Efficacy and safety of tenofovir disoproxil fumarate in preventing vertical transmission of hepatitis B in pregnancies with high viral load.

Sci Rep. 2017 Jun 23;7(1):4132

Authors: Chen JZ, Liao ZW, Huang FL, Su RK, Wang WB, Cheng XY, Chen JQ, Liu JQ, Huang Z

Abstract
This study was a meta-analysis of the literature on the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission of hepatitis B in pregnancies with high viral load. Four observational studies and one randomized controlled trial involving 585 pregnant women and 595 newborns were included in the meta-analysis. TDF was more effective than the placebo in reducing vertical transmission in HBeAg-positive chronic hepatitis B (CHB) pregnancies with high serum HBV-DNA levels (OR = 0.21, 95% CI = 0.07-0.61) at 4-12 months, infant HBV DNA seropositivity at delivery (OR = 0.16, 95% CI = 0.07-0.37), and a severe flair in maternal alanine aminotransferase (ALT) levels (OR = 0.43, 95% CI = 0.19-0.95) during pregnancy. In addition, TDF showed more improvement in HBV DNA suppression at delivery (OR = 254.46, 95% CI = 28.39-2280.79). No significant differences were found in HBeAg seroconversion or ALT normalization; or in rates of cesarean section, emergent cesarean section, postpartum hemorrhage, prematurity, congenital malformations, or infant death. However, TDF induced more drug-related adverse events (OR = 2.33, 95% CI = 1.39-3.89) and elevated creatine kinase (CK) (OR = 9.56, 95% CI = 1.17-78.09) than in controls. The available evidence suggests that TDF is effective and safe in preventing vertical transmission of hepatitis B in pregnancies exhibiting a high viral load.

PMID: 28646142 [PubMed - in process]

Drug repurposing by simulating flow through protein-protein interaction networks.

Clin Pharmacol Ther. 2017 Jun 23;:

Authors: Manczinger M, Bodnár V, Papp BT, Bolla BS, Szabó K, Balázs B, Csányi E, Szél E, Erős G, Kemény L

Abstract
As drug development is extremely expensive, the identification of novel indications for in-market drugs is financially attractive. Multiple algorithms are used to support such drug repurposing, but highly reliable methods combining simulation of intracellular networks and machine learning are currently not available. We developed an algorithm that simulates drug effects on the flow of information through protein-protein interaction networks, and uses Support Vector Machine to identify potentially effective drugs in our model disease, psoriasis. Using this method, we screened about 1500 marketed and investigational substances, identified fifty-one drugs that were potentially effective and selected three of them for experimental confirmation. All drugs inhibited TNF-induced NFκB activity in vitro, suggesting they might be effective for treating psoriasis in humans. Additionally, these drugs significantly inhibited imiquimod-induced ear thickening and inflammation in the mouse model of the disease. All results suggest high prediction performance for the algorithm. This article is protected by copyright. All rights reserved.

PMID: 28643328 [PubMed - as supplied by publisher]

Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy.

Br J Cancer. 2017 Jun 22;:

Authors: Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG

Abstract
BACKGROUND: Complete tumour response (pCR) to neo-adjuvant chemo-radiotherapy for rectal cancer is associated with a reduction in local recurrence and improved disease-free and overall survival, but is achieved in only 20-30% of patients. Drug repurposing for anti-cancer treatments is gaining momentum, but the potential of such drugs as adjuncts, to increase tumour response to chemo-radiotherapy in rectal cancer, is only just beginning to be recognised.
METHODS: A systematic literature search was conducted and all studies investigating the use of drugs to enhance response to neo-adjuvant radiation in rectal cancer were included. 2137 studies were identified and following review 12 studies were extracted for full text review, 9 studies were included in the final analysis.
RESULTS: The use of statins or aspirin during neo-adjuvant therapy was associated with a significantly higher rate of tumour downstaging. Statins were identified as a significant predictor of pCR and aspirin users had a greater 5-year progression-free survival and overall survival. Metformin use was associated with a significantly higher overall and disease-free survival, in a subset of diabetic patients.
CONCLUSIONS: Aspirin, metformin and statins are associated with increased downstaging of rectal tumours and thus may have a role as adjuncts to neoadjuvant treatment, highlighting a clear need for prospective randomised controlled trials to determine their true impact on tumour response and overall survival.British Journal of Cancer advance online publication, 22 June 2017; doi:10.1038/bjc.2017.175 www.bjcancer.com.

PMID: 28641310 [PubMed - as supplied by publisher]

Drug-Repositioning Screening for Keap1-Nrf2 Binding Inhibitors using Fluorescence Correlation Spectroscopy.

Sci Rep. 2017 Jun 21;7(1):3945

Authors: Yoshizaki Y, Mori T, Ishigami-Yuasa M, Kikuchi E, Takahashi D, Zeniya M, Nomura N, Mori Y, Araki Y, Ando F, Mandai S, Kasagi Y, Arai Y, Sasaki E, Yoshida S, Kagechika H, Rai T, Uchida S, Sohara E

Abstract
The Kelch-like ECH-associating protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. The Cul3/Keap1 E3 ubiquitin ligase complex interacts with Nrf2, leading to Nrf2 ubiquitination and degradation. In this study, we focused on the disruption of the Keap1-Nrf2 interaction to upregulate Nrf2 expression and the transcription of ARE-controlled cytoprotective oxidative stress response enzymes, such as HO-1. We completed a drug-repositioning screening for inhibitors of Keap1-Nrf2 protein-protein interactions using a newly established fluorescence correlation spectroscopy (FCS) screening system. The binding reaction between Nrf2 and Keap1 was successfully detected with a KD of 2.6 μM using our FCS system. The initial screening of 1,633 drugs resulted in 12 candidate drugs. Among them, 2 drugs significantly increased Nrf2 protein levels in HepG2 cells. These two promising drugs also upregulated ARE gene promoter activity and increased HO-1 mRNA expression, which confirms their ability to dissociate Nrf2 and Keap1. Thus, drug-repositioning screening for Keap1-Nrf2 binding inhibitors using FCS enabled us to find two promising known drugs that can induce the activation of the Nrf2-ARE pathway.

PMID: 28638054 [PubMed - in process]

Update on the genetic architecture of rheumatoid arthritis.

Nat Rev Rheumatol. 2017 Jan;13(1):13-24

Authors: Kim K, Bang SY, Lee HS, Bae SC

Abstract
Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.

PMID: 27811914 [PubMed - indexed for MEDLINE]

[Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment].

Vnitr Lek. Fall 2016;62(11):887-894

Authors: Češka R, Štulc T, Votavová L, Schwarzová L, Vaclová M, Freiberger T

Abstract
Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by a very early manifestation of a cardiovascular disease. Myocardial infarction is not an exception even in childhood. The therapy is based on high-dose statins, statins in combination with ezetimib and now also newly on PCSK9 inhibitors. Lomitapid and partly also mipomersen hold great promise for patients. LDL apheresis then represents an aggressive form of treatment. Lipoprotein lipase deficiency (type I HLP) is mainly characterized by severe hypertriglyceridemia, serum milky in colour, and xanthomatosis. A fatal complication is acute recurrent pancreatitis. A critical part of the treatment is diet, however it alone is not enough to control a genetic disorder. The only approved treatment is gene therapy. Experimentally, as an "off label" therapy, it is used in case studies with a lomitapid effect. We have our own experience with this experimental therapy. Dysbetalipoproteinemia is a congenital disorder of lipoprotein metabolism, characterized by high cholesterol (CH) and triglyceride (TG) levels. The underlying cause of this disease is the defect of the gene providing for apolipoprotein E. It is clinically manifested by xanthomatosis, however primarily by an early manifestation of atherosclerosis (rather peripheral than coronary).Key words: Lipoprotein lipase deficiency - dysbetalipoproteinemia - familial hypercholesterolemia - gene therapy - homozygous FH - LDL apheresis - lomitapid - mipomersen - PCSK9 inhibitors - rare diseases.

PMID: 28128575 [PubMed - indexed for MEDLINE]

Current rare indications and future directions for implantable loop recorders.

Herzschrittmacherther Elektrophysiol. 2016 Dec;27(4):366-370

Authors: Wechselberger S, Piorkowski C, Pohl M

Abstract
The scope of application for implantable loop recorders has shifted away from the evaluation of unclear palpitations and syncope episodes to more complex conditions. This article focuses on rare indications of growing importance such as rhythm monitoring after ablation of atrial fibrillation or after cryptogenic stroke. Furthermore, forthcoming applications in various clinical settings are described, e. g., arrhythmia detection after myocardial infarction, after catheter-based valve interventions, in heart failure, and in cardiomyopathies. Enhancement of the capabilities of implantable loop recorders could broaden their fields of use.

PMID: 27873022 [PubMed - indexed for MEDLINE]

Rare Syndromes and Common Variants of the Brain-Derived Neurotrophic Factor Gene in Human Obesity.

Prog Mol Biol Transl Sci. 2016;140:75-95

Authors: Han JC

Abstract
Rare genetic disorders that cause BDNF haploinsufficiency, such as WAGR syndrome, 11p deletion, and 11p inversion, serve as models for understanding the role of BDNF in human energy balance and neurocognition. Patients with BDNF haploinsufficiency or inactivating mutations of the BDNF receptor exhibit hyperphagia, childhood-onset obesity, intellectual disability, and impaired nociception. Prader-Willi, Smith-Magenis, and ROHHAD syndromes are separate genetic disorders that do not directly affect the BDNF locus but share many similar clinical features with BDNF haploinsufficiency, and BDNF insufficiency is believed to possibly contribute to the pathophysiology of each of these conditions. In the general population, common variants of BDNF that affect BDNF gene expression or BDNF protein processing have also been associated with modest alterations in energy balance and cognitive functioning. Thus, variable degrees of BDNF insufficiency appear to contribute to a spectrum of excess weight gain and cognitive impairment that ranges in phenotypic severity. In this modern era of precision medicine, genotype-specific therapies aimed at increasing BDNF signaling in patients with rare and common disorders associated with BDNF insufficiency could serve as useful approaches for treating obesity and neurodevelopmental disorders.

PMID: 27288826 [PubMed - indexed for MEDLINE]

Robust Web Image Annotation via Exploring Multi-facet and Structural Knowledge.

IEEE Trans Image Process. 2017 Jun 19;:

Authors: Hu M, Yang Y, Shen F, Zhang L, Shen HT, Li X

Abstract
Driven by the rapid development of Internet and digital technologies, we have witnessed the explosive growth of Web images in recent years. Seeing that labels can reflect the semantic contents of the images, automatic image annotation, which can further facilitate the procedure of image semantic indexing, retrieval and other image management tasks, has become one of the most crucial research directions in multimedia. Most of the existing annotation methods heavily rely on well-labeled training data (expensive to collect) and/or single view of visual features (insufficient representative power). In this paper, inspired by the promising advance of feature engineering (e.g., CNN feature and SIFT feature) and inexhaustible image data (associated with noisy and incomplete labels) on the Web, we propose an effective and robust scheme, termed Robust Multi-view Semi-supervised Learning (RMSL), for facilitating image annotation task. Specifically, we exploit both labeled images and unlabeled images to uncover the intrinsic data structural information. Meanwhile, to comprehensively describe an individual datum, we take advantage of the correlated and complemental information derived from multiple facets of image data (i.e. multiple views or features). We devise a robust pair-wise constraint on outcomes of different views to achieve annotation consistency. Furthermore, we integrate a robust classifier learning component via ℓ2,p loss, which can provide effective noise identification power during the learning process. Finally, we devise an efficient iterative algorithm to solve the optimization problem in RMSL. We conduct comprehensive experiments on three different datasets, and the results illustrate that our proposed approach is promising for automatic image annotation.

PMID: 28641261 [PubMed - as supplied by publisher]

Economic Evaluation of Tobramycin Inhalation Powder for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Patients with Cystic Fibrosis.

Clin Drug Investig. 2017 Jun 22;:

Authors: Panguluri S, Gunda P, Debonnett L, Hamed K

Abstract
BACKGROUND: Chronic lung infection with Pseudomonas aeruginosa occurs in approximately 50% of patients with cystic fibrosis (CF). This infection further compromises lung function, and significantly contributes to the increased healthcare costs.
OBJECTIVES: Inhaled tobramycin, used to manage P. aeruginosa infection in CF patients, is available as powder (tobramycin inhalation powder, TIP) and solution (tobramycin inhalation solution, TIS). Evidence suggests increased adherence with the use of TIP over TIS. Hence, this analysis aimed to evaluate the potential pharmacoeconomic benefit of increased adherence with TIP over TIS in the US setting.
METHODS: A patient-level simulation model was developed to compare TIP with TIS. Both costs and benefits were predicted over a 10-year time horizon from a payer's perspective, and were discounted annually at 3%. All costs were presented in 2016 US dollars.
RESULTS: TIP was associated with greater quality-adjusted life-years (by 0.27) and lower total costs (by US$36,168) as compared with TIS over a 10-year time horizon. TIP-treated patients experienced a decreased mean number of exacerbations than TIS-treated patients (39.24 vs 50.20). Furthermore, administration of TIP via the T-326 Inhaler was associated with significant cost savings per patient, because of the nebulizer required for administering TIS (by US$1596) and exacerbation costs (by US$76,531). Probabilistic sensitivity analysis showed that TIP was dominant over TIS in 100% of the simulations.
CONCLUSION: TIP is likely to be a more cost-effective treatment than TIS, and therefore may reduce the economic burden of CF.

PMID: 28643178 [PubMed - as supplied by publisher]

Structure of O-Antigen and Hybrid Biosynthetic Locus in Burkholderia cenocepacia Clonal Variants Recovered from a Cystic Fibrosis Patient.

Front Microbiol. 2017;8:1027

Authors: Hassan AA, Maldonado RF, Dos Santos SC, Di Lorenzo F, Silipo A, Coutinho CP, Cooper VS, Molinaro A, Valvano MA, Sá-Correia I

Abstract
Burkholderia cenocepacia is an opportunistic pathogen associated with chronic lung infections and increased risk of death in patients with cystic fibrosis (CF). In this work, we investigated the lipopolysaccharide (LPS) of clinical variants of B. cenocepacia that were collected from a CF patient over a period of 3.5 years, from the onset of infection until death by necrotizing pneumonia (cepacia syndrome). We report the chemical structure of the LPS molecule of various sequential isolates and the identification of a novel hybrid O-antigen (OAg) biosynthetic cluster. The OAg repeating unit of the LPS from IST439, the initial isolate, is a [→2)-β-D-Ribf-(1→4)-α-D-GalpNAc-(1→] disaccharide, which was not previously described in B. cenocepacia. The IST439 OAg biosynthetic gene cluster contains 7 of 23 genes that are closely homologous to genes found in B. multivorans, another member of the Burkholderia cepacia complex. None of the subsequent isolates expressed OAg. Genomic sequencing of these isolates enabled the identification of mutations within the OAg cluster, but none of these mutations could be associated with the loss of OAg. This study provides support to the notion that OAg LPS modifications are an important factor in the adaptation of B. cenocepacia to chronic infection and that the heterogeneity of OAgs relates to variation within the OAg gene cluster, indicating that the gene cluster might have been assembled through multiple horizontal transmission events.

PMID: 28642745 [PubMed - in process]

Cellular distribution and function of ion channels involved in transport processes in rat tracheal epithelium.

Physiol Rep. 2017 Jun;5(12):

Authors: Hahn A, Faulhaber J, Srisawang L, Stortz A, Salomon JJ, Mall MA, Frings S, Möhrlen F

Abstract
Transport of water and electrolytes in airway epithelia involves chloride-selective ion channels, which are controlled either by cytosolic Ca(2+) or by cAMP The contributions of the two pathways to chloride transport differ among vertebrate species. Because rats are becoming more important as animal model for cystic fibrosis, we have examined how Ca(2+)- dependent and cAMP- dependent Cl(-) secretion is organized in the rat tracheal epithelium. We examined the expression of the Ca(2+)-gated Cl(-) channel anoctamin 1 (ANO1), the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel, the epithelial Na(+) channel ENaC, and the water channel aquaporin 5 (AQP5) in rat tracheal epithelium. The contribution of ANO1 channels to nucleotide-stimulated Cl(-) secretion was determined using the channel blocker Ani9 in short-circuit current recordings obtained from primary cultures of rat tracheal epithelial cells in Ussing chambers. We found that ANO1, CFTR and AQP5 proteins were expressed in nonciliated cells of the tracheal epithelium, whereas ENaC was expressed in ciliated cells. Among nonciliated cells, ANO1 occurred together with CFTR and Muc5b and, in addition, in a different cell type without CFTR and Muc5b. Bioelectrical studies with the ANO1-blocker Ani9 indicated that ANO1 mediated the secretory response to the nucleotide uridine-5'-triphosphate. Our data demonstrate that, in rat tracheal epithelium, Cl(-) secretion and Na(+) absorption are routed through different cell types, and that ANO1 channels form the molecular basis of Ca(2+)-dependent Cl(-) secretion in this tissue. These characteristic features of Cl(-)-dependent secretion reveal similarities and distinct differences to secretory processes in human airways.

PMID: 28642338 [PubMed - in process]

Cystic fibrosis: Current aspects and perspectives.

Presse Med. 2017 Jun;46(6 Pt 2):e85-e86

Authors: Burgel PR, Fajac I

PMID: 28641709 [PubMed - in process]

Transmembrane helical interactions in the CFTR channel pore.

PLoS Comput Biol. 2017 Jun 22;13(6):e1005594

Authors: Das J, Aleksandrov AA, Cui L, He L, Riordan JR, Dokholyan NV

Abstract
Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF). Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants. Several CFTR homology models have been developed using bacterial ABC transporters as templates but these have low sequence similarity to CFTR and are not ion channels. Here, we refine an earlier model in an outward (OWF) and develop an inward (IWF) facing model employing an integrated experimental-molecular dynamics simulation (200 ns) approach. Our IWF structure agrees well with a recently solved cryo-EM structure of a CFTR IWF state. We utilize cysteine cross-linking to verify positions and orientations of residues within trans-membrane helices (TMHs) of the OWF conformation and to reconstruct a physiologically relevant pore structure. Comparison of pore profiles of the two conformations reveal a radius sufficient to permit passage of hydrated Cl- ions in the OWF but not the IWF model. To identify structural determinants that distinguish the two conformations and possible rearrangements of TMHs within them responsible for channel gating, we perform cross-linking by bifunctional reagents of multiple predicted pairs of cysteines in TMH 6 and 12 and 6 and 9. To determine whether the effects of cross-linking on gating observed are the result of switching of the channel from open to close state, we also treat the same residue pairs with monofunctional reagents in separate experiments. Both types of reagents prevent ion currents indicating that pore blockage is primarily responsible.

PMID: 28640808 [PubMed - as supplied by publisher]

Multisystem Imaging Findings of Cystic Fibrosis in Adults: Recognizing Typical and Atypical Patterns of Disease.

AJR Am J Roentgenol. 2017 Jul;209(1):3-18

Authors: Averill S, Lubner MG, Menias CO, Bhalla S, Mellnick VM, Kennedy TA, Pickhardt PJ

Abstract
OBJECTIVE: There is an expanding and increasingly heterogeneous population of adult patients with cystic fibrosis (CF). Although CF is usually diagnosed in children with progressive multisystem involvement, up to 7% of CF cases are currently diagnosed de novo in adults with subtle manifestations distinct from the typical features of classic CF. The purpose of this article is to present the wide spectrum of CF in adults, including both classic and nonclassic variants, with an emphasis on the nonclassic imaging findings.
CONCLUSION: Recurrent pancreatitis, chronic sinusitis, and congenital bilateral absence of the vas deferens (CBAVD) are several of the ways in which CF is identified in adult patients with relatively rare mutations and with overall milder manifestations. It is important for radiologists to recognize the wide spectrum of CF to optimally monitor disease progression and response to therapeutic interventions in distinct adult patient populations.

PMID: 28639921 [PubMed - in process]

Enzymatic Mechanisms Involved in Evasion of Fungi to the Oxidative Stress: Focus on Scedosporium apiospermum.

Mycopathologia. 2017 Jun 21;:

Authors: Staerck C, Vandeputte P, Gastebois A, Calenda A, Giraud S, Papon N, Bouchara JP, Fleury MJJ

Abstract
The airways of patients with cystic fibrosis (CF) are frequently colonized by various filamentous fungi, mainly Aspergillus fumigatus and Scedosporium species. To establish within the respiratory tract and cause an infection, these opportunistic fungi express pathogenic factors allowing adherence to the host tissues, uptake of extracellular iron, or evasion to the host immune response. During the colonization process, inhaled conidia and the subsequent hyphae are exposed to reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by phagocytic cells, which cause in the fungal cells an oxidative stress and a nitrosative stress, respectively. To cope with these constraints, fungal pathogens have developed various mechanisms that protect the fungus against ROS and RNS, including enzymatic antioxidant systems. In this review, we summarize the different works performed on ROS- and RNS-detoxifying enzymes in fungi commonly encountered in the airways of CF patients and highlight their role in pathogenesis of the airway colonization or respiratory infections. The potential of these enzymes as serodiagnostic tools is also emphasized. In addition, taking advantage of the recent availability of the whole genome sequence of S. apiospermum, we identified the various genes encoding ROS- and RNS-detoxifying enzymes, which pave the way for future investigations on the role of these enzymes in pathogenesis of these emerging species since they may constitute new therapeutics targets.

PMID: 28639066 [PubMed - as supplied by publisher]

Inflammation and Oxidation Biomarkers in Patients with Cystic Fibrosis: The Influence of Azithromycin.

Eurasian J Med. 2017 Jun;49(2):118-123

Authors: Olveira C, Padilla A, Dorado A, Contreras V, Garcia-Fuentes E, Rubio-Martin E, Porras N, Doña E, Carmona A, Olveira G

Abstract
OBJECTIVE: In addition to their antibiotic effect, macrolides appear to modulate the inflammatory response in cystic fibrosis (CF) and could influence oxidative stress. The objective of this study was to assess oxidation biomarkers and levels of inflammation and to determine whether there is an association between these parameters and the intake of macrolides.
MATERIALS AND METHODS: The subjects included in this cross-sectional study were, on the one hand, clinically stable patients with CF and, on the other, healthy controls. The following serum and plasma inflammatory and oxidative stress biomarkers were measured: interleukin-6 (IL-6), reactive C protein (RCP), tumor necrosis alpha (TNF-α), glutathione peroxidase (GPx), total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD), together with markers of lipid peroxidation (8-isoprostanes and thiobarbituric acid reactive substances [TBARS]). Clinical, anthropometric, lung function, radiological, and analytical variables (albumin, prealbumin, vitamins, and zinc) were also recorded.
RESULTS: We studied 36 adults with CF and 41 controls. No differences were observed in age, gender, or anthropometric variables. The patients had significantly higher levels of IL-6, TNF-α, RCP, TBARS, and isoprostanes, and lower levels of SOD than the controls. Twenty-three of the patients were treated with azithromycin, and they had more severe clinical and radiological parameters than those who were not but nevertheless presented significantly lower levels of TNF-α. No differences were observed in the markers of oxidation.
CONCLUSION: Inflammation and oxidation biomarkers were increased in patients with CF compared with controls. The use of azithromycin was associated with reduced TNF-α levels and did not influence oxidation parameters.

PMID: 28638254 [PubMed - in process]

Dietary Salt Exacerbates Experimental Colitis.

J Immunol. 2017 Jun 21;:

Authors: Tubbs AL, Liu B, Rogers TD, Sartor RB, Miao EA

Abstract
The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10-deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD.

PMID: 28637899 [PubMed - as supplied by publisher]

Modeling and Simulation of Mucus Flow in Human Bronchial Epithelial Cell Cultures - Part I: Idealized Axisymmetric Swirling Flow.

PLoS Comput Biol. 2016 Aug;12(8):e1004872

Authors: Vasquez PA, Jin Y, Palmer E, Hill D, Forest MG

Abstract
A multi-mode nonlinear constitutive model for mucus is constructed directly from micro- and macro-rheology experimental data on cell culture mucus, and a numerical algorithm is developed for the culture geometry and idealized cilia driving conditions. This study investigates the roles that mucus rheology, wall effects, and HBE culture geometry play in the development of flow profiles and the shape of the air-mucus interface. Simulations show that viscoelasticity captures normal stress generation in shear leading to a peak in the air-mucus interface at the middle of the culture and a depression at the walls. Linear and nonlinear viscoelastic regimes can be observed in cultures by varying the hurricane radius and mean rotational velocity. The advection-diffusion of a drug concentration dropped at the surface of the mucus flow is simulated as a function of Peclet number.

PMID: 27494700 [PubMed - indexed for MEDLINE]

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response.

Mol Ther. 2016 Oct;24(10):1873-1880

Authors: Farinelli G, Jofra Hernandez R, Rossi A, Ranucci S, Sanvito F, Migliavacca M, Brombin C, Pramov A, Di Serio C, Bovolenta C, Gentner B, Bragonzi A, Aiuti A

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.

PMID: 27456061 [PubMed - indexed for MEDLINE]