Phenobarbital-induced phosphorylation converts nuclear receptor RORα from a repressor to an activator of the estrogen sulfotransferase gene Sult1e1 in mouse livers.

FEBS Lett. 2018 Jul 19;:

Authors: Fashe M, Hashiguchi T, Yi M, Moore R, Negishi M

Abstract
The estrogen sulfotransferase SULT1E1 sulfates and inactivates estrogen, which is reactivated via desulfation by steroid sulfatase, thus regulating estrogen homeostasis. Phenobarbital (PB), a clinical sedative, activates Sult1e1 gene transcription in mouse livers. Here, the molecular mechanism by which the nuclear receptors CAR, which is targeted by PB, and RORα communicate through phosphorylation to regulate Sult1e1 activation has been studied. RORα, a basal activity repressor of the Sult1e1 promoter, becomes phosphorylated at serine 100 and converts to an activator of the Sult1e1 promoter in response to PB. CAR regulates both the RORα phosphorylation and conversion. Our findings suggest that PB signals CAR to communicate with RORα via serine 100 phosphorylation, converting RORα from transcription repressor to activator of the Sult1e1 gene and inducing SULT1E1 expression in mouse livers. This article is protected by copyright. All rights reserved.

PMID: 30025153 [PubMed - as supplied by publisher]

Association of ABCC2  polymorphism and gender with high-density lipoprotein cholesterol response to simvastatin.

Pharmacogenomics. 2018 Jul 19;:

Authors: Liu N, Yang G, Hu M, Cai Y, Hu Z, Jia C, Zhang M

Abstract
AIM: The clinical benefits of lipid-lowering therapy with statins are widely recognized. However, the lipid-lowering efficacy of statins shows significant differences between individuals. ABCC2 has been demonstrated to contribute to the transmembrane transport of the substrate compounds. The ABCC2 SNPs may be important factors that affect individual differences in clinical drug response. The aim of this study was to evaluate the association of rs717620 of ABCC2 with treatment response to simvastatin in a Chinese Han population.
METHODS: A total of 318 subjects were medicated with simvastatin 20 mg/day for 12 weeks after enrollment. Venous blood was obtained before and after simvastatin treatment for measurement of blood lipid profile. Subjects were classified into high-response and low-response groups depending on whether their lipid profile change was higher or lower than median change values. The ABCC2 SNP rs717620 was genotyped from blood samples with a snapshot assay.
RESULTS: A total of 12 weeks of treatment with simvastatin significantly decreased low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TGs) and significantly increased high-density lipoprotein cholesterol (HDL-C; p < 0.05). In multivariate analysis, there were no significant genetic effects of SNP rs717620 on the incidence of high- or low-response patients among TC, TG and LDL-C groups. However, rs717620 A-allele and female gender are significantly associated with the risk of low-response of HDL-C elevation after simvastatin treatment.
CONCLUSION: ABCC2 rs717620 and female gender may be related to the low-effect of simvastatin treatment on the HDL-C level in the Chinese Han population. Female Chinese patients with hyperlipidemia carrying rs717620 GA/AA genotypes might have reduced benefit from simvastatin treatment.

PMID: 30024814 [PubMed - as supplied by publisher]

Effect of CYP2C19 and CYP2D6 genotype on tamoxifen treatment outcome indicates endogenous and exogenous interplay.

Pharmacogenomics. 2018 Jul 19;:

Authors: Sim S, Lövrot J, Lindh JD, Bergh J, Xie H

Abstract
AIM: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients.
MATERIALS & METHODS: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival.
RESULTS & CONCLUSION: We show that the group with worst outcome and highest risk of relapse is that of 2C19↑-2D6↓ (hazard ratio: 2.94), when adjusting for age, Nottingham prognostic index and adjuvant chemotherapy. Furthermore, the effect of 2C19↑-2D6↓genotype-predicted phenotype is greatly enhanced in premenopausal patients (hazard ratio: 21.08). We hypothesize that poor bioactivation of tamoxifen in patients with low CYP2D6 activity and high CYP2C19 metabolism represents a tamoxifen-treated patient group that has the worst clinical outcome.

PMID: 30022682 [PubMed - as supplied by publisher]

Early Onset of Obesity and Adult Onset of Obesity as Factors Affecting Patient Characteristics Prior to Bariatric Surgery.

Obes Surg. 2018 Jul 18;:

Authors: Wrzosek M, Wiśniewska K, Sawicka A, Tałałaj M, Nowicka G

Abstract
BACKGROUND: Patients who are slated for bariatric surgery vary in terms of their age at onset of obesity, duration of obesity, and their health complications. Therefore, we aimed to explore a relationship between the age at onset of obesity, metabolic parameters, and health problems in bariatric surgery candidates.
METHODS: A total of 469 unrelated adults with obesity prior to bariatric surgery were included in this study. The study group consisted of 246 individuals who became obese < 20 years of age, and 223 individuals who became obese ≥ 20 years. Clinical, biochemical, anthropometric assessments, and DXA-derived measures were taken.
RESULTS: Patients with early onset of obesity had a higher total body fat mass, and higher body fat percentage, and a 1.84 times higher risk of BMI above 40 kg/m2 than patients with adult onset of obesity (≥ 20 years). Multivariable logistic regression demonstrated that, among bariatric surgery candidates with early onset of obesity, the frequency of hypertension and type 2 diabetes was significantly lower than that in cases with an adult onset of obesity, despite a longer duration of obesity and higher BMI.
CONCLUSIONS: The age at which an individual reaches obesity has a significant impact on patient characteristics on the day he or she is evaluated for bariatric surgery. A younger age at obesity onset is a predicting factor for a higher BMI in patients, but they are less likely to clinically manifest well-established consequences of obesity, such as diabetes or hypertension, compared to patients with adult onset of obesity.

PMID: 30022421 [PubMed - as supplied by publisher]

Pharmacotranscriptomic Biomarkers in Glucocorticoid Treatment of Pediatric Inflammatory Bowel Disease.

Curr Med Chem. 2018;25(24):2855-2871

Authors: Lucafò M, Stankovic B, Kotur N, Di Silvestre A, Martelossi S, Ventura A, Zukic B, Pavlovic S, Decorti G

Abstract
BACKGROUND: Pharmacotranscriptomics aims to reach more accurate drug dosing based on interindividual transcriptome variations. Here, we provide an overview of RNA biomarkers that could predict the response to glucocorticoids (GCs), considered the standard for treatment of inflammatory bowel diseases (IBD), both in adult and pediatric patients. Although new biological agents are very effective in IBD treatment, GCs are still widely used for induction of remission in patients with moderate to severe disease. It is important to identify patients that are poor responders to GCs therapy, because suboptimal response is frequent and associated with various side effects. A number of genetic variants related to GC mechanism of action has been studied. However, the majority of reported associations are not consistent. In this regard, pharmacogenomic research is now exploring the world of RNAs. An appropriate regulation of the transcriptome, which mainly comprises mRNAs and non-coding RNAs that control gene expression, has a strong impact in the modulation of GC activity.
AIM: The aim of this review is to present the current knowledge of the role of the transcriptome in modulating GC response in pediatric IBD.
RESULTS: We will discuss the available literature, concerning the development of pharmacotranscriptomic biomarkers, focusing particularly on non-coding RNAs, and present the results in this field that elucidate a concrete benefit of translating the knowledge gained in the "omics" studies into clinical practice.

PMID: 28933291 [PubMed - indexed for MEDLINE]

Polysaccharides from Burkholderia species as targets for vaccine development, immunomodulation and chemical synthesis.

Nat Prod Rep. 2018 Jul 19;:

Authors: Cloutier M, Muru K, Ravicoularamin G, Gauthier C

Abstract
Covering: up to 2018Burkholderia species are a vast group of human pathogenic, phytopathogenic, and plant- or environment-associated bacteria. B. pseudomallei, B. mallei, and B. cepacia complex are the causative agents of melioidosis, glanders, and cystic fibrosis-related infections, respectively, which are fatal diseases in humans and animals. Due to their high resistance to antibiotics, high mortality rates, and increased infectivity via the respiratory tract, B. pseudomallei and B. mallei have been listed as potential bioterrorism agents by the Centers for Disease Control and Prevention. Burkholderia species are able to produce a large network of surface-exposed polysaccharides, i.e., lipopolysaccharides, capsular polysaccharides, and exopolysaccharides, which are virulence factors, immunomodulators, major biofilm components, and protective antigens, and have crucial implications in the pathogenicity of Burkholderia-associated diseases. This review provides a comprehensive and up-to-date account regarding the structural elucidation and biological activities of surface polysaccharides produced by Burkholderia species. The chemical synthesis of oligosaccharides mimicking Burkholderia polysaccharides is described in detail. Emphasis is placed on the recent research efforts toward the development of glycoconjugate vaccines against melioidosis and glanders based on synthetic or native Burkholderia oligo/polysaccharides.

PMID: 30023998 [PubMed - as supplied by publisher]

Feasibility and challenges of using multiple breath washout in COPD.

Int J Chron Obstruct Pulmon Dis. 2018;13:2113-2119

Authors: Bell AS, Lawrence PJ, Singh D, Horsley A

Abstract
Background: Lung clearance index (LCI), derived from multiple-breath washout (MBW), is a well-established assessment of ventilation inhomogeneity in cystic fibrosis but has not been widely applied in other conditions characterized by heterogeneous airways disease, such as COPD. The aim of this study was to evaluate the sensitivity, repeatability, and practicality of LCI in patients with COPD.
Methods: Fifty-four COPD patients completed MBW using nitrogen as the washout tracer gas (MBWN2, measured using an Exhalyzer™ device), spirometry, and plethysmography. Twenty patients repeated MBWN2, MBWSF6 (using a separate Innocor™ gas analyzer to measure washout of the exogenous trace sulphur hexafluoride), and spirometry at a second visit ≥24 hours later.
Results: Mean (SD) COPD LCI measured by nitrogen washout (LCIN2) was 12.1 (2.2); mean (SD) LCI Z-score 5.8 (2.0). LCIN2 increased across Global Initiative for Obstructive Lung Disease stages 1 to 3 and was abnormal (Z-score >1.65) in all COPD patients, including those with forced expiratory volume in 1 second (FEV1) ≥80% predicted. LCI was repeatable (median intra-test coefficient of variation 4.1%) and reproducible (limits of agreement -1.8 to 1.6) after mean of 16 days. Functional residual capacity (FRC) measurements were significantly greater using nitrogen than SF6 or plethysmography: mean FRC measured by nitrogen washout (FRCN2) 139% predicted versus FRC measured by plethysmography 125% predicted, p<0.0001.
Conclusion: LCI is most suitable as a measure of early airways disease in COPD in those with well-preserved FEV1, with similar repeatability and limitations to that observed in cystic fibrosis. Using the Exhalyzer system to perform MBWN2, however, appeared to substantially over-read FRC. This discrepancy needs addressing before FRCN2 measurements made using this device can be reliably deployed.

PMID: 30022817 [PubMed - in process]

Reduced insulin sensitivity is correlated with impaired sleep in adolescents with cystic fibrosis.

Pediatr Diabetes. 2018 Jul 18;:

Authors: Simon SL, Vigers T, Campbell K, Pyle L, Branscomb R, Nadeau KJ, Chan CL

Abstract
BACKGROUND: Prevalence of cystic fibrosis-related diabetes (CFRD) rises sharply in adolescence/young-adulthood and is associated with increased morbidity/mortality. Sleep may be a modifiable risk factor for diabetes but its relationship with metabolic function has not been fully examined in youth with CF. The aim of the study was to examine the relationship between objectively-measured sleep and glucose metabolism in youth with CF.
METHODS: Adolescents (43 with CF and 11 healthy controls) completed one-week of concurrent home continuous glucose monitoring (CGM) and actigraphy. Fasting labs and an oral glucose tolerance test were obtained. T-tests and ANOVA were used to test differences between actigraphy outcomes in CF participants and controls. Spearman's rank correlation coefficients were used to test for correlations between actigraphy, CGM, and insulin sensitivity measures.
RESULTS: All participants averaged insufficient sleep (mean=7.5h per night) compared to the 8-10 hours recommended for this age group. CF participants had poorer sleep by actigraphy measures than healthy controls. Higher minimum daytime glucoses on CGM correlated with shorter total sleep time (TST) and worse sleep efficiency (SE). Reduced insulin sensitivity in CF participants with dysglycemia was correlated with shorter TST, longer sleep latency, more wake after sleep onset, and poorer SE.
CONCLUSIONS: Poor sleep appears to correlate with higher blood glucose and lower insulin sensitivity in CF adolescents with dysglycemia. Further research is needed to better understand the mechanisms and directionality behind this relationship. This article is protected by copyright. All rights reserved.

PMID: 30022572 [PubMed - as supplied by publisher]

Angiogenesis in the lung.

J Physiol. 2018 Jul 18;:

Authors: Eldridge L, Wagner EM

Abstract
Both systemic (tracheal and bronchial) and pulmonary circulations perfuse the lung. However, documentation of angiogenesis of either is complicated by the presence of the other. Well-documented angiogenesis of the systemic circulations have been identified in asthma, cystic fibrosis, chronic thromboembolism, and primary carcinomas. Angiogenesis of the vasa vasorum, which are branches of bronchial arteries, is seen in the walls of large pulmonary vessels after a period of chronic hypoxia. Documentation of increased pulmonary capillaries has been shown in models of chronic hypoxia, after pneumonectomy, and in some carcinomas. Although endothelial cell proliferation may occur as part of the repair process in several pulmonary diseases, it is separate from the unique establishment of new functional perfusing networks defined as angiogenesis. Identification of the mechanisms driving the expansion of new vascular beds in the adult needs further investigation. Yet the growth factors and molecular mechanisms of lung angiogenesis remain difficult to separate from underlying disease sequelae. This article is protected by copyright. All rights reserved.

PMID: 30022479 [PubMed - as supplied by publisher]

The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins.

Gene Ther. 2018 Jul 18;:

Authors: Paul-Smith MC, Pytel KM, Gelinas JF, McIntosh J, Pringle I, Davies L, Chan M, Meng C, Bell R, Cammack L, Moran C, Cameron L, Inoue M, Tsugumine S, Hironaka T, Gill DR, Hyde SC, Nathwani A, Alton EWFW, Griesenbach U

Abstract
We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using human α1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV.F/HN carrying either the secreted reporter gene Gaussia luciferase or the hAAT or hFVIII cDNAs by nasal sniffing. rSIV.F/HN-hAAT transduction lead to therapeutically relevant hAAT levels (70 μg/ml) in epithelial lining fluid, with stable expression persisting for at least 19 months from a single application. Secreted proteins produced in the lung were released into the circulation and stable expression was detectable in blood. The levels of hFVIII in murine blood approached therapeutically relevant targets. rSIV.F/HN was also able to produce secreted hAAT and hFVIII in transduced human primary airway cells. rSIV.F/HN transduction of the murine lungs leads to long-lasting and therapeutically relevant levels of secreted proteins in the lung and systemic circulation. These data broaden the use of this vector platform for a large range of disease indications.

PMID: 30022127 [PubMed - as supplied by publisher]

Dietary interventions for managing glucose abnormalities in cystic fibrosis: a systematic review protocol.

Syst Rev. 2018 Jul 18;7(1):98

Authors: Birch L, Lithander FE, Hewer SL, Harriman K, Hamilton-Shield J, Perry R

Abstract
BACKGROUND: Glucose abnormalities in cystic fibrosis (CF) are common, but there is limited evidence to guide their dietary management. Progressive impaired glucose tolerance eventually leads to cystic fibrosis-related diabetes (CFRD), the most prevalent complication of CF, which is associated with increased morbidity and mortality. Optimising glycaemic control improves clinical status and reduces mortality; insulin therapy is the primary means of controlling glycaemia in CFRD, but its role in managing pre-diabetes is less clear. CF dietary therapy requires a high calorie diet due to increased energy expenditure and malabsorption, but this energy-dense diet is typically high in fat and sugar, and high sugar intakes often result in hyperglycaemia in individuals who have impaired glucose handling. Current guidelines for the dietary management of glucose abnormalities in CF are based on clinical consensus rather than empirical evidence. A systematic review conducted in 2012 on the effects of low glycaemic index dietary intervention in CF concluded that there is a dearth of evidence in this area. This review will update the systematic review by Balzer et al. in 2012 and will broaden the scope of their review to include any type of dietary intervention for managing glucose abnormalities in CF.
METHODS: Quantitative studies of dietary interventions to manage glucose abnormalities in individuals aged over 5 years with CF and glucose abnormalities will be reviewed. No limits will be placed on language or study design. The comparator will be standard CF dietary therapy (energy dense, high-fat diet) in addition to insulin therapy for individuals with CFRD. Electronic databases will be searched for completed quantitative studies published in peer-review journals that focus on dietary interventions for managing glucose abnormalities in CF. Searches will be conducted from 2000 up to the present day to reflect the evolving improvements in CF management. No restrictions will be placed on study design or language. Duration of the dietary intervention must be a minimum of 2 months and only interventions in out-patient or community settings will be included. Studies must report on dietary intervention, glycaemic control, anthropometry and lung function. Evidence will be assessed for heterogeneity and a narrative review or meta-analysis conducted as appropriate.
DISCUSSION: This systematic review will elucidate current knowledge of the effects of dietary interventions for managing glucose abnormalities in the vulnerable CF clinical population.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42018085569 www.crd.york.ac.uk/prospero/.

PMID: 30021636 [PubMed - in process]

Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology.

Respir Res. 2018 07 18;19(1):136

Authors: Rout-Pitt N, Farrow N, Parsons D, Donnelley M

Abstract
Cystic Fibrosis (CF) is a genetic disorder that arises due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene, which encodes for a protein responsible for ion transport out of epithelial cells. This leads to a disruption in transepithelial Cl-, Na + and HCO3- ion transport and the subsequent dehydration of the airway epithelium, resulting in infection, inflammation and development of fibrotic tissue. Unlike in CF, fibrosis in other lung diseases including asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis has been well characterised. One of the driving forces behind fibrosis is Epithelial Mesenchymal Transition (EMT), a process where epithelial cells lose epithelial proteins including E-Cadherin, which is responsible for tight junctions. The cell moves to a more mesenchymal phenotype as it gains mesenchymal markers such as N-Cadherin (providing the cells with migration potential), Vimentin and Fibronectin (proteins excreted to help form the extracellular matrix), and the fibroblast proliferation transcription factors Snail, Slug and Twist. This review paper explores the EMT process in a range of lung diseases, details the common links that these have to cystic fibrosis, and explores how understanding EMT in cystic fibrosis may open up novel methods of treating patients with cystic fibrosis.

PMID: 30021582 [PubMed - in process]

Variation in treatment strategies for the eradication of Pseudomonas aeruginosa in primary ciliary dyskinesia across European centers.

Chron Respir Dis. 2018 Jan 01;:1479972318787919

Authors: Crowley S, Holgersen MG, Nielsen KG

Abstract
Primary ciliary dyskinesia (PCD) is a rare disease causing motile cilia dysfunction, recurrent airway infection, and bronchiectasis. Airway infection management strategies are borrowed from cystic fibrosis. The aim of this study is to describe the management of airway infection with Pseudomonas aeruginosa ( PA) in children and adults with PCD across European centers. An online survey questionnaire was sent electronically using SurveyMonkey® to 55 PCD centers in 36 European countries. Fifty-two responded from 43 centers in 26 countries, a response rate of 70%. Most (89%) countries did not have written guidelines for PCD management. Airway sampling for infection detection at each clinic visit was more likely when follow-up was frequent. Eighty-seven percent of centers chose to treat the first PA isolate, most prescribing combined oral ciprofloxacin and inhaled colistimethate sodium (43%, n = 18). The preferred treatment for chronic infection with PA was nebulized colistimethate in 51% ( n = 22). In summary, considerable variation exists across European centers in the frequency of patient follow-up and airway sampling for infection, treatment goals, and the management of PA infection. Few centers had written guidelines for PCD management. Clinical trials to determine optimal treatment of PA in PCD patients are urgently needed.

PMID: 30021461 [PubMed - as supplied by publisher]

Genome-Wide Association Studies of Coronary Artery Disease: Recent Progress and Challenges Ahead.

Curr Atheroscler Rep. 2018 Jul 18;20(9):47

Authors: Clarke SL, Assimes TL

Abstract
PURPOSE OF REVIEW: Genome-wide association studies (GWAS) have been the primary tool for unbiased assessment of the genetic basis of coronary artery disease (CAD) for more than a decade. We summarize successes as well as shortcomings of recent studies in this context.
RECENT FINDINGS: The number of CAD-associated loci has more than doubled in the past year to 161. This rapid progress has been in large part due to the release of genome-wide genotyping data for the largely European participants of the UK Biobank study which has been combined with existing GWAS from the CARDIoGRAMplusC4D consortium. Additional discoveries have been achieved through large-scale genotyping of participants using custom high-yield genotyping arrays including the Metabochip and the Exome chip. As a consequence, the ability of genetic risk scores in predicting incident CAD events has improved but that improvement has only been shown in European populations. GWAS have proven to be a fruitful approach for uncovering the genetic drivers of CAD. However, determining the mechanisms of association of GWAS findings remains a challenging endeavor requiring long-term investment. Genetic risk scores offer an opportunity for recent findings to have an immediate clinical impact. Going forward, CAD genetics will benefit greatly from the release of more genetic data produced by mega-biobanks. These new data will allow for the more comprehensive examination of underrepresented populations.

PMID: 30022313 [PubMed - in process]

Cardiomyopathy and Preeclampsia: Shared Genetics?

Circulation. 2018 Jul 18;:

Authors: Gammill HS, Chettier R, Brewer A, Roberts JM, Shree R, Tsigas E, Ward K

Abstract
Background -Preeclampsia (PE), is associated with diastolic dysfunction, peripartum cardiomyopathy (CM), and both preexisting and subsequent maternal cardiovascular disease (CVD). Gene mutations causing idiopathic CM were recently implicated in peripartum CM. We sought to determine whether CM gene mutations are also a contributory factor in PE. Methods -Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of PE completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing (WES) was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with CM. Missense variants were deemed "damaging missense" if so classified by any of 7 standard function prediction algorithms. Variants were defined as "loss-of-function" if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from two control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium (ExAC). PE was not excluded in control groups. Results -Of 181 subjects with confirmed PE, 96% were Caucasian. 72% had ≥1 preterm PE delivery <37 weeks. Among PE subjects, WES demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 CM genes considered. The prevalence of these loss-of-function variants was significantly higher in PE subjects (5.5%) compared to the local control (2.5%) population (p=0.014). 68% of women with PE carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum CM, most mutations (55%) were found in the TTN gene. 73% of PE subjects had TTN mutations in PE cohort versus 48% in local controls (p=1.36E-11). Conclusions -Women who develop PE are more likely to carry protein-altering mutations in genes associated with CM, particularly in TTN. Mutations promoting CM are prevalent in PE, idiopathic CM, and peripartum CM, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.

PMID: 30021846 [PubMed - as supplied by publisher]

Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats.

J Am Heart Assoc. 2017 Oct 28;6(11):

Authors: Peng W, Li M, Li H, Tang K, Zhuang J, Zhang J, Xiao J, Jiang H, Li D, Yu Y, Sham PC, Nattel S, Xu Y

Abstract
BACKGROUND: There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial-selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light-chain 4 (MYL4), encoding the atrial-selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of MYL4 in atrial cardiomyopathy.
METHODS AND RESULTS: Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of MYL4 (c.31G>A [p.E11K]) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with MYL4 mutation knock-in confirmed the causative role of the mutation. MYL4 knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4-amino-acid deletion showed no phenotype. Both MYL4 p.E11K knock-in rats and MYL4 knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of MYL4 p.E11K mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial-cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in vitro adenoviral transfer of the mutant gene to neonatal-rat cardiomyocytes.
CONCLUSIONS: Loss-of-function MYL4 gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify MYL4 as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.

PMID: 29080865 [PubMed - indexed for MEDLINE]

Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms.

Leuk Res. 2018 Jun 30;71:82-88

Authors: Berdeja J, Palandri F, Baer MR, Quick D, Kiladjian JJ, Martinelli G, Verma A, Hamid O, Walgren R, Pitou C, Li PL, Gerds AT

Abstract
BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing.
METHODS: A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug.
FINDINGS: Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively.
INTERPRETATIONS: LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a ≥50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.

PMID: 30025280 [PubMed - as supplied by publisher]

Antiarrhythmic drug-induced smell and taste disturbances: A case report and literature review.

Medicine (Baltimore). 2018 Jul;97(29):e11112

Authors: Che X, Li Y, Fang Y, Reis C, Wang H

Abstract
RATIONALE: Metoprolol and amiodarone are common antiarrhythmic drugs used in clinics throughout the world. The taste and smell alterations induced by antiarrhythmic drugs remain uncommon throughout the world, with less than 10 reported cases.
PATIENT CONCERNS: In this case report, we describe a case of a 73-year-old female, diagnosed with arrhythmias, was treated for metoprolol. At the third week of metoprolol treatment, the patient noticed a qualitative change in her ability to smell, also called dysosmia. After the metoprolol was tapered, her ability to smell was recovered. However, her arrhythmia was getting worse and the patient was given amiodarone. After using amiodarone for about 2 weeks, the patient felt hypogeusia, or loss of taste sensation.
DIAGNOSES: The patient was diagnosed as dysosmia and taste disturbance induced by the antiarrhythmic drugs.
INTERVENTIONS: After noticed the side effects of the antiarrhythmic drugs, we asked the patient to abandon the drugs and have a radiofrequency ablation.
OUTCOMES: Her ability of smell and taste were recovered after withdrawing the antiarrhythmic drugs. Also, in the follow-up appointment, she reported no complaints of smell or taste anymore.
LESSONS: These rare sensory disorders induced by anti-arrhythmic drugs were less documented in past literature. Our case report describes a patient with an arrhythmia who suffered reversible dysosmia and hypogeusia after taking metoprolol and amiodarone, respectively. We conclude that smell and taste disorders should be made aware to patients during the anti-arrhythmic treatment, helping to promote the safety of patients and drug compliance.

PMID: 30024498 [PubMed - in process]

[Recording and assessment of medication errors : Experience of the Drug Commission of the German Medical Association].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2018 Jul 18;:

Authors: Köberle U, Stammschulte T, Gundert-Remy U, Pitzer M, Bräutigam K

Abstract
Adverse drug reactions (ADRs) are a common problem in daily clinical practice and they may in part result from medication errors. According to the extended interpretation in the new European pharmacovigilance guideline, medication error-related reactions are classified as ADRs. Therefore, the pharmacovigilance system needs to be adjusted to record medication errors. As a partner in the German pharmacovigilance system, the Drug Commission of the German Medical Association (DCGMA) has set up a project for developing a subsystem for the recording and assessment of medication errors within the existing spontaneous reporting system for ADRs. The aim of the project was to evaluate the feasibility of recording and assessing medication errors within the existing structures and to investigate whether it is possible to deduce risk-reducing strategies from the information obtained by the case reports. In the present narrative review, the experience of the DCGMA with the recording and assessment of medication errors is described. The conclusions and recommendations from the analysis of the reports of medication errors show how they can be used to improve medication safety. The project has closed a gap in pharmacovigilance.

PMID: 30022236 [PubMed - as supplied by publisher]

Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3).

Mov Disord. 2017 Dec;32(12):1701-1709

Authors: Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Trenkwalder C, Ehret R, Azulay JP, Isaacson S, Felt L, Stempien MJ

Abstract
BACKGROUND: The treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy.
OBJECTIVE: The purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial.
METHODS: PD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure.
RESULTS: At week 12, least-squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P < .0001), indicating improvement in levodopa-induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS-5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference -1.1 hours, 95% confidence interval -2.0 to -0.2, P = .0199). The most common adverse events (ADS-5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively.
CONCLUSION: ADS-5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa-induced dyskinesia and improving OFF time. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

PMID: 28833562 [PubMed - indexed for MEDLINE]