Literature Watch
Acute retinal vein occlusion and cystic fibrosis.
Acute retinal vein occlusion and cystic fibrosis.
Int J Retina Vitreous. 2018;4:26
Authors: Starr MR, Norby SM, Scott JP, Bakri SJ
Abstract
Background: The ocular manifestations of cystic fibrosis typically present with surface irritation or nyctalopia due to Vitamin A deficiency, however, there have been two previous reports of patients with cystic fibrosis that developed retinal vein occlusions. These reports hypothesized that either elevated fibrinogen levels due to chronic infections or elevated homocysteine levels have predisposed patients with cystic fibrosis to develop retinal vein occlusions.
Case presentation: We present a case of a 35-year-old male with cystic fibrosis complicated by chronic sinusitis with no history of organ transplantation or chronic pulmonary infections who presented with an acute branch retinal vein occlusion in his left eye with associated macular edema. Evaluation revealed an elevated fibrinogen level, while the rest of his workup was relatively unremarkable including a normal homocysteine level. His vision remained 20/20 throughout his care and he did not require treatment of his macular edema.
Conclusions: Patients with cystic fibrosis are at an increased risk of developing retinal vein occlusions likely due to a variety of systemic thrombogenic factors rather than a single risk factor which had been reported previously. Elevated fibrinogen levels in these patients may not be due to chronic infections, but inherent to the cystic fibrosis.
PMID: 30026964 [PubMed]
Recent advances in understanding and managing acute pancreatitis.
Recent advances in understanding and managing acute pancreatitis.
F1000Res. 2018;7:
Authors: Mandalia A, Wamsteker EJ, DiMagno M
Abstract
This review highlights advances made in recent years in the diagnosis and management of acute pancreatitis (AP). We focus on epidemiological, clinical, and management aspects of AP. Additionally, we discuss the role of using risk stratification tools to guide clinical decision making. The majority of patients suffer from mild AP, and only a subset develop moderately severe AP, defined as a pancreatic local complication, or severe AP, defined as persistent organ failure. In mild AP, management typically involves diagnostic evaluation and supportive care resulting usually in a short hospital length of stay (LOS). In severe AP, a multidisciplinary approach is warranted to minimize morbidity and mortality over the course of a protracted hospital LOS. Based on evidence from guideline recommendations, we discuss five treatment interventions, including intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis. This review also highlights the importance of preventive interventions to reduce hospital readmission or prevent pancreatitis, including alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis. Our review aims to consolidate guideline recommendations and high-quality studies published in recent years to guide the management of AP and highlight areas in need of research.
PMID: 30026919 [PubMed]
Electrochemically Synthesized Silver Nanoparticles Are Active Against Planktonic and Biofilm Cells of Pseudomonas aeruginosa and Other Cystic Fibrosis-Associated Bacterial Pathogens.
Electrochemically Synthesized Silver Nanoparticles Are Active Against Planktonic and Biofilm Cells of Pseudomonas aeruginosa and Other Cystic Fibrosis-Associated Bacterial Pathogens.
Front Microbiol. 2018;9:1349
Authors: Pompilio A, Geminiani C, Bosco D, Rana R, Aceto A, Bucciarelli T, Scotti L, Di Bonaventura G
Abstract
A novel, electrochemically synthesized, silver nanoparticles (AgNPs) formulation was evaluated in vitro against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Staphylococcus aureus strains from cystic fibrosis (CF) patients. AgNPs were particularly active against P. aeruginosa and B. cepacia planktonic cells (median MIC: 1.06 and 2.12 μg/ml, respectively) by a rapid, bactericidal and concentration-dependent effect. AgNPs showed to be particularly effective against P. aeruginosa and S. aureus biofilm causing a viability reduction ranging from 50% (1×MIC) to >99.9% (4×MIC). Electron microscopy showed that AgNPs deconstruct extracellular matrix of P. aeruginosa biofilm, and accumulate at the cell surface causing cell death secondary to membrane damage. Compared to Tobramycin, AgNPs showed comparable, or even better, activity against planktonic and biofilm P. aeruginosa cells. AgNPs at concentrations effective against B. cepacia and P. aeruginosa were not toxic to G. mellonella larvae. Our silver-based formulation might be an alternative to antibiotics in CF patients. Further in vitro and in vivo studies are warranted to confirm this therapeutic potential.
PMID: 30026732 [PubMed]
Metabolic Phenotyping and Strain Characterisation of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients Using Rapid Evaporative Ionisation Mass Spectrometry.
Metabolic Phenotyping and Strain Characterisation of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients Using Rapid Evaporative Ionisation Mass Spectrometry.
Sci Rep. 2018 Jul 19;8(1):10952
Authors: Bardin EE, Cameron SJS, Perdones-Montero A, Hardiman K, Bolt F, Alton EWFW, Bush A, Davies JC, Takáts Z
Abstract
Rapid evaporative ionisation mass spectrometry (REIMS) is a novel technique for the real-time analysis of biological material. It works by conducting an electrical current through a sample, causing it to rapidly heat and evaporate, with the analyte containing vapour channelled to a mass spectrometer. It was used to characterise the metabolome of 45 Pseudomonas aeruginosa (P. aeruginosa) isolates from cystic fibrosis (CF) patients and compared to 80 non-CF P. aeruginosa. Phospholipids gave the highest signal intensity; 17 rhamnolipids and 18 quorum sensing molecules were detected, demonstrating that REIMS has potential for the study of virulence-related metabolites. P. aeruginosa isolates obtained from respiratory samples showed a higher diversity, which was attributed to the chronic nature of most respiratory infections. The analytical sensitivity of REIMS allowed the detection of a metabolome that could be used to classify individual P. aeruginosa isolates after repeated culturing with 81% accuracy, and an average 83% concordance with multilocus sequence typing. This study underpins the capacities of REIMS as a tool with clinical applications, such as metabolic phenotyping of the important CF pathogen P. aeruginosa, and highlights the potential of metabolic fingerprinting for fine scale characterisation at a sub-species level.
PMID: 30026575 [PubMed - in process]
Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales.
Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales.
Thorax. 2018 Jul 19;:
Authors: Schlüter DK, Griffiths R, Adam A, Akbari A, Heaven ML, Paranjothy S, Nybo Andersen AM, Carr SB, Pressler T, Diggle PJ, Taylor-Robinson D
Abstract
BACKGROUND: Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth.
METHODS: We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available.
RESULTS: Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be -178.8 g (95% CI -225.43 to -134.47 g) in the Danish population and -210.08 g (95% CI -281.97 to -141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age.
CONCLUSIONS: CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation.
PMID: 30026297 [PubMed - as supplied by publisher]
Assessing effects of inhaled antibiotics in adults with non-cystic fibrosis bronchiectasis - experiences from recent clinical trials.
Assessing effects of inhaled antibiotics in adults with non-cystic fibrosis bronchiectasis - experiences from recent clinical trials.
Expert Rev Respir Med. 2018 Jul 19;:
Authors: Paredes Aller S, Quittner AL, Salathe MA, Schmid A
Abstract
INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) results from a permanent and progressive destruction of the airways leading to poor lung function. NCFB is characterized by recurrent lung infection, sputum production, and cough, often requiring long-term antibiotic therapy and hospitalization. At present, there are no approved therapies available. Clinical trials of inhaled antibiotics have shown promise against sputum bacterial load, but mixed results on clinical outcomes. Areas covered: The objective of this review is to provide an overview of NCFB and critically evaluate the evidence supporting the outcome measures used in recent clinical trials of inhaled antibiotics. These include quantitative changes in bacterial load, sputum purulence and yield, inflammatory markers, and lung function, as well as clinical changes in exacerbations, exacerbation frequency, hospitalizations, and health-related quality of life. Expert commentary: Recently completed large trials of inhaled antibiotics in NCFB did not consistently meet pre-specified endpoints, suggesting that we have not yet found the best enrollment criteria or outcome measures to evaluate efficacy, although reduced exacerbation frequency may be clinically most meaningful. Future trials may focus on specific patient populations at high risk with new information obtained through analyses of large international patient registries.
PMID: 30025482 [PubMed - as supplied by publisher]
Addressing challenges in the clinical applications associated with CRISPR/Cas9 technology and ethical questions to prevent its misuse.
Addressing challenges in the clinical applications associated with CRISPR/Cas9 technology and ethical questions to prevent its misuse.
Protein Cell. 2017 11;8(11):791-795
Authors: Kang XJ, Caparas CIN, Soh BS, Fan Y
PMID: 28986765 [PubMed - indexed for MEDLINE]
"systems biology"; +14 new citations
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Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques.
Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques.
ACS Omega. 2018 Mar 31;3(3):2564-2568
Authors: Shave S, McGuire K, Pham NT, Mole DJ, Webster SP, Auer M
Abstract
In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing.
PMID: 30023839 [PubMed]
Calcium Signaling in Liver Injury and Regeneration.
Calcium Signaling in Liver Injury and Regeneration.
Front Med (Lausanne). 2018;5:192
Authors: Oliva-Vilarnau N, Hankeova S, Vorrink SU, Mkrtchian S, Andersson ER, Lauschke VM
Abstract
The liver fulfills central roles in metabolic control and detoxification and, as such, is continuously exposed to a plethora of insults. Importantly, the liver has a unique ability to regenerate and can completely recoup from most acute, non-iterative insults. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease (NAFLD), long-term alcohol abuse and chronic use of certain medications, can cause persistent injury in which the regenerative capacity eventually becomes dysfunctional, resulting in hepatic scaring and cirrhosis. Calcium is a versatile secondary messenger that regulates multiple hepatic functions, including lipid and carbohydrate metabolism, as well as bile secretion and choleresis. Accordingly, dysregulation of calcium signaling is a hallmark of both acute and chronic liver diseases. In addition, recent research implicates calcium transients as essential components of liver regeneration. In this review, we provide a comprehensive overview of the role of calcium signaling in liver health and disease and discuss the importance of calcium in the orchestration of the ensuing regenerative response. Furthermore, we highlight similarities and differences in spatiotemporal calcium regulation between liver insults of different etiologies. Finally, we discuss intracellular calcium control as an emerging therapeutic target for liver injury and summarize recent clinical findings of calcium modulation for the treatment of ischemic-reperfusion injury, cholestasis and NAFLD.
PMID: 30023358 [PubMed]
Comparison of different analysis algorithms to calculate multiple-breath washout outcomes.
Comparison of different analysis algorithms to calculate multiple-breath washout outcomes.
ERJ Open Res. 2018 Jul;4(3):
Authors: Anagnostopoulou P, Kranz N, Wolfensberger J, Guidi M, Nyilas S, Koerner-Rettberg C, Yammine S, Singer F, Latzin P
Abstract
Lung clearance index (LCI) is the main outcome of the multiple-breath washout (MBW) test. Current recommendations for LCI acquisition are based on low-grade evidence. The aim of this study was to challenge those recommendations using alternative methods for LCI analysis. Nitrogen MBW measurements from school-aged children, 20 healthy controls, 20 with cystic fibrosis (CF) and 17 with primary ciliary dyskinesia (PCD), were analysed using 1) current algorithms (standard), 2) three alternative algorithms to detect with higher precision the end of MBW testing and 3) two alternative algorithms to determine exhaled tracer gas concentrations. LCI values, intra-test repeatability, and ability to discriminate between health and lung disease were compared between these methods. The analysis methods strongly influenced LCI (mean±sd overall differences (%) between standard and alternative analysis methods: -4.9±5.7%; range: -66-19%), but did not improve intra-test variability. Discrimination between health and disease was comparable as areas under the receiver operator curves were not greater than that from standard analysis. This study supports current recommendations for LCI calculation in children. Alternative methods influence LCI estimates and hamper comparability between MBW setups. Alternative algorithms, whenever used, should be carefully reported.
PMID: 30023402 [PubMed]
Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators.
Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators.
Front Pharmacol. 2018;9:719
Authors: Laselva O, Marzaro G, Vaccarin C, Lampronti I, Tamanini A, Lippi G, Gambari R, Cabrini G, Bear CE, Chilin A, Dechecchi MC
Abstract
The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4.
PMID: 30022950 [PubMed]
Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement.
Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement.
Mol Genet Metab Rep. 2018 Jun;15:11-14
Authors: Mohammad AN, Bruno KA, Hines S, Atwal PS
Abstract
Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in NEU1 which encodes lysosomal sialidase (neuraminidase 1). Lysosomal neuraminidase catalyzes the removal of terminal sialic acid molecules from glycolipids, glycoproteins and oligosaccharides. Sialidosis is classified into two types, based on phenotype and age of onset. Patients with the milder type 1 typically present late, usually in the second or third decade, with myoclonus, ataxia and visual defects. Type 2 is more severe and presents earlier with coarse facial features, developmental delay, hepatosplenomegaly and dysostosis multiplex. Presentation and severity of the disease are related to whether lysosomal sialidase is inactive or there is some residual activity. Diagnosis is suspected based on clinical features and increased urinary bound sialic acid excretion and confirmed by genetic testing showing pathogenic variants in NEU1. We report a patient with type 1 sialidosis who presented mainly with ataxia and both generalized and myoclonic seizures but no visual involvement. Whole exome sequencing of the proband detected compound heterozygous likely pathogenic variants (S182G and G227R) in NEU1.
PMID: 30023283 [PubMed]
The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants.
The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants.
J Thorac Dis. 2018 Jun;10(Suppl 17):S1923-S1929
Authors: Pasipoularides A
PMID: 30023082 [PubMed]
Communicating risk of medication side-effects: role of communication format on risk perception.
Communicating risk of medication side-effects: role of communication format on risk perception.
Pharm Pract (Granada). 2018 Apr-Jun;16(2):1174
Authors: Sawant R, Sansgiry S
Abstract
Background: Medication side-effects often arouse fear in the minds of consumers and therefore need to be communicated in a manner such that the intended message is clearly understood, without causing undue fear.
Objectives: Considering the message format and contextual factors that influence perceptions of risk, this study aimed at assessing the interaction effects of message format and contextual factors (rate of occurrence and severity) on risk perception of medication side-effects.
Methods: Using Rhormann's risk communication process model, a 2 (message format: words-only vs. words + numeric) X 2 (rate of occurrence: high vs low) X 2 (severity: mild vs severe) experimental factorial study was designed. Participants were presented with four of eight possible combinations of the three factors and were asked to indicate the risk perception with the associated side-effects. Repeated measures analysis was conducted while adjusting for control variables.
Results: A total of 196 completed surveys were collected. Communication format did not have significant main effect on risk perception (P=0.4237) but demonstrated a significant interaction with rate of occurrence (P=0.0001). As compared to words-only format, least square means for words + numeric format were lower among low-rate side-effects but were higher among high-rate side-effects. Rate of occurrence (P<0.0001) and severity (P<0.0001) had significant main effects on risk perception as well as interaction effect with each other (P<0.0001).
Conclusions: The results indicated that effect of communication format on risk perception of side-effect is dependent on the underlying rate of occurrence of side-effect. Healthcare providers should therefore carefully construct risk communication messages for effective communication with patients.
PMID: 30023029 [PubMed]
Pilot Projects Investigating Understudied G Protein-Coupled Receptors, Ion Channels, and Protein Kinases (R03 Clinical Trial Not Allowed)
Research Innovations for Scientific Knowledge (RISK) for Musculoskeletal Diseases (R61/R33 Clinical Trial Not Allowed)
Pre-Application: Research Innovation for Scientific Knowledge (RISK) for Musculoskeletal Diseases (X02 Clinical Trial Not Allowed)
Delayed Enforcement and Short-Term Flexibilities for Some Requirements Affecting Prospective Basic Science Studies Involving Human Participants
Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.
Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.
Curr Med Chem. 2018;25(24):2783-2796
Authors: Marcuzzi A, Loganes C, Celeghini C, Kleiner G
Abstract
BACKGROUND: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.
OBJECTIVE: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life.
METHODS: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.
RESULTS: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.
CONCLUSIONS: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.
PMID: 28901277 [PubMed - indexed for MEDLINE]
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