patients. However, Th2 cells ratio decreased after blocking the Notch signaling pathway by DAPT and the Th2/Th1 ratio in TB patients were DAPT dose-dependent, accompanied by the decrease of IL-4 and GATA3. But, its influence on Th1 ratio and Th1 related T-bet and IFN-γ levels were not significant. In conclusion, our results suggest that blocking Notch signaling by DAPT could inhibit Th2 responses and restore Th1/Th2 imbalance in TB patients.



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The role of human chorionic gonadotropin in regulation of naïve and memory T cells activity in vitro

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): S.A. Zamorina, L.S. Litvinova, K.A. Yurova, O.G. Khaziakhmatova, V.P. Timganova, M.S. Bochkova, P.V. Khramtsov, M.B. Rayev
The role of human chorionic gonadotropin (hCG) in the regulation of molecular genetics factors determining the functional activity of human naïve and memory T cells in vitro was studied. It was found that hCG (10 and 100IU/ml) inhibited CD28 and CD25 expression on the naïve T cells (CD45RA+) and CD25 expression on the memory T cells (CD45R0+). hCG didn't affect the CD71 proliferation marker expression in total. Nevertheless, hCG reduced the percentage of proliferating memory T cells with simultaneous suppression of CD71 expression on proliferating CD45R0+cells.In parallel, expression of U2af1l4, Gfi1, and hnRNPLL genes, which are Ptprc gene alternative splicing regulators was evaluated. It was established that hCG stimulated the expression of U2af1l4 and hnRNPLL genes, responsible for the assembly of CD45R0 in memory T cells, but reduced the expression of Gfi1 in these cells. In general, hCG promotes the differentiation of memory T cells by increasing of CD45R0 expression, but inhibits proliferation and CD25 expression which reflects their functional activity.

Graphical abstract

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Nafamostat mesilate, a serine protease inhibitor, suppresses interferon-gamma-induced up-regulation of programmed cell death ligand 1 in human cancer cells

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Sadamu Homma, Kazumi Hayashi, Kosaku Yoshida, Yukiko Sagawa, Yuko Kamata, Masaki Ito
Programmed cell death ligand-1 (PD-L1) plays a pivotal role in the suppression of antitumour immunity by binding to programmed cell death-1 (PD-1) on tumouricidal cytotoxic T lymphocytes (CTLs), rendering them inactive. As blockade of PD-1/PD-L1 interaction by the monoclonal antibodies induced effective T cell-mediated antitumour response, suppression of PD-L1 expression in tumour cells by the chemical agent might contribute to treatment against malignant tumours. Nafamostat mesilate (NM), a serine protease inhibitor that is frequently used in the clinic, potently suppressed interferon-gamma (IFN-gamma)-induced up-regulation of PD-L1 in cultured human lung cancer cells (HLC-1) at both the messenger RNA (mRNA) and protein levels. Interestingly, suppression of IFN-gamma-induced up-regulation of human leukocyte antigen (HLA)-ABC by NM was limited, suggesting that NM did not block CTL responses to tumour cells. NM treatment did not affect the activation status of signal transducer and activator of transcription (STAT) 1 or the induction of interferon regulatory factor (IRF)-1 expression in IFN-gamma-treated HLC-1 cells. Although NM treatment promoted the phosphorylation of extracellular signal-regulated kinases (Erk) 1/2, an Erk inhibitor, U0126, could not reverse the suppression of PD-L1 up-regulation by IFN-gamma. Suppression of IFN-gamma-induced up-regulation of PD-L1 by NM was not associated with the inhibition of nuclear factor kappa B (NF-kB) or protease-activated receptor (PAR)-1 pathway. Besides HLC-1 cells, NM suppressed IFN-gamma-induced PD-L1 up-regulation in three human pancreatic cancer cell lines. NM could potentiate the antitumour effect of cancer vaccines or immune checkpoint inhibitors by preventing IFN-gamma-induced PD-L1 up-regulation and blocking immune checkpoint suppression.



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Inside front cover

Publication date: December 2017
Source:International Immunopharmacology, Volume 53





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Stigmasterol inhibits lipopolysaccharide-induced innate immune responses in murine models

Publication date: December 2017
Source:International Immunopharmacology, Volume 53
Author(s): Aaron O. Antwi, David D. Obiri, Newman Osafo, Arnold D. Forkuo, Leslie B. Essel
Stigmasterol is a naturally occurring steroid alcohol which occurs in vegetables, soya and a large variety of medicinal plants. Stigmasterol and other phytosterols have been documented as immunomodulators with huge therapeutic potential. We assessed the mitigating effect of stigmasterol on non-fatal and fatal innate immune responses in murine models after intraperitoneal challenge with an endotoxin, lipopolysaccharide, LPS. The effect of stigmasterol on LPS-induced febrile response, inflammatory cell proliferation, multiple organ damage and mortality were respectively investigated. Pretreatment with stigmasterol 10, 50 and 100mg/kg reduced total LPS-induced fever response by 39.93±10.52%, 53.05±5.84% and 77.27±6.25% respectively. Neutrophil proliferation both in blood and recovered peritoneal fluid was significantly reversed by stigmasterol at 50 and 100mg/kg. Lung and liver histopathology showed stigmasterol effectively controlled organ damage. The lung inflammation score of 9.20±0.73 for the polyethylene glycol, PEG-treated disease control mice was reduced respectively to 6.50±0.54, 4.60±0.40 and 4.10±0.42 with 10, 50 and 100mg/kg of stigmasterol. Serum levels of liver enzyme markers, alanine transaminase, ALT and aspartate transaminase, AST were consistent with the observed histological changes. Stigmasterol at 50 and 100mg/kg significantly protected mice from LPS-induced mortality with 40% survival. Overall, stigmasterol inhibits LPS-induced innate immune responses in murine models.

Graphical abstract

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Swertiamarin, a natural steroid, prevent bone erosion by modulating RANKL/RANK/OPG signaling

Publication date: December 2017
Source:International Immunopharmacology, Volume 53
Author(s): M.I. Hairul-Islam, S. Saravanan, K. Thirugnanasambantham, M. Chellappandian, C. Simon Durai Raj, K. Karikalan, M. Gabriel Paulraj, S. Ignacimuthu
Bone erosion is a central feature of rheumatoid arthritis (RA) that is characterized by the infiltration of the synovial lining by osteoclasts and lymphocytes. In the present study, swertiamarin a major secoiridoid glycoside was evaluated for anti-osteoclastogenic property to prevent bone erosion in Freund's complete adjuvant (FCA) induced in-vivo model, in-vitro osteoblast and osteoclasts as well as in co-culture system and in-silico molecular docking analysis. The swertiamarin treatment decreased the expression of TRAP, RANKL, and RANK levels and increased the levels of OPG levels significantly in both in vitro and in vivo models. In in vitro, the compound treatment significantly increased the cell proliferation and ALP levels in osteoblast cells; the high proliferation (153.8600±5.23%) and ALP release (165.6033±4.13%) were observed at 50μg/ml concentration of swertiamarin treatment. At the same time the treatment decreased the TRAP positive cells in osteoclast cells; the high reductions of TRAP positive cells (39.32±3.19%) were observed at 50μg/ml of swertiamarin treatment. The treatment modulated the levels of pro-inflammatory cytokines, MMPs and NF-κB levels in osteoblast and osteoclast co-culture system. In in silico analysis swertiamarin had affinity towards the proteins RANK, RANKL and OPG residues with low binding energy −4.5, −3.92 and −5.77kcal/mol respectively. Thus, the results of this study revealed the anti-osteoclastogenic activity of swertiamarin on the prevention of bone destruction.



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HMGB1 mediates Aspergillus fumigatus-induced inflammatory response in alveolar macrophages of COPD mice via activating MyD88/NF-κB and syk/PI3K signalings

Publication date: December 2017
Source:International Immunopharmacology, Volume 53
Author(s): Pengpeng Zhang, Xiaofeng Xin, Liping Fang, Hao Jiang, Xiaoyong Xu, Xin Su, Yi Shi
The incidence and mortality of Aspergillus fumigatus (A. fumigatus) infected chronic obstructive pulmonary disease (COPD) patients are increasing. HMGB1, which mediates inflammatory response, is increased in COPD patients. However, the role and mechanism of HMGB1 in A. fumigatus-infected alveolar macrophages of COPD mice remain unknown. Alveolar macrophages isolated from COPD mice were infected with A. fumigatus conidia and then HMGB1 expression was assayed. The levels of pro-inflammatory cytokines, which was confirmed by TLR2/4 or Dectin-1 siRNA, RAGE, Dectin-1, and TLR2/4 levels were assayed after HMGB1 knockdown. The effects of HMGB1 on MyD88/NF-κB and syk/PI3K signaling pathways were explored with PDTC (NF-κB inhibitor) and R406 (syk inhibitor). The potential role of HMGB1 was also confirmed in A. fumigatus-infected COPD mice. HMGB1 expression was increased in A. fumigatus-infected COPD alveolar macrophages. The levels of pro-inflammatory cytokines induced in A. fumigatus-infected COPD but not control alveolar macrophages were reduced by HMGB1, TLR2/4 or Dectin-1 siRNA. The expression of Dectin-1 and TLR2/4, but not RAGE was decreased by HMGB1 siRNA. The expression of MyD88, p-p65, p-syk, and PI3K was decreased and IκB increased by HMGB1 knockdown. PDTC and R406 showed the similar effects as HMGB1 siRNA on levels of pro-inflammatory cytokines. The expression of HMGB1, TNF-α, IL-1β, TLR2/4 and Dectin-1, and the activation of MyD88/NF-κB and syk/PI3K signalings in mice were consistent with the in vitro study. In conclusion, HMGB1 is responsible for A. fumigatus-induced inflammatory response in COPD alveolar macrophage via Dectin-1 and TLR2/4 receptor through activating MyD88/NF-κB and syk/PI3K signalings.



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Current and future treatment options for pemphigus: Is it time to move towards more effective treatments?

Publication date: December 2017
Source:International Immunopharmacology, Volume 53
Author(s): Soheil Tavakolpour
Systemic administration of corticosteroid (CS) remains the standard gold treatment for pemphigus. However, because of several long-term adverse effects, steroid-sparing agents are usually prescribed in combination with CSs. Despite the high number of available studies, the choice of best drugs to treat pemphigus remains controversial. Therapeutic approaches for pemphigus can be divided into traditional treatment and emerging ones. Personalized medicine, which aims to increase the efficacy as well as reduce adverse effects of treatments, could be considered as the future option. Here, the most common agents, including azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclophosphamide (CP), rituximab (RTX) and intravenous immunoglobulin (IVIg) have been discussed in detail and compared. Besides, the efficacy and safety profiles of the less frequently used agents such as cyclosporine, dapsone, mizoribine, chlorambucil, plasmapheresis, immunoadsorption and hematopoietic stem cell transplantation have been evaluated. Moreover, some emerging therapeutic options for pemphigus patients, such as B cell activating factor (BAFF), proliferation-inducing ligand (APRIL) inhibitors, anti-cytokine therapy, co-stimulatory and co-inhibitors manipulators and inhibitors of pathogenic signaling pathways (e.g., p38MAPK, c-Myc and EGFR) have been described. In addition to the conventional approaches, some clues to moving towards personalized medicine for the treatment of pemphigus have been proposed. According to the last evidence, seven available first-line combination therapies, including RTX+IVIg, CS+RTX, CS+MMF, CS+AZA, CS+MTX, CS+CP and CS+IVIg were suggested and compared. Subsequently, the most optimum drugs for three different conditions, including patients with no pregnancy or infection, those at high risk of development/reactivation of infection or pregnant women were suggested.



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Tim-3 enhances brain inflammation by promoting M1 macrophage polarization following intracerebral hemorrhage in mice

Publication date: December 2017
Source:International Immunopharmacology, Volume 53
Author(s): Anyong Yu, Xiaojun Zhang, Mo Li, Peng Ye, Haizhen Duan, Tianxi Zhang, Zhao Yang
Macrophage polarization contributes to brain inflammation following spontaneous intracerebral hemorrhage (ICH). T cell immunoglobulin and mucin domain-3 (Tim-3) has been identified to induce macrophage mediated inflammation following ICH. However, the regulation of Tim-3 on macrophage polarization following ICH has not been fully studied. In current experiment, we explored Tim-3 expression, macrophage polarization, brain water content and neurological function in WT and Tim-3⁻/⁻ ICH mice. In addition, downstream transcriptional factor TRIF and IRF3 were also analyzed. We found that ICH promoted Tim-3 expression and M1 polarization in the perihematomal region of WT mice, leading to increased brain water content and neurological impairment. However, deletion of Tim-3 expression attenuated M1 polarization, decreased rain water content and improved neurological function of ICH mice. Furthermore, Tim-3 signal promoted transcriptional factors TRIF and IRF3 levels, regulating macrophage polarization. The data suggested that Tim-3 played a crucial role in the macrophage polarization and brain inflammation following ICH, and might represent a promising way in ICH therapy.



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Oxymatrine protects against DSS-induced colitis via inhibiting the PI3K/AKT signaling pathway

Publication date: December 2017
Source:International Immunopharmacology, Volume 53
Author(s): Qianyun Chen, Xueyun Duan, Heng Fan, Meng Xu, Qing Tang, Lijuan Zhang, Zhexing Shou, Xingxing Liu, Dongmei Zuo, Jia Yang, Shuangjiao Deng, Yalan Dong, Hui Wu, Yujin Liu, Zhen Nan
Oxymatrine (OMT), an alkaloid derived from the root of the Sophora flavescens, has been reported to possess a significant effect on relieving UC owing to its anti-inflammatory property. But the other therapeutic mechanism of OMT remains unclear. Recent studies have found, PI3K/AKT signaling pathway is involved in the pathogenesis of UC by pro-inflammatory effects and activating T cells. Moreover, PI3K/AKT pathway is one of the most important pathways for regulating cell apoptosis. Thus, we aim to explore whether OMT protects against UC by targeting PI3K/AKT pathway. We established the UC mice models, using LY294002 (a specific inhibitor of PI3K/AKT) as a positive control, to observe the effect of low, medium and high dose of OMT on UC and its influence on PI3K/AKT signaling pathway. Our data indicated that OMT can significantly ameliorate UC through anti-inflammatory, pro-apoptotic, down-regulating the differentiation of Th1 and Th17 cells via PI3K/AKT pathway. This study reveals that PI3K/AKT signaling pathway is a potential mechanism of OMT-induced UC remission and suggests that OMT is a promising therapeutic agent for the treatment of UC.

Graphical abstract

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IFC (Journal of Ethnopharmacology)

Publication date: 30 January 2018
Source:Journal of Ethnopharmacology, Volume 211





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Is the hype around the reproductive health claims of maca (Lepidium meyenii Walp.) justified?

Publication date: 30 January 2018
Source:Journal of Ethnopharmacology, Volume 211
Author(s): Shruti Beharry, Michael Heinrich
Ethnopharmacological relevanceMaca – Lepidium meyenii Walp. has been cultivated and used by Andean people for over 1300–2000 years in Peru as food and medicine. Starting in the late 1990's it has developed into an important herbal medicine in China and is now cultivated there widely, tooAim of studyThis study aims to provide an insight into the emergence of maca on the global market as an alternative remedy to treat reproductive health related problems in both men and women and to critically assess these health claims.MethodologyA search of electronic databases such as EMBASE and a hand-search was done to acquire peer-reviewed articles and reports about maca.Results and discussionLepidium meyenii is used traditionally as a tonic, fertility enhancer for both humans and cattle, and to treat a variety of ailments such as rheumatism, respiratory disorders and anaemia among others. Maca root is cooked, baked, fermented as a drink and made into porridge. In the last twenty years, maca was introduced onto the global market and demand has dramatically grown over this time with its promotion on the internet, as the 'Peruvian Ginseng' for libido and fertility enhancement. It has also been said to treat menopausal symptoms, erectile dysfunction and benign prostatic hyperplasia. The sky-rocketing demand for the plant has seen a shift from traditional cultivation methods to mass production practices with the use of fertilisers and also pesticides; as maca is now grown in areas other than the Andes such as in the Yunnan province in China. This can potentially affect the phytochemistry and composition of the plant and thus, the quality, safety and efficacy of maca products. Meanwhile, research into maca's medicinal properties has followed the spike in popularity of maca and has been focused mainly on maca's aphrodisiac and fertility enhancing properties. So far, the in vivo studies and clinical trials conducted have yielded inconclusive results. Some of the key limitations reside in methodology and sample size. Chemical profiling, led to the discovery of new compounds unique to maca, such as, 'macamides' and also other active metabolites like the glucosinolates; to which the medicinal effects of maca have been ascribed but cannot be confirmed due to lack of data.ConclusionsTo date, the health claims of maca cannot be fully supported from a scientific standpoint and more research is needed. It appears that the indigenous local knowledge about the health benefits of maca has been dragged out of context to fit the demands of a growing market for herbal remedies. This globalisation (or hype esp. in China) also has had serious consequences for the local producers in Peru. The lack of protocols to regulate the production and marketing of maca during this rapid expansion, poses a threat to both the safety of consumers and the sustainability of supply.

Graphical abstract

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The memory ameliorating effects of DHP1402, an herbal mixture, on cholinergic blockade-induced cognitive dysfunction in mice

Publication date: 30 January 2018
Source:Journal of Ethnopharmacology, Volume 211
Author(s): Haneul Kim, Hyung Eun Lee, In Ho Jung, Se Jin Jeon, Jiabao Zhang, Yubeen Kwon, Dae Sik Jang, Jong Hoon Ryu
Ethnopharmacological relevanceThe seeds of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F Chow (Rhamnaceae) and the roots of Codonopsis lanceolata (Siedbold & Zucc.) Benth. & Hook. f ex Trautv. (Campanulaceae), contained in the DHP1402, have long been used for treating dementia or hypomnesia as folk medicine.Aim of the studyIt has been reported that Z. jujuba var. spinosa and C. lanceolata are effective in improving cognitive function, but via different mechanisms. Therefore, in the present study, we evaluated the synergistic effects of Z. jujuba var. spinosa and C. lanceolata on scopolamine-induced memory impairment.Materials and methodsScopolamine, a cholinergic muscarinic receptor antagonist, was used to induce cognitive dysfunction. We employed several behavioral tasks to estimate the synergistic effect of the seeds of Z. jujuba var. spinosa and the roots of C. lanceolata. In addition, we introduced the Western blotting, the antagonism passive avoidance task to investigate a synergistic effect of an herbal formulation.ResultsSynergistic effects of a combination of Z. jujuba var. spinosa and C. lanceolata at a 5:1 ratio [(w/w), DHP1402] were observed against cognitive dysfunction in the passive avoidance and Y-maze tasks. DHP1402 also ameliorated memory deficits in a dose-dependent manner in these behavioral tasks, as well as in the Morris water maze task. According to the Western blot results, the phosphorylation levels of protein kinase A (PKA), extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus were also increased in a synergistic manner after the administration of DHP1402. In addition, we found that the effects of DHP1402 on cognitive function were mediated by N-methyl-D-aspartate (NMDA) receptor signalling, based on the antagonism studies. Furthermore, we found that DHP1402 has inhibitory activity against acetylcholinesterase (AChE).ConclusionDHP1402 attenuates cholinergic blockade-induced cognitive dysfunction through NMDA receptor modulation, PKA-ERK-CREB pathway activation, and AChE inhibition. Therefore, DHP1402 could be a candidate for alleviating cognitive dysfunction.

Graphical abstract

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Neuronal expression patterns of the PlexinA family during zebrafish development

Publication date: Available online 28 October 2017
Source:Gene Expression Patterns
Author(s): Sarah E. Emerson, Sarah E. Light, Alicia M. Ebert
Plexins (Plxns) and Semaphorins (Semas) are key signaling molecules that regulate many aspects of development. Plxns are a family of transmembrane protein receptors that are activated upon extracellular binding by Semas. Activated Plxns trigger intracellular signaling cascades, which regulate a range of developmental processes, including axon guidance, neuronal positioning and vasculogenesis. Semas are a large family of both transmembrane and secreted signaling molecules, and show subtype specific binding to different Plxn family members. Each Plxn can play different roles in development, and so tightly regulated temporal and spatial expression of receptor subtypes is critical to ensure appropriate signaling. Here we elucidate the expression profiles of the plxnA family, plxnA1a, A1b, A2, A3 and A4 at 18, 24, 36, 48, 60 and 72 h post fertilization in the developing zebrafish. We show that PlxnA family members are expressed in neuronal tissues during zebrafish development, but exhibit key differences in expression within these tissues. We also highlight that plxnA1 has two genes in zebrafish, A1a and A1b, which show divergences in expression patterns during early development.



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Editorial Board

Publication date: November 2017
Source:Cancer Treatment Reviews, Volume 60





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Cutaneous T-cell lymphomas: focusing on novel agents in relapsed and refractory disease

Publication date: Available online 28 October 2017
Source:Cancer Treatment Reviews
Author(s): Lisa Argnani, Alessandro Broccoli, Pier Luigi Zinzani
Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory CTCL. Three FDA approved compounds are used as single agents including the oral retinoid bexarotene and histone deacetylase inhibitors romidepsin and vorinostat. Brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody, has received from European Commission the orphan designation but has not been approved by EMA yet. Several other molecules have demonstrated their activity in the same context and combination strategies are being explored. Participation in a well designed clinical trial is encouraged, as the introduction of novel agents will continue to expand the therapeutics options available in the management of CTCL.



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The Unsolved Problem of How Cells Sense Micron-Scale Curvature

Publication date: Available online 28 October 2017
Source:Trends in Biochemical Sciences
Author(s): Kevin S. Cannon, Benjamin L. Woods, Amy S. Gladfelter
Membrane curvature is a fundamental feature of cells and their organelles. Much of what we know about how cells sense curved surfaces comes from studies examining nanometer-sized molecules on nanometer-scale curvatures. We are only just beginning to understand how cells recognize curved topologies at the micron scale. In this review, we provide the reader with an overview of our current understanding of how cells sense and respond to micron-scale membrane curvature.



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Long-term outcomes of APBI via multicatheter interstitial HDR brachytherapy: Results of a prospective single-institutional registry

Publication date: Available online 28 October 2017
Source:Brachytherapy
Author(s): Prashant Gabani, Amy E. Cyr, Jacqueline E. Zoberi, Laura L. Ochoa, Melissa A. Matesa, Maria A. Thomas, Jose Garcia, Julie A. Margenthaler, Michael J. Naughton, Cynthia Ma, Souzan Sanati, Imran Zoberi
PurposeLong-term outcome reports of accelerated partial-breast irradiation (APBI) are limited. Here, we report the 10-year outcomes of APBI delivered using multicatheter interstitial implant (ISI) brachytherapy.Methods and materialsPatients with early-stage breast cancer treated with APBI via ISI brachytherapy were enrolled in a prospective registry. Selection criteria included age ≥40 years, ductal carcinoma in situ or invasive tumor ≤3 cm, negative margins (≥2 mm), and negative axillary nodes. 34 Gy in 10 twice-daily fractions was administered to 2 cm of breast tissue surrounding the surgical bed. Toxicity and cosmetic outcomes were collected prospectively.ResultsA total of 175 patients were included. The median followup time was 10.0 years. Ten-year ipsilateral breast tumor control, regional control, freedom from distant metastasis, breast cancer–specific survival, and overall survival were 92.1%, 96.9%, 97.4%, 97.1%, and 81.2%, respectively. High-grade disease was correlated with increase in the rate of ipsilateral breast tumor recurrence. Grade 1 or 2 skin toxicity was present in 44 patients, and Grade 3 skin toxicity was present in only 1 patient. There were no Grade 4 or higher toxicities observed. Thirty-seven patients developed fat necrosis. Dose Homogeneity Index of ≤0.85 and integrated reference air-kerma of >3400 cGycm²/h correlated with higher rates of fat necrosis. There were 115 (66%), 51 (29%), 8 (5%), and 0 (0%) patients having excellent, good, fair, and poor cosmetic outcomes, respectively.ConclusionsAPBI using ISI brachytherapy offers excellent clinical outcomes in appropriately selected patients with excellent cosmetic outcomes and low rates of toxicities such as symptomatic fat necrosis.



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Long-term evaluation of urinary, sexual, and quality of life outcomes after brachytherapy for penile carcinoma

Publication date: Available online 28 October 2017
Source:Brachytherapy
Author(s): Dimitri Gambachidze, Cédric Lebacle, Pierre Maroun, Alexandre Escande, Alberto Bossi, Pierre Blanchard, Eric Deutsch, Christine Haie-Meder, Cyrus Chargari
PurposeBrachytherapy (BT) is an effective organ-preserving treatment for selected localized penile carcinoma, providing high local control rates. Long-term functional results however, are still insufficiently evaluated.Methods and MaterialsAll consecutive patients treated with low-dose-rate or pulse-dose-rate BT in our institute for a localized penile cancer and who were in first complete remission and followed for at least 3 years were included. A self-reporting questionnaire was sent, to assess: 1/urinary function, 2/sexual function, 3/cosmetic aspect of the penis, and 4/quality of life.ResultsThirty-nine patients fulfilled inclusion criteria and were sent the questionnaire. Twenty-three patients (59%) answered. Median age was 63.4 years, (interquartile range [IR]: 49.7–67.0). Median followup was 5.9 years (IR: 5.2–6.7). The urinary scores showed moderate lower urinary tract symptoms. During the followup, a urethral dilation or self-catheterization had been necessary in 30% and 13%, respectively. Sixteen (70%) patients continued to maintain a sexual activity and the erectile dysfunction was mild. Finally, quality of life was good with a median score of 80/100 (IR = 65–90) and was only impacted by pain (p = 0.02). Overall, 57% and 39% declared having none or moderate pain/discomfort, respectively.ConclusionsAlthough this questionnaire needs to be validated in an independent cohort, our results show the moderate impact of BT on functional outcomes, confirming that it is an adequate first-intent organ-sparing strategy in patients with localized penile carcinoma.



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Effect of controlled cortical impact on the passage of pituitary adenylate cyclase activating polypeptide (PACAP) across the blood-brain barrier

Publication date: Available online 28 October 2017
Source:Peptides
Author(s): Elizabeth M. Rhea, Kristin M Bullock, William A. Banks
Injuries to the central nervous system can affect the blood-brain barrier (BBB), including disruption and influencing peptide transport across the BBB. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a potent neurotrophic and neuroprotective peptide currently being investigated for its therapeutic role following injury to the central nervous system and can cross the BBB in a saturable manner. The goal of the current study was to investigate for the first time PACAP38 uptake by the brain following traumatic brain injury (TBI). Using radioactively labeled PACAP38, we measured the levels of PACAP38 present in the injured, ipsilateral cortex in Sham-treated mice compared to mice receiving a controlled cortical impact (CCI), a model of TBI. Experiments were conducted at 6 different time points (from 2hours up to 4 weeks) following CCI to determine temporal changes in PACAP38 transport. PACAP38 uptake was increased at 2 and 72hours post-CCI compared to Sham. We did not detect changes in PACAP38 uptake in the contralateral cortex and cerebellum between Sham and CCI-treatment. The rate of PACAP38 transport into the ipsilateral cortex following CCI was increased 3.6-fold 72hours after compared to 2hours post-CCI. In addition, the rate of transport into the cerebellum was greater than that of the cortices. The data presented here shows PACAP38 transport is temporally altered following CCI-treatment and PACAP38 uptake is greater in the cerebellum compared to the cortices.



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Safety and Efficacy of the New Micromesh-Covered Stent CGuard in Patients Undergoing Carotid Artery Stenting: Early Experience From a Single Centre

Publication date: Available online 28 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Renato Casana, Valerio Tolva, Andrea Odero, Chiara Malloggi, Aldo Paolucci, Fabio Triulzi, Vincenzo Silani
Objective/BackgroundPlaque protrusion through stent struts represents one of the principal causes of cerebral embolisation during carotid artery stenting (CAS) and the stent healing period. The aim of this study was to evaluate the safety (technical success) and efficacy (clinical success) of the CGuard stent system – a new nitinol stent covered by a closed-cell polyethylene terephthalate mesh designed to prevent embolic events.MethodsEighty-two consecutive patients who underwent CAS with CGuard from June 2015 were included in this study. The same surgeon performed all procedures. Primary endpoints included technical and clinical success. Clinical success was considered to be absence of death, major or minor stroke. The incidence of new ischaemic brain lesions was also evaluated by diffusion weighted magnetic resonance imaging (DW-MRI) in a subgroup of patients as a secondary endpoint.ResultsIn this study, 82 patients (73.8 ± 8.5 years, 75% male, 19% symptomatic) underwent CAS procedures. Immediate technical success was 100%, with the stenosis diameter reduced from 81.4 ± 4.9% to 11.0 ± 3.5%. There was peri-operative technical and clinical success in 100% of symptomatic patients, and in 98.5% of asymptomatic patients, because of the occurrence of one acute stent thrombosis 4 hours post-CAS followed by a minor stroke. In the post-operative period (30 days), no new events were registered. The most recent 21 patients (24%) underwent DW-MRI in the peri-operative period: new ischaemic brain lesions were recorded in 23.8% of patients and the average lesion volume per patients was 0.039 ± 0.025 cm³.ConclusionsThe technical and clinical outcomes of this single centre study suggest that the CGuard may be a safe and effective device for endovascular treatment of symptomatic and asymptomatic subjects, independent of aortic arch anatomy. Further larger comparative studies are needed to confirm these benefits.



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Occurrence and Classification of Proximal Type I Endoleaks After EndoVascular Aneurysm Sealing Using the Nellix™ Device

Publication date: Available online 28 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Leo H. van den Ham, Andrew Holden, Janis Savlovskis, Andrew Witterbottom, Kenneth Ouriel, Michel M.P.J. Reijnen
Objective/BackgroundProximal type I endoleaks are associated with abdominal aortic aneurysm (AAA) growth and rupture and necessitate repair. The Nellix™ EndoVascular Aneurysm Sealing (EVAS) system is a unique approach to AAA repair, where the appearance and treatment of endoleaks is also different. This study aimed to analyse and categorise proximal endoleaks in an EVAS treated cohort.MethodsAll patients, treated from February 2013 to December 2015, in 15 experienced EVAS centres, presenting with proximal endoleak were included. Computed tomography scans were analysed by a core laboratory. A consensus meeting was organised to discuss and qualify each case for selection, technical aspects, and possible causes of the endoleak. Endoleaks were classified using a novel classification system for EVAS.ResultsDuring the study period 1851 patients were treated using EVAS at 15 centres and followed for a median of 494 ± 283 days. Among these, 58 cases (3.1%) developed a proximal endoleak (1.5% early and 1.7% late); of these, 84% of 58 patients were treated outside the original and 96% outside the current, refined, instructions for use. Low stent positioning was the most likely cause in 44.6%, a hostile anatomy in 16.1%, and a combination of both in 33.9%. Treatment, by embolisation or proximal extension, was performed in 47% of cases, with a technical success of 97%.ConclusionThe overall incidence of proximal endoleak after EVAS is 3.1% after a mean follow-up period of 16 months, with 1.5% occurring within 30 days. Their occurrence is related to patient selection and stent positioning. Early detection and classification is crucial to avoid the potential of sac rupture.



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The relationship between gluten free diet adherence and depressive symptoms in adults with coeliac disease: A systematic review with meta-analysis

Publication date: 1 January 2018
Source:Appetite, Volume 120
Author(s): Kirby Sainsbury, Marta M. Marques
PurposeDepressive symptoms are common in patients with coeliac disease (CD) and may represent a barrier to gluten free diet (GFD) adherence. The aims of this meta-analysis were: (1) to synthesise the evidence on the relationship between depression or depressive symptoms and degree of adherence to a GFD in patients with CD who are already attempting a GFD (i.e., post-diagnosis and onset of GFD), and (2) to summarise the direction of causation of any observed relationship.MethodsA random effects meta-analysis of 8 cross-sectional studies (N = 1644) was conducted. Included studies measured self-reported depressive symptoms and GFD adherence using either a dietitian interview or validated self-report questionnaire that considered unintentional gluten consumption.ResultsThere was a moderate association between poorer GFD adherence and greater depressive symptoms (r = 0.398, 95% CI = 0.321–0.469), with marked heterogeneity in the effects (I² = 66.8%). A sensitivity analysis excluding studies with a moderate/high (k = 1) or unclear risk of bias (k = 1) did not change the results.ConclusionThe low number of studies meeting inclusion criteria limits the strength of the conclusions. Available evidence suggests there is an association between poorer GFD adherence and self-reported depressive symptoms; however, studies using longitudinal and prospective designs, and reliable measures, particularly for adherence, are needed to confirm this association. The direction of causation between depression and adherence remains unclear.



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Central theta amplitude as a negative correlate of performance proficiency in a dynamic visuospatial task

Publication date: Available online 28 October 2017
Source:Biological Psychology
Author(s): Fernando Cross-Villasana, Peter Gröpel, Felix Ehrlenspiel, Jürgen Beckmann
Dynamic visuospatial tasks, requiring continuous engagement of attention over long time periods, have been little studied with the electroencephalogram. Specifically, the role of the theta band in these tasks is unclear, with task-related theta enhancements improving performance in some studies, and hindering it in others. In this study, 30 participants performed the Pong videogame as a dynamic visuospatial task to analyze the influence of theta and alpha amplitude as well as alpha asymmetry on performance. The theta band increased significantly at central-parietal regions and correlated negatively with performance, especially at anterior regions. The alpha band showed a significant decrease, greater at right over left parietal regions, but neither the amplitude nor the asymmetry ratio correlated with performance. With theta being an indicator of top-down cognitive control, it may be concluded that proficient performance in dynamic visuospatial tasks depends on a bottom-up guidance of attention with little top-down intervention.



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Parent Emotion Socialization and Pre-Adolescent’s Social and Emotional Adjustment: Moderating Effects of Autonomic Nervous System Reactivity

Publication date: Available online 28 October 2017
Source:Biological Psychology
Author(s): Julia D. McQuade, Rosanna P. Breaux
This study examined whether measures of children's autonomic nervous system (ANS) reactivity to social stress moderated the effect of parent emotion socialization on children's social and emotional adjustment. Sixty-one children (9 to 13 years) completed a peer rejection task while their respiratory sinus arrhythmia reactivity (RSA-R) and skin conductance level reactivity (SCL-R) were assessed. Parents' report of supportive and non-supportive reactions to their child's negative emotions served as measures of emotion socialization. Measures of children's social and emotional adjustment included: teacher-rated peer rejection, aggression, and prosocial behavior and parent-rated aggressive/dysregulated behavior and emotion regulation skills. Measures of children's ANS reactivity moderated the effect of parent emotion socialization on children's adjustment. Supportive responses were more protective for children evidencing RSA augmentation whereas non-supportive responses were more detrimental for children evidencing low SCL-R. Thus children's ANS reactivity during social stress may represent a biological vulnerability that influences sensitivity to parent emotion socialization.



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Identification of nitroimidazole-oxime derivatives targeting the polo-box domain of polo-like kinase 1

Publication date: Available online 28 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Juan Sun, Han-Yu Liu, Ruo-Fei Xu, Hai-Liang Zhu
Recent progress in the development of small molecular skeleton-derived Polo-like kinase (PLK1) catalytic domain (KD) inhibitors has led to the synthesis of multiple ligands with high binding affinity. However, few systematic analyses have been conducted to identify key PLK1-PBD domain and characterize their interactions with potent PLK1 inhibitors. Therefore, we designed a series of PLK1-PBD inhibitors with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. The biological profile of 4v suggests that this compound may be developed as a potential anticancer agent.

Graphical abstract

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A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Takayuki Shiratsuchi, Urvashi Rai, Izumi Kaneko, Min Zhang, Shiroh Iwanaga, Masao Yuda, Moriya Tsuji
Adenovirus (Ad) is thought to be one of the most promising platforms for a malaria vaccine targeted against its liver stages, because of its ability to induce a strong T-cell response against a transgene. However, a further improvement of this platform is needed in order to elicit another arm of the immunity, i.e. humoral response, against malaria.In order to augment immunogenicity and protective efficacy of Ad-based malaria vaccine, we inserted B-cell, as well as CD4+ T-cell, epitopes of Plasmodium falciparum circumsporozoite protein (PfCSP) into the capsid protein, Hexon, and the core protein, VII (pVII), of Ad, respectively, in addition to the PfCSP transgene. Insertion of PfCSP-derived B cell epitope to Hexon significantly enhanced the epitope-specific antibody response compared to AdPfCSP, an Ad vaccine expressing only PfCSP transgene. PfCSP-derived CD4+ T-cell epitope insertion into pVII augmented not only PfCSP-specific CD4+ T-cell response but also anti-PfCSP antibody response. Finally, mice immunized with AdPfCSP having both Hexon and pVII modifications were more protected than AdPfCSP or Hexon-modified AdPfCSP against challenge with transgenic rodent malaria parasites expressing the PfCSP.Overall, this study has demonstrated that Hexon and pVII-modified AdPfCSP vaccine is a promising malaria vaccine which induces strong PfCSP-specific humoral, CD4+ T-cell, and CD8+ T-cell responses and protects against infection with transgenic malaria parasites expressing the PfCSP.



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A multi-site feasibility study to assess fever and wheezing in children after influenza vaccines using text messaging

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Melissa S. Stockwell, Colin D. Marchant, A. Patrica Wodi, Elizabeth D. Barnett, Karen R. Broder, Kathleen Jakob, Paige Lewis, Meyer Kattan, Anne Marie Rezendes, Angela Barrett, Devindra Sharma, Nadira Fernandez, Philip LaRussa
BackgroundUsing text messaging for vaccine safety monitoring, particularly for non-medically attended events, would be valuable for pandemic influenza and emergency vaccination program preparedness. We assessed the feasibility and acceptability of text messaging to evaluate fever and wheezing post-influenza vaccination in a prospective, observational, multi-site pediatric study.MethodsChildren aged 2–11 years old, with an emphasis on children with asthma, were recruited during the 2014–2015 influenza season from three community-based clinics in New York City, and during the 2014–2015 and 2015–2016 seasons from a private practice in Fall River, Massachusetts. Parents of enrolled children receiving quadrivalent live attenuated (LAIV4) or inactivated influenza vaccine (IIV4) replied to text messages assessing respiratory symptoms (day 3 and 7, then weekly through day 42), and temperature on the night of vaccination and the next seven nights (day 0–7). Missing data were collected via diary (day 0–7 only) and phone. Phone confirmation was obtained for both presence and absence of respiratory symptoms. Reporting rates, fever (T≥100.4 °F) frequency, proportion of wheezing and/or chest tightness reports captured via text message versus all sources (text, phone, diary, electronic health record) and parental satisfaction were assessed.ResultsAcross both seasons, 266 children were analyzed; 49.2% with asthma. Parental text message response rates were high (>70%) across sites. Overall, fever frequency was low (day 0–2: 4.1% [95% confidence interval (CI) 2.3–7.4%]; d3–7: 6.7% [95% CI 4.1–10.8%]). A third (39.2%) of parents reported a respiratory problem in their child, primarily cough. Most (88.2%) of the 52 wheezing and/or chest tightness reports were by text message. Most (88.1%) participants preferred text messaging over paper reporting.ConclusionsText messaging can provide information about pediatric post-vaccination fever and wheezing and was viewed positively by parents. It could be a helpful tool for rapid vaccine safety monitoring during a pandemic or other emergency vaccination program.Trial registration: clinicaltrials.gov Identifier: NCT02295007.



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Use of surveillance data to calculate the sample size and the statistical power of randomized clinical trials testing Staphylococcus aureus vaccine efficacy in orthopedic surgery

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Marie-Paule Gustin, Robin Ohannessian, Marine Giard, Emmanuelle Caillat-Vallet, Anne Savey, Philippe Vanhems
BackgroundPatients undergoing primary total hip arthroplasty (THA) would be a worthy population for anti-staphylococcal vaccines. The objective is to assess sample size for significant vaccine efficacy (VE) in a randomized clinical trial (RCT).MethodsData from a surveillance network of surgical site infection in France between 2008 and 2011 were used. The outcome was S. aureus SSI (SASSI) within 30 days after surgery. Statistical power was estimated by simulations repeated for theoretical VE ranging from 20% to 100% and for sample sizes from 250 to 8000 individuals per arm.Results18,688 patients undergoing THA were included; 66 (0.35%) SASSI occurred. For a 1% SASSI rate, the sample size would be at least 1316 patients per arm to detect significant VE of 80% with 80% power.ConclusionSimulations with real-life data from surveillance of hospital acquired infections allow estimation of power for RCT and sample size to reach the required power.



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Superior immunogenicity of HCV envelope glycoproteins when adjuvanted with cyclic-di-AMP, a STING activator or archaeosomes

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): A. Landi, J. Law, D. Hockman, M. Logan, K. Crawford, C. Chen, J. Kundu, T. Ebensen, C.A. Guzman, L. Deschatelets, L. Krishnan, D.L.J. Tyrrell, M. Houghton
Three decades after the discovery, hepatitis C virus (HCV) is still the leading cause of liver transplantation and poses a major threat to global health. In spite of recent advances in the development of direct acting antivirals, there is still a need for a prophylactic vaccine to limit the virus spread and protect at-risk populations, especially in developing countries, where the cost of the new treatments may severely limit access. The use of recombinant HCV glycoproteins E1E2 (rE1E2) in combination with the MF59, an oil-in-water emulsion-based adjuvant, has previously been shown to reduce the rate of chronicity in chimpanzees and to induce production of cross-neutralizing antibodies and cellular immune responses in human volunteers. To further improve neutralizing antibody responses in recipients along with robust T cell responses, we have explored the immunogenicity of different adjuvants when formulated with the HCV rE1E2 vaccine in mice.Our data show that cyclic di-adenosine monophosphate (c-di-AMP) and archaeosomes elicit strong neutralizing antibodies similar to those elicited using aluminum hydroxide/monophosphoryl lipid A (Alum/monophos. /MPLA) and MF59. However, both c-di-AMP and archaeosomes induced a more robust cellular immune response, which was confirmed by the detection of vaccine-specific poly-functional CD4⁺ T cells. We conclude that these adjuvants may substantially boost the immunogenicity of our E1E2 vaccine. In addition, our data also indicates that use of a partial or exclusive intranasal immunization regimen may also be feasible using c-di-AMP as adjuvant.



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Driving immunization through the Medicare Annual Wellness Visit: A growing opportunity

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Angela K. Shen, Rob Warnock, Jeffrey A. Kelman
IntroductionThe Annual Wellness Visit (AWV) is a Medicare benefit designed to help prevent disease and disability based on individualized health and risk factors.MethodsThis study analyzes Medicare Part B fee-for-service claims from 2011 to 2016 to assess AWV and seasonal influenza and pneumococcal conjugate vaccinations utilization over time.ResultsUtilization of the AWV has increased from 8% of Medicare beneficiaries in 2011 to 19% in 2015. In each year, influenza and PCV13 vaccination rates are higher among those who utilize the benefit. More than one-third (33%) of patients who had an AWV in 2015 received a PCV13 vaccination in that same year, compared to 14% of those who did not. Similarly, the seasonal influenza vaccination rate was 64% among those with an AWV and 44% among those without.ConclusionThe AWV demonstrates promise for improving immunization rates among Medicare beneficiaries particularly at the point of care.



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Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy?

Publication date: Available online 28 October 2017
Source:Radiotherapy and Oncology
Author(s): Catharina T.G. Roos, Veerle A.B. van den Bogaard, Marcel J.W. Greuter, Rozemarijn Vliegenthart, Ewoud Schuit, Johannes A. Langendijk, Arjen van der Schaaf, Anne P.G. Crijns, John H. Maduro
Background and purposeThe main objective of this study was to test whether pre-treatment coronary artery calcium (CAC) was associated with the cumulative incidence of acute coronary events (ACE) among breast cancer (BC) patients treated with postoperative radiotherapy (RT).Material and methodsThe study population consisted of 939 consecutive female BC patients treated with RT. The association between CAC and ACE was tested using Cox-proportional hazard models. Known risk factors for ACE and the mean heart dose (MHD), collected from three-dimensional computed tomography planning data, were tested for confounding.ResultsCAC scores varied from 0 to 2,859 (mean 27.3). The 9-year cumulative incidence of ACE was 3.2%, this was significantly associated with the pre-treatment CAC score. After correction for confounders, age, history of ischemic heart disease, diabetes, Body Mass Index ≥30, MHD, hypercholesterolemia and hypertension, the hazard ratio for ACE for the low and the combined intermediate and high CAC score category were 1.42 (95%CI: 0.49–4.17; p = 0.519) and 4.95 (95%CI: 1.69–14.53; p = 0.004) respectively, compared to the CAC zero category.ConclusionsHigh pre-treatment CAC is associated with ACE in BC patients treated with postoperative RT, even after correction for confounding factors such as MHD.



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