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Inhaled Antimicrobials for Ventilator-Associated Pneumonia: Practical Aspects.

Drugs. 2017 Jul 24;:

Authors: Poulakou G, Matthaiou DK, Nicolau DP, Siakallis G, Dimopoulos G

Abstract
Positive experience with inhaled antibiotics in pulmonary infections of patients with cystic fibrosis has paved the way for their utilization in mechanically ventilated, critically ill patients with lower respiratory tract infections. A successful antibiotic delivery depends upon the size of the generated particle and the elimination of drug impaction in the large airways and the ventilator circuit. Generated droplet size is mainly affected by the type of the nebulizer employed. Currently, jet, ultrasonic, and vibrating mesh nebulizers are marketed; the latter can deliver optimal antibiotic particle size. Promising novel drug-device combinations are able to release drug concentrations of 25- to 300-fold the minimum inhibitory concentration of the targeted pathogens into the pulmonary alveoli. The most important practical steps of nebulization include pre-assessment and preparation of the patient (suctioning, sedation, possible bronchodilation, adjustment of necessary ventilator settings); adherence to the procedure (drug preparation, avoidance of unnecessary tubing connections, interruption of heated humidification, removal of heat-moisture exchanger); inspection of the procedure (check for residual in drug chamber, change of expiratory filter, return sedation, and ventilator settings to previous status); and surveillance of the patient for adverse events (close monitoring of the patient and particularly of peak airway pressure and bronchoconstriction). Practical aspects of nebulization are very important to ensure optimal drug delivery and safe procedure for the patient. Therefore, the development of an operational checklist is a priority for every department adopting this modality.

PMID: 28741229 [PubMed - as supplied by publisher]

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Bile salt stimulated lipase: Inhibition by phospholipids and relief by phospholipase A2.

J Cyst Fibros. 2017 Jul 21;:

Authors: Venuti E, Shishmarev D, Kuchel PW, Dutt S, Blumenthal CS, Gaskin KJ

Abstract
INTRODUCTION: Bile salt stimulated lipase (BSSL; Enzyme Commission (EC) number 3.1.1.13) has been a candidate triglyceridase for improving enzyme therapy for pancreatic insufficiency; however, its efficacy is near absent. We hypothesise that similarly to pancreatic lipase, BSSL is inhibited by phospholipids and this inhibition is relieved by Phospholipase A2 (PLA2; EC 3.1.1.4), and the present study was undertaken to explore this possibility.
MATERIALS AND METHODS: Synthetic emulsions of triglyceride and phosphatidylcholine (PC) or lysophosphatidylcholine (LPC)/bile salt mixed micelles were used as a model of intestinal digestion-media. The effect of PLA2 treatment of systems containing PC on BSSL activity was also explored. Automatic titration at constant pH (pH-stat) and nuclear magnetic resonance (NMR) spectroscopy were used to measure the rate and identify products of lipolysis.
RESULTS: PC was inhibitory to BSSL activity, while LPC became inhibitory only above an LPC/bile salt concentration ratio of 0.3. PLA2 treatment relieved the inhibition only below this ratio, despite its complete phospholipid-hydrolysing action. Thus, LPC had an inhibitory effect at higher concentrations.
CONCLUSIONS: These results may implicate a change in the design of enzyme therapy in patients with pancreatic exocrine insufficiency. Supplementation of BSSL with PLA2 could improve patient health with adequate manipulation of phospholipid and lysophospholipid concentrations in the intestinal fluid.

PMID: 28739210 [PubMed - as supplied by publisher]

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Analytical and biological variation in repeated sweat chloride concentrations in clinical trials for CFTR modulator therapy.

J Cyst Fibros. 2017 Jul 21;:

Authors: LeGrys VA, Moon TC, Laux J, Rock MJ, Accurso F

Abstract
BACKGROUND: Using sweat chloride as a biomarker for CFTR modifying drugs requires knowledge of analytical and biological variation.
METHODS: 979 sweat chloride concentrations from 128 subjects enrolled in the placebo arm of 2 multicenter, investigational drug trials were analyzed to determine coefficients of variation (CV) as well as reference change value (RCV) and index of individuality (II).
RESULTS: For these populations, calculated values for the two studies were: analytical variation (3.9, 4.1%); within-subject variation (4.4, 6.0%); between-subject variation (8.9, 7.0%); RCV (13.7, 17.0%) and II (0.7, 1.0). Sweat chloride variation was not affected by sex, collection site or sample weight; but was slightly affected by age in one of the two studies.
CONCLUSION: Through determination of analytical as well as between- and within-subject variation, and with a larger sample size, our data allows improved estimates of the RCV and II, and can contribute to future trials of CFTR modulators and inform the design and interpretation of n of 1 trials in both research and clinical settings.

PMID: 28739209 [PubMed - as supplied by publisher]

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A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer: Authors.

Int J Cancer. 2017 Jul 25;:

Authors: Lin HM, Mahon KL, Weir JM, Mundra PA, Spielman C, Briscoe K, Gurney H, Mallesara G, Marx G, Stockler MR, Consortium P, Parton RG, Hoy AJ, Daly RJ, Meikle PJ, Horvath LG

Abstract
Lipids are known to influence tumour growth, inflammation, and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, P=0.0005). The levels of 46 lipids were individually prognostic, and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0), and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, P=0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome. This article is protected by copyright. All rights reserved.

PMID: 28741687 [PubMed - as supplied by publisher]

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The Pharmacogenomic and Metabolomic Predictors of ACE Inhibitor and Angiotensin II Receptor Blocker Effectiveness and Safety.

Cardiovasc Drugs Ther. 2017 Jul 24;:

Authors: Flaten HK, Monte AA

Abstract
Hypertension (HTN) is the most common chronic disease in the USA. Hypertensive patients frequently require repeat primary care visits to find an effective drug or drug combination to control their disease. Currently, patients are prescribed drugs for HTN based on race, age, and comorbidities and although the current guidelines are reasonable starting points for prescribing, 50% of hypertensive patients still fail to achieve target blood pressures. Despite numerous strategies to improve compliance, drug effectiveness, and optimization of initial drug choice, effectiveness has remained largely unchanged over the past two decades. Therefore, it is important to pursue alternative strategies to more effectively treat patients and to decrease medical costs. Additional precision medicine work is needed to identify factors associated with effectiveness of commonly used antihypertensive medications. The objective of this manuscript is to present a comprehensive review of the pharmacogenomic and metabolomic factors associated with ACEI and ARB effectiveness and safety.

PMID: 28741243 [PubMed - as supplied by publisher]

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Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: a case-control study.

BMC Med Genet. 2017 Jul 24;18(1):76

Authors: Sikhayeva N, Iskakova A, Saigi-Morgui N, Zholdybaeva E, Eap CB, Ramanculov E

Abstract
BACKGROUND: We evaluated the associations between single nucleotide polymorphisms and different clinical parameters related to type 2 diabetes mellitus (T2DM), obesity risk, and metabolic syndrome (MS) in a Kazakh cohort.
METHODS: A total of 1336 subjects, including 408 T2DM patients and 928 control subjects, were recruited from an outpatient clinic and genotyped for 32 polymorphisms previously associated with T2DM and obesity-related phenotypes in other ethnic groups. For association studies, the chi-squared test or Fisher's exact test for binomial variables were used. Logistic regression was conducted to explore associations between the studied SNPs and the risk of developing T2DM, obesity, and MS, after adjustments for age and sex.
RESULTS: After excluding four SNPs due to Hardy-Weinberg disequilibrium, significant associations in age-matched cohorts were found betweenT2DM and the following SNPs: rs9939609 (FTO), rs13266634 (SLC30A8), rs7961581 (TSPAN8/LGR5), and rs1799883 (FABP2). In addition, examination of general unmatched T2DM and control cohorts revealed significant associations between T2DM and SNPsrs1799883 (FABP2) and rs9939609 (FTO). Furthermore, polymorphisms in the FTO gene were associated with increased obesity risk, whereas polymorphisms in the FTO and FABP2 genes were also associated with the risk of developing MS in general unmatched cohorts.
CONCLUSION: We confirmed associations between polymorphisms within the SLC30A8, TSPAN8/LGR5, FABP2, and FTO genes and susceptibility to T2DM in a Kazakh cohort, and revealed significant associations with anthropometric and metabolic traits. In particular, FTO and FABP2 gene polymorphisms were significantly associated with susceptibility to MS and obesity in this cohort.

PMID: 28738793 [PubMed - in process]

Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia.

Br J Cancer. 2017 Jul 25;:

Authors: Schubert SA, Ruano D, Elsayed FA, Boot A, Crobach S, Sarasqueta AF, Wolffenbuttel B, van der Klauw MM, Oosting J, Tops CM, van Eijk R, Vasen HF, Vossen RH, Nielsen M, Castellví-Bel S, Ruiz-Ponte C, Tomlinson I, Dunlop MG, Vodicka P, Wijnen JT, Hes FJ, Morreau H, de Miranda NF, Sijmons RH, van Wezel T

Abstract
BACKGROUND: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders.
METHODS: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level.
RESULTS: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues.
CONCLUSIONS: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.British Journal of Cancer advance online publication: 25 July 2017; doi:10.1038/bjc.2017.240 www.bjcancer.com.

PMID: 28742792 [PubMed - as supplied by publisher]

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MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.

Am J Med Genet A. 2017 Jul 25;:

Authors: Balasubramanian K, Li B, Krakow D, Nevarez L, Ho PJ, Ainsworth JA, Nickerson DA, Bamshad MJ, Immken L, Lachman RS, Cohn DH

Abstract
Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80-85% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.

PMID: 28742282 [PubMed - as supplied by publisher]

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Whole exome sequencing identified genetic variations in Chinese hemangioblastoma patients.

Am J Med Genet A. 2017 Jul 25;:

Authors: Ma D, Yang J, Wang Y, Huang X, Du G, Zhou L

Abstract
Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel-Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients. Genes harboring the most significant mutations include PCDH9, KLHL12, DCAF4L1, and VHL in sporadic HBs, and ZNF814, DLG2, RIMS1, PNN, and MUC7 in familial HBs. The frequency of CNV varied considerably within sporadic HBs but was relatively similar within familial HBs. Five genes, including OTOGL, PLCB4, SCEL, THSD4, and WWOX, have CNVs in the six patients with sporadic HBs, and three genes, including ABCA6, CWC27, and LAMA2, have CNVs in the five patients with familial HBs. We found new genetic mutations and CNVs that might be involved in HBs; these findings highlight the complexity of the tumorigenesis of HBs and pinpoint potential therapeutic targets for the treatment of HBs.

PMID: 28742274 [PubMed - as supplied by publisher]

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A Gene Implicated in Activation of Retinoic Acid Receptor Targets is a Novel Renal Agenesis Gene in Humans.

Genetics. 2017 Jul 24;:

Authors: Brophy PD, Rasmussen M, Parida M, Bonde G, Darbro BW, Hong X, Clarke JC, Peterson KA, Denegre J, Schneider M, Sussman CR, Sunde L, Lildballe DL, Hertz JM, Cornell RA, Murray SA, Manak JR

Abstract
Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end stage renal disease. Genetic investigations have identified several gene variants which cause RA, including EYA1, LHX1, and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.

PMID: 28739660 [PubMed - as supplied by publisher]

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Mutations in the ABCG8 gene are associated with sitosterolaemia in the homozygous form and xanthelasmas in the heterozygous form.

Eur J Dermatol. 2017 Jul 25;:

Authors: Bardawil T, Rebeiz A, Chaabouni M, El Halabi J, Kambris Z, Abbas O, Abou Hassan O, Hamie L, Bitar F, Ghani Kibbi A, Nemer G, Kurban M

Abstract
Sitosterol is the most abundant plant sterol found in our diet. Sitosterolemia (OMIM 210250), also known as phytosterolaemia, is a rare autosomal recessive disease caused by the inability to efficiently excrete plant sterol, and is characterized by cutaneous xanthomas and accelerated atherosclerosis. Sitosterolaemia is caused by homozygous or compound heterozygous mutations in either ABCG5 or ABCG8 (both on chromosome 2p21), which encode the sterol efflux transporter ABCG5 (sterolin-1) and ABCG8 (sterolin-2), respectively. To investigate a Tunisian family with several members who manifested with generalized cutaneous xanthomas, whereas others had only isolated xanthelasmas. Genetic analysis was performed based on exome sequencing of DNA obtained from five affected individuals and one unaffected individual from a Tunisian family.
RESULTS: A novel mutation in the ABCG8 gene, designated c.965-1G>C, was identified by exome sequencing in the members of this family. The homozygous form was associated with generalized cutaneous xanthomatosis while the heterozygous form was linked to isolated xanthelasmas. Our results indicate a gene dosage effect of ABCG8 and suggest that individuals at risk should be followed closely.

PMID: 28739549 [PubMed - as supplied by publisher]

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No Effect of Levothyroxine and Levothyroxine-induced Subclinical Thyrotoxicosis on the Pharmacokinetics of Sorafenib in Healthy Male Subjects.

Thyroid. 2017 Jul 25;:

Authors: Huang F, Ajavon-Hartmann A, Huang E, Lettieri J, Liu R, Pena C, Berse M

Abstract
<b>Background</b>: Patients receiving the multikinase inhibitor sorafenib for locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine often receive concomitant levothyroxine for thyroid-stimulating hormone (TSH) suppression. In the phase 3 DTC trial (DECISION), sorafenib exposure was ~2-fold higher than that observed in other cancers. We assessed sorafenib pharmacokinetics without and with concomitant levothyroxine to examine whether a levothyroxine interaction or levothyroxine-induced subclinical thyrotoxicosis results in increased sorafenib exposure in DTC patients. <b>Methods</b>: This was an open-label, 2-period sequential treatment study in healthy males. Period 1, day 1: subjects received a single oral dose of sorafenib 400 mg, followed by a minimal 10-day washout. Period 2, day 1: levothyroxine 300μg was administered orally once daily (QD) for 14 days; after 10 days, a single oral concomitant dose of sorafenib 400mg was given. Blood samples for sorafenib pharmacokinetic analyses were obtained predose and at time points up to 96 hours after sorafenib dosing. Samples for thyroid tests were collected before and after levothyroxine dosing. <b>Results</b>: Twenty-five subjects completed the study and were evaluable for pharmacokinetic analysis. Levothyroxine 300 µg QD was well tolerated and induced subclinical thyrotoxicosis, producing full suppression of TSH (mean±SD, 0.032±0.027 mU/L) and increased free thyroxine (0.94±0.09 to 1.77±0.33 ng/dL) and free tri-iodothyronine (2.87±0.28 to 4.24±0.66 pg/mL) levels by day 11 of period 2. The geometric mean (%CV) sorafenib maximum concentration (C_max) without and with levothyroxine was 2.09 (68.1) and 1.78 (63.9) mg/L, respectively, with a corresponding geometric mean area under the curve of 68.1 (68.2) and 64.3 (66.3) mg·h/L. Median (range) time to C_max was 4.00 (2.98-16.0) and 4.02 (1.98-36.0) hours, respectively; mean (%CV) half-life was 24.0 (25.3) and 25.7 (21.0) hours. All study drug-related adverse events were mild and included headache and fatigue for sorafenib, and headache, increased alanine aminotransferase and glutamate dehydrogenase, fatigue, and nervousness for levothyroxine. <b>Conclusions</b>: Levothyroxine 300 µg QD for 14 days was well tolerated, induced subclinical thyrotoxicosis, and did not affect sorafenib pharmacokinetics. The findings suggest that concomitant use of levothyroxine with sorafenib is not likely responsible for the previously reported increase in sorafenib exposure in DTC patients; however, the effects of long-term levothyroxine dosing were not assessed.

PMID: 28741453 [PubMed - as supplied by publisher]

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

Funding Opportunity RFA-HG-17-008 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications to participate in the Implementing Genomics in Practice (IGNITE) II: Pragmatic Clinical Trials Network. This network will conduct pragmatic clinical trials to measure the clinical utility and cost-effectiveness of genomic medicine interventions; assess approaches for real-world application of genomic medicine in diverse clinical settings; and produce generalizable knowledge on the types of genomic medicine interventions requiring randomized clinical trials and effective methods for conducting them. Applicants to this FOA are expected to recruit a minimum of 35% of patients who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes. In contrast, applicants to the companion RFA HG-17-009 are expected to recruit a minimum of 75% of such patients.

Funding Opportunity RFA-HG-17-009 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications to participate in the Implementing Genomics in Practice (IGNITE) II: Pragmatic Clinical Trials Network. This network will conduct pragmatic clinical trials to measure the clinical utility and cost-effectiveness of genomic medicine interventions; assess approaches for real-world application of genomic medicine in diverse clinical settings; and produce generalizable knowledge on the types of genomic medicine interventions requiring randomized clinical trials and effective methods for conducting them. Applicants to this FOA are expected to recruit a minimum of 75% of patients who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes. In contrast, applicants to the companion RFA HG-17-008 are expected to recruit a minimum of 35% of such patients.

Funding Opportunity RFA-HG-17-010 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications to participate in the Implementing Genomics in Practice (IGNITE) II: Pragmatic Clinical Trials Network. This network will conduct pragmatic clinical trials to measure the clinical utility and cost-effectiveness of genomic medicine interventions; assess approaches for real-world application of genomic medicine in diverse clinical settings; and produce generalizable knowledge on the types of genomic medicine interventions requiring randomized clinical trials and effective methods for conducting them. IGNITE II will include multiple clinical groups including enhanced diversity clinical groups, and a single Coordinating Center (CC). This FOA invites applications for the Coordinating Center (CC) and runs in parallel with companion FOAs that invite applications for the CGs (RFA-HG-17-008) and the enhanced diversity CGs (RFA-HG-17-009).

Funding Opportunity RFA-HD-18-008 from the NIH Guide for Grants and Contracts. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the Fertility and Infertility (FI) Branch, provides funding for a limited number of research centers in the reproductive sciences. These centers provide an arena for multidisciplinary interactions among basic and clinical scientists interested in establishing high quality translational research programs in this scientific area. The centers also serve as national resources for the training and career development of junior scientists electing to pursue biomedical research careers in reproduction and infertility. Finally, center investigators develop and participate in community outreach and education efforts to increase awareness and convey the importance and implications of their research activities to the general public. The purpose of this FOA is to announce the re-competition of the National Centers for Translational Research in Reproduction and Infertility (NCTRI). The NCTRI will be administered through the Specialized Research Center (P50) award mechanism. These centers will form a national network that facilitates and accelerates bidirectional knowledge transfer between the laboratory and clinic with the ultimate goal of improving human reproductive health through research excellence and innovation.

Notice NOT-NS-17-025 from the NIH Guide for Grants and Contracts

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