Associations of MAP2K3 Gene Variants With Superior Memory in SuperAgers.

Front Aging Neurosci. 2018;10:155

Authors: Huentelman MJ, Piras IS, Siniard AL, De Both MD, Richholt RF, Balak CD, Jamshidi P, Bigio EH, Weintraub S, Loyer ET, Mesulam MM, Geula C, Rogalski EJ

Abstract
Introduction: SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). Methods: Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer's disease Neuroimaging Initiative (ADNI). Results: The SuperAging phenotype was associated with variants in the Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) gene. Three single nucleotide polymorphisms (SNPs) contributed to the significance (rs2363221 [intron 1], rs2230435 [exon 5], rs736103 [intron 7]). Conclusions: MAP2K3 resides in a biological pathway linked to memory. It is in a signaling cascade associated with beta-amyloid mediated apoptosis and has enriched expression in microglia. This preliminary work suggests MAP2K3 may represent a novel therapeutic target for age-related memory decline and perhaps Alzheimer's disease (AD).

PMID: 29896098 [PubMed]

Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent.

Sci Rep. 2018 Jun 12;8(1):8959

Authors: Ayoub BM, Mowaka S, Safar MM, Ashoush N, Arafa MG, Michel HE, Tadros MM, Elmazar MM, Mousa SA

Abstract
Drug repositioning is a revolution breakthrough of drug discovery that presents outstanding privilege with already safer agents by scanning the existing candidates as therapeutic switching or repurposing for marketed drugs. Sitagliptin, vildagliptin, saxagliptin & linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin & trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight & lipophilic properties suggesting its repositioning as antiparkinsonian agent. The results of BBB crossing will be of interest for researchers interested in Parkinson's disease. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing & antimicrobial properties. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group.

PMID: 29895906 [PubMed - in process]

[Benign aggressive vascular anomalies in children].

Bull Cancer. 2018 Jun;105(6):610-625

Authors: Boccara O, Maruani A, Léauté-Labrèze C

Abstract
Superficial vascular anomalies constitute a large group of malformative and tumoral conditions developed from all types of vessels. Vascular tumors are the result of cellular hyperplasia, whereas vascular malformations (VMs) are constituted of dysplastic vessels. The classification from International Society for the Study of Vascular Anomalies (ISSVA) is based on this pathogenic difference. The most common vascular tumor is infantile hemangioma, which treatment, when necessary, is propranolol. Congenital hemangiomas and tumors that might be complicated with Kasabach-Merritt phenomenon, i.e. deep thrombocytopenia, are much rarer. Management of Kasabach-Merritt phenomenon is now largely based on sirolimus. Low-flow VMs include capillary, venous and lymphatic malformations; arteriovenous malformations are high-flow malformations. These different types of VMs might be combined. Currently, there is an increasing work in delineating the different entities based on molecular findings. Treatment of VMs depends on the impairment linked to them, and is decided case by case, in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient, and management of patients with VMs increasingly involves medical drugs. First-line treatment of coagulation disorders associated with venous malformations is based on low molecular weight heparin; sirolimus seems efficient in hemorrhagic complications refractory to usual treatment. Sirolimus is about to become the standard treatment in painful inflammatory manifestations of mixed and/or complicated lymphatic malformations.

PMID: 29571951 [PubMed - indexed for MEDLINE]

Novel phenotype-disease matching tool for rare genetic diseases.

Genet Med. 2018 Jun 12;:

Authors: Chen J, Xu H, Jegga A, Zhang K, White PS, Zhang G

Abstract
PURPOSE: To improve the accuracy of matching rare genetic diseases based on patient's phenotypes.
METHODS: We introduce new methods to prioritize diagnosis of genetic diseases based on integrated semantic similarity (method 1) and ontological overlap (method 2) between the phenotypes expressed by a patient and phenotypes annotated to known diseases.
RESULTS: We evaluated the performance of our methods by two sets of simulated data and one set of patient's data derived from electronic health records. We demonstrated that the two methods achieved significantly improved performance compared with previous methods in correctly prioritizing candidate diseases in all of the three sets. Our methods are freely available as a web application ( https://gddp.
RESEARCH: cchmc.org/ ) to aid diagnosis of genetic diseases.
CONCLUSION: Our methods can capture the diagnostic information embedded in the phenotype ontology, consider all phenotypes exhibited by a patient, and are more robust than the existing methods when phenotypes are incorrectly or imprecisely specified. These methods can assist the diagnosis of rare genetic diseases and help the interpretation of the results of DNA tests.

PMID: 29895857 [PubMed - as supplied by publisher]

Clinical trials in neonates: How to optimise informed consent and decision making? A European Delphi survey of parent representatives and clinicians.

PLoS One. 2018;13(6):e0198097

Authors: Neyro V, Elie V, Thiele N, Jacqz-Aigrain E

Abstract
OBJECTIVES: Parental consent for the participation of their neonate in neonatal research is influenced by the quality of the information delivered and the interaction between parents and investigators. Failure to provide important information may lead to difficulties in the decision making process of parents. This Delphi survey aims to establish a consensus between parent representatives of neonatal associations and healthcare professionals concerning the information deemed essential by both parties in order to improve the recruitment of neonates into clinical trials.
METHOD: This study was conducted in Europe among parent representatives and healthcare professionals. In this 3-phase study, 96 items were defined by the Scientific Committee (CS), composed of 11 clinicians (from 8 countries) and 1 parent representative of the European network of neonatal associations. Then the Committee of Experts (CE) composed of 16 clinicians were matched by country with 16 national parent representatives and evaluated these items in two rounds. The importance of each item was evaluated by each member of the CE on a scale between 1 and 9 based on their personal experience.
RESULTS: Fifty eight items reached the second and final level of consensus. In contrast to clinicians, parent representatives preferred to be informed about the study by the physician in charge of their child. They also favoured additional support during the informed consent process and stated that both parents need to agree and sign.
CONCLUSION: The set of 58 items on which parents and clinicians reached consensus will be helpful to healthcare professionals seeking parental consent for the inclusion of a neonate in a clinical trial. Providing parents with information about the trial by the investigator in the presence of the patient's neonatologist, developing closer contacts with parents and informing them of the available support by parents associations may be helpful for parents.

PMID: 29897934 [PubMed - in process]

Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation.

Psychol Med. 2018 Jun 13;:1-10

Authors: Wolf EJ, Logue MW, Morrison FG, Wilcox ES, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Miller MW

Abstract
BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock).
METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments.
RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging.
CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

PMID: 29897034 [PubMed - as supplied by publisher]

An investigation into the prediction of the plasma concentration-time profile and its inter-individual variability for a range of flavin-containing monooxygenase substrates using a mechanistic physiologically based pharmacokinetic modelling approach.

Drug Metab Dispos. 2018 Jun 12;:

Authors: Pilla Reddy V, Jones BC, Colclough N, Srivastava A, Wilson J, Li D

Abstract
Our recent paper (Jones et al., 2017) demonstrated the ability to predict in vivo clearance of Flavin-containing Monooxygenases (FMO) drug substrates, using in vitro human hepatocyte and human liver microsomal intrinsic clearance (CLint) with standard scaling approaches. In this paper, we apply physiologically based pharmacokinetic (PBPK) modelling & simulation approaches (M&S) to predict the clearance, AUC and Cmax together with the plasma profile of a range of drugs from the original study. The human physiological parameters for FMO, such as enzyme abundance in liver, kidney, gut were derived from in vitro data and clinical pharmacogenetics studies. The drugs investigated include itopride, benzydamine, tozasertib, tamoxifen, moclobemide, imipramine, clozapine, ranitidine, and olanzapine. The fraction metabolised (Fm) by FMO for these drugs ranged from 21 to 96%. The developed PBPK models were verified with data from multiple clinical studies. An attempt was made to estimate the scaling factor for recombinant FMO (rFMO) using a parameter estimation approach and an automated sensitivity analysis (ASA) within the PBPK platform. Simulated oral clearance (CLpo), using in vitro hepatocyte data and associated extrahepatic FMO data, predicts the observed in vivo plasma concentration profile reasonably well and predicts AUC for all of the FMO substrates within 2-fold of the observed clinical data, while, 7 out of 9 compounds fell within 2-fold when human liver microsomal data was used. rFMO over-predicted the AUC by approximately 2.5-fold for 3 out of 9 compounds. Applying a calculated inter-system extrapolation scalar or tissue specific scalar for rFMO data resulted in better prediction of clinical data. PBPK M&S results from this study demonstrate that human hepatocytes and human liver microsomes can be used along with our standard scaling approaches to predict human in vivo PK parameters for FMO substrates.

PMID: 29895591 [PubMed - as supplied by publisher]

Glucose elicits serine/threonine kinase VRK1 to phosphorylate nuclear pregnane X receptor as a novel hepatic gluconeogenic signal.

Cell Signal. 2017 Dec;40:200-209

Authors: Gotoh S, Miyauchi Y, Moore R, Negishi M

Abstract
Low glucose stimulated phosphorylation of pregnane X receptor (PXR) at Ser350 in correlation with an increased gluconeogenesis in human hepatoma-derived HepG2 cells. Only glucose, but neither insulin nor glucagon, stimulated this phosphorylation. Here, serine/threonine kinase, vaccinia related kinase 1 (VRK1)-mediated phosphorylation of PXR is now defined as this glucose-elicited novel signal. In low glucose conditions, VRK1 directly phosphorylates PXR at Ser350, enabling PO3-PXR to scaffold protein phosphatase PP2Cα. This PP2Cα dephosphorylates serine/threonine kinase 2 (SGK2) at Thr193. This dephosphorylation dissociates SGK2 from and actives the phosphoenolpyruvate carboxykinase 1 (PCK1) gene as phosphorylated SGK2 binds and represses the gene. Conversely, VRK1 self-represses its activity to phosphorylate PXR through cyclin-dependent kinase 2 (CDK2) in high glucose conditions, resulting in the repression of the PCK1 gene. This PXR phosphorylation was also observed in fasting mouse livers. Thus, the VRK1-CDK2-PXR-PP2Cα-SGK2 pathway can be a novel physiological cell signaling that regulates gluconeogenesis in response to glucose.

PMID: 28911860 [PubMed - indexed for MEDLINE]

Optimism, opportunities, outcomes: the Australian Cystic Fibrosis Data Registry.

Intern Med J. 2018 Jun;48(6):721-723

Authors: Ahern S, Sims G, Earnest A, C Bell S

Abstract
The Australian Cystic Fibrosis Data Registry is positioning itself as an exemplar of a rare disease registry for the future. While it continues to inform cystic fibrosis (CF) clinicians of patterns of CF disease and quality of care, its capability is increasing as a resource for further research into CF subpopulations, as a platform for clinical trials, and as an interface for patient experiences.

PMID: 29898272 [PubMed - in process]

Epidemiology of Pulmonary Nontuberculous Mycobacterial Sputum Positivity in Patients with Cystic Fibrosis in the United States, 2010-2014.

Ann Am Thorac Soc. 2018 Jun 13;:

Authors: Adjemian J, Olivier KN, Prevots DR

Abstract
RATIONALE: Pulmonary nontuberculous mycobacterial (NTM) disease represents a significant threat to cystic fibrosis (CF) patients, with an estimated annual prevalence of 12%. Prior studies report an increasing annual NTM prevalence in the general population, though similar trends in persons with CF have not been assessed.
OBJECTIVES: This study aimed to identify the prevalence, geographic patterns, temporal trends and risk factors for NTM positivity by mycobacterial species among persons with CF throughout the United States.
METHODS: Using annualized CF Patient Registry (CFPR) data from 2010-2014, we identified patients with mycobacterial culture results to estimate annual and period prevalence of pathogenic NTM species by demographic and geographic factors. Regression models were used to estimate the annual percent change over time and risk factors for NTM isolation. Geographic patterns were described and mapped.
RESULTS: Of 16,153 included persons with CF, 3,211 (20%) had a pathogenic NTM species isolated at least once over the 5-year period; 1,949 (61%) had Mycobacterium avium complex (MAC) and 1,249 (39%) M. abscessus. Period prevalence for MAC was 12% (CI:12-13%), for M. abscessus 8% (CI: 7-8%), and for other NTM species 4% (CI: 3.8-4.3%). Period prevalence for MAC was nearly three-times greater among patients ≥60 years old with a body mass index <19 (33% [CI: 16-51%]); this trend was not present for M. abscessus patients (4% [CI: 0-11%]). NTM prevalence showed a significant relative increase of 5% per year, from 11.0% in 2010 to 13.4% in 2014 (p=0.0008), although this varied by geographic area. For M. abscessus, the highest prevalence states were Hawaii (50%), Florida (17%) and Louisiana (16%), while for MAC it was Nevada (24%), Kansas (21%), and Hawaii and Arizona (both 20%). Study participants with either MAC or M. abscessus were significantly more likely to have been diagnosed with CF at an older age (p<0.0001), have a lower BMI (p<0.0001), higher forced expiratory volume in one second (FEV1) percent predicted (p<0.01), and fewer years on chronic macrolide therapy (p<0.0001).
CONCLUSION: NTM remains highly prevalent among adults and children with CF in the U.S., with one in five affected, and appears to be increasing over time. Variation in prevalence exists by geographic region and by patient-level factors, including older age and receiving an initial CF diagnosis later in life. Routine screening for NTM, including mycobacterial speciation, especially in high-risk geographic areas, is critical for better understanding its epidemiology and changes in prevalence over time.

PMID: 29897781 [PubMed - as supplied by publisher]

Genomic characterisation of an international Pseudomonas aeruginosa reference panel indicates that the two major groups draw upon distinct mobile gene pools.

FEMS Microbiol Lett. 2018 Jun 12;:

Authors: Freschi L, Bertelli C, Jeukens J, Moore MP, Kukavica-Ibrulj I, Emond-Rheault JG, Hamel J, Fothergill JL, Tucker NP, McClean S, Klockgether J, de Soyza A, Brinkman FSL, Levesque RC, Winstanley C

Abstract
Pseudomonas aeruginosa is an important opportunistic pathogen, especially in the context of infections of cystic fibrosis (CF). In order to facilitate coordinated study of this pathogen, an international reference panel of P. aeruginosa isolates was assembled. Here we report the genome sequencing and analysis of 33 of these isolates and 7 reference genomes to further characterise this panel. Core genome single nucleotide variant phylogeny demonstrated that the panel strains are widely distributed amongst the P. aeruginosa population. Common loss of function mutations reported as adaptive during CF (such as in mucA and mexA) were identified amongst isolates from chronic respiratory infections. From the 40 strains analysed, 37 unique resistomes were predicted, based on the Resistance Gene Identifier method using the Comprehensive Antibiotic Resistance Database. Notably, hierarchical clustering and phylogenetic reconstructions based on the presence/absence of genomic islands (GIs), prophages and other Regions of Genome Plasticity (RGPs) supported the subdivision of P. aeruginosa into two main groups. This is the largest, most diverse analysis of GIs and associated RGPs to date, and the results suggest that, at least at the largest clade grouping level (Group 1 vs Group 2), each group may be drawing upon distinct mobile gene pools.

PMID: 29897457 [PubMed - as supplied by publisher]

Insights into the genome diversity and virulence of two clinical isolates of Burkholderia cenocepacia.

J Med Microbiol. 2018 Jun 13;:

Authors: Salloum T, Nassour E, Araj GF, Abboud E, Tokajian S

Abstract
PURPOSE: Burkholderia cenocepacia is among the most common members of the Burkholderia cepacia complex (Bcc) isolated from patients with cystic fibrosis (CF). The factors triggering the high rates of morbidity and mortality in CF patients are not well elucidated. In this study, we aim to highlight the genome diversity of two clinical isolates of B. cenocepacia through comparative genome analysis.
METHODOLOGY: The repertoire of virulence factors and resistance genes compared to reference strains J2315 and K56-2 was elucidated. The isolates were screened for the presence of phages and insertion sequences. Two methods were combined to obtain an accurate prediction of genomic islands (GIs): the cumulative GC profile and the IslandViewer web tool. To study evolutionary relatedness, whole genome-based single-nucleotide polymorphism (wgSNP) analysis was also performed with 43 publically available strains of the Bcc of various sequence types.Results/Key findings. Genome-based species identification of the two isolates BC-AUH and BC-BMEH confirmed the species as B. cenocepacia. Both belonged to ST-602, a double-locus variant of ST-32 (CC31), genomovar IIIA, and carried a large number of antibiotic resistance genes. Eighteen GIs were predicted in BC-AUH and BC-BMEH, occupying 9.3 and 6.1 % of the respective genomes. Comparison to J2315 revealed 89 and 85 genes unique to BC-BMEH and BC-AUH, respectively. Additionally, 1823 intergenic SNPs were detected between BC-BMEH and BC-AUH.
CONCLUSION: This study mapped existing genetic variations in B. cenocepacia associated with notorious outcomes in CF patients, and the data obtained provide comprehensive, genome-inferred insights and multifactorial examination of an important human pathogen.

PMID: 29897328 [PubMed - as supplied by publisher]

Trends in ceftazidime-avibactam activity against multidrug-resistant organisms recovered from respiratory samples of cystic fibrosis patients.

Transpl Infect Dis. 2018 Jun 13;:e12955

Authors: Farfour E, Trochu E, Devin C, Cardot Martin E, Limousin L, Roux A, Picard C, Jolly E, Vasse M, Lesprit P

Abstract
Cystic fibrosis (CF) patient are frequently colonized by multidrug resistant micro-organisms. About 5% and 10% of patients are colonized by Burkholderia cepacia complex (Bcc) and Stenotrophomonas maltophilia respectively, and up to 50% of Pseudomonas aeruginosa isolates are multidrug resistant. 1,2 Ceftazidime-avibactam is a new cephalosporin-inhibitor combination with a potent activity against multidrug-resistant organisms (MDRO) such as KPC and OXA-48 like producing Enterobacteriacae and multidrug resistant P. aeruginosa. However, there is a lack of knowledge of its activity against MDRO recovered in CF, 3 although it has shown an in vitro activity against some strains of Burkholderia spp. This article is protected by copyright. All rights reserved.

PMID: 29896802 [PubMed - as supplied by publisher]

Epithelial disruption: a new paradigm enabling human airway stem cell transplantation.

Stem Cell Res Ther. 2018 Jun 13;9(1):153

Authors: Farrow N, Cmielewski P, Donnelley M, Rout-Pitt N, Moodley Y, Bertoncello I, Parsons D

Abstract
BACKGROUND: Airway disease is a primary cause of morbidity and early mortality for patients with cystic fibrosis (CF). Cell transplantation therapy has proven successful for treating immune disorders and may have the potential to correct the airway disease phenotype associated with CF. Since in vivo cell delivery into unconditioned mouse airways leads to inefficient engraftment, we hypothesised that disrupting the epithelial cell layer using the agent polidocanol (PDOC) would facilitate effective transplantation of cultured stem cells in mouse nasal airways.
METHODS: In this study, 4 μL of 2% PDOC in phosphate-buffered saline was administered to the nasal airway of mice to disrupt the epithelium. At 2 or 24 h after PDOC treatment, two types of reporter gene-expressing cells were transplanted into the animals: luciferase-transduced human airway basal cells (hABC-Luc) or luciferase-transduced human amnion epithelial cells (hAEC-Luc). Bioluminescence imaging was used to assess the presence of transplanted luciferase-expressing cells over time. Data were evaluated by using two-way analysis of variance with Sidak's multiple comparison.
RESULTS: Successful transplantation was observed when hABCs were delivered 2 h after PDOC but was absent when transplantation was performed 24 h after PDOC, suggesting that a greater competitive advantage for the donor cells is present at the earlier time point. The lack of transplantation of hAECs 24 h after PDOC supports the importance of choosing the correct timing and cell type to facilitate transplantation.
CONCLUSIONS: These studies into factors that may enable successful airway transplantation of human stem cells showed that extended functioning cell presence is feasible and further supports the development of methods that alter normal epithelial layer integrity. With improvements in efficacy, manipulating the airway epithelium to make it permissive towards cell transplantation may provide another option for safe and effective correction of CF transmembrane conductance regulator function in CF airways.

PMID: 29895311 [PubMed - in process]

Genome-wide sequencing in acutely ill infants: genomic medicine's critical application?

Genet Med. 2018 Jun 12;:

Authors: Friedman JM, Bombard Y, Cornel MC, Fernandez CV, Junker AK, Plon SE, Stark Z, Knoppers BM, Paediatric Task Team of the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream

Abstract
Diagnostic genome-wide sequencing (exome or genome sequencing and data analysis for high-penetrance disease-causing variants) in acutely ill infants appears to be clinically useful, but the value of this diagnostic test should be rigorously demonstrated before it is accepted as a standard of care. This white paper was developed by the Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Work Stream to address the question of how we can determine the clinical value of genome-wide sequencing in infants in an intensive care setting. After reviewing available clinical and ethics literature on this question, we conclude that evaluating diagnostic genome-wide sequencing as a comprehensive scan for major genetic disease (rather than as a large panel of single-gene tests) provides a practical approach to assessing its clinical value in acutely ill infants. Comparing the clinical value of diagnostic genome-wide sequencing to chromosomal microarray analysis, the current evidence-based standard of care, per case of serious genetic disease diagnosed provides a practical means of assessing clinical value. Scientifically rigorous studies of this kind are needed to determine if clinical genome-wide sequencing should be established as a standard of care supported by healthcare systems and insurers for diagnosis of genetic disease in seriously ill newborn infants.

PMID: 29895853 [PubMed - as supplied by publisher]

Distinct molecular profile of diffuse cerebellar gliomas.

Acta Neuropathol. 2017 Dec;134(6):941-956

Authors: Nomura M, Mukasa A, Nagae G, Yamamoto S, Tatsuno K, Ueda H, Fukuda S, Umeda T, Suzuki T, Otani R, Kobayashi K, Maruyama T, Tanaka S, Takayanagi S, Nejo T, Takahashi S, Ichimura K, Nakamura T, Muragaki Y, Narita Y, Nagane M, Ueki K, Nishikawa R, Shibahara J, Aburatani H, Saito N

Abstract
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

PMID: 28852847 [PubMed - indexed for MEDLINE]

Too much of a good thing: a retrospective study of β-lactam concentration-toxicity relationships.

J Antimicrob Chemother. 2017 Oct 01;72(10):2891-2897

Authors: Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I

Abstract
Objectives: To determine the existence of concentration-toxicity relationships for common β-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely.
Patients and methods: Retrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation.
Results: TDM results from 378 patients (piperacillin = 223, meropenem = 94 and flucloxacillin = 61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (Cmin) was found in patients diagnosed with neurotoxicity (piperacillin, P < 0.01; meropenem, P = 0.04; flucloxacillin, P = 0.01) and those who developed nephrotoxicity whilst being treated with piperacillin (P < 0.01) or meropenem (P < 0.01). Incidence of hepatotoxicity and C. difficile was not related to Cmin. Threshold concentrations for which there is 50% risk of developing a neurotoxicity event (piperacillin, Cmin >361.4 mg/L; meropenem, Cmin >64.2 mg/L; flucloxacillin, Cmin >125.1 mg/L) or nephrotoxicity (piperacillin, Cmin >452.65 mg/L; meropenem, Cmin >44.45 mg/L) varied across antibiotics.
Conclusions: Our data reveal an association between toxic concentrations for a number of β-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.

PMID: 29091190 [PubMed - indexed for MEDLINE]

Successful outpatient parenteral antibiotic therapy delivery via telemedicine.

J Antimicrob Chemother. 2017 Oct 01;72(10):2898-2901

Authors: Tan SJ, Ingram PR, Rothnie AJ, Whitmore TJ, Robinson JO, Hatch JB, Italiano CM, Heath CH

Abstract
Objectives: Most outpatient parenteral antimicrobial therapy (OPAT) services use a hospital-based model of care in which patients remain in proximity to large hospitals facilitating clinical review. We aimed to evaluate clinical outcomes and complication rates for patients living in geographically isolated locations managed by telemedicine-supported OPAT. Methods: This was a retrospective cohort study.
Results: Between 2011 and 2015, we delivered 88 episodes of care involving 83 adult patients resulting in 2261 days of OPAT. The median age was 56 years, 8 of 83 (10%) were indigenous Australian and the median Charlson comorbidity index score was 2 (IQR 1-4). The median distance of patients' residence from our hospital was 288 km (IQR 201-715) and the median duration on the programme was 26 days (IQR 14-34). Bone and joint infections accounted for 75% of infections treated. Favourable clinical outcomes (improvement or cure) were achieved in 87% of patients and the unplanned, OPAT-related readmission rate was 8%. Nineteen percent and 10% of patients had drug-related and line-related adverse effects, respectively.
Conclusions: Despite a complex case mix, our adverse event and readmission rates are similar to the published literature describing a non-telemedicine model to deliver OPAT. High rates of favourable clinical outcomes and likely cost benefits suggest that telemedicine-supported OPAT is an efficacious and safe substitute for inpatient care in our setting.

PMID: 29091189 [PubMed - indexed for MEDLINE]

Radiological manifestations of immune-related adverse effects observed in patients with melanoma undergoing immunotherapy.

J Med Imaging Radiat Oncol. 2017 Dec;61(6):759-766

Authors: Sidhu P, Menzies AM, Long G, Carlino M, Lorens S, Kapoor R

Abstract
Immunotherapy drugs work by stimulating the patient's own immune system to recognize and destroy cancer cells. This subclass of drugs is increasingly administered to patients with advanced melanoma. They are also commonly incorporated into other cancer therapies such as non-small cell lung cancer, renal cancer, head and neck cancers and Hodgkin lymphoma. The most commonly administered immunotherapeutic agents in the treatment of melanoma include programmed cell death protein 1 (PD-1) inhibitors, cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors and a subclass of cytokines. During treatment with these antibodies, a unique set of adverse effects may occur which are often called immune-related adverse events (irAEs). It is vital for radiologists to be aware of and document these side effects during routine staging or body imaging during therapy. Some of these include pneumonitis, colitis, hypophysitis, lymphadenopathy or sarcoid-like syndrome and myositis. IrAEs such as sarcoid-like lymphadenopathy can mimic progression of disease. Serious side effects are seen in less than 10% of patients, and typically emerge between 6 and 12 weeks after commencing treatment. The clinical manifestations of these side effects typically vary from mild to severe and so do the radiological findings. Patients with mild side effects are often treated successfully with systemic corticosteroids, while severe cases require cessation of immunotherapy. We provide a pictorial article on the common irAEs and the associated radiological manifestations.

PMID: 29024572 [PubMed - indexed for MEDLINE]

Poisoning deaths in Poland: Types and frequencies reported in Łódź, Kraków, Sosnowiec, Gdańsk, Wrocław and Poznań during 2009-2013.

Int J Occup Med Environ Health. 2017 Oct 06;30(6):897-908

Authors: Krakowiak A, Piekarska-Wijatkowska A, Kobza-Sindlewska K, Rogaczewska A, Politański P, Hydzik P, Szkolnicka B, Kłopotowski T, Picheta S, Porębska B, Antończyk A, Waldman W, Sein Anand J, Matuszkiewicz E, Łukasik-Głębocka M

Abstract
OBJECTIVES: The aim of this study has been to assess the characteristics of acute poisoning deaths in Poland over a period of time 2009-2013.
MATERIAL AND METHODS: The analysis was based on the data obtained from the patient records stored in toxicology departments in 6 cities - Łódź, Kraków, Sosnowiec, Gdańsk, Wrocław and Poznań. Toxicological analyses were routinely performed in blood and/or urine. Major toxic substances were classified to one of the following categories: pharmaceuticals, alcohol group poisonings (ethanol and other alcohols), gases, solvents, drugs of abuse, pesticides, metals, mushrooms, others. Cases were analyzed according to the following criteria: year, age and gender of analyzed patients, toxic substance category and type of poisoning. The recorded fatal poisonings were classified according to the International Classification of Diseases.
RESULTS: The record of 261 deaths were retrospectively reviewed. There were 187 males (71.64%) and 74 females (28.36%) and the male to female ratio was 2.52. Alcohol group poisonings were more frequently responsible for deaths in men compared to all poisonings, 91.1% vs. 71.6%, respectively (p < 0.05), and pharmaceutical agents were more frequently responsible for deaths in women, 47.4% vs. 28.4%, (p < 0.05). Methanol was the most common agent in the alcohol group poisonings, accounting for 43.75% (N = 49), followed by ethylene glycol, 39.29% (N = 44), and ethanol, 16.96% (N = 19).
CONCLUSIONS: Epidemiological profile data from investigation of poisoning deaths in Poland may be very useful for the development of preventive programs. Int J Occup Med Environ Health 2017;30(6):897-908.

PMID: 28832029 [PubMed - indexed for MEDLINE]