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Archibald Percy Norman.

BMJ. 2017 Jan 19;356:j312

Authors: Watts G

PMID: 28104584 [PubMed - indexed for MEDLINE]

Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X.

Invest Ophthalmol Vis Sci. 2017 Mar 01;58(3):1834-1842

Authors: Orosz O, Rajta I, Vajas A, Takács L, Csutak A, Fodor M, Kolozsvári B, Resch M, Sényi K, Lesch B, Szabó V, Berta A, Balogh I, Losonczy G

Abstract
Purpose: Rare interchange haplotypes in exon 3 of the OPN1LW and OPN1MW opsin genes cause X-linked myopia, color vision defect, and cone dysfunction. The severity of the disease varies on a broad scale from nonsyndromic high myopia to blue cone monochromatism. Here, we describe a new genotype-phenotype correlation attributed to rare exon 3 interchange haplotypes simultaneously present in the long- and middle-wavelength sensitive opsin genes (L- and M-opsin genes).
Methods: A multigenerational family with X-linked high myopia and cone dystrophy was investigated.
Results: Affected male patients had infantile onset myopia with normal visual acuity and color vision until their forties. Visual acuity decreased thereafter, along with the development of severe protan and deutan color vision defects. A mild decrease in electroretinography response of cone photoreceptors was detected in childhood, which further deteriorated in middle-aged patients. Rods were also affected, however, to a lesser extent than cones. Clinical exome sequencing identified the LVAVA and MVAVA toxic haplotypes in the OPN1LW and OPN1MW opsin genes, respectively.
Conclusion: Here, we show that LVAVA haplotype of the OPN1LW gene and MVAVA haplotype of the OPN1MW gene cause apparently nonsyndromic high myopia in young patients but lead to progressive cone-rod dystrophy with deuteranopia and protanopia in middle-aged patients corresponding to a previously unknown disease course. To the best of our knowledge, this is the first report on the joint effect of these toxic haplotypes in the two opsin genes on chromosome X.

PMID: 28358949 [PubMed - in process]

Exome sequencing reveals novel IRXI mutation in congenital heart disease.

Mol Med Rep. 2017 Mar 30;:

Authors: Guo C, Wang Q, Wang Y, Yang L, Luo H, Cao XF, An L, Qiu Y, Du M, Ma X, Li H, Lu C

Abstract
Genetic variation in specific transcription factors during heart formation may lead to congenital heart disease (CHD) or even miscarriage. The aim of the present study was to identify CHD‑associated genes using next generation sequencing (NGS). The whole exome DNA sequence was obtained from a stillborn fetus diagnosed with tricuspid atresia and complete transposition of the great arteries using high‑throughput sequencing methods. Subsequently, genetic variants of CHD‑associated genes were selected and verified in 215 non‑syndromic CHD patients and 249 healthy control subjects using polymerase chain reaction combined with Sanger sequencing. Genetic variants of previously reported CHD‑inducing genes, such as cysteine rich with EGF like domains 1 and cbp/p300‑interacting transactivator with Glu/Asp rich carboxy‑terminal domain 2, were discovered through the NGS analysis. In addition, a novel non‑synonymous mutation of the iroquois homeobox 1 (IRX1) gene (p.Gln240Glu) was identified. A total of three non‑synonymous mutations (p.Gln240Glu, p.Ser298Asn and p.Ala381Glu) of the IRX1 gene were verified in 215 non‑syndromic CHD patients, but not in 249 healthy volunteers. The results demonstrated that NGS is a powerful tool to study the etiology of CHD. In addition, the results suggest that genetic variants of the IRX1 gene may contribute to the pathogenesis of CHD.

PMID: 28358424 [PubMed - as supplied by publisher]

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Novel splice-site mutation in TTLL5 causes cone dystrophy in a consanguineous family.

Mol Vis. 2017;23:131-139

Authors: Dias MS, Hamel CP, Meunier I, Varin J, Blanchard S, Boyard F, Sahel JA, Zeitz C

Abstract
PURPOSE: To report the clinical and genetic findings of one family with autosomal recessive cone dystrophy (CD) and to identify the causative mutation.
METHODS: An institutional study of three family members from two generations. The clinical examination included best-corrected Snellen visual acuity measurement, fundoscopy, the Farnsworth D-15 color vision test, a full-field electroretinogram (ERG) that incorporated the International Society for Clinical Electrophysiology of Vision standards and methodology, fundus autofluorescence (FAF) and infrared (IR), and spectral-domain optical coherence tomography (SD-OCT). Genetic findings were achieved with DNA analysis using whole exome sequencing (WES) and Sanger sequencing.
RESULTS: The proband, a 9-year-old boy, presented with a condition that appeared to be congenital and stationary. The clinical presentation initially reflected incomplete congenital stationary night blindness (icCSNB) because of myopia, a decrease in visual acuity, abnormal oscillatory potentials, and reduced amplitudes on the 30 Hz flicker ERG but was atypical because there were no clear electronegative responses. However, no disease-causing mutations in the genes underlying icCSNB were identified. Following WES analysis of family members, a homozygous splice-site mutation in intron 3 of TTLL5 (c.182-3_182-1delinsAA) was found cosegregating within the phenotype in the family.
CONCLUSIONS: The distinction between icCSNB and CD phenotypes is not always straightforward in young patients. The patient was quite young, which most likely explains why the progression of the CD was not obvious. WES analysis provided prompt diagnosis for this family; thus, the use of this technique to refine the diagnosis is highlighted in this study.

PMID: 28356705 [PubMed - in process]

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PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis.

Am J Kidney Dis. 2017 Mar 26;:

Authors: Cornec-Le Gall E, Audrézet MP, Renaudineau E, Hourmant M, Charasse C, Michez E, Frouget T, Vigneau C, Dantal J, Siohan P, Longuet H, Gatault P, Ecotière L, Bridoux F, Mandart L, Hanrotel-Saliou C, Stanescu C, Depraetre P, Gie S, Massad M, Kersalé A, Séret G, Augusto JF, Saliou P, Maestri S, Chen JM, Harris PC, Férec C, Le Meur Y

Abstract
BACKGROUND: PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort.
STUDY DESIGN: Case series, January 2010 to March 2016.
SETTINGS & PARTICIPANTS: Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease.
OUTCOMES: Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate.
RESULTS: The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD.
LIMITATIONS: Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers.
CONCLUSIONS: Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

PMID: 28356211 [PubMed - as supplied by publisher]

Notice NOT-HL-17-501 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-241 from the NIH Guide for Grants and Contracts. The National Cancer Institute (NCI) is committed to reducing cancer related health disparities that affect all health disparity and underserved populations in the United States and to supporting research education, training and capacity building within, and near these communities. The NCI established the Center to Reduce Cancer Health Disparities (CRCHD) to strengthen cancer research by: addressing cancer health disparities; advising on strategic priorities, program direction, and scientific policy to strengthen cancer disparities research and training; and leading NCIs efforts to enhance scientific workforce diversity through the training of students and investigators from underrepresented backgrounds.

Funding Opportunity PA-17-239 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) encourages applications that propose to conduct secondary data analysis and integration of existing datasets and database resources, with the ultimate aim to elucidate the genetic architecture of cancer risk and related outcomes. The goal of this initiative is to address key scientific questions relevant to cancer epidemiology by supporting the analysis of existing genetic or genomic datasets, possibly in combination with environmental, outcomes, behavioral, lifestyle, and molecular profiles data. Applications to this FOA are encouraged to leverage existing genetic data and perform innovative analyses of the existing data. Applications may include new research aims that are being addressed with existing data, new or advanced methods of analyses, or novel combinations and integration of datasets that allow the exploration of important scientific questions in cancer research.

Funding Opportunity PA-17-243 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) encourages applications that propose to conduct secondary data analysis and integration of existing datasets and database resources, with the ultimate aim to elucidate the genetic architecture of cancer risk and related outcomes. The goal of this initiative is to address key scientific questions relevant to cancer epidemiology by supporting the analysis of existing genetic or genomic datasets, possibly in combination with environmental, outcomes, behavioral, lifestyle, and molecular profiles data. Applications to this FOA are encouraged to leverage existing genetic data and perform innovative analyses of the existing data. Applications may include new research aims that are being addressed with existing data, new or advanced methods of analyses, or novel combinations and integration of datasets that allow the exploration of important scientific questions in cancer research.

Funding Opportunity PAR-17-240 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications for the development of innovative research projects in cancer nanotechnology. This initiative, to be known as Innovative Research in Cancer Nanotechnology (IRCN), is a component of a broader program that is the NCI Alliance for Nanotechnology in Cancer. IRCN awards are designed to enable multidisciplinary research and transformative discoveries in cancer biology and/or oncology through the use of nanotechnology. Proposed projects should address major barriers in cancer biology and/or oncology using nanotechnology and should emphasize fundamental understanding of nanomaterial and/or nanodevice interactions with biological systems. This scope includes research concerning the delivery of nanoparticles and/or nanodevices to desired and intended cancer targets in vivo and/or characterization of in vitro detection and diagnostic devices.

Funding Opportunity RFA-NS-17-010 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to invite applications to continue support of a national program of mentored research career development for junior neurosurgeon faculty at institutions nationwide that support neurosurgical research. The goal of the program is to expand the cadre of neurosurgeon investigators trained to conduct research into neurological disorders, making use of their neurosurgical training.

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Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus.

Nat Commun. 2017 Mar 28;8:14550

Authors: Sundaram V, Choudhary MN, Pehrsson E, Xing X, Fiore C, Pandey M, Maricque B, Udawatta M, Ngo D, Chen Y, Paguntalan A, Ray T, Hughes A, Cohen BA, Wang T

Abstract
Cis-regulatory modules contain multiple transcription factor (TF)-binding sites and integrate the effects of each TF to control gene expression in specific cellular contexts. Transposable elements (TEs) are uniquely equipped to deposit their regulatory sequences across a genome, which could also contain cis-regulatory modules that coordinate the control of multiple genes with the same regulatory logic. We provide the first evidence of mouse-specific TEs that encode a module of TF-binding sites in mouse embryonic stem cells (ESCs). The majority (77%) of the individual TEs tested exhibited enhancer activity in mouse ESCs. By mutating individual TF-binding sites within the TE, we identified a module of TF-binding motifs that cooperatively enhanced gene expression. Interestingly, we also observed the same motif module in the in silico constructed ancestral TE that also acted cooperatively to enhance gene expression. Our results suggest that ancestral TE insertions might have brought in cis-regulatory modules into the mouse genome.

PMID: 28348391 [PubMed - in process]

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Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

Infect Dis Poverty. 2017 Mar 28;6(1):74

Authors: Bergquist R, Utzinger J, Keiser J

Abstract
The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis.

PMID: 28351414 [PubMed - in process]

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Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov.

PeerJ. 2017;5:e3154

Authors: Su EW, Sanger TM

Abstract
Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts "Serious Adverse Events" (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer).

PMID: 28348935 [PubMed - in process]

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Association of Vogt Koyanagi Harada Syndrome and Seronegative Rheumatoid Arthritis.

Ethiop J Health Sci. 2016 Mar;26(2):193-6

Authors: Aydin T, Taspinar O, Guneser M, Keskin Y

Abstract
BACKGROUND: Vogt Koyanagi Harada (VKH) Syndrome is a rarely-seen multi-systemic, autoimmune and inflammatory disease. It observed frequently with neurologic, auditory and skin manifestations and characterized with bilateral, chronic and diffused granulomatous panuveitis. It generally affects women in young-adult period.
CASE: A 57 year-old female patient applied to a special center one year ago with a complaint of decrease in the sight acuity of the right eye. The right eye was operated on with cataract diagnosis. Uveitis was developed firstly in the right eye and then in the left eye after the operation. Having complaints about uveitis, tinnitus and hear loss, the patient was diagnosed with VKH syndrome. The pains started to be felt in small hand joints and both of the two ankles. The pains were increasing especially in the mornings and during rest. The duration of morning stiffness was two hours in hand and foot joints. The patient had had lumbar pain with mechanic characteristic for five years.
CONCLUSION: Being diagnosed with seronegative rheumatoid arthritis (RA), our case is presented because VKH syndrome is rarely seen in Turkey, and the joint findings are at the forefront.

PMID: 27222633 [PubMed - indexed for MEDLINE]

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The Patient Educator Presentation in Dental Education: Reinforcing the Importance of Learning About Rare Conditions.

J Dent Educ. 2016 May;80(5):533-41

Authors: Edwards PC, Graham J, Oling R, Frantz KE

Abstract
The aim of this study was to determine whether a patient educator presentation (PEP) on pemphigus vulgaris would increase second-year dental students' awareness of the importance of learning about rare conditions and improve their retention of rare disease knowledge. The study involved students' subjective assessments of a PEP experience at two U.S. dental schools. In this mixed methods study, cross-sectional data were obtained by surveys and in-depth interviews. Questions focused on students' assessment of the messages acquired from the PEP and its likely impact on their future clinical care. At University 1, students completed paper surveys with open-ended questions and participated in a focus group. At University 2, students completed an online survey consisting of rating scale and open-ended questions. Responses to open-ended questions were categorized into themes. At University 1, 79 students (out of a possible 102; response rate 77.5%) completed the survey, and an additional ten students participated in a focus group. At University 2, 30 students (out of a possible 104; response rate 28.8%) completed the survey. At Universities 1 and 2, 88% and 100%, respectively, of respondents stated the PEP would influence their future clinical decision making. The vast majority of respondents (94% and 100% at University 1 and University 2, respectively) were of the opinion that the personal testimonial from a patient would help them recall information about pemphigus vulgaris in five years' time. Respondents from both universities commented that the PEP emphasized the importance of not dismissing a patient's concerns. These results suggest that a presentation by a patient with a rare condition can be an effective educational tool for preclinical dental students.

PMID: 27139204 [PubMed - indexed for MEDLINE]

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Erratum to: InteGO2: a web tool for measuring and visualizing gene semantic similarities using Gene Ontology.

BMC Genomics. 2017 Mar 28;18(1):262

Authors: Peng J, Li H, Liu Y, Juan L, Jiang Q, Wang Y, Chen J

PMID: 28351382 [PubMed - in process]

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Defective postsecretory maturation of MUC5B mucin in cystic fibrosis airways.

JCI Insight. 2017 Mar 23;2(6):e89752

Authors: Abdullah LH, Evans JR, Wang TT, Ford AA, Makhov AM, Nguyen K, Coakley RD, Griffith JD, Davis CW, Ballard ST, Kesimer M

Abstract
In cystic fibrosis (CF), airway mucus becomes thick and viscous, and its clearance from the airways is impaired. The gel-forming mucins undergo an ordered "unpacking/maturation" process after granular release that requires an optimum postsecretory environment, including hydration and pH. We hypothesized that this unpacking process is compromised in the CF lung due to abnormal transepithelial fluid transport that reduces airway surface hydration and alters ionic composition. Using human tracheobronchial epithelial cells derived from non-CF and CF donors and mucus samples from human subjects and domestic pigs, we investigated the process of postsecretory mucin unfolding/maturation, how these processes are defective in CF airways, and the probable mechanism underlying defective unfolding. First, we found that mucins released into a normal lung environment transform from a compact granular form to a linear form. Second, we demonstrated that this maturation process is defective in the CF airway environment. Finally, we demonstrated that independent of HCO3(-) and pH levels, airway surface dehydration was the major determinant of this abnormal unfolding process. This defective unfolding/maturation process after granular release suggests that the CF extracellular environment is ion/water depleted and likely contributes to abnormal mucus properties in CF airways prior to infection and inflammation.

PMID: 28352653 [PubMed - in process]