Literature Watch

Accumulating physical activity in at least 10-minute bouts predicts better lung function after 3-years in adults with cystic fibrosis.

Cystic Fibrosis - Wed, 2018-04-11 17:37

Accumulating physical activity in at least 10-minute bouts predicts better lung function after 3-years in adults with cystic fibrosis.

ERJ Open Res. 2018 Apr;4(2):

Authors: Cox NS, Alison JA, Button BM, Wilson JW, Morton JM, Holland AE

Abstract
Achieving physical activity guidelines by undertaking multiple bouts of moderate-vigorous physical activity ≥10 min duration, but not shorter periods of activity, was independently associated with less decline in FEV1over 3 years among adults with CF http://ow.ly/yk6930ivCV8.

PMID: 29637075 [PubMed]

Categories: Literature Watch

Performance of Molecular Approaches for Aspergillus Detection and Azole Resistance Surveillance in Cystic Fibrosis.

Cystic Fibrosis - Wed, 2018-04-11 17:37

Performance of Molecular Approaches for Aspergillus Detection and Azole Resistance Surveillance in Cystic Fibrosis.

Front Microbiol. 2018;9:531

Authors: Guegan H, Chevrier S, Belleguic C, Deneuville E, Robert-Gangneux F, Gangneux JP

Abstract
Aspergillus fumigatus triazole resistance is an emerging concern for treating chronically infected/colonized patients. This study sought to evaluate the performance of PCR assays to detect Aspergillus fungi together with azole resistance in sputum samples from cystic fibrosis (CF) patients. In total, 119 sputum samples from 87 CF patients were prospectively processed for Aspergillus detection by means of mycological culture and four qPCR assays, 2 in-house methods and two commercial multiplex real-time PCR assays simultaneously detecting Aspergillus and the most relevant cyp51A gene mutations (MycoGENIE® and AsperGenius®). Azole susceptibility of A. fumigatus isolates was assessed using Etest® method and cyp51A gene mutation were characterized by sequencing. The overall rate of Aspergillus detection with the four qPCR assays ranged from 47.9 to 57.1%, contrasting with 42/119 (35.3%) positive cultures with A. fumigatus. The high sensitivity of PCR on sputum could then contribute to more effective grading of Aspergillus disease in CF patients. Five out of 41 isolated strains (12.2%) exhibited azole-resistant MIC patterns, three of which harbored cyp51A mutations and only 1/3 with the sequence TR34/L98H. Combined with culture, PCR assay achieved high sensitivity Aspergillus screening in CF samples. However, cyp51A targeting was only moderately effective for azole resistance monitoring, while Aspergillus resistance remains of great concern.

PMID: 29636731 [PubMed]

Categories: Literature Watch

Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa.

Cystic Fibrosis - Wed, 2018-04-11 17:37

Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa.

MBio. 2018 Apr 10;9(2):

Authors: La Rosa R, Johansen HK, Molin S

Abstract
Evolution by natural selection under complex and dynamic environmental conditions occurs through intricate and often counterintuitive trajectories affecting many genes and metabolic solutions. To study short- and long-term evolution of bacteria in vivo, we used the natural model system of cystic fibrosis (CF) infection. In this work, we investigated how and through which trajectories evolution of Pseudomonas aeruginosa occurs when migrating from the environment to the airways of CF patients, and specifically, we determined reduction of growth rate and metabolic specialization as signatures of adaptive evolution. We show that central metabolic pathways of three distinct Pseudomonas aeruginosa lineages coevolving within the same environment become restructured at the cost of versatility during long-term colonization. Cell physiology changes from naive to adapted phenotypes resulted in (i) alteration of growth potential that particularly converged to a slow-growth phenotype, (ii) alteration of nutritional requirements due to auxotrophy, (iii) tailored preference for carbon source assimilation from CF sputum, (iv) reduced arginine and pyruvate fermentation processes, and (v) increased oxygen requirements. Interestingly, although convergence was evidenced at the phenotypic level of metabolic specialization, comparative genomics disclosed diverse mutational patterns underlying the different evolutionary trajectories. Therefore, distinct combinations of genetic and regulatory changes converge to common metabolic adaptive trajectories leading to within-host metabolic specialization. This study gives new insight into bacterial metabolic evolution during long-term colonization of a new environmental niche.IMPORTANCE Only a few examples of real-time evolutionary investigations in environments outside the laboratory are described in the scientific literature. Remembering that biological evolution, as it has progressed in nature, has not taken place in test tubes, it is not surprising that conclusions from our investigations of bacterial evolution in the CF model system are different from what has been concluded from laboratory experiments. The analysis presented here of the metabolic and regulatory driving forces leading to successful adaptation to a new environment provides an important insight into the role of metabolism and its regulatory mechanisms for successful adaptation of microorganisms in dynamic and complex environments. Understanding the trajectories of adaptation, as well as the mechanisms behind slow growth and rewiring of regulatory and metabolic networks, is a key element to understand the adaptive robustness and evolvability of bacteria in the process of increasing their in vivo fitness when conquering new territories.

PMID: 29636437 [PubMed - in process]

Categories: Literature Watch

Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis.

Pediatr Pulmonol. 2018 Apr 10;:

Authors: Pereira SVN, Ribeiro JD, Bertuzzo CS, Marson FAL

Abstract
BACKGROUND: Cystic fibrosis (CF) is due to dysfunction of the CFTR channel and function of this channel is, in turn, affected by modifier genes that can impact the clinical phenotype. In this context, we analyzed the interaction among rs3788766*SLC6A14, rs7512462*SLC26A9, rs17235416*SLC11A1, and rs17563161*SLC9A3 variants, CFTR mutations and 40 CF severity markers by the Multifactor Dimensionality Reduction (MDR) model.
METHODS: A total of 164 patients with CF were included in the study. The variants in the modifier genes were identified by real-time PCR and the genotype of the CFTR gene in the diagnostic routine. Analysis of interaction between variants, CFTR mutations groupings and demographic, clinical and laboratory data were performed by the MDR.
RESULTS: There were interaction between the rs3788766, rs7512462, rs17235416, and rs17563161 variants, and CFTR mutations with pancreatic insufficiency (PI), onset of digestive symptoms, and presence of mucoid Pseudomonas aeruginosa. Regarding PI, the interaction was observed for CFTR*rs17563161 (P-value = 0.015). Also, for onset of digestive symptoms the interaction was observed for CFTR*rs3788766*rs7512462*rs17235416*rs17563161 (P-value = 0.036). Considering the presence of mucoid P. aeruginosa, the interaction occurred for CFTR*rs3788766*rs7512462*rs17563161 (P-value = 0.035).
CONCLUSION: Interaction between variants in the SLC family genes and the grouping for CFTR mutations were associated with PI, onset of digestive symptoms and mucoid P. aeruginosa, being important to determine one of the factors that may cause the diversity among the patients with CF.

PMID: 29635781 [PubMed - as supplied by publisher]

Categories: Literature Watch

Surfactant Dysfunction in ARDS and Bronchiolitis is Repaired with Cyclodextrins.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Surfactant Dysfunction in ARDS and Bronchiolitis is Repaired with Cyclodextrins.

Mil Med. 2018 Mar 01;183(suppl_1):207-215

Authors: Al-Saiedy M, Gunasekara L, Green F, Pratt R, Chiu A, Yang A, Dennis J, Pieron C, Bjornson C, Winston B, Amrein M

Abstract
Objectives: Acute respiratory distress syndrome (ARDS) is caused by many factors including inhalation of toxicants, acute barotrauma, acid aspiration, and burns. Surfactant function is impaired in ARDS and acute airway injury resulting in high surface tension with alveolar and small airway collapse, edema, hypoxemia, and death. In this study, we explore the mechanisms whereby surfactant becomes dysfunctional in ARDS and bronchiolitis and its repair with a cyclodextrin drug that sequesters cholesterol.
Methods: We used in vitro model systems, a mouse model of ARDS, and samples from patients with acute bronchiolitis. Surface tension was measured by captive bubble surfactometry.
Results: Patient samples showed severe surfactant inhibition even in the absence of elevated cholesterol levels. Surfactant was also impaired in ARDS mice where the cholesterol to phospholipid ratio (W/W%) was increased. Methyl-β-cyclodextrin (MβCD) restored surfactant function to normal in both human and animal samples. Model studies showed that the inhibition of surfactant was due to both elevated cholesterol and an interaction between cholesterol and oxidized phospholipids. MβCD was also shown to have anti-inflammatory effects.
Conclusions: Inhaled cyclodextrins have potential for the treatment of ARDS. They could be delivered in a portable device carried in combat and used following exposure to toxic gases and fumes or shock secondary to hemorrhage and burns.

PMID: 29635617 [PubMed - in process]

Categories: Literature Watch

Multifaceted structures and mechanisms of ABC transport systems in health and disease.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Multifaceted structures and mechanisms of ABC transport systems in health and disease.

Curr Opin Struct Biol. 2018 Apr 07;51:116-128

Authors: Thomas C, Tampé R

Abstract
ATP-binding cassette (ABC) transporters are found in all domains of life and constitute one of the largest protein superfamilies. ABC transporters harness the energy of ATP binding and hydrolysis to shuttle a diverse range of substrates across cell membranes. While higher-resolution structures of ABC transporters have so far exclusively been obtained by X-ray crystallography, recent advances in single-particle cryogenic electron microscopy (cryo-EM) have provided a deluge of exciting new structures of medically relevant bacterial and human ABC proteins, including those of the cystic fibrosis transmembrane conductance regulator (CFTR), and of supramolecular assemblies involving ABC transporters, like the ATP-sensitive potassium (KATP) channel and the peptide-loading complex (PLC), which is crucially involved in the presentation of antigens in adaptive immunity.

PMID: 29635113 [PubMed - as supplied by publisher]

Categories: Literature Watch

ETHICS EVALUATION REVEALING DECISION-MAKER MOTIVES: A CASE OF NEONATAL SCREENING.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

ETHICS EVALUATION REVEALING DECISION-MAKER MOTIVES: A CASE OF NEONATAL SCREENING.

Int J Technol Assess Health Care. 2018 Apr 10;:1-7

Authors: Raimond V, Sambuc C, Pibouleau L

Abstract
OBJECTIVES: This paper aims to describe the added value of combining cost-effectiveness and ethical evaluations when the preferences of the decision maker toward cost-effectiveness evaluation outcomes are not known, with the French national neonatal screening of cystic fibrosis (CF) as a case-study.
METHODS: A cost-effectiveness analysis comparing four CF neonatal screening strategies, with or without DNA testing, was performed. Ethical positions toward their outcomes were described. In addition, a post-hoc analysis of the ethical issues being considered relevant from the decision-makers' perspective was conducted.
RESULTS: Two strategies were found equally cost-effective. Among them, choosing the non-DNA or a DNA-based strategy constrains the decision maker to render a judgement between different ethical issues or disagreements associated with the screening program.
CONCLUSIONS: The analysis supports the relevance of combining cost-effectiveness and ethics evaluation in developing health policy, as a way to reveal or clarify the motives associated with health. The choice of the decision maker to favor the DNA-based strategy, which was not originally recommended, creates the opportunity to make explicit the role played by ethical issues in the decision.

PMID: 29633672 [PubMed - as supplied by publisher]

Categories: Literature Watch

Who's Who of Pulmonary Hypertension: Redefining Classification to Advance Precision Care.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Who's Who of Pulmonary Hypertension: Redefining Classification to Advance Precision Care.

Circ Genom Precis Med. 2018 Apr;11(4):e002116

Authors: Cirulis MM, Ryan JJ

PMID: 29631996 [PubMed - in process]

Categories: Literature Watch

Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency.

J Cyst Fibros. 2018 Apr 06;:

Authors: Thursfield RM, Naderi K, Leaver N, Rosenthal M, Alton EWFW, Bush A, Davies JC

Abstract
BACKGROUND: Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF.
METHODS: Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded.
RESULTS: 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences in infective or inflammatory markers between vitamin D sufficient and deficient groups. Vitamin D deficient patients (<50 nmol/L) did not have a worse FEV1 (CF: 66 (58-71)% vs. 71.5 (61-76)%, ns; non-CF CSLD: 69 (36-88)% vs. 70 (62-95)%, ns).
CONCLUSIONS: In the first bronchoscopic study exploring this question, we demonstrate that vitamin D deficiency is not associated with immunological, infective or clinical markers of disease severity in patients with CF or CSLD.

PMID: 29631774 [PubMed - as supplied by publisher]

Categories: Literature Watch

Detection and proteomic characterization of extracellular vesicles in human pancreatic juice.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Detection and proteomic characterization of extracellular vesicles in human pancreatic juice.

Biochem Biophys Res Commun. 2018 04 30;499(1):37-43

Authors: Osteikoetxea X, Benke M, Rodriguez M, Pálóczi K, Sódar BW, Szvicsek Z, Szabó-Taylor K, Vukman KV, Kittel Á, Wiener Z, Vékey K, Harsányi L, Szűcs Á, Turiák L, Buzás EI

Abstract
AIMS: The prognosis of patients with pancreatic cancer has remained virtually unchanged with a high mortality rate compared to other types of cancers. An earlier detection would provide a time window of opportunity for treatment and prevention of deaths. In the present study we investigated extracellular vesicle (EV)-associated potential biomarkers for pancreatic cancer by directly assessing EV size-based subpopulations in pancreatic juice samples of patients with chronic pancreatitis or pancreatic cancer. In addition, we also studied blood plasma and pancreatic cancer cell line-derived EVs.
METHODS: Comparative proteomic analysis was performed of 102 EV preparations from human pancreatic juices, blood, and pancreatic cancer cell lines Capan-1 and MIA PaCa-2. EV preparations were also characterized by electron microscopy, tunable resistive pulse sensing, and flow cytometry.
RESULTS: Here we describe the presence of EVs in human pancreatic juice samples. Pancreatic juice EV-associated proteins that we identified as possible candidate markers for pancreatic cancer included mucins, such as MUC1, MUC4, MUC5AC, MUC6 and MUC16, CFTR, and MDR1 proteins. These candidate biomarkers could also be detected by flow cytometry in EVs found in pancreatic juice and those secreted by pancreatic cancer cell lines.
CONCLUSIONS: Together our data show that detection and characterization of EVs directly in pancreatic juice is feasible and may prove to be a valuable source of potential biomarkers of pancreatic cancer.

PMID: 29550476 [PubMed - indexed for MEDLINE]

Categories: Literature Watch

Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis.

Cystic Fibrosis - Wed, 2018-04-11 17:37
Related Articles

Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis.

Paediatr Respir Rev. 2017 Jun;23:27-32

Authors: Nagiub M, Kanaan U, Simon D, Guglani L

Abstract
OBJECTIVES: Preterm infants with bronchopulmonary dysplasia (BPD) are at increased risk for development of Pulmonary Hypertension (PHT). We performed a systematic review and meta-analysis to identify risk factors for development of PHT in infants with BPD.
STUDY DESIGN: A systematic review identified risk factors for the development of PHT in infants with BPD. A meta-analysis of the pooled data was performed for each individual risk factor.
RESULT: Of the 20 risk factors identified, 10 were repeated more than once in nine studies. Meta analysis showed that duration of mechanical ventilation, length of stay, oligohydramnios, use of high frequency ventilation, small for gestational age, sepsis and severity of BPD were significant risk factors; while birth weight and gestational age were inversely related.
CONCLUSION: Several clinical variables are predictive of the development of PHT in infants with BPD. Prospective studies are needed to transform these risk factors into a risk-based scoring system.

PMID: 28188008 [PubMed - indexed for MEDLINE]

Categories: Literature Watch

Clinical pharmacogenomics testing in the era of next generation sequencing: challenges and opportunities for precision medicine.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

Clinical pharmacogenomics testing in the era of next generation sequencing: challenges and opportunities for precision medicine.

Expert Rev Mol Diagn. 2018 Apr 10;:

Authors: Ji Y, Si Y, McMillin GA, Lyon E

Abstract
Introduction The rapid development and dramatic decrease in cost of sequencing techniques have ushered the implementation of genomic testing in patient care. Next generation DNA sequencing (NGS) techniques have been used increasingly in clinical laboratories to scan the whole or part of the human genome in order to facilitate diagnosis and/or prognostics of genetic disease. Despite many hurdles and debates, pharmacogenomics (PGx) is believed to be an area of genomic medicine where precision medicine could have immediate impact in the near future. Areas covered This review focuses on lessons learned through early attempts of clinically implementing PGx testing; the challenges and opportunities that PGx testing brings to precision medicine in the era of NGS. Expert commentary Replacing targeted analysis approach with NGS for PGx testing is neither technically feasible nor necessary currently due to several technical limitations and uncertainty involved in interpreting variants of uncertain significance for PGx variants. However, reporting PGx variants out of clinical whole exome or whole genome sequencing (WES/WGS) might represent additional benefits for patients who are tested by WES/WGS.

PMID: 29634383 [PubMed - as supplied by publisher]

Categories: Literature Watch

ERCC6L2-associated inherited bone marrow failure syndrome.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

ERCC6L2-associated inherited bone marrow failure syndrome.

Mol Genet Genomic Med. 2018 Apr 06;:

Authors: Shabanova I, Cohen E, Cada M, Vincent A, Cohn RD, Dror Y

Abstract
BACKGROUND: ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto.
METHODS: Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations.
RESULTS: All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication.
CONCLUSIONS: ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.

PMID: 29633571 [PubMed - as supplied by publisher]

Categories: Literature Watch

New Common and Rare Variants Influencing Metabolic Syndrome and Its Individual Components in a Korean Population.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

New Common and Rare Variants Influencing Metabolic Syndrome and Its Individual Components in a Korean Population.

Sci Rep. 2018 Apr 09;8(1):5701

Authors: Lee HS, Kim Y, Park T

Abstract
To identify novel loci for susceptibility to MetS, we conducted genome-wide association and exome wide association studies consisting of a discovery stage cohort (KARE, 1946 cases and 6427 controls), and a replication stage cohort (HEXA, 430 cases and 3,264 controls). For finding genetic variants for MetS, with its components, we performed multivariate analysis for common and rare associations, using a standard logistic regression analysis for MetS. From the discovery and replication GWA studies, we confirmed 21 genome-wide signals significantly associated with MetS. Of these 21, four were previously unreported to associate with any MetS components: rs765547 near LPL; rs3782889 in MYL2; and rs11065756 and rs10849915 in CCDC63. Using exome chip variants, gene-based analysis of rare variants revealed three genes, CETP, SH2B1, and ZFP2, in the discovery stage, among which only CETP was confirmed in the replication stage. Finally, CETP D442G (rs2303790) associated, as a less common variant, with decreased risk of MetS. In conclusion, we discovered a total of five new MetS-associated loci, and their overlap with other disease-related components, suggest roles in the various etiologies of MetS, and its possible preventive strategies.

PMID: 29632305 [PubMed - in process]

Categories: Literature Watch

Biallelic TSC2 Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

Biallelic TSC2 Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus.

J Natl Compr Canc Netw. 2018 Apr;16(4):352-358

Authors: Maroto P, Anguera G, Roldan-Romero JM, Apellániz-Ruiz M, Algaba F, Boonman J, Nellist M, Montero-Conde C, Cascón A, Robledo M, Rodríguez-Antona C

Abstract
mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in TSC2, a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed TSC2 inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy.

PMID: 29632054 [PubMed - in process]

Categories: Literature Watch

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

Blood. 2018 Apr 09;:

Authors: Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, Mace EM, Vogel TP, Abhyankar HA, Diaz MI, Heslop HE, Krance RA, Martinez CA, Nguyen TC, Bashir DA, Goldman JR, Stray-Pedersen A, Pedroza LA, Poli MC, Aldave Becerra JC, McGhee SA, Al-Herz W, Chamdin A, Coban-Akdemir ZH, Jhangiani SN, Muzny DM, Cao TN, Hong DN, Gibbs RA, Lupski JR, Orange JS, McClain KL, Allen CE

Abstract
The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation below 1 year of age (p < 0.0001). "Digenic" fHLH variants were observed but lacked statistical support for disease association. In 28 of 48 subjects (58%), research whole exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%; increased mortality correlated with HLH triggered by infection or malignancy (p < 0.05). Differences in survival did not correlate with genetic profile or extent of therapy. "HLH" should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most HLH patients, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole exome sequencing, however, may identify specific therapeutic opportunities and impact hematopoietic stem cell transplantation options for these patients.

PMID: 29632024 [PubMed - as supplied by publisher]

Categories: Literature Watch

Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults.

Circ Genom Precis Med. 2018 Apr;11(4):e001887

Authors: Zhu N, Gonzaga-Jauregui C, Welch CL, Ma L, Qi H, King AK, Krishnan U, Rosenzweig EB, Ivy DD, Austin ED, Hamid R, Nichols WC, Pauciulo MW, Lutz KA, Sawle A, Reid JG, Overton JD, Baras A, Dewey F, Shen Y, Chung WK

Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although BMPR2 mutations underlie ≈70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood.
METHODS: We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing.
RESULTS: We observed similar frequencies of rare, deleterious BMPR2 mutations in pediatric- and adult-onset patients: ≈55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of TBX4 mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset), and TBX4 carriers had younger mean age-of-onset compared with BMPR2 carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene-damaging and predicted deleterious missense variants.
CONCLUSIONS: Mutations in known PAH risk genes accounted for ≈70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in TBX4 are enriched in pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases.

PMID: 29631995 [PubMed - in process]

Categories: Literature Watch

Lipogranulomatous subconjunctival nodules: a novel presentation in Blau syndrome.

Deep learning - Wed, 2018-04-11 17:37
Related Articles

Lipogranulomatous subconjunctival nodules: a novel presentation in Blau syndrome.

J AAPOS. 2017 Jun;21(3):249-251

Authors: Ahmad M, Hermanson ME, Enzenauer R, Palestine A, Lin C, Meeks N, McCourt E

Abstract
Blau syndrome is an early-onset granulomatous disease known to affect the skin, joints, and eyes. We report a child with diffuse rash, arthritis, and subconjunctival nodules. Biopsy of the bulbar conjunctiva revealed noncaseating lipogranulomas that lead to a diagnosis of Blau syndrome. To our knowledge, noncaseating lipogranulomas of the conjunctiva have not been reported previously as a presenting finding in Blau syndrome. Although uveitis is the classic manifestation, it is important to broaden the awareness of other ocular signs, as these variations can aid in diagnosis.

PMID: 28532706 [PubMed - indexed for MEDLINE]

Categories: Literature Watch

Pages

Subscribe to Anil Jegga aggregator - Literature Watch