Radiology

Original Research

Breast Imaging   Age-based versus Risk-based Mammography Screening in Women 40–49 Years Old: A Cross-sectional Study   Hypothetical screening scenarios show that for women 40–49 years old, initiating age-based mammography screening starting at age 45 reveals more cancers and results in more false-positive mammograms and benign biopsy results than risk-based screening; however, short-term outcome differences depended on age range: 40–44-year-olds in both scenarios had similar outcomes, which resembled those of not screening, while 45–49-year-olds showed significant differences for all outcomes.    Elizabeth S. Burnside, Amy Trentham-Dietz...Lee G. Wilke

Cardiac Imaging   Prognostic Value and Risk Continuum of Noninvasive Fractional Flow Reserve Derived from Coronary CT Angiography   A CT-derived fractional flow reserve (FFRCT) of 0.8 or less is a predictor of long-term clinical outcomes and is superior to clinically significant stenosis on coronary CT angiograms. A normal FFRCT is associated with favorable long-term prognosis and the numeric value of FFRCT also demonstrates an independent and inversely related risk continuum.     Abdul Rahman Ihdayhid, Bjarne L. Norgaard...Brian S. Ko

Editorial: On the Voyage from Anatomic to Physiologic Guidelines for Coronary Intervention Carole Dennie, Fraser D. Rubens

Health Policy and Practice   Evaluation of the Patient Request Process for Radiology Imaging in U.S. Hospitals   Patient access to radiologic imaging results is primarily limited to obtaining imaging studies on a compact disc, with less online availability of their imaging studies.    Carolyn T. Lye, Harlan M. Krumholz...Howard P. Forman

Neuroradiology   Quantitative Brain Sodium MRI Depicts Corticospinal Impairment in Amyotrophic Lateral Sclerosis   Sodium MRI depicts disease-relevant regional alterations in sodium homeostasis in the precentral gyri, corticospinal tracts, and corpus callosum of patients with amyotrophic lateral sclerosis.     Aude-Marie Grapperon, Ben Ridley...Wafaa Zaaraoui

Special Report   PI-RADS Steering Committee: The PI-RADS Multiparametric MRI and MRI-directed Biopsy Pathway   The Prostate Imaging Reporting and Data System MRI-directed biopsy pathway enables the delivery of key diagnostic benefits to men suspected of having cancer according to their clinical priorities.     Anwar R. Padhani, Jelle Barentsz...Jeffrey C. Weinreb

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Oral and Maxillofacial Radiology

Orbital cavity evaluation in a Brazilian population Alanalaiz Magalhaes Pereira, Antonio Azoubel Antunes, Evelyne Pessoa Soriano, Breno Henrique Mara Rodrigues, Vinicius Balan Santos Pereira, Gabriela Granja Porto Journal of Oral and Maxillofacial Radiology 2019 7(1):1-5 Objective: The main objective is to analyze the differences between the orbital cavities according to age and sex in a population from the Northeast of Brazil and compare with a specific Chinese population. Methodology: Linear measurements on 8 points of the orbit were made in a sample of 113 patients, based on each sex and age range (<19, 20–39, 40–59 and ≥ 60 years old). The distances were orbital width, orbital height, medial orbital wall, lateral orbital wall, superior orbital wall, inferior orbital wall, interorbital width, and biorbital width. Results: It was noticed that the orbital cavities of men were higher in all measures than those of women (P < 0.001), except for the orbital height and the distance between the orbits. Younger patients showed a tendency to have smaller orbits. Comparing the measurements obtained for the Brazilian participants with those of Chinese, the orbits of Brazilians were significantly higher on all measures (P < 0.001), except for biorbital breath. Conclusion: There were significant differences between most measures of orbital cavities between men and women in the Brazilian population, while differences were seen in all measurements between Brazilian and Chinese population.

Entrance skin dose of the thyroid gland area following exposure with different protocols of two panoramic and cone-beam computed tomography devices Bardia Vadiati Saberi, Negar Khosravifard, Tahereh Mohtavipour, Farnoosh Khaksari, Sara Abbasi, Ataollah Shahmalakpoor Journal of Oral and Maxillofacial Radiology 2019 7(1):6-11 Background: Cone-beam computed tomography (CBCT) has gained considerable use, while radiation burden remains an important concern. Aims: This study aimed at determining the entrance skin dose of the thyroid gland area through exposure with the normal, soft, and hard modes of Vatech (Pax-i) panoramic device as well as different field of views (FOVs) of Vatech (Pax-i 3D) CBCT system. Materials and Methods: Dose measurements were performed on a head-and-neck phantom by an ion chamber dosimeter. Panoramic imaging was done in three normal, soft, and hard modes, each entailing woman, man, and child options. CBCT examinations were performed with various FOVs, each having normal, soft, and hard modes as well as woman, man, and child choices. Doses obtained from different protocols of the two imaging modalities were compared by paired t-test. Results: All FOVs in CBCT resulted in greater radiation dose than panoramic in each of the normal, soft, and hard exposure modes (P < 0.05). Dose amounts for the child and adult modes differed statistically significant in panoramic radiography as well as 80 × 80 and 90 × 120 FOVs of CBCT while in 50 × 50 maxilla, 50 × 50 mandible, 50 × 80 and 150 × 150 FOVs of CBCT, The child and adult doses were almost similar. Conclusions: Even the smallest size of FOV in the soft exposure mode which is expected to have the lowest amount of radiation among CBCT protocols resulted in greater thyroid exposure compared to panoramic examination. Furthermore, care should be taken in the selection of FOV, particularly for CBCT examinations of the children.

Isolated cysticercosis of masseter muscle in a young boy with trismus: Report of a case misdiagnosed as unilateral temporomandibular joint ankylosis Jyoti Prajapat, Rajesh Prajapat, Puneeta Vohra Journal of Oral and Maxillofacial Radiology 2019 7(1):12-17 Cysticercosis is a parasitic infection caused by the larval stages of Taenia solium. Cysticercosis is a potentially fatal parasitic disease that was rarely found in the maxillofacial region. This report suggests that cysticercosis should be considered in the differential diagnosis of chronic swelling in the oral and maxillofacial region and the importance of noninvasive modality ultrasonography (USG) in diagnosis. This paper reports a case of cysticercosis in the right masseter muscle in an 11-year-old boy who presented with recurrent swelling on the right side of the face with inability to open mouth, its clinical features, diagnostic modalities used, and management of the case. Cysticercosis should be considered in the differential diagnosis of chronic oral and maxillofacial swelling. High-resolution USG is an excellent noninvasive and cost-effective modality for the diagnosis and also suggests that this parasitic infection can be successfully treated with conservative management using antihelminthic medication.

Prostatic adenocarcinoma with mandibular metastasis Kritika Saxena Journal of Oral and Maxillofacial Radiology 2019 7(1):18-20 Metastatic lesions of primary tumors comprise almost 1% of different types of oral cancers. These lesions can affect either bones or soft tissues in the maxillofacial region. Whenever the maxillofacial area is affected, the most common location is in the molar region of the mandible. A 70-year-old male patient, presented with swelling in the jaw region, of acute onset. Clinical, radiological, and histological examinations were carried out. Finally, it was diagnosed to be a metastatic lesion in the jaw, with the primary lesion being in the prostate gland. The clinical presentation of mandibular metastasis follows a pattern characterized by irradiated dental pain in the third molar region. Differential diagnosis and treatment of these patients can be extremely difficult because there are several pathologic conditions with similar symptoms.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Molecular and Cellular Neuroscience

Cross talk between SOD1 and the mitochondrial UPR in cancer and neurodegeneration Publication date: July 2019 Source: Molecular and Cellular Neuroscience, Volume 98 Author(s): Maria Gomez, Doris Germain Abstract The mitochondrial unfolded protein response (UPRmt) is rapidly gaining attention. While the CHOP (ATF4/5) axis of the UPRmt was the first to be described, other axes have subsequently been reported. Validation of this complex pathway in C. elegans has been extensively studied. However, validation of the UPRmt in mouse models of disease known to implicate mitochondrial reprogramming or dysfunction, such as cancer and neurodegeneration, respectively, is only beginning to emerge. This review summarizes recent findings and highlights the major role of the superoxide dismutase SOD1 in the communication between the mitochondria and the nucleus in these settings. While SOD1 has mostly been studied in the context of familial amyotrophic lateral sclerosis (fALS), recent studies suggest that SOD1 may be a potentially important mediator of the UPRmt and converge to emphasize an increasingly vital role of SOD1 as a therapeutic target in cancer.

An FTLD-associated SQSTM1 variant impacts Nrf2 and NF-κB signalling and is associated with reduced phosphorylation of p62 Publication date: July 2019 Source: Molecular and Cellular Neuroscience, Volume 98 Author(s): A. Foster, D. Scott, R. Layfield, S.L. Rea Abstract Elevated oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In response to oxidative stress, the Nrf2 transcription factor activates protective antioxidant genes. A critical regulator of Nrf2 is the inhibitory protein Keap1, which mediates Nrf2 degradation. In response to cellular stress an interaction between Keap1 and SQSTM1/p62 (p62), a signalling adaptor protein, allows for increased Nrf2 signalling as it escapes degradation. Mutations in SQSTM1 (encoding p62) are linked with ALS-FTLD. Previously, two ALS-FTLD-associated p62 mutant proteins within the Keap1 interacting region (KIR) of p62 were found to be associated with decreased Keap1-p62 binding and Nrf2 activation. Here we report that a non-KIR domain FTLD-associated variant of p62 (p.R110C), affecting a residue close to the N-terminal PB1 oligomerisation domain, also reduces Keap1-p62 binding in cellulo and thereby reduces Nrf2 activity in reporter assays. Further, we observed that expression of p.R110C increased NF-κB activation compared with wild type p62. Altered signalling appeared to be linked with reduced phosphorylation of p62 at Serine residues −349 and −403. Our results confirm that ALS-FTLD mutations affecting multiple domains of p62 result in a reduced stress response, suggesting that altered stress signalling may directly contribute to the pathology of some ALS-FTLD cases.

Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density Publication date: July 2019 Source: Molecular and Cellular Neuroscience, Volume 98 Author(s): Kelly A. Jones, Michiko Sumiya, Kevin M. Woolfrey, Deepak P. Srivastava, Peter Penzes Abstract EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of Epac2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2−/−) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2−/− mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2−/− mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs.

Klotho deficiency affects the spine morphology and network synchronization of neurons Publication date: July 2019 Source: Molecular and Cellular Neuroscience, Volume 98 Author(s): Hai T. Vo, Mary L. Phillips, Jeremy H. Herskowitz, Gwendalyn D. King Abstract Klotho-deficient mice rapidly develop cognitive impairment and show some evidence of the onset of neurodegeneration. However, it is impossible to investigate the long-term consequences on the brain because of the dramatic shortening of lifespan caused by systemic klotho deficiency. As klotho expression is downregulated with advancing organismal age, understanding the mechanisms of klotho action is important for developing novel strategies to support healthy brain aging. Previously, we reported that klotho-deficient mice show enhanced long-term potentiation prior to the onset of cognitive impairment. To inform this unusual phenotype, herein, we examined neuronal structure and in vitro synaptic function. Our results indicate that klotho deficiency causes the population of dendritic spines to shift towards increased head diameter and decreased length consistent with mature, mushroom type spines. Multi-electrode array recordings from klotho-deficient neurons show increased synchronous firing and activity changes reflective of increased neuronal network activity. Supplementation of the neuronal growth media with recombinant shed klotho corrected some but not all of the activity changes caused by klotho deficiency. Last, in vivo we found that klotho-deficient mice have a decreased latency to induced seizure activity. Together these data show that klotho-deficient memory impairments are underpinned by structural and functional changes that may preclude ongoing normal cognition.

Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene Publication date: July 2019 Source: Molecular and Cellular Neuroscience, Volume 98 Author(s): Toshihiko Shirafuji, Haruo Shimazaki, Tatsuhiro Miyagi, Takehiko Ueyama, Naoko Adachi, Shigeru Tanaka, Izumi Hide, Naoaki Saito, Norio Sakai Abstract Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia with myoclonus, dystonia, spasticity, and rigidity. Although missense mutations and a deletion mutation have been found in the protein kinase C gamma (PRKCG) gene encoding protein kinase C γ (PKCγ) in SCA14 families, a nonsense mutation has not been reported. The patho-mechanisms underlying SCA14 remain poorly understood. However, gain-of-function mechanisms and loss-of-function mechanisms, but not dominant negative mechanisms, were reported the patho-mechanism of SCA14. We identified the c.226C>T mutation of PRKCG, which caused the p.R76X in PKCγ by whole-exome sequencing in patients presenting cerebellar atrophy with cognitive and hearing impairment. To investigate the patho-mechanism of our case, we studied aggregation formation, cell death, and PKC inhibitory effect by confocal microscopy, western blotting with cleaved caspase 3, and pSer PKC motif antibodies, respectively. PKCγ(R76X)-GFP have aggregations the same as wild-type (WT) PKCγ-GFP. The PKCγ(R76X)-GFP inhibited PKC phosphorylation activity more than GFP alone. It also induced more apoptosis in COS7 and SH-SY5Y cells compared to WT-PKCγ-GFP and GFP. We first reported SCA14 patients with p.R76X in PKCγ who have cerebellar atrophy with cognitive and hearing impairment. Our results suggest that a dominant negative mechanism due to truncated peptides produced by p.R76X may be at least partially responsible for the cerebellar atrophy.

Embryonic and postnatal development of mouse olfactory tubercle Publication date: Available online 11 June 2019 Source: Molecular and Cellular Neuroscience Author(s): Eduardo Martin-Lopez, Christine Xu, Teresa Liberia, Sarah J. Meller, Charles A. Greer Abstract The olfactory tubercle (OT) is located in the ventral-medial region of the brain where it receives primary input from olfactory bulb (OB) projection neurons and processes olfactory behaviors related to motivation, hedonics of smell and sexual encounters. The OT is part of the dopamine reward system that shares characteristics with the striatum. Together with the nucleus accumbens, the OT has been referred to as the "ventral striatum". However, despite its functional importance little is known about the embryonic development of the OT and the phenotypic properties of the OT cells. Here, using thymidine analogs, we establish that mouse OT neurogenesis occurs predominantly between E11-E15 in a lateral-to-medial gradient. Then, using a piggyBac multicolor technique we characterized the migratory route of OT neuroblasts from their embryonic point of origin. Following neurogenesis in the ventral lateral ganglionic eminence (vLGE), neuroblasts destined for the OT followed a dorsal-ventral pathway we named "ventral migratory course" (VMC). Upon reaching the nascent OT, neurons established a prototypical laminar distribution that was determined, in part, by the progenitor cell of origin. A phenotypic analysis of OT neuroblasts using a single-color piggyBac technique, showed that OT shared the molecular specification of striatal neurons. In addition to primary afferent input from the OB, the OT also receives a robust dopaminergic input from ventral tegmentum (Ikemoto, 2007). We used tyrosine hydroxylase (TH) expression as a proxy for dopaminergic innervation and showed that TH onset occurs at E13 and progressively increased until postnatal stages following an 'inside-out' pattern. Postnatally, we established the myelination in the OT occurring between P7 and P14, as shown with CNPase staining, and we characterized the cellular phenotypes populating the OT by immunohistochemistry. Collectively, this work provides the first detailed analysis of the developmental and maturation processes occurring in mouse OT, and demonstrates the striatal nature of the OT as part of the ventral striatum (vST).

Disease signatures: Biomarkers/indicators of neurodegeneration Publication date: Available online 25 May 2019 Source: Molecular and Cellular Neuroscience Author(s): Henrik Zetterberg, Mathias Bähr

Hippocampal sub-regional differences in the microRNA response to forebrain ischemia Publication date: Available online 23 May 2019 Source: Molecular and Cellular Neuroscience Author(s): Oiva Arvola, Georgia Kaidonis, Lijun Xu, Brian Griffiths, Creed M. Stary Abstract Transient forebrain ischemia, as occurs with cardiac arrest and resuscitation, results in impaired cognitive function secondary to delayed neuronal cell death in hippocampal cornu ammonis-1 (CA1). Comparatively, hippocampal neurons in the adjacent dentate gyrus (DG) survive, suggesting that elucidating the molecular mechanisms underpinning hippocampal sub-regional differences in ischemic tolerance could be central in the development of novel interventions to improve outcome in survivors of forebrain ischemia. MicroRNAs (miRNAs) are non-coding RNAs that modulate the translation of target genes and have been established as an effective therapeutic target for other models of injury. The objective of the present study was to assess and compare post-injury miRNA profiles between CA1 and DG using a rat model of forebrain ischemia. CA1 and DG sub-regions were dissected from rat hippocampi following 10 min of forebrain ischemia at three time points (3 h, 24 h, and 72 h) and at baseline. Pronounced differences between CA1 and DG were observed for several select miRNAs, including miR-181a-5p, a known regulator of cerebral ischemic injury. We complexed fluorescent in situ hybridization with immunohistochemistry to observe cell-type specific and temporal differences in mir-181a-5p expression between CA1 and DG in response to injury. Using established miRNA-mRNA prediction algorithms, we extended our observations in CA1 miRNA dysregulation to identify key functional pathways as potential modulators of CA1 ischemic vulnerability. In summary, our observations support a central role for miRNAs in selective CA1 ischemic vulnerability and suggest that cell-specific miRNA targeting could be a viable clinical approach to preserve CA1 neurons and improve cognitive outcomes for survivors of transient forebrain ischemia.

Exposing immature hippocampal neurons to excitotoxins reveals distinct transcriptome and protein regulation with induction of common survival signaling pathways Publication date: Available online 11 May 2019 Source: Molecular and Cellular Neuroscience Author(s): L.K. Friedman, N. Osei-tutu, B. Zhang Abstract Early life traumas lead to neuroprotection by preconditioning mechanisms. To determine which genes and pathways are most likely involved in specific adaptive effects, immature hippocampal cultures were exposed to a single high dose of glutamate (250 μM), NMDA (100 μM), or KA (300 μM) for 48 h (5–7 DIV) based on our prior "two hit" in vitro model of preconditioning. Transcriptome profiling and immunocytochemistry of gene candidates were performed 7 days later when cultured neurons mature (14 DIV). Many genes were up- and down- regulated involving distinct Ca2+-binding protein families, G-coupled proteins, various growth factors, synaptic vesicle docking factors, certain neurotransmitter receptors, heat shock, oxidative stress, and certain anti-apoptotic Bcl-2 gene members that influence neuronal survival. Immunohistochemistry showed a marked decrease in the number of Calb1 and Calm2 positive neurons following NMDA but not after glutamate exposure whereas ryanodine and Cav1.2 voltage gated channel expression was less affected. Survivors had marked increases in Calm2 immunostaining; however, high-density neural clusters observed in controls, were depleted after NMDA and partly diminished after glutamate. While NR1 mRNA expression was decreased in the microarray, specific antibodies revealed selective loss of the NR1 C1 splice variant. Calm2 which can inactivate NMDA receptors by binding to C1 but not C2 regions of its NR1 subunit suggests that loss of the C1 splice variant will reduce co-regulation with Calm2 and alter NR1 trafficking, phosphorylation, and NMDA currents following early life NMDA exposure. A dramatic reduction in the density of GABAAα5 and GABAB receptor expressing neurons was observed after NMDA exposure but immunodensity measurements were unchanged as was the expression of the GABA synthesizing enzyme, GAD, suggesting that fast inhibitory neurotransmission and response to benzodiazepines and GABAB-mediated IPSPs may be preserved in matured survivors. Selective upregulation of Chat and CNRIP was detected after glutamate treatment suggesting this condition would decrease cholinergic and excitatory neurotransmission by decreasing Ach content and CB1 interacting protein function. This decrease likely contributes to memory and attention tasks deficits that follow a single early neurological insult. Diverse changes that follow overactivation of excitatory networks of immature neurons appear long-lasting or permanent and are expected to have profound effects on network function and adaptive responses to further insult.

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy Publication date: April 2019 Source: Molecular and Cellular Neuroscience, Volume 96 Author(s): Mariana Oliveira Mendes, Alexandra Isabel Rosa, Andreia Neves Carvalho, Maria João Nunes, Pedro Dionísio, Elsa Rodrigues, Daniela Costa, Sara Duarte-Silva, Patrícia Maciel, Cecília Maria Pereira Rodrigues, Maria João Gama, Margarida Castro-Caldas Abstract Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD. Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells. Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Drugs & Therapy Perspectives

Correction to: Midazolam oral solution (Ozalin ® ): a profile of its use for procedural sedation or premedication before anaesthesia in children The article Midazolam oral solution (Ozalin®): a profile of its use for procedural sedation or premedication before anaesthesia in children, written by Katherine A. Lyseng-Williamson, was originally published Online First without open access. After publication in volume 35, issue 6, pages 255-262, Primex Pharmaceuticals AG requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Primex Pharmaceuticals AG. The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

First reports of adverse drug reactions

No difference in relevant potential allergens in SPF-containing facial moisturizers: implications in frontal fibrosing alopecia Abstract Background Although controversial, it has been proposed that the use of leave-on facial skin care products, namely daily facial moisturizers with sun protection factor (SPF), is associated with frontal fibrosing alopecia (FFA). In accordance, several authors have previously reported on patch testing results in cross-sectional studies of patients with FFA. Aims The aim was to survey the top-selling facial moisturizers for the prevalence of potential allergens identified in FFA patient patch testing and to then distinguish if those moisturizers containing SPF were statistically more likely to have relevant potential allergens than moisturizers without SPF. Methods Three online retailers were surveyed for the best-selling facial moisturizers, and ingredient lists were reviewed for allergens found in FFA-patient patch testing and fragrance and botanical cross-reactors. Results Out of 100 unique facial moisturizers, 87 contained at least one potential allergen identified in previous patch testing results of FFA patients. There was no significant difference in the prevalence of indicated allergens in facial moisturizers with SPF in comparison to those without SPF. Conclusion It does not appear that the presence of additional identified allergens in facial moisturizers with SPF explains the reported association with FFA. Further prospective, comparative studies are necessary to understand the potential role of personal cosmetic products in the development of FFA.

Assessment of anticoagulation management in outpatients attending a warfarin clinic in Windhoek, Namibia Abstract Background Warfarin, an anticoagulant with a low therapeutic index, requires frequent international normalized ratio (INR) monitoring to ensure efficacy and safety. Little is known about anticoagulation management in Namibia. Objective The purpose of this study was to investigate the level of anticoagulation control among outpatients requiring maintenance warfarin therapy. Setting Clinical records of patients attending the warfarin anticoagulation clinic at Windhoek Central Hospital (Windhoek, Namibia) during a 1-year period were reviewed. Methods Of the 294 outpatients who visited the warfarin anticoagulation monitoring clinic in 2017, 215 patients were included in the data analysis. The following information was available and used for data analysis: age and sex of the patient, indication for warfarin use, number of visits, warfarin dose and INR values. The individual's time in therapeutic range (iTTR) was the primary outcome, which was calculated both using the Rosendaal method and as the percentage of the reported INR values in the therapeutic range. Results The patients' mean iTTR was 29.4%, well below the 65% target, when estimated by the Rosendaal method and 25.2% when calculated as the percentage of INR values within the therapeutic range. Only 22 of the 215 patients (10%) had an iTTR ≥ 65%. Conclusions Anticoagulation control at this outpatient clinic was low relative to the target iTTR of 65%. Consequently, patients were at risk for further embolic events or bleeding events based on the high numbers of sub- and supratherapeutic INRs during the time period studied.

K-haler ® breath-triggered inhaler: a profile of the properties of the device Abstract The k-haler® device is a new breath-triggered pressurized metered-dose inhaler (BTI). Its breath-triggered mechanism employs unique 'kinked-hose valve' technology (k-valve™) and is easy to actuate. In vitro, the k-haler device required less respiratory power, which is affected by the resistance of the device, for dose release than a dry powder inhaler (DPI), potentially making it suitable for a wider range of patients, including those with a low inspiratory flow rate. It has a lower, more consistent plume force than conventional press-and-breathe pressurized metered-dose inhalers (pMDIs), has high fine-particle fraction and pulmonary deposition rates, and, in contrast to conventional pMDIs (but like other BTIs and DPIs), does not require actuation-inhalation coordination. The k-haler device is compact, has an easy-to-read dose counter, a connected mouthpiece and is simple to use, with limited data indicating that more patients are satisfied with the device than they are with some DPIs and that many patients prefer it over some commonly used inhalers. To facilitate correct use, the packaging of the k-haler contains simple how-to-use instructions and diagrams, as well as a patient information leaflet. A number of inhaled products may be suitable for administration via the k-haler device.

Minimize exposure to antidopaminergic drugs whenever possible to reduce the risk of drug-induced parkinsonism and tardive dyskinesia Abstract Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are iatrogenic consequences of antidopaminergic drugs, and are most common in the elderly. To reduce the risk of DIP and TD, exposure to antidopaminergic drugs should be minimized, with the lowest effective dosage possible being used for the shortest treatment duration. Prevention and early detection of DIP and TD are essential, as evidence supporting the use of available treatment options is limited.

Take a multifaceted approach when treating onychomycosis Abstract Onychomycosis is difficult to treat, particularly due to factors at the patient, organism, treatment and environmental levels that increase disease susceptibility or impact treatment. Along with taking these into consideration and addressing them as required, performing diagnostic tests is necessary when selecting the appropriate treatment and administration route, thereby maximizing the chances of successful treatment. Because onychomycosis has a high recurrence rate, preventive measures are recommended even after achieving a cure.

Effect of GSTP1 polymorphism on efficacy and safety of cyclophosphamide aggressive therapy in lupus nephropathy patients Abstract Background Lupus nephritis (LN) occurs in up to 60% of adults with systemic lupus erythematosus (SLE) and is a predictor of poor survival. Cyclophosphamide (CYC) is regarded as the most effective immunosuppressive medication to improve survival for patients with LN. Objective This prospective hospital-based study was conducted to identify the effect of glutathione S transferase Pi-1 (GSTP1) genotypes on the efficacy and safety of CYC aggressive therapy. Methods We enrolled SLE nephropathy patients admitted to the Department of Rheumatology of the 500-bed Yangon Specialty Hospital (YSH), Yangon, Myanmar, who received CYC aggressive therapy for 6 months according to treatment guidelines for SLE patients with renal involvement. The frequencies of I/I, I/V and V/V GSTP1 genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism method. The efficacy of CYC aggressive therapy between LN patients with wild GSTP1 (I/I) and those with polymorphic GSTP1 (I/V or V/V) genotypes was evaluated by comparing 24-h urinary protein levels and assessing the remission rates at 3 and 6 months after initiation of CYC. CYC-related myelotoxicity was assessed by reviewing complete blood picture results on the 10th day after CYC treatment. Results In total, 95 eligible patients were recruited. The frequencies of I/I, I/V and V/V GSTP1 genotypes were 54.7, 41.1 and 4.2%, respectively. At 3 and 6 months after CYC treatment, mean 24-h urinary protein had significantly decreased from baseline in both wild and polymorphic genotype groups (p < 0.001). No significant differences were seen between the wild and polymorphic genotype groups with regard to changes in 24-h urinary protein levels, remission at 3 and 6 months or myelotoxicity. Conclusion CYC aggressive therapy had similar efficacy and caused no significant differences in myelotoxicity in wild GSTP1 (I/I) and polymorphic GSTP1 (I/V or V/V) genotypes in patients treated according to YSH guidelines for SLE patients with renal involvement.

Omadacycline in community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections: a profile of its use Abstract Omadacycline (Nuzyra™) is an orally bioavailable, first-in-class, semisynthetic aminomethylcycline antibacterial. A derivative of minocycline, omadacycline has a novel structure that overcomes common mechanisms of tetracycline resistance. In vitro, omadacycline had broad-spectrum activity against Gram-positive, Gram-negative, and atypical bacteria that can cause community-acquired bacterial pneumonia (CABP), and acute bacterial skin and skin structure infections (ABSSSI). In clinical trials, omadacycline was noninferior to moxifloxacin and linezolid in terms of early clinical response rates in patients with CABP and ABSSSI, respectively. Omadacycline was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity.

High-dose hydroxocobalamin in end-stage liver disease and liver transplantation Abstract Distributive shock is a serious complication in patients with chronic or end-stage liver disease, and can be exacerbated by vasoplegia in this patient population. Vasoplegic syndrome (VS) is a state of shock refractory to catecholamines and vasopressin that is often multifactorial in liver failure patients, and can occur in any phase of liver transplantation (LT) [i.e., pre-transplantation, intraoperative, and post-transplantation]. Methylene blue (MB) has been a well-established pharmacologic therapy for VS. However, it has been known to cause dose-related toxicity. Hydroxocobalamin (HXC) is not currently FDA approved for the management of VS, but studies have demonstrated its ability to cause an increase in systolic blood pressure by hypothesized mechanisms with only minimal side effects. To date, only three other reports have demonstrated the use of HXC in LT patients, which highlighted its use both intraoperatively and post-transplantation. Our report illustrates the utility of HXC in four LT patients with VS. Two of these cases illustrate the usefulness of HXC in the pre-transplantation period, which has never been previously reported. HXC is a useful pharmaceutical agent in the management of VS, especially if contraindications to MB exist or in cases of MB-resistant vasoplegia. Further studies with large sample sizes are necessary to ascertain the optimal dosage of HXC in LT patients.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Radiology

Correction to: Radiomics on multi-modalities MR sequences can subtype patients with non-metastatic nasopharyngeal carcinoma (NPC) into distinct survival subgroups The original version of this article, published on 14 March 2019, unfortunately contained a mistake.

Encouraging MSK imaging research towards clinical impact is a necessity: opinion paper of the European Society of Musculoskeletal Radiology (ESSR) Abstract Radiology has not been spared in recent economic crises with a substantial reduction in the turnover of imaging equipment. These problems are exacerbated by increasing demand for healthcare across Europe. Therefore, using existing radiological services while rigorously following evidence-based guidelines might improve patient care. Thus, diagnostic pathways should be assessed not only for technical and diagnostic performance but also for their impact on medical and social outcome. In this paper, we report the advice of the Research Committee of ESSR on how we may guide musculoskeletal radiological research towards studies that have useful clinical impact. The ESSR Research Committee intends to encourage research with potential to influence treatment, patient outcome, and social impact. Key Points • Research in medical imaging has the potential to improve human health. • High-level studies have the potential to place radiology at the pinnacle of quality in evidence-based practice. • The ESSR Research Committee intends to encourage research with potential to influence treatment, patient outcome, and social impact.

Transoral ultrasound: a helpful and easy diagnostic method in obstructive salivary gland diseases Key Points • Transoral ultrasound is a simple technique, very helpful for the evaluation of obstructive diseases of the salivary glands. • It overcomes most of the limitations of transcutaneous ultrasound.

Obituary for Professor Werner Wenz

Making useful clinical guidelines: the ESGAR perspective

Epicardial fat volume measured on nongated chest CT is a predictor of coronary artery disease Abstract Objective To investigate whether epicardial fat volume (EFV) quantified on ECG-nongated noncontrast CT (nongated-NCCT) could be used as a reliable and reproducible predictor for coronary artery disease (CAD). Methods One hundred seventeen subjects (65 men, mean age 66.6 ± 11.9 years) underwent coronary CT angiography (CCTA) and nongated-NCCT during a single session because of symptoms suggestive of CAD. Two observers independently quantified EFV on both images. Correlation between CCTA-EFV and nongated-NCCT-EFV was assessed using Pearson's correlation coefficient and Bland–Altman plots. Inter-observer agreement was analyzed using concordance correlation coefficients (CCC). Coronary risk factors including EFV were compared between CAD-positive (> 50% stenosis) and CAD-negative groups. The association between EFV and CAD was analyzed using multivariate logistic regression. ROC analysis was performed, and AUC was compared with DeLong's method. Results Seventy-four subjects were diagnosed with CAD. An excellent correlation was noted between CCTA-EFV and nongated-NCCT-EFV (r = 0.948, p < 0.001), despite the systematic difference between both measurements (mean bias, 1.26). Inter-observer agreement was nearly perfect (CCC, 0.988 and 0.985 for CCTA and nongated-NCCT, respectively, p < 0.001). Significant differences were noted between subjects with versus without CAD in age, hypertension, and EFV on both types of images (p ≤ 0.026). Multivariate analysis revealed that increased EFV on CCTA (odds ratio 1.185, p = 0.003) and nongated-NCCT (odds ratio 1.20, p = 0.015) was independently associated with CAD. There was no significant difference between CCTA-EFV and nongated-NCCT-EFV in AUC for the prediction of CAD (0.659 vs 0.665, p = 0.706). Conclusions Despite the absence of ECG gating, EFV measured on NCCT may serve as a reproducible predictor for CAD with accuracy equivalent to EFV measured on CCTA. Key Points • Despite the absence of ECG gating, the EFV on NCCT provides nearly perfect inter-observer reproducibility and shows excellent correlation with measurements on gated CCTA. • EFV on nongated-NCCT may serve as an independent biomarker for predicting coronary artery disease with accuracy equivalent to that of EFV on gated CCTA.

The vertebral 3′-deoxy-3′- 18 F-fluorothymidine uptake predicts the hematological toxicity after systemic chemotherapy in patients with lung cancer Abstract Objectives Although hematological toxicities (HT) are the leading adverse events of systemic chemotherapy, the estimation of severe HT is challenging. Recently, 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) accumulation with PET has been considered a biomarker of the cell proliferation. This study aims to elucidate whether the vertebral accumulation of 18F-FLT could estimate severe HT during platinum-doublet chemotherapy. Methods In this Institutional Review Board–approved retrospective study, 50 patients with primary lung cancer underwent 18F-FLT PET scan before platinum-doublet chemotherapy. We evaluated the standardized uptake value, total vertebral proliferation (TVP), and TVP/body surface area (TVP/BSA) of the vertebral body (Th4, Th8, Th12, and L4), and then the associations between those parameters and frequency of severe HT during platinum-doublet chemotherapy were assessed. Results Severe HT (grade 3/4) was observed in 40.0% of patients during the first cycle. The ROC curve analyses revealed that the TVP/BSA of L4 was the most discriminative parameter among PET parameters for the prediction of severe HT. The multivariate logistic regression analysis revealed the TVP/BSA of L4 (odds ratio [OR], 0.94; p = 0.0036) and the frequency of the grade 3/4 hematological toxicity in previous clinical trials (OR, 1.03; p = 0.023) were independent predictors. Furthermore, the sensitivity, specificity, and accuracy of the TVP/BSA of L4 cut-off of 68.7 to predict grade 3/4 HT were 80.0%, 86.7%, and 84.0%, respectively. A low TVP/BSA of L4 (< 68.7) as a binary variable was a significant indicator of severe HT (OR, 26.0; p = 0.000026). Conclusions The low 18F-FLT uptake in the lower vertebral body is a predictor of severe HT in patients with lung cancer who receive platinum-doublet chemotherapy. Trial registration Trial registration: UMIN000027540 Key Points • The vertebral 18 F-FLT uptake with PET is an independent predictor of the severe hematological toxicity during the first cycle of platinum-doublet chemotherapy. • The 18 F-FLT uptake in L4 vertebral body estimated hematological toxicities better than that in the upper vertebra (Th4, Th8, and Th12). • The evaluation of the amount and activity of hematopoietic cells in the bone marrow cavity using 18 F-FLT PET imaging could provide predictive data of severe hematological toxicities and help determine an appropriate drug combination or dose intensity in patients with advanced malignant diseases.

Proposed achievable levels of dose and impact of dose-reduction systems for thrombectomy in acute ischemic stroke: an international, multicentric, retrospective study in 1096 patients Abstract Background International dose reference levels are lacking for mechanical thrombectomy in acute ischemic stroke patients with large vessel occlusions. We studied whether radiation dose-reduction systems (RDS) could effectively reduce exposure and propose achievable levels. Materials and methods We retrospectively included consecutive patients treated with thrombectomy on a biplane angiography system (BP) in five international, high-volume centers between January 2014 and May 2017. Institutional Review Board approvals were obtained. Technical, procedural, and clinical characteristics were assessed. Efficacy, safety, radiation dose, and contrast load were compared between angiography systems with and without RDS. Multivariate analyses were adjusted according to Bonferroni's correction. Proposed international achievable cutoff levels were set at the 75th percentile. Results Out of the 1096 thrombectomized patients, 520 (47%) were treated on a BP equipped with RDS. After multivariate analysis, RDS significantly reduced dose–area product (DAP) (91 vs 140 Gy cm2, relative effect 0.74 (CI 0.66; 0.83), 35% decrease, p < 0.001) and air kerma (0.46 vs 0.97 Gy, relative effect 0.63 (CI 0.56; 0.71), 53% decrease, p < 0.001) with 75th percentile levels of 148 Gy cm2 and 0.73 Gy, respectively. There was no difference in contrast load, rates of successful recanalization, complications, or clinical outcome. Conclusion Radiation dose-reduction systems can reduce DAP and air kerma by a third and a half, respectively, without affecting thrombectomy efficacy or safety. The respective thresholds of 148 Gy cm2 and 0.73 Gy represent achievable levels that may serve to optimize current and future radiation exposure in the setting of acute ischemic stroke treatment. As technology evolves, we expect these values to decrease. Key Points • Internationally validated achievable levels may help caregivers and health authorities better assess and reduce radiation exposure of both ischemic stroke patients and treating staff during thrombectomy procedures. • Radiation dose-reduction systems can reduce DAP and air kerma by a third and a half, respectively, without affecting thrombectomy efficacy or safety in the setting of acute ischemic stroke due to large vessel occlusion.

Usefulness of the inchworm sign on DWI for predicting pT1 bladder cancer progression Abstract Objective To evaluate the significance of the presence or absence of an "inchworm sign" on DWI for the recurrence and progression of T1 bladder cancer. Materials and methods We retrospectively analyzed 91 patients with pT1 urothelial carcinoma who underwent DWI prior to transurethral resection between 2007 and 2016. DWI of the dominant tumors was scrutinized for inchworm signs at b = 1000 s/mm2. The association of the presence of the inchworm sign with progression and recurrence was analyzed; progression was defined as recurrence to stage T2 or higher and/or N+, and/or M1. Results An inchworm sign was seen in 65 cases (71%), while it was absent in 26 cases. Among the 65, 25 (38%) had confirmed tumor recurrence, while in the remaining 26, 14 (54%) had confirmed recurrence (median time post TURB = 7.9 and 10.1 months for each). At the time of recurrence, the tumor had progressed in one (2%) inchworm-sign-positive and seven (27%) inchworm-sign-negative cases. The progression rate of inchworm-sign-negative cases was significantly higher than that of inchworm-sign-positive cases (hazard ratio = 17.2, p = 0.0017), whereas there was no significant difference in the recurrence rate between two groups. The absence of an inchworm sign and histological grade 3 were independent risk factors for progression (p < 0.001 and 0.010, respectively). Conclusions The absence of an inchworm sign on DWI was a significant prognostic factor for progression of T1 bladder cancer. Morphological evaluation of DWI signals may therefore be a useful adjunct to preoperative assessment of biological aggressiveness. Key Points • An inchworm sign is a simple diagnostic criterion that characterizes only the shape of the tumor signal on DWI, and potentially serves as an imaging biomarker to predict clinical aggressiveness. • The absence of an inchworm sign on DWI is a significant indicator of progression of T1 bladder cancer.

CT of acute rejection after liver transplantation: a matched case–control study Abstract Purpose This study was conducted in order to investigate computed tomography (CT) findings associated with acute cellular rejection (ACR) following liver transplantation (LT) and their relevance to clinical outcomes. Materials and methods We analyzed 120 patients with newly diagnosed ACR following LT for various liver diseases and 119 controls matched for age, sex, type of liver graft, and date of CT exam following LT. Two radiologists analyzed the images for morphological characteristics of the graft, morphological change in the major draining vein, graft enhancement in the portal venous phase, graft attenuation on noncontrast CT, and periportal halo. Univariate analysis was used to determine the association between radiological findings and ACR. Clinical outcomes, including treatment response and graft survival, were compared between patients with and without associated radiological findings. Results Morphological characteristics of the graft (i.e., globular swelling), morphological change in the major draining vein (i.e., nonanastomotic luminal narrowing), and heterogeneous enhancement were significantly associated with ACR (all p < 0.001). On univariate analysis, the severity of morphological characteristics of the grafts (mild/severe: odds ratio [OR], 19.98/32.24) and morphological change in the major draining vein (without/with prestenotic dilatation: OR, 4.17/22.5) were significantly associated with the increased possibility of an ACR diagnosis. Clinical outcomes for treatment response and graft survival were not significantly different between patients with and without associated radiological findings. Conclusions Globular swelling, nonanastomotic stenosis with or without prestenotic dilatation of the major draining vein, and heterogeneous enhancement of the graft on portal venous-phase CT were significantly associated with ACR. Key Points • Globular swelling of the graft, nonanastomotic narrowing in the major vein, and heterogeneous graft enhancement on CT were significantly associated with acute cellular rejection (ACR). • Associated CT findings were highly specific but not sensitive for differentiating ACRs from matched controls.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Behavior Genetics

Genetics of Perceived Family Interaction From 12 to 17 Years of Age Abstract We analyzed how the effects of genetic and environmental factors on the perceptions of family interaction change from early to late adolescence. The data were collected by postal surveys on Finnish twins (N = 4808) at 12, 14 and 17 years of age and analyzed using genetic twin modeling. Additive genetic factors explained a modest share of the variation in perceived relational support (a2 = 0.30 in boys and 0.18 in girls) and relational tensions (a2 = 0.13 and 0.14, respectively) at 12 years of age, with the proportions becoming larger through 17 years of age (a2 = 0.53 in boys and 0.49 in girls for relational support; a2 = 0.35 in boys and 0.33 in girls for relational tensions). Simultaneously, the role of environment shared by co-twins decreased. These findings suggest that the associations between perceived family interaction and other factors in adulthood should be interpreted with caution, because they partly reflect genetic background, whereas in childhood, they may provide more reliable information on parental characteristics.

Half the Genetic Variance in Vitamin D Concentration is Shared with Skin Colour and Sun Exposure Genes Abstract This study assessed the heritability of 25 hydroxyvitamin D3 (25(OH)D3) in a large twin cohort and the shared effect of sun exposure and skin colour on 25(OH)D3 variance. Study participants included 1604 twin pairs and their siblings (n = 4020). Twin correlations for 25(OH)D3 concentration were rMZ=0.79 (584 pairs) and rDZ = 0.52 (1020 pairs) consistent with an average h2 = 0.50 throughout the year. Significant phenotypic and genetic seasonal fluctuation was observed in 25(OH)D3 concentrations with heritability decreasing during the winter (h2 = 0.37) compared to summer (h2 = 0.62). Skin colour (measured both ordinally and quantitatively) and self-reported sun exposure were found to significantly affect 25(OH)D3 concentration. Twins with olive/dark skin had significantly lower 25(OH)D3 concentrations than those with fair/pale skin and multivariate genetic analysis showed that approximately half of the total additive genetic variation in 25(OH)D3 results from genes whose primary influence is on skin colour and sun exposure. Additionally, 37% of the total variance was attributed to shared environmental effects on vitamin D, skin colour and sun exposure measures. These results support a moderate estimate of vitamin D heritability and suggest significant influence of season, skin colour and sun exposure on the genetic variance.

Significance of IL-6 Deficiency in Recognition Memory in Young Adult and Aged Mice Abstract Chronic peripheral elevation of interleukin 6 (IL-6) in humans is associated with cognitive deficits. 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and reference wild-type (WT) mice were tested in an object recognition test. Discrimination ratios and recognition indexes were significantly lower in 4-month-old IL-6KO and in 24-month-old WT mice vs 4-month-old WT animals. Their discrimination ratios had negative values and recognition indexes were below 50% indicating inability to differentiate the novel from the familiar object after 1-hour delay. In 24-month-old IL-6KO mice recognition index reached 53.17% indicating that their recognition memory was not worsened with age in comparison with younger IL-6-deficient animals. Results of holeboard and elevated plus maze indicated that this effect was memory specific. Inborn IL-6 deficiency attenuated recognition memory in 4-month-old mice and did not altered recognition memory in aged animals. IL-6 signalling may constitute a target for development of the protection against memory disturbances connected with IL-6 overexpression.

Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects Abstract Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.

The Genetic and Environmental Etiology of Shyness Through Childhood Abstract The objective of this study was to examine the genetic and environmental contributions to shyness throughout the school-age period. Participants were 553 twin pairs from the ongoing prospective longitudinal Quebec Newborn Twin Study. Teacher-rated measures of shyness were collected at five time-points from age 6–12 years. On average, shyness was moderately stable over time (r = 0.23–0.33) and this stability was almost entirely accounted for by genetic factors. Genetic factors at age 6 accounted for 44% of individual differences and these early genetic factors also explained individual differences at all subsequent ages (6–22%). Non-shared environmental factors explained most of individual differences at single time-points (51–63%), and did not account for stability in shyness. Contributions of shared environment were not significant. Our results suggest that the stability in shyness is mostly accounted for by early and persistent genetic contributions.

Systematic Review of Polygenic Gene–Environment Interaction in Tobacco, Alcohol, and Cannabis Use Abstract Studies testing the effect of single genetic variants on substance use have had modest success. This paper reviewed 39 studies using polygenic measures to test interaction with any type of environmental exposure (G×E) in alcohol, tobacco, and cannabis use. Studies using haplotype combinations, sum scores of candidate-gene risk alleles, and polygenic scores (PS) were included. Overall study quality was moderate, with lower ratings for the polygenic methods in the haplotype and candidate-gene score studies. Heterogeneity in investigated environmental exposures, genetic factors, and outcomes was substantial. Most studies (N = 30) reported at least one significant G×E interaction, but overall evidence was weak. The majority (N = 26) found results in line with differential susceptibility and diathesis-stress frameworks. Future studies should pay more attention to methodological and statistical rigor, and focus on replication efforts. Additional work is needed before firm conclusions can be drawn about the importance of G×E in the etiology of substance use.

Cognitive Performance in Young APOE ε4 Carriers: A Latent Variable Approach for Assessing the Genotype–Phenotype Relationship Abstract The ε4 allele of the apolipoprotein (APOE) gene is a widely recognized genetic risk factor for developing Alzheimer's disease in older age. However, it is controversial whether there is a positive impact of the APOE ε4 allele on human cognitive performance in young adulthood, possibly representing a case of antagonistic pleiotropy. Here we explored associations of the APOE ε4 allele with cognitive ability in young adulthood. In contrast to previous studies, we used structural equation modeling that allows a multivariate measurement of the cognitive phenotype. Results based on four independent samples (N1 = 245; N2 = 300; N3 = 244; N4 = 206) overall revealed a complex effect of the APOE ε4 genotype on cognitive ability in young adulthood: Whereas the ε4 allele tends to be negatively associated with cognitive performance in individuals with lower education levels, there might be a weak positive association in persons with higher education—a finding that is partly in line with the antagonistic pleiotropy view on APOE and cognitive ability. The education-related findings support protective effects of environmental factors.

Correction to: A Genetic Investigation of the Well-Being Spectrum In the original version of this article, unfortunately, in the acknowledgement section "National Institutes of Health (NIH, R37 AG033590‐08) to J Cacioppo" was omitted. This has been corrected by publishing this erratum.

Correction to: Behavioral Genetics and Attributions of Moral Responsibility The original version of this article unfortunately contained a few mistakes in the Introduction section.

A Genetic Investigation of the Well-Being Spectrum Abstract The interrelations among well-being, neuroticism, and depression can be captured in a so-called well-being spectrum (3-phenotype well-being spectrum, 3-WBS). Several other human traits are likely linked to the 3-WBS. In the present study, we investigate how the 3-WBS can be expanded. First, we constructed polygenic risk scores for the 3-WBS and used this score to predict a series of traits that have been associated with well-being in the literature. We included information on loneliness, big five personality traits, self-rated health, and flourishing. The 3-WBS polygenic score predicted all the original 3-WBS traits and additionally loneliness, self-rated health, and extraversion (R2 between 0.62% and 1.58%). Next, using LD score regression, we calculated genetic correlations between the 3-WBS and the traits of interest. From all candidate traits, loneliness and self-rated health were found to have the strongest genetic correlations (rg = − 0.79, and rg= 0.64, respectively) with the 3-WBS. Lastly, we use Genomic SEM to investigate the factor structure of the proposed spectrum. The best model fit was obtained for a two-factor model including the 5-WBS traits, with two highly correlated factors representing the negative- and positive end of the spectrum. Based on these analyses we propose to include loneliness and self-rated health in the WBS and use a 5-phenotype well-being spectrum in future studies to gain more insight into the determinants of human well-being.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com