Abdominal Pain due to a Wandering Liver.

J Gastrointest Surg. 2017 May;21(5):923-925

Authors: Bruneau A, Sandri GBL, Rayar M, Sulpice L, Boudjema K

Abstract
Wandering liver syndrome is an extremely rare congenital disorder. It is mainly diagnosed within the first years of life. Herein we report the case of a 40-year-old woman with hepatoptosis due to the absence of anatomical peritoneal attachments of the liver. Surgical treatment consisted in inserting the floppy right lobe of the liver in a subphrenic retroperitoneal pouch. This original technique provided excellent postoperative result.

PMID: 27659790 [PubMed - indexed for MEDLINE]

Pyoderma gangrenosum-like oral ulcerations in an elderly patient.

Gerodontology. 2015 Dec;32(4):309-13

Authors: Kaomongkolgit R, Subbalekha K, Sawangarun W, Thongprasom K

Abstract
OBJECTIVE: To present a case of pyoderma gangrenosum (PG)-like oral ulcerations in an elderly patient.
BACKGROUND: PG is an uncommon idiopathic, ulcerative, chronic inflammatory cutaneous disorder of unknown etiology, which is associated with systemic diseases found in more than 50% of patients. Oral lesions of PG are extremely rare and have not been previously reported on chronic leukemia patient.
CLINICAL REPORT: This report presents the first case of a 73 year-old man who had PG-like oral ulcerations which offered the possibility of an initial finding of chronic myeloid leukemia.
CONCLUSION: Clinicians should always take into consideration that PG in the oral mucosa is a recalcitrant ulcer and can precede the development of underlying clonal malignancy.

PMID: 26768815 [PubMed - indexed for MEDLINE]

Population modelling integrating pharmacokinetics, pharmacodynamics, pharmacogenetics and clinical outcome in sunitinib-treated cancer patients.

CPT Pharmacometrics Syst Pharmacol. 2017 Jun 01;:

Authors: Diekstra MH, Fritsch A, Kanefendt F, Swen JJ, Moes D, Sörgel F, Kinzig M, Stelzer C, Schindele D, Gauler T, Hauser S, Houtsma D, Roessler M, Moritz B, Mross K, Bergmann L, Oosterwijk E, Kiemeney LA, Guchelaar HJ, Jaehde U

Abstract
The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics. Inter-individual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic and pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662 and the soluble VEGF receptors sVEGFR-2 and sVEGFR-3 were measured in 26 mRCC patients within the EuroTARGET project and 21 metastasized colorectal cancer (mCRC) patients from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in mRCC patients, whereas active drug pharmacokinetics seemed to be more predictive in mCRC patients. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies. This article is protected by copyright. All rights reserved.

PMID: 28571114 [PubMed - as supplied by publisher]

Cytokine signal suppressor (SOCS) 1-1478 CA/del gene polymorphism in Turkish patients with polycystic ovary syndrome.

J Obstet Gynaecol. 2017 Jun 01;:1-6

Authors: Oz Gul O, Cander S, Gul CB, Budak F, Oral B, Ersoy C

Abstract
Eighty-four subjects, premenopausal female patients (n = 42, mean (SD) age: 26.4 (4.2) years) diagnosed with polycystic ovary syndrome (PCOS) and age-matched healthy volunteers (n = 42, mean (SD) age: 27.6(3.4) years), were included in this study. Data on physical examination, anthropometric measurements and blood biochemistry analysis were recorded for each subject along with analysis for SOCS1-1478 CA/del polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The relation of SOCS1-1478 CA/del polymorphism to PCOS status and insulin resistance was analysed via logistic regression analysis. Mean (SD) levels for BMI (28.5(6.5) vs.22.5 (4.9) kg/m(2), p < .001), HOMA-IR (3.1(1.8) vs.1.5 (1.0), p < .001), LDL-cholesterol (115.9(32.7) vs.100.7 (27.3)mg/dL, p = .03) and triglyceride (113.8(64.9) vs.83.3(36.3)mg/dL, p = .017) were significantly higher in patients. Groups were similar in terms of SOCS1-1478 CA/del polymorphism. No significant relation of this polymorphism was noted to PCOS and HOMA-IR. Our findings revealed no difference between groups in terms of the rate of SOCS1-1478 CA/del polymorphism, and no significant relation of this polymorphism to insulin resistance and PCOS status. Impact statement Polycystic ovary syndrome (PCOS), the most common cause of anovulation and the most commonly encountered form of female endocrine disease. SOCS proteins have been suggested to play a fundamental role in the negative feedback regulation of the JAK-STAT pathway, which is the major signalling pathway involved in a wide range of physiologic and pathologic processes, including inflammatory diseases, malignancies and immune disorders. Pathways involving the induction of suppression of SOCS proteins were also shown likely to be involved in mediating cytokine-induced insulin resistance. The present study was designed to determine the frequency of SOCS1-1478 CA/del gene polymorphism in patients with PCOS in relation to healthy controls and insulin resistance. Our findings revealed significantly higher rates of insulin resistance, obesity and dyslipidaemia in Turkish patients with PCOS compared with age-matched healthy controls, while no difference between study groups in terms of the rate of SOCS1-1478 CA/del polymorphism along with no significant relation of SOCS1-1478 CA/del polymorphism to insulin resistance and PCOS status. Future larger scale studies with the application of standardised diagnostic methods and criteria, and of state-of-the-art modern techniques including genomics, proteomics and pharmacogenetics would provide better understanding of the association between PCOS and genomic variants.

PMID: 28569589 [PubMed - as supplied by publisher]

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis.

Genome Med. 2017 May 31;9(1):50

Authors: Ross CJ, Towfic F, Shankar J, Laifenfeld D, Thoma M, Davis M, Weiner B, Kusko R, Zeskind B, Knappertz V, Grossman I, Hayden MR

Abstract
BACKGROUND: Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials.
METHODS: Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials.
RESULTS: A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA).
CONCLUSIONS: This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.

PMID: 28569182 [PubMed - in process]

Mitochondrial DNA analysis of ancient sheep from Altai.

Anim Genet. 2017 May 31;:

Authors: Dymova MA, Zadorozhny AV, Mishukova OV, Khrapov EA, Druzhkova AS, Trifonov VA, Kichigin IG, Tishkin AA, Grushin SP, Filipenko ML

Abstract
A comparative analysis of the genetic diversity of ancient and modern sheep can shed light on the origin of these animals and their distribution as well as help to evaluate the role of humans at each formation stage of different sheep breeds. Here we isolated ancient DNA and performed sequencing of the mitochondrial DNA D-loop from 17 sheep bone remains (~4000-1000 years old) found in the archaeological complexes in the south of Altai (Western Siberia). The length of the sequences obtained ranged between 318 and 586 bp. The haplotype diversity and nucleotide diversity were 0.801 ± 0.081 and 0.0096 ± 0.0014 respectively. The average number of nucleotide differences was ~3.1. Nucleotide sequence analysis revealed that 15 specimens were nested within previously described A,B,C,D and E lineages and that two specimens had a basal position relative to the rest of the analyzed samples. A relatively high diversity of sheep haplotypes, including the presence of two basal haplotypes, indicates that the Altai region may have been a transport route of human migration. Further ancient DNA analysis of other specimens and deeper genome sequencing of samples with novel haplotypes is needed to better understand the demographic history of sheep in Southern Siberia.

PMID: 28568904 [PubMed - as supplied by publisher]

From the Viewpoint of Drug Metabolism Research.

Yakugaku Zasshi. 2017;137(6):697-705

Authors: Nakajima M

Abstract
 Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed.

PMID: 28566576 [PubMed - in process]

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

Diabetes. 2017 May 31;:

Authors: Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M, Pervjakova N, Pers TH, Johnson AD, Eicher JD, Jackson AU, Ferreira T, Lee Y, Ma C, Steinthorsdottir V, Thorleifsson G, Qi L, Van Zuydam NR, Mahajan A, Chen H, Almgren P, Voight BF, Grallert H, Müller-Nurasyid M, Ried JS, Rayner WN, Robertson N, Karssen LC, van Leeuwen EM, Willems SM, Fuchsberger C, Kwan P, Teslovich TM, Chanda P, Li M, Lu Y, Dina C, Thuillier D, Yengo L, Jiang L, Sparso T, Kestler HA, Chheda H, Eisele L, Gustafsson S, Frånberg M, Strawbridge RJ, Benediktsson R, Hreidarsson AB, Kong A, Sigurðsson G, Kerrison ND, Luan J, Liang L, Meitinger T, Roden M, Thorand B, Esko T, Mihailov E, Fox C, Liu CT, Rybin D, Isomaa B, Lyssenko V, Tuomi T, Couper DJ, Pankow JS, Grarup N, Have CT, Jørgensen ME, Jørgensen T, Linneberg A, Cornelis MC, van Dam RM, Hunter DJ, Kraft P, Sun Q, Edkins S, Owen KR, Perry JR, Wood AR, Zeggini E, Tajes-Fernandes J, Abecasis GR, Bonnycastle LL, Chines PS, Stringham HM, Koistinen HA, Kinnunen L, Sennblad B, Mühleisen TW, Nöthen MM, Pechlivanis S, Baldassarre D, Gertow K, Humphries SE, Tremoli E, Klopp N, Meyer J, Steinbach G, Wennauer R, Eriksson JG, Mӓnnistö S, Peltonen L, Tikkanen E, Charpentier G, Eury E, Lobbens S, Gigante B, Leander K, McLeod O, Bottinger EP, Gottesman O, Ruderfer D, Blüher M, Kovacs P, Tonjes A, Maruthur NM, Scapoli C, Erbel R, Jöckel KH, Moebus S, de Faire U, Hamsten A, Stumvoll M, Deloukas P, Donnelly PJ, Frayling TM, Hattersley AT, Ripatti S, Salomaa V, Pedersen NL, Boehm BO, Bergman RN, Collins FS, Mohlke KL, Tuomilehto J, Hansen T, Pedersen O, Barroso I, Lannfelt L, Ingelsson E, Lind L, Lindgren CM, Cauchi S, Froguel P, Loos RJ, Balkau B, Boeing H, Franks PW, Gurrea AB, Palli D, van der Schouw YT, Altshuler D, Groop LC, Langenberg C, Wareham NJ, Sijbrands E, van Duijn CM, Florez JC, Meigs JB, Boerwinkle E, Gieger C, Strauch K, Metspalu A, Morris AD, Palmer CN, Hu FB, Thorsteinsdottir U, Stefansson K, Dupuis J, Morris AP, Boehnke M, McCarthy MI, Prokopenko I, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

Abstract
To characterise type 2 diabetes (T2D) associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). We identified 13 novel T2D-associated loci (p<5×10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common SNVs. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion, and in adipocytes, monocytes and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

PMID: 28566273 [PubMed - as supplied by publisher]

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

Lancet Diabetes Endocrinol. 2017 May 26;:

Authors: Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, Direk K, Laufs U, Werner C, Koenig W, Rothenbacher D, Mons U, Breitling LP, Brenner H, Jennings RT, Petrakis I, Triem S, Klug M, Filips A, Blankenberg S, Waldeyer C, Sinning C, Schnabel RB, Lackner KJ, Vlachopoulou E, Nygård O, Svingen GFT, Pedersen ER, Tell GS, Sinisalo J, Nieminen MS, Laaksonen R, Trompet S, Smit RAJ, Sattar N, Jukema JW, Groesdonk HV, Delgado G, Stojakovic T, Pilbrow AP, Cameron VA, Richards AM, Doughty RN, Gong Y, Cooper-DeHoff R, Johnson J, Scholz M, Beutner F, Thiery J, Smith JG, Vilmundarson RO, McPherson R, Stewart AFR, Cresci S, Lenzini PA, Spertus JA, Olivieri O, Girelli D, Martinelli NI, Leiherer A, Saely CH, Drexel H, Mündlein A, Braund PS, Nelson CP, Samani NJ, Kofink D, Hoefer IE, Pasterkamp G, Quyyumi AA, Ko YA, Hartiala JA, Allayee H, Tang WHW, Hazen SL, Eriksson N, Held C, Hagström E, Wallentin L, Åkerblom A, Siegbahn A, Karp I, Labos C, Pilote L, Engert JC, Brophy JM, Thanassoulis G, Bogaty P, Szczeklik W, Kaczor M, Sanak M, Virani SS, Ballantyne CM, Lee VV, Boerwinkle E, Holmes MV, Horne BD, Hingorani A, Asselbergs FW, Patel RS, GENIUS-CHD consortium, Krämer BK, Scharnagl H, Fliser D, März W, Speer T

Abstract
BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.
METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.
FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.
INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

PMID: 28566218 [PubMed - as supplied by publisher]

The genetics of gout: towards personalised medicine?

BMC Med. 2017 May 31;15(1):108

Authors: Dalbeth N, Stamp LK, Merriman TR

Abstract
Over the last decade, there have been major advances in the understanding of the genetic basis of hyperuricaemia and gout as well as of the pharmacogenetics of urate-lowering therapy. Key findings include the reporting of 28 urate-associated loci, the discovery that ABCG2 plays a central role on extra-renal uric acid excretion, the identification of genes associated with development of gout in the context of hyperuricaemia, recognition that ABCG2 variants influence allopurinol response, and the impact of HLA-B*5801 testing in reducing the prevalence of allopurinol hypersensitivity in high-risk populations. These advances, together with the reducing cost of whole genome sequencing, mean that integrated personalised medicine approaches may soon be possible in clinical practice. Genetic data may inform assessment of disease prognosis in individuals with hyperuricaemia or established gout, personalised lifestyle advice, selection and dosing of urate-lowering therapy, and prevention of serious medication adverse effects. In this article, we summarise the discoveries from genome-wide association studies and discuss the potential for translation of these findings into clinical practice.

PMID: 28566086 [PubMed - in process]

Pharmacological management of non-alcoholic fatty liver disease: Atorvastatin versus pentoxifylline.

Exp Ther Med. 2017 May;13(5):2375-2381

Authors: Cioboată R, Găman A, Traşcă D, Ungureanu A, Docea AO, Tomescu P, Gherghina F, Arsene AL, Badiu C, Tsatsakis AM, Spandidos DA, Drakoulis N, Călina D

Abstract
In this study, we aimed to evaluate the efficacy of pentoxifylline and atorvastatin in the treatment of non-alcoholic fatty liver disease (NAFLD). The study included 98 patients with histologically confirmed NAFLD divided into 2 groups as follows: group I (57 dyslipidemic patients, receiving atorvastatin 20 mg/day and group II (41 non-dyslipidemic patients, treated with pentoxifylline, 800 mg/day). The present study was conducted for a mean of 32.8±3.4 weeks. For all patients, we determined the body mass index, a liver biopsy was performed, and we measured the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total cholesterol (TC) and triglycerides (TG) at the beginning and at the end of the study period. The NAFLD activity score (NAS) was used to evaluate the liver biopsies for steatosis, fibrosis and necroinflammation. The patients in group I exhibited a considerable reduction in ALT, AST, GGT, TC, AP and TG levels (P<0.0001). Histologically, there were no changes in fibrosis and necroinflammation, although the extent steatosis was reduced. The improvement in the ALT, AST and GGT values (P<0.05) in group II were similar to those in group I; however, no statistically significant decrease was noted in the levels of ALP, TC and TG in this group. Our results thus demonstrated that atorvastatin attenuated steatosis and improved liver function parameters in patients with NAFLD associated with dyslipidemia. Similar results were obtained in the non-dyslipidemic patients administered pentoxifylline.

PMID: 28565851 [PubMed - in process]

High Efficacy of Primaquine Treatment for Plasmodium vivax in Western Thailand.

Am J Trop Med Hyg. 2016 Nov 02;95(5):1086-1089

Authors: Longley RJ, Sripoorote P, Chobson P, Saeseu T, Sukasem C, Phuanukoonnon S, Nguitragool W, Mueller I, Sattabongkot J

Abstract
Primaquine is the only licensed antimalarial drug that is capable of clearing dormant Plasmodium vivax liver stage parasites. To date, there is no clear evidence of resistance of the liver stage parasite against this drug, because of the difficulty in ascertaining the cause of recurrent infection. We followed 52 Thai P. vivax patients for 9 months after directly observed treatment of 15 mg primaquine daily for 14 days. Blood samples taken at 2-4 weekly intervals were assessed by microscopy and polymerase chain reaction (PCR) for the presence of parasites. Only four of 52 (7.7%) volunteers had recurrent P. vivax infections, all at least 8 weeks after treatment. This demonstrates that primaquine retains a high efficacy in this population. Although a risk of new infections could not be ruled out, parasite genotyping at two polymorphic markers suggested a high probability of late relapsing infections in these volunteers. Continued monitoring of primaquine efficacy in this region is advisable.

PMID: 27601524 [PubMed - indexed for MEDLINE]

Electrochemical sensors for identifying pyocyanin production in clinical Pseudomonas aeruginosa isolates.

Biosens Bioelectron. 2017 May 24;97:65-69

Authors: Sismaet HJ, Pinto AJ, Goluch ED

Abstract
In clinical practice, delays in obtaining culture results impact patient care and the ability to tailor antibiotic therapy. Despite the advancement of rapid molecular diagnostics, the use of plate cultures inoculated from swab samples continues to be the standard practice in clinical care. Because the inoculation culture process can take between 24 and 48h before a positive identification test can be run, there is an unmet need to develop rapid throughput methods for bacterial identification. Previous work has shown that pyocyanin can be used as a rapid, redox-active biomarker for identifying Pseudomonas aeruginosa in clinical infections. However, further validation is needed to confirm pyocyanin production occurs in all clinical strains of P. aeruginosa. Here, we validate this electrochemical detection strategy using clinical isolates obtained from patients with hospital-acquired infections or with cystic fibrosis. Square-wave voltammetric scans of 94 different clinical P. aeruginosa isolates were taken to measure the concentration of pyocyanin. The results showed that all isolates produced measureable concentrations of pyocyanin with production rates correlated with patient symptoms and comorbidity. Further bioinformatics analysis confirmed that 1649 genetically sequenced strains (99.9%) of P. aeruginosa possess the two genes (PhzM and PhzS) necessary to produce pyocyanin, supporting the specificity of this biomarker. Confirming the production of pyocyanin by all clinically-relevant strains of P. aeruginosa is a significant step towards validating this strategy for rapid, point-of-care diagnostics.

PMID: 28570940 [PubMed - as supplied by publisher]

Preserving Lung Function: The Holy Grail in Managing Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Jun;14(6):833-835

Authors: Sly PD, Wainwright CE

PMID: 28570157 [PubMed - in process]

Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis.

Paediatr Respir Rev. 2017 Apr 27;:

Authors: Aslam A, Jahnke N, Remmington T, Southern KW

PMID: 28566196 [PubMed - as supplied by publisher]

Post-infectious persistent cough: pathogenesis and therapeutic options.

Minerva Pediatr. 2017 May 31;:

Authors: Capristo C, Rossi GA

Abstract
Post-infectious cough is a common symptom associated with common colds and/or upper respiratory tract infection. This cough is expected to last for only for few days and resolve spontaneously, whilst when persists for longer than three weeks is defined "persistent" and is associated tickling or an irritating sensation in the throat which often leads to paroxysms of coughing. Persistent post-infectious cough can cause morbidity since it may interfere with usual living. Despite the recent advances in understanding the mechanisms that regulate cough, in physiological and pathological conditions, current therapeutic options for post-infectious cough are little or only moderately effective.

PMID: 28565899 [PubMed - as supplied by publisher]

Phosphatidylcholine passes through lateral tight junctions for paracellular transport to the apical side of the polarized intestinal tumor cell-line CaCo2.

Biochim Biophys Acta. 2016 09;1861(9 Pt A):1161-9

Authors: Stremmel W, Staffer S, Gan-Schreier H, Wannhoff A, Bach M, Gauss A

Abstract
Phosphatidylcholine (PC) is the most abundant phospholipid in intestinal mucus, indicative of a specific transport system across the mucosal epithelium to the intestinal lumen. To elucidate this transport mechanism, we employed a transwell tissue culture system with polarized CaCo2 cells. It was shown that PC could not substantially be internalized by the cells. However, after basal application of increasing PC concentrations, an apical transport of 47.1±6.3nmolh(-1)mMPC(-1) was observed. Equilibrium distribution studies with PC applied in equal concentrations to the basal and apical compartments showed a 1.5-fold accumulation on the expense of basal PC. Disruption of tight junctions (TJ) by acetaldehyde or PPARγ inhibitors or by treatment with siRNA to TJ proteins suppressed paracellular transport by at least 50%. Transport was specific for the choline containing the phospholipids PC, lysoPC and sphingomyelin. We showed that translocation is driven by an electrochemical gradient generated by apical accumulation of Cl(-) and HCO3(-) through CFTR. Pretreatment with siRNA to mucin 3 which anchors in the apical plasma membrane of mucosal cells inhibited the final step of luminal PC secretion. PC accumulates in intestinal mucus using a paracellular, apically directed transport route across TJs.

PMID: 27365309 [PubMed - indexed for MEDLINE]

Feasibility of Hypoxic Challenge Testing in Children and Adolescents with Congenital Heart and Lung Disease.

Aerosp Med Hum Perform. 2016 Dec 01;87(12):1004-1009

Authors: Spoorenberg ME, Hulzebos EH, Takken T

Abstract
BACKGROUND: This is a cross-sectional observational study to investigate the safety and feasibility of integrating changing body positions and physical activity in a hypoxic challenge test (HCT). The secondary objective was to compare oxygen saturation (Spo2) in two different locations (forehead and finger).
METHODS: Included were 12 pediatric to young adult patients with congenital heart (N = 7) or lung disease (N = 5). An HCT was performed using breathing room air (21% oxygen) while sitting and breathing a normobaric hypoxic gas mixture (15% oxygen) through a facemask while seated, lying supine, standing, walking 3 km/h, and walking 5 km/h in a nonrandomized order.
RESULTS: All patients, except one, successfully passed the HCT. Three patients reported symptoms, possibly related to hypoxia. Median Spo2 during the HCT decreased in all body positions compared with room air. In 9/12 (finger oximeter) vs. 6/12 (forehead oximeter) patients Spo2 decreased below 90% in one or more body positions at rest. In 11/12 (finger oximeter) vs. 3/12 (forehead oximeter) patients Spo2 decreased below 90% during mild exercise. There was no significant difference in Spo2 between the different body positions. However, patients desaturated significantly more during mild exercise (walking 3km/h and 5 km/h). Spo2% measured at the forehead gave significantly higher values compared to the index finger.
DISCUSSION: HCT is safe and feasible in children and adolescents with congenital heart or lung disease, and gives additional information about oxygenation during physical activity in addition to resting conditions. Simulated hypoxia of 8202 ft (2500 m) induced a small but significant decrease in Spo2%.Spoorenberg ME, Hulzebos EHJ, Takken T. Feasibility of hypoxic challenge testing in children and adolescents with congenital heart and lung disease. Aerosp Med Hum Perform. 2016; 87(12):1004-1009.

PMID: 28323585 [PubMed - indexed for MEDLINE]

Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis.

PLoS One. 2017;12(6):e0178630

Authors: Chiereghin C, Robusto M, Mastrangelo A, Castorina P, Montini G, Giani M, Duga S, Asselta R, Soldà G

Abstract
Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. Despite simultaneous screening of these genes being widely available, mutation detection still remains incomplete in a non-marginal portion of patients. Here, we applied whole-exome sequencing (WES) in 3 Italian families negative after candidate-gene analyses. In Family 1, we identified a novel heterozygous intronic variant (c.2245-40A>G) -outside the conventionally screened candidate region for diagnosis- potentially disrupting COL4A5 exon29 splicing. Using a minigene-based approach in HEK293 cells we demonstrated that this variant abolishes exon29 branch site, causing exon skipping. Moreover, skewed X-inactivation of the c.2245-40A>G allele correlated with disease severity in heterozygous females. In Family 2, WES highlighted a novel COL4A5 hemizygous missense mutation (p.Gly491Asp), which segregates with the phenotype and impacts on a highly-conserved residue. Finally, in Family 3, we detected a homozygous 24-bp in-frame deletion in COL4A3 exon1 (NM_000091.4:c.30_53del:p.Val11_Leu18del or c.40_63del24:p.Leu14_Leu21del), which is ambiguously annotated in databases, although it corresponds to a recurrent AS mutation. Functional analyses showed that this deletion disrupts COL4A3 signal peptide, possibly altering protein secretion. In conclusion, WES -together with functional studies- was fundamental for molecular diagnosis in 3 AS families, highlighting pathogenic variants that escaped previous screenings.

PMID: 28570636 [PubMed - in process]

An evaluation of copy number variation detection tools for cancer using whole exome sequencing data.

BMC Bioinformatics. 2017 May 31;18(1):286

Authors: Zare F, Dow M, Monteleone N, Hosny A, Nabavi S

Abstract
BACKGROUND: Recently copy number variation (CNV) has gained considerable interest as a type of genomic/genetic variation that plays an important role in disease susceptibility. Advances in sequencing technology have created an opportunity for detecting CNVs more accurately. Recently whole exome sequencing (WES) has become primary strategy for sequencing patient samples and study their genomics aberrations. However, compared to whole genome sequencing, WES introduces more biases and noise that make CNV detection very challenging. Additionally, tumors' complexity makes the detection of cancer specific CNVs even more difficult. Although many CNV detection tools have been developed since introducing NGS data, there are few tools for somatic CNV detection for WES data in cancer.
RESULTS: In this study, we evaluated the performance of the most recent and commonly used CNV detection tools for WES data in cancer to address their limitations and provide guidelines for developing new ones. We focused on the tools that have been designed or have the ability to detect cancer somatic aberrations. We compared the performance of the tools in terms of sensitivity and false discovery rate (FDR) using real data and simulated data. Comparative analysis of the results of the tools showed that there is a low consensus among the tools in calling CNVs. Using real data, tools show moderate sensitivity (~50% - ~80%), fair specificity (~70% - ~94%) and poor FDRs (~27% - ~60%). Also, using simulated data we observed that increasing the coverage more than 10× in exonic regions does not improve the detection power of the tools significantly.
CONCLUSIONS: The limited performance of the current CNV detection tools for WES data in cancer indicates the need for developing more efficient and precise CNV detection methods. Due to the complexity of tumors and high level of noise and biases in WES data, employing advanced novel segmentation, normalization and de-noising techniques that are designed specifically for cancer data is necessary. Also, CNV detection development suffers from the lack of a gold standard for performance evaluation. Finally, developing tools with user-friendly user interfaces and visualization features can enhance CNV studies for a broader range of users.

PMID: 28569140 [PubMed - in process]