Pancreatic lipomatosis in cystic fibrosis: Rare manifestation of an uncommon disease.

Intractable Rare Dis Res. 2017 May;6(2):150-151

Authors: Mandavdhare HS, Kumar A, Sharma V, Rana SS

Abstract
Cystic fibrosis is deemed to be uncommon in India. The presentation is usually in the childhood although more cases are now being recognized in adolescence and adulthood. We report a case of an adolescent male who had been treated for recurrent pulmonary infections and received anti-tubercular therapy for a possible diagnosis of sputum negative pulmonary tuberculosis and was evaluated for steatorrhea. The presence of pancreatic exocrine insufficiency along with pancreatic lipomatosis suggested the diagnosis of cystic fibrosis.

PMID: 28580220 [PubMed - in process]

Complications of long and intermediate term venous catheters in cystic fibrosis patients: A multicenter study.

J Cyst Fibros. 2017 Jun 01;:

Authors: May TL, Gifford AH, Lahiri T, Black A, Trang J, Cornell AG, Gonzalez K, Morin S, Napier M, Duarte CW, Zuckerman JB

Abstract
BACKGROUND: Totally implantable venous access devices (TIVADs) or peripherally inserted central venous catheters (PICCs) are commonly used in the care of patients with cystic fibrosis (CF), but they are associated with various complications, including thrombosis, infection, and insertion site symptoms.
METHODS: We conducted a retrospective review of PICC and TIVAD use in adults and children with CF over an 8-year period at 3 accredited care centers. Patient attributes included CFTR genotype, comorbidities, lung function, body mass index, use of anticoagulation, and respiratory tract microbiology. Catheter data included line type, caliber, and lumen number. We assessed practice variation by surveying physicians.
RESULTS: In a population of 592 CF patients, 851 PICC and 61 TIVADs were placed between January 1, 2003 and July 1, 2011. Larger catheter caliber and increased lumen number were risk factors for PICC complications in adults. Patient-related risk factors for PICC complications included poor nutritional status, infection with Burkholderia cepacia spp., and having ≥5 lines inserted during the study period. The probability of a PICC complication varied across centers (2.6% to 14.1%, p=0.001) and remained significant after adjustment for patient-and line-related risk factors. The median complication-free survival of TIVADs, however, did not vary significantly by center (p=0.85).
CONCLUSIONS: This is the first longitudinal, multicenter assessment of complication rates for PICCs and TIVADs in a large cohort of adults and children with CF. Specific patient- and catheter-related characteristics were associated with increased risk of complications. Center effects on complication rates were observed for PICCs.

PMID: 28579360 [PubMed - as supplied by publisher]

Related Articles

Filtration and Normalization of Sequencing Read Data in Whole-Metagenome Shotgun Samples.

PLoS One. 2016;11(10):e0165015

Authors: Chouvarine P, Wiehlmann L, Moran Losada P, DeLuca DS, Tümmler B

Abstract
Ever-increasing affordability of next-generation sequencing makes whole-metagenome sequencing an attractive alternative to traditional 16S rDNA, RFLP, or culturing approaches for the analysis of microbiome samples. The advantage of whole-metagenome sequencing is that it allows direct inference of the metabolic capacity and physiological features of the studied metagenome without reliance on the knowledge of genotypes and phenotypes of the members of the bacterial community. It also makes it possible to overcome problems of 16S rDNA sequencing, such as unknown copy number of the 16S gene and lack of sufficient sequence similarity of the "universal" 16S primers to some of the target 16S genes. On the other hand, next-generation sequencing suffers from biases resulting in non-uniform coverage of the sequenced genomes. To overcome this difficulty, we present a model of GC-bias in sequencing metagenomic samples as well as filtration and normalization techniques necessary for accurate quantification of microbial organisms. While there has been substantial research in normalization and filtration of read-count data in such techniques as RNA-seq or Chip-seq, to our knowledge, this has not been the case for the field of whole-metagenome shotgun sequencing. The presented methods assume that complete genome references are available for most microorganisms of interest present in metagenomic samples. This is often a valid assumption in such fields as medical diagnostics of patient microbiota. Testing the model on two validation datasets showed four-fold reduction in root-mean-square error compared to non-normalized data in both cases. The presented methods can be applied to any pipeline for whole metagenome sequencing analysis relying on complete microbial genome references. We demonstrate that such pre-processing reduces the number of false positive hits and increases accuracy of abundance estimates.

PMID: 27760173 [PubMed - indexed for MEDLINE]

Region-based association tests for sequencing data on survival traits.

Genet Epidemiol. 2017 Jun 04;:

Authors: Chien LC, Bowden DW, Chiu YF

Abstract
Family-based designs enriched with affected subjects and disease associated variants can increase statistical power for identifying functional rare variants. However, few rare variant analysis approaches are available for time-to-event traits in family designs and none of them applicable to the X chromosome. We developed novel pedigree-based burden and kernel association tests for time-to-event outcomes with right censoring for pedigree data, referred to FamRATS (family-based rare variant association tests for survival traits). Cox proportional hazard models were employed to relate a time-to-event trait with rare variants with flexibility to encompass all ranges and collapsing of multiple variants. In addition, the robustness of violating proportional hazard assumptions was investigated for the proposed and four current existing tests, including the conventional population-based Cox proportional model and the burden, kernel, and sum of squares statistic (SSQ) tests for family data. The proposed tests can be applied to large-scale whole-genome sequencing data. They are appropriate for the practical use under a wide range of misspecified Cox models, as well as for population-based, pedigree-based, or hybrid designs. In our extensive simulation study and data example, we showed that the proposed kernel test is the most powerful and robust choice among the proposed burden test and the existing four rare variant survival association tests. When applied to the Diabetes Heart Study, the proposed tests found exome variants of the JAK1 gene on chromosome 1 showed the most significant association with age at onset of type 2 diabetes from the exome-wide analysis.

PMID: 28580640 [PubMed - as supplied by publisher]

Case Report: Making a diagnosis of familial renal disease - clinical and patient perspectives.

F1000Res. 2017;6:470

Authors: Iqbal Z, Sayer JA

Abstract
BACKGROUND: A precise molecular genetic diagnosis has become the gold standard for the correct identification and management of many inherited renal diseases.
METHODS: Here we describe a family with familial focal segmental glomerulosclerosis, and include a clinical and patient perspective on the diagnostic workup and relaying of genetic results following whole exome sequencing.
RESULTS: Through next generation sequencing approaches, we identified a pathogenic mutation in TRPC6, the underlying cause of the phenotype. The identification of this mutation had important clinical consequences for the family, including allowing a living-unrelated kidney transplant to proceed in the index case. There are also wider ranging social and ethical dilemmas presented when reaching a genetic diagnosis like this one, which are explored here by both physicians and the index case.
CONCLUSIONS: Through physician and patient perspectives in a family with inherited renal failure we explore the implications and the magnitude of a molecular genetic diagnosis.

PMID: 28580132 [PubMed - in process]

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NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations.

Neurology. 2016 Sep 13;87(11):1131-9

Authors: Bend EG, Si Y, Stevenson DA, Bayrak-Toydemir P, Newcomb TM, Jorgensen EM, Swoboda KJ

Abstract
OBJECTIVE: To perform genotype-phenotype analysis in an infant with congenital arthrogryposis due to a de novo missense mutation in the NALCN ion channel and explore the mechanism of pathogenicity using a Caenorhabditis elegans model.
METHODS: We performed whole-exome sequencing in a preterm neonate with congenital arthrogryposis and a severe life-threatening clinical course. We examined the mechanism of pathogenicity of the associated NALCN mutation by engineering the orthologous mutation into the nematode C elegans using CRISPR-Cas9.
RESULTS: We identified a de novo missense mutation in NALCN, c.1768C>T, in an infant with a severe neonatal lethal form of the recently characterized CLIFAHDD syndrome (congenital contractures of the limbs and face with hypotonia and developmental delay). We report novel phenotypic features including prolonged episodes of stimulus-sensitive sustained muscular contraction associated with life-threatening episodes of desaturation and autonomic instability, extending the severity of previously described phenotypes associated with mutations in NALCN. When engineered into the C elegans ortholog, this mutation results in a severe gain-of-function phenotype, with hypercontraction and uncoordinated movement. We engineered 6 additional CLIFAHDD syndrome mutations into C elegans and the mechanism of action could be divided into 2 categories: half phenocopied gain-of-function mutants and half phenocopied loss-of-function mutants.
CONCLUSIONS: The clinical phenotype of our patient and electrophysiologic studies show sustained muscular contraction in response to transient sensory stimuli. In C elegans, this mutation causes neuronal hyperactivity via a gain-of-function NALCN ion channel. Testing human variants of NALCN in C elegans demonstrates that CLIFAHDD can be caused by dominant loss- or gain-of-function mutations in ion channel function.

PMID: 27558372 [PubMed - indexed for MEDLINE]

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A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.

Ann Neurol. 2016 Oct;80(4):

Authors: Helbig KL, Hedrich UB, Shinde DN, Krey I, Teichmann AC, Hentschel J, Schubert J, Chamberlin AC, Huether R, Lu HM, Alcaraz WA, Tang S, Jungbluth C, Dugan SL, Vainionpää L, Karle KN, Synofzik M, Schöls L, Schüle R, Lehesjoki AE, Helbig I, Lerche H, Lemke JR

Abstract
The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.

PMID: 27543892 [PubMed - indexed for MEDLINE]

Related Articles

Stratification of endometrioid endometrial cancer patients into risk levels using somatic mutations.

Gynecol Oncol. 2016 Jul;142(1):150-7

Authors: Dai D, Thiel KW, Salinas EA, Goodheart MJ, Leslie KK, Gonzalez Bosquet J

Abstract
OBJECTIVE: Patients with endometrioid endometrial cancer are stratified as high risk and low risk for extrauterine disease by surgical staging. Since patients with low-grade, minimally invasive disease do not benefit from comprehensive staging, pre-surgery stratification into a risk category may prevent unnecessary surgical staging in low risk patients. Our objective was to develop a predictive model to identify risk levels using somatic mutations that could be used preoperatively.
METHODS: We classified endometrioid endometrial cancer patients in The Cancer Genome Atlas (TCGA) dataset into high risk and low risk categories: high risk patients presented with stage II, III or IV disease or stage I with high-intermediate risk features, whereas low risk patients consisted of the remaining stage I patients with either no myometrial invasion or low-intermediate risk features. Three strategies were used to build the prediction model: 1) mutational status for each gene; 2) number of somatic mutations for each gene; and 3) variant allele frequencies for each somatic mutation for each gene.
RESULTS: Each prediction strategy had a good performance, with an area under the curve (or AUC) between 61% and 80%. Analysis of variant allele frequency produced a superior prediction model for risk levels of endometrial cancer as compared to the other two strategies, with an AUC=91%. Lasso and Ridge methods identified 53 mutations that together had the highest predictability for high risk endometrioid endometrial cancer.
CONCLUSIONS: This prediction model will assist future retrospective and prospective studies to categorize endometrial cancer patients into high risk and low risk in the preoperative setting.

PMID: 27181389 [PubMed - indexed for MEDLINE]

Notice NOT-AG-17-010 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-305 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support the development of imaging approaches to identify and characterize persistent HIV reservoirs in patients undergoing suppressive antiretroviral therapy (ART) and to quantify the nature and size of these reservoirs in response to therapeutic interventions.

Notice NOT-OD-17-070 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-303 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) issued by the National Institutes of Health (NIH) invites eligible United States small business concerns (SBCs) to submit Small Business Technology Transfer (STTR) grant applications. United States SBCs that have the research capabilities and technological expertise to contribute to the R and D mission(s) of the NIH awarding components identified in this FOA are encouraged to submit STTR grant applications in response to identified topics (see PHS 2017-2 SBIR/STTR Program Descriptions and Research Topics for NIH.

Funding Opportunity PA-17-302 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA), issued by the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA), invites eligible United States small business concerns (SBCs) to submit Small Business Innovation Research (SBIR) grant applications. United States SBCs that have the research capabilities and technological expertise to contribute to the R and D mission(s) of the NIH, CDC, and FDA awarding components identified in this FOA are encouraged to submit SBIR grant applications in response to identified topics (see PHS 2017-2 SBIR/STTR Program Descriptions and Research Topics for NIH, CDC, and FDA.

Notice NOT-OD-17-074 from the NIH Guide for Grants and Contracts

Notice NOT-AT-17-012 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-17-300 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages small business applications for exploratory clinical trials of investigational agents (drugs, biologics, surgical therapies or devices) that may contribute to the justification for and provide the data required for designing clinical studies. Diseases chosen for study should be based on the NINDS' strategic plan and clinical research interests (www.ninds.nih.gov/funding/areas/index.htm ).

Funding Opportunity PAR-17-301 from the NIH Guide for Grants and Contracts. The Office of Research Infrastructure Programs (ORIP) within the Division of Program Coordination, Planning, and Strategic Initiatives announces a program that provides ORIP-supported Special Emphasis Research Career Award (SERCA) K01 awardees who have completed the first two years (24 months) of their K01 award the opportunity to apply for Small Grant support. Through the use of this mechanism, ORIP is seeking to enhance the capability of ORIP SERCA K01 awardees to conduct research as they complete their transition to fully independent investigator status. The R03 mechanism supports different types of projects, including but not limited to pilot and feasibility studies; secondary analysis of existing data; small, self-contained research projects; development of research methodology, and development of new research technology. The R03 is therefore intended to support research projects that can be achieved in a short period of time with limited resources and that provide preliminary data to support a subsequent R01 or equivalent application.

Dopaminergic Regulation of Innate Immunity: a Review.

J Neuroimmune Pharmacol. 2017 Jun 03;:

Authors: Pinoli M, Marino F, Cosentino M

Abstract
Dopamine (DA) is a neurotransmitter in the central nervous system as well as in peripheral tissues. Emerging evidence however points to DA also as a key transmitter between the nervous system and the immune system as well as a mediator produced and released by immune cells themselves. Dopaminergic pathways have received so far extensive attention in the adaptive branch of the immune system, where they play a role in health and disease such as multiple sclerosis, rheumatoid arthritis, cancer, and Parkinson's disease. Comparatively little is known about DA and the innate immune response, although DA may affect innate immune system cells such as dendritic cells, macrophages, microglia, and neutrophils. The present review aims at providing a complete and exhaustive summary of currently available evidence about DA and innate immunity, and to become a reference for anyone potentially interested in the fields of immunology, neurosciences and pharmacology. A wide array of dopaminergic drugs is used in therapeutics for non-immune indications, such as Parkinson's disease, hyperprolactinemia, shock, hypertension, with a usually favorable therapeutic index, and they might be relatively easily repurposed for immune-mediated disease, thus leading to innovative treatments at low price, with benefit for patients as well as for the healthcare systems.

PMID: 28578466 [PubMed - as supplied by publisher]

Increased in synthetic cannabinoids-related harms: Results from a longitudinal web-based content analysis.

Int J Drug Policy. 2017 Jun 01;44:121-129

Authors: Lamy FR, Daniulaityte R, Nahhas RW, Barratt MJ, Smith AG, Sheth A, Martins SS, Boyer EW, Carlson RG

Abstract
BACKGROUND: Synthetic Cannabinoid Receptor Agonists (SCRA), also known as "K2" or "Spice," have drawn considerable attention due to their potential of abuse and harmful consequences. More research is needed to understand user experiences of SCRA-related effects. We use semi-automated information processing techniques through eDrugTrends platform to examine SCRA-related effects and their variations through a longitudinal content analysis of web-forum data.
METHOD: English language posts from three drug-focused web-forums were extracted and analyzed between January 1st 2008 and September 30th 2015. Search terms are based on the Drug Use Ontology (DAO) created for this study (189 SCRA-related and 501 effect-related terms). EDrugTrends NLP-based text processing tools were used to extract posts mentioning SCRA and their effects. Generalized linear regression was used to fit restricted cubic spline functions of time to test whether the proportion of drug-related posts that mention SCRA (and no other drug) and the proportion of these "SCRA-only" posts that mention SCRA effects have changed over time, with an adjustment for multiple testing.
RESULTS: 19,052 SCRA-related posts (Bluelight (n=2782), Forum A (n=3882), and Forum B (n=12,388)) posted by 2543 international users were extracted. The most frequently mentioned effects were "getting high" (44.0%), "hallucinations" (10.8%), and "anxiety" (10.2%). The frequency of SCRA-only posts declined steadily over the study period. The proportions of SCRA-only posts mentioning positive effects (e.g., "High" and "Euphoria") steadily decreased, while the proportions of SCRA-only posts mentioning negative effects (e.g., "Anxiety," 'Nausea," "Overdose") increased over the same period.
CONCLUSION: This study's findings indicate that the proportion of negative effects mentioned in web forum posts and linked to SCRA has increased over time, suggesting that recent generations of SCRA generate more harms. This is also one of the first studies to conduct automated content analysis of web forum data related to illicit drug use.

PMID: 28578250 [PubMed - as supplied by publisher]

RAS Genetic Variants in Interaction with ACE Inhibitors Drugs Influences Essential Hypertension Control.

Arch Med Res. 2017 Jan;48(1):88-95

Authors: Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, Arkani M

Abstract
BACKGROUNDS AND AIMS: Essential Hypertension (EH) is a common disorder associated with increased cardiovascular morbidity and mortality in Malaysia. To investigate how genetic polymorphisms of the renin-angiotensin-aldosterone system (RAS) influence EH control with angiotensin-converting enzyme inhibitor drugs (ACEI).
METHODS: A case-control, cross-sectional population-based nested study (n = 142) included hypertensive subjects treated with ACEI drugs, either lisinopril or enalapril (20 mg, once daily) as monotherapy for 24 weeks. In total seven possible polymorphisms of RAS genes were genotyped. The association between those polymorphisms and the changes in blood pressure were observed in the 24 week treatment.
RESULTS: Statistically significant associations of I, G, T, M and G alleles of ACE (I/D, G2350A), AGT (M235T, T175M and G-6A) respectively were observed in essential hypertensive subjects. The decrease in systolic blood pressure and diastolic blood pressure after 24 weeks of treatment of the patients carrying II, GG, and TT genotypes were greater than the groups carrying DD, AA, MM, MM and GG of I/D, G2350A, M235T, T174M and G-6A genotypes respectively. In contrast, No significant difference was observed between renin gene polymorphisms (Bg/I and MboI) and hypertensives.
CONCLUSIONS: Although this study shows a possible association of polymorphisms of RAS genes with the risk of non-control of HT in ACEI-treated patients and indicates the importance of all this system's components in regulating HT, it needs to be replicated in other data sources.

PMID: 28577874 [PubMed - in process]