Artificial DnaJ Protein for protein production and conformational diseases.

Sci Rep. 2017 Aug 17;7(1):8531

Authors: Hishiya A, Koya K

Abstract
For secreted proteins, proper protein folding is essential not only for biological function but also for secretion itself. Proteins with folding problems are trapped in the endoplasmic reticulum (ER) and are eventually degraded in the cytoplasm. In this study, we exploited co-expression of an artificial fusion protein, based on the sequence of a DnaJ protein, which could interact as co-chaperones in the Hsp70-based protein-folding system, with target recombinant secreted proteins to enhance their production and secretion. The J-domain sequence or a fragment thereof was conjugated to a target protein-binding domain that was capable of binding to a portion of the target-protein sequence. Production of many of the target proteins was significantly upregulated when co-expressed with the J-domain fusion protein. Surprisingly, the enhancement of secretion was observed even when the J-domain had a mutation in the HPD motif, which is necessary for J-protein-Hsp70 interactions, suggesting the phenomenon observed is independent on functional J-protein-Hsp70 interactions. This technology has great potential for not only enhancing the production of recombinant proteins, but also to treat conformational diseases such as cystic fibrosis, and Alpha-1 antitrypsin deficiency.

PMID: 28819167 [PubMed - in process]

Pathways to Pulmonary Hypertension In Sickle Cell Disease: The Search For Prevention And Early Intervention.

Expert Rev Hematol. 2017 Aug 18;:

Authors: Shilo NR, Morris CR

Abstract
INTRODUCTION: Pulmonary hypertension (PH) develops in a significant number of patients with sickle cell disease (SCD), resulting in increased morbidity and mortality. This review focuses on PH pathophysiology, risk stratification, and new recommendations for screening and treatment for patients with SCD. Areas covered: An extensive PubMed literature search was performed. While the pathophysiology of PH in SCD is yet to be fully deciphered, it is known that the etiology is multifactorial; hemolysis, hypercoagulability, hypoxemia, ischemic-reperfusion injury, oxidative stress, and genetic susceptibility all contribute in varying degrees to endothelial dysfunction. Hemolysis, in particular, seems to play a key role by inciting an imbalance in the regulatory axis of nitric oxide and arginine metabolism. Systematic risk stratification starting in childhood based on clinical features and biomarkers that enable early detection is necessary. Multi-faceted, targeted interventions, before irreversible vasculopathy develops, will allow for improved patient outcomes and life expectancy. Expert Commentary: Despite progress in our understanding of PH in SCD, clinically proven therapies remain elusive and additional controlled clinical trials are needed. Prevention of disease starts in childhood, a critical window for intervention. Given the complex and multifactorial nature of SCD, patients will ultimately benefit from combination therapies that simultaneously targets multiple mechanisms.

PMID: 28817980 [PubMed - as supplied by publisher]

Risk Factors and Outcomes of Thalidomide-induced Peripheral Neuropathy in a Pediatric Inflammatory Bowel Disease Cohort.

Inflamm Bowel Dis. 2017 Aug 16;:

Authors: Bramuzzo M, Stocco G, Montico M, Arrigo S, Calvi A, Lanteri P, Costa S, Pellegrino S, Magazzù G, Barp J, Ghione S, Lionetti P, Zuin G, Fontana M, Di Chio T, Maggiore G, Lazzerini M, Lucafò M, Udina C, Pellegrin MC, Chicco A, Carrozzi M, Decorti G, Ventura A, Martelossi S

Abstract
BACKGROUND: Thalidomide is an effective therapy in children with inflammatory bowel disease refractory to standard treatments, but thalidomide-induced peripheral neuropathy (TiPN) limits its long-term use. We aimed to investigate the risk factors and the outcome of TiPN in children with inflammatory bowel disease.
METHODS: Within a retrospective multicenter cohort study, we evaluated prevalence and evolution of TiPN. Clinical data and candidate genetic profiles of patients with and without TiPN were compared with detect predisposing factors.
RESULTS: One hundred forty-two patients were identified. TiPN was found in 72.5% of patients (38.7% clinical and instrumental alterations, 26.8% exclusive electrophysiological anomalies, and 7.0% exclusive neurological symptoms). Median TiPN-free period of treatment was 16.5 months; percentage of TiPN-free patients was 70.0% and 35.6% at 12 and 24 months of treatment, respectively. The risk of TiPN increased depending on the mean daily dose (50-99 mg/d adjusted hazard ratio 2.62; 95% confidence interval [CI], 1.31-5.21; 100-149 mg/d adjusted hazard ratio 6.16; 95% CI, 20.9-13.06; >150 mg/d adjusted hazard ratio 9.57; 95% CI, 2.6-35.2). Single nucleotide polymorphisms in ICAM1 (rs1799969) and SERPINB2 (rs6103) genes were found to be protective against TiPN (odds ratio 0.15; 95% CI, 0.03-0.82 and 0.36; 95% CI, 0.14-0.88, respectively). TiPN was the cause of drug suspension in 41.8% of patients. Clinical symptoms resolved in 89.2% of cases, whereas instrumental alteration persisted in more than half of the patients during a short follow-up.
CONCLUSIONS: In children with inflammatory bowel disease, TiPN is common but mild and generally reversible. Cumulative dose seems to be the most relevant risk factor, whereas polymorphisms in genes involved in neuronal inflammation may be protective.

PMID: 28817461 [PubMed - as supplied by publisher]

Infants with cystic fibrosis still lag on some growth measures: Babies' weight on par with healthy peers, but growth is still stunted.

Am J Med Genet A. 2017 Sep;173(9):2303-2304

Authors:

PMID: 28816423 [PubMed - in process]

Liver transplantation in adult cystic fibrosis: Clinical, imaging and pathological evidence of obliterative portal venopathy.

Liver Transpl. 2017 Aug 16;:

Authors: Hillaire S, Cazals-Hatem D, Bruno O, De Miranda S, Grenet D, Poté N, Soubrane O, Erlinger S, Lacaille F, Mellot F, Vilgrain V, Paradis V

PMID: 28816015 [PubMed - as supplied by publisher]

Incident Stenotrophomonas maltophilia infection and lung function decline in cystic fibrosis.

Pediatr Pulmonol. 2017 Aug 16;:

Authors: Barsky EE, Williams KA, Priebe GP, Sawicki GS

Abstract
OBJECTIVES: To determine whether incident detection of Stenotrophomonas maltophilia (SM) in patients with cystic fibrosis (CF) is associated with accelerated lung function decline and increased hospitalizations and to determine whether this effect is more pronounced in individuals with subsequent chronic infection.
METHODS: We performed a longitudinal, retrospective single-center, pre-post study of 88 patients with CF, ages 6-51 years, with first positive respiratory culture for SM between 2008 and 2014. Rate of decline in FEV1 and hospitalization rates prior to and following incident SM infection were analyzed using segmented regression analysis of interrupted time series.
RESULTS: Mean (SD) age was 17.4 (9.2) years and the mean (SD) FEV1 % predicted at acquisition was 90.0% (25.2). A total of 44% developed chronic SM infection. In regression analysis adjusted for clinical and demographic factors, there was worsening of the mean annual decline in FEV1 % predicted from -1.79 (95%CI: -2.43, -1.15) pre-acquisition to -2.14 (95%CI: -2.61, -1.67) post-acquisition (P = 0.005). A significant change was observed in those with either subsequent intermittent or chronic infection. The mean annual hospitalization rate increased significantly in the subgroup with chronic infection from 0.46 (95%CI: 0.33, 0.60) to 0.88 (95%CI: 0.68, 1.07) (P = 0.007).
CONCLUSIONS: In this single-center cohort, acquisition of SM in CF was associated with an acceleration in lung function decline. Among those with chronic colonization, acquisition was also associated with increased hospitalization rates.

PMID: 28815999 [PubMed - as supplied by publisher]

The airway microbiota in early cystic fibrosis lung disease.

Pediatr Pulmonol. 2017 Aug 16;:

Authors: Frayman KB, Armstrong DS, Grimwood K, Ranganathan SC

Abstract
Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie.

PMID: 28815937 [PubMed - as supplied by publisher]

Both Ways at Once: Keeping Small Airways Clean.

Physiology (Bethesda). 2017 Sep;32(5):380-390

Authors: Quinton PM

Abstract
The small airways of the lungs are under constant assault from the pathogens and debris in the air that they must conduct to alveoli. Although hygiene is of paramount importance for respiratory health, the underlying principles of airway clearance have not been well integrated or established. Newly emerging concepts of simultaneous absorption and secretion of airway surface liquid (ASL) and the role of [Formula: see text] in the maturation of mucins have advanced from experimental evidence as well as observations from the congenital disease cystic fibrosis (CF) to present a novel model that integrates microanatomy with organ physiology to meet the constant challenge of cleaning small airways.

PMID: 28814498 [PubMed - in process]

Diagnosis and management of pancreatic exocrine insufficiency.

Med J Aust. 2017 Aug 21;207(4):161-165

Authors: Nikfarjam M, Wilson JS, Smith RC, Australasian Pancreatic Club Pancreatic Enzyme Replacement Therapy Guidelines Working Group

Abstract
INTRODUCTION: In 2015, the Australasian Pancreatic Club (APC) published the Australasian guidelines for the management of pancreatic exocrine insufficiency (http://pancreas.org.au/2016/01/pancreatic-exocrine-insufficiency-guidelines). Pancreatic exocrine insufficiency (PEI) occurs when normal digestion cannot be sustained due to insufficient pancreatic digestive enzyme activity. This may be related to a breakdown, at any point, in the pancreatic digestive chain: pancreatic stimulation; synthesis, release or transportation of pancreatic enzymes; or synchronisation of secretions to mix with ingested food. Main recommendations: The guidelines provide advice on diagnosis and management of PEI, noting the following: A high prevalence of PEI is seen in certain diseases and conditions, such as cystic fibrosis, acute and chronic pancreatitis, pancreatic cancer and pancreatic surgery. The main symptoms of PEI are steatorrhoea or diarrhoea, abdominal pain, bloating and weight loss. These symptoms are non-specific and often go undetected and untreated. PEI diagnosis is predominantly based on clinical findings and the presence of underlying disease. The likelihood of PEI in suspected patients has been categorised into three groups: definite, possible and unlikely. If left untreated, PEI may lead to complications related to fat malabsorption and malnutrition, and have an impact on quality of life. Pancreatic enzyme replacement therapy (PERT) remains the mainstay of PEI treatment with the recommended adult initial enzyme dose being 25 000-40 000 units of lipase per meal, titrating up to a maximum of 75 000-80 000 units of lipase per meal. Adjunct acid-suppressing therapy may be useful when patients still experience symptoms of PEI on high dose PERT. Nutritional management by an experienced dietitian is essential. Changes in management as a result of these guidelines: These are the first guidelines to classify PEI as being definite, possible or unlikely, and provide a diagnostic algorithm to facilitate the early diagnosis of PEI and appropriate use of PERT.

PMID: 28814218 [PubMed - in process]

Emended description of Mycobacterium abscessus, Mycobacterium abscessus subsp. abscessus and Mycobacteriumabscessus subsp. bolletii and designation of Mycobacteriumabscessus subsp. massiliense comb. nov.

Int J Syst Evol Microbiol. 2016 Nov;66(11):4471-4479

Authors: Tortoli E, Kohl TA, Brown-Elliott BA, Trovato A, Leão SC, Garcia MJ, Vasireddy S, Turenne CY, Griffith DE, Philley JV, Baldan R, Campana S, Cariani L, Colombo C, Taccetti G, Teri A, Niemann S, Wallace RJ, Cirillo DM

Abstract
The taxonomic position of members of the Mycobacterium abscessus complex has been the subject of intensive investigation and, in some aspects confusion, in recent years as a result of varying approaches to genetic data interpretation. Currently, the former species Mycobacterium massiliense and Mycobacterium bolletii are grouped together as Mycobacterium abscessus subsp. bolletii. They differ greatly, however, as the former M. bolletii has a functional erm(41) gene that confers inducible resistance to macrolides, the primary therapeutic antimicrobials for M. abscessus, while in the former M. massiliense the erm(41) gene is non-functional. Furthermore, previous whole genome studies of the M. abscessus group support the separation of M. bolletii and M. massiliense. To shed further light on the population structure of Mycobacterium abscessus, 43 strains and three genomes retrieved from GenBank were subjected to pairwise comparisons using three computational approaches: verage ucleotide dentity, enome to enome istance and single nucleotide polymorphism analysis. The three methods produced overlapping results, each demonstrating three clusters of strains corresponding to the same number of taxonomic entities. The distances were insufficient to warrant distinction at the species level, but met the criteria for differentiation at the subspecies level. Based on prior erm(41)-related phenotypic data and current genomic data, we conclude that the species M. abscessus encompasses, in adjunct to the presently recognized subspecies M. abscessus subsp. abscessus and M. abscessus subsp. bolletii, a third subspecies for which we suggest the name M. abscessus subsp. massiliense comb. nov. (type strain CCUG 48898T=CIP 108297T=DSM 45103T=KCTC 19086T).

PMID: 27499141 [PubMed - indexed for MEDLINE]

The IL-17F/IL-17RC Axis Promotes Respiratory Allergy in the Proximal Airways.

Cell Rep. 2017 Aug 15;20(7):1667-1680

Authors: De Luca A, Pariano M, Cellini B, Costantini C, Villella VR, Jose SS, Palmieri M, Borghi M, Galosi C, Paolicelli G, Maiuri L, Fric J, Zelante T

Abstract
The interleukin 17 (IL-17) cytokine and receptor family is central to antimicrobial resistance and inflammation in the lung. Mice lacking IL-17A, IL-17F, or the IL-17RA subunit were compared with wild-type mice for susceptibility to airway inflammation in models of infection and allergy. Signaling through IL-17RA was required for efficient microbial clearance and prevention of allergy; in the absence of IL-17RA, signaling through IL-17RC on epithelial cells, predominantly by IL-17F, significantly exacerbated lower airway Aspergillus or Pseudomonas infection and allergic airway inflammation. In contrast, following infection with the upper respiratory pathogen Staphylococcus aureus, the IL-17F/IL-17RC axis mediated protection. Thus, IL-17A and IL-17F exert distinct biological effects during pulmonary infection; the IL-17F/IL-17RC signaling axis has the potential to significantly worsen pathogen-associated inflammation of the lower respiratory tract in particular, and should be investigated further as a therapeutic target for treating pathological inflammation in the lung.

PMID: 28813677 [PubMed - in process]

Risk factors for totally implantable venous access device-associated complications in cystic fibrosis.

Ir J Med Sci. 2017 Aug 15;:

Authors: McCarthy C, O'Carroll O, O'Brien ME, McEnery T, Franciosi A, Gunaratnam C, McElvaney NG

Abstract
BACKGROUND: Candidaemia is an important nosocomial infection, seen frequently in immunocompromised and critically ill patients and increasingly recognised in cystic fibrosis (CF) patients with totally implantable venous access devices (TIVADs). This study aims to investigate the incidence and risk factors for the development of TIVAD-associated candidaemia and to assess the rate of TIVAD-related complications in CF patients.
METHODS: A 10-year retrospective study was carried out on adult CF patients attending a single centre. Complications were recorded including the incidence of candidaemia and correlated to clinical parameters. Complication rates were calculated based on incidence per 1000 catheter days. Statistical analysis was performed using Mann-Whitney U test and Fisher's exact test.
RESULTS: Fourteen cases of candidaemia were observed in the CF cohort, primarily caused by Candida parapsilosis and Candida albicans. Candidaemia was associated with lower FEV1 (p = 0.0117) and higher frequency of pulmonary exacerbation (p < 0.0001). A TIVAD complication rate of 0.337/1000 catheter days was observed in the CF cohort. Complications included venous thrombosis, stenosis, and port extrusion; complications were independently associated with more frequent pulmonary exacerbations (p = 0.04).
CONCLUSIONS: TIVAD complications are observed more commonly in those with lower FEV1 and frequent pulmonary exacerbations, suggesting that candidaemia may be related to antibiotic use and furthermore can occur following invasive procedures causing translocation of fungal species allowing transformation from colonisation to pathogenic infection.

PMID: 28812224 [PubMed - as supplied by publisher]

Clinical and laboratory profile of children with Cystic Fibrosis: Experience of a tertiary care center in Pakistan.

Pak J Med Sci. 2017 May-Jun;33(3):554-559

Authors: Aziz DA, Billoo AG, Qureshi A, Khalid M, Kirmani S

Abstract
OBJECTIVE: To determine the clinical presentation, diagnostic investigations and laboratory workup done in admitted children with cystic fibrosis at Aga Khan University Hospital Karachi, Pakistan.
METHODS: This is athree years retrospective study from January 2013 to December 2015 conducted at The Aga Khan University Hospital Karachi Pakistan, enrolling admitted patient from birth to 15 years of either gender, diagnosed with CF on the basis of clinical features and positive sweat chloride test. Different clinical presentations were noted including initial presentations. Sweat chloride values more than 60mmol/L were labeled as positive and consistent with diagnosis of CF. Available Delta F-508 mutation analyses were noted. Relevant laboratory and radiological investigations including sputum culture and HR-CT chest findings were documented. Results were analyzed using SPSS version 20.
RESULTS: Total 43 children were selected according to the inclusion criteria. Chronic cough (69.76%) was the most common initial clinical presentation. Mean age at onset of symptoms was 14.41± 26.18 months and mean age at diagnosis was 47.20 ± 45.80 months Respiratory features were most common in our cohort including chronic productive cough (90.71%), recurrent bronchopneumonia (72.09%) and asthma like presentation (44.19%) with wheezing and cough. 86% patients presented with failure to thrive. Gastroenterological features including steatorrhea were seen in 55.81% patients and 44.19% patients had abdominal distension. Mean sweat chloride value in our population was 82.70± 22.74. Gene analysis for Delta F-508 was identified in 12 (27.90%) patients. Bronchiectatic pulmonary changes on HRCT were seen in 18 patients (41.86%). Pseudomonas grew in 12 patients (27.90%) in sputum cultures at the time of diagnosis.
CONCLUSION: Respiratory presentations predominate in CF children followed by gastrointestinal features. Nearly half of our patient had bronchiectatic changes on CT scan chest and more than quarter had pseudomonas colonization in the airways at the time of diagnosis. Delta F-508 mutation was found to be uncommon in our study population. There is significant delay in diagnosing patients with CF.

PMID: 28811770 [PubMed]

Regenerative medicine and cell-based approaches to restore pancreatic function.

Nat Rev Gastroenterol Hepatol. 2017 Aug 16;:

Authors: Ellis C, Ramzy A, Kieffer TJ

Abstract
The pancreas is a complex organ with exocrine and endocrine components. Many pathologies impair exocrine function, including chronic pancreatitis, cystic fibrosis and pancreatic ductal adenocarcinoma. Conversely, when the endocrine pancreas fails to secrete sufficient insulin, patients develop diabetes mellitus. Pathology in either the endocrine or exocrine pancreas results in devastating economic and personal consequences. The current standard therapy for treating patients with type 1 diabetes mellitus is daily exogenous insulin injections, but cell sources of insulin provide superior glycaemic regulation and research is now focused on the goal of regenerating or replacing β cells. Stem-cell-based models might be useful to study exocrine pancreatic disorders, and mesenchymal stem cells or secreted factors might delay disease progression. Although the standards that bioengineered cells must meet before being considered as a viable therapy are not yet established, any potential therapy must be acceptably safe and functionally superior to current therapies. Here, we describe progress and challenges in cell-based methods to restore pancreatic function, with a focus on optimizing the site for cell delivery and decreasing requirements for immunosuppression through encapsulation. We also discuss the tools and strategies being used to generate exocrine pancreas and insulin-producing β-cell surrogates in situ and highlight obstacles to clinical application.

PMID: 28811674 [PubMed - as supplied by publisher]

Three-center feasibility of lung clearance index in infants and preschool children with cystic fibrosis and other lung diseases.

J Cyst Fibros. 2017 Aug 12;:

Authors: Stahl M, Graeber SY, Joachim C, Barth S, Ricklefs I, Diekmann G, Kopp MV, Naehrlich L, Mall MA

Abstract
BACKGROUND: Lung clearance index (LCI) detects early ventilation inhomogeneity and has been suggested as sensitive endpoint in multicenter intervention trials in infants and preschoolers with cystic fibrosis (CF). However, the feasibility of multicenter LCI in this age group has not been determined. We, therefore, investigated the feasibility of LCI in infants and preschoolers with and without CF in a three-center setting.
METHODS: Following central training, standardized SF6-MBW measurements were performed in 73 sedated children (10 controls, 49 with CF and 14 with other lung diseases), mean age 2.3±1.2years across three centers, and data were analyzed centrally.
RESULTS: Overall success rate of LCI measurements was 91.8% ranging from 78.9% to 100% across study sites. LCI was increased in patients with CF (P<0.05) and with other lung diseases (P<0.05) compared to controls.
CONCLUSION: Our results support feasibility of LCI as multicenter endpoint in clinical trials in infants and preschoolers with CF.

PMID: 28811149 [PubMed - as supplied by publisher]

Deferasirox for managing iron overload in people with thalassaemia.

Cochrane Database Syst Rev. 2017 Aug 15;8:CD007476

Authors: Bollig C, Schell LK, Rücker G, Allert R, Motschall E, Niemeyer CM, Bassler D, Meerpohl JJ

Abstract
BACKGROUND: Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusions. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone are effective; however, a review of the effectiveness and safety of the newer oral chelator deferasirox in people with thalassaemia is needed.
OBJECTIVES: To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and iron overload.
SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 August 2016.We also searched MEDLINE, Embase, the Cochrane Library, Biosis Previews, Web of Science Core Collection and three trial registries: ClinicalTrials.gov; the WHO International Clinical Trials Registry Platform; and the Internet Portal of the German Clinical Trials Register: 06 and 07 August 2015.
SELECTION CRITERIA: Randomised controlled studies comparing deferasirox with no therapy or placebo or with another iron-chelating treatment.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information.
MAIN RESULTS: Sixteen studies involving 1807 randomised participants (range 23 to 586 participants) were included. Twelve two-arm studies compared deferasirox to placebo (two studies) or deferoxamine (seven studies) or deferiprone (one study) or the combination of deferasirox and deferoxamine to deferoxamine alone (one study). One study compared the combination of deferasirox and deferiprone to deferiprone in combination with deferoxamine. Three three-arm studies compared deferasirox to deferoxamine and deferiprone (two studies) or the combination of deferasirox and deferiprone to deferiprone and deferasirox monotherapy respectively (one study). One four-arm study compared two different doses of deferasirox to matching placebo groups.The two studies (a pharmacokinetic and a dose-escalation study) comparing deferasirox to placebo (n = 47) in people with transfusion-dependent thalassaemia showed that deferasirox leads to net iron excretion. In these studies, safety was acceptable and further investigation in phase II and phase III studies was warranted.Nine studies (1251 participants) provided data for deferasirox versus standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared. In the phase III study, similar or superior efficacy for the intermediate markers ferritin and liver iron concentration (LIC) could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg per day and 51.6 mg per day respectively. The pooled effects across the different dosing ratios are: serum ferritin, mean difference (MD) 454.42 ng/mL (95% confidence interval (CI) 337.13 to 571.71) (moderate quality evidence); LIC evaluated by biopsy or SQUID, MD 2.37 mg Fe/g dry weight (95% CI 1.68 to 3.07) (moderate quality evidence) and responder analysis, LIC 1 to < 7 mg Fe/g dry weight, risk ratio (RR) 0.80 (95% CI 0.69 to 0.92) (moderate quality evidence). The substantial heterogeneity observed could be explained by the different dosing ratios. Data on mortality (low quality evidence) and on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was better with deferasirox among those who had previously received deferoxamine treatment, RR 2.20 (95% CI 1.89 to 2.57) (moderate quality evidence). The rate of discontinuations was similar for both drugs (low quality evidence).For the remaining comparisons in people with transfusion-dependent thalassaemia, the quality of the evidence for outcomes assessed was low to very low, mainly due to the very small number of participants included. Four studies (205 participants) compared deferasirox to deferiprone; one of which (41 participants) revealed a higher number of participants experiencing arthralgia in the deferiprone group, but due to the large number of different types of adverse events reported and compared this result is uncertain. One study (96 participants) compared deferasirox combined with deferiprone to deferiprone with deferoxamine. Participants treated with the combination of the oral iron chelators had a higher adherence compared to those treated with deferiprone and deferoxamine, but no participants discontinued the study. In the comparisons of deferasirox versus combined deferasirox and deferiprone and that of deferiprone versus combined deferasirox and deferiprone (one study, 40 participants), and deferasirox and deferoxamine versus deferoxamine alone (one study, 94 participants), only a few patient-relevant outcomes were reported and no significant differences were observed.One study (166 participants) included people with non-transfusion dependent thalassaemia and compared two different doses of deferasirox to placebo. Deferasirox treatment reduced serum ferritin, MD -306.74 ng/mL (95% CI -398.23 to -215.24) (moderate quality evidence) and LIC, MD -3.27 mg Fe/g dry weight (95% CI -4.44 to -2.09) (moderate quality evidence), while the number of participants experiencing adverse events and rate of discontinuations (low quality evidence) was similar in both groups. No participant died, but data on mortality were limited due to a follow-up period of only one year (moderate quality evidence).
AUTHORS' CONCLUSIONS: Deferasirox offers an important treatment option for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy and will translate to similar benefits in the long term, as has been shown for deferoxamine, needs to be confirmed. Data from randomised controlled trials on rare toxicities and long-term safety are still limited. However, after a detailed discussion of the potential benefits and risks, deferasirox could be offered as the first-line option to individuals who show a strong preference for deferasirox, and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine.

PMID: 28809446 [PubMed - as supplied by publisher]

The Saudi Thoracic Society guidelines for diagnosis and management of noncystic fibrosis bronchiectasis.

Ann Thorac Med. 2017 Jul-Sep;12(3):135-161

Authors: Al-Jahdali H, Alshimemeri A, Mobeireek A, Albanna AS, Al Shirawi NN, Wali S, Alkattan K, Alrajhi AA, Mobaireek K, Alorainy HS, Al-Hajjaj MS, Chang AB, Aliberti S

Abstract
This is the first guideline developed by the Saudi Thoracic Society for the diagnosis and management of noncystic fibrosis bronchiectasis. Local experts including pulmonologists, infectious disease specialists, thoracic surgeons, respiratory therapists, and others from adult and pediatric departments provided the best practice evidence recommendations based on the available international and local literature. The main objective of this guideline is to utilize the current published evidence to develop recommendations about management of bronchiectasis suitable to our local health-care system and available resources. We aim to provide clinicians with tools to standardize the diagnosis and management of bronchiectasis. This guideline targets primary care physicians, family medicine practitioners, practicing internists and respiratory physicians, and all other health-care providers involved in the care of the patients with bronchiectasis.

PMID: 28808486 [PubMed]

Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis.

Proc Natl Acad Sci U S A. 2017 Aug 14;:

Authors: Sandefur CI, Boucher RC, Elston TC

Abstract
Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways.

PMID: 28808008 [PubMed - as supplied by publisher]

Bedaquiline inhibits the ATP synthase in Mycobacterium abscessus and is effective in infected zebrafish.

Antimicrob Agents Chemother. 2017 Aug 14;:

Authors: Dupont C, Viljoen A, Thomas S, Roquet-Banères F, Herrmann JL, Pethe K, Kremer L

Abstract
Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug resistant, fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multi-drug resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered as major pathophysiological signs in infected zebrafish. Mode of action studies revealed that BDQ triggered a rapid ATP depletion in M. abscessusin vitro, consistent with the drug targeting the FoF1 ATP synthase. Importantly, despite failure to select in vitro for spontaneous mutants highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus Overall, this study indicates that BDQ is active against M. abscessusin vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections.

PMID: 28807917 [PubMed - as supplied by publisher]

The impact of the recent AAP changes in palivizumab authorization on RSV-induced bronchiolitis severity and incidence.

Ital J Pediatr. 2017 Aug 14;43(1):71

Authors: Capizzi A, Silvestri M, Orsi A, Cutrera R, Rossi GA, Sacco O

Abstract
Following the most recent modification by the American Academy of Pediatrics, based on American studies on RSV epidemiology, the Italian Drug Agency (AIFA) decided to limit the total financial coverage of the palivizumab prescription by the National Health Service only to the < 29 wGA group and age ≤ 12 months at the beginning of the RSV epidemic season. However, the vulnerability of otherwise healthy premature infants ≥ 29 wGA has been demonstrated in Italian analyses. We retrospectively reviewed records from children ≤ 1 years of age admitted for RSV-induced ALRI at the Gaslini Hospital, over three consecutive RSV epidemic seasons (RES) (2014-2017). We found that the prescription limitation on RSV immunoprophylaxis in preterms was associated in the 2016-2017 RES with: a) a high proportion of admission for the < 36 wGA infants, the great majority born at 33- < 36 wGA and a chronological age of < 6 months; b) a high proportion of preterms treated with high flow nasal cannula ventilation. These results strongly point to a need to reevaluate the role of palivizumab prophylaxis in the >= 29 wGA subpopulation when specific risk factors are present.

PMID: 28807039 [PubMed - in process]